Publications and Scientific Articles

Published Articles on Fibrolamellar

The table below contains a complete listing of scientific publications on fibrolamellar carcinoma along with their abstracts, where available. Specific articles can be found by using the search box, or clicking on the column headers to sort the table contents.

Aloysius, MM, P Iskander, K Ahmed, U Asija, E Mohammed, A Iskander, NJ Shah, H Goyal, V Khurana, N Simin, G Aswath and S John 2023Fibrolamellar hepatocellular carcinoma: An epidemiologic and 5-year cancer survival assessment based off SEER data. Clin Res Hepatol Gastroenterol 47(7): 102162. The fibrolamellar variant of hepatocellular carcinoma makes up a small percentage of liver tumors. Despite being a subset, it has been noted in the literature to have variations in terms of its epidemiology and intervention recommendations. Using the Surveillance, Epidemiology, and End Results database, 339 cases from 1988 to 2016 were studied. Favorable prognostic epidemiological factors included male sex, younger ages, and white race. Those who underwent any lymph node resection (combined with liver resection) did better than those without lymph node resection; chemotherapy proved beneficial for those where surgery was contraindicated. To our knowledge, this report is the largest conglomerate dataset analyzing prognostic profiles and treatment strategies for fibrolamellar hepatocellular carcinoma.
Alshareefy, Y, CY Shen and RJ Prekash 2023Exploring the molecular pathogenesis, diagnosis and treatment of fibrolamellar hepatocellular carcinoma: A state of art review of the current literature. Pathol Res Pract 248: 154655. This paper aims to present a detailed overview of fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC) that accounts for approximately 1-9% of all cases a. according to the SEER database. Despite ongoing research, the aetiology of FLC tumours remains unclear. Nevertheless, FLC is believed to have a better overall prognosis than other primary liver tumours, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. This study aims to present a comprehensive overview of fibrolamellar carcinoma (FLC), with a focus on its epidemiology, pathogenesis, diagnosis, treatment, and prognosis. FLC frequently incorporate features of stomach pain, weight loss, and malaise in their clinical signs and symptoms, which are generally nonspecific Ultimately, the most common physical finding is an abdominal mass or hepatomegaly. With this said, several unusual presentations have been documented such as Budd Chiari syndrome, severe anaemia, non-bacterial thrombotic endocarditis and many more. In regards to this tumour's genetic analysis, it is characterised by a 400 kb deletion on chromosome 19 leading to a functional DNAJB1-PRKACA chimeric transcript in addition to tetraploidy in 50% of cases. FLC is chromosomally stable as compared to typical HCC. mTOR pathway activation has also been found to play a critical role in 47% of these tumours and EFGR over-expression is also evident. Fibrolamellar carcinomas (FLCs) exhibit a distinctive gross appearance, characterized by a yellow to pale tan colour, with a consistency that can vary from soft to firm and hard. In addition, a central scar is observed in 60-70% of FLC cases. The central scar is typically white or grey in colour and has a fibrous appearance, which is often surrounded by nodular, tumour-like tissue. Its histologic appearance is characterized by large polygonal cells with abundant eosinophilic cytoplasm, large vesiculated nuclei, large nucleoli, and arranged in lamellar bands of collagen fibres. Lamellar bands of fibrosis, consisting of collagen type I, III and IV, have also been identified as a distinctive histologic feature that is observed under low power magnification. Ultrasound, CT and MRI along with image guided biopsy are the primary modalities in diagnosis. Current management options include systemic therapy which has thus far been unremarkable with platinum-based therapies as well combination therapy with interferon alpha-2b being the most successful options. Surgical resection remains the primary treatment modality and there have been no advances in targeted therapies. Although the prognosis for FLC is favourable as compared to other hepatic cancer subtypes such as intrahepatic cholangiocarcinoma, there is a high rate of recurrence ranging from 33% to 100% with a median recurrence-free survival of 20-48 months. As a result of this there is a low overall cure rate associated with this tumour type and much more research is required to gain an in-depth understanding of the molecular mechanisms occurring in order to provide more adequate treatment to patients who suffer from this condition.
Auer, TA, S Halskov, U Fehrenbach, NF Nevermann, U Pelzer, R Mohr, B Hamm, W Schoning, D Horst, J Ihlow and D Geisel 2023Gd-EOB MRI for HCC subtype differentiation in a western population according to the 5(th) edition of the World Health Organization classification.Eur Radiol 33(10): 6902-6915. OBJECTIVES: To investigate the value of gadoxetic acid (Gd-EOB)-enhanced magnetic resonance imaging (MRI) for noninvasive subtype differentiation of HCCs according to the 5(th) edition of the WHO Classification of Digestive System Tumors in a western population. METHODS: This retrospective study included 262 resected lesions in 240 patients with preoperative Gd-EOB-enhanced MRI. Subtypes were assigned by two pathologists. Gd-EOB-enhanced MRI datasets were assessed by two radiologists for qualitative and quantitative imaging features, including imaging features defined in LI-RADS v2018 and area of hepatobiliary phase (HBP) iso- to hyperintensity. RESULTS: The combination of non-rim arterial phase hyperenhancement with non-peripheral portal venous washout was more common in "not otherwise specified" (nos-ST) (88/168, 52%) than other subtypes, in particular macrotrabecular massive (mt-ST) (3/15, 20%), chromophobe (ch-ST) (1/8, 13%), and scirrhous subtypes (sc-ST) (2/9, 22%) (p = 0.035). Macrovascular invasion was associated with mt-ST (5/16, p = 0.033) and intralesional steatosis with steatohepatitic subtype (sh-ST) (28/32, p < 0.001). Predominant iso- to hyperintensity in the HBP was only present in nos-ST (16/174), sh-ST (3/33), and clear cell subtypes (cc-ST) (3/13) (p = 0.031). Associations were found for the following non-imaging parameters: age and sex, as patients with fibrolamellar subtype (fib-ST) were younger (median 44 years (19-66), p < 0.001) and female (4/5, p = 0.023); logarithm of alpha-fetoprotein (AFP) was elevated in the mt-ST (median 397 microg/l (74-5370), p < 0.001); type II diabetes mellitus was more frequent in the sh-ST (20/33, p = 0.027). CONCLUSIONS: Gd-EOB-MRI reproduces findings reported in the literature for extracellular contrast-enhanced MRI and CT and may be a valuable tool for noninvasive HCC subtype differentiation. CLINICAL RELEVANCE STATEMENT: Better characterization of the heterogeneous phenotypes of HCC according to the revised WHO classification potentially improves both diagnostic accuracy and the precision of therapeutic stratification for HCC. KEY POINTS: * Previously reported imaging features of common subtypes in CT and MRI enhanced with extracellular contrast agents are reproducible with Gd-EOB-enhanced MRI. * While uncommon, predominant iso- to hyperintensity in the HBP was observed only in NOS, clear cell, and steatohepatitic subtypes. * Gd-EOB-enhanced MRI offers imaging features that are of value for HCC subtype differentiation according to the 5(th) edition of the WHO Classification of Digestive System Tumors.
Aziz, H, ZJ Brown, S Panid Madani, IR Kamel and TM Pawlik 2023Fibrolamellar hepatocellular carcinoma: Comprehensive review of diagnosis, imaging, and management. J Am Coll Surg 236(2): 399-410. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare malignancy that primarily affects patients in late adolescence and young adulthood. FLC tumors are characterized by their unique histologic features and a recently discovered genomic alteration, a chimeric fusion protein found in nearly all tumors. This review article provides the latest advancements in diagnosing, imaging, and managing FLC. STUDY DESIGN: A comprehensive systematic review was performed using MEDLINE/PubMed and Web of Science databases, with the end of search date being July 1, 2022, regarding FLC diagnosis, imaging, and management. RESULTS: Surgical resection remains the mainstay of therapy offering a chance for cure; however, given the incidence of metastatic disease at diagnosis and high rates of distant relapse, systemic therapies remain a crucial component of disease control. Unfortunately, few systemic therapies have demonstrated proven benefits. Consequently, recent efforts have galvanized around single-institute or small consortia-based studies specifically focused on enrolling patients with FLC or using agents with a biologic rationale. CONCLUSIONS: FLC has unique demographic, radiologic, and pathologic features. The rarity of these tumors, coupled with the only recent acknowledgment of the genomic abnormality, has likely led to disease underrecognition and deprioritization of collaborative efforts to establish an evidence-based standard of care. Despite R0 resection, most patients experience recurrence. However, surgical resection is feasible for many recurrences and is associated with good survival. The role of chemotherapy is evolving, and further research is required to define its role in managing this disease.
Chan, GKL, S Maisel, YC Hwang, BC Pascual, RRB Wolber, P Vu, KC Patra, M Bouhaddou, HL Kenerson, HC Lim, D Long, RS Yeung, P Sethupathy, DL Swaney, NJ Krogan, RE Turnham, KJ Riehle, JD Scott, N Bardeesy and JD Gordan 2023Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms. Elife 12. Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar carcinoma (FLC) line that expresses a DNAJ-PKAc fusion and a PKA-addicted melanoma model with a mutant type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.
Glavas, D, QR Bao, M Scarpa, C Ruffolo, ZJ Brown, TM Pawlik and G Spolverato 2023Treatment and Prognosis of Fibrolamellar Hepatocellular Carcinoma: a Systematic Review of the Recent Literature and Meta-analysis. J Gastrointest Surg 27(4): 705-715. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare disease and current efforts are focused on the prognosis and on the development of efficient and specific treatments. This study aimed to review the latest evidence regarding FL-HCC treatment and prognosis. METHODS: A systematic review of the literature over the past 10 years regarding FL-HCC, and meta-analysis of 1-, 3-, and 5-year overall survival (OS) comparing FL-HCC and conventional HCC were performed. RESULTS: Overall, 1567 articles were screened, of them 21 were selected for the systematic review, and 6 for meta-analysis. Twenty-one studies included a total of 2168 patients with FL-HCC, with a median age ranging from 11 to 56 years. The majority of patients underwent surgical resection or liver transplantation. After a median follow-up ranging from 24 to 58 months, 1-year OS was 67-100% and 5-year OS was 28-65%. A total of 743 patients with FL-HCC and 163,472 with conventional HCC were included in the meta-analysis. There was a significantly improved 1-, 3-, and 5-years OS in the FL-HCC group compared to the conventional HCC group, although high heterogeneity was found. When excluding population-based studies, and including 96 FL-HCC and 221 conventional HCC patients, the heterogeneity was low, and the meta-analysis showed a significantly longer 1-year OS in patients with FL-HCC than conventional HCC; however, there were no differences at 3- and 5-years OS. CONCLUSIONS: Surgical resection for FL-HCC is currently the only curative treatment available. FL-HCC is plagued by high-recurrence rates and poor long-term outcomes which may be related to the absence of specific treatment for advanced and recurrent disease.
Greenwald, E, C Posner, A Bharath, A Lyons, C Salmeron, K Sriram, SZ Wiley, PA Insel and J Zhang 2023GPCR signaling measurement and drug profiling with an automated live-cell microscopy system.ACS Sens 8(1): 19-27. A major limitation of time-lapse microscopy combined with fluorescent biosensors, a powerful tool for quantifying spatiotemporal dynamics of signaling in single living cells, is low-experimental throughput. To overcome this limitation, we created a highly customizable, MATLAB-based platform: flexible automated liquid-handling combined microscope (FALCOscope) that coordinates an OpenTrons liquid handler and a fluorescence microscope to automate drug treatments, fluorescence imaging, and single-cell analysis. To test the feasibility of the FALCOscope, we quantified G protein-coupled receptor (GPCR)-stimulated Protein Kinase A activity and cAMP responses to GPCR agonists and antagonists. We also characterized cAMP dynamics induced by GPR68/OGR1, a proton-sensing GPCR, in response to variable extracellular pH values. GPR68-induced cAMP responses were more transient in acidic than neutral pH values, suggesting a pH-dependence for signal attenuation. Ogerin, a GPR68 positive allosteric modulator, enhanced cAMP response most strongly at pH 7.0 and sustained cAMP response for acidic pH values, thereby demonstrating the capability of the FALCOscope to capture allosteric modulation. At a high concentration, ogerin increased cAMP signaling independent of GPR68, likely via phosphodiesterase inhibition. The FALCOscope system thus enables enhanced throughput single-cell dynamic measurements and is a versatile system for interrogating spatiotemporal regulation of signaling molecules in living cells and for drug profiling and screening.
Gummadi, J, X Wang and C Xie 2023Current advances in the treatment of fibrolamellar carcinoma of liver. J Hepatocell Carcinoma 10: 745-752. Fibrolamellar carcinoma (FLC) of the liver is a rare type of liver cancer that is prevalent in children and young adults, often less than 40 years old. The etiology is unclear. It presents without underlying liver disease with distinctive histological features such as fibrous collagen bands surrounding the tumor cells. Fusion protein DNAJB1-PRKACA is found in most of the cases. The prognosis of FLC is poor. Even though curative treatment option is surgery for a certain patient population, other treatment modalities including radiation, chemotherapy are currently being used without significant improvement of overall survival. Recently, targeted therapy and immunotherapy have been studied which may provide survival advantage in the future. This review sought to compile data from clinical trials and case reports/series to outline the current state of FLC treatment.
Han, W, B Wang, X Yong, Y Zhang, M Shao and C Wang 2023Indolent T-lymphoblastic proliferation with fibrolamellar hepatocellular carcinoma developed after colorectal adenocarcinoma: a case report. Pathol Oncol Res 29: 1611151. Objective: Indolent T-lymphoblastic proliferation (iT-LBP) is a non-neoplastic disease with an indolent clinical course, manifesting as hyperplasia of immature extrathymic T-lymphoblastic cells. Isolated iT-LBP has been observed, but the majority of iT-LBP cases has been seen in conjunction with other diseases. iT-LBP is easily misdiagnosed as T-lymphoblastic lymphoma/leukemia, and understanding the disease of indolent T-lymphoblastic proliferation may prevent misdiagnosis and missed diagnosis in pathological diagnosis. Case presentation: We report a case morphology, immunophenotypic, and molecular features of iT-LBP combined with fibrolamellar hepatocellular carcinoma developed after colorectal adenocarcinoma and review relevant literature. Conclusion: iT-LBP combined with fibrolamellar hepatocellular carcinoma developed after colorectal adenocarcinoma is relatively rare and should always be considered as a differential diagnosis of T-lymphoblastic lymphoma and scirrhous hepatocellular carcinoma as the two disorders show highly similar clinical features.
Hui, M, SG Uppin, MS Uppin, TV Madhav, GS Ramachandra Varma, TR Paul and N Bheerappa 2023Hepatocellular carcinoma: A clinicopathological and immunohistochemical study of 116 cases from a tertiary care hospital in Southern India. Indian J Cancer 60(2): 191-198. BACKGROUND: Diagnosis of hepatocellular carcinoma (HCC) is difficult on morphology alone in poorly differentiated tumors and metastatic carcinomas. Appropriate immunohistochemical markers are required for definite diagnosis. In this article, we have analyzed the histopathological and immunohistochemical features of HCC and elucidate the best possible immunohistochemistry (IHC) marker combination by comparing the sensitivity of various markers in different grades of tumor. METHODS: A total of 116 consecutive cases were analyzed retrospectively. The hematoxylin and eosin stained sections were reviewed in all the cases. IHC was done using hepatocellular specific antigen (HSA), arginase-1, glypican-3, and polyclonal carcinoembryonic antigen (pCEA). The sensitivity of various immunohistochemical markers individually as well as in combination for different tumor grades was determined. RESULTS: Histologically, the predominant subtype comprised of classic variant (109,93.9%) followed by combined hepatocellular and cholangiocarcinoma (4,3.4%) and fibrolamellar variant (3,2.6%). Trabecular pattern was the most common histological pattern. On grading, 65,56.03% were moderately differentiated, 34,29.31% well differentiated, and17, 14.65% poorly differentiated. HSA and polyclonal-CEA showed higher sensitivity than arginase-1 and glypican-3 in well and moderately differentiated tumors. In contrast arginase-1 and glypican-3 showed better sensitivity in poorly differentiated HCC. The overall sensitivity increased to greater than 90% if HSA/polyclonal-CEA is combined with either arginase-1/glypican-3 irrespective of tumor grade. CONCLUSION: Majority of the tumors were classic variants and moderately differentiated. HSA along with either arginase-1 or glypican-3 is the best combination of immunomarker for identification of hepatocellular differentiation irrespective of tumor grade.
Kamdar, Z, T Lopez-Vidal, K Howe, K Munjal, A Saeed, D Zabransky, D Shu, G Longway, E Kartalia, J Leatherman, A Mohan, P Khare, C Zhang, A Le, E Pearce, M Furth, M Baretti, R Leone, E Jaffee and M Yarchoan 2023DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma induces glutamine addiction and an immunosuppressive tumor microenvironment. Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3679.Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults. A fusion between DNAJB1, a heat shock chaperone protein, and PRKACA, the catalytic domain of protein kinase A (PKA) has been identified as a signature genomic event in FLC, but the effect of this fusion on the tumor immune microenvironment is not understood. We created an orthotopic, syngeneic model of FLC (TIBx-FLC) by inducing the DNAJB1-PRKACA fusion in a murine hepatoblastoma-derived cell line (TIBx). CD8 T cells isolated from TIBx-FLC tumors demonstrated markedly impaired activation as compared to CD8 T cells isolated from control TIBx tumors. We investigated metabolic programming as a potential mechanism for DNAJB1-PRKACA immunosuppression in FLC. Labeled glucose metabolomics performed on TIBx-FLC and TIBx tumor cells demonstrated a metabolic shift away from aerobic metabolism to an increased glucose contribution towards the hexosamine biosynthetic pathway and purine synthesis, which requires glutamine as a nitrogen source. As compared to the parental TIBx cell line, the TIBx-FLC cell line demonstrated high sensitivity to glutamine antagonism in vitro, consistent with glutamine addiction. Systemic treatment of BALB/c mice bearing TIBx-FLC tumors with JHU-083, a glutamine antagonist, in combination with immune checkpoint inhibitor therapy enhanced survival as compared to vehicle or monotherapy. These data identify altered glutamine metabolism as a target in FLC, and may provide an explanation for immune suppression seen in the FLC tumor microenvironment.
Kim, J, Y Kim and B Lee 2023Identification of long non-coding RNA profiles and potential therapeutic agents for fibrolamellar carcinoma based on RNA-sequencing data. Genes (Basel) 14(9). BACKGROUND: Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that primarily affects adolescents and young adults without prior liver disease or viral infections. Patients with FLC generally have non-specific symptoms, are often diagnosed at a later stage, and experience a higher frequency of metastases compared to patients with other liver cancers. A fusion transcript of DNAJB1 and PRKACA, which can lead to increased activity of PKA and cellular proliferation, has been identified in all FLC patients, but the exact mechanism through which FLC develops remains unclear. In this study, we investigated common lncRNA profiles in various FLC samples using bioinformatics analyses. METHODS: We analyzed differentially expressed (DE) lncRNAs from three RNA sequencing datasets. Using lncRNAs and DE mRNAs, we predicted potential lncRNA target genes and performed Gene Ontology (GO) and KEGG analyses with the DE lncRNA target genes. Moreover, we screened for small-molecule compounds that could act as therapeutic targets for FLC. RESULTS: We identified 308 DE lncRNAs from the RNA sequencing datasets. In addition, we performed a trans-target prediction analysis and identified 454 co-expressed pairs in FLC. The GO analysis showed that the lncRNA-related up-regulated mRNAs were enriched in the regulation of protein kinase C signaling and cAMP catabolic processes, while lncRNA-related down-regulated mRNAs were enriched in steroid, retinol, cholesterol, and xenobiotic metabolic processes. The analysis of small-molecule compounds for FLC treatment identified vitexin, chlorthalidone, triamterene, and amiloride, among other compounds. CONCLUSIONS: We identified potential therapeutic targets for FLC, including lncRNA target genes as well as small-molecule compounds that could potentially be used as treatments. Our findings could contribute to furthering our understanding of FLC and providing potential avenues for diagnosis and treatment.
Lauer, SM, MH Omar, M Golkowski, H Kenerson, K Collins, FD Smith, S-E Ong, R Yeung and J Scott 2023Enzyme-catalyzed proximity proteomics reveals new mechanisms of pathogenic kinase signaling in fibrolamellar carcinoma. Journal Biol Chem 299(3): S756. [Meeting Abstract]
Lauer, SM, MH Omar, MG Golkowski, HL Kenerson, BC Pascual, K Forbush, FD Smith, J Gordan, SE Ong, RS Yeung and JD Scott 2023Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma. bioRxiv. The DNAJ-PKAc fusion kinase is a defining feature of the adolescent liver cancer fibrolamellar carcinoma (FLC). A single lesion on chromosome 19 generates this mutant kinase by creating a fused gene encoding the chaperonin binding domain of Hsp40 (DNAJ) in frame with the catalytic core of protein kinase A (PKAc). FLC tumors are notoriously resistant to standard chemotherapies. Aberrant kinase activity is assumed to be a contributing factor. Yet recruitment of binding partners, such as the chaperone Hsp70, implies that the scaffolding function of DNAJ- PKAc may also underlie pathogenesis. By combining proximity proteomics with biochemical analyses and photoactivation live-cell imaging we demonstrate that DNAJ-PKAc is not constrained by A-kinase anchoring proteins. Consequently, the fusion kinase phosphorylates a unique array of substrates. One validated DNAJ-PKAc target is the Bcl-2 associated athanogene 2 (BAG2), a co-chaperone recruited to the fusion kinase through association with Hsp70. Immunoblot and immunohistochemical analyses of FLC patient samples correlate increased levels of BAG2 with advanced disease and metastatic recurrences. BAG2 is linked to Bcl-2, an anti-apoptotic factor that delays cell death. Pharmacological approaches tested if the DNAJ- PKAc/Hsp70/BAG2 axis contributes to chemotherapeutic resistance in AML12 (DNAJ-PKAc) hepatocyte cell lines using the DNA damaging agent etoposide and the Bcl-2 inhibitor navitoclax. Wildtype AML12 cells were susceptible to each drug alone and in combination. In contrast, AML12 (DNAJ-PKAc) cells were moderately affected by etoposide, resistant to navitoclax, but markedly susceptible to the drug combination. These studies implicate BAG2 as a biomarker for advanced FLC and a chemotherapeutic resistance factor in DNAJ-PKAc signaling scaffolds.
Leiting, JL, MC Hernandez, JR Bergquist, JA Yonkus, AM Abdelrahman, MS Torbenson, NH Tran, TR Halfdanarson, RP Graham, RL Smoot and MJ Truty 2023Therapeutic efficacy of Temsirolimus in a patient-derived model of metastatic fibrolamellar hepatocellular carcinoma. In Vivo 37(5): 1940-1950. BACKGROUND/AIM: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumor presenting in younger patients without chronic liver disease. Up to 80-100% develop recurrent disease, necessitating additional surgery or systemic treatment. Systemic options and pre-clinical treatment studies are lacking. We previously described patient-derived xenograft (PDX) development, allowing for pre-clinical studies. Herein, we develop FLHCC PDX models and utilize these to define tumor characteristics and determine the efficacy of systemic agents. MATERIALS AND METHODS: Primary and lymph node metastatic tumor tissues were obtained at the time of FLHCC resection in two patients. Tumor lysates were screened for protein upregulation. Cell lines were generated from metastatic and primary tumor tissue. The viability of the cell lines was assessed after treatment with temsirolimus, gemcitabine/oxaliplatin, and FOLFIRINOX. Two PDX models were developed from metastatic tissue. For in vivo studies, tumor-bearing mice were treated with temsirolimus, FOLFIRINOX, and Gemcitabine/oxaliplatin. RESULTS: PDX models were successfully generated from metastatic FLHCC, which closely recapitulated the original tumor. Upregulation of mTOR was seen in metastatic tissue compared to primary tumors. Cell lines from metastatic tissue demonstrated significant sensitivity to temsirolimus. In vivo testing of PDX models demonstrated a significant response to single-agent temsirolimus with minimal toxicity. CONCLUSION: Herein, we demonstrate the feasibility of developing PDX models that closely recapitulate FLHCC. Upregulation of mTOR was seen in metastatic tissue compared to primary tissue. The efficacy of mTOR inhibition with temsirolimus treatment suggests that the upregulation of the mTOR pathway may be a significant mechanism for growth in metastatic lesions and a potential target for therapeutics.
Levin, SN, MD Tomasini, J Knox, M Shirani, B Shebl, D Requena, J Clark, S Heissel, H Alwaseem, R Surjan, R Lahasky, H Molina, MS Torbenson, B Lyons, RD Migler, P Coffino and SM Simon 2023Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma.Sci Adv 9(25): eadg7038. Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased. We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.
Marasciulo, F, I Passerini, A Fichera, F Ferrari, FE Odicino and F Prefumo 2023Hepatocellular carcinoma in pregnancy: A systematic review.Acta Obstet Gynecol Scand. INTRODUCTION: Hepatocellular carcinoma (HCC) is the most frequent primary malignant liver tumor and typically develops in the context of chronic liver disease, such as liver cirrhosis or chronic hepatitis B virus infection. Ultrasound evaluation, CT scan, and MRI are used to detect HCC. alpha-fetoprotein (AFP) is a common marker used to detect HCC in the non-pregnant population, which notoriously increases in pregnant women in relation to gestational age. Treatment is driven by the extent of the disease and the severity of underlying liver disease. Pregnancy may represent an obstacle to diagnosis and appropriate treatment of HCC. The aim of this descriptive systematic review was to describe the clinical features and maternal and neonatal outcomes of HCC in pregnancy. MATERIAL AND METHODS: We performed a systematic review of the literature about HCC diagnosed in pregnancy and the postpartum period, with signs or symptoms arising in pregnancy. We included case reports and case series describing the clinical features of women diagnosed with HCC, fibrolamellar variant of HCC, and mixed HCC and cholangiocarcinoma during pregnancy or the postpartum period (with onset of symptoms during pregnancy), from inception to March 2023. The study protocol was registered with the PROSPERO database (Registration number: ID CRD42021275584). RESULTS: We identified 180 records. The articles included in this systematic review were 47 case reports and 5 case series, for a total of 63 pregnancies. The two most frequent predisposing conditions were hepatitis B virus infection (30/63; 47%) and liver cirrhosis (14/63; 22%). Ultrasound evaluation was the most used technique to detect HCC. AFP was higher than normal in 28/46 patients tested (61%). Surgical treatment was the most used therapy, both during pregnancy and after delivery. Twenty-six patients (26/63; 42%) died within 6 months of diagnosis. Survival >24 months was 9% (4/46) in symptomatic and 29% (5/17) in asymptomatic women. No patient with cirrhotic liver survived more than 12 months. Thirty-eight newborns were alive at 28 days of age (38/63; 61%). CONCLUSIONS: Hepatocellular carcinoma in pregnancy is associated with a high risk of maternal and neonatal mortality. Diagnosis in asymptomatic high-risk women or following abnormal maternal serum AFP screening is associated with better maternal outcomes.
Matsuki, R, N Okano, N Hasui, S Kawaguchi, H Momose, K Kitahama, K Nagahama, M Kogure, Y Suzuki, F Nagashima, J Shibahara, H Mori and Y Sakamoto 2023Atezolizumab and bevacizumab combination therapy and sequential conversion hepatectomy for advanced fibrolamellar hepatocellular carcinoma presenting pseudoprogression. Liver Cancer 12(2): 180-183.
Minami, Y, N Nishida and M Kudo 2023Imaging diagnosis of various hepatocellular carcinoma subtypes and its hypervascular mimics: Differential diagnosis based on conventional interpretation and artificial intelligence. Liver Cancer 12(2): 103-115. BACKGROUND: Hepatocellular carcinoma (HCC) is unique among malignancies, and its characteristics on contrast imaging modalities allow for a highly accurate diagnosis. The radiological differentiation of focal liver lesions is playing an increasingly important role, and the Liver Imaging Reporting and Data System adopts a combination of major features including arterial phase hyper-enhancement (APHE) and the washout pattern. SUMMARY: Specific HCCs such as well or poorly differentiated type, subtypes including fibrolamellar or sarcomatoid and combined hepatocellular-cholangiocarcinoma do not often demonstrate APHE and washout appearance. Meanwhile, hypervascular liver metastases and hypervascular intrahepatic cholangiocarcinoma can demonstrate APHE and washout. There are still other hypervascular malignant liver tumors (i.e., angiosarcoma, epithelioid hemangioendothelioma) and hypervascular benign liver lesions (i.e., adenoma, focal nodular hyperplasia, angiomyolipoma, flash filling hemangioma, reactive lymphoid hyperplasia, inflammatory lesion, arterioportal shunt), which need to be distinguished from HCC. When a patient has chronic liver disease, differential diagnosis of hypervascular liver lesions can be even more complicated. Meanwhile, artificial intelligence (AI) in medicine has been widely explored, and recent advancement in the field of deep learning has provided promising performance for the analysis of medical images, especially radiological imaging data contain diagnostic, prognostic, and predictive information which AI can extract. The AI research studies have demonstrated high accuracy (over 90% accuracy) for classifying lesions with typical imaging features from some hepatic lesions. The AI system has a potential to be implemented in clinical routine as decision support tools. However, for the differential diagnosis of many types of hypervascular liver lesions, further large-scale clinical validation is still required. KEY MESSAGES: Clinicians should be aware of the histopathological features, imaging characteristics, and differential diagnoses of hypervascular liver lesions to a precise diagnosis and more valuable treatment plan. We need to be familiar with such atypical cases to prevent a diagnostic delay, but AI-based tools also need to learn a large number of typical and atypical cases.
Nalwa, A, T Nakra, R Yadav, R Walia, S Agarwala, M Jana, D Jain, P Das, SR Mathur and VK Iyer 2023Cytomorphology of paediatric hepatocellular carcinoma: A useful diagnostic adjunct.Cytopathology 34(5): 479-488. INTRODUCTION: Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver but is rare in the paediatric age group; thus, it may be misdiagnosed as the more common tumour, hepatoblastoma. Management varies in both these tumours, and pathological diagnosis thus plays an important role for definitive therapy. Only a few case reports available in the literature have described the cytological characteristics of paediatric HCC. The present study was thus planned to evaluate the cytomorphological features of paediatric HCC. METHODS: Cases diagnosed with HCC on ultrasound-guided fine needle aspiration cytology over a period of 14 years were retrieved. The cases were evaluated for detailed cytological features including cellularity, architecture, sinusoidal wrapping, trabecular thickness, necrosis, anisonucleosis, chromatin, nucleoli, nuclear contours, bi- or multinucleation, intranuclear and intracytoplasmic inclusions, naked nuclei, extra-medullary haematopoiesis, monomorphism, and nuclear overlapping. RESULTS: Twelve cases of HCC were included in the study. The median age at diagnosis was 10 years. Serum alpha-fetoprotein level was raised in most of them. Five of the 12 cases were characterised as moderately differentiated, three as poorly differentiated, two as well differentiated, and two as the fibrolamellar type of HCC. Cytohistological correlation was performed in seven cases. CONCLUSIONS: Ultrasound-guided fine needle aspiration serves as a useful tool to diagnose paediatric HCC and differentiate it from other primary hepatic malignancies, especially hepatoblastoma which closely mimics HCC in this age group, as serum alpha protein levels and imaging findings are unable to distinguish these two tumours.
Neumayer, C, D Ng, CS Jiang, A Qureshi, G Lalazar, R Vaughan and SM Simon 2023Oncogenic addiction of fibrolamellar hepatocellular carcinoma to the fusion kinase DNAJB1-PRKACA. Clin Cancer Res 29(1): 271-278. PURPOSE: Gene fusions are drivers of many pediatric tumors. In fibrolamellar hepatocellular carcinoma (FLC), a fusion of DNAJB1 and PRKACA is the dominant recurrent mutation. Expression of the DNAJB1-PRKACA fusion gene in mice results in a tumor that recapitulates FLC. However, it is not known whether transient expression of DNAJB1-PRKACA is sufficient only to trigger tumor formation or whether ongoing expression is necessary for maintenance and progression. EXPERIMENTAL DESIGN: We screened short hairpin RNAs (shRNA) tiled over the fusion junction and identified several potent and specific candidates in vitro and two independent FLC patient-derived xenografts (PDX). RESULTS: We show that continued DNAJB1-PRKACA expression is not only required for continued tumor growth, but additionally its inhibition results in cell death. Inhibition of DNAJB1-PRKACA by an inducible shRNA in cells of PDX of FLC resulted in cell death in vitro. Induction of the shRNA inhibits FLC tumors growing in mice with no effect on xenografts from a hepatocellular carcinoma cell line engineered to express DNAJB1-PRKACA. CONCLUSIONS: Our results validate DNAJB1-PRKACA as the oncogene in FLC and demonstrate both a continued requirement for the oncogene for tumor growth as well as an oncogenic addiction that can be exploited for targeted therapies. We anticipate our approach will be useful for investigations of other fusion genes in pediatric cancers and spur development of precision therapies.
Nukaya, M, C Cafferty, K Zahed, I Yun, DP Al-Adra, NA Kazim, AR Farghli, M Chan, JD Kratz, ME Berres, A Yen, TS Gujral, P Sethupathy, CA Bradfield and SM Ronnekleiv-Kelly 2023CDK7 is a novel therapeutic vulnerability in fibrolamellar carcinoma. bioRxiv. Fibrolamellar carcinoma (FLC) is a rare and lethal cancer that afflicts young individuals. The tumor arises in the background of a healthy liver, and patients typically present with advanced cancer at the time of diagnosis. Unfortunately, for these patients with advanced or recurrent cancer, no proven systemic therapies exist resulting in only 30-45% of patients surviving to 5 years. Investigations into the molecular underpinning of FLC have revealed a unique gene fusion between heat shock protein 40 (DNAJB1) and the catalytic subunit alpha of protein kinase A (PRKACA), leading to the formation of an oncoprotein (DNAJ-PKAc) that retains kinase activity and is a proven tumor-causing event in FLC. To uncover potential therapeutic targets, we engineered an FLC cell line by introducing the DNAJB1-PRKACA oncogene rearrangement into human hepatocellular cells using CRISPR/Cas9. We identified aberrant cell cycle progression, and follow-up molecular analysis revealed evidence of enhanced cyclin dependent kinase 7 (CDK7) activation in the DNAJB1-PRKACA expressing FLC cells. These findings were confirmed in human samples of FLC. In turn, targeting CDK7 with selective inhibitors demonstrated efficacy in several patient-derived models of FLC, with minimal toxicity to normal liver. Collectively, this work uncovers a novel candidate therapeutic vulnerability in FLC.
Omar, MH, M Kihiu, DP Byrne, KS Lee, TM Lakey, E Butcher, PA Eyers and JD Scott 2023Classification of Cushing's syndrome PKAc mutants based upon their ability to bind PKI. Biochem J 480(12): 875-890. Cushing's syndrome is an endocrine disorder caused by excess production of the stress hormone cortisol. Precision medicine strategies have identified single allele mutations within the PRKACA gene that drive adrenal Cushing's syndrome. These mutations promote perturbations in the catalytic core of protein kinase A (PKAc) that impair autoinhibition by regulatory subunits and compartmentalization via recruitment into AKAP signaling islands. PKAcL205R is found in approximately 45% of patients, whereas PKAcE31V, PKAcW196R, and L198insW and C199insV insertion mutants are less prevalent. Mass spectrometry, cellular, and biochemical data indicate that Cushing's PKAc variants fall into two categories: those that interact with the heat-stable protein kinase inhibitor PKI, and those that do not. In vitro activity measurements show that wild-type PKAc and W196R activities are strongly inhibited by PKI (IC50 < 1 nM). In contrast, PKAcL205R activity is not blocked by the inhibitor. Immunofluorescent analyses show that the PKI-binding variants wild-type PKAc, E31V, and W196R are excluded from the nucleus and protected against proteolytic processing. Thermal stability measurements reveal that upon co-incubation with PKI and metal-bound nucleotide, the W196R variant tolerates melting temperatures 10 degrees C higher than PKAcL205. Structural modeling maps PKI-interfering mutations to a approximately 20 A diameter area at the active site of the catalytic domain that interfaces with the pseudosubstrate of PKI. Thus, Cushing's kinases are individually controlled, compartmentalized, and processed through their differential association with PKI.
Omar, MH, SM Lauer, HT Lau, M Golkowski, SE Ong and JD Scott 2023Proximity biotinylation to define the local environment of the protein kinase A catalytic subunit in adrenal cells. STAR Protoc 4(1): 101992. Mutant protein kinase A catalytic subunit (PKAc) drives adrenal Cushing's syndrome, though its signaling interactions remain unclear. This protocol details steps to use live-cell proximity labeling to identify subcellular compartments and proteins closely associated with variants of PKAc in human adrenal cells. We include instructions for clonal cell line generation, live biotin labeling of proximal proteins, isolation of biotinylated proteins, and sample processing for proteomic analysis using the biotin ligase miniTurbo with wild-type and mutant PKAc.(1)(,)(2) For complete details on the use and execution of this protocol, please refer to Omar et al. (2022).(3).
Pinter, M, B Scheiner and DJ Pinato 2023Immune checkpoint inhibitors in hepatocellular carcinoma: emerging challenges in clinical practice. Lancet Gastroenterol Hepatol 8(8): 760-770. Systemic therapy for advanced hepatocellular carcinoma has expanded at an unprecedented pace over the past 5 years. After tyrosine kinase inhibitors dominated the field for more than a decade, immune checkpoint inhibitor (ICI)-based therapies have become the main component in systemic first-line treatment of this cancer. Delivery of immunotherapy in routine clinical practice recognises several challenges. In this Viewpoint, we discuss the major gaps in knowledge around the role of ICI-based therapies in patients with Child-Pugh class B. We discuss the challenges in individuals with rare histological subtypes of primary liver cancer, including combined hepatocellular-cholangiocarcinoma, fibrolamellar hepatocellular carcinoma, and sarcomatoid hepatocellular carcinoma. We also review data on ICI rechallenge in patients previously treated with ICIs, and discuss atypical patterns of progression related to immunotherapy (ie, hyperprogressive disease and pseudoprogression).
Qiu, S, R Chen, J Hu and T Han 2023The prognosis of fibrolamellar carcinoma versus conventional hepatocellular carcinoma: a study based on propensity score matching. Scand J Gastroenterol: 1-8. BACKGROUND: The prognosis of fibrolamellar carcinoma (FLC) versus conventional hepatocellular carcinoma (HCC) remains controversial. Thus, this study aimed to compare the prognosis of FLC and HCC. METHODS: Patients with FLC and HCC in the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2015 were included. Propensity score matching (PSM) was performed to balance the clinical characteristics between FLC and HCC. Cox regression and Kaplan-Meier analysis were applied to identify the effect of pathology in prognosis before and after match in the whole cohort, as well as in subgroups of fibrosis score, AJCC stage and therapy. RESULTS: A total of 213 patients with FLC and 33365 patients with HCC between 2000 and 2015 were identified. Before matching, the overall survival (OS) and cancer-specific survival (CSS) were significantly better in FLC than HCC. After matching, FLC patients had better OS than HCC patients, but the CSS was similar between groups. Further analyses found that in patients at early stage (AJCC I-III) and/or accepted curative therapy, the prognosis was comparable between HCC and FLC. In patients without cirrhosis (F0), the HCC patients had similar prognosis with FLC patients. Prognosis benefit of FLC was observed in subgroups of AJCC stage IV and non-curative therapy, however, the concomitant diseases may affect the results. CONCLUSIONS: The prognosis of FLC was significantly better than HCC before matching. However, after matching for clinical characteristics, the CSS was comparable between FLC and HCC.
Ruland, L, F Andreatta, S Massalini, S Chuva de Sousa Lopes, H Clevers, D Hendriks and B Artegiani 2023Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss.Nat Commun 14(1): 2377. Fibrolamellar carcinoma (FLC) is a lethal primary liver cancer, affecting young patients in absence of chronic liver disease. Molecular understanding of FLC tumorigenesis is limited, partly due to the scarcity of experimental models. Here, we CRISPR-engineer human hepatocyte organoids to recreate different FLC backgrounds, including the predominant genetic alteration, the DNAJB1-PRKACA fusion, as well as a recently reported background of FLC-like tumors, encompassing inactivating mutations of BAP1 and PRKAR2A. Phenotypic characterizations and comparisons with primary FLC tumor samples revealed mutant organoid-tumor similarities. All FLC mutations caused hepatocyte dedifferentiation, yet only combined loss of BAP1 and PRKAR2A resulted in hepatocyte transdifferentiation into liver ductal/progenitor-like cells that could exclusively grow in a ductal cell environment. BAP1-mutant hepatocytes represent primed cells attempting to proliferate in this cAMP-stimulating environment, but require concomitant PRKAR2A loss to overcome cell cycle arrest. In all analyses, DNAJB1-PRKACA(fus) organoids presented with milder phenotypes, suggesting differences between FLC genetic backgrounds, or for example the need for additional mutations, interactions with niche cells, or a different cell-of-origin. These engineered human organoid models facilitate the study of FLC.
Simon, SM 2023Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma. Nat Rev Cancer 23(5): 335-346. The fight against rare cancers faces myriad challenges, including missed or wrong diagnoses, lack of information and diagnostic tools, too few samples and too little funding. Yet many advances in cancer biology, such as the realization that there are tumour suppressor genes, have come from studying well-defined, albeit rare, cancers. Fibrolamellar hepatocellular carcinoma (FLC), a typically lethal liver cancer, mainly affects adolescents and young adults. FLC is both rare, 1 in 5 million, and problematic to diagnose. From the paucity of data, it was not known whether FLC was one cancer or a collection with similar phenotypes, or whether it was genetically inherited or the result of a somatic mutation. A personal journey through a decade of work reveals answers to these questions and a road map of steps and missteps in our fight against a rare cancer.
Singh, A, S Goyal, V Mehta, C Kakkar, V Narang and A Sood 2023Fibrolamellar hepatocellular carcinoma presenting as cholestatic jaundice: An unusual presentation of a rare disease. Indian J Pathol Microbiol 66(2): 385-387. Fibrolamellar hepatocellular carcinoma is a rare primary hepatic tumor that usually occurs in youth. The common presenting features are vague abdominal pain, nausea, vomiting and weight loss. We present a case report of a young male who presented with cholestatic jaundice and on evaluation was diagnosed to have fibrolamellar hepatocellular carcinoma. He underwent successful surgical resection of the tumor. In young individuals presenting with unexplained cholestasis, fibrolamellar hepatocellular carcinoma should be considered.
Smith, M, PJ Tomboc and B Markovich 2023Fibrolamellar hepatocellular carcinoma. StatPearls. Treasure Island (FL). Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare cancer of the liver and it displays features that make it very different in its behavior and clinical findings from conventional hepatocellular carcinoma (HCC). FL-HCC accounts for a negligible percentage of primary liver cancers (1%). Patients affected by FL-HCC are usually in a lower age group as opposed to HCC. The presenting complaints, blood tests, radiological evaluation, and treatment strategies are different from HCC. Prompt diagnosis and initiation of appropriate care plans play a very important role in this disease entity, which eventually affects the outcome. This article aims at reviewing the salient features of FL-HCC, comparing it to HCC.
Sullivan, KM, X Jiang, P Guha, C Lausted, JA Carter, C Hsu, KP Labadie, K Kohli, HL Kenerson, SK Daniel, X Yan, C Meng, A Abbasi, M Chan, YD Seo, JO Park, IN Crispe, RS Yeung, TS Kim, TS Gujral, Q Tian, SC Katz and VG Pillarisetty 2023Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.Gut 72(2): 325-337. OBJECTIVE: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures. DESIGN: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (alphaIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy. RESULTS: alphaIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. alphaIL-10 significantly increased proportions of CD8(+) T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of alphaIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, alphaIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function. CONCLUSION: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.
Surjan, RCT, TM de Lima, HP de Souza, MCC Machado and JC Ardengh 2023Molecular basis of hyperammonemic encephalopathy in fibrolamellar hepatocellular carcinoma. Cureus 15(1): e33750. Hyperammonemic encephalopathy is a potentially fatal condition associated with fibrolamellar hepatocellular carcinoma. The mechanism involved in hyperammonemia in patients with fibrolamellar carcinoma was unclear until a possible physiopathological pathway was recently proposed. An ornithine transcarboxylase dysfunction was suggested as a result of increased ornithine decarboxylase activity induced by c-Myc overexpression. This c-Myc overexpression resulted from Aurora kinase A overexpression derived from the activity of a chimeric kinase that is the final transcript of a deletion in chromosome 19, common to all fibrolamellar carcinomas. We performed the analysis of the expression of all enzymes involved and tested for the mutation in chromosome 19 in fresh frozen samples of fibrolamellar hepatocellular carcinoma, non-tumor liver, and hepatic adenomatosis. The specific DNAJB-PRKACA fusion protein that results from the recurrent mutation on chromosome 19 common to all fibrolamellar carcinoma was detected only in the fibrolamellar carcinoma sample. Fibrolamellar carcinoma and adenomyomatosis samples presented increased expression of Aurora kinase A, c-MYC, and ornithine decarboxylase when compared to normal liver, while ornithine transcarbamylase was decreased. The proposed physiopathological pathway is correct and that overexpression of c-Myc may also be responsible for hyperammonemia in patients with other types of rapidly growing hepatomas. This gives further evidence to apply new and adequate treatment to this severe complication.
Suthar, RR, N Purandare, S Shah, A Agrawal, A Puranik and V Rangarajan 2023FAPI PET positivity in fibrolamellar hepatocellular carcinoma. Clin Nucl Med 48(7): e332-e333. Fibrolamellar hepatocellular carcinoma (HCC) is a variant of HCC. It is a malignant tumor, but its imaging features often overlap focal nodular hyperplasia, which is a benign entity. FDG PET/CT is also not much help in these cases because both lesions do not concentrate FDG. We present one such case of fibrolamellar HCC with FAPI PET/CT positivity.
Taheri, N and RP Graham 2023How molecular discoveries have changed liver tumor pathology: A brief review. Arch Pathol Lab Med. CONTEXT.-: Recent molecular discoveries have led to improved understanding of tumor biology and the development of new diagnostic assays. OBJECTIVE.-: To review primarily 3 examples of liver tumors and to briefly illustrate how recent molecular discoveries have altered clinical liver pathology practice. DATA SOURCES.-: First, we will discuss fibrolamellar carcinoma, which will be the main focus of discussion, as an example for new diagnostic tests that have been developed as a result of molecular discoveries. Additional information on the role of molecular diagnostics in hepatocellular adenoma and hepatocellular carcinoma will be provided. Second, we will use the example of epithelioid hemangioendothelioma as an example of how new diagnostic tools, based on molecular discoveries, may support improved prognostication. Finally, we will use the example of intrahepatic cholangiocarcinoma as an example of a liver tumor where new molecular discoveries have identified tractable therapeutic targets and led to new effective therapies. This portion of the manuscript will also include a description of the anatomic and molecular differences between intrahepatic, hilar, and extrahepatic cholangiocarcinoma. CONCLUSIONS.-: Fueled by molecular discoveries, new and better diagnostic tests and therapeutic targets have improved clinical care in patients affected by liver tumors.
Ugonabo, O, Y Pulipati, A Elghezewi, V Miller, L Logan and P Pramod 2023An unusual case of hepatocellular carcinoma in a healthy teenager. J Investig Med High Impact Case Rep 11: 23247096231165744. Hepatocellular carcinoma (HCC) is a primary liver malignancy known to occur majorly in patients with liver cirrhosis or those with a harbinger of risk factors like viral hepatitis, autoimmune liver disease, alpha-1 antitrypsin deficiency, alcoholic liver disease, and nonalcoholic fatty liver disease. The incidence of HCC has risen in the past 2 decades and currently ranks as the sixth most common cause of cancer-related death worldwide. Most cases are seen in adulthood, and only a very small percentage have been reported in adolescents with risk factors. The 2 pathologic subtypes of pediatric HCC are classic and fibrolamellar. Here, we discussed a very interesting rare case of a healthy male teenager with no apparent liver disease or risk factor who presented with right-upper-quadrant pain, normal alpha-fetoprotein level, and abdominal ultrasound showing a large hepatic mass. A liver biopsy was positive for HCC with fluorescent in situ hybridization showing a PRKACA complex gene pattern, favoring the fibrolamellar type.
Watanabe, A, N Harimoto, H Saito, R Kawabata-Iwakawa, T Seki, R Muranushi, K Hoshino, K Hagiwara, N Ishii, M Tsukagoshi, T Igarashi, K Araki, H Ikota, T Ishige, K Mimori and K Shirabe 2023Fibrolamellar hepatocellular carcinoma: a case report and gene analysis. Surg Case Rep 9(1): 168. BACKGROUND: Fibrolamellar hepatocellular carcinoma (HCC) (FL-HCC) is rare in Japan. FL-HCC develops in young patients with no history of cirrhosis and tends to manifest lymphatic metastasis with clinical features similar to those of HCC. We present a case of FL-HCC in a young male patient. CASE PRESENTATION: A 14-year-old male patient underwent abdominal computed tomography (CT) to diagnose appendicitis, wherein a hepatic tumor was detected. Dynamic enhanced CT revealed a 35-mm solid tumor, which contrasted at the early phase of dynamic enhanced study of the right hepatic segments, with occlusion of the right portal vein. We performed right hepatectomy for these lesions. The patient experienced a single lymphatic recurrence on the hepatoduodenal ligament 12 months after the initial surgery. We performed lymphadenectomy for the recurrent tumor. We performed RNA sequencing (RNA-seq) and targeted DNA sequencing of the resected specimens (primary tumor, lymphatic metastasis, and normal liver). RNA-seq detected DNAJB1-PRKACA in both primary and metastatic lesions as previously reported. Furthermore, The Cancer Genome Atlas (TCGA) database was used to compare other gene expressions in this case with those of previously reported cases of FL-HCC and HCC in young patients. Principal component analysis of differentially expressed genes in the top 10% revealed that the gene expression in our case was similar to that of previous FL-HCC cases but was a different cluster from that in HCC cases in young patients. Mutational analysis did not detect any somatic mutations associated with carcinogenesis, including previously reported mutations (Kastenhuber et al. in Proc Natl Acad Sci USA 114: 13076-84, 2017). CONCLUSION: We encountered a case of FL-HCC, a rare hepatic tumor in an adolescent patient, and evaluated the genetic background. Our findings could contribute to the elucidation of the mechanisms underlying carcinogenesis and progression in patients with FL-HCC and thereby contribute to the development of new therapeutic strategies in the future that may improve patient prognosis.
Whyte, SS, R Karns, KW Min, JH Cho, S Lee, C Lake, A Bondoc, JH Yoon and S Shin 2023Integrated analysis using ToppMiR uncovers altered miRNA- mRNA regulatory networks in pediatric hepatocellular carcinoma-A pilot study.Cancer Rep (Hoboken) 6(1): e1685.BACKGROUND: Pediatric hepatocellular carcinoma (HCC) is a group of liver cancers whose mechanisms behind their pathogenesis and progression are poorly understood. AIM: We aimed to identify alterations in the expression of miRNAs and their putative target mRNAs in not only tumor tissues of patients with pediatric HCC but also in corresponding non-tumorous background livers by using liver tissues without underlying liver disease as a control. METHODS AND RESULTS: We performed a small-scale miRNA and mRNA profiling of pediatric HCC (consisting of fibrolamellar carcinoma [FLC] and non-FLC HCC) and paired liver tissues to identify miRNAs whose expression levels differed significantly from control livers without underlying liver disease. ToppMiR was used to prioritize both miRNAs and their putative target mRNAs in a gene-annotation network, and the mRNA profile was used to refine the prioritization. Our analysis generated prioritized lists of miRNAs and mRNAs from the following three sets of analyses: (a) pediatric HCC versus control; (b) FLC versus control; and (c) corresponding non-tumorous background liver tissues from the same patients with pediatric HCC versus control. No liver disease liver tissues were used as the control group for all analyses. Many miRNAs whose expressions were deregulated in pediatric HCC were consistent with their roles in adult HCC and/or other non-hepatic cancers. Our gene ontology analysis of target mRNAs revealed enrichment of biological processes related to the sustenance and propagation of cancer and significant downregulation of metabolic processes. CONCLUSION: Our pilot study indicates that alterations in miRNA-mRNA networks were detected in not only tumor tissues but also corresponding non-tumorous liver tissues from patients with pediatric HCC, suggesting multi-faceted roles of miRNAs in disease progression. Our results may lead to novel hypotheses for future large-scale studies.
Wildner, D, HJ Schlitt, T Bauerle and M Haibach 2023[Contrast-enhanced ultrasound of fibrolamellar hepatocellular carcinoma].Z Gastroenterol. We present the case of a 24-year-old male patient, who was admitted for endoscopy due to sustained pain in the upper abdomen with nausea and postprandial fullness without vomiting for more than 5 months. In the physical examination, an epigastric induration was found. Endoscopy revealed an external impression of the proximal duodenum. Beyond that, normal findings could be ascertained in gastroscopy and ileo-colonoscopy. Abdominal ultrasound identified a large hypoechoic lesion in the left liver lobe with a sharp delineation. Along the upper mesenteric vessels, enlarged lymphnodes were visible with contact to the proximal duodenum. Contrast-enhanced ultrasound (CE-US) was conducted and revealed the typical perfusion pattern of hepatocellular carcinoma. For further assessment, an ultrasound-guided core-biopsy of the lesion was performed. The histopathological evaluations resulted in the diagnosis of a hepatocellular carcinoma of fibrolamellar subtype.With the present case, we want to illustrate the perfusion pattern of a fibrolamellar hepatocellular carcinoma in contrast-enhanced ultrasound. Even though the tumor tissue is surrounded by lamellar bands of fibrosis with collagen-rich fibers, the perfusion pattern is consistent with the previously known appearance of HCC in CE-US.
Yasir, S, S Thompson, ZE Chen, R Knudson, D Knutson, S Kloft-Nelson, RP Graham, D Jain, SM Simon, TT Wu and M Torbenson 2023Alternative lengthening of telomeres in primary hepatic neoplasms. Hum Pathol 131: 79-86. The alternative lengthening of telomeres (ALT) phenotype is characterized by ultra-bright telomeres on fluorescence in situ hybridization (FISH) and is a marker of a unique mechanism of telomere maintenance in tumors. ALT does not occur in normal tissues. ALT has been described in hepatocellular carcinoma (5-10%) and in primary hepatic angiosarcomas (75%). To study the frequency of ALT in other primary hepatic tumors, a wide range of primary hepatic neoplasms were retrieved. The tumors included the following: intrahepatic and hilar cholangiocarcinomas (N = 110), hepatic adenomas (N = 35), hepatocellular carcinomas (N = 30), fibrolamellar carcinomas (n = 11), combined cholangiocarcinoma-hepatocellular carcinomas (N = 8), carcinosarcoma (N = 10), hepatoblastomas (N = 5), hemangiomas (N = 4), angiosarcomas (N = 8), epithelioid hemangioendotheliomas (N = 10), calcified nested stromal epithelial tumor (N = 2), embryonal sarcoma (N = 2), rhabdoid tumor (N = 1), bile duct adenoma (N = 1), and angiomyolipoma (N = 1). For epithelial tumors, ALT-FISH was positive in one carcinosarcoma (10% of cases), one cholangiocarcinoma (1% of cases), and one combined hepatocellular carcinoma-cholangiocarcinoma (13% of cases). In the hepatocellular carcinoma component of both the carcinosarcoma and the combined hepatocellular carcinoma-cholangiocarcinoma, the tumor cells showed patchy marked nuclear pleomorphism akin to that described previously for chromophobe hepatocellular carcinoma, which are typically ALT FISH positive. The ALT-positive cholangiocarcinoma also showed patchy, striking nuclear pleomorphism. For soft tissue tumors, ALT was positive in two angiosarcomas (N = 2; 25% of cases). In summary, this study shows that ALT-FISH is positive in rare carcinosarcomas, cholangiocarcinomas, and combined cholangiocarcinoma-hepatocellular carcinoma. ALT is not a significant mechanism of telomere maintenance in hepatocellular adenomas or fibrolamellar carcinomas and was negative in all other tested primary hepatic neoplasms. ALT-FISH is also positive in a subset of primary hepatic angiosarcomas.
Zack, T, KP Losert, SM Maisel, J Wild, A Yaqubie, M Herman, JJ Knox, RJ Mayer, AP Venook, A Butte, AF O'Neill, GK Abou-Alfa and JD Gordan 2023Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of clinical data. NPJ Precis Oncol 7(1): 29. The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is a rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of the electronic medical record and national payer data and found that FLC incidence is likely five to eight times higher than previous estimates. By employing unsupervised learning on clinical laboratory data from patients with hyperammonemia, we find that FLC-associated hyperammonemia mirrors metabolic dysregulation in urea cycle disorders. Our findings demonstrate that advanced computational analysis of rich clinical datasets can provide key clinical and biochemical insights into rare cancers.
Zhang, W, Y Xu, X Wang, T Oikawa, G Su, E Wauthier, G Wu, P Sethupathy, Z He, J Liu and LM Reid 2023Fibrolamellar carcinomas-growth arrested by paracrine signals complexed with synthesized 3-O sulfated heparan sulfate oligosaccharides. Matrix Biol 121: 194-216. Fibrolamellar carcinomas (FLCs), lethal tumors occurring in children to young adults, have genetic signatures implicating derivation from biliary tree stem cell (BTSC) subpopulations, co-hepato/pancreatic stem cells, involved in hepatic and pancreatic regeneration. FLCs and BTSCs express pluripotency genes, endodermal transcription factors, and stem cell surface, cytoplasmic and proliferation biomarkers. The FLC-PDX model, FLC-TD-2010, is driven ex vivo to express pancreatic acinar traits, hypothesized responsible for this model's propensity for enzymatic degradation of cultures. A stable ex vivo model of FLC-TD-2010 was achieved using organoids in serum-free Kubota's Medium (KM) supplemented with 0.1% hyaluronans (KM/HA). Heparins (10 ng/ml) caused slow expansion of organoids with doubling times of approximately 7-9 days. Spheroids, organoids depleted of mesenchymal cells, survived indefinitely in KM/HA in a state of growth arrest for more than 2 months. Expansion was restored with FLCs co-cultured with mesenchymal cell precursors in a ratio of 3:7, implicating paracrine signaling. Signals identified included FGFs, VEGFs, EGFs, Wnts, and others, produced by associated stellate and endothelial cell precursors. Fifty-three, unique heparan sulfate (HS) oligosaccharides were synthesized, assessed for formation of high affinity complexes with paracrine signals, and each complex screened for biological activity(ies) on organoids. Ten distinct HS-oligosaccharides, all 10-12 mers or larger, and in specific paracrine signal complexes elicited particular biological responses. Of note, complexes of paracrine signals and 3-O sulfated HS-oligosaccharides elicited slowed growth, and with Wnt3a, elicited growth arrest of organoids for months. If future efforts are used to prepare HS-oligosaccharides resistant to breakdown in vivo, then [paracrine signal-HS-oligosaccharide] complexes are potential therapeutic agents for clinical treatments of FLCs, an exciting prospect for a deadly
Abdelhamed, W and M El-Kassas 2022Fibrolamellar hepatocellular carcinoma: A rare but unpleasant event.World J Gastrointest Oncol 14(6): 1103-1114. Fibrolamellar carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), comprising 1%-9% of all HCCs. FLC is a poorly understood malignancy, which seems to be more prevalent in young patients with no underlying liver diseases. The term "fibrolamellar" is derived from thick fibrous collagen bands surrounding the tumor cells. Unlike HCC, cirrhosis and viral hepatitis infection are not predisposing to FLC, and it is not associated with elevations in serum alpha-fetoprotein. FLC patients often present with vague abdominal pain, nausea, malaise, and weight loss. Most cases present are at an advanced stage at the time of initial diagnosis. However, curative treatment options can still be offered to up to 70% of patients. Surgery (resection/liver transplantation) is the mainstay of treatment and the only potentially curative option. FLCs have been less chemo-responsive than the conventional HCC, however, in advanced cases, multimodality treatments can be effective. Recent advances in molecular studies of FLC have found a unique DNAJB1-PRKACA fusion transcript in most of the cases studied. The review aims to describe clinical characteristics, diagnostic methods, and therapeutic modalities for this rare tumor to raise awareness among clinicians and surgeons.
Ahmed, A, F Ata, M Gaber, M Petkar, A Mahfouz, P Schirmacher, S Musa and A Hashim 2022Refractory hyperammonemic encephalopathy in fibrolamellar hepatocellular carcinoma, a case report and literature review.Curr Probl Cancer 46(3): 100847. Fibrolamellar hepatocellular carcinoma is a rare type of hepatocellular carcinoma with unclear etiology. Its prevalence ranges from 0.6%-5%. One of the rare manifestations of FHCC includes hyperammonemic hepatic encephalopathy (HAE). Data regarding HAE in FHCC is limited to case reports, and much is unknown, including its precipitating factors, clinical course, and management. We have reported one such case of FHCC associated HAE and presented an extensive literature review on the topic. We report the case of a 26-year-old Pakistani male who was diagnosed with fibrolamellar hepatocellular carcinoma. On day five after the first chemotherapy, he presented with nausea, vomiting, and confusion. His serum ammonia level was raised, and he was treated with lactulose and rifaximin. The patient continued chemotherapy and had recurrent admissions with HAE. A detailed workup revealed acquired ornithine transcarbamylase deficiency. Ammonia level peaked at 694 umol/L during the clinical course of his disease. He received treatment with multiple ammonia scavengers, including sodium benzoate + phenylacetate, with relief of symptoms and reduction in ammonia level. The patient was eventually lost to follow-up. HAE presents as a paraneoplastic manifestation of FHCC. Patients have laboratory features suggestive of acquired ornithine transcarbamylase deficiency. There is a variable frequency of episodes reported in the literature. Most patients respond well to ammonia scavenger therapies rather than conventional HE management with lactulose or rifaxmin.
Akbulut, S, A Tuncer, Z Ogut, TT Sahin and C Koc 2022High-Level Procalcitonin in Patient with Mixed Fibrolamellar Hepatocellular Carcinoma: A Case Report and Literature Review. J Gastrointest Cancer 53(4): 1130-1134. Course of blood procalcitonin levels by days.
Alsadery, HA, H Almaiman, R Alibrah, M Mnayan, A Alblowi, R Alzayyat and A Alshahrani 2022Case Report of Fibrolamellar Hepatocellular Carcinoma in A 15-Year-old Male. Med Arch 76(5): 387-390. BACKGROUND: A rare form of hepatocellular cancer is called fibrolamellar hepatocellular carcinoma (FL-HCC) which occurs mostly in young adults who are medically free, regardless of their gender. It usually presents with abdominal pain with right upper quadrant palpable mass, nausea, and weight loss associated with higher Alpha-Fetoprotein (AFP) in some cases. OBJECTIVE: We report a case of a 15-year-old male patient who was diagnosed with (FL-HCC), successfully treated with surgical resection and is currently free of relapses. CASE PRESENTATION: A 15-year-old male patient with no previous medical or surgical history, presented with recurrent vomiting for two months, weight loss, and loss of appetite. Patient presented with normal systemic examination except for abdominal examination which revealed a generalized distended abdomen with mild tenderness in the right upper quadrant with the presence of hepatomegaly. Laboratory and radiological investigation showed high level of (AFP). CT and liver MRI showed large right hepatic lobe lesion then TRU-CUT needle biopsy was performed which showed Fibrolamellar hepatocellular carcinoma and patient underwent surgical resection with no postoperative complication followed by multiple cycle of chemotherapy and no signs of relapse with 3 year follow up. CONCLUSION: Fibrolamellar hepatocellular carcinoma is rear type hepatocellular carcinoma which occurs mostly in young adults who are medically free with vague symptom and to diagnose it need high index of suspicion and variers Laboratory and radiological investigation including biopsy. However, it can be treated successfully by surgical resection followed by chemotherapy in selected cases if diagnosis in timely manner.
Amani, M, A Bavali and P Parvin 2022Optical characterization of the liver tissue affected by fibrolamellar hepatocellular carcinoma based on internal filters of laser-induced fluorescence. Sci Rep 12(1): 6116. Laser-induced fluorescence (LIF) spectroscopy has recently gained regards for diagnosis of the cancer in various tissues of the human body. This method in its conventional form, when used for assay of highly scattering media, encounters a lot of noise due to multiple scattering and inner filter effects which overshadows the sensitivity and specificity of the method. Here, angular dependence of the LIF spectral shift due to the reabsorption events have been investigated for characterization of the bio-tissues. The aim was to determine the tissue morphological changeovers due to the cancer progression. The assessment of a rare type of the liver cancer i. e. fibrolamellar hepatocellular carcinoma revealed the significant difference in optical anisotropy of the parenchyma and liver tumor. As a result, utilizing LIF spectroscopy as a fast, highly sensitive and easy-to-use method one can evaluate the optical anisotropy for diagnosing tissues during the cancer progression.
Bauer, J, N Kohler, Y Maringer, P Bucher, T Bilich, M Zwick, S Dicks, A Nelde, M Dubbelaar, J Scheid, M Wacker, JS Heitmann, S Schroeder, J Rieth, M Denk, M Richter, R Klein, I Bonzheim, J Luibrand, U Holzer, M Ebinger, IB Brecht, M Bitzer, M Boerries, J Feucht, HR Salih, HG Rammensee, S Hailfinger and JS Walz 2022The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma. Nat Commun 13(1): 6401. The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease lacking specific therapies. This study reports on the identification, characterization, and immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in fibrolamellar hepatocellular carcinoma. DNAJB1-PRKACA-derived HLA class I and HLA class II ligands induce multifunctional cytotoxic CD8(+) and T-helper 1 CD4(+) T cells, and their cellular processing and presentation in DNAJB1-PRKACA expressing tumor cells is demonstrated by mass spectrometry-based immunopeptidome analysis. Single-cell RNA sequencing further identifies multiple T cell receptors from DNAJB1-PRKACA-specific T cells. Vaccination of a fibrolamellar hepatocellular carcinoma patient, suffering from recurrent short interval disease relapses, with DNAJB1-PRKACA-derived peptides under continued Poly (ADP-ribose) polymerase inhibitor therapy induces multifunctional CD4(+) T cells, with an activated T-helper 1 phenotype and high T cell receptor clonality. Vaccine-induced DNAJB1-PRKACA-specific T cell responses persist over time and, in contrast to various previous treatments, are accompanied by durable relapse free survival of the patient for more than 21 months post vaccination. Our preclinical and clinical findings identify the DNAJB1-PRKACA protein as source for immunogenic neoepitopes and corresponding T cell receptors and provide efficacy in a single-patient study of T cell-based immunotherapy specifically targeting this oncogenic fusion.
Bawashkhah, AS, GA Sindi, SB Almatrafi, EF Obaid and RI Bakhsh 2022Fibrolamellar Hepatocellular Carcinoma in the Absence of Risk Factors: A Case Report. Cureus 14(12): e32483. Cancer of the liver and intrahepatic bile ducts is the sixth most frequently diagnosed cancer worldwide. In addition, primary liver cancer is the fourth leading cause of cancer-related mortality worldwide, and the second most lethal tumor after pancreatic cancer. Early diagnosis and rapid workup for the suspected case are the only paths for treating the patient with curative intent. Hepatocellular carcinoma (HCC) is usually associated with risk factors like chronic viral hepatitis and alcohol ingestion. Since HCC typically progresses silently, clinical diagnosis can be challenging, and the diagnosis may require the use of one or more imaging modalities and liver biopsy. In this case, the patient is a 29-year-old man with no risk factors, who was diagnosed early and treated without the need for a liver transplant.
Berger, R, G Dinstag, O Tirosh, E Schiff, D Kleiner, KD Aldape, E Ruppin, T Beker and R Kurzrock 2022Fibrolamellar carcinoma transcriptomic-based treatment prediction: complete response after nivolumab and ipilimumab. J Immunother Cancer 10(12). Fibrolamellar carcinoma (FLC) is a rare cancer of the liver that most commonly affects children and young adults. There is no clear standard of care for the disease, whose response to treatment seems to be very different from that of hepatocellular carcinoma. We present a case of FLC in a patient in her mid 30s that recurred and persisted despite resection and multiple lines of treatment. Following transcriptomic analysis, a combination of ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) led to complete remission, although common biomarkers for immune checkpoint blockade were all negative in this case. The patient is still in remission. Here, combined checkpoint blockade guided by novel transcriptomic analysis led to complete remission after failure of several lines of treatment.
Berkovitz, A, RD Migler, A Qureshi, C Rosemore, MS Torbenson, R Vaughan, E Marcotte and SM Simon 2022Clinical and demographic predictors of survival for fibrolamellar carcinoma patients-A patient community, registry-based study.Hepatol Commun. Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer that affects primarily adolescents and young adults. It is associated with a poor overall prognosis. There is a need to better define risk factors, but small sample size has limited such studies. An FLC patient registry now provides data sufficient for statistically robust inferences. We leveraged a unique patient community-based FLC registry to analyze the prognostic impact of demographic and clinical characteristics evident at diagnosis. Variables were analyzed using Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). In multivariable models of 149 patients (88 females and 61 males), female gender was associated with statistically significant improved survival with HR of 0.52 (95% CI 0.29-0.93). Factors evident at diagnosis that are associated with worse survival included the presence of 10 or more tumors within the liver (HR 7.1; 95% CI 2.4-21.04), and metastases at diagnosis (HR 2.17; 95% CI 1.19-3.94). Positive lymph nodes at diagnosis, despite being found significantly associated with worse survival in a univariate analysis, did not remain significant when adjusted for covariates in a multivariable analysis. We found no statistically significant effect of age at diagnosis nor tumor size at diagnosis on survival. Female gender may confer a favorable prognosis in FLC. Established high-risk prognostic factors that we confirmed in this Registry included the diagnostic presence of numerous intrahepatic tumors, and metastases. This is the first study derived from a FLC patient community-based registry, and highlights how registries of rare tumors can empower patients to meaningfully advance clinical and scientific discoveries.
Bernon, MM, K Gandhi, H Allam, S Singh, J Kloppers and E Jonas 2022Trans-arterial therapy for Fibrolamellar carcinoma: A case report and literature review. Int J Surg Case Rep 94: 106980. INTRODUCTION: Fibrolamellar carcinoma (FLC) is a rare pathologically distinct primary liver cancer. Surgical resection is the only treatment associated with prolonged survival. Trans-arterial embolization (TAE), which is a recognised treatment for hepatocellular carcinoma has been used to treat FLC. We present a case and performed a literature review of patients with FLC treated with TAE. CASE PRESENTATION: We present a 19-year old female with a large potentially resectable FLC which was initially treated with trans-arterial chemo-embolization (TACE) with drug eluting beads. The TACE was followed by surgical resection. Histology confirmed tumour necrosis related to the previous TACE. DISCUSSION & LITERATURE REVIEW: We identified seven case reports and one case series of TAE for FLC. TAE was either used as a neo-adjuvant therapy to facilitate subsequent tumour resection or as a palliative treatment modality. We propose an algorithm for the treatment of FLC that includes TAE. CONCLUSION: The rarity of FLC and the paucity of data precludes establishing clear evidence-based standards of care. We propose an algorithm for the treatment of FLC. The establishment of an international registry may facilitate the collection of better quality evidence.
Chen, KY, A Popovic, D Hsiehchen, M Baretti, P Griffith, R Bista, A Baghdadi, IR Kamel, SM Simon, RD Migler and M Yarchoan 2022Clinical outcomes in fibrolamellar hepatocellular carcinoma treated with immune checkpoint inhibitors.Cancers (Basel) 14(21). BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. METHODS: We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan-Meier statistics were used for progression-free survival (PFS) and overall survival (OS). RESULTS: FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/- cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3-4 immune related adverse events were observed in 4/19 (21.1%) patients. CONCLUSIONS: ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed.
Chen, X, Y Lu, X Shi, G Han, L Zhang, C Ni, J Zhao, Y Gao and X Wang 2022Epidemiological and Clinical Characteristics of Five Rare Pathological Subtypes of Hepatocellular Carcinoma.Front Oncol 12: 864106. Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor with several rare pathological subtypes and which is still poorly understood. This study aimed to describe the epidemiological and clinical spectrum of five rare HCC subtypes and develop a competing risk nomogram for cancer-specific survival prediction. Methods: The study cohort was recruited from the Surveillance, Epidemiology, and End Results database. The clinicopathological data of 50,218 patients histologically diagnosed with classic HCC and five rare subtypes (ICD-O-3 Histology Code = 8170/3-8175/3) between 2004 and 2018 were reviewed. The annual percent change (APC) was calculated utilizing Joinpoint regression. The nomogram was developed based on multivariable competing risk survival analyses. Akaike information criterion, Bayesian information criterion, C-index, calibration curve, and area under the receiver operating characteristic curve were obtained to evaluate the prognostic performance. A decision curve analysis was introduced to examine the clinical value of the models. Results: Despite scirrhous carcinoma, which showed a decreasing trend (APC = -6.8%, P = 0.025), the morbidity of other rare subtypes remained stable from 2004 to 2018. The incidence-based mortality was plateau in all subtypes during the period. Clear cell carcinoma is the most common subtype (n = 551, 1.1%), followed by subtypes of fibrolamellar (n = 241, 0.5%), scirrhous (n = 82, 0.2%), spindle cell (n = 61, 0.1%), and pleomorphic (n = 17, ~0%). The patients with fibrolamellar carcinoma were younger and more likely to have a non-cirrhotic liver and better prognoses. Scirrhous carcinoma shared almost the same macro-clinical characteristics and outcomes as the classic HCC. Clear cell carcinoma tended to occur in the Asia-Pacific elderly male population, and more than half of them were large HCC (Size>5cm). Sarcomatoid (including spindle cell and pleomorphic) carcinoma was associated with a larger tumor size, poorer differentiation, and more dismal prognoses. The pathological subtype, T stage, M stage, surgery, alpha-fetoprotein, and cancer history were confirmed as the independent predictors in patients with rare subtypes. The nomogram showed good calibration, discrimination, and net benefits in clinical practice. Conclusion: The rare subtypes had unique clinicopathological features and biological behaviors compared with the classic HCC. Our findings could provide a valuable reference for clinicians. The constructed nomogram could predict the prognoses with good performance, which is meaningful to individualized management.
Commander, SJ, M Cerullo, N Arjunji, HJ Leraas, S Thornton, K Ravindra and ET Tracy 2022Improved survival and higher rates of surgical resection associated with hepatocellular carcinoma in children as compared to young adults.Int J Cancer. Hepatocellular adenocarcinoma (HCC) is the second most common primary hepatic malignancy in children with a 5-year overall survival of 30%. Few studies have examined the similarities and differences between pediatric and adult HCC. This article aims to examine the relationship between tumor characteristics, treatments and outcomes in pediatric and adult patients with HCC. The 2019 National Cancer Database was queried for patients with HCC. Patients were stratified by age: pediatric <21 years (n = 214) and young adults 21 to 40 (n = 1102). Descriptive statistics and chi square were performed. The mean age at diagnosis was 15.5 years (SD 5.6) in the pediatric and 33 years (5.3) in the adult group. Children had a comparable rate of metastasis (30% vs 28%, P = .47) and increased fibrolamellar histology (32% vs 9%). Surgical resection was more common in children compared to adults (74% vs 62%, P < .001), children also had more lymph nodes examined (39% vs 19%, P < .001), positive lymph nodes (35% vs 17%, P = .02) and surgical resection when metastasis were present at diagnosis (46% vs 18%, P < .001). The 1-, 3- and 5-year overall survival was higher for pediatric patients than adults (81%, 65%, 55%, vs 70%, 54%, 48%). Despite higher prevalence of fibrolamellar histology, greater number of positive lymph nodes and comparable rates of metastasis at diagnosis, children with HCC have improved overall survival compared to adults. Age did not significantly contribute to survivorship, so it is likely that the more aggressive surgical approach contributed to the improved overall survival in pediatric patients.
Dasgupta, A, E Tsay, N Federman, MG Lechner and MA Su 2022Polyendocrine autoimmunity and diabetic ketoacidosis following Anti-PD-1 and interferon alpha. Pediatrics. Immune checkpoint inhibitor (ICI) therapies are now first-line therapy for many advanced malignancies in adults, with emerging use in children. With increasing ICI use, prompt recognition and optimal management of ICI-associated immune-related adverse events (IRAEs) are critical. Nearly 60% of ICI-treated adults develop IRAEs, which commonly manifest as autoimmune skin, gastrointestinal, and endocrine disease and can be life-threatening. The incidence, presentation, and disease course of spontaneous autoimmune diseases differ between adults and children, but the pattern of pediatric IRAEs is currently unclear. We report a case of a pediatric patient presenting with new onset autoimmune diabetes mellitus and diabetic ketoacidosis during ICI treatment of fibrolamellar hepatocellular carcinoma (FLC). Distinct from spontaneous type 1 diabetes mellitus (T1DM), this patient progressed rapidly and was negative for known beta cell autoantibodies. Additionally, the patient was positive for 21-hydroxylase autoantibodies, suggesting development of concomitant adrenal autoimmunity. Current guidelines for the management of IRAEs in adults may not be appropriate for the management of pediatric patients, who may have different autoimmune risks in a developmental context.
Dinh, TA, AF Utria, KC Barry, R Ma, GK Abou-Alfa, JD Gordan, EM Jaffee, JD Scott, J Zucman-Rossi, AF O'Neill, ME Furth and P Sethupathy 2022A framework for fibrolamellar carcinoma research and clinical trials.Nat Rev Gastroenterol Hepatol 19(5): 328-342. Fibrolamellar carcinoma (FLC), a rare, lethal hepatic cancer, occurs primarily in adolescents and young adults. Unlike hepatocellular carcinoma, FLC has no known association with viral, metabolic or chemical agents that cause cirrhosis. Currently, surgical resection is the only treatment demonstrated to achieve cure, and no standard of care exists for systemic therapy. Progress in FLC research illuminates a transition from an obscure cancer to one for which an interactive community seems poised to uncover fundamental mechanisms and initiate translation towards novel therapies. In this Roadmap, we review advances since the seminal discovery in 2014 that nearly all FLC tumours express a signature oncogene (DNAJB1-PRKACA) encoding a fusion protein (DNAJ-PKAc) in which the J-domain of a heat shock protein 40 (HSP40) co-chaperone replaces an amino-terminal segment of the catalytic subunit of the cyclic AMP-dependent protein kinase (PKA). Important gains include increased understanding of oncogenic pathways driven by DNAJ-PKAc; identification of potential therapeutic targets; development of research models; elucidation of immune mechanisms with potential for the development of immunotherapies; and completion of the first multicentre clinical trials of targeted therapy for FLC. In each of these key areas we propose a Roadmap for future progress.
Francisco, AB, M Kanke, AP Massa, TA Dinh, R Sritharan, K Vakili, N Bardeesy and P Sethupathy 2022Multiomic analysis of microRNA-mediated regulation reveals a proliferative axis involving miR-10b in fibrolamellar carcinoma.JCI Insight 7(11). Fibrolamellar carcinoma (FLC) is an aggressive liver cancer primarily afflicting adolescents and young adults. Most patients with FLC harbor a heterozygous deletion on chromosome 19 that leads to the oncogenic gene fusion, DNAJB1-PRKACA. There are currently no effective therapeutics for FLC. To address that, it is critical to gain deeper mechanistic insight into FLC pathogenesis. We assembled a large sample set of FLC and nonmalignant liver tissue (n = 52) and performed integrative multiomic analysis. Specifically, we carried out small RNA sequencing to define altered microRNA expression patterns in tumor samples and then coupled this analysis with RNA sequencing and chromatin run-on sequencing data to identify candidate master microRNA regulators of gene expression in FLC. We also evaluated the relationship between DNAJB1-PRKACA and microRNAs of interest in several human and mouse cell models. Finally, we performed loss-of-function experiments for a specific microRNA in cells established from a patient-derived xenograft (PDX) model. We identified miR-10b-5p as the top candidate pro-proliferative microRNA in FLC. In multiple human cell models, overexpression of DNAJB1-PRKACA led to significant upregulation of miR-10b-5p. Inhibition of miR-10b in PDX-derived cells increased the expression of several potentially novel target genes, concomitant with a significant reduction in metabolic activity, proliferation, and anchorage-independent growth. This study highlights a potentially novel proliferative axis in FLC and provides a rich resource for further investigation of FLC etiology.
Gordan, JD, T Zack, AP Venook, J Wild, AJ Butte, S Maisel, A Yaqubie, G Abou-Alfa, JJ Knox, R Mayer and AC O’Neill 2022Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of multiple clinical data types. Research Square. The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is one such rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of electronic medical record and national payee data and find that FLC incidence is likely 6–8 times higher than previous estimates. By deploying unsupervised learning modes on clinical laboratory data on patients with hyperammonemia, we find that FLC-associated hyperammonemia mirrors metabolic dysregulation in Urea Cycle Disorders. We demonstrate that advanced computational analysis of rich clinical datasets can provide key clinical and biochemical insights into rare cancers.
Gulati, R, MA Hanlon, M Lutz, T Quitmeyer, J Geller, G Tiao, L Timchenko and N Timchenko 2022Phosphorylation-Mediated Activation of beta-Catenin-TCF4-CEGRs/ALCDs Pathway Is an Essential Event in Development of Aggressive Hepatoblastoma. Cancers (Basel) 14(24). BACKGROUND AND AIMS: Hepatoblastoma (HBL), a deadly malignancy in children, is the most common type of pediatric liver cancer. We recently demonstrated that beta-catenin, phosphorylated at S675 (ph-S675-beta-catenin), causes pathological alterations in fibrolamellar hepatocellular carcinoma (FLC), by activating oncogenes and fibrotic genes via human genomic regions, known as cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs). The aim of this study was to determine the role of the ph-S675-beta-catenin-TCF4-CEGRs/ALCDs pathway in HBL. METHODS: The ph-S675-beta-catenin-TCF4-CEGRs/ALCDs pathway was examined in a large cohort of HBL specimens, in HBL cell lines HepG2 and Huh6, and in patient-derived xenografts (PDXs). RESULTS: beta-catenin is phosphorylated at S675 in a large portion of tested HBL patients. In these patients, ph-S675-beta-catenin forms complexes with TCF4 and opens CEGRs/ALCDs-dependent oncogenes for transcription, leading to a massive overexpression of the oncogenes. The inhibition of the beta-catenin-TCF4-CEGRs/ALCDs axis inhibits the proliferation of cancer cells and tumor growth in HBL cell lines and HBL-PDXs. The ph-S675-beta-catenin is abundant in mitotic cells. We found that markers of HBL Glypican 3 (GPC3) and Alpha Fetoprotein (AFP) are increased in HBL patients by beta-catenin-TCF4-p300 complexes. CONCLUSIONS: The phosphorylation-mediated activation of the beta-catenin-TCF4-p300-CEGRs/ALCDs pathway increases oncogene expression in patients with aggressive liver cancer and promotes the development of hepatoblastoma.
Gulati, R, M Johnston, M Rivas, A Cast, M Kumbaji, MA Hanlon, S Lee, P Zhou, C Lake, E Schepers, KW Min, JH Yoon, R Karns, LM Reid, D Lopez-Terrada, L Timchenko, S Parameswaran, MT Weirauch, S Ranganathan, A Bondoc, J Geller, G Tiao, S Shin and N Timchenko 2022beta-catenin cancer-enhancing genomic regions axis is involved in the development of fibrolamellar hepatocellular carcinoma. Hepatol Commun 6(10): 2950-2963. Fibrolamellar hepatocellular carcinoma (FLC) is a disease that occurs in children and young adults. The development of FLC is associated with creation of a fusion oncoprotein DNAJB1-PKAc kinase, which activates multiple cancer-associated pathways. The aim of this study was to examine the role of human genomic regions, called cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs), in the development of FLC. Previous studies revealed that CEGRs/ALCDs are located in multiple oncogenes and cancer-associated genes, regularly silenced in normal tissues. Using the regulatory element locus intersection (RELI) algorithm, we searched a large compendium of chromatin immunoprecipitation-sequencing (ChIP) data sets and found that CEGRs/ALCDs contain regulatory elements in several human cancers outside of pediatric hepatic neoplasms. The RELI algorithm further identified components of the beta-catenin-TCF7L2/TCF4 pathway, which interacts with CEGRs/ALCDs in several human cancers. Particularly, the RELI algorithm found interactions of transcription factors and chromatin remodelers with many genes that are activated in patients with FLC. We found that these FLC-specific genes contain CEGRs/ALCDs, and that the driver of FLC, fusion oncoprotein DNAJB1-PKAc, phosphorylates beta-catenin at Ser675, resulting in an increase of beta-catenin-TCF7L2/TCF4 complexes. These complexes increase a large family of CEGR/ALCD-dependent collagens and oncogenes. The DNAJB1-PKAc-beta-catenin-CEGR/ALCD pathway is preserved in lung metastasis. The inhibition of beta-catenin in FLC organoids inhibited the expression of CEGRs/ALCDs-dependent collagens and oncogenes, preventing the formation of the organoid's structure. Conclusion: This study provides a rationale for the development of beta-catenin-based therapy for patients with FLC.
Hernandez-Silva, D, J Canton-Sandoval, FJ Martinez-Navarro, H Perez-Sanchez, S de Oliveira, V Mulero, F Alcaraz-Perez and ML Cayuela 2022Senescence-independent anti-inflammatory activity of the senolytic drugs dasatinib, navitoclax, and venetoclax in zebrafish models of chronic inflammation. Int J Mol Sci 23(18). Telomere shortening is the main molecular mechanism of aging, but not the only one. The adaptive immune system also ages, and older organisms tend to develop a chronic pro-inflammatory status with low-grade inflammation characterized by chronic activation of the innate immune system, called inflammaging. One of the main stimuli that fuels inflammaging is a high nutrient intake, triggering a metabolic inflammation process called metainflammation. In this study, we report the anti-inflammatory activity of several senolytic drugs in the context of chronic inflammation, by using two different zebrafish models: (i) a chronic skin inflammation model with a hypomorphic mutation in spint1a, the gene encoding the serine protease inhibitor, kunitz-type, 1a (also known as hai1a) and (ii) a non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) model with inflammation induced by a high-fat diet. Our results show that, although these models do not manifest premature aging, the senolytic drugs dasatinib, navitoclax, and venetoclax have an anti-inflammatory effect that results in the amelioration of chronic inflammation.
Holczbauer, A, KJ Wangensteen and S Shin 2022Cellular origins of regenerating liver and hepatocellular carcinoma. JHEP Rep 4(4): 100416. Hepatocellular carcinoma (HCC) is the predominant primary cancer arising from the liver and is one of the major causes of cancer-related mortality worldwide. The cellular origin of HCC has been a topic of great interest due to conflicting findings regarding whether it originates in hepatocytes, biliary cells, or facultative stem cells. These cell types all undergo changes during liver injury, and there is controversy about their contribution to regenerative responses in the liver. Most HCCs emerge in the setting of chronic liver injury from viral hepatitis, fatty liver disease, alcohol, and environmental exposures. The injuries are marked by liver parenchymal changes such as hepatocyte regenerative nodules, biliary duct cellular changes, expansion of myofibroblasts that cause fibrosis and cirrhosis, and inflammatory cell infiltration, all of which may contribute to carcinogenesis. Addressing the cellular origin of HCC is the key to identifying the earliest events that trigger it. Herein, we review data on the cells of origin in regenerating liver and HCC and the implications of these findings for prevention and treatment. We also review the origins of childhood liver cancer and other rare cancers of the liver.
Hu, J, Y Wang, L Deng, H Yu, K Chen, W Bao, K Chen and G Chen 2022Development and validation of a nomogram for predicting the cancer-specific survival of fibrolamellar hepatocellular carcinoma patients.Updates Surg 74(5): 1589-1599. Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of hepatocellular carcinoma. Our study aimed to construct a nomogram to predict the cancer-specific survival (CSS) of FLC. Data of 200 FLC patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) database were divided into the training group and the validation group. Prognostic factors identified in the univariate and multivariate Cox regression analyses were used to construct the nomogram. The concordance index (C-index), calibration curves, time-dependent receiver operating characteristic curve (ROC), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram. As a result, age >/= 59, N1 stage, M1 stage, tumor size
Jain, A, B Mazer, Y Deng, M Ciarleglio, D Jain, T Taddei and X Zhang 2022Hepatocellular carcinoma: Does the background liver with or without cirrhosis matter? Am J Clin Pathol 157(2): 305-313. OBJECTIVES: The pathologic differences between hepatocellular carcinoma (HCC) arising in noncirrhotic and cirrhotic livers have not been well studied. METHODS: We performed a retrospective analysis of 378 HCC cases (95 in noncirrhotic, 283 in cirrhotic livers) from pathology archives (2010-2017). RESULTS: Patients without cirrhosis were more likely to have hepatitis B (13.68% vs 2.83%, P < .001) or no known liver disease (30.53% vs 4.24%, P < .001), while hepatitis C was more common in patients with cirrhosis (65.72% vs 30.53%, P < .001). HCCs in noncirrhotic livers were larger in size (P < .001); were more likely to have a macrotrabecular histologic pattern (13.68% vs 4.95%, P < .01); were more likely to have fibrolamellar (3.16% vs 0%, P = .02), macrotrabecular-massive (13.68% vs 6.01%, P = .03), and clear cell (16.84% vs 6.71%, P < .01) subtypes; have a higher histologic grade (P < .01); be anaplastic tumor cells (P < .001); have a higher rate of vascular invasion (P < .01); and have a higher tumor stage (P = .04). CONCLUSIONS: The findings indicate that HCCs in noncirrhotic livers demonstrate a larger tumor size; have a more macrotrabecular histologic pattern; have fibrolamellar, macrotrabecular-massive, and clear cell subtypes; have a higher tumor grade and stage; have a higher rate of vascular invasion; and have more anaplastic tumor cells compared with cirrhotic livers. Further studies to explore different pathways that promote oncogenesis in noncirrhotic livers are needed to better understand the pathogenesis of HCC.
Kakos, CD, IA Ziogas, CD Demiri, SM Esagian, KP Economopoulos, D Moris, G Tsoulfas and SP Alexopoulos 2022Liver transplantation for pediatric hepatocellular carcinoma: A systematic review. Cancers (Basel) 14(5). Liver transplantation (LT) is the only potentially curative option for children with unresectable hepatocellular carcinoma (HCC). We performed a systematic review of the MEDLINE, Scopus, Cochrane Library, and Web of Science databases (end-of-search date: 31 July 2020). Our outcomes were overall survival (OS) and disease-free survival (DFS). We evaluated the effect of clinically relevant variables on outcomes using the Kaplan-Meier method and log-rank test. Sixty-seven studies reporting on 245 children undergoing LT for HCC were included. DFS data were available for 150 patients and the 1-, 3-, and 5-year DFS rates were 92.3%, 89.1%, and 84.5%, respectively. Sixty of the two hundred and thirty-eight patients (25.2%) died over a mean follow up of 46.8 +/- 47.4 months. OS data were available for 222 patients and the 1-, 3-, and 5-year OS rates were 87.9%, 78.8%, and 74.3%, respectively. Although no difference was observed between children transplanted within vs. beyond Milan criteria (p = 0.15), superior OS was observed in children transplanted within vs. beyond UCSF criteria (p = 0.02). LT can yield favorable outcomes for pediatric HCC beyond Milan but not beyond UCSF criteria. Further research is required to determine appropriate LT selection criteria for pediatric HCC.
Kang, E, M Martinez, H Moisander-Joyce, YM Saenger, AD Griesemer, T Kato, DJ Yamashiro, H Remotti and RD Gartrell 2022Stable liver graft post anti-PD1 therapy as a bridge to transplantation in an adolescent with hepatocellular carcinoma. Pediatr Transplant 26(3): e14209. BACKGROUND: Immunotherapy, specifically immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (anti-PD1), has recently received clinical approval for the treatment of adult hepatocellular carcinoma (HCC). However, the safety and efficacy of ICIs prior to solid organ transplant are unknown, especially in pediatrics. Safety reports are variable in adults, with some series describing subsequent allograft rejection and loss while others report successful transplants without allograft rejection.As ICIs stimulate the immune system by blocking the interaction between PD1 and the ligand-receptor pair programmed cell death-ligand 1 (PDL1), the downstream effects of T-cell activation increase the risk of graft rejection. METHODS: Here, we present a case of an adolescent with moderately differentiated non-fibrolamellar HCC treated with pembrolizumab, an anti-PD1 therapy, who subsequently underwent successful orthotopic liver transplantation (OLT). RESULTS: Our patient received an OLT 138 days from the last pembrolizumab dose with graft preservation. The patient has no evidence of recurrent disease or any episode of allograft rejection 48 months post OLT. Staining of tumor and normal tissues from longitudinal specimens finds PDL1 positive Kupffer cells present in normal liver and peritumoral areas with no changes post anti-PD1 therapy. In contrast, tumor cells were negative for PDL1. CONCLUSION: This case represents a basis for optimism in potential use of anti-PD1 therapy in liver transplant candidates and supports further investigation of immune checkpoint inhibitors use in this unique patient population.
Kang, S, J Magliocca, M Sellers, G Roccaro, W Zheng, M Pectasides, A Draper, J Guadagno, B El-Rayes and M Akce 2022Successful Liver Transplantation of Recurrent Fibrolamellar Carcinoma following Clinical and Pathologic Complete Response to Triple Immunochemotherapy: A Case Report. Oncol Res Treat 45(7-8): 430-437. INTRODUCTION: Fibrolamellar carcinoma (FLC) is a rare liver cancer that predominantly affects younger patients without a history of liver disease. Surgical resection is the cornerstone of therapy and represents the best potentially curative treatment option. Modest objective responses with cytotoxic chemotherapy alone or combined with immune checkpoint inhibitors (ICIs) have been reported; however, there are no established systemic therapy regimens for unresectable or metastatic FLC. CASE PRESENTATION: We report a case of a 23-year-old woman with FLC who presented with a 11.5 x 8.3 cm left liver mass and subsequently underwent resection as initial therapy. Molecular analysis of her surgical tissue revealed a DNAJB1-PRKACA fusion gene. The patient developed biopsy-proven recurrent FLC with multiple liver lesions but without any distant metastatic disease only 3 months after initial resection. In light of emerging data, the patient was treated with a novel triple therapy regimen including 5-fluorouracil (5-FU), interferon (IFN) alfa-2b, and nivolumab. Partial radiographic response was achieved after 4 treatments and complete response was achieved after 12 cycles with the combination. The patient received 2 more doses of 5-FU/IFN alfa-2b without nivolumab and underwent orthotopic liver transplantation (OLT) 6 months after the last dose of ICI. Pathological examination of the explanted liver remarkably confirmed pathologic complete response. She remains recurrence-free and is on active surveillance. DISCUSSION/CONCLUSION: For patients with unresectable/recurrent FLC with no distant disease, the combination of 5-FU, IFN alfa-2b, and nivolumab could be an effective systemic therapy option. The use of this chemoimmunotherapy regimen to downstage FLC prior to OLT may be worth investigating further.
Katabathina, VS, L Khanna, VR Surabhi, M Minervini, K Shanbhogue, AK Dasyam and SR Prasad 2022Morphomolecular Classification Update on Hepatocellular Adenoma, Hepatocellular Carcinoma, and Intrahepatic Cholangiocarcinoma. Radiographics 42(5): 1338-1357. Hepatocellular adenomas (HCAs), hepatocellular carcinomas (HCCs), and intrahepatic cholangiocarcinomas (iCCAs) are a highly heterogeneous group of liver tumors with diverse pathomolecular features and prognoses. High-throughput gene sequencing techniques have allowed discovery of distinct genetic and molecular underpinnings of these tumors and identified distinct subtypes that demonstrate varied clinicobiologic behaviors, imaging findings, and complications. The combination of histopathologic findings and molecular profiling form the basis for the morphomolecular classification of liver tumors. Distinct HCA subtypes with characteristic imaging findings and complications include HNF1A-inactivated, inflammatory, beta-catenin-activated, beta-catenin-activated inflammatory, and sonic hedgehog HCAs. HCCs can be grouped into proliferative and nonproliferative subtypes. Proliferative HCCs include macrotrabecular-massive, TP53-mutated, scirrhous, clear cell, fibrolamellar, and sarcomatoid HCCs and combined HCC-cholangiocarcinoma. Steatohepatitic and beta-catenin-mutated HCCs constitute the nonproliferative subtypes. iCCAs are classified as small-duct and large-duct types on the basis of the level of bile duct involvement, with significant differences in pathogenesis, molecular signatures, imaging findings, and biologic behaviors. Cross-sectional imaging modalities, including multiphase CT and multiparametric MRI, play an essential role in diagnosis, staging, treatment response assessment, and surveillance. Select imaging phenotypes can be correlated with genetic abnormalities, and identification of surrogate imaging markers may help avoid genetic testing. Improved understanding of morphomolecular features of liver tumors has opened new areas of research in the targeted therapeutics and management guidelines. The purpose of this article is to review imaging findings of select morphomolecular subtypes of HCAs, HCCs, and iCCAs and discuss therapeutic and prognostic implications. Online supplemental material is available for this article.
Kelley, RK, L Rimassa, AL Cheng, A Kaseb, S Qin, AX Zhu, SL Chan, T Melkadze, W Sukeepaisarnjaroen, V Breder, G Verset, E Gane, I Borbath, JDG Rangel, BY Ryoo, T Makharadze, P Merle, F Benzaghou, K Banerjee, S Hazra, J Fawcett and T Yau 2022Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 23(8): 995-1008. BACKGROUND: Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma. METHODS: COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with, NCT03755791. FINDINGS: Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15.8 months (IQR 14.5-17.2) in the progression-free survival ITT population and 13.3 months (10.5-16.0) in the ITT population. Median progression-free survival was 6.8 months (99% CI 5.6-8.3) in the combination treatment group versus 4.2 months (2.8-7.0) in the sorafenib group (hazard ratio [HR] 0.63, 99% CI 0.44-0.91, p=0.0012). Median overall survival (interim analysis) was 15.4 months (96% CI 13.7-17.7) in the combination treatment group versus 15.5 months (12.1-not estimable) in the sorafenib group (HR 0.90, 96% CI 0.69-1.18; p=0.44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage). INTERPRETATION: Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed. FUNDING: Exelixis and Ipsen.
Kim, SS, I Kycia, M Karski, RK Ma, EA Bordt, J Kwan, A Karki, E Winter, RG Aktas, Y Wu, A Emili, DE Bauer, P Sethupathy and K Vakili 2022DNAJB1-PRKACA in HEK293T cells induces LINC00473 overexpression that depends on PKA signaling.PLoS ONE 17(2): e0263829. Fibrolamellar carcinoma (FLC) is a primary liver cancer that most commonly arises in adolescents and young adults in a background of normal liver tissue and has a poor prognosis due to lack of effective chemotherapeutic agents. The DNAJB1-PRKACA gene fusion (DP) has been reported in the majority of FLC tumors; however, its oncogenic mechanisms remain unclear. Given the paucity of cellular models, in particular FLC tumor cell lines, we hypothesized that engineering the DP fusion gene in HEK293T cells would provide insight into the cellular effects of the fusion gene. We used CRISPR/Cas9 to engineer HEK293T clones expressing DP fusion gene (HEK-DP) and performed transcriptomic, proteomic, and mitochondrial studies to characterize this cellular model. Proteomic analysis of DP interacting partners identified mitochondrial proteins as well as proteins in other subcellular compartments. HEK-DP cells demonstrated significantly elevated mitochondrial fission, which suggests a role for DP in altering mitochondrial dynamics. Transcriptomic analysis of HEK-DP cells revealed a significant increase in LINC00473 expression, similar to what has been observed in primary FLC samples. LINC00473 overexpression was reversible with siRNA targeting of PRKACA as well as pharmacologic targeting of PKA and Hsp40 in HEK-DP cells. Therefore, our model suggests that LINC00473 is a candidate marker for DP activity.
Kundakcioglu, H, S Destek, Z Gucin and KC Deger 2022Fibrolamellar hepatocellular carcinoma presenting with early recurrent thrombosis. Prz Gastroenterol 17(4): 344-347.
LaQuaglia, MP and JT Gerstle 2022Advances in the treatment of pediatric solid tumors: A 50-year perspective.J Surg Oncol 126(5): 933-942. In the United States, more than 10 000 cancers occur annually in children aged 0-14 years, and more than 5000 in adolescents aged 15-19. In the last 50 years, significant advances have been made in imaging, molecular pathology, stage and risk assessment, surgical approach, multidisciplinary treatment, and survival for pediatric solid tumors (particularly neuroblastoma, Wilms tumor, rhabdomyosarcoma, and hepatoblastoma). Moreover, the molecular driver for fibrolamellar hepatocellular carcinoma, which occurs in adolescence and young adulthood, has been identified.
Lee, S, F Duan, S Jindal, S Basu, S Yadav, J Allison, P Sharma, Y Mohamed and A Kaseb 2022Combination of 5-fluorouracil (FU), interferon (IFN)-alpha2, and nivolumab in unresectable fibrolamellar liver cancer.IOTECH. Fibrolamellar liver cancer (FLC) is a rare malignancy involving multidisciplinary approaches including surgery, liver-directed, and systemic treatment. Combination therapy with 5-fluorouracil (FU) and interferon (IFN)-a2 has long been used for FLC. We hypothesized that addition of anti-PD1 to 5-FU+IFN-a2 may further improve clinical outcome and lead to a favorable modulation of tumor microenvironment.Methods:We treated 3 patients with unresectable FLC with 5-FU+IFN-a2+nivolumab (N): 5-FU 200 mg/m2 7-day-on/7-day-off, IFN-a2 (4 million U/m2 3 times/week with 5-FU) for 8 weeks, followed by on-treatment biopsy and addition of N 480 mg every 4 weeks to 5-FU+IFN-a2. Tumor tissues were collected under an IRB-approved protocol.Results:Two patients (26, 29 years) initially had unresectable FLC with a 6.1 cm tumor in seg IV liver invading the common hepatic duct, and a 19.5 cm tumor, peritoneal nodules, and abdominal lymph nodes. After 9 and 5 months of therapy, unresectable tumors were converted to resectable ones: the former had L hepatectomy and bile duct resection; the latter, L hepatectomy, resection of the omentum, spleen, L diaphragm, and lymph node dissection. Both patients completed adjuvant therapy with the same regimen, having no recurrence. The third patient (20 years) had multifocal liver tumors with peritoneal carcinomatosis and lymph nodes. He received treatment for 5 months and achieved stable disease, followed by hepatic tumor bleeding leading to treatment discontinuation. All 3 patients had an increase of CD8+T cells in on-treatment (5-FU+IFN-a2, week 8), compared to pre-treatment biopsies. The available surgical tumor tissues (s/p 5-FU+IFN-a2+N) were also evaluated in patients who underwent surgery with conversation of unresectable to resectable disease, showing a further increase of CD8+T cells.Conclusions:This clinical outcome of converting an unresectable disease to a resectable one with tumors significantly decreasing in size suggests synergy of 5-FU+IFN-a2 combined with anti-PD1. The robust increased infiltration of CD8+T cells on 5-FU+IFN-a2+N may explain this clinical efficacy. Detailed immune analyses with gene expression profiling will be presented at ESMO Immuno-Oncology Meeting.
Loy, LM, HM Low, JY Choi, HJ Rhee, CF Wong and CH Tan 2022Variant hepatocellular carcinoma subtypes according to the 2019 who classification: An imaging-focused review. AJR Am J Roentgenol. The 2019 5th edition of the WHO Classification of Digestive System Tumors estimates that up to 35% of hepatocellular carcinomas (HCCs) can be classified as one of eight subtypes defined by molecular characteristics: steatohepatitic, clear cell, macrotrabecular massive, scirrhous, chromophobe, fibrolamellar, neutrophil-rich, and lymphocyte-rich HCC. Due to their distinct cellular and architectural characteristics, these subtypes may not display the classic MRI features of HCC of arterial phase hyperenhancement (APHE) and washout appearance, creating challenges in noninvasively diagnosing such lesions as HCC. Moreover, certain subtypes with atypical imaging features have a worse prognosis than other HCCs. A range of distinguishing imaging features may help raise suspicion that a liver lesion represents one of these HCC subtypes. In this review, we describe the MRI features that have been reported in association with various HCC subtypes according to the 2019 WHO classification, with attention to current understanding of these subtypes' pathologic and molecular bases and relevance to clinical practice. Imaging findings that differentiate the subtypes from benign liver lesions and non-HCC malignancies are highlighted. Familiarity with these subtypes and their imaging features may allow the radiologist to suggest their presence, though histologic analysis remains needed to establish the diagnosis.
Narayan, NJC, D Requena, G Lalazar, L Ramos-Espiritu, D Ng, S Levin, B Shebl, R Wang, WJ Hammond, JA Saltsman, 3rd, H Gehart, MS Torbenson, H Clevers, MP LaQuaglia and SM Simon 2022Human liver organoids for disease modeling of fibrolamellar carcinoma. Stem Cell Reports 17(8): 1874-1888. Fibrolamellar carcinoma (FLC) is a rare, often lethal, liver cancer affecting adolescents and young adults, for which there are no approved therapeutics. The development of therapeutics is hampered by a lack of in vitro models. Organoids have shown utility as a model system for studying many diseases. In this study, tumor tissue and the adjacent non-tumor liver were obtained at the time of surgery. The tissue was dissociated and grown as organoids. We developed 21 patient-derived organoid lines: 12 from metastases, three from the liver tumor and six from adjacent non-tumor liver. These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochemistry, and transcriptome of the patient tumor. Patient-derived FLC organoids were used in a preliminary high-throughput drug screen to show proof of concept for the identification of therapeutics. This model system has the potential to improve our understanding of this rare cancer and holds significant promise for drug testing and development.
Omar, MH, DP Byrne, KN Jones, TM Lakey, KB Collins, KS Lee, LA Daly, KA Forbush, HT Lau, M Golkowski, GS McKnight, DT Breault, AM Lefrancois-Martinez, A Martinez, CE Eyers, GS Baird, SE Ong, FD Smith, PA Eyers and JD Scott 2022Mislocalization of protein kinase A drives pathology in Cushing's syndrome. Cell Rep 40(2): 111073. Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing's syndrome. We define mechanisms of action for the PKAc-L205R and W196R variants. Proximity proteomic techniques demonstrate that both Cushing's mutants are excluded from A kinase-anchoring protein (AKAP)-signaling islands, whereas live-cell photoactivation microscopy reveals that these kinase mutants indiscriminately diffuse throughout the cell. Only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate PKAc mutants into AKAP complexes abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Analyses of adrenal-specific PKAc-W196R knockin mice and Cushing's syndrome patient tissue reveal defective signaling mechanisms of the disease. Surprisingly each Cushing's mutant engages a different mitogenic-signaling pathway, with upregulation of YAP/TAZ by PKAc-L205R and ERK kinase activation by PKAc-W196R. Thus, aberrant spatiotemporal regulation of each Cushing's variant promotes the transmission of distinct downstream pathogenic signals.
Polychronidis, G, J Feng, A Murtha-Lemekhova, U Heger, A Mehrabi and K Hoffmann 2022Factors influencing overall survival for patients with fibrolamellar hepatocellular carcinoma: Analysis of the surveillance, epidemiology, and end results database. Int J Gen Med 15: 393-406. Background: The study aimed to develop a nomogram to predict overall survival (OS) for patients with FLC using a national database. Methods: The Surveillance, Epidemiology, and End Results database of the National Cancer Institute was reviewed to identify FLC cases with histological confirmation between 2004 and 2014. Cox proportional hazards models were used to identify factors associated with OS. The validation of the nomogram was performed using concordance index (C-index) and calibration curves. Results: Out of 170 cases with complete follow-up, 87 received surgery/ablation and 12 received transplantation with significantly higher OS than chemotherapy alone while transplantation combined with chemotherapy showed better survival than solely transplantation. The combination of surgery and chemotherapy showed worse OS than surgery alone. Survival was negatively influenced by T4 stadium (HR = 5.91), while young age and surgery were positive predictive factors. There was no influence of gender, ethnicity or nodal status on survival. The rate of AFP positivity was comparable with and without the presence of distal metastases. Conclusion: FLC survival is greatly dependent upon appropriate surgical management irrespective of tumor stadium.
Polychronidis, G, A Murtha-Lemekhova, J Fuchs, E Karathanasi and K Hoffmann 2022mA ultidisciplinary approach to the management of fibrolamellar carcinoma: Current perspectives and future prospects. Onco Targets Ther 15: 1095-1103. Fibrolamellar carcinoma (FLC) is a rare primary liver tumor affecting predominantly younger and otherwise healthy patients. Typically, FLC presents with advanced disease due to the paucity of typical symptoms and no history of underlying liver disease. Depending on tumor characteristics and the patient's general condition, surgical treatment is the most promising treatment modality. Aggressive resection and liver transplantation have been utilized and are presently indispensable curative treatment options. Under certain circumstances surgical resection is also possible for metachronous metastases or local recurrence. Recent tumor biology discoveries have contributed to improved diagnostic specificity and systemic treatment options.
Rahi, H, MC Olave, KJ Fritchie, PT Greipp, KC Halling, BR Kipp and RP Graham 2022Gene fusions in gastrointestinal tract cancers.Genes Chromosomes Cancer. Fusion genes have been identified a wide array of human neoplasms including hematologic and solid tumors, including gastrointestinal tract neoplasia. A fusion gene is the product of parts of two genes which are joined together following a deletion, translocation or chromosomal inversion. Together with single nucleotide variants, insertions, deletions, and amplification, fusion genes represent one of the key genomic mechanisms for tumor development. Detecting fusions in the clinic is accomplished by a variety of techniques including break-apart fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), and next-generation sequencing (NGS). Some recurrent gene fusions have been successfully targeted by small molecule or monoclonal antibody therapies (i.e. targeted therapies), while others are used for as biomarkers for diagnostic and prognostic purposes. The purpose of this review article is to discuss the clinical utility of detection of gene fusions in carcinomas and neoplasms arising primarily in the digestive system. This article is protected by copyright. All rights reserved.
Razik, A, S Malla, A Goyal, S Gamanagatti, D Kandasamy, CJ Das, R Sharma and AK Gupta 2022Unusual primary neoplasms of the adult liver: Review of imaging appearances and differential diagnosis. Curr Probl Diagn Radiol 51(1): 73-85. The radiological appearance of common primary hepatic tumors such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is widely recognized. Hepatic masses with unusual histology are occasionally encountered, but seldom suspected on imaging. However, many possess characteristic imaging findings, which when assessed along with the clinical and demographic background and serum tumor markers, may enable a prospective diagnosis. This review attempts to familiarize the reader with the clinicopathological characteristics, imaging manifestations, and differential diagnosis of these unusual liver tumors in adults. Biphenotypic primary liver carcinoma is suspected in masses showing distinct areas of HCC and CCA-type enhancement pattern in cirrhotic livers. Fibrolamellar carcinoma occurs in young individuals without underlying chronic liver disease and shows a characteristic T2-hypointense scar frequently showing calcification. Perivascular epithelioid cell tumors are differentials for any arterial hyperenhancing mass in the noncirrhotic liver, particularly in patients with tuberous sclerosis. Multifocal subcapsular tumors showing target-like morphology, capsular retraction and "lollipop" sign are suspicious for epithelioid hemangioendothelioma. On the other hand, multiple hemorrhagic lesions showing patchy areas of bizarre-shaped arterial phase hyperenhancement are suspicious for angiosarcoma. Primary hepatic lymphoma (PHL) is suspected when patients with immunosuppression present with solitary or multifocal masses that insinuate around vessels and bile ducts without causing luminal narrowing. Intense diffusion restriction and low-level homogeneous or target-like enhancement are also ancillary features of PHL. Primary hepatic neuroendocrine tumor shows uptake on Ga-68 DOTANOC PET/CT. Although a straightforward diagnosis may be difficult in these cases, awareness of the characteristic imaging appearances is helpful in suspecting the diagnosis.
Renzulli, M, L Braccischi, A D'Errico, A Pecorelli, N Brandi, R Golfieri, E Albertini and F Vasuri 2022State-of-the-art review on the correlations between pathological and magnetic resonance features of cirrhotic nodules. Histol Histopathol: 18487. Hepatocellular carcinoma (HCC) has become the second greatest cause of cancer-related mortality worldwide and the newest advancements in liver imaging have improved the diagnosis of both overt malignancies and premalignant lesions, such as cirrhotic or dysplastic nodules, which is crucial to improve overall patient survival rate and to choose the best treatment options. The role of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) has grown in the last 20 years. In particular, the introduction of hepatospecific contrast agents has strongly increased the definition of precursor nodules and detection of high-grade dysplastic nodules and early HCCs. Nevertheless, the diagnosis of liver tumours in cirrhotic patients sometimes remains challenging for radiologists, thus, in doubtful cases, biopsy and histological analysis become critical in clinical practice. This current review briefly summarizes the history of imaging and histology for HCC, covering the newest techniques and their limits. Then, the article discusses the links between radiological and pathological characteristics of liver lesions in cirrhotic patients, by describing the multistep process of hepatocarcinogenesis. Explaining the evolution of pathologic change from cirrhotic nodules to malignancy, the list of analyzed lesions provides regenerative nodules, low-grade and high-grade dysplastic nodules, small HCC and progressed HCC, including common subtypes (steatohepatitic HCC, scirrhous HCC, macrotrabecular massive HCC) and more rare forms (clear cell HCC, chromophobe HCC, neutrophil-rich HCC, lymphocyte-rich HCC, fibrolamellar HCC). The last chapter covers the importance of the new integrated morphological-molecular classification and its association with radiological features.
Schalm, SS, E O’Hearn, K Wilson, TP Labranche, G Silva, Z Zhang, L DiPietro, N Bifulco, R Woessner, N Stransky, D Sappal, R Campbell, R Lobbardi, M Palmer, J Kim, Y Chaoyang, M Dorsch, C Lengauer, T Guzi, V Kadambi, A Garner and KP Hoeflich 2022Evaluation of PRKACA as a therapeutic target for fibrolamellar carcinoma. bioRxiv. Background & Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods: FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to developprior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD- SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as above. Results: Knockdown ofDNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment versus control (P = 0.003 and P = 0.0005, respectively). Conclusions: We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.
Schultz, SP, T Holtestaul, CW Marenco, JO Bader, JD Horton and DW Nelson 2022Prognostic Role of Lymph Node Sampling in Adolescent and Young Adults With Fibrolamellar Carcinoma. J Surg Res 276: 261-271 INTRODUCTION: Hepatocellular carcinoma (HCC) is rare among adolescent and young adult (AYA) patients, and resection or transplant remains the only curative therapy. The role of lymph node (LN) sampling is not well-defined. The aim of this study was to describe practice patterns, as well as investigate the impact of LN sampling on survival outcomes in this population. MATERIALS AND METHODS: A retrospective cohort study using the 2004-2018 National Cancer Database (NCDB) was performed. Patients 5 cm; 87 (64%) of patients with sampled nodes had fibrolamellar carcinoma (FLC), which was an independent risk factor for predicting positive nodes (P = 0.001). There was no difference in overall survival between patients who underwent LN sampling and those who did not; however, 5-y overall survival for node-positive patients was 40% versus 79% for node-negative patients (P < 0.0001). CONCLUSIONS: In AYA patients with HCC, LN sampling was not associated with an independent survival benefit. However, FLC was an independent risk factor for LN positivity, suggesting a role for routine LN sampling in these patients.
Sempokuya, T, A Forlemu, M Azawi, K Silangcruz, N Khoury, J Ma and LL Wong 2022Survival characteristics of fibrolamellar hepatocellular carcinoma: A Surveillance, Epidemiology, and End Results database study.World J Clin Oncol 13(5): 352-365. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinct type of hepatocellular carcinoma that frequently presents in an advanced stage in younger patients with no underlying liver disease. Currently, there is a limited understanding of factors that impact outcomes in FL-HCC. AIM: To characterize the survival of FL-HCC by age, race, and surgical intervention. METHODS: This is a retrospective study of The Surveillance, Epidemiology, and End Results database. We identified patients with FL-HCC between 2000-2018 by using an ICD-O-3 site code C22.0 and a histology code 8171/3: Hepatocellular carcinoma, fibrolamellar. In addition, demographics, tumor characteristics, types of surgical procedure, stages, and survival data were obtained. We conducted three separate survival analyses by age groups; /= 60-year-old, and race; White, Black, Hispanic, Asian and Pacific islanders (API), and surgical types; Wedge resection or segmental resection, lobectomy, extended lobectomy (lobectomy + locoregional therapy or resection of the other lobe), and transplant. The Chi-Square test analyzed categorical variables, and continuous variables were examined using the Mann-Whitney U test. The Kaplan-Meier survival curve was used to compare survival. Multivariate analysis was done with Cox regression analysis. RESULTS: We identified 225 FL-HCC patients with a mean age of 36.9. Overall median survival was 34 (95%CI: 27-41) mo. Patients /= 60 years was 12 (95%CI: 7-31) mo (P < 0.001). There were no differences in stage, lymph node status, metastasis status, and surgical treatment among races. The median survival were; Whites had 39 (95%CI: 29-63), Blacks 26 (95%CI: 5-92), Hispanics 31 (95%CI: 11-54), and APIs 28 (95%CI: 5-39) mo (P = 0.28). Of 225 patients, 111 FL-HCC patients had surgical procedures. Median survivals for a wedge or segmental resection was 112 (95%CI: 78-NA), lobectomy was 92 (95%CI: 57-NA), extended lobectomy was 54 (95%CI: 23-NA), and a transplant was 63 (95%CI: 20-NA) mo (P < 0.001). The median survival was better in patients who had surgical treatments regardless of lymph nodes or metastasis status (P < 0.001). CONCLUSION: FL-HCC occurs in a primarily younger population, but survival can be prolonged despite the aggressive disease. There were no racial differences in the survival of FL-HCC; however, Asians with FL-HCC tended to be older than in other races. Surgical treatment provided better survival even in those patients with nodal disease or metastases. Although future studies are needed to explore other therapies for FL-HCC, surgical options should be considered in all cases of FL-HCC unless contraindicated.
Shebl, B, D Ng, G Lalazar, C Rosemore, TM Finkelstein, RD Migler, G Zheng, P Zhang, CS Jiang, A Qureshi, R Vaughan, M Yarchoan, YP de Jong, CM Rice, P Coffino, MV Ortiz, D Zhou and SM Simon 2022Targeting BCL-XL in fibrolamellar hepatocellular carcinoma. JCI Insight 7(17). Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition of the antiapoptotic protein BCL-XL was found to synergize with a variety of systemic therapies in vitro using cells dissociated from patient-derived xenografts (PDX) of FLC or cells dissociated directly from surgical patient resections. As BCL-XL is physiologically expressed in platelets, prior efforts to leverage this vulnerability in other cancers have been hampered by severe thrombocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.
Shimada, T, H Igarashi, E Ozaki, M Fujikawa, R Machinami, S Ohni and H Yamashita 2022[A case of fibrolamellar hepatocellular carcinoma mimicking a liver abscess].Nihon Shokakibyo Gakkai Zasshi 119(11): 1036-1042. A 23-year-old woman was presented with fever and epigastric pain. Contrast enhanced computed tomography revealed a 40mm mass in the lateral segment. Blood tests showed the elevation of WBC and CRP. With the diagnosis of liver abscess, the antibiotics were administered, and the clinical findings were promptly improved. One year later, she complained of the same symptoms, and the mass had increased to 50mm in diameter. Percutaneous liver biopsy led to the diagnosis of fibrolamellar hepatocellular carcinoma.
Short, SS, ZJ Kastenberg, G Wei, A Bondoc, R Dasgupta, GM Tiao, E Watters, TE Heaton, D Lotakis, MP La Quaglia, AJ Murphy, AM Davidoff, SA Mansfield, MR Langham, TB Lautz, RA Superina, KC Ott, MM Malek, KM Morgan, ES Kim, A Zamora, D Lascano, J Roach, JT Murphy, DH Rothstein, SA Vasudevan, R Whitlock, DR Lal, B Hallis, A Butter, RM Baertschiger, E Lapidus-Krol, J Putra, ER Tracy, JH Aldrink, J Apfeld, HD Le, KY Park, BS Rich, RD Glick, EA Fialkowski, AF Utria, RL Meyers and KJ Riehle 2022Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.Cancer 128(14): 2786-2795. BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated alpha-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.
Toyota, A, M Goto, M Miyamoto, Y Nagashima, S Iwasaki, T Komatsu, T Momose, K Yoshida, T Tsukada, T Matsufuji, A Ohno, M Suzuki, O Ubukata and Y Kaneta 2022Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model. Biochem Biophys Res Commun 621: 157-161. Fibrolamellar hepatocellular carcinoma (FL-HCC) is known as a highly aggressive liver cancer that typically affects young adults without virus infection. Since this type of cancer does not respond to chemotherapy, surgery is the only known effective therapeutic option. Most FL-HCC patients express the fusion gene DNAJB1-PRKACA, which has been recognized as the signature of FL-HCC. It has also been reported that PRKACA kinase activity is essential for its oncogenic activity, suggesting that PRKACA kinase inhibition could be considered as an useful therapeutic target. In this study, we established an evaluation system for PRKACA kinase inhibitors and synthesized DS89002333, a novel PRKACA inhibitor. DS89002333 showed potent PRKACA inhibitory activity and inhibited fusion protein-dependent cell growth both in vitro and in vivo. Furthermore, this compound showed anti-tumor activity in an FL-HCC patient-derived xenograft model expressing the DNAJB1-PRKACA fusion gene. Our data suggest that DS89002333 could be considered as a potential therapeutic agent for FL-HCC.
Van Treeck, BJ, RK Moreira, T Mounajjed, L Ferrell, Y Xue, E Jessen, J Davila and RP Graham 2022Transcriptomic Analysis of Cirrhosis-Like Hepatocellular Carcinoma Reveals Distinct Molecular Characteristics and Pathologic Staging Implications. Am J Clin Pathol. OBJECTIVES: Cirrhosis-like hepatocellular carcinoma (CL-HCC) is a rare hepatocellular malignancy characterized by multiple tumor nodules that clinically, radiologically, macroscopically, and microscopically mimic cirrhosis. We aimed to elucidate the molecular biology of CL-HCC and determine tumor nodule clonality. METHODS: We performed RNA sequencing on formalin-fixed, paraffin-embedded tissue from confirmed CL-HCC cases (n = 6), along with corresponding nonneoplastic hepatic tissue (n = 4) when available. Transcriptomes from our previous work on steatohepatitic hepatocellular carcinoma and The Cancer Genome Atlas (TCGA) were used for comparison purposes. RESULTS: Histologically, CL-HCC displayed innumerable nodules and extensive vascular invasion. Intratumoral nodule comparison indicated that the multiple nodules were all clonally related, not independent primaries. The unique histomorphologic appearance corresponded with a distinct transcriptome compared with other HCCs, including fibrolamellar HCC (n = 6), steatohepatitic HCC (n = 8), and conventional HCC in TCGA (n = 424). Tumor-normal gene expression analysis revealed consistent overexpression of several genes involved in degradation of tissue matrix. No recurrent translocations or point mutations were identified. CL-HCC showed a gene expression profile indicative of zone 2 hepatocytes. CONCLUSIONS: CL-HCC's distinctive clinicopathologic features correspond to a unique gene expression profile, increased expression of invasive markers, features of zone 2 hepatocytes, and features suggestive of intratumoral nodule monoclonality.
Vasireddi, AK, ME Leo and JH Squires 2022Magnetic resonance imaging of pediatric liver tumors. Pediatr Radiol 52(2): 177-188. Liver tumors in children can be benign or malignant. Although several clinical factors are important in the evaluation of these lesions, MRI is particularly important for lesion characterization and tumor staging. In children, use of a hepatobiliary contrast agent is recommended to evaluate a known or suspected liver lesion. In this review, we discuss the most common benign and malignant pediatric liver tumors, including vascular tumors, mesenchymal hamartoma, focal nodular hyperplasia, hepatocellular adenoma, hepatoblastoma, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, undifferentiated embryonal sarcoma and metastases, with emphasis on relevant clinical information and imaging appearance at MRI using hepatobiliary agents.
Weiel, JJ, B Forgo, J Sage, A Rangaswami and FK Hazard 2022The Use of Fluorescence in situ Hybridization to Confirm PRKACA Gene Rearrangement in Fibrolamellar Hepatocellular Carcinoma: A Validation Study. Ann Clin Lab Sci 52(3): 475-483. OBJECTIVE: The objectives of this study are to define the specificity of the DNAJB1-PRKACA fusion transcript for the fibrolamellar subtype of hepatocellular carcinoma (FL-HCC) by testing a targeted sampling of other hepatic neoplasms/proliferations and extrahepatic neoplasms seen in children and young adults and to develop a FISH assay using a commercially available PRKACA break apart probe for use in a CLIA-certified clinical laboratory. METHODS: Formalin fixed paraffin embedded tissue sections from 12 FL-HCC cases, 142 cases of other hepatic neoplasms/proliferations (conventional HCC, focal nodular hyperplasia (FNH), hepatocellular adenoma (HA) and hepatoblastoma (HB)) and extrahepatic neoplasms (neuroblastoma (NB), Wilms tumor (WT) and Gastrointestinal neuroendocrine tumor (GNET)) and 60 matched background normal control tissues underwent fluorescence in situ hybridization (FISH) testing using a break apart probe targeting the PRKACA gene locus on chromosome 19 using standard techniques. RESULTS: The PRKACA gene rearrangement was detected in 11/12 (92%) FL-HCC cases and 1/94 (1%) of conventional HCC cases. All other cases and background control tissues were negative for the PRKACA gene rearrangement. These findings establish a test sensitivity of 91.7% and specificity of 99.5%. CONCLUSION: This study shows that, using standard techniques, FISH testing with a commercially available break apart probe targeting the PRKACA gene can be used as a surrogate for the DNAJB1-PRKACA fusion commonly found in FL-HCC. Also, the PRKACA gene rearrangement is not expressed in other hepatic neo-plasms/proliferations or extrahepatic neoplasms seen in children and young adults. Finally, FISH testing can be used as a diagnostic tool to confirm the diagnosis of FL-HCC, in the appropriate clinical setting.
Yoon, JK, JY Choi, H Rhee and YN Park 2022MRI features of histologic subtypes of hepatocellular carcinoma: correlation with histologic, genetic, and molecular biologic classification. Eur Radiol 32(8): 5119-5133. HCC is a heterogeneous group of tumors in terms of histology, genetic aberration, and protein expression. Advancements in imaging techniques have allowed imaging diagnosis to become a critical part of managing HCC in the clinical setting, even without pathologic diagnosis. With the identification of many HCC subtypes, there is increasing correlative evidence between imaging phenotypes and histologic, molecular, and genetic characteristics of various HCC subtypes. In this review, current knowledge of histologic heterogeneity of HCC correlated to features on gadolinium-enhanced dynamic liver MRI will be discussed. In addition, HCC subtype classification according to transcriptomic profiles will be outlined with descriptions of histologic, genetic, and molecular characteristics of some relatively well-established morphologic subtypes, namely the low proliferation class (steatohepatitic HCC and CTNNB1-mutated HCC) and the high proliferation class (macrotrabecular-massive HCC (MTM-HCC), scirrhous HCC, and CK19-positive HCC). Characteristics of sarcomatoid HCC and fibrolamellar HCC will also be discussed. Further research on radiological characteristics of HCC subtypes may ultimately enable non-invasive diagnosis and serve as a biomarker in predicting prognosis, molecular characteristics, and therapeutic response. In the era of precision medicine, a multidisciplinary effort to develop an integrated radiologic and clinical diagnostic system of various HCC subtypes is necessary. KEY POINTS: * HCC is a heterogeneous group of tumors in terms of histology, genetic aberration, and protein expression, which can be divided into many subtypes according to transcriptome profiles. * There is increasing evidence of a correlation between imaging phenotypes and histologic, genetic, and molecular biologic characteristics of various HCC subtypes. * Imaging characteristics may ultimately enable non-invasive diagnosis and subtype characterization, serving as a biomarker for predicting prognosis, molecular characteristics, and therapeutic response.
Abou-Alfa, GK, T Meyer, J Zhang, S Sherrin, A Yaqubie, AC O’Neill, F Xu, LD Eli, JJ Harding, EM O'Reilly, AS Lalani, R Bryce and JD Gordan 2021Evaluation of neratinib (N), pembrolizumab (P), everolimus (E), and nivolumab (V) in patients (pts) with fibrolamellar carcinoma (FLC). J Clin Oncol. 39: 310-310.Background: FLC, a rare liver cancer of young adults, has no effective systemic therapies. Surgical resection is used extensively with non-curative intent. FLC is associated with a DNAJB1-PRKACA chimeric transcript that produces a fusion protein with retained kinase activity and increased expression of several oncogenic signaling pathways including, but not limited to, HER2 (ERBB2). Methods: N (240 mg oral daily) was studied in FLC pts in the SUMMIT study (NCT01953926); and later under compassionate use for N-based combinations (combo): P (2 mg/kg q3w), E (7.5 mg daily), and V (240 mg q2w) in doublet or triplet regimens. Eligible pts: ?12y; histologically confirmed FLC; adequate organ function; any number of prior therapies. Primary endpoint: objective response rate (ORR; RECIST v1.1). Secondary endpoints: duration of response; clinical benefit rate (CBR); safety (CTCAE v4.0); somatic and germline sequencing (MSK IMPACT). Results: As of 03-Sep-2020, 15 pretreated pts received N in SUMMIT (confirmed ORR 0%; CBR 13%). Efficacy data for 5 pts from SUMMIT and 2 more pts receiving combo under compassionate use (4 male, 3 female, median age 26 years, median 0 [range 0–4] prior systemic therapies) are in shown in the table. The most common adverse events (AE) with single-agent N (n = 5) were diarrhea (grade 1 80%; grade 2 20%) and nausea (grade 1 60%); other AEs were grade ?1 in ?20% of pts. Conclusions: N monotherapy had limited benefit as a single agent in FLC pts. Several case studies evaluating N-based combo with checkpoint inhibitors administered under compassionate use demonstrated that NP led to 1 PR, and the triplet of NPE to prolonged SD. These are case-limited observations but are critical and worth evaluating further in upcoming clinical trials given the continued lack of a standard of care therapy for pts with FLC. Clinical trial information: NCT01953926. Patient sequential numberSomatic IMPACTCombo receivedResponse (DOR, months)Current statusGermline IMPACTN Combo1TERT non-coding mutation, DNAJB1-PRKACA deletionNVSD (6)PD (3) Alive, off combo; receiving GOGermline negative2N/A1NPPD (2)SD (9)Alive, off combo; receiving GONPESD (10)3TERT inversion, DNAJB1-PRKACA fusionNESD (4)SD (6)Alive, off combo; unknown current treatmentGermline negativeNPEPD (3)42N/A1NPPD (2)SD (3)Alive, off combo; receiving G5TERT non-coding mutation, DNAJB1-PRKACA fusion, HIST1H3I mis-, IRS1 exon 1 mis-, PIK3R3 exon 7 mis-, SF3B1 exon 19 mis-NPSD (4)PR (6)Alive, on treatmentGermline BLM pathogenic variant6DNAJB1-PRKACA fusionNPE3N/ASD (4)Alive, on treatment; allergy to E, pending sunitinibGermline negative7N/A1NPN/APD (2)Alive, on treatment; pending E1Not done or results not available; 2Pt stopped from treatment due P-related AE; 3Not evaluable; E stopped due to AE.DOR, duration of response; G, gemcitabine; mis-, missense; O, oxaliplatin; PD, progressive disease; PR, partial response; SD, stable disease.
Al Zahrani, A and A Alfakeeh 2021Fibrolamellar hepatocellular carcinoma treated with atezolizumab and bevacizumab: two case reports. J Med Case Rep 15(1): 132. BACKGROUND: Fibrolamellar hepatocellular carcinoma is a unique tumor of the liver that differs from the classical hepatocellular carcinoma in diagnosis, behavior, and possibly treatment. There is usually absent underlying liver disease, and it usually occurs in young patients. The survival outcomes in localized fibrolamellar hepatocellular carcinoma are perhaps better than in classical hepatocellular carcinoma if treated early and radically. On the other hand, the prognosis remains poor for locally advanced and metastatic fibrolamellar hepatocellular carcinoma. Many reports suggested a limited benefit from systemic chemotherapy. Sorafenib also did not show major effects on fibrolamellar hepatocellular carcinoma. Given the rarity of fibrolamellar hepatocellular carcinoma, lack of large studies, and absence of standard treatment, the treatment decisions rely on case reports, previously reported cases series, and expert opinions. Recent studies have shown promising effects of immunotherapy with checkpoint inhibitors in the first- and second-line therapy of hepatocellular carcinoma. Atezolizumab with bevacizumab regimen has been approved recently as a first-line treatment for classical hepatocellular carcinoma. Currently, there are no reports yet on the use of atezolizumab with bevacizumab for fibrolamellar hepatocellular carcinoma. CASE REPORT: In this article, we present two Arabic patients with advanced fibrolamellar hepatocellular carcinoma who received atezolizumab and bevacizumab combinations but did not show any clinical benefits. CONCLUSION: While atezolizumab and bevacizumab combinations had shown benefits in classical hepatocellular carcinoma, the current data showed a lack of benefit and tumor response in fibrolamellar hepatocellular carcinoma.
Arias, GA, I Siddiqui, OM Navarro, F Shaikh, BA Sayed and GB Chavhan 2021Imaging and clinical features of pediatric hepatocellular carcinoma. Pediatr Radiol. BACKGROUND: Hepatocellular carcinoma (HCC) is rare in children and there is limited data on its imaging features. OBJECTIVE: To describe imaging features of pediatric HCC and correlate them with clinical and laboratory findings. MATERIALS AND METHODS: We retrospectively reviewed imaging in all pediatric HCC cases seen between January 2000 and January 2019. Imaging features defined in LI-RADS (Liver Imaging Reporting and Data System) and tumor extent by PRETEXT (pretreatment extent of disease) criteria were noted by two radiologists. Patient charts were reviewed to collect clinical features, alpha-fetoprotein (AFP) level and pathology findings. RESULTS: Of the 15 children (7 boys, 8 girls; mean age: 11.8 years, age range: 6-17 years) included in the study, 12/15 had computed tomography, 9/15 had magnetic resonance imaging and 9/15 had ultrasound exams available for review. Pathological types of HCC included classic (11/15, 73%), fibrolamellar (3/15, 20%) and mixed cholangiocarcinoma-HCC (1/15, 7%). Eighty percent occurred de novo in normal liver and 67% showed elevated AFP levels. Arterial phase hyperenhancement was seen in 83% of cases, washout in 86%, capsule in 50% and tumor-in-vein in 33%. The mean tumor size was 9.8 cm and 40% were multifocal on imaging. Staging revealed PRETEXT II tumors in 47%, III in 20% and IV in 33%. There were no PRETEXT I tumors. The two most common PRETEXT annotation factors were portal vein and caudate lobe involvement in 71% and 43% of cases, respectively. Fibrolamellar HCC demonstrated central scar, normal AFP levels and normal background liver. CONCLUSION: Pediatric HCC are large heterogeneous tumors, as reflected by high PRETEXT staging, and commonly include portal vein and caudate involvement. This affects resectability of these tumors at presentation. Central scar, normal AFP level and normal liver background may help differentiate fibrolamellar HCC from other types of HCC.
Chan, GKL, S Maisel, YC Hwang, RRB Wolber, P Vu, KC Patra, M Bouhaddou, HL Kenerson, RS Yeung, DL Swaney, NJ Krogan, RE Turnham, JD Scott, KJ Riehle, N Bardeesy and JD Gordan 2021Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism. bioRxiv: 2021.2004.2016.438110. Genetic alterations that activate protein kinase A (PKA) signaling are found across many tumor types, but their downstream oncogenic mechanisms are poorly understood. We used global phosphoproteomics and kinome activity profiling to map the conserved signaling outputs driven by diverse genetic changes that activate PKA in human cancer, including melanoma and fibrolamellar carcinoma (FLC). We define two consensus networks of effectors downstream of PKA in cancer models. One is centered on RAS/MAPK components, and a second involves Aurora Kinase A (AURKA). We find that AURKA stabilizes c-MYC and n-MYC protein levels and expression programs in PKA-dependent tumor models, in part via a positive feedback loop mediated by the oncogenic kinase PIM2. This process can be suppressed by conformation-disrupting AURKA inhibitors such as CD-532. Our findings elucidate two independent mechanisms of PKA-driven tumor cell growth and offer insight into drug targets for study in FLC and other PKA-dependent malignancies.
Chang, WI, C Lin, N Liguori, JN Honeyman, B DeNardo and W El-Deiry 2021Molecular targets for novel therapeutics in pediatric fusion-positive non-CNS solid tumors. Front Pharmacol 12: 747895. Chromosomal fusions encoding novel molecular drivers have been identified in several solid tumors, and in recent years the identification of such pathogenetic events in tumor specimens has become clinically actionable. Pediatric sarcomas and other rare tumors that occur in children as well as adults are a group of heterogeneous tumors often with driver gene fusions for which some therapeutics have already been developed and approved, and others where there is opportunity for progress and innovation to impact on patient outcomes. We review the chromosomal rearrangements that represent oncogenic events in pediatric solid tumors outside of the central nervous system (CNS), such as Ewing Sarcoma, Rhabdomyosarcoma, Fibrolamellar Hepatocellular Carcinoma, and Renal Cell Carcinoma, among others. Various therapeutics such as CDK4/6, FGFR, ALK, VEGF, EGFR, PDGFR, NTRK, PARP, mTOR, BRAF, IGF1R, HDAC inhibitors are being explored among other novel therapeutic strategies such as ONC201/TIC10.
Chen, DA, A Koehne de Gonzalez, L Fazlollahi, A Coffey, HE Remotti and SM Lagana 2021In situ hybridisation for albumin RNA in paediatric liver cancers compared with common immunohistochemical markers. J Clin Pathol 74(2): 98-101. AIMS: In situ hybridisation (ISH) for albumin mRNA is a sensitive marker of primary liver tumours in adults. However, paediatric tumours, such as hepatoblastoma (HB) and fibrolamellar hepatocellular carcinoma (FLC), have not been tested thoroughly and may require ancillary tests to diagnose with confidence. We aim to determine if albumin ISH is useful in the pathological evaluation of these malignancies and to compare it to commonly used immunohistochemical markers HepPar 1 (HEPA) and arginase-1 (ARG). METHODS: Tissue microarrays of 26 HB and 10 FLC were constructed. Controls included 4 embryonal undifferentiated sarcomas of the liver, 51 neuroblastomas and 64 Wilms tumours. We evaluated a commercially available RNA ISH to detect albumin mRNA. Immunohistochemistry for HEPA and ARG was performed in the usual fashion. RESULTS: Twenty-six of 26 HB showed positive staining by albumin ISH including 14 fetal, 8 embryonal and 4 mixed variants. All 10 FLC were diffusely positive. The sensitivity and specificity of albumin ISH were 100% for HB and FLC. ARG had 100% sensitivity and specificity for HB (26 of 26 cases) and FLC (9 of 9). HEPA stained 22 of 26 HB (85% sensitivity, 99.2% specificity) and 7 of 9 FLC (78% sensitivity, 99.1% specificity). CONCLUSION: Albumin RNA ISH is a useful test to determine hepatocytic origin in HB and FLC. ARG was equally sensitive and easy to interpret, while HEPA was inferior to both in HB and FLC.
Chen, P, QX Fang, DB Chen and HS Chen 2021Neoantigen vaccine: An emerging immunotherapy for hepatocellular carcinoma. World J Gastrointest Oncol 13(7): 673-683. Tumor-specific neoantigens, which are expressed on tumor cells, can induce an effective antitumor cytotoxic T-cell response and mediate tumor regression. Among tumor immunotherapies, neoantigen vaccines are in early human clinical trials and have demonstrated substantial efficiency. Compared with more neoantigens in melanoma, the paucity and inefficient identification of effective neoantigens in hepatocellular carcinoma (HCC) remain enormous challenges in effectively treating this malignancy. In this review, we highlight the current development of HCC neoantigens in its generation, screening, and identification. We also discuss the possibility that there are more effective neoantigens in hepatitis B virus (HBV)-related HCC than in non-HBV-related HCC. In addition, since HCC is an immunosuppressive tumor, strategies that reverse immunosuppression and enhance the immune response should be considered for the practical exploitation of HCC neoantigens. In summary, this review offers some strategies to solve existing problems in HCC neoantigen research and provide further insights for immunotherapy.
Depauw, L, G De Weerdt, B Gys, S Demeulenaere, W Mebis and D Ysebaert 2021Pediatric fibrolamellar hepatocellular carcinoma: case report and review of the literature. Acta Chir Belg 121(3): 204-210. BACKGROUND: A 13-year-old boy presented with acute abdominal pain in the right upper quadrant without previous trauma. Abdominal ultrasound (US) revealed a mass in the right liver lobe with free intraperitoneal fluid, suggestive for hemoperitoneum. Magnetic resonance imaging confirmed a subcapsular lesion (5.7 x 4.6 x 4.1 cm), suggestive for fibrolamellar hepatocellular carcinoma (FL-HCC). Positron emission tomography-computed tomography revealed mild to moderate fluorodeoxyglucose (FDG) avidity, with no other FDG avid lesions. Hepatic tumor markers were negative. CASE REPORT: An elective right hepatectomy with cholecystectomy and hilar lymph node resection was performed. RESULTS: Histology showed a central fibrous scar and confirmed a FL-HCC (pT1bN0M0). The resected lymph nodes were tumor-free. Treatment of FL-HCC should consist of complete tumor resection with concurrent lymph node resection +/- orthotopic liver transplantation. Long-term follow-up is advised. A follow-up interval of 3-4 months in the first 2 years after surgical resection can be justified as FL-HCC have a high recurrence rate of more than 50% within 10-33 months. CONCLUSIONS: Malignancy can be a rare cause of abdominal pain in pediatric patients. An abdominal US is essential to prevent misdiagnosis. Treatment of FL-HCC should consist of R0 tumor resection with concurrent lymphadenectomy +/- orthotopic liver transplantation.
Dhaliwal, A, A Braseth, BS Dhindsa, D Ramai and FA Rochling 2021Liver transplantation in a patient with hepatic angiosarcoma. Cureus 13(1): e12609. Liver transplantation (LT) is an accepted form of therapy for selected cases of malignant tumors of the liver that include primary and fibrolamellar hepatocellular carcinoma, cholangiocarcinoma limited to Klatskin distribution, neuroendocrine tumors, epithelioid hemangioendothelioma, and hepatoblastoma. This is the case of a 61-year-old previously healthy female transferred from an outside hospital for a second opinion for a liver transplant. Computed tomography of the abdomen with contrast showed cirrhosis and multiple masses with arterial enhancement in her liver. She underwent a liver biopsy that showed a low-grade vascular tumor. She underwent an exploratory laparotomy with open liver biopsy which showed no visual evidence of omental spread. The pathology was reported as a low-grade vascular lesion, which was likely a small vessel neoplasm. After denial for LT secondary to an unknown low-grade vascular tumor, she presented to our medical center. Oncology was consulted and diagnosed with her liver vascular tumors as benign with an overall favorable prognosis. She was listed for liver transplant with a model for end-stage liver disease-sodium score of 25 and developed hepatorenal syndrome type 1. She was on hemodialysis for approximately 10 weeks prior to her LT and was eventually listed for simultaneous liver and kidney transplants. She underwent an orthotopic liver transplant 10 weeks after presenting to UNMC. The amount of necrosis and the elevated mitotic rate was sufficient to classify the tumor as a Federation Nationale des Centres de Lutte le Cancer grade 3 of three angiosarcomas. She was scheduled for a living donor kidney transplant three days after her liver transplant, but it was postponed after she continued to have increased urine output that responded to a trial of diuretics with continued improvement in kidney function. She successfully completed 16 months post-LT without any known recurrence of primary angiosarcoma.
Dong, Y, WP Wang, F Mao, Q Zhang, D Yang, A Tannapfel, MF Meloni, H Neye, DA Clevert and CF Dietrich 2021Imaging features of fibrolamellar hepatocellular carcinoma with contrast-enhanced ultrasound.Ultraschall Med 42(3): 306-313. PURPOSE: Fibrolamellar hepatocellular carcinoma (f-HCC) is a rare primary liver tumor. Imaging plays an important role in diagnosis. The aim of this retrospective study was to analyze contrast-enhanced ultrasound (CEUS) features of histologically proven f-HCC in comparison to benign focal nodular hyperplasia (FNH). MATERIALS & METHODS: 16 patients with histologically proven f-HCC lesions and 30 patients with FNH lesions were retrospectively reviewed regarding CEUS features to determine the malignant or benign nature of the focal liver lesions (FLL). Five radiologists assessed the CEUS enhancement pattern and came to a consensus using the EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) guideline criteria. RESULTS: Fibrolamellar hepatocellular carcinoma manifested as a single and huge FLL. On CEUS, f-HCC showed heterogeneous hyperenhancement in the arterial phase and hypoenhancement (16/16, 100 %) in the portal venous and late phases (PVLP) as a sign of malignancy. In contrast to the hypoenhancement of f-HCC in the PVLP, all patients with FNH showed hyperenhancement as the most distinctive feature (P < 0.01). 8 f-HCC lesions showed a central scar as an unenhanced area (8/16, 50.0 %), which could also be detected in 53.3 % (16/30) of FNH lesions (P > 0.05). CONCLUSION: By analyzing the hypoenhancement in the PVLP, CEUS imaging reliably diagnosed f-HCC as a malignant FLL. CEUS also showed differentiation between f-HCC and FNH lesions, showing similar non-enhanced central scars, whereas f-HCC lesions showed peripheral hyperenhancement in the arterial phase and early washout in the PVLP.
du Toit, M and AP Aldera 2021Fibrolamellar carcinoma with predominantly pseudoglandular architecture: A potential diagnostic pitfall.Int J Surg Pathol 29(1): 69-72. Biopsies of liver mass lesions are encountered frequently in general surgical pathology practice. The clinical differential diagnosis is typically hepatocellular carcinoma (HCC) versus metastatic adenocarcinoma. There are a variety of HCC variants that show a range of morphological appearances. The presence of malignant glands in the liver prompts the pathologist to consider adenocarcinoma, either metastatic or primary intrahepatic cholangiocarcinoma. It is important to remember that some variant patterns of HCC can show pseudoglandular growth. In this article, we present a case of fibrolamellar carcinoma that showed predominantly pseudoglandular growth to highlight the importance of a systematic approach and the routine use of a panel of immunohistochemical stains (HepPar1, CK7, and CD68).
Feliz-Norberto, M, C Michael and S de Oliveira 2021Neutrophil reverse migration from liver fuels neutrophilic inflammation to tissue injury in Nonalcoholic Steatohepatitis. bioRxiv: 2021.2010.2003.462893. Inflammation is a hallmark in the progression of nonalcoholic-fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Patients with NAFLD are characterized by a chronic low-grade systemic metabolic inflammation (i.e., metainflammation), which contributes to exacerbated however dysfunctional immune response. Neutrophils play an important pathological role in NAFLD progression to NASH; however, how NASH and associated chronic systemic inflammation impact overall the neutrophil response to injury is completely unexplored. Here, we investigated how neutrophil response to tissue injury is altered by the presence of NASH. We used a diet-induced NASH zebrafish model combined with tailfin transection in transgenic zebrafish larvae to study neutrophilic inflammation. Live non-invasive confocal microscopy was used to investigate neutrophil recruitment to tailfin injury through time. Photoconvertion of neutrophils at the liver area followed by time-lapse microscopy was performed to evaluate migration of neutrophils from liver to tailfin injury. Metformin and Pentoxifylline were used to pharmacologically reduce NASH and liver inflammation. We found that larvae with NASH display systemic inflammation and increased myelopoiesis. NASH larvae display a dysfunctional and exacerbated neutrophil response to tailfin injury, characterized by increased neutrophil recruitment, and delayed resolution of inflammation. Interestingly, we showed that neutrophils undergo reverse migration from the NASH liver to the wounded tailfin area. Finally, pharmacological treatment of NASH with Pentoxifylline and Metformin significantly reduced systemic chronic inflammation and the exacerbated recruitment of neutrophils to tissue injury. Taken together, our findings suggest that NASH exacerbates neutrophilic inflammation probably via neutrophil priming at the liver, which can further undergo reverse migration and respond to secondary inflammatory triggers such as tissue injury. Reverse migration of primed neutrophils from the liver might be an important mechanism that fuels the exacerbated neutrophil response observed in NASH conditions and associated metainflammation contributing to poor prognosis and increasing death in patients with metabolic syndrome.
Francisco, AB, J Li, AR Farghli, M Kanke, B Shui, PD Soloway, Z Wang, LM Reid, J Liu and P Sethupathy 2021Chemical, molecular, and single cell analysis reveal chondroitin sulfate proteoglycan aberrancy in fibrolamellar carcinoma. Cancer Res Commun 2(7): 663-678.Fibrolamellar carcinoma (FLC) is an aggressive liver cancer with no effective therapeutic options. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer growth and/or metastasis. To bridge this knowledge gap, we assessed pathways relevant to proteoglycans, a major component of the extracellular matrix. We first analyzed gene expression data from FLC and nonmalignant liver tissue (n = 27) to identify changes in glycosaminoglycan (GAG) biosynthesis pathways and found that genes associated with production of chondroitin sulfate, but not other GAGs, are significantly increased by 8-fold. We then implemented a novel LC/MS-MS based method to quantify the abundance of different types of GAGs in patient tumors (n = 16) and found that chondroitin sulfate is significantly more abundant in FLC tumors by 6-fold. Upon further analysis of GAG-associated proteins, we found that versican (VCAN) expression is significantly upregulated at the mRNA and protein levels, the latter of which was validated by IHC. Finally, we performed single-cell assay for transposase-accessible chromatin sequencing on FLC tumors (n = 3), which revealed for the first time the different cell types in FLC tumors and also showed that VCAN is likely produced not only from FLC tumor epithelial cells but also activated stellate cells. Our results reveal a pathologic aberrancy in chondroitin (but not heparan) sulfate proteoglycans in FLC and highlight a potential role for activated stellate cells. Significance: This study leverages a multi-disciplinary approach, including state-of-the-art chemical analyses and cutting-edge single-cell genomic technologies, to identify for the first time a marked chondroitin sulfate aberrancy in FLC that could open novel therapeutic avenues in the future.
Fu, T, H Ding, C Xu, Y Zhu, L Xue and F Lin 2021Imaging findings of fibrolamellar hepatocellular carcinomas on ultrasonography: A comparison with conventional hepatocellular carcinomas. Clin Hemorheol Microcirc 77(1): 49-60. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLHCC) is an unusual variant of hepatocellular carcinoma (HCC). Revealing the imaging features is important to the diagnosis of FLHCC. OBJECTIVE: The aim of this study was to investigate the imaging characteristics of FLHCCs. METHODS: This retrospective study included 29 patients with histopathologically proved FLHCC and 96 patients proved HCC. All patients underwent an ultrasound examination pre-operation. RESULTS: The average maximum diameters of the FLHCC and HCC lesions were 7.4+/-4.1 cm and 4.1+/-3.0 cm, respectively. On the ultrasound, 79.3% of the FLHCCs and 12.3% of the HCCs showed the internal hyperechoic area; 48.3% of the FLHCCs and 3.3% of the HCCs displayed a strip-like attenuation. Calcification was noted in 20.7% of the FLHCCs, while none in HCCs. On the contrast-enhanced ultrasound (CEUS), all FLHCC lesions and 87.7% of the HCCs displayed hyperenhancement in the arterial phase. An internal, unenhanced central scar appeared in all FLHCCs, while none in HCCs. CONCLUSIONS: The ultrasonographic features of FLHCC lesions indicate that they are relatively large masses showing the internal hyperechoic area or strip-like attenuation or calcification on the US and hypervascularity with an unenhanced central scar on the CEUS as compared with conventional HCC lesions.
Gigante, E, V Paradis, M Ronot, F Cauchy, O Soubrane, N Ganne-Carrie and JC Nault 2021New insights into the pathophysiology and clinical care of rare primary liver cancers. JHEP Rep 3(1): 100174. Hepatocholangiocarcinoma, fibrolamellar carcinoma, hepatic haemangioendothelioma and hepatic angiosarcoma represent less than 5% of primary liver cancers. Fibrolamellar carcinoma and hepatic haemangioendothelioma are driven by unique somatic genetic alterations (DNAJB1-PRKCA and CAMTA1-WWTR1 fusions, respectively), while the pathogenesis of hepatocholangiocarcinoma remains more complex, as suggested by its histological diversity. Histology is the gold standard for diagnosis, which remains challenging even in an expert centre because of the low incidences of these liver cancers. Resection, when feasible, is the cornerstone of treatment, together with liver transplantation for hepatic haemangioendothelioma. The role of locoregional therapies and systemic treatments remains poorly studied. In this review, we aim to describe the recent advances in terms of diagnosis and clinical management of these rare primary liver cancers.
Gottlieb, S, A Gliksberg, E Schadde and P Kent 2021Novel systemic therapies in the treatment of fibrolamellar carcinoma.J Clin Oncol. 39: e16161. Background: Fibrolamellar carcinoma (FLC) is an exceedingly rare liver cancer affecting children and young adults without underlying liver disease. Complete surgical resection is the primary treatment option, but recurrence is common. There are currently no established systemic therapies. We have treated patients in both the neoadjuvant and adjuvant setting with three novel combination therapies: 5-fluorouracil/interferon/nivolumab (“Triple Therapy” or TT), gemcitabine/oxaliplatin/lenvatinib (GOL), and nivolumab/lenvatinib/quercetin (NLQ). The purpose of this study was to evaluate objective responses and tolerability of three multi-agent systemic therapies in the treatment of FLC. Methods: Data from all patients with FLC who received TT, GOL, or NLQ between May 2018 and February 2021 were reviewed. Patients who received a minimum of six cycles of systemic therapy with follow up scans at least two months after initiation were assessed based on objective response, survival, and toxicity. Results: Twenty-nine patients with FLC who were treated with novel multi-agent systemic therapy were evaluable based on the above criteria. Median age at start of treatment was 20 (7-52; 16F, 12M, 1 non-disclosed). Twenty-three patients received one combination therapy (13 TT, 8 GOL, 2 NLQ), five received two different lines (3 TT/NLQ, 2 TT/GOL), and one patient received all three novel combinations. Between our 29 patients, they had relapsed 36 total times, and 11 had already tried 2+ systemic therapies. Best RECIST 1.1 objective response (clinical remission + partial response) and tumor control rate (clinical remission + partial response + stable disease) were 58%/95%, 55%/100%, and 33%/83% for TT, GOL, and NLQ respectively. The median longest Progression Free Survival (PFS) on any novel multi-agent regimen was 9 months (2-29; 9.5 for TT, 7 for GOL, 6.5 for NLQ), with 18 patients still receiving the therapy extending their PFS. Of those with previous relapses, 56% have a PFS longer than their previous longest remission and 69% have a PFS longer than their previous shortest time to relapse. Half of patients with previous relapses are still receiving the treatment responsible for their longest PFS. Fever, chills, and nausea were the most common adverse effects experienced throughout all three regimens. Seven patients experienced 1+ grade 3 adverse event. There were no toxic deaths or organ failure. Two patients died as a result of disease; their longest PFS (1 on GOL, 1 on TT) were nine and 10 months. Conclusions: FLC is a devastating cancer with patients often relapsing even after successful surgical remission. There is a strong need for effective and tolerable systemic therapies for those with unresectable, relapsed, progressive, or metastatic disease. We have had promising results in treating FLC and prolonging survival with minimal toxicities using novel multi-agent regimens.
Gottlieb, S, C O'Grady, A Gliksberg and P Kent 2021Early experiences with triple immunochemotherapy in adolescents and young adults with high-risk fibrolamellar carcinoma. Oncology: 1-8.INTRODUCTION: There are no standard systemic therapies for the treatment of fibrolamellar carcinoma (FLC
Hasegawa, T, H Kuroda, N Sakakura, Y Sato, S Chatani, S Murata, H Yamaura, T Nakada, Y Oya and Y Inaba 2021Novel strategy to treat lung metastases: Hybrid therapy involving surgery and radiofrequency ablation.Thorac Cancer. BACKGROUND: This study was performed to evaluate the clinical outcomes of hybrid treatment involving surgical resection and percutaneous radiofrequency ablation for patients with multiple lung metastases. METHODS: Seventeen patients (6 men, 11 women; median age, 52 years; range, 16-78 years) underwent hybrid treatment involving surgery and radiofrequency ablation to treat multiple lung metastases (median number, 4; range, 2-26) between May 2014 and February 2020. The primary lesions were colorectal carcinoma (n = 9), uterine endometrial carcinoma (n = 3), osteosarcoma (n = 2), renal cell carcinoma (n = 1), glottic carcinoma (n = 1), and fibrolamellar hepatocellular carcinoma (n = 1). Twenty-four sessions each of surgery and radiofrequency ablation were performed. Safety, disease-free survival, and overall survival were evaluated. Safety was assessed according to the Clavien-Dindo Classification. RESULTS: A grade IVa adverse event of empyema developed in one patient (4%, 1/24) after surgery. A grade IIIa adverse event of pneumothorax and a grade II adverse event of lung abscess occurred in four (17%, 4/24) and one session (4%, 1/24) after radiofrequency ablation, respectively. During the median follow up of 34 months (range, 8-67 months), 10 patients (59%, 10/17) developed new metastases. The 5-year disease-free survival rate was 32%. Four or fewer lung metastases (p = 0.008) and metastases from colorectal carcinoma (p = 0.02) were factors significantly associated with longer disease-free survival. One patient (6%, 1/17) died of tumor progression 29 months after initial treatment. The 5-year overall survival rate was 88%. CONCLUSIONS: The strategy of hybrid treatment involving surgery and radiofrequency ablation may offer good outcomes for patients with multiple lung metastases.
Kim, SS, I Kycia, M Karski, RK Ma, EA Bordt, J Kwan, A Karki, E Winter, RG Aktas, Y Wu, A Emili, DE Bauer, P Sethupathy and K Vakili 2021DNAJB1-PRKACA in HEK293T cells induces LINC00473 overexpression that depends on PKA signaling. bioRxiv. Fibrolamellar carcinoma (FLC) is a primary liver cancer that most commonly arises in adolescents and young adults in a background of normal liver tissue and has an poor prognosis due to lack of effective chemotherapeutic agents. The DNAJB1-PRKACA gene fusion (DP) has been reported in the majority of FLC tumors, however its oncogenic mechanisms remain unclear. Given the paucity of cellular models, in particular FLC tumor cell lines, we hypothesized that engineering the DP fusion gene in HEK293T cells would provide insight into the cellular effects of the fusion gene. We used CRISPR/Cas9 to engineer HEK293T clones expressing DPfusion gene (HEK-DP) and performed transcriptomic, proteomic, and mitochondrial studies to characterize this cellular model. Proteomic analysis of DP interacting partners identified mitochondrial proteins as well as proteins in other subcellular compartments. HEK-DP cells demonstrated significantly elevated mitochondrial fission, which suggests a role for DP in altering mitochondrial dynamics. Transcriptomic analysis of HEK-DP cells revealed a significant increase in LINC00473 expression, similar to what has been observed in primary FLC samples. LINC00473 overexpression was reversible with siRNA targeting of PRKACA as well as pharmacologic targeting of PKA and Hsp40 in HEK-DP cells. Therefore, our model suggests that LINC00473 is a candidate marker for DP activity.
Kubli, SP, T Berger, DV Araujo, LL Siu and TW Mak 2021Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov. The success of checkpoint inhibitors has accelerated the clinical implementation of a vast mosaic of single agents and combination immunotherapies. However, the lack of clinical translation for a number of immunotherapies as monotherapies or in combination with checkpoint inhibitors has clarified that new strategies must be employed to advance the field. The next chapter of immunotherapy should examine the immuno-oncology therapeutic failures, and consider the complexity of immune cell-cancer cell interactions to better design more effective anticancer drugs. Herein, we briefly review the history of immunotherapy and checkpoint blockade, highlighting important clinical failures. We discuss the critical aspects - beyond T cell co-receptors - of immune processes within the tumour microenvironment (TME) that may serve as avenues along which new therapeutic strategies in immuno-oncology can be forged. Emerging insights into tumour biology suggest that successful future therapeutics will focus on two key factors: rescuing T cell homing and dysfunction in the TME, and reappropriating mononuclear phagocyte function for TME inflammatory remodelling. New drugs will need to consider the complex cell networks that exist within tumours and among cancer types.
Lalazar, G, D Requena, L Ramos-Espiritu, D Ng, PD Bhola, YP de Jong, R Wang, NJC Narayan, B Shebl, S Levin, E Michailidis, M Kabbani, KOA Vercauteren, AM Hurley, BA Farber, WJ Hammond, JA Saltsman, 3rd, EM Weinberg, JF Glickman, BA Lyons, J Ellison, E Schadde, M Hertl, JL Leiting, MJ Truty, RL Smoot, F Tierney, T Kato, HG Wendel, MP LaQuaglia, CM Rice, A Letai, P Coffino, MS Torbenson, MV Ortiz and SM Simon 2021Identification of novel therapeutic targets for fibrolamellar carcinoma using patient-derived xenografts and direct-from-patient screening.Cancer Discov 11(10): 2544-2563. To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor.
Lee, JS, HY Jin, JM Ko, SH Kim, N Han, BK Park, M Park, HJ Park and JA Lee 2021Hyperammonemic encephalopathy mimicking ornithine transcarbamylase deficiency in fibrolamellar hepatocellular carcinoma: Successful treatment with continuous venovenous hemofiltration and ammonia scavengers. Cancer Res Treat 53(1): 283-288. Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver cancer affecting adolescents and young adults without any pre existing liver disease. Hyperammonemic encephalopathy (HAE) is a serious paraneoplastic syndrome, and several cases of HAE have been reported in patients with FLHCC. This condition is rare; hence, there are currently no management guidelines for cancer-related HAE. Herein, we report a case of an 18-year-old man with advanced FLHCC who developed HAE during the first course of chemotherapy consisting of cisplatin, doxorubicin, 5-fluorouracil, and interferon-alpha. He was successfully treated with continuous venovenous hemofiltration, sodium benzoate, sodium phenylbutyrate, and amino acid supplementation for HAE. After the second course of chemotherapy, he underwent surgery, and thereafter, his ammonia levels were normal without any ammonia scavenger therapy. Treatments for HAE described here will be helpful for this rare, but serious metabolic complication of FLHCC and could partially applied to HAE related to any malignancies.
Limaiem, F and S Bouraoui 2021Mixed fibrolamellar hepatocellular carcinoma. Clin Case Rep 9(6): e04318. Pure and mixed fibrolamellar hepatocellular carcinomas display distinct clinical presentations and epigenetic backgrounds leading to different prognoses and as such may be regarded as separate clinical entities.
Matsumoto, K, K Kikuchi, A Hara, H Tsunashima, K Tsuneyama and S Doi 2021Immunohistochemical detection of procalcitonin in fibrolamellar hepatocellular carcinoma. Clin J Gastroenterol. A 25-year-old woman with fever and epigastric pain was referred to our hospital. Blood examination showed significant liver dysfunction, markedly high C-reactive protein (CRP 19.1 mg/dL) and procalcitonin (48.3 ng/mL) levels. Dynamic computed tomography showed a tumor approximately 120 mm in size in the right lobe of the liver, but with no abscess formation. The patient was hospitalized and started on antibiotics; her CRP level improved, but the procalcitonin level did not decrease. Histopathological examination of the liver tumor biopsy revealed fibrolamellar hepatocellular carcinoma (FLC). Positive staining of the FLC with an anti-procalcitonin antibody suggested the production of procalcitonin.
Michael, C, FJ Martinez-Navarro and S de Oliveira 2021Analysis of liver microenvironment during early progression of non-alcoholic fatty liver disease-associated hepatocellular carcinoma in zebrafish. J Vis Exp(170). Liver cancer is currently the third leading cause of cancer related death worldwide, and Hepatocellular Carcinoma (HCC) accounts for 75-90% of all liver cancer cases. With the introduction of effective treatments to prevent and treat hepatitis B/C, non-alcoholic fatty liver disease (NAFLD), and the more aggressive form know as non-alcoholic steatohepatitis (NASH), are quickly becoming the number one risk factors to develop HCC in modern societies. To better understand the role NASH has on the development of HCC we designed a NASH-associated HCC zebrafish. The optical clarity and genetic tractability of the zebrafish larvae make them an appealing and powerful model to study the liver microenvironment and immune cell composition using non-invasive fluorescent live imaging. This protocol describes how to use a NASH-associated HCC zebrafish model to investigate the effect of cholesterol surplus in the liver microenvironment and its impact on immune cell composition at early stages of the disease. First, we feed HCC larvae (s704Tg), which express hepatocyte-specific activated beta-catenin, with a 10% high cholesterol diet for 8 days to develop a NASH-associated HCC model. Here we describe how to make use of different transgenic lines to evaluate several early malignancy features in the liver by non-invasive confocal microscopy, such as liver area, cell, and nuclear morphology (hepatocytes area, nuclear area, nuclear:cytoplasmic ratio (N:C ratio), nuclear circularity, micronuclei/nuclear herniation scoring) and angiogenesis. Then, using transgenic lines with tagged immune cells (neutrophils, macrophages, and T cells) we show how to analyze liver immune cell composition in NASH-associated HCC larvae. The described techniques are useful to evaluate liver microenvironment and immune cell composition at early hepatocarcinogenesis stages, but they can also be modified to study such features in other liver disease models.
Murtha-Lemekhova, A, J Fuchs, E Schulz, AS Sterkenburg, P Mayer, J Pfeiffenberger and K Hoffmann 2021Scirrhous Hepatocellular Carcinoma: Systematic Review and Pooled Data Analysis of Clinical, Radiological, and Histopathological Features. J Hepatocell Carcinoma 8: 1269-1279. BACKGROUND: Aberrant subtypes of hepatocellular carcinoma (HCC) account for 20-30% of all HCCs and habitually present a challenge in diagnosis and treatment. Scirrhous hepatocellular carcinoma (s-HCC) is often misdiagnosed as cholangiocarcinoma, fibrolamellar hepatocellular carcinoma, or metastasis. METHODS: Electronic databases (PubMed, Web of Knowledge, Google Scholar, Cochrane Library, and WHO International Clinical Trials Registry Platform) were searched for publications on scirrhous hepatocellular carcinoma without date or language restrictions. Quality assessment was performed using a tool proposed by Murad et al for case reports and series. For observational studies, MINORS quality assessment tool was used. This study was registered at PROSPERO (CRD42020212323). RESULTS: S-HCC arises in patients with chronic hepatitis (hepatitis B in 60% and hepatitis C in 21%). S-HCC primarily affects men with a mean age of 55.8 years. Serum AFP is elevated above 20IU/mL in 66.7% of the patients. On ultrasound, s-HCC presents as hypoechoic or mosaic pattern lesions (47.6% each) and causes a retraction of the liver surface (70%) when near the capsule. Delayed enhancement of the tumor is evident in 87.0%. On MRI, 65.0% of s-HCCs show a target appearance. Histopathologic pattern is mostly irregular (97.6%). Lesions show a bulging appearance (100%), septae (85.6%) and a central scar (63.5%), and usually lack central necrosis (75%). Immunohistochemistry shows HepPar 1 positivity in 64.6%, CK7 in 40.7%, and EMA in 41.9%. The 5-year overall survival rate estimates 45.2% and 45.5% of the patients experience a recurrence after hepatectomy. CONCLUSION: S-HCC is a rare subtype of HCC primarily arising in hepatitis- or cirrhosis-afflicted livers and incorporates atypical radiological and histopathological HCC features. Despite lower recurrence rates, overall survival of patients with s-HCC is poorer than generally for HCC, underlining the need for individualized treatment. Patients with atypical lesions of the liver should be referred to tertiary hospitals for interdisciplinary assessment and treatment.
O'Neill, AF, AJ Church, AR Perez-Atayde, R Shaikh, KJ Marcus and K Vakili 2021Fibrolamellar carcinoma: An entity all its own. Curr Probl Cancer: 100770. Fibrolamellar carcinoma (FLC) is a rare malignant entity arising from the liver and primarily affecting patients in late adolescence and young adulthood. FLC tumors are characterized by their unique histologic features and an only recently discovered genomic alteration: a chimeric fusion protein found in nearly all tumors. The rarity of these tumors coupled with the only recent acknowledgement of this genomic abnormality has likely led to disease under-recognition and de-prioritization of collaborative efforts aimed at establishing an evidence-guided standard of care. Surgical resection undoubtedly remains a mainstay of therapy and a necessity for cure but given the incidence of metastatic disease at diagnosis and high rates of distant relapse, systemic therapies remain a key component of disease control. There are few systemic therapies that have demonstrated proven benefit. Recent efforts have galvanized around single-institute or small consortia-based studies specifically focused on the enrollment of patients with FLC or use of agents with biologic rationale. This review will outline the current state of FLC epidemiology, histology, biology and trialed therapies derived from available published literature.
Olivieri, C, C Walker, A Karamafrooz, Y Wang, VS Manu, F Porcelli, DK Blumenthal, DD Thomas, DA Bernlohr, SM Simon, SS Taylor and G Veglia 2021Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A. Commun Biol 4(1): 321. An aberrant fusion of the DNAJB1 and PRKACA genes generates a chimeric protein kinase (PKA-C(DNAJB1)) in which the J-domain of the heat shock protein 40 is fused to the catalytic alpha subunit of cAMP-dependent protein kinase A (PKA-C). Deceivingly, this chimeric construct appears to be fully functional, as it phosphorylates canonical substrates, forms holoenzymes, responds to cAMP activation, and recognizes the endogenous inhibitor PKI. Nonetheless, PKA-C(DNAJB1) has been recognized as the primary driver of fibrolamellar hepatocellular carcinoma and is implicated in other neoplasms for which the molecular mechanisms remain elusive. Here we determined the chimera's allosteric response to nucleotide and pseudo-substrate binding. We found that the fusion of the dynamic J-domain to PKA-C disrupts the internal allosteric network, causing dramatic attenuation of the nucleotide/PKI binding cooperativity. Our findings suggest that the reduced allosteric cooperativity exhibited by PKA-C(DNAJB1) alters specific recognitions and interactions between substrates and regulatory partners contributing to dysregulation.
Panetta, JC, O Campagne, J Gartrell, W Furman and CF Stewart 2021Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study. Clin Transl Sci. Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady-state exposures (area under the concentration curve from 0 to 12-h [AUC0->12 h ]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m(2) /dose) or a pharmacokinetically guided dose targeting an AUC0->12 h between 20 and 55 h microg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in-target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.
Postler, TS 2021A most versatile kinase: The catalytic subunit of PKA in T-cell biology. Int Rev Cell Mol Biol 361: 301-318. The cAMP-dependent protein kinase, more commonly referred to as protein kinase A (PKA), is one of the most-studied enzymes in biology. PKA is ubiquitously expressed in mammalian cells, can be activated in response to a plethora of biological stimuli, and phosphorylates more than 250 known substrates. Indeed, PKA is of central importance to a wide range of organismal processes, including energy homeostasis, memory formation and immunity. It serves as the primary effector of the second-messenger molecule 3',5'-cyclic adenosine monophosphate (cAMP), which is believed to have mostly inhibitory effects on the adaptive immune response. In particular, elevated levels of intracellular cAMP inhibit the activation of conventional T cells by limiting signal transduction through the T-cell receptor and altering gene expression, primarily in a PKA-dependent manner. Regulatory T cells have been shown to increase the cAMP levels in adjacent T cells by direct and indirect means, but the role of cAMP within regulatory T cells themselves remains incompletely understood. Paradoxically, cAMP has been implicated in promoting T-cell activation as well, adding another functional dimension beyond its established immunosuppressive effects. Furthermore, PKA can phosphorylate the NF-kappaB subunit p65, a transcription factor that is essential for T-cell activation, independently of cAMP. This phosphorylation of p65 drastically enhances NF-kappaB-dependent transcription and thus is likely to facilitate immune activation. How these immunosuppressive and immune-activating properties of PKA balance in vivo remains to be elucidated. This review provides a brief overview of PKA regulation, its ability to affect NF-kappaB activation, and its diverse functions in T-cell biology.
Ramai, D, A Ofosu, JK Lai, ZH Gao and DG Adler 2021Fibrolamellar hepatocellular carcinoma: A population-based observational study. Dig Dis Sci 66(1): 308-314. BACKGROUND: In the USA, fibrolamellar hepatocellular carcinoma (FLC) accounts for 1-2% of all cases of hepatocellular carcinoma. FLC remains poorly understood. AIM: We aim to investigate the incidence, demographics, tumor characteristics, treatment, and prognosis of patients with FLC. METHODS: Data on FLC between 2000 and 2016 were extracted from the SEER database and analyzed. RESULTS: A total of 300 patients with FLC were identified where 126 were male. Median age at diagnosis was 27 +/- 22 years. The overall age-adjusted incidence of FLC between 2000 and 2016 was 0.02 per 100,000 per year. A bimodal distribution was observed where the highest incidences occurred between 15-19 years and 70-74 years. Most tumors on presentation were moderately differentiated (20.7%), while the most common stage at presentation was stage 1 (21.7%) followed by stages 3 and 4 (20.0% and 20.3%, respectively); 50.3% of these tumors were surgically resected, while 8.0% received radiation and 45.3% received chemotherapy. One- and 5-year cause-specific survival for FLC was 72.0% and 32.9%, respectively, with a median survival of 32.9 months. HCC had a median survival time of 11.7 months. Patients who were not treated with surgical intervention had about 3 times increased risk for death (HR 2.8, 95% CI 1.68-4.72, P = 0.000). Radiation and chemotherapy did not significantly affect outcomes. CONCLUSION: FLC presents with a bimodal distribution in both early and elderly individuals. Compared to HCC, FLC has a higher recurrence rate but better survival outcome. Surgical intervention is superior to chemotherapy and radiation.
Rimassa, L, N Personeni, C Czauderna, F Foerster and P Galle 2021Systemic treatment of HCC in special populationsJ Hepatol 74(4): 931-943.Recent years have seen significant progress in the systemic treatment of hepatocellular carcinoma (HCC), including the advent of immunotherapy. While several large phase III trials have provided the evidence for a multi-line treatment paradigm, they have focused on a highly selected group of patients by excluding potentially confounding comorbidities. As a result, high quality evidence for the systemic treatment of HCC in patients with various comorbidities is missing. This review summarises current knowledge on the use of approved medicines in patients with HIV, autoimmune disease, cardiovascular disease, diabetes, fibrolamellar HCC, mixed HCC-cholangiocarcinoma, decompensated cirrhosis (Child-Pugh B and C), a significant bleeding history, vascular invasion or portal vein thrombosis, as well as the elderly, those on haemodialysis, and those after solid organ transplantation. The article highlights relevant knowledge gaps and current clinical challenges. To improve the safety and efficacy of HCC treatment in these subgroups, future trials should be designed to specifically include patients with comorbidities.
Rivas, M, ME Johnston, 2nd, R Gulati, M Kumbaji, TF Margues Aguiar, L Timchenko, A Krepischi, S Shin, A Bondoc, G Tiao, J Geller and N Timchenko 2021HDAC1-dependent repression of markers of hepatocytes and P21 is involved in development of pediatric liver cancer. Cell Mol Gastroenterol Hepatol 12(5): 1669-1682. BACKGROUND & AIMS: Epigenetic regulation of gene expression plays a critical role in the development of liver cancer; however, the molecular mechanisms of epigenetic-driven liver cancers are not well understood. The aims of this study were to examine molecular mechanisms that cause the dedifferentiation of hepatocytes into cancer cells in aggressive hepatoblastoma and test if the inhibition of these mechanisms inhibits tumor growth. METHODS: We have analyzed CCAAT/Enhancer Binding Protein alpha (C/EBPalpha), Transcription factor Sp5, and histone deacetylase (HDAC)1 pathways from a large biobank of fresh hepatoblastoma (HBL) samples using high-pressure liquid chromatography-based examination of protein-protein complexes and have examined chromatin remodeling on the promoters of markers of hepatocytes and p21. The HDAC1 activity was inhibited in patient-derived xenograft models of HBL and in cultured hepatoblastoma cells and expression of HDAC1-dependent markers of hepatocytes was examined. RESULTS: Analyses of a biobank showed that a significant portion of HBL patients have increased levels of an oncogenic de-phosphorylated-S190-C/EBPalpha, Sp5, and HDAC1 compared with amounts of these proteins in adjacent regions. We found that the oncogenic de-phosphorylated-S190-C/EBPalpha is created in aggressive HBL by protein phosphatase 2A, which is increased within the nucleus and dephosphorylates C/EBPalpha at Ser190. C/EBPalpha-HDAC1 and Sp5-HDAC1 complexes are abundant in hepatocytes, which dedifferentiate into cancer cells. Studies in HBL cells have shown that C/EBPalpha-HDAC1 and Sp5-HDAC1 complexes reduce markers of hepatocytes and p21 via repression of their promoters. Pharmacologic inhibition of C/EBPalpha-HDAC1 and Sp5-HDAC1 complexes by Suberoylanilide hydroxamic acid (SAHA) and small interfering RNA-mediated inhibition of HDAC1 increase expression of hepatocyte markers, p21, and inhibit proliferation of cancer cells. CONCLUSIONS: HDAC1-mediated repression of markers of hepatocytes is an essential step for the development of HBL, providing background for generation of therapies for aggressive HBL by targeting HDAC1 activities.
Rudolphi-Solero, T, EM Trivino-Ibanez, A Medina-Benitez, J Fernandez-Fernandez, DJ Rivas-Navas, AJ Perez-Alonso, M Gomez-Rio, T Aroui-Luquin and A Rodriguez-Fernandez 2021Differential diagnosis of hepatic mass with central scar: Focal nodular hyperplasia mimicking fibrolamellar hepatocellular carcinoma. Diagnostics (Basel) 12(1). Fibrolamellar hepatocellular carcinoma is a primary hepatic tumor that usually appears in young adults. Radical surgery is considered curative for this kind of tumor, so early diagnosis becomes essential for the prognosis of the patients. The main characteristic of this entity is the central scar, which is the center of differential diagnosis. We report the case of a 30-year-old man who was diagnosed with fibrolamellar hepatocellular carcinoma by ultrasonography. Contrast-enhanced CT confirmed this diagnosis, and the patient underwent a [(18)F] fluorocholine PET/CT. Hypermetabolism and the morphology in the nuclear medicine exploration suggest neoplastic nature of the lesion. Radical surgery was performed, and histopathologic analysis was performed, which resulted in focal nodular hyperplasia. Hepatic masses with central scar could have a difficult differential diagnosis, and focal nodular hyperplasia could mimic fibrolamellar hepatocellular carcinoma imaging patterns. These morphofunctional characteristics have not been described in [(18)F] Fluorocholine PET/CT, so there is a need to find out the potential role PET/CT in the differential diagnosis of hepatic mass with central scar.
Sergi, CM 2021Carcinoma of the liver in children and adolescents.Liver Cancer. C. M. Sergi. Brisbane (AU). Liver cancer, predominantly hepatocellular carcinoma, is the second most common cause of cancer-related death in adults. Although infrequent in children, hepatocellular carcinoma is a terrifying diagnosis. Rising levels of obesity and obesity-associated lipid metabolic reprogramming of hepatocytes are increasing the prevalence of lipid-rich hepatocellular carcinoma in young adults. Most pediatric liver cancers occur in otherwise healthy liver, with some exceptions such as progressive familial intrahepatic cholestasis, hereditary tyrosinemia, alpha-1-antitrypsin deficiency, and genetic hemochromatosis. In the last decade, although aggressive multidisciplinary treatments including surgical resection and chemotherapy have remarkably improved patient outcomes in terms of decreased recurrence rate and increased overall survival rate, in children with unresectable liver cancer, the 5-year survival rate is still less than 20%. This chapter provides an overview of malignant epithelial tumors of the liver in children and adolescents. Hepatocellular carcinoma, lipid-rich hepatocellular carcinoma, fibrolamellar carcinoma, and cholangiocellular carcinoma are discussed.
Solipuram, V, M Baretti, AY Kim, LX Chen, JA Fahrner, M Gunay-Aygun, XP Peng, D Hardenbergh, A Ferguson, P Griffith, Y Wang, M Brancati, H Gopalakrishna, T Kato, C Shubert, D Laheru and M Yarchoan 2021Surgical debulking for refractory hyperammonemic encephalopathy in fibrolamellar hepatocellular carcinoma.Hepatology. A 26-year-old male with a two-year history of FLC developed progressive somnolence and disorientation. Treatment history for FLC had included cytotoxic chemotherapy, lenvatinib, and immunotherapy. A CT scan confirmed extensive stage FLC with numerous liver, lung, and pelvic metastasis. Laboratory results showed bilirubin 0.3 mg/dL, creatinine 0.4 mg/dl, leukocytes of 9.5x10(9) /L, hemoglobin 11.2 g/dL, platelets 369x10(9) /L, and ammonia 247 micromol/L (reference range: 0-32 micromol/L). Plasma amino acid analysis revealed relatively low citrulline (14 micromol/L), arginine (32 micromol/L), and ornithine (35 micromol/L). Urinary orotic acid excretion was markedly elevated at 149 mmol/mol creat (reference range: 0.68-3.52 mmol/mol creat).
Sutthatarn, P, CE Morin, J Gartrell, WL Furman, MR Langham, T Santiago and AJ Murphy 2021Bilateral diffuse nodular pulmonary ossification mimicking metastatic disease in a patient with fibrolamellar hepatocellular carcinoma. Children (Basel) 8(3). Pulmonary ossification (PO) is a rare finding, characterized by mature bone formation in the lung parenchyma. We report a 20-year-old female patient diagnosed with fibrolamellar hepatocellular carcinoma (FL-HCC) and bilateral diffuse nodular PO. The patient presented with a unifocal left liver mass and multiple bilateral pulmonary lesions, which were treated as metastatic disease. The patient received neoadjuvant chemotherapy, followed by left hepatectomy, and bilateral staged thoracotomies for clearance of the pulmonary disease. The histology of the pulmonary nodules demonstrated nodular type PO. We present the history, the course of treatment, imaging, and histologic findings of this rare disease process that could mimic metastatic pulmonary disease.
Timchenko, NA 2021Help for sick kids: New insights into hepatoblastoma. Cell Mol Gastroenterol Hepatol 12(1): 350-351.
Torbenson, MS 2021Hepatocellular carcinoma: making sense of morphological heterogeneity, growth patterns, and subtypes.Hum Pathol 112: 86-101. Hepatocellular carcinomas are not a homogenous group of tumors but have multiple layers of heterogeneity. This heterogeneity has been studied for many years with the goal to individualize care for patients and has led to the identification of numerous hepatocellular carcinoma subtypes, defined by morphology and or molecular methods. This article reviews both gross and histological levels of heterogeneity within hepatocellular carcinoma, with a focus on histological findings, reviewing how different levels of histological heterogeneity are used as building blocks to construct morphological hepatocellular carcinoma subtypes. The current best practice for defining a morphological subtype is outlined. Then, the definition for thirteen distinct hepatocellular carcinoma subtypes is reviewed. For each of these subtypes, unresolved issues regarding their definitions are highlighted, including recommendations for these problematic areas. Finally, three methods for improving the research on hepatocellular carcinoma subtypes are proposed: (1) Use a systemic, rigorous approach for defining hepatocellular carcinoma subtypes (four-point model); (2) Once definitions for a subtype are established, it should be followed in research studies, as this common denominator enhances the ability to compare results between studies; and (3) Studies of subtypes will be more effective when morphological and molecular results are used in synergistic and iterative study designs where the results of one approach are used to refine and sharpen the results of the other. These and related efforts to better understand heterogeneity within hepatocellular carcinoma are the most promising avenue for improving patient care by individualizing patient care.
Vij, M and J Calderaro 2021Pathologic and molecular features of hepatocellular carcinoma: An update.World J Hepatol 13(4): 393-410.Morphological diversity and several new distinct pathologic subtypes of hepatocellular carcinoma (HCC) are now well-recognized. Recent advances in tumor genomics and transcriptomics have identified several recurrent somatic/genetic alterations that are closely related with histomorphological subtypes and have therefore, greatly improved our understanding of HCC pathogenesis. Pathologic subtyping allows for a diagnosis which is clinically helpful and can have important implication in patient prognostication as some of these subtypes are extremely aggressive with vascular invasion, early recurrence, and worst outcomes. Several targeted treatments are now being considered in HCC, and the reporting of subtypes may be quite useful for personalized therapeutic purpose. This manuscript reviews the recently identified histomorphological subtypes and molecular alterations in HCC.
Whitlock, RS, C Loo, K Patel, R Bista, JA Goss, A Heczey, O Khan, D Lopez-Terrada, P Masand, H Nguyen, A Mahvash, SA Vasudevan and K Kukreja 2021Transarterial radioembolization treatment as a bridge to surgical resection in pediatric hepatocellular carcinoma. J Pediatr Hematol Oncol. BACKGROUND: Children with unresectable hepatocellular carcinoma (HCC) have a poor prognosis and limited treatment options. Transarterial radioembolization (TARE) using Yttrium-90 (Y90) has emerged as a potential bridge therapy to hepatic resection or transplantation for HCC with very limited studies in children. OBSERVATIONS: Here we present the clinical course of 2 children successfully treated with TARE Y90 for initially unresectable fibrolamellar HCC (FL-HCC) and bridged to partial hemihepatectomy with >1-year overall survival post-TARE. CONCLUSION: Although there have been prior published reports of pediatric patients with HCC being treated with TARE Y90 and some being able to undergo subsequent orthotopic liver transplantation, this is the first report of pediatric HCC patients treated with TARE Y90 as a bridge to nontransplant resections and going on to have >1-year overall survival.
Yang, S, S Lin, K Liu, Y Liu, P Xu, Y Zheng, Y Deng, D Zhang, Z Zhai, N Li, X Ren, Z Dai and H Kang 2021Identification of an immune-related RNA-binding protein signature to predict survival and targeted therapy responses in liver cancer.Genomics 113(2): 795-804. RNA-binding proteins (RBPs) play crucial roles in multiple cancers. However, very few RBPs and their association with immune genes have been systematically studied in liver cancer (LC). We aimed to identify an immune-related RBP signature to predict the survival of LC patients. Bioinformatics methods were used to identify differentially expressed, immune-related, and prognostic RBPs and to develop an immune-related RBP signature based on data from the Cancer Genome Atlas (TCGA) cohort. We obtained eight differentially expressed, immune-related, and prognostic RBPs to construct a risk signature. The signature could effectively distinguish between high- and low-risk patients, and its predictive capacity was validated in the International Cancer Genomics Consortium (ICGC) cohort. We speculated that the high-risk group was more sensitive to targeted therapy. The immune-related RBP signature is an independent prognostic biomarker for LC patients and can expand the application of targeted therapy through patient stratification.
Zack, T, S Maisel, AF O’Neill, MP La Quaglia, M Herman, JJ Knox, A Yaqubie, AP Venook, RJ Mayer, JD Gordan and GK Abou-Alfa 2021Computational extraction and analysis of de-identified medical records to characterize hyperammonemia in patients with fibrolamellar carcinoma (FLC). J Clin Oncol 39: abstr e16169. Background: Rare cancers including FLC make up 25% of adult tumors, but are difficult to study due to low incidence and incomplete case identification. FLC occurs in adolescents and young adults without liver dysfunction. Hyperammonemia has been frequently reported in FLC patients, but is poorly understood. Methods: Data from three clinical trials allowed us to establish the incidence of hyperammonemia (serum ammonia value > 75 µmol/L) in FLC. In these studies, FLC patients received everolimus, estrogen deprivation therapy (EDT) with leuprolide + letrozole or everolimus + EDT (Oncologist. 2020 25(11):925-e1603), ENMD-2076 (Oncologist. 2020 25(12):e1837-e1845), or neratinib (J Clin Oncol 39, 2021 (suppl 3; abstr 310); ammonia was tested prospectively in the latter two studies. To assess impacts of cancer therapy or liver dysfunction, we studied hyperammonemia in FLC and non-FLC patients at UCSF in parallel. Using Natural Language Processing (NLP) of pathology reports and oncology notes from > 2300 liver cancer patients from the last 12 years of UCSF records, we identified a cohort of patients with FLC, contrasting their laboratory data to all UCSF patients with ammonia testing for the last 10 years. We used leiden clustering and umap dimensionality reduction to contrast FLC and other patients to assess the clinical context of hyperammonemia. Results: Data from the 3 trials showed hyperammonemia in 10 of 32 (31.3%) FLC patients during study participation, independent of the therapy received. These patients exhibited hyperammonemia with varying levels, and at different points in their treatment. NLP identified 37 patients with FLC ( < 0.1% of liver cancer patients), with 33% showing hyperammonemia. Across all UCSF patients, we found 24,000 independent visits where ammonia was tested, with > 2400 demonstrating hyperammonemia. Using leidan clustering on all encounters with ammonia > 75 µmol/L, we found distinct subsets of hyperammonemia corresponding to known metabolic and physiologic processes (e.g., fulminant liver failure, tumor lysis syndrome, etc). FLC patients clustered separately from hepatocellular carcinoma patients with hyperammonemic encephalopathy due to cirrhosis.Conclusions: NLP of large EMRs is a valuable tool to study FLC, a rare cancer. Herein, we have defined hyperammonemia as a frequent event in FLC, not directly linked to hepatic dysfunction or individual therapies. Further investigation may determine whether is related to FLC tumor biology.
Zhao, P, Y Lu, C Wang, L Wang, J Li and M Li 2021Clinical, pathological and genetic characteristics of pediatric hepatocellular carcinoma associated with Hepatitis B virus infection.J Hepatocell Carcinoma 8: 361-367. Introduction: Hepatocellular carcinoma (HCC) remains the major challenge in the management of patients with hepatitis B virus (HBV) infection. To date, limited studies have been done on pediatric HBV-associated HCC specifically. Methods: Pediatric patients younger than 16 years with HBV-associated HCC were included in the study. HBV integration detection was performed using a high-throughput viral integration detection (HIVID) method. Results: Among the 13 included pediatric patients, boys predominated (10, 76.9%). The median age at diagnosis of HCC was 13 years and the youngest age was 6 years. Nine patients had initially seronegative hepatitis B e antigen (HBeAg) and 4 had seropositive HBeAg. All patients had cirrhosis and elevated alpha-fetoprotein. Splenomegaly was present in all patients. Intrahepatic HBsAg was not detected in any tumor tissues from 5 patients who underwent biopsy or excision, while it was positive in all matched non-tumor tissues. In the tumor and matched non-tumor tissues from 3 individuals, HBV integration was identified except in the neoplastic specimen from 1 patient. Integration into the reported genes associated with hepatocarcinogenesis was not found in the tumor tissues from the 3 patients. Discussion: Hypervigilance for HCC development is required in HBeAg-negative cirrhotic children. The findings based on the immunohistochemical and genetic results expand the knowledge of pediatric HCC development.
Ziogas, IA, DJ Benedetti, LK Matsuoka, M Izzy, MA Rauf, AK Pai, CE Bailey and SP Alexopoulos 2021Surgical management of pediatric hepatocellular carcinoma: An analysis of the National Cancer Database. J Pediatr Surg 56(4): 772-777. PURPOSE: This study evaluates overall survival (OS) between liver transplantation (LT) and liver resection (LR), while assessing the effect of margin status, in children with hepatocellular carcinoma (HCC). METHODS: The National Cancer Database was queried (2004-2015) for children (<18years) with non-metastatic HCC undergoing surgery. RESULTS: One hundred six children with HCC treated surgically (LT 34, LR 72) were identified. For T1 stage, no difference in OS was observed for LT vs. margin-negative liver resection [LR(-)] (log-rank, p=0.47). For T2/T3/T4 stage, no difference in OS was observed for LT vs. LR(-) (log-rank, p=0.08); both subgroups exhibited superior OS vs. margin-positive liver resection [LR(+)] (log-rank, LT vs. LR(+): p=0.001 and LR(-) vs. LR(+): p=0.04). On multivariable Cox regression: (i) histology (fibrolamellar vs. not) and T stage (T1 vs. T2/T3/T4) were not associated with OS (both p=0.06), (ii) chemotherapy and size >5cm were not associated with OS (both p>/=0.42), (iii) when compared to LT, both LR(-) (p=0.03) and LR(+) (p=0.001) were associated with increased likelihood of mortality. CONCLUSION: Although margin-negative resection may be obtained with LT or LR, early LT consultation is warranted for children at high risk of LR(+) regardless of Milan criteria due to the negative impact of LR(+) on OS. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: III.
Abou-Alfa, GK, R Mayer, AP Venook, AF O'Neill, MS Beg, M LaQuaglia, PT Kingham, R Kobos, O Basturk, C Brennan, A Yopp, JJ Harding, S Leong, J Crown, E Hoti, G Leonard, M Ly, M Bradley, E Valentino, D Markowitz, A Zukiwski, K Ren and JD Gordan 2020Phase II multicenter, open-label study of oral ENMD-2076 for the treatment of patients with advanced fibrolamellar carcinoma.Oncologist 25(12): e1837-e1845. LESSONS LEARNED: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. BACKGROUND: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. METHODS: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study. RESULTS: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076. CONCLUSION: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.
Alison, MR 2020The cellular origins of cancer with particular reference to the gastrointestinal tract. Int J Exp Pathol. Stem cells or their closely related committed progenitor cells are the likely founder cells of most neoplasms. In the continually renewing and hierarchically organized epithelia of the oesophagus, stomach and intestine, homeostatic stem cells are located at the beginning of the cell flux, in the basal layer of the oesophagus, the isthmic region of gastric oxyntic glands and at the bottom of gastric pyloric-antral glands and colonic crypts. The introduction of mutant oncogenes such as Kras(G12D) or loss of Tp53 or Apc to specific cell types expressing the likes of Lgr5 and Mist1 can be readily accomplished in genetically engineered mouse models to initiate tumorigenesis. Other origins of cancer are discussed including 'reserve' stem cells that may be activated by damage or through disruption of morphogen gradients along the crypt axis. In the liver and pancreas, with little cell turnover and no obvious stem cell markers, the importance of regenerative hyperplasia associated with chronic inflammation to tumour initiation is vividly apparent, though inflammatory conditions in the renewing populations are also permissive for tumour induction. In the liver, hepatocytes, biliary epithelial cells and hepatic progenitor cells are embryologically related, and all can give rise to hepatocellular carcinoma and cholangiocarcinoma. In the exocrine pancreas, both acinar and ductal cells can give rise to pancreatic ductal adenocarcinoma (PDAC), although the preceding preneoplastic states are quite different: acinar-ductal metaplasia gives rise to pancreatic intraepithelial neoplasia culminating in PDAC, while ducts give rise to PDAC via. mucinous cell metaplasia that may have a polyclonal origin.
Assi, HA, S Mukherjee, M Machiorlatti, S Vesely, V Pareek and H Hatoum 2020Predictors of outcome in patients with fibrolamellar carcinoma: Analysis of the national cancer database.Anticancer Res 40(2): 847-855. BACKGROUND: Fibrolamellar carcinoma (FLC) is a very rare liver tumor. We aimed to retrospectively analyze the clinicopathological factors and treatment modalities affecting overall survival (OS) in FLC. The objective of the study was to identify predictors of survival in FLC. PATIENTS AND METHODS: Using the National Cancer Database, we identified 496 patients diagnosed with FLC between 2004 and 2015. Clinicopathological, treatment, and survival data were collected. RESULTS: Hepatic resection was performed on 254 (51.2%) patients, liver-directed therapy on 13 (2.6%) patients, and liver transplantation on 15 (3.0%) patients. Median OS by stage were 142.1, 87.2, 32.3, and 14.1 months for stages 1, 2, 3, and 4, respectively. Metastatectomy was not associated with superior median OS (23.4 vs. 10.5 months, p=0.163). Age
Balbeur, S, A Dumortier, J Mergen, L Libbrecht, M Torbenson, C Boulanger, M de Ville de Goyet, A Van Damme and B Brichard 2020DNAJB1-PRKACA-positive metastatic fibrolamellar carcinoma with unknown primary in a pediatric patient. Pediatr Blood Cancer 67(2): e28060. Fibrolamellar carcinoma (FLC) is a rare variant of hepatocellular carcinoma, occurring in children and young adults without underlying liver disease. The diagnosis is based on morphological characteristics of the tumor, supplemented by immunohistochemistry and/or genetic testing. Recently, the presence of a characteristic DNAJB1-PRKACA fusion gene has been associated with FLC. Herein, we report a case of FLC presenting as peritoneal carcinomatosis in a 14-year-old female. Interestingly, no liver tumor was seen on imaging, and an alternative possibility is that the tumor arose outside the liver as a hepatoid carcinoma with fibrolamellar features.
Cebrian, A, A Elosua, B Gonzalez-de la Higuera, R Irisarri and D Ruiz-Clavijo 2020Clavicle tumor as an initial manifestation of fibrolamellar hepatocellular carcinoma.Rev Gastroenterol Mex (Engl Ed) 85(1): 104-106.
D'Souza, AM, AJ Towbin, A Gupta, M Alonso, JD Nathan, A Bondoc, G Tiao and JI Geller 2020Clinical heterogeneity of pediatric hepatocellular carcinoma. Pediatr Blood Cancer 67(6): e28307. BACKGROUND: Hepatocellular carcinoma (HCC) is often a chemoresistant neoplasm with a poor prognosis. Pediatric HCC may reflect unique biological and clinical heterogeneity. PROCEDURE: An IRB-approved retrospective institutional review of patients with HCC treated between 2004 and 2015 was undertaken. Clinical, radiographic, and histologic data were collected from all patients. RESULTS: Thirty-two patients with HCC, median age 11.5 years (range 1-20) were identified. Seventeen patients had a genetic or anatomic predisposition. Histology was conventional HCC (25) and fibrolamellar HCC (7). Evans staging was 1 (12); 2 (1); 3 (10); 4 (9). Sixteen patients underwent resection at diagnosis and five patients after neoadjuvant chemotherapy. Surgical procedures included liver transplantation (LT, 11), hemihepatectomy (9), and segmentectomy (1). Eighteen patients had medical therapy (13 neoadjuvant, 5 adjuvant). Most common initial medical therapy included sorafenib alone (7) and cisplatin/doxorubicin-based therapy (8). Overall, 14 (43.8%) patients survived with a median follow-up of 58.8 months (range 26.5-157.6). Cause of death was most often linked to lack of primary tumor surgery (11). Of the survivors, Evans stage was 1 (11), 2 (1), and 3 (2, both treated with LT). Four of 18 patients (22%) who received medical therapy, 8 of 17 patients with a predisposition (47%), and 14 of 21 patients (66%) who underwent surgery remain alive. CONCLUSIONS: Genetic and anatomic predisposing conditions were seen in over half of this cohort. Evans stage 1 or 2 disease was linked to improved survival. LT trended toward improved survival. Use of known chemotherapy agents may benefit a smaller group of pediatric HCC and warrants formal prospective study through cooperative group trials.
De Toni, EN and D Roessler 2020Using dual checkpoint blockade to treat fibrolamellar hepatocellular carcinoma.Gut 69(11): 2056-2058.
Dinh, TA, R Sritharan, FD Smith, AB Francisco, RK Ma, RP Bunaciu, M Kanke, CG Danko, AP Massa, JD Scott and P Sethupathy 2020Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal candidate oncogenic pathways and therapeutic vulnerabilities. Cell Rep 31(2): 107509. Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the chromatin regulatory landscape and the genes most critical for tumor cell survival remain unclear. Here, we use chromatin run-on sequencing to discover approximately 7,000 enhancers and 141 enhancer hotspots activated in FLC relative to nonmalignant liver. Bioinformatic analyses reveal aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also define the genes most strongly associated with hotspots of FLC enhancer activity, including CA12 and SLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduce cell viability and/or significantly enhance the effect of the MEK inhibitor cobimetinib. These findings highlight molecular targets for drug development, as well as drug combination approaches.
El Dika, I, AS Bowman, MF Berger, M Capanu, JF Chou, R Benayed, A Zehir, J Shia, EM O'Reilly, DS Klimstra, DB Solit and GK Abou-Alfa 2020Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver.Cancer 126(18): 4126-4135. BACKGROUND: Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in-frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets. METHODS: Archival fresh, formalin-fixed, paraffin-embedded samples from patients with FLC who prospectively consented to an institutional review board-approved protocol were analyzed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA-Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations. RESULTS: A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1-PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK-IMPACT did not detect the fusion, its presence was confirmed by targeted RNA-Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6-153 months). The 3-year overall survival rate was 84% (95% CI, 61%-93%). CONCLUSIONS: The DNAJB1-PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1-PRKACA fusion transcript or any therapeutic target identified from next-generation sequencing in patients with FLC.
El Dika, I, RJ Mayer, AP Venook, M Capanu, MP LaQuaglia, R Kobos, AF O'Neill, JF Chou, M Ly, C Ang, EM O'Reilly, JD Gordan and GK Abou-Alfa 2020A multicenter randomized three-arm Phase II study of (1) everolimus, (2) estrogen deprivation therapy (EDT) with leuprolide + letrozole, and (3) everolimus + EDT in patients with unresectable fibrolamellar carcinoma.Oncologist 25(11): 925-e1603. LESSONS LEARNED: FLC is a complex cancer with many implicated oncogenic pathways. Single or dual targeting does not appear to alter the natural history of the cancer, and novel therapeutics are needed. Estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma. The study drugs were well tolerated when administered as single agents or in combination in this patient population. This study demonstrates that, despite the rarity of FLC, multicenter therapeutic clinical trials are feasible and support the value of this consortium. BACKGROUND: Fibrolamellar carcinoma (FLC) is an uncommon malignancy in young people and is sometimes associated with pregnancy and oral contraceptive use. Immunohistochemical staining and genetic profiling of FLC tumor specimens have revealed aromatase overexpression. The overexpression of mTOR and S6 kinase has been noted in 25% of FLC. On the basis of interaction between estrogen and the PI3K/Akt/mTOR pathway, we hypothesized that suppression of estrogen and mTOR signaling could have antineoplastic activity in FLC. METHODS: Patients were randomized to arm A (everolimus), arm B (letrozole/leuprolide; estrogen deprivation therapy [EDT]), or arm C (everolimus/letrozole/leuprolide). Upon disease progression, patients in arm A or B could proceed to part 2 (everolimus/letrozole/leuprolide). The primary endpoint was progression-free survival (PFS) at 6 months (PFS6) assessed using a Simon's minimax two-stage design, hypothesizing an improvement in PFS6 from 40% to 64% with the study regimen. RESULTS: Twenty-eight patients were enrolled. An unplanned analysis was performed because of perceived concern for lack of efficacy. Stable disease was observed in 9 of 26 evaluable patients (35%). PFS6 was 0%. Median overall survival (OS) was 12.4 months (95% confidence interval [CI], 7.4-20.9) for the whole study cohort. Grade 3 adverse events in >/=10% of patients were nausea (11%), vomiting (11%), anemia (11%), elevated aspartate transaminase (AST; 32%), alanine transaminase (ALT; 36%), and alkaline phosphatase (14%). All 28 patients experienced an event for PFS outcome, and four deaths were due to disease progression. CONCLUSION: Neither EDT nor mTOR inhibition improved outcomes in FLC. Other treatment strategies are needed.
Erickson, LA 2020Fibrolamellar carcinoma.Mayo Clin Proc 95(6): 1298-1299.
Geoerger, B, CM Zwaan, LV Marshall, J Michon, F Bourdeaut, M Casanova, N Corradini, G Rossato, M Farid-Kapadia, CS Shemesh, KE Hutchinson, F Donaldson, M Liao, H Caron and T Trippett 2020Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study. Lancet Oncol 21(1): 134-144. BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression. METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with, number NCT02541604. FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses). INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. FUNDING: F Hoffmann-La Roche.
Gliksberg, A, C O'Grady and P Kent 2020Novel systemic therapies in hard to treat fibrolamellar hepatocellular carcinoma. J Clin Oncol. 38: e16653-e16653. Background: Fibrolamellar Carcinoma (FLC) is a very rare liver malignancy of young adults without underlying liver disease (0.02 per 100,000 in the US).. Complete resection is the primary therapy, but recurrence rates are still > 50%. Currently there are no established systemic treatments, especially for high-risk disease (unresectable, relapse, progression, or metastatic disease). At our institution triple therapy “TT” with Nivolumab/5FU/Interferon ?-2b is our first line, followed by other novel combination therapies such as Gemcitabine/Oxaliplatin/Lenvantinib (GOL) or Nivolumb/Lenvantinib/Quecertin (NLQ). Objective: To evaluate the tolerability and early response of multi-agent systemic therapies in patients with high-risk FLC. Methods: Data from all patients with FLC who received systemic therapies from 5/2018 to 2/2020 was reviewed to assess tolerability, survival and toxicity. Results: Nineteen patients were treated with systemic therapies of which 16 (10F, 6M median age of 19) were evaluable based on follow up scans. Between our 16 patients they had relapsed 28 times, 12 had metastatic disease and 7 had tried 2+ systemic therapies. RECIST 1.1 objective response (CR+PR) and tumor control (CR+PR+SD) are 44% and 69%. Since starting multi-agent therapy, all 6 patients who had previously been treated with monotherapy, have already exceeded their previous longest time to progression. Thirteen patients were treated with “TT” [12.5 median cycles (6-38)]. Three patients were treated with NLQ including 2 who failed TT. Of these, the 1 evaluable patient achieved CR. Two patients were treated with GOL, 1 who failed TT and one who was post liver transplant, both had sustained PR of 6 and 9 months. Subsequently one died and one achieved CR. For the 6 patients who achieved remission before or during therapy, only 1 has relapsed. To date the period of response is already 68% longer than the previous best length of response. There was 1 withdrawal due to grade 3 colitis and 2 dose adjustments. All experienced mild adverse effects, most commonly fever, headache, and hypertension, with 3 patients with grade 3 toxicities. Conclusions: FLC is a devastating disease with patients often relapsing even after successful surgical remission. Currently there is a need for tolerable systemic therapies. Although at our institution, TT is our frontline therapy, there are other combinations of immunochemotherapies that we have used to treat FLC with preliminary success and minimal toxicities. Our early results show that multi-agent systemic therapy in hard-to-treat FLC is worthy of further study.
Golkowski, M, HT Lau, M Chan, H Kenerson, VN Vidadala, A Shoemaker, DJ Maly, RS Yeung, TS Gujral and SE Ong 2020Pharmacoproteomics identifies kinase pathways that drive the epithelial-mesenchymal transition and drug resistance in hepatocellular carcinoma. Cell Syst 11(2): 196-207 e197. Hepatocellular carcinoma (HCC) is a complex and deadly disease lacking druggable genetic mutations. The limited efficacy of systemic treatments for advanced HCC implies that predictive biomarkers and drug targets are urgently needed. Most HCC drugs target protein kinases, indicating that kinase-dependent signaling networks drive HCC progression. To identify HCC signaling networks that determine responses to kinase inhibitors (KIs), we apply a pharmacoproteomics approach integrating kinome activity in 17 HCC cell lines with their responses to 299 KIs, resulting in a comprehensive dataset of pathway-based drug response signatures. By profiling patient HCC samples, we identify signatures of clinical HCC drug responses in individual tumors. Our analyses reveal kinase networks promoting the epithelial-mesenchymal transition (EMT) and drug resistance, including a FZD2-AXL-NUAK1/2 signaling module, whose inhibition reverses the EMT and sensitizes HCC cells to drugs. Our approach identifies cancer drug targets and molecular signatures of drug response for personalized oncology.
Golkowski, M, VN Vidadala, HT Lau, A Shoemaker, M Shimizu-Albergine, J Beavo, DJ Maly and SE Ong 2020Kinobead/LC-MS phosphokinome profiling enables rapid analyses of kinase-dependent cell signaling networks. J Proteome Res 19(3): 1235-1247. Kinase-catalyzed protein phosphorylation is fundamental to eukaryotic signal transduction, regulating most cellular processes. Kinases are frequently dysregulated in cancer, inflammation, and degenerative diseases, and because they can be inhibited with small molecules, they became important drug targets. Accordingly, analytical approaches that determine kinase activation states are critically important to understand kinase-dependent signal transduction and to identify novel drug targets and predictive biomarkers. Multiplexed inhibitor beads (MIBs or kinobeads) efficiently enrich kinases from cell lysates for liquid chromatography-mass spectrometry (LC-MS) analysis. When combined with phosphopeptide enrichment, kinobead/LC-MS can also quantify the phosphorylation state of kinases, which determines their activation state. However, an efficient kinobead/LC-MS kinase phospho-profiling protocol that allows routine analyses of cell lines and tissues has not yet been developed. Here, we present a facile workflow that quantifies the global phosphorylation state of kinases with unprecedented sensitivity. We also found that our kinobead/LC-MS protocol can measure changes in kinase complex composition and show how these changes can indicate kinase activity. We demonstrate the utility of our approach in specifying kinase signaling pathways that control the acute steroidogenic response in Leydig cells; this analysis establishes the first comprehensive framework for the post-translational control of steroid biosynthesis.
Hirsch, TZ, A Negulescu, B Gupta, S Caruso, B Noblet, G Couchy, Q Bayard, L Meunier, G Morcrette, JY Scoazec, JF Blanc, G Amaddeo, JC Nault, P Bioulac-Sage, M Ziol, A Beaufrere, V Paradis, J Calderaro, S Imbeaud and J Zucman-Rossi 2020BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA. J Hepatol 72(5): 924-936. BACKGROUND & AIMS: DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) that occurs in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered. METHODS: A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome sequencing. Western blots were performed to validate genomic discoveries. Results were validated using the TCGA database. RESULTS: Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors, which all had mutations or translocations inactivating BAP1, the gene encoding BRCA1-associated protein-1. Like FLC, BAP1-HCC were significantly enriched in females, patients with a lack of chronic liver disease, and fibrotic tumors compared to non-BAP1 HCC. However, patients were older and had a poorer prognosis than those with FLC. BAP1 tumors were immune hot, showed progenitor features and did not show DNAJB1-PRKACA fusion, while almost none of these tumors had mutations in CTNNB1, TP53 and TERT promoter. In contrast, 80% of the BAP1 tumors showed a chromosome gain of PRKACA at 19p13, combined with a loss of PRKAR2A (coding for the inhibitory regulatory subunit of PKA) at 3p21, leading to a high PRKACA/PRKAR2A ratio at the mRNA and protein levels. CONCLUSION: We have characterized a subgroup of BAP1-driven HCC with fibrolamellar-like features and a dysregulation of the PKA pathway, which could be at the root of the clinical and histological similarities between BAP1 tumors and DNAJB1-PRKACA FLCs. LAY SUMMARY: Herein, we have defined a homogeneous subgroup of hepatocellular carcinomas in which the BAP1 gene is inactivated. This leads to the development of cancers with features similar to those of fibrolamellar carcinoma. These tumors more frequently develop in females without chronic liver disease or cirrhosis. The presence of PKA activation and T cell infiltrates suggest that these tumors could be treated with PKA inhibitors or immunomodulators.
Jabbari, N, HL Kenerson, C Lausted, X Yan, C Meng, KM Sullivan, P Baloni, D Bergey, VG Pillarisetty, LE Hood, RS Yeung and Q Tian 2020Modulation of immune checkpoints by chemotherapy in human colorectal liver metastases. Cell Rep Med 1(9): 100160. Metastatic colorectal cancer (CRC) is a major cause of cancer-related death, and incidence is rising in younger populations (younger than 50 years). Current chemotherapies can achieve response rates above 50%, but immunotherapies have limited value for patients with microsatellite-stable (MSS) cancers. The present study investigates the impact of chemotherapy on the tumor immune microenvironment. We treat human liver metastases slices with 5-fluorouracil (5-FU) plus either irinotecan or oxaliplatin, then perform single-cell transcriptome analyses. Results from eight cases reveal two cellular subtypes with divergent responses to chemotherapy. Susceptible tumors are characterized by a stemness signature, an activated interferon pathway, and suppression of PD-1 ligands in response to 5-FU+irinotecan. Conversely, immune checkpoint TIM-3 ligands are maintained or upregulated by chemotherapy in CRC with an enterocyte-like signature, and combining chemotherapy with TIM-3 blockade leads to synergistic tumor killing. Our analyses highlight chemomodulation of the immune microenvironment and provide a framework for combined chemo-immunotherapies.
Jewell, ML, JR Gibson, CD Guy, J Hyun, K Du, SH Oh, RT Premont, DS Hsu, T Ribar, SG Gregory and AME Diehl 2020Single-cell RNA sequencing identifies Yes-Associated Protein 1-dependent hepatic mesothelial progenitors in fibrolamellar carcinoma. Am J Pathol 190(1): 93-107. Fibrolamellar carcinoma (FLC) is characterized by in-frame fusion of DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1) with protein kinase cAMP-activated catalytic subunit alpha (PRKACA) and by dense desmoplasia. Surgery is the only effective treatment because mechanisms supporting tumor survival are unknown. We used single-cell RNA sequencing to characterize a patient-derived FLC xenograft model and identify therapeutic targets. Human FLC cells segregated into four discrete clusters that all expressed the oncogene Yes-associated protein 1 (YAP1). The two communities most enriched with cells coexpressing FLC markers [CD68, A-kinase anchoring protein 12 (AKAP12), cytokeratin 7, epithelial cell adhesion molecule (EPCAM), and carbamoyl palmitate synthase-1] also had the most cells expressing YAP1 and its proproliferative target genes (AREG and CCND1), suggesting these were proliferative FLC cell clusters. The other two clusters were enriched with cells expressing profibrotic YAP1 target genes, ACTA2, ELN, and COL1A1, indicating these were fibrogenic FLC cells. All clusters expressed the YAP1 target gene and mesothelial progenitor marker mesothelin, and many mesothelin-positive cells coexpressed albumin. Trajectory analysis predicted that the four FLC communities were derived from a single cell type transitioning among phenotypic states. After establishing a novel FLC cell line that harbored the DNAJB1-PRKACA fusion, YAP1 was inhibited, which significantly reduced expression of known YAP1 target genes as well as cell growth and migration. Thus, both FLC epithelial and stromal cells appear to arise from DNAJB1-PRKACA fusion in a YAP1-dependent liver mesothelial progenitor, identifying YAP1 as a target for FLC therapy.
Karam, C, IU Haque, M Fewtrell and A Das 2020Fibrolamellar hepatocellular carcinoma with paraneoplastic neuropsychiatric manifestations.ANZ J Surg 90(10): 2114-2115.
Kelley, RK, WO J, S Hazra, F Benzaghou, T Yau, AL Cheng and L Rimassa 2020Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design.Future Oncol 16(21): 1525-1536. Cabozantinib is an oral tyrosine kinase inhibitor that targets VEGFR, MET and the TAM (TYRO3, AXL, MER) family of kinase receptors. In addition to their role in tumor growth and angiogenesis, cabozantinib targets promote an immune-suppressive microenvironment. Cabozantinib is approved as single-agent therapy for patients with advanced hepatocellular carcinoma who received prior sorafenib. Owing to its antitumor and immunomodulatory properties, cabozantinib is being developed in combination with immune checkpoint inhibitors. Early studies of these combinations have shown promising antitumor activity and tolerability in patients with solid tumors. Here, we describe the rationale and design of COSMIC-312, a Phase III study evaluating the safety and efficacy of cabozantinib in combination with atezolizumab (anti-PD-L1 monoclonal antibody) versus sorafenib for treatment-naive patients with advanced hepatocellular carcinoma. Registration: NCT03755791.
Kenerson, HL, KM Sullivan, YD Seo, KM Stadeli, C Ussakli, X Yan, C Lausted, VG Pillarisetty, JO Park, KJ Riehle, M Yeh, Q Tian and RS Yeung 2020Tumor slice culture as a biologic surrogate of human cancer.Ann Transl Med 8(4): 114. BACKGROUND: The tumor microenvironment (TME) is critical to every aspect of cancer biology. Organotypic tumor slice cultures (TSCs) preserve the original TME and have demonstrated utility in predicting drug sensitivity, but the association between clinicopathologic parameters and in vitro TSC behavior has not been well-defined. METHODS: One hundred and eight fresh tumor specimens from liver resections at a tertiary academic center were procured and precisely cut with a Vibratome to create 250 mum x 6 mm slices. These fixed-dimension TSCs were grown on polytetrafluoroethylene inserts, and their metabolic activities were determined by a colorimetric assay. Correlation between baseline activities and clinicopathologic parameters was assessed. Tissue CEA mRNA expression was determined by RNAseq. RESULTS: By standardizing the dimensions of a slice, we found that adjacent tumor slices have equivalent metabolic activities, while those derived from different tumors exhibit >30-fold range in baseline MTS absorbances, which correlated significantly with the percentage of tumor necrosis based on histologic assessment. Extending this to individual cancers, we were able to detect intra-tumoral heterogeneity over a span of a few millimeters, which reflects differences in tumor cell density and Ki-67 positivity. For colorectal cancers, tissue CEA expression based on RNAseq of tumor slices was found to correlate with clinical response to chemotherapies. CONCLUSIONS: We report a standardized method to assess and compare human cancer growth ex vivo across a wide spectrum of tumor samples. TSC reflects the state of tumor behavior and heterogeneity, thus providing a simple approach to study of human cancers with an intact TME.
Kim, H, M Jang and YN Park 2020Histopathological variants of hepatocellular carcinomas: An update according to the 5th edition of the WHO classification of digestive system tumors.Journal of Liver Cancer 20(1): 17-24. Hepatocellular carcinoma (HCC) is heterogeneous in pathogenesis, phenotype and biological behavior. Various histopathological features of HCC had been sporadically described, and with the identification of common molecular alterations of HCC and its genomic landscape over the last decade, morpho-molecular correlation of HCC has become possible. As a result, up to 35% of HCCs can now be classified into histopathological variants, many of which have unique molecular characteristics. This review will provide an introduction to the variously described histopathological variants of HCC in the updated WHO Classification of Digestive System Tumor.
Kovac, JD, T Milovanovic, V Dugalic and I Dumic 2020Pearls and pitfalls in magnetic resonance imaging of hepatocellular carcinoma.World J Gastroenterol 26(17): 2012-2029. Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, which usually arises in cirrhotic liver. When the typical enhancement pattern, consisting of late arterial hyperenhancement followed by washout, is present in nodules larger than 1 cm, HCC can be confidently diagnosed without the need for tissue biopsy. Nevertheless, HCC can display an atypical enhancement pattern, either as iso or hypovascular lesion, or hypervascular lesion without washout. Not only the enhancement pattern of HCC could be atypical, but also a variety of histological types of HCC, such as steatotic, scirrhous, fibrolamellar, or combined hepatocellular-cholangiocellular carcinoma could raise diagnostic dilemmas. In addition, distinct morphological types of HCC or different growth pattern can occur. Awareness of these atypical and rare HCC presentations on magnetic resonance imaging is important for accurate differentiation from other focal liver lesions and timely diagnosis, which allows optimal treatment of patients.
Kyziridis, D, A Kalakonas, K Zarambouka, C Hristakis and AK Tentes 2020Cytoreductive surgery and HIPEC for recurrent fibrolamellar hepatocellular carcinoma with peritoneal carcinomatosis.J Gastrointest Cancer 51(1): 300-303.
La Bella, T, S Imbeaud, C Peneau, I Mami, S Datta, Q Bayard, S Caruso, TZ Hirsch, J Calderaro, G Morcrette, C Guettier, V Paradis, G Amaddeo, A Laurent, L Possenti, L Chiche, P Bioulac-Sage, JF Blanc, E Letouze, JC Nault and J Zucman-Rossi 2020Adeno-associated virus in the liver: natural history and consequences in tumour development. Gut 69(4): 737-747. OBJECTIVE: Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35%-80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterise the natural history of AAV infection in the liver and its consequence in tumour development. DESIGN: Viral DNA was quantified in tumour and non-tumour liver tissues of 1461 patients. Presence of episomal form and viral mRNA expression were analysed using a DNAse/TaqMan-based assay and quantitative RT-PCR. In silico analyses using viral capture data explored viral variants and new clonal insertions. RESULTS: AAV DNA was detected in 21% of the patients, including 8% of the tumour tissues, equally distributed in two major viral subtypes: one similar to AAV2, the other hybrid between AAV2 and AAV13 sequences. Episomal viral forms were found in 4% of the non-tumour tissues, frequently associated with viral RNA expression and human herpesvirus type 6, the candidate natural AAV helper virus. In 30 HCC, clonal AAV insertions were recurrently identified in CCNA2, CCNE1, TERT, TNFSF10, KMT2B and GLI1/INHBE. AAV insertion triggered oncogenic overexpression through multiple mechanisms that differ according to the localisation of the integration site. CONCLUSION: We provided an integrated analysis of the wild-type AAV infection in the liver with the identification of viral genotypes, molecular forms, helper virus relationship and viral integrations. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.
Lamarca, A, M Frizziero, A Fulton, MG McNamara, R Filobbos, RA Hubner, S Wardell and JW Valle 2020Fibrolamellar carcinoma: Challenging the challenge. Eur J Cancer 137: 144-147. Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon alpha-2B (IFN-alpha-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-alpha-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-alpha-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC.
Lambrecht, J, LA van Grunsven and F Tacke 2020Current and emerging pharmacotherapeutic interventions for the treatment of liver fibrosis. Expert Opin Pharmacother 21(13): 1637-1650. INTRODUCTION: Chronic liver disease is due to various causes of persistent liver damage and will eventually lead to the development of liver fibrosis. If no treatment is initiated, this condition may progress to cirrhosis and hepatocellular carcinoma. Current treatments comprise the elimination of the cause of injury, such as by lifestyle changes, alcohol abstinence, and antiviral agents. However, such etiology-driven therapy is often insufficient in patients with late-stage fibrosis/cirrhosis, therefore maintaining the need for efficient antifibrotic pharmacotherapeutic interventions. AREAS COVERED: The authors discuss the recent advances in the development of antifibrotic drugs, which target various pathways of the fibrogenesis process, including cell death, inflammation, gut-liver axis, and myofibroblast activation. Due to the significant burden of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), various agents which specifically target metabolic pathways and their related receptors/ligands have been developed. For some of them, e.g., obeticholic acid, advanced stage clinical trials indicate antifibrotic efficacy in NAFLD and NASH. EXPERT OPINION: Significant advances have been made in the development of novel antifibrotic pharmacotherapeutics. The authors expect that the development of combinatorial therapies, which combine compounds that target various pathways of fibrosis progression, will have a major impact as future etiology-independent therapies.
Lemekhova, A, D Hornuss, G Polychronidis, P Mayer, C Rupp, T Longerich, KH Weiss, M Buchler, A Mehrabi and K Hoffmann 2020Clinical features and surgical outcomes of fibrolamellar hepatocellular carcinoma: retrospective analysis of a single-center experience.World J Surg Oncol 18(1): 93. BACKGROUND: Clinicopathological features and surgical outcomes of patients with fibrolamellar hepatocellular carcinoma (FL-HCC) are underreported. The aim of this study is to describe clinical characteristics and surgical outcomes for patients with this rare tumor to raise awareness among clinicians and surgeons. METHODS: Retrospective review of records of a tertiary referral center and specialized liver unit was performed. Out of 3623 patients who underwent liver resection, 366 patients received surgical treatment for HCC; of them, eight (2.2%) had FL-HCC and were resected between October 2001 and December 2018. RESULTS: Eight patients (3 males and 5 females) with FL-HCC (median age 26 years) underwent primary surgical treatment. All patients presented with unspecific symptoms or were diagnosed as incidental finding. No patient had cirrhosis or other underlying liver diseases. Coincidentally, three patients (37.5%) had a thromboembolic event prior to admission. The majority of patients had BCLC stage C and UICC stage IIIB/IVA; four patients (50%) presented with lymph node metastases. The median follow-up period was 33.5 months. The 1-year survival was 71.4%, and 3-year survival was 57.1%. Median survival was at 36.4 months. Five patients (62.5%) developed recurrent disease after a median disease-free survival of 9 months. Two patients (25.0%) received re-resection. CONCLUSION: FL-HCC is a rare differential diagnosis of liver masses in young patients. Since the prognosis is limited, patients with incidental liver tumors or lesions with suspicious features in an otherwise healthy liver should be presented at a specialized hepatobiliary unit. Thromboembolism might be an early paraneoplastic symptom and needs to be elucidated further in the context of FL-HCC.
Lu, TW, PC Aoto, JH Weng, C Nielsen, JN Cash, J Hall, P Zhang, SM Simon, MA Cianfrocco and SS Taylor 2020Structural analyses of the PKA RIIbeta holoenzyme containing the oncogenic DnaJB1-PKAc fusion protein reveal protomer asymmetry and fusion-induced allosteric perturbations in fibrolamellar hepatocellular carcinoma.PLoS Biol 18(12): e3001018. When the J-domain of the heat shock protein DnaJB1 is fused to the catalytic (C) subunit of cAMP-dependent protein kinase (PKA), replacing exon 1, this fusion protein, J-C subunit (J-C), becomes the driver of fibrolamellar hepatocellular carcinoma (FL-HCC). Here, we use cryo-electron microscopy (cryo-EM) to characterize J-C bound to RIIbeta, the major PKA regulatory (R) subunit in liver, thus reporting the first cryo-EM structure of any PKA holoenzyme. We report several differences in both structure and dynamics that could not be captured by the conventional crystallography approaches used to obtain prior structures. Most striking is the asymmetry caused by the absence of the second cyclic nucleotide binding (CNB) domain and the J-domain in one of the RIIbeta:J-C protomers. Using molecular dynamics (MD) simulations, we discovered that this asymmetry is already present in the wild-type (WT) RIIbeta2C2 but had been masked in the previous crystal structure. This asymmetry may link to the intrinsic allosteric regulation of all PKA holoenzymes and could also explain why most disease mutations in PKA regulatory subunits are dominant negative. The cryo-EM structure, combined with small-angle X-ray scattering (SAXS), also allowed us to predict the general position of the Dimerization/Docking (D/D) domain, which is essential for localization and interacting with membrane-anchored A-Kinase-Anchoring Proteins (AKAPs). This position provides a multivalent mechanism for interaction of the RIIbeta holoenzyme with membranes and would be perturbed in the oncogenic fusion protein. The J-domain also alters several biochemical properties of the RIIbeta holoenzyme: It is easier to activate with cAMP, and the cooperativity is reduced. These results provide new insights into how the finely tuned allosteric PKA signaling network is disrupted by the oncogenic J-C subunit, ultimately leading to the development of FL-HCC.
Maynard, H, ZK Stadler, MF Berger, DB Solit, M Ly, MA Lowery, D Mandelker, L Zhang, E Jordan, I El Dika, Y Kemel, M Ladanyi, ME Robson, EM O'Reilly and GK Abou-Alfa 2020Germline alterations in patients with biliary tract cancers: A spectrum of significant and previously underappreciated findings.Cancer 126(9): 1995-2002. BACKGROUND: With limited information on germline mutations in biliary tract cancers, this study performed somatic and germline testing for patients at Memorial Sloan Kettering Cancer Center with known biliary tract carcinoma with the aim of determining the frequency and range of pathogenic germline alterations (PGAs). METHODS: Patients with biliary tract carcinoma were consented for somatic tumor and matched blood testing of up to 468 genes via the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing platform. A germline variant analysis was performed on a panel of up to 88 genes associated with an increased predisposition for cancer. Demographic and diagnostic details were collected. RESULTS: Germline mutations were tested in 131 patients. Intrahepatic cholangiocarcinoma was the most common cancer (63.4%), and it was followed by gallbladder adenocarcinoma (16.8%), extrahepatic cholangiocarcinoma (16%), and otherwise unspecified biliary tract cancer (3.8%). Known and likely PGAs were present in 21 patients (16.0%), with 9.9% harboring a PGA in a high/moderate-penetrance cancer predisposition gene. Among high-penetrance cancer susceptibility genes, PGAs were most commonly observed in BRCA1 and BRCA2 (33.3%), which made up 5.3% of the entire cohort, and they were followed by PALB2, BAP1, and PMS2. Mutations in ATM, MITF, and NBN, moderate-penetrance cancer susceptibility genes, were identified in 1 patient each. There was no observed difference in the types of mutations among the subtypes of biliary tract cancer. CONCLUSIONS: The frequency of PGAs found was comparable to existing data on the prevalence of germline mutations in other solid tumor types with matched tumor analysis. This provides support for the role of the BRCA1/2, ATM, and BAP1 genes in biliary tract cancer susceptibility.
McDonald, JD, S Gupta, ML Shindorf, LA Gamble, SM Ruff, J Drake, T Heller, JY Wan, PV Dickson, ES Glazer, JL Davis, JL Deneve and JM Hernandez 2020Elevated serum alpha-fetoprotein is associated with abbreviated survival for patients with fibrolamellar hepatocellular carcinoma who undergo a curative resection. Ann Surg Oncol 27(6): 1900-1905. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), with most clinical data stemming from single-institution series. The variability in the literature lends support for analysis using a large national dataset. In doing so, we sought to (1) define the characteristics and outcomes of patients with FLC; (2) determine factors associated with survival in patients undergoing resection; and (3) compare the overall survival (OS) of patients with FLC with a matched group of patients with HCC. METHODS: The National Cancer Database was queried for patients with FLC, and their clinicopathologic features were recorded. Univariate and multivariate analyses were performed to delineate factors associated with survival. RESULTS: Between 2004 and 2015, 496 patients were diagnosed with FLC, 229 of whom underwent a curative resection. The median OS for patients with FLC undergoing curative resection was 78.5 months. Factors associated with abbreviated OS in this surgical cohort include multiple tumors [hazard ratio (HR) 3.15, p = 0.025], positive regional lymph nodes (HR 2.83, p = 0.023), and elevated serum alpha-fetoprotein (AFP; HR 2.81, p = 0.034). When the OS of patients with FLC was compared with a matched group of patients with HCC, no difference was detected (p = 0.748); however, patients with FLC and elevated AFP had abbreviated OS compared with patients with HCC and elevated AFP (43 vs. 82 months, p
McDonald, JD and JM Hernandez 2020ASO author reflections: Fibrolamellar hepatocellular carcinoma and alpha-fetoprotein. Ann Surg Oncol 27(6): 1906-1907.
Nagtegaal, ID, RD Odze, D Klimstra, V Paradis, M Rugge, P Schirmacher, KM Washington, F Carneiro, IA Cree and WHOCoTE Board 2020The 2019 WHO classification of tumours of the digestive system.Histopathology 76(2): 182-188.
Nelson, R 2020Organisations for patients with cancer feel the brunt of COVID-19 pandemic. Lancet Oncol 21(8): 1020.
O'Grady, C, A Gliksberg and P Kent 2020Early experiences with triple immunochemotherapy in young adults with high-risk fibrolamellar carcinoma. J Clin Oncol. 38: 510-510. Background: Fibrolamellar Carcinoma (FLC) is a rare liver cancer affecting young adults without underlying liver disease. Surgery is the only proven therapy, and recurrence is common. There are no proven systemic treatments, especially for high-risk FLC (unresectable, relapse, progression, metastatic). Research suggests that immunotherapy may work. We share our experience using systemic “triple immunochemotherapy” (TT): 2 week cycles of 7 days continuous infusion 5FU or oral capecitabine, interferon alpha-2b on days 1,3,5,7 or PEG-Interferon and nivolumab on day 1. Methods: Data from all patients who received TT from 5/2018 to 9/2019 was reviewed to assess tolerability, survival and toxicity. Results: 14 patients were treated with TT of which 10 (8F,2M with a median age of 20) were evaluable. They received a median of 13 cycles (6-31). At time of analysis, the median progression free survival was 6 months, 22% longer than prior to TT, with 80% of patients (8) stable or improving, 1 progression, and 1 who died 2 months after initiating TT. For the 4 patients who achieved surgical remission, none have relapsed (PFS 9 months). Overall objective response (CR+PR) and tumor control rate (CR+PR+SD) were 60% and 80%, respectively. There were no withdrawals from treatment due to side effects, though 2 had dose adjustments. All experienced mild adverse effects, most commonly fever and headache, but only 2 patients had grade 3 toxicity. Conclusions: Our early results of TT for high-risk FLC are promising, with good tolerability and treatment response, particularly in patients who have achieved surgical CR. Further longitudinal data is needed to confirm outcomes, especially in patients still early in their treatment.
de Oliveira, S, RA Houseright, BG Korte and A Huttenlocher 2020DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of fibrolamellar carcinoma. Dis Model Mech 13(4). Fibrolamellar carcinoma (FLC) is a rare liver cancer that affects adolescents and young adults. Genomic analysis of FLC has revealed a 400 kb deletion in chromosome 19 that leads to the chimeric transcript DNAJB1-PRKACA (DnaJ-PKAc), comprised of the first exon of heat shock protein 40 (DNAJB1) and exons 2-10 of the catalytic subunit of protein kinase A (PRKACA). Here, we report a new zebrafish model of FLC induced by ectopic expression of zebrafish Dnaja-Pkaca (zfDnaJa-Pkaca) in hepatocytes that is amenable to live imaging of early innate immune inflammation. Expression of zfDnaJa-Pkaca in hepatocytes induces hepatomegaly and increased hepatocyte size. In addition, FLC larvae exhibit early innate immune inflammation characterized by early infiltration of neutrophils and macrophages into the liver microenvironment. Increased Caspase-a (the zebrafish homolog for human caspase-1) activity was also found in the liver of FLC larvae, and pharmacological inhibition of Tnfalpha and caspase-a decreased liver size and inflammation. Overall, these findings show that innate immune inflammation is an early feature in a zebrafish model of FLC and that pharmacological inhibition of TNFalpha or caspase-1 activity might be targets to treat inflammation and progression in FLC patients.This article has an associated First Person interview with the first author of the paper.
Omar, MH and JD Scott 2020AKAP signaling islands: Venues for precision pharmacology. Trends Pharmacol Sci 41(12): 933-946. Regulatory enzymes often have different roles in distinct subcellular compartments. Yet, most drugs indiscriminately saturate the cell. Thus, subcellular drug-delivery holds promise as a means to reduce off-target pharmacological effects. A-kinase anchoring proteins (AKAPs) sequester combinations of signaling enzymes within subcellular microdomains. Targeting drugs to these 'signaling islands' offers an opportunity for more precise delivery of therapeutics. Here, we review mechanisms that bestow protein kinase A (PKA) versatility inside the cell, appraise recent advances in exploiting AKAPs as platforms for precision pharmacology, and explore the impact of methodological innovations on AKAP research.
Partridge, BR, TJ O'Brien, MF Lorenzo, SL Coutermarsh-Ott, SL Barry, K Stadler, N Muro, M Meyerhoeffer, IC Allen, RV Davalos and NG Dervisis 2020High-frequency irreversible electroporation for treatment of primary liver cancer: A proof-of-principle study in canine hepatocellular carcinoma. J Vasc Interv Radiol 31(3): 482-491 e484. PURPOSE: To determine the safety and feasibility of percutaneous high-frequency irreversible electroporation (HFIRE) for primary liver cancer and evaluate the HFIRE-induced local immune response. MATERIALS AND METHODS: HFIRE therapy was delivered percutaneously in 3 canine patients with resectable hepatocellular carcinoma (HCC) in the absence of intraoperative paralytic agents or cardiac synchronization. Pre- and post-HFIRE biopsy samples were processed with histopathology and immunohistochemistry for CD3, CD4, CD8, and CD79a. Blood was collected on days 0, 2, and 4 for complete blood count and chemistry. Numeric models were developed to determine the treatment-specific lethal thresholds for malignant canine liver tissue and healthy porcine liver tissue. RESULTS: HFIRE resulted in predictable ablation volumes as assessed by posttreatment CT. No detectable cardiac interference and minimal muscle contraction occurred during HFIRE. No clinically significant adverse events occurred secondary to HFIRE. Microscopically, a well-defined ablation zone surrounded by a reactive zone was evident in the majority of samples. This zone was composed primarily of maturing collagen interspersed with CD3(+)/CD4(-)/CD8(-) lymphocytes in a proinflammatory microenvironment. The average ablation volumes for the canine HCC patients and the healthy porcine tissue were 3.89 cm(3) +/- 0.74 and 1.56 cm(3) +/- 0.16, respectively (P = .03), and the respective average lethal thresholds were 710 V/cm +/- 28.2 and 957 V/cm +/- 24.4 V/cm (P = .0004). CONCLUSIONS: HFIRE can safely and effectively be delivered percutaneously, results in a predictable ablation volume, and is associated with lymphocytic tumor infiltration. This is the first step toward the use of HFIRE for treatment of unresectable liver tumors.
Patel, A, NJ Espat and P Somasundar 2020Fibrolamellar carcinoma: Novel insights into a rare subtype.Ann Surg Oncol 27(6): 1733-1734.
Ranganathan, S, D Lopez-Terrada and R Alaggio 2020Hepatoblastoma and pediatric hepatocellular carcinoma: An update. Pediatr Dev Pathol 23(2): 79-95. Hepatoblastomas (HBs) and pediatric hepatocellular carcinomas (HCCs) together account for almost 80% of primary malignant liver tumors in children and adolescents/young adults. Children's Hepatic International Collaboration (CHIC), Children's Oncology Group (COG), SocieteInternationale d'Oncologie Pediatrique (SIOP), and International Childhood Liver Tumors Strategy Group trials have contributed to define prognostic factors and risk stratification in these tumors. The recently proposed histologic International Consensus classification of HB and HCC in children based on retrospective analysis from CHIC cases represents the base to define entities with homogeneous clinicopathologic and molecular features. This review will provide a morphologic guide for the upcoming International Liver Tumor treatment trial (Pediatric Hepatic International Tumour Trial) to be conducted through several continents. There will be an emphasis on molecular features and immunohistochemical markers for the definition of the individual histologic subtypes of HB and to better characterize the group of liver tumors in the provisional category of hepatocellular neoplasm-not otherwise specified. A brief overview of HCC in children will also be provided.
Samdanci, ET, AN Akatli and NK Soylu 2020Clinicopathological features of two extremely rare hepatocellular carcinoma variants: A brief review of fibrolamellar and scirrhous hepatocellular carcinoma. J Gastrointest Cancer 51(4): 1187-1192. PURPOSE: We aimed to distinguish between fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma histopathologically. METHODS AND RESULTS: In this review, fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma two specific and rare variants of hepatocellular carcinoma, which are difficult to diagnose histopathologically are discussed. CONCLUSION: The clinical, radiological, gross, histopathological, immunohistochemical, and molecular features of these two tumors, which are defined by the World Health Organization (WHO), are mentioned.
Schooler, GR, JH Squires, A Alazraki, GB Chavhan, V Chernyak, JT Davis, G Khanna, R Krishnamurthy, MP Lungren, PM Masand, DJ Podberesky, CB Sirlin and AJ Towbin 2020Pediatric hepatoblastoma, hepatocellular carcinoma, and other hepatic neoplasms: Consensus imaging recommendations from American College of Radiology Pediatric Liver Reporting and Data System (LI-RADS) working group. Radiology 296(3): 493-497.Appropriate imaging is imperative in evaluating children with a primary hepatic malignancy such as hepatoblastoma or hepatocellular carcinoma. For use in the adult patient population, the American College of Radiology created the Liver Imaging Reporting and Data System (LI-RADS) to provide consistent terminology and to improve imaging interpretation. At present, no similar consensus exists to guide imaging and interpretation of pediatric patients at risk for developing a liver neoplasm or how best to evaluate a pediatric patient with a known liver neoplasm. Therefore, a new Pediatric Working Group within American College of Radiology LI-RADS was created to provide consensus for imaging recommendations and interpretation of pediatric liver neoplasms. The article was drafted based on the most up-to-date existing information as interpreted by imaging experts comprising the Pediatric LI-RADS Working Group. Guidance is provided regarding appropriate imaging modalities and protocols, as well as imaging interpretation and reporting, with the goals to improve imaging quality, to decrease image interpretation errors, to enhance communication with referrers, and to advance patient care. An expanded version of this document that includes broader background information on pediatric hepatocellular carcinoma and rationale for recommendations can be found in Appendix E1 (online).
Seyfried, TN, G Arismendi-Morillo, P Mukherjee and C Chinopoulos 2020On the origin of ATP synthesis in cancer. iScience 23(11): 101761. ATP is required for mammalian cells to remain viable and to perform genetically programmed functions. Maintenance of the DeltaG'(ATP) hydrolysis of -56 kJ/mole is the endpoint of both genetic and metabolic processes required for life. Various anomalies in mitochondrial structure and function prevent maximal ATP synthesis through OxPhos in cancer cells. Little ATP synthesis would occur through glycolysis in cancer cells that express the dimeric form of pyruvate kinase M2. Mitochondrial substrate level phosphorylation (mSLP) in the glutamine-driven glutaminolysis pathway, substantiated by the succinate-CoA ligase reaction in the TCA cycle, can partially compensate for reduced ATP synthesis through both OxPhos and glycolysis. A protracted insufficiency of OxPhos coupled with elevated glycolysis and an auxiliary, fully operational mSLP, would cause a cell to enter its default state of unbridled proliferation with consequent dedifferentiation and apoptotic resistance, i.e., cancer. The simultaneous restriction of glucose and glutamine offers a therapeutic strategy for managing cancer.
Singhi, AD, LD Wood, E Parks, MS Torbenson, M Felsenstein, RH Hruban, MN Nikiforova, AI Wald, C Kaya, YE Nikiforov, L Favazza, J He, K McGrath, KE Fasanella, RE Brand, AM Lennon, A Furlan, AK Dasyam, AH Zureikat, HJ Zeh, K Lee, DL Bartlett and A Slivka 2020Recurrent rearrangements in PRKACA and PRKACB in intraductal oncocytic papillary neoplasms of the pancreas and bile duct. Gastroenterology 158(3): 573-582 e572. BACKGROUND & AIMS: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes. METHODS: We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls). RESULTS: All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions. CONCLUSIONS: We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.
Smith, M, C Marcus and B Markovich 2020Cancer, fibrolamellar hepatocellular carcinoma. StatPearls. Treasure Island (FL). Fibrolamellar hepatocellular carcinoma (FL-HCC) is a liver cancer that is different in its clinical features from conventional hepatocellular carcinoma (HCC).[1] A nearly negligible amount of liver cancers are attributed to FL-HCC. FL-HCC affects patients from a different and lower demographic age than HCC. Prompt initiation of treatment is of utmost importance since it can have a positive impact on patient outcomes. This article aims at reviewing the salient clinical and imaging features of FL-HCC, in contrast to HCC.
Surjan, RCT, ESD Santos, SDP Silveira, FF Makdissi and MAC Machado 2020Fibrolamellar hepatocellular carcinoma-related hyperammonemic encephalopathy: Up to now and next steps.Clin Mol Hepatol 26(2): 231-232.
Surjan, RCT, SP Silveira, JLS Pinheiro, PHS Pinheiro, MFA Barros and SRP Soares 2020Acute onset hyperammonemic encephalopathy related to fibrolamellar carcinoma: Another one bites the dust. Am J Med Sci 359(4): 242-244.
Thakral, N and DA Simonetto 2020Hyperammonemic encephalopathy: An unusual presentation of fibrolamellar hepatocellular carcinoma.Clin Mol Hepatol 26(1): 74-77.
Vyas, M, JF Hechtman, Y Zhang, R Benayed, A Yavas, G Askan, J Shia, DS Klimstra and O Basturk 2020DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma. Mod Pathol 33(4): 648-656. Recently discovered DNAJB1-PRKACA oncogenic fusions have been considered diagnostic for fibrolamellar hepatocellular carcinoma. In this study, we describe six pancreatobiliary neoplasms with PRKACA fusions, five of which harbor the DNAJB1-PRKACA fusion. All neoplasms were subjected to a hybridization capture-based next-generation sequencing assay (MSK-IMPACT), which enables the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving >/=410 genes (n = 6) and/or to a custom targeted, RNA-based panel (MSK-Fusion) that utilizes Archer Anchored Multiplex PCR technology and next-generation sequencing to detect gene fusions in 62 genes (n = 2). Selected neoplasms also underwent FISH analysis, albumin mRNA in-situ hybridization, and arginase-1 immunohistochemical labeling (n = 3). Five neoplasms were pancreatic, and one arose in the intrahepatic bile ducts. All revealed at least focal oncocytic morphology: three cases were diagnosed as intraductal oncocytic papillary neoplasms, and three as intraductal papillary mucinous neoplasms with mixed oncocytic and pancreatobiliary or gastric features. Four cases had an invasive carcinoma component composed of oncocytic cells. Five cases revealed DNAJB1-PRKACA fusions and one revealed an ATP1B1-PRKACA fusion. None of the cases tested were positive for albumin or arginase-1. Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present. Moreover, considering DNAJB1-PRKACA fusions lead to upregulated protein kinase activity and that this upregulated protein kinase activity has a significant role in tumorigenesis of fibrolamellar hepatocellular carcinoma, protein kinase inhibition could have therapeutic potential in the treatment of these pancreatobiliary neoplasms as well, once a suitable drug is developed.
Wei, L, Z Delin, Y Kefei, W Hong, H Jiwei and Z Yange 2020A classification based on tumor budding and immune score for patients with hepatocellular carcinoma. Oncoimmunology 9(1): 1672495. Background: The role of immune profiling and tumor budding in hepatocellular carcinoma (HCC) remains largely unknown. This study evaluated the association between tumor budding and lymphocytic infiltration in HCC. Meanwhile, HCC patients were stratified based on tumor budding grade and immune score. Patients and methods: A total of 423 HCC patients were divided into training (n = 212) and validation (n = 211) cohort. Tumor slides from resected HCC samples were used for tumor budding assessment. A prognosis-relevant immune score was developed based on five types of immune cells out of eleven immune markers. A classification based on tumor budding grade and immune type was established (IS-TB type). To explore the association of IS-TB type and molecular alterations of HCC, 100 HCC samples and adjacent non-tumor tissues from 100 patients were investigated by whole-exome sequencing. Results: Tumor budding was an independent adverse prognostic factor for OS and DFS in both of the training and validation cohorts (all P values <.05). The rate of high-grade tumor budding was significantly higher in HCC with immature stroma (P < .001), strong alpha-SMA expression (P = .005), non-steatotic tumors and non-fibrolamellar-HCC (P < .001). Additionally, tumor budding was related to both anti- and pro-tumor immune responses. Patients were classified into immune type A and immune type B according to the immune score. Based on tumor budding grade and immunotype, patients were classified into four subgroups: ISA-TBhigh (type I), ISB-TBhigh (type II), ISA-TBlow (type III) and ISB-TBlow (type IV). Patients with type III tumor had the best OS and DFS, whereas OS and DFS were the worst for cases with type II tumor. TP53 mutation was more frequent in IS-TB type I (ISATBhigh) patients, while IS-TB type IV (ISBTBlow) harbored high number of CTNNB1 mutation. Conclusion: Tumor-immune cell interactions in HCC is heterogeneous. HCC classification based on tumor budding and immune score correlates with patient survival and molecular alterations. The defined subtypes may have significance for utilizing individualized treatment in patients with HCC.
Zhang, JZ, TW Lu, LM Stolerman, B Tenner, JR Yang, JF Zhang, M Falcke, P Rangamani, SS Taylor, S Mehta and J Zhang 2020Phase separation of a PKA regulatory subunit controls cAMP compartmentation and oncogenic signaling. Cell 182(6): 1531-1544 e1515. The fidelity of intracellular signaling hinges on the organization of dynamic activity architectures. Spatial compartmentation was first proposed over 30 years ago to explain how diverse G protein-coupled receptors achieve specificity despite converging on a ubiquitous messenger, cyclic adenosine monophosphate (cAMP). However, the mechanisms responsible for spatially constraining this diffusible messenger remain elusive. Here, we reveal that the type I regulatory subunit of cAMP-dependent protein kinase (PKA), RIalpha, undergoes liquid-liquid phase separation (LLPS) as a function of cAMP signaling to form biomolecular condensates enriched in cAMP and PKA activity, critical for effective cAMP compartmentation. We further show that a PKA fusion oncoprotein associated with an atypical liver cancer potently blocks RIalpha LLPS and induces aberrant cAMP signaling. Loss of RIalpha LLPS in normal cells increases cell proliferation and induces cell transformation. Our work reveals LLPS as a principal organizer of signaling compartments and highlights the pathological consequences of dysregulating this activity architecture.
Ziogas, IA, F Ye, Z Zhao, LK Matsuoka, MI Montenovo, M Izzy, DJ Benedetti, HN Lovvorn, 3rd, LA Gillis and SP Alexopoulos 2020Population-based analysis of hepatocellular carcinoma in children: Identifying optimal surgical treatment. J Am Coll Surg 230(6): 1035-1044 e1033. BACKGROUND: Hepatocellular carcinoma (HCC) constitutes 0.5% of childhood malignancies and exhibits poor prognosis. Complete tumor extirpation either by partial liver resection (LR) or liver transplantation (LT) is the only curative treatment. Due to the poor initial outcomes of LT, LR has remained the mainstay of treatment for all but select children fulfilling the Milan criteria (originally designed for adults). METHODS: We conducted a retrospective cohort study of pediatric HCC patients (younger than 18 years of age) registered in the Surveillance, Epidemiology, and End Results database between 2004 and 2015. Survival analysis was performed by means of Kaplan-Meier methods, 2-sided stratified log-rank tests, and Cox regression models. RESULTS: Of 127 children with HCC, 46 did not undergo operation (36.2%), 32 underwent LT (25.2%), and 49 underwent LR (38.6%). Using the Kaplan-Meier method, the 5-year cancer-specific survival (CSS) rates for LT and LR were 87% and 63%, respectively. LT exhibited superior CSS vs LR (log-rank, p = 0.007). For T1 stage, LT showed equivalent CSS compared with LR (log-rank, p = 0.23), and for T2 and T3 stage, LT exhibited superior CSS (log-rank, p = 0.047 and p = 0.01, respectively). On multivariable Cox regression analysis, T3/T4 stage (adjusted hazard ratio 13.63; 95% CI, 2.9 to 64.07; p = 0.001), and LR (adjusted hazard ratio 7.51; 95% CI, 2.07 to 27.29; p = 0.002) were found to be independently associated with cancer-specific mortality. Fibrolamellar histology and lymph node status were not found to be associated with mortality. CONCLUSIONS: Our findings suggest that children diagnosed with nonmetastatic advanced-stage HCC have a favorable prognosis after LT compared with LR. Early inclusion of an LT consultation after the initial diagnosis is warranted, especially in children with unresectable HCC or when complete tumor extirpation with LR is not feasible.
Zucman-Rossi, J and JC Nault 2020Mutations and genomic alterations in liver cancer.The Liver: Biology and Pathobiology. I. M. Ariias, H. J. Alter, J. L. Boyer et al. Hoboken, NJ, John Wiley & Sons Ltd.:773-781.Liver cancers include various types of carcinoma according to their cell of origin and hepatocellular versus cholangiocellular differentiation. Various subtypes of tumors are also defined at histopathology. This diversity is highly related to specific gene mutations and profiles of expression (Figure 60.3).Etiologies underlining the cause of chronic liver disease influence the mechanism of liver carcinogenesis and the types of mutations/chomosomal aberrations that accumulate in cancerous hepatocytes. Understanding the basis of carcinogenesis will help us to better understand various cancer phenotypes and to improve patient care in the future.
Anysz-Grodzicka, A, J Podgorska and A Cieszanowski 2019State-of-the-art MR imaging of uncommon hepatocellular tumours: Fibrolamellar hepatocellular carcinoma and combined hepatocellularcholangiocarcinoma.Curr Med Imaging Rev 15(3): 269-280. BACKGROUND: Fibrolamellar Carcinoma (FLC) and Combined Hepatocellular- Cholangiocarcinoma (CHC) are rare primary liver tumours, which are related to different clinical settings. In both tumours, correlation with clinical data and laboratory tests are extremely important. DISCUSSION: Typically, FLC is diagnosed in young patients without any chronic disease and with normal biochemical tests, whereas CHC arises in cirrhotic patients with elevated tumour markers: AFP and/or CA 19-9. The review describes epidemiology, aetiology, pathogenesis, radiological features and treatment of these tumours. Imaging features typical for FLC are: The presence of central scar, calcifications, the large size, heterogeneous and early contrast-enhancement. CONCLUSION: The diagnosis of CHC may be suggested in case of elevation of both AFP and CA 19- 9 or inconsistency between elevated tumour markers and imaging findings (i.e., elevated CA 19-9 and radiological features of HCC, or elevated AFP with imaging findings characteristic of ICC).
Averill, AM, HT Rehman, JW Charles, TA Dinh, K Danyal, CF Verschraegen, GS Stein, WR Dostmann and JE Ramsey 2019Inhibition of the chimeric DNAJ-PKAc enzyme by endogenous inhibitor proteins. J Cell Biochem 120(8): 13783-13791. The chimeric DnaJ-PKAc enzymeresulting from an approximately 400-kb deletion of chromosome 19 is a primary contributor to the oncogenic transformation that occurs in fibrolamellar hepatocellular carcinoma, also called fibrolamellar carcinoma (FLC). This oncogenic deletion juxtaposes exon 1 of the DNAJB1 heat shock protein gene with exon 2 of the PRKACA gene encoding the protein kinase A catalytic subunit, resulting in DnaJ-PKAc fusion under the transcriptional control of the DNAJB1 promoter. The expression of DnaJ-PKAc is approximately 10 times that of wild-type (wt) PKAc catalytic subunits, causing elevated and dysregulated kinase activity that contributes to oncogenic transformation. In normal cells, PKAc activity is regulated by a group of endogenous proteins, termed protein kinase inhibitors (PKI) that competitively inhibit PKAc and assist with the nuclear export of the enzyme. Currently, it is scarcely known whether interactions with PKI are perturbed in DnaJ-PKAc. In this report, we survey existing data sets to assess the expression levels of the various PKI isoforms that exist in humans to identify those that are candidates to encounter DnaJ-PKAc in both normal liver and FLC tumors. We then compare inhibition profiles of wtPKAc and DnaJ-PKAc against PKI and demonstrate that extensive structural homology in the active site clefts of the two enzymes confers similar kinase activities and inhibition by full-length PKI and PKI-derived peptides.
Bauer, U, C Mogler, RF Braren, H Algul, RM Schmid and U Ehmer 2019Progression after immunotherapy for fibrolamellar carcinoma.Visc Med 35(1): 39-42. Background: Fibrolamellar carcinoma (FLC) is a rare malignancy of the liver that differs from typical hepatocellular carcinoma (HCC) in several aspects such as the absence of underlying liver disease and occurrence in younger patients. Even though the survival rates in FLC are slightly better than in typical HCC, the prognosis of metastatic FLC remains deleterious. Several reports suggest that systemic chemotherapy regimens can successfully be used to halt disease progression in FLC, while targeted tumor therapy with sorafenib seems to be of limited efficiency. However, results from controlled clinical trials investigating systemic therapies in FLC are virtually nonexistent. Therefore, the choice of treatment often relies on case series with limited numbers of patients. Immunotherapy with checkpoint inhibitors is an emerging cancer therapy in several solid malignancies including HCC. Currently, there do not exist any reports on the use of checkpoint inhibitors in FLC. Case Report: Here, we describe a case of advanced FLC in a young man receiving immunotherapy, who progressed after 3 months of treatment - similar to 2 other patients with advanced FLC at our hospital. Conclusion: While immunotherapy seems to be a promising treatment with limited side effects in several other tumor entities, there is currently no data supporting tumor response in FLC.
Calderaro, J, M Ziol, V Paradis and J Zucman-Rossi 2019Molecular and histological correlations in liver cancer. J Hepatol. Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, both at the molecular and histological level. High-throughput sequencing and gene expression profiling have identified distinct transcriptomic subclasses and numerous recurrent genetic alterations, and several HCC subtypes characterized by histological features have also been identified. HCC phenotype appears to be closely related to particular gene mutations, tumor subgroups and/or oncogenic pathways. Non-proliferative tumors display a well-differentiated phenotype, and among this molecular subgroup, CTNNB1 mutated HCC constitute a homogeneous subtype with cholestasis and microtrabecular and pseudoglandular architectural patterns. Another non-proliferative subtype has a gene expression pattern close to that of mature hepatocytes (G4) and displays a steatohepatitic phenotype. In contrast, proliferative HCC are most often poorly differentiated, and noticeably include tumors with progenitor features. A novel morphological variant of proliferative HCC, designated as "macrotrabecular-massive", was recently shown to be associated with angiogenesis activation and poor prognosis. Altogether, these findings may help in the near future to translate our knowledge of HCC biology into clinical practice, and are expected to improve precision medicine for patients with this highly aggressive malignancy. This manuscript reviews the most recent data on this exciting field, and discusses the future directions and challenges ahead.
Cao, B, TW Lu, JA Martinez Fiesco, M Tomasini, L Fan, SM Simon, SS Taylor and P Zhang 2019Structures of the PKA RIalpha holoenzyme with the FLHCC driver J-PKAcalpha or wild-type PKAcalpha.Structure 27(5): 816-828 e814. Fibrolamellar hepatocellular carcinoma (FLHCC) is driven by J-PKAcalpha, a kinase fusion chimera of the J domain of DnaJB1 with PKAcalpha, the catalytic subunit of protein kinase A (PKA). Here we report the crystal structures of the chimeric fusion RIalpha2:J-PKAcalpha2 holoenzyme formed by J-PKAcalpha and the PKA regulatory (R) subunit RIalpha, and the wild-type (WT) RIalpha2:PKAcalpha2 holoenzyme. The chimeric and WT RIalpha holoenzymes have quaternary structures different from the previously solved WT RIbeta and RIIbeta holoenzymes. The WT RIalpha holoenzyme showed the same configuration as the chimeric RIalpha2:J-PKAcalpha2 holoenzyme and a distinct second conformation. The J domains are positioned away from the symmetrical interface between the two RIalpha:J-PKAcalpha heterodimers in the chimeric fusion holoenzyme and are highly dynamic. The structural and dynamic features of these holoenzymes enhance our understanding of the fusion chimera protein J-PKAcalpha that drives FLHCC as well as the isoform specificity of PKA.
Chakrabarti, S, SH Tella, A Kommalapati, BM Huffman, S Yadav, IB Riaz, G Goyal, K Mody, M Borad, S Cleary, RL Smoot and A Mahipal 2019Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma.J Gastrointest Oncol 10(3): 554-561. Background: Clinicopathological features and the outcomes of patients with fibrolamellar hepatocellular carcinoma (FLHCC) are not clearly defined. Methods: Data were collected by retrospective chart review on 42 patients with FLHCC treated between 1990 and 2017 at Mayo Clinic. Results: Of 42 patients (median age at diagnosis 22 years), 10 patients (23.8%) had stage I disease and 32 patients (76.2%) had stage II to IVB disease. All 10 patients with stage I disease and 21 of 32 patients with stage II-IVB disease underwent resection at presentation. In stage I patient group, 6 patients experienced recurrence with a median time to recurrence of 30.5 months and a 5-year overall survival (OS) of 86%. Patients with stage II to IVB disease who underwent resection (n=21) upfront had a median OS of 32.5 months and 5-year OS of 44%. In the upfront surgery group, 71% of patients experienced recurrence. The median OS of patients with unresectable disease (n=11) was 10 months. Four out of nine patients treated with sorafenib had stable disease and one patient with programmed cell death ligand-1 (PD-L1) expressing tumor had a near complete response after 2 months of therapy with nivolumab. Conclusions: In FLHCC, surgical resection was associated with prolonged OS; although most patients had a disease recurrence regardless of disease stage and resection margin status. The response to kinase inhibitor, sorafenib, was variable. In select cases, therapy with a checkpoint inhibitor may provide a viable treatment option.
Chavhan, GB, I Siddiqui, KM Ingley and AA Gupta 2019Rare malignant liver tumors in children.Pediatr Radiol 49(11): 1404-1421. Malignant hepatic tumors in children are rare, comprising 1.3% of all pediatric malignancies. Following hepatoblastoma, hepatocellular carcinoma is the second most common. Other malignant hepatic tumors seen in childhood include those of mesenchymal origin including undifferentiated embryonal sarcoma, angiosarcoma, rhabdomyosarcoma and epithelioid hemangioendothelioma, as well as biliary tumors such as cholangiocarcinoma. Diagnosis can be challenging because of their rarity, and the recognition of distinctive imaging features for certain tumors such as epithelioid hemangioendothelioma and biliary rhabdomyosarcoma can focus the differential diagnosis and expedite the diagnostic process. A complete MRI examination with hepatocyte-specific contrast media and diffusion-weighted imaging helps to focus the differential diagnosis, and, although findings are often nonspecific, in some cases typical features on MRI can be helpful in diagnosis. Histopathological analysis is usually required for definitive diagnosis. Hepatic tumors tend to be aggressive, and full staging is imperative to establish disease extent. Significant proportions are not amenable to upfront surgical resection and often require a multimodality approach including neoadjuvant chemotherapy within a multidisciplinary setting. Facilitating complete surgical resection is usually required for better survival. In this review, we emphasize pathology and imaging features for rare liver tumors that are useful in reaching a prompt diagnosis. We also discuss general clinical findings, prognosis and management of these tumors.
Cho, J, JCY Chen, J Paludo, EE Conboy, BC Lanpher, SR Alberts and TR Halfdanarson 2019Hyperammonemic encephalopathy in a patient with fibrolamellar hepatocellular carcinoma: case report and literature review. J Gastrointest Oncol 10(3): 582-588. Fibrolamellar hepatocellular carcinoma (fHCC) is a rare primary liver cancer that affects young adults with no prior liver disease. fHCC-associated hyperammonemic encephalopathy (HAE) is an uncommon and life-threatening complication. Hyperammonemia has been reported in both typical and fHCC as a result of intrahepatic shunting, side effect from immunotherapy or chemotherapy, or as a paraneoplastic phenomenon. We present a case of a 32-year-old woman with recurrent metastatic fHCC who developed HAE in the setting of steroid administration. Her hyperammonemia was exacerbated by steroid-induced protein catabolism. She was treated with ammonia scavenging medications, a low protein diet, and was placed on chronic ammonia scavenger therapy while undergoing chemotherapy. In this case report, we discuss the proposed mechanisms of HAE, and we review the literature regarding clinical presentation and treatment.
Cowell, E, K Patel, A Heczey, M Finegold, R Venkatramani, H Wu, D Lopez-Terrada and T Miloh 2019Predisposing conditions to pediatric hepatocellular carcinoma and association with outcomes: Single-center experience.J Pediatr Gastroenterol Nutr 68(5): 695-699. OBJECTIVES: Hepatocellular carcinoma (HCC) has been linked to chronic viral or metabolic liver disease and other conditions. The characteristics of children with HCC have not been fully elucidated and outcomes in children with predisposing liver disease are not well defined. METHODS: Patients 4 cm (20% vs 100%, P < 0.05). In patients treated at our institution, 5 of 7 with predisposing conditions received liver transplant and achieved complete remission, whereas only 3 of 9 patients with de novo HCC received curative surgery and this group had decreased median overall survival (P < 0.05). CONCLUSIONS: The majority of children with HCC did not have predisposing liver or associated disease. These patients were diagnosed later with more advanced stage disease and had significantly decreased overall survival.
Dinh, TA, ML Jewell, M Kanke, A Francisco, R Sritharan, RE Turnham, S Lee, ER Kastenhuber, E Wauthier, CD Guy, RS Yeung, SW Lowe, LM Reid, JD Scott, AM Diehl and P Sethupathy 2019MicroRNA-375 suppresses the growth and invasion of fibrolamellar carcinoma. Cell Mol Gastroenterol Hepatol 7(4): 803-817. BACKGROUND & AIMS: Fibrolamellar carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. It is characterized by a heterozygous approximately 400-kb deletion on chromosome 19 that results in a unique fusion between DnaJ heat shock protein family member B1 (DNAJB1) and the alpha catalytic subunit of protein kinase A (PRKACA). The role of microRNAs (miRNAs) in FLC remains unclear. We identified dysregulated miRNAs in FLC and investigated whether dysregulation of 1 key miRNA contributes to FLC pathogenesis. METHODS: We analyzed small RNA sequencing (smRNA-seq) data from The Cancer Genome Atlas to identify dysregulated miRNAs in primary FLC tumors and validated the findings in 3 independent FLC cohorts. smRNA-seq also was performed on a FLC patient-derived xenograft model as well as purified cell populations of the liver to determine whether key miRNA changes were tumor cell-intrinsic. We then used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (Cas9) technology and transposon-mediated gene transfer in mice to determine if the presence of DNAJB1-PRKACA is sufficient to suppress miR-375 expression. Finally, we established a new FLC cell line and performed colony formation and scratch wound assays to determine the functional consequences of miR-375 overexpression. RESULTS: We identified miR-375 as the most dysregulated miRNA in primary FLC tumors (27-fold down-regulation; P = .009). miR-375 expression also was decreased significantly in a FLC patient-derived xenograft model compared to 4 different cell populations of the liver. Introduction of DNAJB1-PRKACA by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 engineering and transposon-mediated somatic gene transfer in mice was sufficient to induce significant loss of miR-375 expression (P < .05). Overexpression of miR-375 in FLC cells inhibited Hippo signaling pathway proteins, including yes-associated protein 1 and connective tissue growth factor, and suppressed cell proliferation and migration (P < .05). CONCLUSIONS: We identified miR-375 as the most down-regulated miRNA in FLC tumors and showed that overexpression of miR-375 mitigated tumor cell growth and invasive potential. These findings open a potentially new molecular therapeutic approach. Further studies are necessary to determine how DNAJB1-PRKACA suppresses miR-375 expression and whether miR-375 has additional important targets in this tumor. Transcript profiling: GEO accession numbers: GSE114974 and GSE125602.
El Jabbour, T, SM Lagana and H Lee 2019Update on hepatocellular carcinoma: Pathologists' review. World J Gastroenterol 25(14): 1653-1665. Histopathologic diversity and several distinct histologic subtypes of hepatocellular carcinoma (HCC) are well-recognized. Recent advances in molecular pathology and growing knowledge about the biology associated with distinct histologic features and immuno-profile in HCC allowed pathologists to update classifications. Improving sub-classification will allow for more clinically relevant diagnoses and may allow for stratification into biologically meaningful subgroups. Therefore, immuno-histochemical and molecular testing are not only diagnostically useful, but also are being incorporated as crucial components in predicting prognosis of the patients with HCC. Possibilities of targeted therapy are being explored in HCC, and it will be important for pathologists to provide any data that may be valuable from a theranostic perspective. Herein, we review and provide updates regarding the pathologic sub-classification of HCC. Pathologic diagnostic approach and the role of biomarkers as prognosticators are reviewed. Further, the histopathology of four particular subtypes of HCC: Steatohepatitic, clear cell, fibrolamellar and scirrhous - and their clinical relevance, and the recent consensus on combined HCC-cholangiocarcinoma is summarized. Finally, emerging novel biomarkers and new approaches to HCC stratification are reviewed.
Faradonbeh, MS 2019Molecular mechanism of protein kinase A in fibrolamellar hepatocellular carcinoma.FASEB Journal. 33: 461.419-461.419. Fibrolamellar Hepatocellular Carcinoma (FL-HCC) is a rare form of liver cancer that affects adolescents and young adults without a prior history of liver disease. Chemotherapy is ineffective in treating FL-HCC, and surgical resection of the primary tumor and metastases is currently the only semi-effective treatment. Reoccurrence rates in FL-HCC are extremely high. A 400kB deletion in chromosome 19 results in the fusion of the first exon of a heat shock protein, DNAJB1, with the catalytic subunit of protein kinaseA, PRKACA (1). The new chimeric protein, DNAJB1-PRKACA, retains the full catalytic activity of protein kinase A. We have performed partial biophysical characterization of DNAJB1-PRKACA in comparison to PRKACA. Our preliminary results indicate the structural stability of DNAJB1-PRKACA may differ from that of PRKACA. We also report the DNAJB1-PRKACA chimera forms a stable complex with its regulatory domains, and differences in structural stability may extend to the chimera/regulatory domain complex. Surface plasmon resonance (SPR) does not reveal any difference in the binding affinity of DNAJB1-PRKACA and wild type PRKACA to their Regulatory subunit type I?. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ferrari, A, IB Brecht, G Gatta, DT Schneider, D Orbach, G Cecchetto, J Godzinski, Y Reguerre, E Bien, T Stachowicz-Stencel, M Ost, C Magni, P Kearns, G Vassal, M Massimino, A Biondi, G Bisogno and A Trama 2019Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126. Although all tumours are rare in childhood, there are some particularly rare paediatric cancers which have not benefited from advances made by the international paediatric oncology network. To establish a shared definition and produce a list of these entities, the European Union Joint Action on Rare Cancers (JARC) promoted a consensus effort. The definition was based on the incidence rates estimated using the information network on rare cancers (RARECAREnet) database, pooling data from 94 population-based cancer registries and 27 countries. The RARECAREnet list of cancers was used to estimate the incidence rates. This list groups cancers by combining the International Classification of Diseases for Oncology, third edition, morphology and topography codes. According to the consensus, very rare paediatric cancers were identified as those with an annual incidence <2/1000000 and corresponded to 11% of all cancers in patients aged 0-14 years. Two subgroups were identified: tumour types typical of childhood (i.e. hepatoblastoma, pleuropulmonary blastoma, pancreatoblastoma) and those typical of adult age (i.e. carcinomas, melanoma). The threshold of 2/1000000 could also be adopted in populations aged 0-19 years: in this case, three tumour types had an incidence rate which was >2/1000000 (i.e. thyroid and testicular cancers and skin melanoma), but the consensus experts considered them as 'very rare' according to their clinical needs (e.g. shortage of knowledge and clinical expertise as the other rare paediatric cancers). The JARC consensus produced a definition and a list of very rare paediatric cancers which may represent a starting point for prioritising research on these tumours, based on data and patients' clinical needs.
Fischer, HP and D Goltz 2019Hepatocellular carcinomas and their mimics.Pathologe. High resolution cross-sectional imaging techniques means that even small, well-differentiated hepatocellular tumors can also be diagnosed with biopsy. In cirrhotic liver tissue, macroregenerative and dysplastic nodules must be discriminated from hepatocellular cancer (HCC). In non-cirrhotic liver tissue the differential diagnosis includes hepatocellular adenoma, macroregeneratory nodules, fibrolamellar carcinoma, as well as primary tumors and metastases. The diagnostic procedure includes matrix diagnosis of the tumor-bearing liver tissue, cyto- and histomorphologic analysis including capillarization of vascular bed, and adapted immunohistological testing with antibodies which underline possible malignancy or hepatocellular differentiation. A flow chart for the diagnosis of hepatocellular carcinomas and their mimics on liver biopsies is presented.
Haines, K, SF Sarabia, KR Alvarez, G Tomlinson, SA Vasudevan, AA Heczey, A Roy, MJ Finegold, DW Parsons, SE Plon and D Lopez-Terrada 2019Characterization of pediatric hepatocellular carcinoma reveals genomic heterogeneity and diverse signaling pathway activation.Pediatr Blood Cancer 66(7): e27745. BACKGROUND: Pediatric hepatocellular carcinoma (HCC) is a rare liver tumor in children with a poor prognosis. Comprehensive molecular profiling to understand the underlying genomic drivers of this tumor has not been completed, and it is unclear whether nonfibrolamellar pediatric HCC is more genomically similar to hepatoblastoma or adult HCC. PROCEDURE: To characterize the molecular landscape of these tumors, we analyzed a cohort of 15 pediatric non-FL-HCCs by sequencing a panel of cancer-associated genes and conducting copy-number and gene-expression analyses. RESULTS: We detected multiple types of molecular alterations in Wnt signaling genes, including APC inversion, AMER1 somatic mutation, and most commonly CTNNB1 intragenic deletions. There were multiple alterations to the telomerase pathway via TERT activation or ATRX mutation. Therapeutically targetable activating mutations in MAPK/ERK signaling pathway genes, including MAPK1 and BRAF, were detected in 20% of tumors. TP53 mutations occurred far less frequently in our pediatric HCC cohort than reported in adult cohorts. Tumors arising in children with underlying liver disease were found to be molecularly distinct from the remainder and lacking detectable oncogenic drivers, as compared with those arising in patients without a history of underlying liver disease; the majority of both types were positive for glypican-3, another potential therapeutic target. CONCLUSION: Our study revealed pediatric HCC to be a molecularly heterogeneous group of tumors. Those non-FL-HCC tumors arising in the absence of underlying liver disease harbor genetic alterations affecting multiple cancer pathways, most notably Wnt signaling, and share some characteristics with adult HCC.
Harding, JJ, S Nandakumar, J Armenia, DN Khalil, M Albano, M Ly, J Shia, JF Hechtman, R Kundra, I El Dika, RK Do, Y Sun, TP Kingham, MI D'Angelica, MF Berger, DM Hyman, W Jarnagin, DS Klimstra, YY Janjigian, DB Solit, N Schultz and GK Abou-Alfa 2019Prospective genotyping of hepatocellular carcinoma: Clinical implications of next-generation sequencing for matching patients to targeted and immune therapies.Clin Cancer Res 25(7): 2116-2126. PURPOSE: Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies. EXPERIMENTAL DESIGN: Matched tumor/normal DNA from patients with HCC (N = 127) were analyzed using a hybridization capture-based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. RESULTS: WNT/beta-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n = 81), oncogenic PI3K-mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (n = 31), activating alteration WNT/beta-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including TSC1/2 (8.5%) inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (<1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics. CONCLUSIONS: Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.
Hyun, J, SH Oh, RT Premont, CD Guy, CL Berg and AM Diehl 2019Dysregulated activation of fetal liver programme in acute liver failure. Gut 68(6): 1076-1087. OBJECTIVE: Uncertainty about acute liver failure (ALF) pathogenesis limits therapy. We postulate that ALF results from excessive reactivation of a fetal liver programme that is induced in hepatocytes when acutely injured livers regenerate. To evaluate this hypothesis, we focused on two molecules with known oncofetal properties in the liver, Yes-associated protein-1 (YAP1) and Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3). DESIGN: We compared normal liver with explanted livers of patients with ALF to determine if YAP1 and IGF2BP3 were induced; assessed whether these factors are upregulated when murine livers regenerate; determined if YAP1 and IGF2BP3 cooperate to activate the fetal programme in adult hepatocytes; and identified upstream signals that control these factors and thereby hepatocyte maturity during recovery from liver injury. RESULTS: Livers of patients with ALF were massively enriched with hepatocytes expressing IGF2BP3, YAP1 and other fetal markers. Less extensive, transient accumulation of similar fetal-like cells that were proliferative and capable of anchorage-independent growth occurred in mouse livers that were regenerating after acute injury. Fetal reprogramming of hepatocytes was YAP1-dependent and involved YAP1-driven reciprocal modulation of let7 microRNAs and IGF2BP3, factors that negatively regulate each other to control fate decisions in fetal cells. Directly manipulating IGF2BP3 expression controlled the fetal-like phenotype regardless of YAP1 activity, proving that IGF2BP3 is the proximal mediator of this YAP1-directed fate. CONCLUSION: After acute liver injury, hepatocytes are reprogrammed to fetal-like cells by a YAP1-dependent mechanism that differentially regulates let7 and IGF2BP3, identifying novel therapeutic targets for ALF.
Jetten, AM 2019Emerging roles of GLI-similar kruppel-like zinc finger transcription factors in leukemia and other cancers.Trends Cancer 5(9): 547-557. GLI-similar 1-3 (GLIS1-3), a subfamily of Kruppel-like zinc finger transcription factors, function as key regulators of several biological processes important to oncogenesis, including control of cell proliferation, differentiation, self-renewal, and epithelial-mesenchymal transition. This review provides a short overview of the critical roles genetic changes in GLIS1-3 play in the development of several malignancies. This includes intrachromosomal translocations involving GLIS2 and ETO2/CBFA2T3 in the development of pediatric non-Down's syndrome (DS), acute megakaryoblastic leukemia (AMKL), a malignancy with poor prognosis, and an association of interchromosomal translocations between GLIS3, GLIS1, and PAX8, and between GLIS3 and CLPTM1L with hyalinizing trabecular tumors (HTTs) and fibrolamellar hepatocellular carcinoma (FHCC), respectively. Targeting upstream signaling pathways that regulate GLIS signaling may offer new therapeutic strategies in the management of cancer.
Karki, A, J Putra, SS Kim, MJ Laquaglia, AR Perez-Atayde, G Sadri-Vakili and K Vakili 2019MDM4 expression in fibrolamellar hepatocellular carcinoma.Oncol Rep 42(4): 1487-1496. Fibrolamellar hepatocellular carcinoma (FLHCC) is a variant of hepatocellular carcinoma (HCC) that most commonly affects adolescents and young adults and is associated with an extremely poor prognosis due to the lack of effective chemotherapeutic agents. Mutations in p53 are a common oncogenic driver in HCC but not in FLHCC. However, in tumors lacking a p53 mutation, the tumor suppressor activity of p53 has been revealed to be dysregulated in several different cancer types. One mechanism has been attributed to the overexpression of mouse double minute 4 protein (MDM4), a negative regulator of p53, which inhibits the normal functions of p53 including induction of apoptosis and DNA repair. Therefore, restoring the normal function of p53 in cancer cells by targeting MDM4 has become a potential therapeutic strategy. Hence, in the present study the components of the DNA damage response (DDR) pathway were examined; ATM, p53, and MDM4 in FLHCC. Seven FLHCC tumors along with their adjacent nonneoplastic hepatic tissues were examined. Ataxiatelangiectasia mutated (ATM), p53, and MDM4 protein expression was assessed using western blot analysis and cellular localization was determined using immunohistochemistry (IHC). MDM4 mRNA transcript levels were assessed using RTqPCR. The present results demonstrated that the DNA damage sensor, ATM, is phosphorylated and localized to the nuclei of tumor cells. While there was a significant increase in total p53 protein in tumor cells, phosphorylated p53 was revealed to preferably localize to the cytoplasmic compartment of tumor cells. Notably, the present results revealed that MDM4 transcript levels were increased in the majority of tumor samples and the nuclear MDM4 levels were significantly increased in tumor tissue compared to their adjacent nonneoplastic liver tissue. The present results indicated that increased MDM4 expression and nuclear localization may be a potential mechanism for p53 dysregulation in FLHCC.
Kastenhuber, ER, J Craig, J Ramsey, KM Sullivan, J Sage, S de Oliveira, KJ Riehle, JD Scott, JD Gordan, N Bardeesy and GK Abou-Alfa 2019Road map for fibrolamellar carcinoma: progress and goals of a diversified approach.J Hepatocell Carcinoma 6: 41-48. Fibrolamellar carcinoma is a rare liver cancer, which primarily afflicts adolescents and young adults worldwide and is frequently lethal. Given the rarity of this disease, patient recruitment for clinical trials remains a challenge. In November 2017, the Second Fibrolamellar Cancer Foundation Scientific Summit (Stamford, CT, USA) provided an opportunity for investigators to discuss recent advances in the characterization of the disease and its surrounding liver and immune context. The Fibrolamellar Cancer Foundation has thus set out a road map to identify and test therapeutic targets in the most efficient possible manner.
Kim, AK, F Gani, AJ Layman, S Besharati, Q Zhu, F Succaria, EL Engle, F Bhaijee, MB Goggins, NJ Llosa, TM Pawlik, M Yarchoan, EM Jaffee, HC Simons, JM Taube and RA Anders 2019Multiple immune-suppressive mechanisms in fibrolamellar carcinoma. Cancer Immunol Res 7(5): 805-812. Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that affects adolescents and young adults. The most effective treatment for FLC is surgical resection, but no standardized systemic therapy exists for patients with recurrent or unresectable FLC. As a first step to understand the immune microenvironment of FLC, we investigated targetable immune-checkpoint pathways, PD-1, PD-L1, B7-H3, IDO-1, and LAG3, in relation to CD8(+) cytotoxic T-lymphocyte density. Thirty-two FLC tumor specimens were analyzed using IHC staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. Sixty-three percent of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1(+) tumor-infiltrating lymphocytes and tumor-associated macrophages (TIL/TAM). Myeloid-derived cells appeared to be a major component of PD-L1(+) tumor-infiltrating immune cells. Forty percent of the cases showed B7-H3 expression in the tumor zone, with 91% cases showing B7-H3 expression in TILs and TAMs. IDO and PD-1 expression was highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8(+) T-cell density. In conclusion, a high proportion of FLC cases showed robust expression of PD-1, PD-L1, B7-H3, and IDO in an adaptive immune-resistance pattern. Our findings provide further basis for targeting these different immune-checkpoint axes in FLC.
Lafaro, KJ, OS Eng, M Raoof, P Ituarte, SG Warner, G Singh, Y Fong and LG Melstrom 2019A prognostic nomogram for patients with resected fibrolamellar hepatocellular carcinoma. Hepatobiliary Surg Nutr 8(4): 338-344. Background: Fibrolamellar hepatocellular carcinoma (FLHC) is a unique entity compared to conventional hepatocellular carcinoma. The aim of this study was to examine post-resection outcomes and prognostic indicators for survival in this group of FLHC patients. Methods: A retrospective analysis of the National Cancer Database (NCDB) for patients with FLHC who underwent resection from 2004 to 2014 was performed. Univariate and multivariate Cox proportional hazard models were used to identify factors associated with overall survival, and a prognostic nomogram was generated. Results: There were 197 patients identified, 171 (86.8%) of whom had long-term follow-up data. Univariate and multivariate analyses were performed using patient and tumor demographics with the outcome variable of overall survival. On multivariate analysis, age [hazard ratio (HR) 1.03, P=0.003], vascular invasion (HR 1.75, P=0.05), tumor size >7 cm (HR 2.18, P=0.044), multifocal disease (HR 3.34, P=0.002), and node positive (pN+) disease (HR 2.75, P=0.003) were all negative predictors of overall survival. A prognostic nomogram was generated using these factors with a c-statistic superior to that of American Joint Committee on Cancer (AJCC) staging (0.710 vs. 0.654). Conclusions: Independent predictors of decreased overall survival in patients with FLHC include age, vascular invasion, tumor size >7 cm, multifocal disease, and pN+ disease. This is the first study to develop a nomogram exclusively for FLHC that may predict survival in future studies.
Luther, J and JL Dienstag 2019Hardened Liver Due to Fibrolamellar Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 17(1): A27.
Matsukuma, KE and MM Yeh 2019Update on the pathology of liver neoplasms.Ann Diagn Pathol 38: 126-137. Many advances have developed in the pathology of liver tumors in the recent decade. Examples of these advances include the use of glutamine synthetase in the diagnosis of focal nodular hyperplasia, subtyping of hepatocellular adenomas using molecular and immunohistochemical methods, the unraveling of the fusion transcript between the DNAJB1 gene and the PRKACA gene in fibrolamellar carcinoma, and the more unified classification and terminology in intrahepatic bile duct tumors and their precursor lesions. Nevertheless, challenges still remain, e.g., the differential diagnosis between well-differentiated hepatocellular carcinoma and hepatocellular adenoma; distinction among poorly differentiated hepatocellular carcinoma, cholangiocarcinoma and metastatic neoplasm; terminology of the combined hepatocellular carcinoma-cholangiocarcinoma, etc. This review aims to address updates in the pathologic diagnosis and clinical relevance of tumors of the liver and intrahepatic bile ducts in adults and their differential diagnosis and diagnostic pitfalls.
Riehle, KJ, HL Kenerson, KM Riggle, R Turnham, K Sullivan, R Bauer, JD Scott and RS Yeung 2019Neurotensin as a source of cyclic AMP and co-mitogen in fibrolamellar hepatocellular carcinoma. Oncotarget 10(49): 5092-5102. Fibrolamellar hepatocellular carcinomas (FL-HCCs) possess a unique mutation that encodes a chimeric form of protein kinase A (DNAJ-PKAc), which includes a chaperonin binding domain. DNAJ-PKAc retains most of the biochemical properties of the native enzyme, however, and activity remains dependent on cAMP. We thus speculated that a persistent source of cAMP is necessary to promote FL-HCC carcinogenesis, and that neurotensin (NTS) may drive cAMP production in this setting, given that NS serum and tumor levels are elevated in many patients with FL-HCC. We examined expression of NTS pathway components in human FL-HCCs and paired normal livers, and determined the role of NTS in driving proliferation in tumor slice cultures. Cultured hepatocytes were used to determine interactions between NTS and other proliferative pathways, and to determine the effects of NTS on cAMP production and PKA activity. We found that the NTS pathway is up-regulated in human FL-HCCs, and that NTS activates cAMP and PKA in hepatocytes. NTS increases proliferation in the presence of epidermal growth factor (EGF), and NTS-induced proliferation is dependent on NTSR1 and the EGFR/MEK pathway. We conclude that NTS serves as a co-mitogen in FL-HCC, and provides a source of cAMP to facilitate ongoing activation of DNAJ-PKAc.
Santiago-Reynoso, J, KS Zamaripa-Martinez, JM Dorantes-Loya, GJ Gaytan-Fernandez, E Apolinar-Jimenez, F Paz-Gomez, F Farias-Serratos and M Maldonado-Vega 2019Hepatocellular carcinoma of fibrolamellar type in an adolescent: case report and literature review. Gastrointest Tumors 6(1-2): 43-50. We present a female patient, 13 years old, with diagnosis of hepatocellular carcinoma of fibrolamellar type, which was rapidly evolving. The fibrolamellar hepatocellular carcinoma invaded more than 80% of the hepatic parenchyma without surgical possibility or liver transplantation. Measures applied corresponded to chemotherapy of 1 cycle of cisplatin 40 mg/s/5 days + vincristine 1.5 mg/m2/day, 5-fluorouracil, doxorubicin, and dexrazoxane. The case presented aggressive evolution of hepatocellular carcinoma, which led to acute liver failure, with hyperammonemia, sepsis, pulmonary focus plus septic shock, grade III-IV encephalopathy, portal hypertension, and ascites with intra-abdominal hypertension. Death occurred due to multiple organ failure, which involved respiratory failure type KDIGO 1 and 2, acute liver failure, severe pneumonia, pericardial effusion, AKIN 2 acute kidney injury, carcinoma, and pulmonary metastasis. This type of ailment is infrequent in children and adolescents, and the first symptoms are crucial to achieve treatment possibilities.
Schalm, SS, E O’Hearn, K Wilson, T LaBranche, G Silva, D L., N Bifulco, R Woessner, N Stransky, D Sappal, A Shutes, R Campbell, R Lobbardi, M Palmer, J Kim, S Miller, M Dorsch, C Lengauer, T Guzi, V Kadambi, A Garner and KP Hoeflich 2019Evaluating PRKACA as a therapeutic target for Fibrolamellar Carcinoma (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B127. doi:10.1158/1535-7163.TARG-19-B127Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B127. doi:10.1158/1535-7163.TARG-19-B127 Introduction: Fibrolamellar Carcinoma (FLC) is a rare primary liver malignancy, affecting children and young adults without chronic liver disease. FLC tumors are largely resistant to chemotherapy, making the identification of effective treatment options urgently needed. Recent genomic data strongly suggest that DNAJB1-PRKACA kinase fusions are the drivers of the vast majority of FLC cases. However, it has not been assessed whether FLC tumors remain dependent on DNAJB1-PRKACA expression and whether PRKACA inhibition could be a therapeutic approach for FLC. Here we summarize the preclinical evaluation of PRKACA as a potential therapeutic target for FLC. Methods: We established a xenograft model from a FLC- patient and then developed inducible PRKACA shRNA cell lines from this model. We also designed potent tool compounds that selectively inhibit the PRKACA protein to assess PRKACA as a potential therapeutic target for FLC. Results: We characterized a patient-derived xenograft (PDX) model of FLC (LI5132) and confirmed DNAJB1-PRKACA fusion expression and constitutive PRKACA pathway activation measured by phospho-VASP. The model also shows fibrolamellar type histology by H&E staining and expression of typical FLC markers like cytokeratin 7 and CD68 by IHC. Using inducible PRKACA-specific shRNA cell lines from this PDX model we demonstrated that the FLC transcriptional gene signature correlates strongly with expression of the DNAJB1-PRKACAfusion protein. Importantly, we demonstrated for three inducible PRKACA shRNA cell-line-derived xenograft models that the in vivo tumor growth remained dependent on DNAJB1-PRKACA fusion expression (TGI-72%-78%, day 22). PRKACA knockdown tumors displayed reduced Ki67 index (6.4 %) when compared to non-induced controls (37.1 %) further confirming that proliferation of the tumors depends on the fusion expression. To investigate the PRKACA catalytic dependency of the FLC model, we designed potent and selective PRKACA inhibitors based on starting points from our proprietary kinase inhibitor library. These investigational compounds are the first selective and potent PRKACA inhibitors and provide excellent tools to assess in vitro and in vivo PRKACA dependency. These compounds achieved potent PRKACA pathway inhibition and dose-dependent inhibition of FLC-specific gene expression, including genes such as carbamoyl phosphate synthetase (CPS1) and forkhead box C1 (FoxC1). We established a pharmacokinetic/ pharmacodynamic relationship and demonstrated in vivo PRKACA pathway inhibition in PDX tumors, as measured by phospho-VASP. Importantly, oral delivery of a potent and selective PRKACA inhibitor achieved up to 80% PRKACA kinase inhibition and led to statistically significant FLC tumor growth inhibition (54%, day 34) on a tolerated schedule. These data demonstrate that FLC depends on PRKACA kinase activity. Conclusion: This study is the first evaluation of PRKACA kinase inhibition as a therapeutic approach for FLC. The results from these preclinical experiments provide strong evidence that FLC depends on PRKACA catalytic activity and that novel PRKACA inhibitors may significantly decrease tumor growth in vivo.
Tsuge, S, B Saberi, Y Cheng, Z Wang, A Kim, H Luu, JM Abraham, MD Ybanez, JP Hamilton, FM Selaru, C Villacorta-Martin, F Schlesinger, B Philosophe, AM Cameron, Q Zhu, R Anders, A Gurakar and SJ Meltzer 2019Detection of novel fusion transcript VTI1A-CFAP46 in hepatocellular carcinoma. Gastrointest Tumors 6(1-2): 11-27. BACKGROUND: Hepatocellular carcinoma (HCC) is now the second-highest cause of cancer death worldwide. Recent studies have discovered a wide range of somatic mutations in HCC. These mutations involve various vital signaling pathways such as: Wnt/beta-Catenin, p53, telome-rase reverse transcriptase (TERT), chromatin remodeling, RAS/MAPK signaling, and oxidative stress. However, fusion transcripts have not been broadly explored in HCC. METHODS: To identify novel fusion transcripts in HCC, in the first phase of our study, we performed targeted RNA sequencing (in HCC and paired non-HCC tissues) on 6 patients with a diagnosis of HCC undergoing liver transplantation. RESULTS: As a result of these studies, we discovered the novel fusion transcript, VTI1A-CFAP46. In the second phase of our study, we measured the expression of wild-type VTI1A in 21 HCC specimens, which showed that 10 of 21 exhibited upregulation of wild-type VTI1A in their tumors. VTI1A (Vesicle Transport via Interaction with t-SNARE homolog 1A) is a member of the Soluble N-ethylmaleimide-Sensitive Factor (NSF) attachment protein receptor (SNARE) gene family, which is essential for membrane trafficking and function in endocytosis, autophagy, and Golgi transport. Notably, it is known that autophagy is involved in HCC. CONCLUSIONS: The link between novel fusion transcript VTI1A-CFAP46 and autophagy as a potential therapeutic target in HCC patients deserves further investigation. Moreover, this study shows that fusion transcripts are worthy of additional exploration in HCC.
Turnham, RE, FD Smith, HL Kenerson, MH Omar, M Golkowski, I Garcia, R Bauer, HT Lau, KM Sullivan, LK Langeberg, SE Ong, KJ Riehle, RS Yeung and JD Scott 2019An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma.Elife 8. Fibrolamellar carcinoma (FLC) is a rare liver cancer. FLCs uniquely produce DNAJ-PKAc, a chimeric enzyme consisting of a chaperonin-binding domain fused to the Calpha subunit of protein kinase A. Biochemical analyses of clinical samples reveal that a unique property of this fusion enzyme is the ability to recruit heat shock protein 70 (Hsp70). This cellular chaperonin is frequently up-regulated in cancers. Gene-editing of mouse hepatocytes generated disease-relevant AML12(DNAJ-PKAc) cell lines. Further analyses indicate that the proto-oncogene A-kinase anchoring protein-Lbc is up-regulated in FLC and functions to cluster DNAJ-PKAc/Hsp70 sub-complexes with a RAF-MEK-ERK kinase module. Drug screening reveals Hsp70 and MEK inhibitor combinations that selectively block proliferation of AML12(DNAJ-PKAc) cells. Phosphoproteomic profiling demonstrates that DNAJ-PKAc biases the signaling landscape toward ERK activation and engages downstream kinase cascades. Thus, the oncogenic action of DNAJ-PKAc involves an acquired scaffolding function that permits recruitment of Hsp70 and mobilization of local ERK signaling.
Ward, E, RL Sherman, SJ Henley, A Jemal, DA Siegel, EJ Feuer, AU Firth, BA Kohler, S Scott, J Ma, RN Anderson, V Benard and K Cronin 2019Annual report to the nation on the status of cancer, 1999-2015, featuring cancer in men and women ages 20-49. J Natl Cancer Inst. BACKGROUND: The American Cancer Society, Centers for Disease Control and Prevention, National Cancer Institute, and North American Association of Central Cancer Registries (NAACCR) provide annual updates on cancer occurrence and trends by cancer type, sex, race, ethnicity, and age in the US. This year's report highlights the cancer burden among men and women ages 20-49 years. METHODS: Incidence data from the Centers for Disease Control and Prevention- and National Cancer Institute- funded population-based cancer registry programs compiled by NAACCR and death data from the National Vital Statistics System were used. Trends in age-standardized incidence and death rates, estimated by joinpoint, were expressed as average annual percent change. RESULTS: Overall cancer incidence rates (per 100,000) for all ages during 2011-2015 were 494.3 among men and 420.5 among women; during the same time period, incidence rates decreased 2.1% (95% confidence interval [CI] = -2.6% to -1.6%) per year in males and were stable in females. During 2012-2016, overall cancer death rates for all ages decreased 1.8% (95% CI = -1.8% to -1.8%) per year in males and 1.4% (95% CI =-1.4% to -1.4%) per year in females. Important changes in trends were stabilization of thyroid cancer incidence rates in women and rapid declines in death rates for melanoma of the skin (both sexes). Among adults ages 20-49, overall cancer incidence rates were substantially lower among males (115.3 per 100,000) than among females (203.3 per 100,000); cancers with the highest incidence rates (per 100,000) among males were colon and rectum (13.1), testis (10.7) and melanoma of the skin (9.8) and among females were breast (73.2), thyroid (28.4) and melanoma of the skin (14.1). During 2011 to 2015, the incidence of all invasive cancers combined among adults ages 20-49 decreased among males (five-year AAPC = -0.7%; 95% CI = -1.0% to -0.4%) and increased among females (1.3%; 95% CI = 0.7% to 1.9%). The death rate (per 100,000) adults ages 20-49 for all cancer sites combined during 2012 to 2016 was 22.8 among males and 27.1 among females; during the same time period, death rates decreased 2.3% (95% CI = -2.4% to -2.2%) per year among males and 1.7% (95% CI = -1.8% to -1.6%) per year among females.. CONCLUSIONS: Among people of all ages and ages 20-49, both favorable and unfavorable trends in site-specific cancer incidence were observed, while trends in death rates were generally favorable. Characterizing the cancer burden may inform research and cancer control efforts.
Weeda, VB, DC Aronson, J Verheij and WH Lamers 2019Is hepatocellular carcinoma the same disease in children and adults? Comparison of histology, molecular background, and treatment in pediatric and adult patients. Pediatr Blood Cancer 66(2): e27475. Pediatric hepatocellular carcinoma (HCC) is rare, resulting in scattered knowledge of tumor biology and molecular background. Thus far, the variant in children has been treated as a different entity from adult HCC. We weigh the hypothesis that HCC in the pediatric and adult groups may be the same entity and may benefit from the same treatment. Although certain differences between adult and pediatric HCC are obvious and certain types of HCC may ask for a customized approach, in conventional HCC, similarities predominate, warranting treatment aiming at common molecular targets in adult and pediatric HCC patients.
Wolosz, D, A Walczak, G Szparecki, M Dwojak, M Winiarska, E Wolinska and B Gornicka 2019Deleted in Liver Cancer 2 (DLC2) protein expression in hepatocellular carcinoma.Eur J Histochem 63(1). Deleted in Liver Cancer (DLC) proteins belong to the family of RhoGAPs and are believed to operate as negative regulators of the Rho family of small GTPases. So far, the role of the first identified member from the DLC family, DLC1, was established as a tumor suppressor in hepatocellular carcinoma. The function of its close family relative, DLC2 is unequivocal. In the present study we attempted to determine whether the loss of DLC2 is a common feature of hepatocellular carcinoma tissue. We examined two types of hepatocellular carcinoma- typical and fibrolamellar one. Our analysis revealed that DLC2 protein is not diminished in cancer tissue when compared to non-cancerous liver specimens. What is more, we observed DLC2 to be more abundantly expressed in cancer tissue, particularly in tumors with the inflammation background. In addition, we found that DLC2 gene status was diploid in virtually all tumor samples examined. Our results indicate that DLC2 is not diminished in hepatocellular carcinoma cells. It appears that members of the DLC family, although structurally highly related, may function differently in cancer cells.
Yeung, R, L Beaton, T Rackley, B Weber, J Hamm, R Lee, M Camborde, M Pearson, C Duzenli, SK Loewen, M Liu, R Ma and D Schellenberg 2019Stereotactic body radiotherapy for small unresectable hepatocellular carcinomas.Clin Oncol (R Coll Radiol) 31(6): 365-373. AIMS: Stereotactic body radiotherapy (SBRT) is an option for the treatment of hepatocellular carcinoma (HCC) in patients ineligible for standard local therapies. This study reports on the safety and efficacy of SBRT in small HCC tumours (/= grade 3 + toxicities. One-year local control and overall survival were 94 and 84%, respectively. One-year progression-free survival was 49%; 81% of patients with disease progression received further HCC therapy. On univariate analysis, small tumour size predicted for improved overall survival (P = 0.01) whereas prescription biological equivalent dose (BED10) >/=100Gy10 approached significance (P = 0.06). CONCLUSION: SBRT provides high local control to small inoperable HCC. SBRT can be delivered safely even after previous liver-directed therapies and further liver therapies can follow treatment with SBRT. Although overall 32% of patients experienced >/= grade 3 + toxicities, and 19% had a deterioration in Child-Pugh score of two or more points, these changes were mainly transient with minimal clinical impact. Despite excellent local control, disease progression outside of the irradiated site remains prominent. Further studies are warranted to examine combined therapy approaches to maximise disease control.
Zakka, K, R Jiang, OB Alese, WL Shaib, C Wu, JP Wedd, MT Sellers, M Behera, BF El-Rayes and M Akce 2019Clinical outcomes of rare hepatocellular carcinoma variants compared to pure hepatocellular carcinoma. J Hepatocell Carcinoma 6: 119-129. Background: HCC variants are rare primary hepatic tumors. The aim of this study is to compare clinical characteristics and outcomes of HCC variants with pure HCC. Methods: Patients diagnosed between 2004 and 2013 with ICD-O-3 8180/3 and 8170/3-8175/3 were identified from the National Cancer Database. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results: 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p<0.001). Pure HCC (10.6%) underwent surgical resection without transplant less often than variants except for scirrhous (9.9%) (p<0.001). More than a third of patients in each histological type received chemotherapy. FLHCC had the best 5-year OS (38.7%), spindle cell and pleomorphic had the worst (9.6% and 13.0%). In multivariate analysis stratified by histology variants, chemotherapy was associated with improved OS in all histologies except for scirrhous and pleomorphic HCC. Conclusion: HCC variants underwent surgical resection more often than pure HCC. FLHCC had the best 5-year OS. Liver transplant was commonly performed in HCC variants.
Abitbol, S, R Dahmani, C Coulouarn, B Ragazzon, B Mlecnik, N Senni, M Savall, P Bossard, P Sohier, V Drouet, E Tournier, F Dumont, R Sanson, J Calderaro, J Zucman-Rossi, M Vasseur-Cognet, PA Just, B Terris, C Perret and H Gilgenkrantz 2018AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of beta-catenin activation. J Hepatol 68(6): 1203-1213. BACKGROUND & AIMS: The Wnt/beta-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Inactivating mutations of the gene encoding AXIN1, a known negative regulator of the Wnt/beta-catenin signaling pathway, are observed in about 10% of HCCs. Whole-genome studies usually place HCC with AXIN1 mutations and CTNNB1 mutations in the group of tumors with Wnt/beta-catenin activated program. However, it has been shown that HCCs with activating CTNNB1 mutations form a group of HCCs, with a different histology, prognosis and genomic signature to those with inactivating biallelic AXIN1 mutations. We aimed to elucidate the relationship between CTNNB1 mutations, AXIN1 mutations and the activation level of the Wnt/beta-catenin program. METHODS: We evaluated two independent human HCC datasets for the expression of a 23-beta-catenin target genes program. We modeled Axin1 loss of function tumorigenesis in two engineered mouse models and performed gene expression profiling. RESULTS: Based on gene expression, we defined three levels of beta-catenin program activation: strong, weak or no activation. While more than 80% CTNNB1-mutated tumors were found in the strong or in the weak activation program, most of the AXIN1-mutated tumors (>70%) were found in the subgroup with no activation. We validated this result by demonstrating that mice with a hepatocyte specific AXIN1 deletion developed HCC in the absence of beta-catenin induction. We defined a 329-gene signature common in human and mouse AXIN1 mutated HCC that is highly enriched in Notch and YAP oncogenic signatures. CONCLUSIONS: AXIN1-mutated HCCs occur independently of the Wnt/beta-catenin pathway and involve Notch and YAP pathways. These pathways constitute potentially interesting targets for the treatment of HCC caused by AXIN1 mutations. LAY SUMMARY: Liver cancer has a poor prognosis. Defining the molecular pathways involved is important for developing new therapeutic approaches. The Wnt/beta-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Mutations of AXIN1, a member of this pathway, represent about 10% of HCC mutations. Using both human HCC collections and engineered mouse models of liver cancers with AXIN1 mutation or deletion, we defined a common signature of liver tumors mutated for AXIN1 and demonstrate that these tumors occur independently of the activation of the Wnt/beta-catenin pathway.
Andrade, RC, M de Lima, PAS de Faria and FR Vargas 2018TP53 germline and somatic mutations in a patient with fibrolamellar hepatocellular carcinoma.Fam Cancer 17(1): 119-122. Li-Fraumeni syndrome is a rare hereditary cancer predisposition syndrome associated with germline pathogenic variants in TP53 gene. The phenotype may vary from classical to variant forms, known as Li-Fraumeni-like phenotypes. We searched for pathogenic variants in TP53 in a 14 year-old female diagnosed with fibrolamellar hepatocellular carcinoma, a rare subtype of hepatocellular carcinoma. The proband is a heterozygote carrier of the TP53 c.467G>A (p.Arg156His) in exon 5, and her mother is an asymptomatic carrier. Analysis of tumor DNA disclosed an additional somatic mutation in TP53, c.461G>A; p.Gly154Asp. The TP53 germline and somatic pathogenic variants may have acted as possible driver mutations, resulting in genomic instability and tumor development. The fibrolamellar subtype of hepatocellular carcinoma may be part of the broad spectrum of tumors associated with Li-Fraumeni phenotype.
Bangru, S, W Arif, J Seimetz, A Bhate, J Chen, EH Rashan, RP Carstens, S Anakk and A Kalsotra 2018Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration.Nat Struct Mol Biol 25(10): 928-939. During liver regeneration, most new hepatocytes arise via self-duplication; yet, the underlying mechanisms that drive hepatocyte proliferation following injury remain poorly defined. By combining high-resolution transcriptome and polysome profiling of hepatocytes purified from quiescent and toxin-injured mouse livers, we uncover pervasive alterations in messenger RNA translation of metabolic and RNA-processing factors, which modulate the protein levels of a set of splicing regulators. Specifically, downregulation of the splicing regulator ESRP2 activates a neonatal alternative splicing program that rewires the Hippo signaling pathway in regenerating hepatocytes. We show that production of neonatal splice isoforms attenuates Hippo signaling, enables greater transcriptional activation of downstream target genes, and facilitates liver regeneration. We further demonstrate that ESRP2 deletion in mice causes excessive hepatocyte proliferation upon injury, whereas forced expression of ESRP2 inhibits proliferation by suppressing the expression of neonatal Hippo pathway isoforms. Thus, our findings reveal an alternative splicing axis that supports regeneration following chronic liver injury.
Barry, KC, J Hsu, ML Broz, FJ Cueto, M Binnewies, AJ Combes, AE Nelson, K Loo, R Kumar, MD Rosenblum, MD Alvarado, DM Wolf, D Bogunovic, N Bhardwaj, AI Daud, PK Ha, WR Ryan, JL Pollack, B Samad, S Asthana, V Chan and MF Krummel 2018A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments.Nat Med 24(8): 1178-1191. Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.
Bartlett, AL, ND Leslie, A Gupta and JI Geller 2018Acquired ornithine transcarbamylase deficiency in pediatric and adolescent patients with fibrolamellar hepatocellular carcinoma. Pediatr Blood Cancer 65(12): e27392. Ornithine transcarbamylase deficiency (OTCD) disrupts the metabolic pathway responsible for converting nitrogenous waste to urea, allowing for excretion. When impaired, ammonia levels accumulate in the blood resulting in severe, sometimes life-threatening toxicities. Abnormalities of the urea cycle are often inherited, though there are some rarer acquired forms. We describe two cases of acquired OTCD in pediatric patients with fibrolamellar hepatocellular carcinoma (FL-HCC). We detail its presentation and management, explore potential underlying pathophysiology, and propose a practice change to optimize care of FL-HCC patients.
Bill, R, M Montani, B Blum, JF Dufour, R Escher and M Buhlmann 2018Favorable response to mammalian target of rapamycin inhibition in a young patient with unresectable fibrolamellar carcinoma of the liver.Hepatology.
Brown, ZJ, SJ Yu, B Heinrich, C Ma, Q Fu, M Sandhu, D Agdashian, Q Zhang, F Korangy and TF Greten 2018Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. Cancer Immunol Immunother 67(8): 1305-1315. Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies has shown promising results in the treatment of patients with advanced HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had progressive disease on the current standard of care. However, a subset of patients with advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy. Here, we provide evidence of adaptive resistance to immune checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO) in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC tumors but not in tumors sensitive to immune checkpoint blockade. Using both subcutaneous and hepatic orthotopic models, we found that the addition of an IDO inhibitor increases the efficacy of treatment in HCC resistant tumors with high IDO induction. Furthermore, in vivo neutralizing studies demonstrated that the IDO induction by immune checkpoint blockade was dependent on IFN-gamma. Similar findings were observed with anti-PD-1 therapy. These results provide evidence that IDO may play a role in adaptive resistance to immune checkpoint inhibitors in patients with HCC. Therefore, inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.
Cano, L, JP Cerapio, E Ruiz, A Marchio, B Turlin, S Casavilca, L Taxa, G Marti, E Deharo, P Pineau and S Bertani 2018Liver clear cell foci and viral infection are associated with non-cirrhotic, non-fibrolamellar hepatocellular carcinoma in young patients from South America. Sci Rep 8(1): 9945. We previously described a divergent clinical and molecular presentation of hepatocellular carcinoma (HCC) in Peru. The present study aimed to further characterize the tissue features associated with this singular nosological form of HCC in order to gain insight into the natural history of the disease. We performed an exploratory analysis of the histology of both tumor and non-tumor liver (NTL) tissues from 50 Peruvian HCC patients, and compared with that of 75 individuals with non-HCC liver tumor or benign liver lesions as a baseline for NTL features. We complemented this approach with a transcriptome analysis in a subset of NTL tissue samples and also performed an ultra-sensitive hepatitis B virus (HBV) detection in liver tissues of the patients. Overall, results highlighted the low rate of liver parenchymal alterations in a young patient cohort (median age: 40 years old), despite a strong prevalence of underlying HBV infection (c. 67%). Withal, liver clear cell foci of cellular alteration were genuinely associated with HCC and appended to some changes in immune and G protein-coupled receptor gene expression ontologies. Our findings confirm the occurrence of a particular setting of HCC in South America, a region where the pathophysiology of liver cancer remains largely unexplored.
Chakraborty, U, TA Dinh and E Alani 2018Genomic instability promoted by overexpression of mismatch repair factors in yeast: A model for understanding cancer progression.Genetics 209(2): 439-456. Mismatch repair (MMR) proteins act in spellchecker roles to excise misincorporation errors that occur during DNA replication. Curiously, large-scale analyses of a variety of cancers showed that increased expression of MMR proteins often correlated with tumor aggressiveness, metastasis, and early recurrence. To better understand these observations, we used The Cancer Genome Atlas and Gene Expression across Normal and Tumor tissue databases to analyze MMR protein expression in cancers. We found that the MMR genes MSH2 and MSH6 are overexpressed more frequently than MSH3, and that MSH2 and MSH6 are often cooverexpressed as a result of copy number amplifications of these genes. These observations encouraged us to test the effects of upregulating MMR protein levels in baker's yeast, where we can sensitively monitor genome instability phenotypes associated with cancer initiation and progression. Msh6 overexpression (two- to fourfold) almost completely disrupted mechanisms that prevent recombination between divergent DNA sequences by interacting with the DNA polymerase processivity clamp PCNA and by sequestering the Sgs1 helicase. Importantly, cooverexpression of Msh2 and Msh6 ( approximately eightfold) conferred, in a PCNA interaction-dependent manner, several genome instability phenotypes including increased mutation rate, increased sensitivity to the DNA replication inhibitor HU and the DNA-damaging agents MMS and 4-nitroquinoline N-oxide, and elevated loss-of-heterozygosity. Msh2 and Msh6 cooverexpression also altered the cell cycle distribution of exponentially growing cells, resulting in an increased fraction of unbudded cells, consistent with a larger percentage of cells in G1. These novel observations suggested that overexpression of MSH factors affected the integrity of the DNA replication fork, causing genome instability phenotypes that could be important for promoting cancer progression.
Chaudhari, VA, K Khobragade, M Bhandare and SV Shrikhande 2018Management of fibrolamellar hepatocellular carcinoma. Chin Clin Oncol 7(5): 51. Fibrolamellar hepatocellular carcinoma (FLHCC) is a primary liver tumor. It is a pathologically distinct variety of hepatocellular carcinoma (HCC). The term 'fibrolamellar' is derived from the presence of thick fibrous collagen bands surrounding the tumor cells. It is a relatively rare tumor of unknown biology. It has a distinctive predilection for adolescents and young adults with no underlying liver disease or cirrhosis. FLHCC patients have higher incidence of lymph node involvement than conventional HCC patients probably owing to larger median tumor size at presentation. Most cases present at an advanced stage at the time of initial diagnosis, however, curative intent treatment options can still be offered to up to 70% of patients. Surgery (resection/liver transplantation) is the current mainstay of treatment and remains the only potentially curative option. As recurrences are common, alternative therapies are under investigation. FLHCCs have traditionally been considered less chemo-responsive than their conventional HCC counterparts, but in advanced cases multimodality treatments can be effective. Compared to stage-matched non-cirrhotic patients with HCC, patients with FLHCC do not have a favourable prognosis and do not respond differently to treatment. The survival advantage observed in FLHCC over conventional HCC is most likely due to younger age at presentation and absence of cirrhosis.
Cho, YS, J Zhu, S Li, B Wang, Y Han and J Jiang 2018Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K. Nat Commun 9(1): 1657. Hippo (Hpo) signaling pathway controls tissue growth by regulating the subcellular localization of Yorkie (Yki)/Yap via a cytoplasmic kinase cassette containing an upstream kinase Hpo/MST1/2 and a downstream kinase Warts (Wts)/Lats1/2. Here we show that PRP4K, a kinase involved in mRNA splicing, phosphorylates Yki/Yap in the nucleus to prevent its nuclear accumulation and restrict Hpo pathway target gene expression. PRP4K inactivation accelerates whereas excessive PRP4K inhibits Yki-driven tissue overgrowth. PRP4K phosphorylates a subset of Wts/Lats1/2 sites on Yki/Yap to inhibit the binding of Yki/Yap to the Scalloped (Sd)/TEAD transcription factor and exclude Yki/Yap nuclear localization depending on nuclear export. Furthermore, PRP4K inhibits proliferation and invasiveness of cultured breast cancer cells and its high expression correlates with good prognosis in breast cancer patients. Our study unravels an unanticipated layer of Hpo pathway regulation and suggests that PRP4K-mediated Yki/Yap phosphorylation in the nucleus provides a fail-safe mechanism to restrict aberrant pathway activation.
D'Souza, AM, R Shah, A Gupta, AJ Towbin, M Alonso, JD Nathan, A Bondoc, G Tiao and JI Geller 2018Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma. Pediatr Blood Cancer: e27293. BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is often chemoresistant. Complete surgical resection remains the mainstay of therapy. The role of liver transplantation (LT) in pediatric HCC is in evolution, as is the role of adjuvant chemotherapy for stage I disease. METHODS: A retrospective review of patients < 18 years of age with completely resected HCC treated with surgical intervention alone at our institution from 2004 to 2015 was conducted. RESULTS: Twelve patients with a median age of 12 years (range = 1-17; number of females = 7) with upfront resected HCC (Evans stage I) were identified. Four patients had HCC without identifiable risk factors (fibrolamellar-HCC = 2; early HCC arising in focal nodular hyperplasia = 1, well-differentiated [wd] HCC = 1). Four patients had early or wd-HCC in the context of portosystemic shunts (Abernethy = 2; mesocaval shunt and portal vein thrombosis = 2). Four patients had moderate to wd-HCC in the context of pre-existing liver disease with cirrhosis (progressive familial intrahepatic cholestasis type-2 = 2, alpha-1 antitrypsin deficiency = 1, Alagille syndrome = 1). Seven patients underwent LT (multifocal = 5; solitary = 2); five exceeded Milan criteria (MC) by imaging. Five patients underwent complete resection (segmentectomy = 2; hemihepatectomy = 3). Ten patients received no adjuvant chemotherapy. All patients are alive without evidence of disease with a median follow-up of 54.1 months (range = 28.1-157.7 months). CONCLUSIONS: Pediatric and adolescent patients with upfront, completely resected HCC can be effectively treated without chemotherapy. LT should be considered for nonmetastatic HCC, especially in the context of pre-existing chronic liver disease, even when the tumor exceeds MC. Distinct pediatric selection criteria are needed to identify patients most suitable for LT.
DeLeon, TT, DH Ahn, JM Bogenberger, PZ Anastasiadis, M Arora, RK Ramanathan, BA Aqel, G Vasmatzis, MJ Truty, R Oklu, TS Bekaii-Saab and MJ Borad 2018Novel targeted therapy strategies for biliary tract cancers and hepatocellular carcinoma. Future Oncol 14(6): 553-566. Worldwide hepatobiliary cancers are the second leading cause of cancer related death. Despite their relevance, hepatobiliary cancers have a paucity of approved systemic therapy options. However, there are a number of emerging therapeutic biomarkers and therapeutic concepts that show promise. In hepatocellular carcinoma, nivolumab appears particularly promising and recently received US FDA approval. In intrahepatic cholangiocarcinoma, therapies targeting FGFR2 and IDH1 and immune checkpoint inhibitors are the furthest along and generating the most excitement. There are additional biomarkers that merit further exploration in hepatobiliary cancers including FGF19, ERRFI1, TERT, BAP1, BRAF, CDKN2A, tumor mutational burden and ERBB2 (HER2/neu). Development of new and innovative therapies would help address the unmet need for effective systemic therapies in advanced and metastatic hepatobiliary cancers.
Dosset, M, TR Vargas, A Lagrange, R Boidot, F Vegran, A Roussey, F Chalmin, L Dondaine, C Paul, E Lauret Marie-Joseph, F Martin, B Ryffel, C Borg, O Adotevi, F Ghiringhelli and L Apetoh 2018PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. Oncoimmunology 7(6): e1433981. BACKGROUND: Chemotherapy is currently evaluated in order to enhance the efficacy of immune checkpoint blockade (ICB) therapy in colorectal cancer. However, the mechanisms by which these drugs could synergize with ICB remains unclear. The impact of chemotherapy on the PD-1/PD-L1 pathway and the resulting anticancer immune responses was assessed in two mouse models of colorectal cancer and validated in tumor samples from metastatic colorectal cancer patients that received neoadjuvant treatment. We demonstrated that 5-Fluorouracil plus Oxaliplatin (Folfox) drove complete tumor cure in mice when combined to anti-PD-1 treatment, while each monotherapy failed. This synergistic effect relies on the ability of Folfox to induce tumor infiltration by activated PD-1(+) CD8 T cells in a T-bet dependent manner. This effect was concomitantly associated to the expression of PD-L1 on tumor cells driven by IFN-gamma secreted by PD-1+ CD8 T cells, indicating that Folfox triggers tumor adaptive immune resistance. Finally, we observed an induction of PD-L1 expression and high CD8 T cell infiltration in the tumor microenvironment of colorectal cancer patients treated by Folfox regimen. Our study delineates a molecular pathway involved in Folfox-induced adaptive immune resistance in colorectal cancer. The results strongly support the use of immune checkpoint blockade therapy in combination with chemotherapies like Folfox.
Du, K, J Hyun, RT Premont, SS Choi, GA Michelotti, M Swiderska-Syn, GD Dalton, E Thelen, BS Rizi, Y Jung and AM Diehl 2018Hedgehog-YAP Signaling Pathway Regulates Glutaminolysis to Control Activation of Hepatic Stellate Cells. Gastroenterology 154(5): 1465-1479 e1413. BACKGROUND & AIMS: Cirrhosis results from accumulation of myofibroblasts derived from quiescent hepatic stellate cells (Q-HSCs); it regresses when myofibroblastic HSCs are depleted. Hedgehog signaling promotes transdifferentiation of HSCs by activating Yes-associated protein 1 (YAP1 or YAP) and inducing aerobic glycolysis. However, increased aerobic glycolysis alone cannot meet the high metabolic demands of myofibroblastic HSCs. Determining the metabolic processes of these cells could lead to strategies to prevent progressive liver fibrosis, so we investigated whether glutaminolysis (conversion of glutamine to alpha-ketoglutarate) sustains energy metabolism and permits anabolism when Q-HSCs become myofibroblastic, and whether this is controlled by hedgehog signaling to YAP. METHODS: Primary HSCs were isolated from C57BL/6 or Smo(flox/flox) mice; we also performed studies with rat and human myofibroblastic HSCs. We measured changes of glutaminolytic genes during culture-induced primary HSC transdifferentiation. Glutaminolysis was disrupted in cells by glutamine deprivation or pathway inhibitors (bis-2-[5-phenylacetamido-1,2,4-thiadiazol-2-yl] ethyl sulfide, CB-839, epigallocatechin gallate, and aminooxyacetic acid), and effects on mitochondrial respiration, cell growth and migration, and fibrogenesis were measured. Hedgehog signaling to YAP was disrupted in cells by adenovirus expression of Cre-recombinase or by small hairpin RNA knockdown of YAP. Hedgehog and YAP activity were inhibited by incubation of cells with cyclopamine or verteporfin, and effects on glutaminolysis were measured. Acute and chronic liver fibrosis were induced in mice by intraperitoneal injection of CCl4 or methionine choline-deficient diet. Some mice were then given injections of bis-2-[5-phenylacetamido-1,2,4-thiadiazol-2-yl] ethyl sulfide to inhibit glutaminolysis, and myofibroblast accumulation was measured. We also performed messenger RNA and immunohistochemical analyses of percutaneous liver biopsies from healthy human and 4 patients with no fibrosis, 6 patients with mild fibrosis, and 3 patients with severe fibrosis. RESULTS: Expression of genes that regulate glutaminolysis increased during transdifferentiation of primary Q-HSCs into myofibroblastic HSCs, and inhibition of glutaminolysis disrupted transdifferentiation. Blocking glutaminolysis in myofibroblastic HSCs suppressed mitochondrial respiration, cell growth and migration, and fibrogenesis; replenishing glutaminolysis metabolites to these cells restored these activities. Knockout of the hedgehog signaling intermediate smoothened or knockdown of YAP inhibited expression of glutaminase, the rate-limiting enzyme in glutaminolysis. Hedgehog and YAP inhibitors blocked glutaminolysis and suppressed myofibroblastic activities in HSCs. In livers of patients and of mice with acute or chronic fibrosis, glutaminolysis was induced in myofibroblastic HSCs. In mice with liver fibrosis, inhibition of glutaminase blocked accumulation of myofibroblasts and fibrosis progression. CONCLUSIONS: Glutaminolysis controls accumulation of myofibroblast HSCs in mice and might be a therapeutic target for cirrhosis.
Elliott, T 2018Antigen processing movers and shakerNature Chemical Biology 14(8): 747-748Monitoring MHC-I dynamics upon binding to its chaperone TAPBPR helps us understand how optimal peptide sequences are selected for presentation and coordinated with release of the chaperone from the ternary peptide–MHC-I–TAPBPR complex.
Eng, JY, SY Soon and HY Winnie Ling 2018Curative lung metastectomy and complete pathological response after neo-adjuvant GEMOX chemotherapy for relapse fibrolamellar hepatocellular carcinoma. Med J Malaysia 73(1): 46-48. Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of hepatocellular carcinoma. It is commonly reported in the younger population with no underlying chronic liver disease and free of viral Hepatitis B and C. Local recurrence and distant metastasis are common despite better prognosis compared to conventional hepatocellular carcinoma. Complete surgical resection is associated with higher median survival and is the mainstay treatment option for localized FL-HCC. Multi-modality therapies such as TACE can be used to downstage upfront unresectable FL-HCC. Complete response with GEMOX chemotherapy has been reported in advanced metastatic FL-HCC and should be considered in upfront unresectable or metastatic disease. We present a case of biopsied proven relapse FL-HCC with oligo- left lung metastasis who successfully underwent a left lung lobectomy after neo-adjuvant GEMOX chemotherapy, and is disease free at 24 months follow up.
Farber, BA, G Lalazar, EP Simon, WJ Hammond, D Requena, UK Bhanot, MP La Quaglia and SM Simon 2018Non coding RNA analysis in fibrolamellar hepatocellular carcinoma. Oncotarget 9(12): 10211-10227.Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer found in adolescents and young adults without underlying liver disease. A deletion of ~400 kD has been found in one copy of chromosome 19 in the tumor tissue of all patients tested. This produces a fusion of the genes DNAJB1 and PRKACA which, in turn, produces a chimeric transcript and protein. Transcriptomic analysis of the tumor has shown upregulation of various oncologically relevant pathways, including EGF/ErbB, Aurora Kinase A, pak21 and wnt. To explore other factors that may contribute to oncogenesis, we examined the microRNA (miRNA) and long non-coding RNA (lncRNA) expression in FLC. The non-coding RNA expression profile in tumor tissue samples is distinctly different from the adjacent normal liver and from other liver tumors. Furthermore, miRZip knock down or over expression of certain miRNAs led to changes in the levels of coding genes that recapitulated changes observed in FLC, suggesting mechanistically that the changes in the cellular levels of miRNA are not merely correlative. Thus, in addition to serving as diagnostic tools for FLC, non-coding RNAs may serve as therapeutic targets.
Ganeshan, D, J Szklaruk, A Kaseb, A Kattan and KM Elsayes 2018Fibrolamellar hepatocellular carcinoma: multiphasic CT features of the primary tumor on pre-therapy CT and pattern of distant metastases. Abdom Radiol (NY). OBJECTIVE: The aim of our study is to describe the multiphasic CT features of fibrolamellar hepatocellular carcinomas (FLHCCs) and pattern of distant metastases. MATERIALS AND METHODS: 33 patients (mean age 28 years: 17M/16F) with pathologically confirmed FLHCC and pre-treatment multiphasic CT were included in the study. Two abdominal radiologists evaluated the multiphasic CT imaging features of these 33 FLHCC patients in consensus. RESULTS: Solitary hepatic mass was seen in 67% (22/33). Mean tumor size was 11.3 cm (range 4.6-22 cm). Tumor was well-defined in 64% (21/33). In the pre-contrast CT, 91% (30/33) were hypoattenuating. Central stellate scar was present in 73% (24/33). In FLHCC having central stellate scar, calcification within the central scar was seen in 88% (21/24). In the hepatic arterial phase, 82% (27/33) were hyperattenuating relative to liver. In the portal venous phase, 36% (12/33) were hyperattenuating, 46% (15/33) were isoattenuating, and 18% (6/33) were hypoattenuating. In the delayed phase images, 24% (8/23) were hyperattenuating, 67% (22/33) were isoattenuating, and 9% (3/33) were hypoattenuating. Delayed enhancement of the central stellate scar was seen in 12% (4/33). Distant metastases were seen in 54% (18/33). The most common site of metastases was lungs and was seen in 89% (16/18) of the patients with metastatic disease. CONCLUSION: FLHCC typically manifests as a large, solitary mass demonstrating heterogeneous hypervascular enhancement in the arterial phase. Most tend to be isoattenuating in delayed phase. Central stellate scar with internal calcification is a useful imaging feature that can help in the diagnosis of FLHCC. Lungs are the most common site of distant metastases in FLHCC.
Gao, Q, WW Liang, SM Foltz, G Mutharasu, RG Jayasinghe, S Cao, WW Liao, SM Reynolds, MA Wyczalkowski, L Yao, L Yu, SQ Sun, G Fusion Analysis Working, N Cancer Genome Atlas Research, K Chen, AJ Lazar, RC Fields, MC Wendl, BA Van Tine, R Vij, F Chen, M Nykter, I Shmulevich and L Ding 2018Driver fusions and their implications in the development and treatment of human cancers. Cell Rep 23(1): 227-238 e223. Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.
Garg, R, R Srinivasan, P Dey, P Singh, N Gupta and A Rajwanshi 2018Utility of Cytokeratin7 immunocytochemistry in the dytopathological diagnosis of fibrolamellar hepatocellular carcinoma.J Cytol 35(2): 75-78. Objective: To distinguish fibrolamellar hepatocellular carcinoma (FL-HCC) variant from the conventional hepatocellular carcinoma (HCC) by cytology, immunocytochemistry, and morphometry. Study Design: Retrospective detailed cytomorphological, immunocytochemical, and morphometric analysis was performed in 6 cases of FL-HCC reported on fine needle aspiration. Cell block immunocytochemistry (CB-ICC) for CK7 and CD68 was performed in four cases. Morphometry was carried out with Cell A software. Area of the cell, nucleus and nucleolus was measured in 50 nuclei per case in 6 cases each of FL-HCC and HCC. Results: The mean age of patients with FL-HCC was 19 years and all had normal serum alpha-fetoprotein levels. Fine needle aspiration smears showed large polygonal cells with abundant cytoplasm, vesicular nucleus and prominent nucleolus, associated with variably cellular fibrous stromal fragments. Intranuclear inclusions, cytoplasmic eosinophilic inclusions, and bile were also noted. FL-HCC showed strong membrano-cytoplasmic CK7 positivity and cytoplasmic granular and canalicular positivity for CD68. In contrast, HCC showed weak focal positivity for CK7 and only canalicular CD68 positivity. Morphometry revealed that FL-HCC cells were 2.19 times the size of HCC. Conclusion: CK7 immunocytochemistry on cell blocks is useful for confirming and distinguishing it from HCC.
Graham, RP 2018Fibrolamellar carcinoma: what Is new and why it matters.Surg Pathol Clin 11(2): 377-387. Fibrolamellar carcinoma is distinctive at clinical and histologic levels. A novel DNAJB1-PRKACA fusion gene characterizes almost all cases, distinguishes it from other hepatocellular neoplasms, and drives the pathogenesis of this unique tumor. A subset of cases of fibrolamellar carcinoma is associated with alternate mechanisms of protein kinase A activation. This review article discusses common and unusual histologic features of fibrolamellar carcinoma, its differential diagnoses, and how to make the diagnosis while avoiding key pitfalls. The impact of the discovery of the fusion gene on the understanding of the tumor and the prognosis of fibrolamellar carcinoma are also discussed.
Graham, RP, C Lackner, L Terracciano, Y Gonzalez-Cantu, JJ Maleszewski, PT Greipp, SM Simon and MS Torbenson 2018Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion.Hepatology 68(4): 1441-1447. Fibrolamellar carcinomas are characterized by activation of protein kinase A, a kinase composed of catalytic and regulatory subunits. PRKACA encodes a catalytic subunit of protein kinase A, and almost all fibrolamellar carcinomas have a heterozygous 400-kb deletion that leads to the fusion of DNAJB1 and PRKACA. The resulting DNAJB1-PRKACA fusion transcript is believed to activate protein kinase A by dysregulation of the catalytic portion of the protein. In contrast, PRKAR1A encodes one of the regulatory subunits of protein kinase A. We hypothesized that loss of function of this regulatory unit could also lead to protein kinase A activation and thus to fibrolamellar carcinoma. Because PRKAR1A mutations underlie the Carney complex, we searched for liver tumors in individuals with the Carney complex. We identified 3 individuals with fibrolamellar carcinomas and a personal history of the Carney complex. All three tumors displayed the typical morphology of fibrolamellar carcinoma and were positive for arginase, cytokeratin 7, and cluster of differentiation 68. Fluorescence in situ hybridization was negative for PRKACA rearrangements. However, PRKAR1A sequencing identified pathogenic mutations in two of two cases with successful sequencing. In addition, all three cases were negative for PRKAR1A protein expression, consistent with inactivation of this key regulatory unit of protein kinase A. We also identified one additional fibrolamellar carcinoma in an individual without a documented history of the Carney complex who was negative for PRKACA rearrangements but had loss of PRKAR1A protein expression as well as PRKAR1A mutations. CONCLUSION: Fibrolamellar carcinoma can be part of the Carney complex; in this setting, fibrolamellar carcinomas have inactivating PRKAR1A mutations instead of the DNAJB1-PRKACA fusion gene found in sporadic fibrolamellar carcinomas, providing an alternate means for activation of protein kinase A.
Graham, RP, MM Yeh, D Lam-Himlin, LR Roberts, L Terracciano, MW Cruise, PT Greipp, RT Zreik, D Jain, N Zaid, SN Salaria, L Jin, X Wang, JG Rustin, SE Kerr, WR Sukov, DA Solomon, S Kakar, E Waterhouse, RM Gill, L Ferrell, VA Alves, D Nart, F Yilmaz, S Roessler, T Longerich, P Schirmacher and MS Torbenson 2018Molecular testing for the clinical diagnosis of fibrolamellar carcinoma. Mod Pathol 31(1): 141-149.Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone.
Hammond, WJ, G Lalazar, JA Saltsman, BA Farber, E Danzer, TC Sherpa, CD Banda, JR Andolina, S Karimi, CW Brennan, MS Torbenson, MP La Quaglia and SM Simon 2018Intracranial metastasis in fibrolamellar hepatocellular carcinoma. Pediatr Blood Cancer 65(4). Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1-PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.
Han, SB, YK Kim, JH Min, SY Ha, WK Jeong and WJ Lee 2018Hepatocellular carcinoma with central scar on gadoxetic acid-enhanced and diffusion-weighted magnetic resonance imaging.Acta Radiol 59(4): 393-401. Background Central scars are rarely reported in conventional hepatocellular carcinoma (HCC). The presence of central scars on imaging might lead to erroneous diagnosis of hepatic tumors. Purpose To determine imaging features of HCC with central scars on magnetic resonance imaging (MRI) including gadoxetic acid-enhanced and diffusion-weighted imaging (DWI). Material and Methods Fifty-one patients with 51 surgically confirmed HCCs with central scars (fibrotic scar: n = 50; myxoid scar: n = 1; range = 1.2-15 cm; mean = 3.7 cm) underwent liver MRI that consisted of T1- and T2-weighted (T2W) imaging, gadoxetic acid-enhanced arterial, portal, 3-min late phase, and 20-min hepatobiliary phase (HBP), and DWI. Two reviewers evaluated morphology, signal intensity, and enhancement features of tumors and central scars for each image and reached consensus. Results Lobulated contour was seen for 30 tumors (58.8%); the rest were round or oval masses. Central scars (range = 0.2-6.0 cm; mean = 0.9 cm) were most commonly seen as defects within hyperenhancement on arterial phase images (n = 47, 92.2%), bright (n = 28, 54.9%) or dark areas (n = 15, 29.4%) on T2W imaging, areas of central darkness on high b-value DWI (b = 800) (n = 31, 60.8%), and/or central enhancement on HBP (n = 36, 70.6%), mimicking a target appearance. Tumor capsule was seen in 35 (39 pathology, 74.5%) and intratumoral septum in 35 (41 pathology, 78.4%) tumors on gadoxetic acid-enhanced MRI. Conclusion Non-fibrolamellar HCC may show central scar. HCC with central scar mimics cholangiocarcinoma by showing a target appearance on HBP and DWI. Tumor capsule and intratumoral septum might be useful for characterizing HCC with central scar.
Hartmann, N and M Kronenberg 2018Cancer immunity thwarted by the microbiome.Science 360(6391): 858-859.
Inarrairaegui, M, I Melero and B Sangro 2018Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes. Clin Cancer Res 24(7): 1518-1524. Treatment of patients with hepatocellular carcinoma (HCC) in the advanced stage remains a great challenge, with very few drugs approved. After decades of failure of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with HCC in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells and mostly provide immunosuppressive signals. Monoclonal antibodies able to block these molecules have shown antitumor activity against a wide spectrum of human cancers. Clinical experience with checkpoint inhibitors in HCC includes early trials with the anti-CTLA-4 agent tremelimumab and a large phase II trial with the anti-PD-1 agent nivolumab. The latter has shown strong activity particularly as second-line therapy, both in terms of tumor response and patient survival. At least three topics should be the focus of future research: (i) the search for activity in patients at less-advanced stages, including the adjuvant treatment of patients with resectable or ablatable tumors; (ii) the enhanced efficacy of combination therapies, including particularly the combination with those targeted and locoregional therapies that may have a synergistic effect or act upon mechanisms of primary or acquired resistance to checkpoint inhibitors; and (iii) the identification of clinical features and serum or tissue biomarkers that would allow a better patient selection for individual treatments. Hopefully, ongoing trials will help to design better treatments in the future.
Ince, V, B Isik, F Ozdemir, D Ozgor, C Ara and S Yilmaz 2018Living-donor liver transplant for fibrolamellar hepatocellular carcinoma with hilar lymph node metastasis: A case report. Exp Clin Transplant. Fibrolamellar hepatocellular carcinoma is a rare primary malignant liver neoplasm. Benefits from liver transplant for patients with fibrolamellar hepatocellular carcinoma have not yet been reported. Here, we report a 19-year-old female patient who presented with abdominal pain. A computed tomography scan revealed bilobar and multiple solid lesions with the largest measuring 15 cm in diameter on the right lobe of her liver. Her blood alpha-fetoprotein level and viral hepatitis markers were normal. A fine-needle biopsy of the largest lesion detected fibrolamellar heptocellular carcinoma. Because no distant metastasis was evident and the carcinoma was unresectable, a right lobe living-donor liver transplant with hilar lymph node dissection was performed. A pathology report revealed poorly differentiated fibrolamellar hepatocellular carcinoma, and further testing indicated microvascular invasion and hilar lymph node metastasis. The largest tumor measured 12 cm. She was discharged on postoperative day 14. During postoperative month 22, multiple vertebral metastases were detected, and she died with diffuse metastasis during postoperative month 26. Our patient, with poor prognostic criteria such as hilar lymph node metastasis, microvascular invasion, and poor differentiation, had 22 months of tumor-free survival and 26 months of overall survival after having undergone living-donor liver transplant.
Karachaliou, N, M Gonzalez-Cao, G Crespo, A Drozdowskyj, E Aldeguer, A Gimenez-Capitan, C Teixido, MA Molina-Vila, S Viteri, M De Los Llanos Gil, SM Algarra, E Perez-Ruiz, I Marquez-Rodas, D Rodriguez-Abreu, R Blanco, T Puertolas, MA Royo and R Rosell 2018Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. Ther Adv Med Oncol 10: 1758834017749748. Background: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-gamma). We have explored whether the expression of IFNG, the gene encoding IFN-gamma, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8(+) T-cells were also evaluated. Progression-free survival and overall survival were estimated. Results: A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. Conclusions: IFN-gamma is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.
Katsuno, Y, J Qin, J Oses-Prieto, H Wang, O Jackson-Weaver, T Zhang, S Lamouille, J Wu, A Burlingame, J Xu and R Derynck 2018Arginine methylation of SMAD7 by PRMT1 in TGF-beta-induced epithelial-mesenchymal transition and epithelial stem-cell generation. J Biol Chem 293(34): 13059-13072. The epithelial-to-mesenchymal transdifferentiation (EMT) is crucial for tissue differentiation in development and drives essential steps in cancer and fibrosis. EMT is accompanied by reprogramming of gene expression and has been associated with the epithelial stem-cell state in normal and carcinoma cells. The cytokine transforming growth factor beta (TGF-beta) drives this program in cooperation with other signaling pathways and through TGF-beta-activated SMAD3 as the major effector. TGF-beta-induced SMAD3 activation is inhibited by SMAD7 and to a lesser extent by SMAD6, and SMAD6 and SMAD7 both inhibit SMAD1 and SMAD5 activation in response to the TGF-beta-related bone morphogenetic proteins (BMPs). We previously reported that, in response to BMP, protein arginine methyltransferase 1 (PRMT1) methylates SMAD6 at the BMP receptor complex, thereby promoting its dissociation from the receptors and enabling BMP-induced SMAD1 and SMAD5 activation. We now provide evidence that PRMT1 also facilitates TGF-beta signaling by methylating SMAD7, which complements SMAD6 methylation. We found that PRMT1 is required for TGF-beta-induced SMAD3 activation, through a mechanism similar to that of BMP-induced SMAD6 methylation, and thus promotes the TGF-beta-induced EMT and epithelial stem-cell generation. This critical mechanism positions PRMT1 as an essential mediator of TGF-beta signaling that controls the EMT and epithelial cell stemness through SMAD7 methylation.
Khanna, R and SK Verma 2018Pediatric hepatocellular carcinoma. World J Gastroenterol 24(35): 3980-3999. Pediatric hepatocellular carcinoma (HCC) is the second common malignant liver tumor in children after hepatoblastoma. It differs from the adult HCC in the etiological predisposition, biological behavior and lower frequency of cirrhosis. Perinatally acquired hepatitis-B virus, hepatorenal tyrosinemia, progressive familial intrahepatic cholestasis, glycogen storage disease, Alagille's syndrome and congenital portosystemic shunts are important predisposing factors. Majority of children (87%) are older than 5 years of age. Following mass immunization against hepatitis-B, there has been a drastic fall in the incidence of new cases of pediatric HCC in the Asia-Pacific region. Management is targeted on complete surgical removal either by resection or liver transplantation. There is a trend towards improving survival of children transplanted for HCC beyond Milan criteria. Chemotherapeutic regimens do not offer good results but may be helpful for down-staging of advanced HCC. Surveillance of children with chronic liver diseases with ultrasound and alpha-fetoprotein may be helpful in timely detection, intervention and overall improvement in outcome of HCC.
Koehne de Gonzalez, A and SM Lagana 2018Update on ancillary testing in the evaluation of high-grade liver tumors. Surg Pathol Clin 11(2): 367-375. Tissue diagnosis is the gold standard for mass lesions of the liver, but needle core biopsies may sometimes prove challenging. Presented here is a review of a panel of immunohistochemical stains, including hepatocyte in paraffin 1, arginase-1, polyclonal carcinoembryonic antigen, CD10, bile salt export pump, glypican-3, as well as in situ hybridization for albumin RNA, to establish hepatocellular origin in cases in which hepatocellular carcinoma is suspected but the sample is limited or the morphology is challenging, as it may be with cases of scirrhous, fibrolamellar carcinoma, intrahepatic cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma.
Lalazar, G and SM Simon 2018Fibrolamellar carcinoma: recent advances and unresolved questions on the molecular mechanisms. Semin Liver Dis 38(1): 51-59. Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of primary liver cancer that affects adolescents and young adults without underlying liver disease. Surgery remains the mainstay of therapy; however, most patients are either not surgical candidates or suffer from recurrence. There is no approved systemic therapy and the overall survival remains poor. Historically classified as a subtype of hepatocellular carcinoma (HCC), FLC has a unique clinical, histological, and molecular presentation. At the genomic level, FLC contains a single 400kB deletion in chromosome 19, leading to a functional DNAJB1-PRKACA fusion protein. In this review, we detail the recent advances in our understanding of the molecular underpinnings of FLC and outline the current knowledge gaps.
Lin, CC and HM Yang 2018Fibrolamellar carcinoma: a concise review.Arch Pathol Lab Med 142(9): 1141-1145. Fibrolamellar carcinoma is a rare primary hepatocellular malignancy arising in noncirrhotic livers of young individuals. Patients commonly present with a large solitary liver mass and nonspecific symptoms. Characteristic histologic features include large polygonal cells with oncocytic cytoplasm and prominent nucleoli separated into trabeculae and cords by dense parallel bands of collagen. Important differential diagnoses include classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma, which may be distinguished by a judicious panel of immunohistochemical studies, including cytokeratin 7, CD68, and hepatocyte paraffin 1 (HepPar-1). In addition, fibrolamellar carcinomas are characterized by activation of protein kinase A. Prognosis of fibrolamellar carcinoma is similar to classical hepatocellular carcinoma occurring in the absence of liver cirrhosis and is strongly correlated with tumor resectability. Other treatment options include liver transplant, chemotherapy, and hepatic artery embolization. In this article, we review the clinical features, gross and microscopic pathology, molecular genetics, differential diagnosis, treatment, and prognosis of this rare and interesting tumor.
Ma, C, M Han, B Heinrich, Q Fu, Q Zhang, M Sandhu, D Agdashian, M Terabe, JA Berzofsky, V Fako, T Ritz, T Longerich, CM Theriot, JA McCulloch, S Roy, W Yuan, V Thovarai, SK Sen, M Ruchirawat, F Korangy, XW Wang, G Trinchieri and TF Greten 2018Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells.Science 360(6391). Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6(+) natural killer T (NKT) cells and heightened interferon-gamma production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria-controlled bile acid metabolism and liver antitumor immunosurveillance.
Machado, MV and AM Diehl 2018Hedgehog signalling in liver pathophysiology. J Hepatol 68(3): 550-562. Liver disease remains a leading cause of mortality worldwide despite recent successes in the field of viral hepatitis, because increases in alcohol consumption and obesity are fuelling an epidemic of chronic fatty liver disease for which there are currently no effective medical therapies. About 20% of individuals with chronic liver injury ultimately develop end-stage liver disease due to cirrhosis. Hence, treatments to prevent and reverse cirrhosis in individuals with ongoing liver injury are desperately needed. The development of successful treatments requires an improved understanding of the mechanisms controlling liver disease progression. The liver responds to diverse insults with a conserved wound healing response, suggesting that it might be generally beneficial to optimise pathways that are crucial for effective liver repair. The Hedgehog pathway has emerged as a potential target based on compelling preclinical and clinical data, which demonstrate that it critically regulates the liver's response to injury. Herein, we will summarise evidence of the Hedgehog pathway's role in liver disease and discuss how modulating pathway activity might be applied to improve liver disease outcomes.
Mafeld, S, J French, D Tiniakos, B Haugk, D Manas and P Littler 2018Fibrolamellar hepatocellular carcinoma: Treatment with Yttrium-90 and subsequent surgical resection. Cardiovasc Intervent Radiol 41(5): 816-820. We describe a 52-year-old female patient who presented with a 9.5-cm fibrolamellar hepatocellular carcinoma (FL-HCC). The patient was initially unsuitable for surgical resection and therefore underwent transarterial chemoembolization followed by selective internal radiation therapy (SIRT) with Yttrium-90 to downsize the tumour. Following SIRT, the tumour decreased in volume from 350 to 20 cm(3) allowing curative (R0) resection with an extended left hepatectomy and reconstruction of IVC. This is the first reported case of FL-HCC treated with SIRT in which, due to the good SIRT response, the patient was downsized to allow curative resection.
Marisa, L, M Svrcek, A Collura, E Becht, P Cervera, K Wanherdrick, O Buhard, A Goloudina, V Jonchere, J Selves, G Milano, D Guenot, R Cohen, C Colas, P Laurent-Puig, S Olschwang, JH Lefevre, Y Parc, V Boige, C Lepage, T Andre, JF Flejou, V Derangere, F Ghiringhelli, A de Reynies and A Duval 2018The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors. J Natl Cancer Inst 110(1). Background: Immune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore. Methods: The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided. Results: The expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004). Conclusions: ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.
Nautsch, F, JM Ludwig, M Xing, KM Johnson and HS Kim 2018Racial Disparities and Sociodemographic Differences in Incidence and Survival Among Pediatric Patients in the United States With Primary Liver Cancer: A Surveillance, Epidemiology, and End Results (SEER) Population Study.J Clin Gastroenterol 52(3): 262-267. BACKGROUND: Primary liver cancer, including Hepatoblastoma (HB) and hepatocellular carcinoma (HCC), in pediatric populations is often fatal. The outcomes are poor despite universal health care access in pediatric patients. AIM: We investigated the sociodemographic factors affecting outcomes in pediatric patients with primary liver cancer. MATERIALS AND METHODS: This is a large population database study of Surveillance, Epidemiology, and End Results cancer registry data from 1973 to 2011. HB and HCC were analyzed regarding age, sex, race, geographic area, and treatment-related information including survival. RESULTS: In total, 998 patients, the median age at time of diagnosis was 1 year for HB [0-19; 95% confidence interval (CI), 1.5-1.9] and 14 years for HCC (0-19; 95% CI, 12.1-13.3) (P<0.001). Overall Survival (OS) in HB was 374 months (25% failures 19) versus HCC 21 months (25% failures 5; P<0.0001). In HCC, the fibrolamellar subgroup OS was 41 months (32-.) versus 16 months (11-21) in all others [hazard ratio (HR) 2.0; P=0.005]. Diagnosis between 2000 and 2011 (HB: 25% failures not reached; HCC: 38) versus diagnosis 1973 to 1999 (HB: 374; HCC: 12) had different survival (P=0.01; HR 1.9). For HB, OS in patients with age of diagnosis under 2, 25% failures was not reached versus 374 months over the age of 2 (HR 1.7; P<0.0007). African American children with HB had OS of 67 (17-.) versus all others (25% failures 21) and 48% of African American children were diagnosed after the age of 2 versus 34% of whites (HR 1.9; P=0.01). CONCLUSIONS: Later diagnosis and decreased survival in African American children with HB warrants further research.
Oh, SH, M Swiderska-Syn, ML Jewell, RT Premont and AM Diehl 2018Liver regeneration requires Yap1-TGFbeta-dependent epithelial-mesenchymal transition in hepatocytes. J Hepatol 69(2): 359-367. BACKGROUND & AIMS: Chronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar tissue, ultimately resulting in cirrhosis. Therefore, defining and optimizing mechanisms that orchestrate effective regeneration might prevent cirrhosis. We hypothesized that effective regeneration of injured livers requires hepatocytes to evade the growth-inhibitory actions of TGFbeta, since TGFbeta signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis. METHODS: Wild-type mice underwent 70% partial hepatectomy (PH); TGFbeta expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24-72h after PH. To determine the role of Yap1 in regulating TGFbeta signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1(flox/flox) mice. RESULTS: TGFbeta expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after PH. Proliferative hepatocytes also upregulated Snai1, a pSmad2 target gene that promotes epithelial-to-mesenchymal transition (EMT), suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1alpha1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation. CONCLUSION: Interactions between the TGFbeta and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGFbeta-enriched microenvironment and regenerate injured livers. LAY SUMMARY: The adult liver has an extraordinary ability to regenerate after injury despite the accumulation of scar-forming factors that normally block the proliferation and reduce the survival of residual liver cells. We discovered that liver cells manage to escape these growth-inhibitory influences by transiently becoming more like fibroblasts themselves. They do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver can control programs that are involved in scarring and cancer may help in the development of new treatments for cirrhosis and liver cancer.v
de Oliveira, S, RA Houseright, AL Graves, N Golenberg, BG Korte, V Miskolci and A Huttenlocher 2018High cholesterol diet modulates macrophage polarization and liver inflammation during early hepatocellular carcinoma progression in zebrafish.bioRxiv: 299016. Diabetes and obesity have been associated with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and increased incidence of hepatocellular carcinoma (HCC). Here we use optically transparent zebrafish to visualize liver inflammation and disease progression in a NAFLD/NASH-HCC model. We combined a high-cholesterol diet (HCD) with a transgenic zebrafish HCC model induced by hepatocyte-specific activated ?-catenin and found that diet induced an increase in liver size and enhanced angiogenesis and neutrophil infiltration in the liver. Although macrophage number was not affected by diet, HCD induced changes in macrophage morphology and polarization with an increase in liver associated TNF?-positive macrophages. Treatment with metformin altered macrophage polarization and reduced liver size in NAFLD/NASH-associated HCC larvae. Moreover, ablation of macrophages limited progression in NAFLD/NASH-associated HCC larvae but not in HCC alone. These findings suggest that HCD alters macrophage polarization and exacerbates the liver inflammatory microenvironment and cancer progression in a zebrafish model of NAFLD/NASH-associated HCC.Abbreviations used in this paperNAFLDNonalcoholic fatty liver diseaseNASHnonalcoholic steatohepatitisHCChepatocellular carcinomaHCDhigh-cholesterol dietTMEtumor microenvironmentTNFtumor necrosis factordpfdays post-fertilizationNDnormal dietMTZmetronidazoleNTRnitroreductase.
Palm, V, R Sheng, P Mayer, KH Weiss, C Springfeld, A Mehrabi, T Longerich, AK Berger, HU Kauczor and TF Weber 2018Imaging features of fibrolamellar hepatocellular carcinoma in gadoxetic acid-enhanced MRI.Cancer Imaging 18(1): 9. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare malignancy occurring in young patients without cirrhosis. Objectives of our study were to analyze contrast material uptake in hepatobiliary phase imaging (HBP) in gadoxetic acid-enhanced liver MRI in patients with FLC and to characterize imaging features in sequence techniques other than HBP. METHODS: In this retrospective study on histology-proven FLC, contrast material uptake in HBP was quantitatively assessed by calculating the corrected FLC enhancement index (CEI) using mean signal intensities of FLC and lumbar muscle on pre-contrast imaging and HBP, respectively. Moreover, enhancement patterns in dynamic contrast-enhanced MRI and relative signal intensities compared with background liver parenchyma were determined by two radiologists in consensus for HBP, diffusion-weighted imaging using high b-values (DWI), and T2 and T1 weighted pre-contrast imaging. RESULTS: In 6 of 13 patients with FLC gadoxetic acid-enhanced liver MRI was available. The CEI suggested presence of HBP contrast material uptake in all FLCs. A mean CEI of 1.35 indicated FLC signal increase of 35% in HBP compared with pre-contrast imaging. All FLCs were hypointense in HBP compared with background liver parenchyma. Three of 6 FLCs had arterial hyperenhancement and venous wash-out. In DWI and T2 weighted imaging, 5 of 6 FLCs were hyperintense. In T1 weighted imaging, 5 of 6 FLCs were hypointense. CONCLUSION: Hepatobiliary uptake of gadoxetic acid was quantitatively measurable in all FLCs investigated in our study. The observation of hypointensity of FLCs in HBP compared with background liver parenchyma emphasizes the role of gadoxetic acid-enhanced liver MRI for non-invasive diagnosis of FLC and its importance in the diagnostic work-up of indeterminate liver lesions.
Pestana, RC, MM Hassan, R Abdel-Wahab, YI Abugabal, LM Girard, D Li, P Chang, K Raghav, J Morris, RA Wolff, A Rashid, HM Amin and A Kaseb 2018Clinical and prognostic significance of circulating levels of angiopoietin-1 and angiopoietin-2 in hepatocellular carcinoma.Oncotarget 9(102): 37721-37732. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) play critical roles in angiogenesis in hepatocellular carcinoma (HCC). In addition, recent data suggest that Ang-1/Ang-2 are involved in regulating the immune response. The aim of our study was to explore the clinical prognostic significance of plasma Ang-1 and Ang-2 in HCC. We prospectively enrolled and collected data and blood samples from 767 HCC patients treated at MD Anderson Cancer Center between 2001 and 2014. Controls consisted of cirrhotic patients (n = 75) and healthy volunteers (n = 200). The cutoff value was the median level of each angiogenic factor. Overall survival (OS) was estimated by Kaplan-Meier curves and compared by the log-rank test. Higher plasma Ang-2 was significantly associated with advanced clinicopathologic features of advanced HCC and lower OS. Median OS was 61.8 months (95% confidence interval [CI], 45.1-78.5 months) for low Ang-2 compared with 28.5 months (95% CI, 24.8-32.1 months) for high Ang-2 (p < 0.001). In contrast, higher Ang-1 was associated with longer OS. Median OS was 37.2 months (95% CI, 31.0-43.4 months) for high Ang-1 compared with 26.2 months (95% CI, 22.2-30.3 months) for those with low Ang-1 (p = 0.043). In conclusion, our findings indicate that plasma Ang-1 and Ang-2 levels are potential diagnostic and prognostic biomarkers in HCC.
Plummer, RJ, Y Guo and Y Peng 2018A CRISPR reimagining: New twists and turns of CRISPR beyond the genome-engineering revolution. J Cell Biochem 119(2): 1299-1308. Despite its explosive applications in genome engineering, CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats) has been developed into a versatile tool beyond its well-known nuclease function. In this prospect article, we summarize a few exciting "off-label" applications of CRISPR including manipulating DNA sequences, visualizing chromosomal loci in living cells, and modulating transcription and chromatin structures. These novel applications will likely elevate CRISPR tools into yet another level of sophistication and diversity, leading to many more exciting cell biological discoveries.
Posadas, K, A Ankola, Z Yang and NS Yee 2018Tumor Molecular Profiling for an Individualized Approach to the Treatment of Hepatocellular Carcinoma: A Patient Case Study.Biomedicines 6(2). Hepatocellular carcinoma (HCC) is increasing in incidence, and the associated mortality rate remains among the highest. For advanced HCC, sorafenib has been shown to slightly prolong survival, and regorafenib and nivolumab, both recently approved by the United States Food and Drug Administration (FDA), may produce clinical benefits to a limited extent. Systemic chemotherapy has been shown to produce a modest response, but there is no clinically valid biomarker that can be used to predict which patients may benefit. In this case study, we present two patients with metastatic HCC, they received systemic treatment using capecitabine, oxaliplatin, and either bevacizumab or sorafenib. The tumor response to treatment was determined by the progression-free survival (PFS). Molecular profiling of the tumors showed differential expression of biochemical markers and different mutational status of the TP53 and β-catenin (CTNNB1) genes. We hypothesize that the PFS correlates with the tumor molecular profiles, which may be predictive of the therapeutic response to systemic chemotherapy. Further investigation is indicated to correlate tumor biomarkers and treatment responses, with the objective of personalizing the therapies for patients with advanced HCC.
Premont, RT, ML Jewell, DS Hsu, CD Guy and AM Diehl 2018Epithelial-stromal signaling in fibrolammelar hepatocelular carcinoma.Gastroenterology. 154: S-172. Background Fibrolamellar hepatocellular carcinoma (FL-HCC) is unusual type of HCC that arises in young patients with apparently healthy livers, unlike typical HCCs that occur in older, cirrhotic patients. FL-HCC are marked by fibrotic stroma that is comprised of nonmalignant cells recruited into the tumor, presumably because the FL-HCC tumor stem cells require these stromal cells to create a niche microenvironment that supports tumor stem cell survival and proliferation. We hypothesized that identifying signaling pathways mediating such FL-HCC - stroma crosstalk might provide targets for therapeutic intervention in FL-HCC. Methods We used a human patient-derived xenografts (PDX) to grow FL- HCC tumors in immunodeficient mice. Explants were harvested, and minced for protein/RNA or fixed for histology. For ex vivo studies, minced tissue was digested with type IV collagenase/DNase I and maintained in ultra-low attachment cell culture dishes in defined Kubota's medium. Relative gene expression was quantified by qRT-PCR. Cell viability was assessed by WST-8 reduction. Single-cell RNA-seq libraries were prepared using a 10X Genomics 3 ?Library Kit and quantified using Illumina NextSeq500. Over 1000 cells were sequenced, with ~4x108 reads. Results FL-HCC explants demonstrate cellular heterogeneity, co-expressing mesenchymal, biliary and immune markers. When PDX-derived cells are maintained in culture, serum exposure causes cells expressing mesenchymal markers to attach to the plate while epitheloid/tumor cells remain suspended. Cell diversity is evident in distinct cell morphology and nuclear size, as well as in staining by tumor markers including CD68 and CK7. Explant tumor cells were dispersed and immediately subjected to single cell RNA-seq. Human FLC cells and tumor-associated mouse stromal cells were cleanly distinguished and were analyzed separately. CDS1, CD68, EpCAM, KRT7, K19, and YAP1 are enriched in the tumor population. Because Yap1 is known to promote stemness and reprogram stem niche to perpetuate stem cell renewal, we derived a self-renewing cell line from human PDX explants (prFL-HCC) to screen YAP1 inhibitors. At baseline, prFL-HCC express EpCam, CK7, IGF2BP3 and YAP1 at similar or greater levels than fresh explant tumor. Treatment with the YAP1 inhibitor verteporfin reduced YAP1, TAZ, Gli2, Krt7, CTGF, CD68, and Cyr61 expression and significantly inhibited prFL-HCC growth. Conclusions FL-HCC PDX contain mouse stroma in addition to human cells, and both express acknowledged markers of FL-HCC. The YAP1 pathway is highly active in PDX-derived cells, and inhibiting YAP1 in our novel prFL-HCC line reduces stemness markers of FL-HCC and inhibits growth. These data suggest that YAP1 inhibition may be a useful therapeutic approach to interfere with epithelial-stromal communication in FL-HCC.
Rammohan, A, MS Reddy, M Farouk, J Vargese and M Rela 2018Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: The silver bullet? Hepatology 67(3): 1166-1168.
Savy, N, D Brossier, C Brunel-Guitton, L Ducharme-Crevier, G Du Pont-Thibodeau and P Jouvet 2018Acute pediatric hyperammonemia: current diagnosis and management strategies. Hepat Med 10: 105-115. Acute hyperammonemia may induce a neurologic impairment leading to an acute life-threatening condition. Coma duration, ammonia peak level, and hyperammonemia duration are the main risk factors of hyperammonemia-related neurologic deficits and death. In children, hyperammonemia is mainly caused by severe liver failure and inborn errors of metabolism. In an acute setting, obtaining reliable plasma ammonia levels can be challenging because of the preanalytical difficulties that need to be addressed carefully. The management of hyperammonemia includes 1) identification of precipitating factors and cerebral edema presence, 2) a decrease in ammonia production by reducing protein intake and reversing catabolism, and 3) ammonia removal with pharmacologic treatment and, in the most severe cases, with extracorporeal therapies. In case of severe coma, transcranial Doppler ultrasound could be the method of choice to noninvasively monitor cerebral blood flow and titrate therapies.
Schramm, C 2018Bile Acids, the Microbiome, Immunity, and Liver Tumors. N Engl J Med 379(9): 888-890.
Semelka, RC, N Nimojan, S Chandana, M Ramalho, SL Palmer, D DeMulder, C Parada Villavicencio, J Woosley, BL Garon, RC Jha, FH Miller and E Altun 2018MRI features of primary rare malignancies of the liver: A report from four university centres.Eur Radiol 28(4): 1529-1539. PURPOSE: To determine if rare primary malignancies of the liver may have consistent features on magnetic resonance imaging (MRI). MATERIALS AND METHODS: This IRB-compliant retrospective study reviewed the records from the pathology departments of four university centres over an 11-year period from 2005-2016 to identify rare primary malignant tumours, which were cross-referenced with MRI records. MRI studies of these patients were reviewed to determine if these tumours exhibited consistent and distinctive features. RESULTS: Sixty patients were identified with rare primary liver tumours. The following distinctive features and frequency of occurrence were observed: mixed hepatocellular carcinoma-cholangiocarcinoma showed regions of wash-out in 7/19 of patients; 6/6 of fibrolamellar carcinomas demonstrated large heterogeneous lesions with large heterogeneous central scars; epithelioid haemangioendothelioma larger than 2 cm showed target-like enhancement in late-phase enhancement in 9/13; sarcomas excluding angiosarcoma had central necrosis in 3/9 and haemorrhage in 5/9; angiosarcomas showed centripedal progressive nodular enhancement in 3/6 and showed regions of haemorrhage in 3/6; and 7/7 of primary hepatic lymphomas showed encasement of vessels. CONCLUSION: Although helpful features for the differentiation of rare primary malignancies of the liver are identified, no MRI features appear to be specific and therefore histopathological confirmation is usually required for definitive diagnosis. KEY POINTS: * No MRI features appear to be specific for rare primary liver malignancies. * Haemorrhage is a helpful sign in diagnosis of primary hepatic sarcomas. * Angiosarcomas may show progressive nodular enhancement towards the centre mimicking haemangioma. * Vessel encasement is a helpful sign in diagnosis of primary hepatic lymphoma.
Shah, SM, AK Kamboj and SP Cleary 2018Large Hepatic Mass in an Adolescent Male. Gastroenterology 155(4): e9-e10.
Shiao, MS, K Chiablaem, V Charoensawan, N Ngamphaiboon and N Jinawath 2018Emergence of Intrahepatic Cholangiocarcinoma: How High-Throughput Technologies Expedite the Solutions for a Rare Cancer Type. Front Genet 9: 309. Intrahepatic cholangiocarcinoma (ICC) is the cancer of the intrahepatic bile ducts, and together with hepatocellular carcinoma (HCC), constitute the majority of primary liver cancers. ICC is a rare disorder as its overall incidence is < 1/100,000 in the United States and Europe. However, it shows much higher incidence in particular geographical regions, such as northeastern Thailand, where liver fluke infection is the most common risk factor of ICC. Since the early stages of ICC are often asymptomatic, the patients are usually diagnosed at advanced stages with no effective treatments available, leading to the high mortality rate. In addition, unclear genetic mechanisms, heterogeneous nature, and various etiologies complicate the development of new efficient treatments. Recently, a number of studies have employed high-throughput approaches, including next-generation sequencing and mass spectrometry, in order to understand ICC in different biological aspects. In general, the majority of recurrent genetic alterations identified in ICC are enriched in known tumor suppressor genes and oncogenes, such as mutations in TP53, KRAS, BAP1, ARID1A, IDH1, IDH2, and novel FGFR2 fusion genes. Yet, there are no major driver genes with immediate clinical solutions characterized. Interestingly, recent studies utilized multi-omics data to classify ICC into two main subgroups, one with immune response genes as the main driving factor, while another is enriched with driver mutations in the genes associated with epigenetic regulations, such as IDH1 and IDH2. The two subgroups also show different hypermethylation patterns in the promoter regions. Additionally, the immune response induced by host-pathogen interactions, i.e., liver fluke infection, may further stimulate tumor growth through alterations of the tumor microenvironment. For in-depth functional studies, although many ICC cell lines have been globally established, these homogeneous cell lines may not fully explain the highly heterogeneous genetic contents of this disorder. Therefore, the advent of patient-derived xenograft and 3D patient-derived organoids as new disease models together with the understanding of evolution and genetic alterations of tumor cells at the single-cell resolution will likely become the main focus to fill the current translational research gaps of ICC in the future.
Silva, G, M Marins, N Chaichanasak, Y Yoon, AL Fachin, VC Pinhanelli, LO Regasini, MB Dos Santos, GM Ayusso, BC Marques, WW Wu, JN Phue, RF Shen and SJ Baek 2018Trans-chalcone increases p53 activity via DNAJB1/HSP40 induction and CRM1 inhibition.PLoS ONE 13(8): e0202263. Naturally-occurring chalcones and synthetic chalcone analogues have been demonstrated to have many biological effects, including anti-inflammatory, anti-malarial, anti-fungal, and anti-oxidant/anti-cancerous activities. Compared to other chalcones, trans-chalcone exhibits superior inhibitory activity in cancer cell growth as shown via in vitro assays, and exerts anti-cancerous effects via the activation of the p53 tumor suppressor protein. Thus, characterization of the specific mechanisms, by which trans-chalcone activates p53, can aid development of new chemotherapeutic drugs that can be used individually or synergistically with other drugs. In this report, we found that trans-chalcone modulates many p53 target genes, HSP40 being the most induced gene in the RNA-Seq data using trans-chalcone-treated cells. CRM1 is also inhibited by trans-chalcone, resulting in the accumulation of p53 and other tumor suppressor proteins in the nucleus. Similar effects were seen using trans-chalcone derivatives. Overall, trans-chalcone could provide a strong foundation for the development of chalcone-based anti-cancer drugs.
Simon, JS, S Botero and SM Simon 2018Sequencing the peripheral blood B and T cell repertoire - Quantifying robustness and limitations. J Immunol Methods 463: 137-147. The adaptive immune response generates a large repertoire of T cells with T-cell receptors (TCRalpha and TCRbeta) and B cells with immunoglobulins (Ig). The repertoire changes in response to antigen stimulation both through amplification of specific cells (clonal expansion) as well as somatic hypermutation of immunoglobulins. Alterations of the immune repertoire have been observed in response to acute disease, such as external pathogens, or chronic diseases, such as autoimmunity and cancer. Here we establish experimental and analytical protocols for quantifying the peripheral blood of healthy human individuals by profiling the immune repertoire for the Complementarity determining region 3 (CDR3) of the variable regions of TCRbeta (CDRbeta3) and the IgG heavy chain (CDRH1, CDRH2, CDRH3). The results demonstrate that 40ml of blood are sufficient to reliably capture the 10,000 most common TCRbeta and 1000 most common IgG and determine their relative frequency in the circulation. We conclude that by using an accessible sample size of human PBMC one is able to robustly monitor alterations in the immune repertoire.
Simon, SM 2018Gunter Blobel (1936-2018). Cell 173(2): 278-280.
Stratakis, CA 2018Cyclic AMP-dependent protein kinase catalytic subunit A (PRKACA): the expected, the unexpected, and what might be next.J Pathol 244(3): 257-259. Protein kinase A (PKA) or cyclic-AMP (cAMP)-dependent kinase was among the first serine-threonine kinases to be molecularly and functionally characterized. For years, it was investigated as the enzyme that mediates cAMP functions in almost all cell systems and organisms studied to date. Despite PKA's critical role in signaling and the long history of investigations of cAMP in oncogenesis (dating back to the 1970s), it was not until relatively recently that PKA defects were found to be directly involved in tumor predisposition. First, PKA's main regulatory subunit, PRKAR1A, was found to be mutated in Carney complex, a genetic syndrome that predisposes to heart tumors (cardiac myxomas) and a variety of other lesions of the endocrine system, including the adrenal cortex, and several cancers, including liver carcinoma. Then, PKA's main catalytic subunit, PRKACA, was found to be mutated in sporadic adrenal tumors and fibrolamellar liver carcinoma. Not surprisingly, therefore, a new research study published in The Journal of Pathology showed PRKACA mutations in sporadic cardiac myxomas. The real question is what other pathologies will be found to be due to PRKACA (or other PKA subunit) defects. The possibilities abound and may show the way for a totally new class of medications that target cAMP signaling to be useful in fighting the corresponding tumors. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
Sullivan, KM, HL Kenerson, VG Pillarisetty, KJ Riehle and RS Yeung 2018Precision oncology in liver cancer. Ann Transl Med 6(14): 285. With the widespread adoption of molecular profiling in clinical oncology practice, many physicians are faced with making therapeutic decisions based upon isolated genomic alterations. For example, epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are effective in EGFR-mutant non-small cell lung cancers (NSCLC) while anti-EGFR monoclonal antibodies are ineffective in Ras-mutant colorectal cancers. The matching of mutations with drugs aimed at their respective gene products represents the current state of "precision" oncology. Despite the great expectations of this approach, only a fraction of cancers responds to 'targeted' interventions, and many early responders will ultimately develop resistance to these agents. The underwhelming success of mutation-driven therapies across all cancer types is not due to an inability to detect genetic changes in tumors; rather a deficit in functional insight into the genomic alterations that give rise to each cancer. The Achilles heel of precision oncology thus remains the lack of a robust functional understanding of an individual cancer genome that then allows prediction of the best therapy and resultant outcome for that patient. Current practice focuses on one 'actionable' mutation at a time, while solid cancers typically possess many mutations that involve different cellular sub-populations within a tumor. No method or platform currently exists to guide the interpretation of these complex data, nor to accurately predict response to treatment. This problem is particularly germane to primary liver cancers (PLC), for which only a handful of targeted therapies have been introduced. Here, we will review strategies aimed at overcoming some of these challenges in precision oncology, using liver cancer as an example.
Takashima, K, H Oshiumi, M Matsumoto and T Seya 2018DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70. J Innate Immun 10(1): 44-55. Melanoma differentiation-associated gene 5 (MDA5) is a pattern recognition receptor that recognizes cytoplasmic viral double-stranded RNA (dsRNA) and initiates rapid innate antiviral responses. MDA5 forms a filament-like multimer along the dsRNA leading to oligomerization, which in turn activates the adaptor protein mitochondrial antiviral signaling protein (MAVS) to provide a signal platform for the induction of type I interferon (IFN) and proinflammatory cytokines. The conformational switch of MDA5 causes antiviral defense, but excessive activation of the MDA5-MAVS pathway may result in autoimmune diseases. The regulatory mechanisms of MDA5 activation remain largely unknown. By yeast 2-hybrid, we identified DNAJB1, a member of the HSP40 (heat shock protein 40) family, as an MDA5-binding protein. HSP40s usually cowork with HSP70s. We found that dsRNA stimulation with physiological conditions upregulated the expression levels of DNAJB1 and HSP70; then the proteins were coupled and translocated into the stress granules, where MDA5 encounters dsRNA. DNAJB1 disrupted MDA5 multimer formation, resulting in the suppression of type I IFN induction. The disruption of endogenous DNAJB1 increased MDA5- and MAVS-mediated IFN promoter activation and rendered cells virus resistant. HSP70 inhibitor also enhanced the IFN-inducing function of MDA5 and MAVS. These results suggest that the DNAJB1-HSP70 complex functions for the natural maintenance of RNA sensing by interacting with MDA5/MAVS.
Tanaka, H, S Hijioka, H Iwaya, N Mizuno, T Kuwahara, N Okuno, A Ito, N Kuraoka, S Matsumoto, M Obata, Y Kurita, M Yasuda, Y Shimizu, H Kuroda, Y Sato, M Haneda, E Sasaki, Y Yatabe and K Hara 2018Fibrolamellar hepatocellular carcinoma with multiple lung metastases treated with multidisciplinary therapy. Intern Med. A 20-year old man was diagnosed with fibrolamellar hepatocellular carcinoma (FLHCC) with multiple lung metastases, and chemotherapy with FOLFOX was administered. Contrast enhanced CT after 3 cycles of FOLFOX showed no disease progression. We therefore performed surgical resection and radiofrequency ablation of the liver lesions and lung metastases, after obtaining the patient's informed consent. The liver lesions and lung metastases tested positive for DNAJB1-PRKACA. The treatment for FLHCC with extrahepatic metastasis has not been established; however, in a few cases, good long-term prognoses were obtained with multidisciplinary therapy. We herein report a case of FLHCC with multiple lung metastases that was treated with multidisciplinary therapies.
Tomasini, MD, Y Wang, A Karamafrooz, G Li, T Beuming, J Gao, SS Taylor, G Veglia and SM Simon 2018Conformational landscape of the PRKACA-DNAJB1 chimeric kinase, the driver for fibrolamellar hepatocellular carcinoma. Sci Rep 8(1): 720. In fibrolamellar hepatocellular carcinoma a single genetic deletion results in the fusion of the first exon of the heat shock protein 40, DNAJB1, which encodes the J domain, with exons 2-10 of the catalytic subunit of protein kinase A, PRKACA. This produces an enzymatically active chimeric protein J-PKAcalpha. We used molecular dynamics simulations and NMR to analyze the conformational landscape of native and chimeric kinase, and found an ensemble of conformations. These ranged from having the J-domain tucked under the large lobe of the kinase, similar to what was reported in the crystal structure, to others where the J-domain was dislodged from the core of the kinase and swinging free in solution. These simulated dislodged states were experimentally captured by NMR. Modeling of the different conformations revealed no obvious steric interactions of the J-domain with the rest of the RIIbeta holoenzyme.
Waidmann, O 2018Recent developments with immunotherapy for hepatocellular carcinoma.Expert Opin Biol Ther 18(8): 905-910. INTRODUCTION: Immunotherapy is on the way to become the new standard of care for advanced hepatocellular carcinoma (HCC) worldwide. With higher rates of objective responses, and overall less side effects compared to tyrosine-kinase inhibitors (TKIs) immunotherapeutics will probably replace sorafenib from standard first-line treatment. Areas covered: This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC focusing on immunotherapy. Expert opinion: In unselected patients with advanced HCC immunotherapeutics, namely the programmed cell death-1 (PD-1) antibodies, nivolumab and pembrolizumab have shown promising efficacy in therapy-naive, as well as pre-treated patients with advanced HCC. However, only 10-20 percent of treated patients show an objective and durable response to the indicated therapeutics. Therefore, combination therapies including different immunotherapeutics, e.g. PD-1/programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies, or combinations of immunotherapeutics and small molecules, or bifunctional antibodies will be needed to improve response rates. ABBREVIATIONS: HCC: hepatocellular carcinoma; TKI: tyrosine-kinase inhibitors; PD-1: programmed death receptor-1; PD-L1: programmed cell death 1 ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated Protein 4; CAR-T: chimeric T cell receptors; TACE: transarterial chemoembolization; SIRT: selective internal radiation therapy; SBRT: stereotactic body radiation therapy; VEGF: vascular endothelial growth factor; MEK: mitogen-activated protein kinase kinase; NK cell: natural killer cell; TGFbeta: transforming growth factor-beta; OV: Oncolytic viruses; PFU: plaque-forming unit.
Wang, J, M Dong, Z Xu, X Song, S Zhang, Y Qiao, L Che, J Gordan, K Hu, Y Liu, DF Calvisi and X Chen 2018Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene 37(24): 3229-3242. Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes. Wild-type, Notch1 (flox/flox) , and Notch2 (flox/flox) mice were used to investigate the role of canonical Notch signaling and Notch receptors in AKT/Yap-driven ICC formation. Human ICC and HCC cell lines were transfected with siRNA against Notch2 to determine whether Notch2 regulates biliary marker expression in liver tumor cells. We found that AKT/Yap-induced ICC formation is hepatocyte derived and this process is strictly dependent on the canonical Notch signaling pathway in vivo. Deletion of Notch2 in AKT/Yap-induced tumors switched the phenotype from ICC to hepatocellular adenoma-like lesions, while inactivation of Notch1 in hepatocytes did not result in significant histomorphological changes. Finally, in vitro studies revealed that Notch2 silencing in ICC and HCC cell lines down-regulates the expression of Sox9 and EpCAM biliary markers. Notch2 is the major determinant of hepatocyte-derived ICC formation in mice.
Wang, S, Y Jung, J Hyun, M Friedersdorf, SH Oh, J Kim, RT Premont, JD Keene and AM Diehl 2018RNA Binding Proteins Control Transdifferentiation of Hepatic Stellate Cells into Myofibroblasts.Cell Physiol Biochem 48(3): 1215-1229. BACKGROUND/AIMS: Myofibroblasts (MF) derived from quiescent nonfibrogenic hepatic stellate cells (HSC) are the major sources of fibrous matrix in cirrhosis. Because many factors interact to regulate expansion and regression of MF-HSC populations, efforts to prevent cirrhosis by targeting any one factor have had limited success, motivating research to identify mechanisms that integrate these diverse inputs. As key components of RNA regulons, RNA binding proteins (RBPs) may fulfill this function by orchestrating changes in the expression of multiple genes that must be coordinately regulated to affect the complex phenotypic modifications required for HSC transdifferentiation. METHODS: We profiled the transcriptomes of quiescent and MF-HSC to identify RBPs that were differentially-expressed during HSC transdifferentiation, manipulated the expression of the most significantly induced RBP, insulin like growth factor 2 binding protein 3 (Igf2bp3), and evaluated transcriptomic and phenotypic effects. RESULTS: Depleting Igf2bp3 changed the expression of thousands of HSC genes, including multiple targets of TGF-beta signaling, and caused HSCs to reacquire a less proliferative, less myofibroblastic phenotype. RNA immunoprecipitation assays demonstrated that some of these effects were mediated by direct physical interactions between Igf2bp3 and mRNAs that control proliferative activity and mesenchymal traits. Inhibiting TGF-beta receptor-1 signaling revealed a microRNA-dependent mechanism that induces Igf2bp3. CONCLUSIONS: The aggregate results indicate that HSC transdifferentiation is ultimately dictated by Igf2bp3-dependent RNA regulons and thus, can be controlled simply by manipulating Igf2bp3.
Weledji, EP 2018Familial hepatocellular carcinoma: 'A model for studying preventive and therapeutic measures'.Ann Med Surg (Lond) 35: 129-132. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with more than 80% of cases found in endemic areas of hepatitis B such as Africa or East Asia. A family history of liver cancer increases HCC risk, independently of hepatitis. The combination of family history of liver cancer and hepatitis B/C serum markers is associated with an over 70-fold elevated HCC risk and poor prognosis. Only limited attention has been given to the role of primary genetic factors in HCC, but scattered anecdotal reports have identified familial aggregations of HCC. This article reviewed the literature on familial hepatocellular carcinoma and suggest that familial HCC may be a good model for studying preventive and therapeutic measures.
Zarouchlioti, C, DA Parfitt, W Li, LM Gittings and ME Cheetham 2018DNAJ Proteins in neurodegeneration: essential and protective factors. Philos Trans R Soc Lond B Biol Sci 373(1738).Maintenance of protein homeostasis is vitally important in post-mitotic cells, particularly neurons. Neurodegenerative diseases such as polyglutamine expansion disorders-like Huntington's disease or spinocerebellar ataxia (SCA), Alzheimer's disease, fronto-temporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease-are often characterized by the presence of inclusions of aggregated protein. Neurons contain complex protein networks dedicated to protein quality control and maintaining protein homeostasis, or proteostasis. Molecular chaperones are a class of proteins with prominent roles in maintaining proteostasis, which act to bind and shield hydrophobic regions of nascent or misfolded proteins while allowing correct folding, conformational changes and enabling quality control. There are many different families of molecular chaperones with multiple functions in proteostasis. The DNAJ family of molecular chaperones is the largest chaperone family and is defined by the J-domain, which regulates the function of HSP70 chaperones. DNAJ proteins can also have multiple other protein domains such as ubiquitin-interacting motifs or clathrin-binding domains leading to diverse and specific roles in the cell, including targeting client proteins for degradation via the proteasome, chaperone-mediated autophagy and uncoating clathrin-coated vesicles. DNAJ proteins can also contain ER-signal peptides or mitochondrial leader sequences, targeting them to specific organelles in the cell. In this review, we discuss the multiple roles of DNAJ proteins and in particular focus on the role of DNAJ proteins in protecting against neurodegenerative diseases caused by misfolded proteins. We also discuss the role of DNAJ proteins as direct causes of inherited neurodegeneration via mutations in DNAJ family genes.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.
Atienza, LG, J Berger, X Mei, MB Shah, MF Daily, A Grigorian and R Gedaly 2017Liver transplantation for fibrolamellar hepatocellular carcinoma: A national perspective.J Surg Oncol 115(3): 319-323.BACKGROUND: Fibrolamellar Hepatocellular Carcinoma (FL-HCC) is a rare primary liver tumor that usually presents in younger patients without underlying liver disease. METHODS: We queried the United Network of Organ Sharing (UNOS) database between October 1988 and January 2013 to evaluate outcomes in patients with FL-HCC undergoing liver transplantation in the United States compared to patients with conventional Hepatocellular Carcinoma (HCC). RESULTS: Sixty-three patients were identified (57% female, mean age 30 years). Only one patient (2%) had an associated Hepatitis C Virus. Mean Model for End-Stage Liver Disease (MELD) score at the time of transplantation was 11.3. Mean waiting time was 325 days and mean cold ischemic time was 6 hr. Overall survival of FL-HCC patients at 1, 3, and 5 years was 96%, 80%, and 48% as compared to HCC patients whose rates were 89%, 77%, and 68%. Six patients had tumor recurrence (10%). The Cox Model demonstrated that MELD and cold ischemic time are the strongest predictors of overall survival in FL-HCC patients. Age and wait time were not associated with poor patient survival in this series. CONCLUSIONS: Good results can be obtained in selected patients transplanted for FL-HCC. FL-HCC patients had similar survival compared to those transplanted for HCC. J. Surg. Oncol. 2017;115:319-323. (c) 2016 Wiley Periodicals, Inc.
Beard, RE, SD Finkelstein, AA Borhani, MI Minervini and JW Marsh 2017A massive hepatic tumor demonstrating hepatocellular, cholangiocarcinoma and neuroendocrine lineages: A case report and review of the literature.Int J Surg Case Rep 37: 26-32.INTRODUCTION: Mixed hepatocellular and cholangiocarcinoma tumors (MHCC) are described in the literature, as are the more rare mixed adenoneuroendocrine carcinomas (MANC) of hepatobiliary origin. Only two cases of tumors with characteristics of all three histologies/phenotypes have been previously described in one Chinese study. PRESENTATION OF CASE: Herein we report clinical, microscopic and molecular features of a 25cm mixed hepatic tumor with hepatocellular, cholangiocarcinoma and neuroendocrine differentiation arising in an otherwise healthy 19-year-old North American Caucasian male without any identifiable risk factors. DISCUSSION: The patient underwent multimodality imaging and the tumor was biopsied preoperatively, and it was initially interpreted to be hepatocellular carcinoma fibrolamellar type. A left trisegmentectomy with lymphadenectomy was performed and the tumor was definitively diagnosed based on the surgically resected specimen. Integrated microscopic and molecular features defined the differing biological aggressiveness of growth pattern components. Cases in the literature of MHCC and rare cases of MANC have largely undergone aggressive surgical resection as well, however the majority of studies on mixed hepatic tumors to date reflect Eastern patient cohorts and populations with underlying liver disease, thereby limiting extrapolation on management or outcomes in this case. CONCLUSION: This is one of the only reports of a hepatic tumor arising from hepatocellular carcinoma, cholangiocarcinoma and neuroendocrine lineages. Increased awareness of this tumor type may optimize improve future management.
Chen, J, L Chen, MA Zern, ND Theise, AM Diehl, P Liu and Y Duan 2017The diversity and plasticity of adult hepatic progenitor cells and their niche. Liver Int 37(9): 1260-1271.The liver is a unique organ for homoeostasis with regenerative capacities. Hepatocytes possess a remarkable capacity to proliferate upon injury; however, in more severe scenarios liver regeneration is believed to arise from at least one, if not several facultative hepatic progenitor cell compartments. Newly identified pericentral stem/progenitor cells residing around the central vein is responsible for maintaining hepatocyte homoeostasis in the uninjured liver. In addition, hepatic progenitor cells have been reported to contribute to liver fibrosis and cancers. What drives liver homoeostasis, regeneration and diseases is determined by the physiological and pathological conditions, and especially the hepatic progenitor cell niches which influence the fate of hepatic progenitor cells. The hepatic progenitor cell niches are special microenvironments consisting of different cell types, releasing growth factors and cytokines and receiving signals, as well as the extracellular matrix (ECM) scaffold. The hepatic progenitor cell niches maintain and regulate stem cells to ensure organ homoeostasis and regeneration. In recent studies, more evidence has been shown that hepatic cells such as hepatocytes, cholangiocytes or myofibroblasts can be induced to be oval cell-like state through transitions under some circumstance, those transitional cell types as potential liver-resident progenitor cells play important roles in liver pathophysiology. In this review, we describe and update recent advances in the diversity and plasticity of hepatic progenitor cell and their niches and discuss evidence supporting their roles in liver homoeostasis, regeneration, fibrosis and cancers.
Cooney, T, MC Wei, A Rangaswami, L Xu, J Sage and FK Hazard 2017CD47 is not over-expressed in fibrolamellar hepatocellular carcinoma.Ann Clin Lab Sci 47(4): 395-402.OBJECTIVES: CD47 is a transmembrane receptor that inhibits phagocytosis. Over-expression of CD47 is associated with an increased risk of tumor growth and metastasis. Clinical trials based on anti-CD47 therapy in adults are underway in a variety of malignancies. CD47 has been shown to be over-expressed in conventional hepatocellular carcinoma (HCC), a common liver tumor in adults. To our knowledge, there have been no studies to evaluate CD47 expression in the fibrolamellar subtype of HCC (FL-HCC), common in children and young adults. This study will evaluate CD47 expression in FL-HCC and shed light on its suitability for anti-CD47 therapy. METHODS: Using immunohistochemistry, 10 samples of FL-HCC from 8 patients were evaluated for CD47 (anti-phagocytic) and calreticulin (pro-phagocytic) expression. By direct comparison, CD47 and calreticulin expression were evaluated in 21 samples of conventional HCC. Additionally, transcriptome sequencing to detect CD47 mRNA expression was performed on fresh tissue from 1 FL-HCC institutional patient and previously published sequencing data from 20 additional samples was reviewed. RESULTS: Immunohistochemistry showed only weak CD47 expression in 20% of FL-HCC samples. In contrast, 57% of conventional HCC samples showed CD47 expression. All (100%) FL-HCC samples showed moderate or strong calreticulin expression. The difference between CD47 and calreticulin expression in FL-HCC is statistically significant (p=0.0007). Transcriptome sequencing revealed no difference in CD47 expression between FL-HCC and normal liver samples. CONCLUSIONS: CD47 is not over-expressed in FL-HCC. Our studies provide no support for expanding ongoing clinical trials in adults to include children and young adults with FL-HCC.
Dika, IHE, M Capanu, MF Berger, ME Arcila, R Benayed, JJ Harding, M Rusek, E Valentino, EM O'Reilly, L Saltz and GK Abou-Alfa 2017. Molecular landscape of fibrolamellar carcinoma (FLC): Beyond the DNAJB1-PRKACA chimera. J Clin Oncol 35(15_suppl): e15668-e15668.FLC is a rare cancer arising in non-cirrhotic liver of young adults. A functional chimeric transcript resulting from the in-frame fusion of DNAJB1 with PRKACA genes on chromosome 19 is thought to be universal and unique in FLC. This chimera has possible role in pathogenesis, yet with no determined prognostic or therapeutic value. Methods: Archival FFPE samples from FLC patients who prospectively consented to an IRB-approved protocol from 2014 onward were analyzed using the MSK-IMPACT platform, a hybridization capture based next generation sequencing assay for targeted deep sequencing of all exons and selected introns of > 400 key cancer genes. Tumor and matched normal libraries were sequenced on an Illumina HiSeq 2500. Sequencing output was processed using a custom analysis pipeline. Archer targeted RNAseq was performed in select cases. Demographic, treatment, and outcome data was prospectively collected. Fisher’s exact tests were performed to look for associations between clinical characteristics and genetic alterations. Results: 18 patients were identified. Median age at diagnosis was 18 years and 61% were women. 17 (94%) underwent upfront surgery, and median number of therapies was 5. The DNAJB1-PRKACA fusion transcript was detected in 100% of cases. 7 samples were negative via MSK-IMPACT, (2 false-negatives, and 5 due to an older panel not including the fusion transcript) and were confirmed positive on Archer targeted RNAseq. The second most common genetic mutation was TERT, detected in 4 patients, whereas CIC, NOTCH1, ERBB3, EPHAS, MCL1, PNRC1, NCOR, INPP4B, ARID1A, CHECK1, NKX3-1, TET1, RAD52, DIS3, SF3B1, MDM2, MED12, MPL, KRAS, PAK7, BCOR, HGF, ROS1, MYCL1, CTNNB1, and YAP1 were detected in 1 patient each. 3-year overall survival (OS) was 98%, median OS was not reached. Conclusions: This limited cohort of patients with FLC exhibited universally the DNABJ1-PRKACA chimera, and demonstrated a favorable outcome compared to a 3-year OS approaching 70% previously reported by the Fibrolamellar Consortium. The fusion transcript did not imply a prognostic value considering its expression among all patients with FLC. Other drivers or the lack of may be responsible for the improved outcome in this small cohort.
Dinh, TA, EC Vitucci, E Wauthier, RP Graham, WA Pitman, T Oikawa, M Chen, GO Silva, KG Greene, MS Torbenson, LM Reid and P Sethupathy 2017Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma.Sci Rep 7: 44653Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.
El-Khoueiry, AB, B Sangro, T Yau, TS Crocenzi, M Kudo, C Hsu, TY Kim, SP Choo, J Trojan, THR Welling, T Meyer, YK Kang, W Yeo, A Chopra, J Anderson, C Dela Cruz, L Lang, J Neely, H Tang, HB Dastani and I Melero 2017Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.Lancet 389(10088): 2492-2502. For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. METHODS: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (> or =18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with, number NCT01658878. FINDINGS: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. INTERPRETATION: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. FUNDING: Bristol-Myers Squibb.
Engelholm, LH, A Riaz, D Serra, F Dagnaes-Hansen, JV Johansen, E Santoni-Rugiu, SH Hansen, F Niola and M Frodin 2017CRISPR/Cas9 engineering of adult mouse liver demonstrates that the Dnajb1-Prkaca gene fusion is sufficient to induce tumors resembling fibrolamellar hepatocellular carcinoma.Gastroenterology 153(6): 1662-1673 e1610.BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects children and young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1-PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1-Prkaca fusion and monitored the mice for liver tumor development. METHODS: We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1-Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8-week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1-Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing. RESULTS: Livers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms. The tumors contained the Dnajb1-Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1-Prkaca fusion revealed a lack of mutations in genes commonly associated with liver cancers, as observed in human FL-HCC. CONCLUSIONS: Using CRISPR/Cas9 technology, we found generation of the Dnajb1-Prkaca fusion gene in wild-type mice to be sufficient to initiate formation of tumors that have many features of human FL-HCC. Strategies to block DNAJB1-PRKACA might be developed as therapeutics for this form of liver cancer.
Espinosa, JA, A Merlo, Jr., MO Arafeh and G Munene 2017An unusual case of jaundice: Biliary tumor thrombus in fibrolamellar hepatocellular carcinoma.Int J Surg Case Rep 36: 50-54.BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and unique variant of hepatocellular carcinoma (HCC) whose presentation remains inadequately described. We present a resectable case of FL-HCC which involved tumor thrombus of the common bile duct. PRESENTATION: A 27 year-old male presenting with jaundice, abdominal pain, vomiting, hepatic dysfunction and hyperbilirubinemia was found to have a large liver mass and lymphadenopathy on preoperative imaging. A right hepatectomy with perihepatic lymph node dissection and cholecystectomy was performed. Intraoperative cholangiogram demonstrated common bile duct (CBD) obstruction. CBD exploration revealed biliary tumor thrombus relieved with biliary thrombectomy. DISCUSSION: FL-HCC can initially present with invading obstructing biliary tumor thrombus of the CBD causing jaundice. CONCLUSION: Preoperative surgical approach should consider CBD exploration on an individual basis for underlying obstructive biliary tumor thrombus.
Feng, D, X Hui, L Shi-Chun, B Yan-Hua, C Li, L Xiao-Hui and Y Jie-Yu 2017Initial experience of anti-PD1 therapy with nivolumab in advanced hepatocellular carcinoma.Oncotarget 8(57): 96649-96655.Purpose: To evaluate efficacy and safety of anti-PD1 therapy with nivolumab for treatment of advanced hepatocellular carcinoma (HCC). Methods: From Jan 2016 to Jan 2017, eleven cases of HCC (average age of 51.8-year), 4 at stage B and 7 at stage C, according to Barcelona Clinic Liver Cancer staging, were treated with nivolumab. There were 4 patients with lung metastasis, 1 with portal vein tumor thrombus, 1 with abdominal metastasis and 1 with bone metastasis. The protocol was nivolumab, 3 mg/kg, on day 1, q3w. All patients were treated for more than 4 cycles. During anti-PD1 treatment period, 6 patients also received sorafenib and 1 patient received cytokine-induced killer cell therapy. Objective response and clinical adverse events were evaluated retrospectively. Results: Patients underwent a total of 80 cycles of nivolumab therapy, ranging between 4 and 18 cycles per patient. Nivolumab was associated with a disease control rate of 81.8%, with an objective response of 63.6% (Modified Response Evaluation Criteria in Solid Tumors). No adverse effects related to nivolumab were noted. Conclusion: Our experience shows that nivolumab could achieve acceptable outcome in HCC patients and may serve as an optional treatment, especially for patients who failed to gain a benefit from routine treatments.
Friend, BD, RS Venick, SV McDiarmid, X Zhou, B Naini, H Wang, DG Farmer, RW Busuttil and N Federman 2017Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma.Pediatr Blood Cancer 64(12). Although checkpoint inhibitor therapies have demonstrated significant efficacy in many malignancies, they have not been well studied in patients with a history of solid organ transplant. We describe two patients with recurrent, refractory, and progressive advanced fibrolamellar hepatocellular carcinoma (HCC) following orthotopic liver transplantation who received programmed cell death protein 1 (PD-1) inhibitor, nivolumab, on a patient access, off-label basis. Both rapidly developed irreversible acute liver rejection shortly after starting therapy, and ultimately died. While checkpoint inhibitors clearly have tremendous potential as a targeted therapy, they should be avoided or used with extreme caution in the context of an organ transplant.
Graham, RP, JR Craig, L Jin, AM Oliveira, JR Bergquist, MJ Truty, T Mounajjed, PT Greipp and MS Torbenson 2017Environmental exposures as a risk factor for fibrolamellar carcinoma.Mod Pathol 30(6): 892-896.Fibrolamellar carcinoma was first described in 1956. Subsequent large studies failed to identify cases before 1939 (the start of the World War II). This finding, combined with the presence of aryl hydrocarbon receptors on the tumor cells, have suggested that fibrolamellar carcinomas may be caused by environmental exposures that are new since World War II. To investigate this possibility, the surgical pathology files before 1939 were reviewed for hepatocellular carcinomas resected in young individuals. Two cases of fibrolamellar carcinoma were identified, from 1915 to 1924. The diagnosis of fibrolamellar carcinoma was confirmed at the histologic, ultrastructural and proteomic levels. These two fibrolamellar carcinoma cases clarify a key aspect of fibrolamellar carcinoma biology, reducing the likelihood that these tumors result exclusively from post World War II environmental exposures.
Graham, RP and MS Torbenson 2017Fibrolamellar carcinoma: A histologically unique tumor with unique molecular findings.Semin Diagn Pathol 34(2): 146-152.Fibrolamellar carcinoma is a unique type of hepatocellular carcinoma with a distinctive predilection for young patients without underlying liver disease, characteristic large neoplastic cells with intervening, dense fibrosis, co-expression of keratin 7 and CD68 and activation of protein kinase A (most often by formation of DNAJB1-PRKACA). Fibrolamellar carcinoma has a similar prognosis to conventional hepatocellular carcinomas arising in non-cirrhotic livers. The current American Joint Cancer Committee staging system does not provide optimal stratification of patients with fibrolamellar carcinoma and an alternate systems should be considered in the future. The only effective treatment for fibrolamellar carcinoma is complete resection. Novel therapies may be on the horizon as investigation into the molecular biology of fibrolamellar carcinoma continues.
Hasegawa, T, S Yoshida, N Sugeno, J Kobayashi and M Aoki 2017DnaJ/Hsp40 family and Parkinson's Disease.Front Neurosci 11: 743.Parkinson's disease (PD) is the second most common devastating neurodegenerative disorder after Alzheimer's disease. The precise molecular and cellular basis underlying PD still remains uncertain; however, accumulating evidence suggests that neuronal cell death is caused by a combination of environmental and genetic factors. Over the previous two decades, more than 20 genes have been identified as the cause of and/or risk for PD. Because sporadic and familial forms of PD have many similarities in clinical and neuropathological features, common molecular pathways, such as aberrant mitochondrial and protein homeostasis, are likely to exist in both conditions. Of the various genes and proteins involved in PD, the versatile DnaJ/Hsp40 co-chaperones have attracted particular attention since several genes encoding this protein family have been successively identified as the cause of the familial forms of PD/Parkinsonism. In this review, we will introduce the current knowledge regarding the integratory and modulatory effect of DnaJ/Hsp40 in various cellular functions and argue how the failure of these proteins may initiate and/or facilitate of the disease.
Jemal, A, EM Ward, CJ Johnson, KA Cronin, J Ma, B Ryerson, A Mariotto, AJ Lake, R Wilson, RL Sherman, RN Anderson, SJ Henley, BA Kohler, L Penberthy, EJ Feuer and HK Weir 2017Annual Report to the Nation on the Status of Cancer, 1975-2014, Featuring Survival.J Natl Cancer Inst 109(9).Background: The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate to provide annual updates on cancer occurrence and trends in the United States. This Annual Report highlights survival rates. Data were from the CDC- and NCI-funded population-based cancer registry programs and compiled by NAACCR. Trends in age-standardized incidence and death rates for all cancers combined and for the leading cancer types by sex were estimated by joinpoint analysis and expressed as annual percent change. We used relative survival ratios and adjusted relative risk of death after a diagnosis of cancer (hazard ratios [HRs]) using Cox regression model to examine changes or differences in survival over time and by sociodemographic factors. Results: Overall cancer death rates from 2010 to 2014 decreased by 1.8% (95% confidence interval [CI] = -1.8 to -1.8) per year in men, by 1.4% (95% CI = -1.4 to -1.3) per year in women, and by 1.6% (95% CI = -2.0 to -1.3) per year in children. Death rates decreased for 11 of the 16 most common cancer types in men and for 13 of the 18 most common cancer types in women, including lung, colorectal, female breast, and prostate, whereas death rates increased for liver (men and women), pancreas (men), brain (men), and uterine cancers. In contrast, overall incidence rates from 2009 to 2013 decreased by 2.3% (95% CI = -3.1 to -1.4) per year in men but stabilized in women. For several but not all cancer types, survival statistically significantly improved over time for both early and late-stage diseases. Between 1975 and 1977, and 2006 and 2012, for example, five-year relative survival for distant-stage disease statistically significantly increased from 18.7% (95% CI = 16.9% to 20.6%) to 33.6% (95% CI = 32.2% to 35.0%) for female breast cancer but not for liver cancer (from 1.1%, 95% CI = 0.3% to 2.9%, to 2.3%, 95% CI = 1.6% to 3.2%). Survival varied by race/ethnicity and state. For example, the adjusted relative risk of death for all cancers combined was 33% (HR = 1.33, 95% CI = 1.32 to 1.34) higher in non-Hispanic blacks and 51% (HR = 1.51, 95% CI = 1.46 to 1.56) higher in non-Hispanic American Indian/Alaska Native compared with non-Hispanic whites. Conclusions: Cancer death rates continue to decrease in the United States. However, progress in reducing death rates and improving survival is limited for several cancer types, underscoring the need for intensified efforts to discover new strategies for prevention, early detection, and treatment and to apply proven preventive measures broadly and equitably.
Kastenhuber, ER, G Lalazar, SL Houlihan, DF Tschaharganeh, T Baslan, CC Chen, D Requena, S Tian, B Bosbach, JE Wilkinson, SM Simon and SW Lowe 2017DNAJB1-PRKACA fusion kinase interacts with beta-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma.Proc Natl Acad Sci U S A 114(50): 13076-13084.A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here we implement CRISPR-Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of either the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild-type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of beta-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which causes tissue injury, inflammation, and fibrosis. Our study validates the DNAJB1-PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC, and establishes a practical model for preclinical studies to identify strategies to treat this disease.
Kersten, CA, EN Sloey, E Zhou, Y Peng, MS Torbenson and Y Guo 2017Fibrolamellar hepatocellular carcinoma: Exploring molecular mechanisms and differentiation pathways to better understand disease outcomes and prognosis.Liver Research 1: 187-192. Fibrolamellar hepatocellular carcinoma (FLC) is a rare but aggressive liver cancer of children that occurs predominantly in teenagers without a history of liver disease. Surgical resection remains the only therapeutic option, and the recurrence rate is extremely high (>50% within 3 years). A newly discovered chromosomal deletion that occurs in the majority of FLCs generates a novel kinase fusion between DnaJ heat shock protein family member B1 (DNAJB1) and protein kinase cAMP-activated catalytic subunit alpha (PRKACA) (DNAJB1-PRKACA). Despite its high penetrance and apparent specificity for FLC, the oncogenic role of this fusion event remains unclear. In this review article, we discuss the histology, presentation and diagnosis, current treatment, and roles of the DNAJB1-PRKACA as well as research models contributing to our understanding of this disease.
Kim, J, J Hyun, S Wang, C Lee, JW Lee, EY Moon, H Cha, AM Diehl and Y Jung 2017Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling. Sci Rep 7(1): 3815. The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down-regulated both integrin linked kinase (ILK), an activator of smoothened, and phosphorylated glycogen synthase kinase 3 beta (pGSK-3B), an inactive form of GSK-3B degrading glioblastoma 2 (GLI2), followed by the decreased expression of both smoothened and GLI2. A TB4 CRISPR also blocked the activation of primary HSCs, with decreased expression of smoothened, GLI2 and ILK compared with cells transfected with nontargeting control CRISPR. Double immunostaining and an immunoprecipitation assay revealed that TB4 interacted with either smoothened at the cytoplasm or GLI2 at the nucleus in LX-2. Smoothened suppression in primary HSCs using a Hh antagonist or adenovirus transduction decreased TB4 expression with the reduced activation of HSCs. Tb4-overexpressing transgenic mice treated with CCl4 were susceptible to the development hepatic fibrosis with higher levels of ILK, pGSK3b, and Hh activity, as compared with wild-type mice. These findings demonstrate that TB4 regulates HSC activation by influencing the activity of Smoothened and GLI2, suggesting TB4 as a novel therapeutic target in liver disease.
Kim, YJ, H Rhee, JE Yoo, VAF Alves, GJ Kim, HM Kim, P Herman, A Chagas, H Kim and YN Park 2017Tumour epithelial and stromal characteristics of hepatocellular carcinomas with abundant fibrous stroma: fibrolamellar versus scirrhous hepatocellular carcinoma. Histopathology 71(2): 217-226. AIMS: The scirrhous variant of hepatocellular carcinoma (S-HCC) and fibrolamellar HCC (FL-HCC) are less common subtypes of HCC that are characterized by abundant fibrous stroma. Here, we aimed to investigate differences in the tumour microenvironment and the tumour epithelial cell characteristics of S-HCC and FL-HCC. METHODS AND RESULTS: Whole tissue sections of 17 S-HCCs and 9 FL-HCCs were subjected to immunohistochemical stains for keratin 7 (K7), K19, EpCAM, CD56/NCAM, CD163, CD68, pSTAT3, FAP, CCN2 and Ki-67. FL-HCC patients were younger than S-HCC patients (P < 0.001), and chronic liver disease was seen in the background of 88.2% of S-HCC and in none of the FL-HCC. CD68 and CD163-positive tumour-infiltrating macrophages, and FAP-positive cancer-associated fibroblasts (CAFs) were more abundant in the stroma of S-HCCs compared to FL-HCCs (all P < 0.05). Tumour epithelial K19 expression was more frequent in S-HCCs compared to FL-HCCs (P = 0.023). Significant positive correlations were seen between pSTAT3 expression status in tumour epithelial cells and CAFs, the extent of stromal CAF and macrophage infiltration and K19 expression status. No significant differences were seen for K7, EpCAM, CD56/NCAM, CCN2 expression and Ki-67 labelling index between S-HCCs and FL-HCCs. CONCLUSION: S-HCC and FL-HCC are subtypes of HCC with extensive fibrosis, and the nature of the fibrous stroma differs between them. While the stroma of FL-HCC is composed of dense lamellated collagenous bands with sparse cellular components, S-HCC demonstrates more abundant CAF and tumour-infiltrating macrophages and stemness-related marker expression, suggesting the presence of a complex tumour microenvironment that may influence the aggressive behaviour of S-HCCs.
Kudo, M 2017Immune Checkpoint Inhibition in Hepatocellular Carcinoma: Basics and Ongoing Clinical Trials. Oncology 92 Suppl 1: 50-62. Clinical trials of antibodies targeting the immune checkpoint inhibitors programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for the treatment of advanced hepatocellular carcinoma (HCC) are ongoing. Expansion cohorts of a phase I/II trial of the anti-PD-1 antibody nivolumab in advanced HCC showed favorable results. Two phase III studies are currently ongoing: a comparison of nivolumab and sorafenib in the first-line setting for advanced HCC, and a comparison of the anti-PD-1 antibody pembrolizumab and a placebo in the second-line setting for patients with advanced HCC who progressed on sorafenib therapy. The combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies is being evaluated in other phase I/II trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. Immune checkpoint inhibitors may therefore open new doors to the treatment of HCC.
Limaiem, F, M Bouhamed, G Sahraoui and S Mzabi 2017Hepatocellular carcinoma: a clinicopathological study of 64 cases. Pan Afr Med J 27: 41. Hepatocellular carcinoma (HCC) is the most common of all liver cancers and is a major worldwide public health problem. The aim of this study was to provide an updated overview on clinicopathological features, treatment and outcome of HCC. In our retrospective study, we reviewed 64 cases of HCC that were diagnosed at the pathology department of Mongi Slim hospital over a fifteen-year period (2000- 2014). Relevant clinical information and microscopic slides were retrospectively reviewed. Our study group included 38 men and 26 women (sex ratio M/F = 1,26) aged between 8 and 83 years (mean = 56,64 years). The presenting clinical symptoms were dominated by abdominal pain (n=34), followed by altered general health (n=25) and jaundice (n=4). Fifty-five patients underwent surgical treatment. Liver transplantation was performed in two cases and transarterial chemoembolization was achieved in seven cases. Histopathological examination of the surgical or biopsy specimen established the diagnosis of conventional HCC in 55 cases, fibrolamellar carcinoma in 6 cases and clear cell HCC in 3 cases. Seven patients with HCC died postoperatively. Local recurrence of the tumour occurred in three cases and two patients had distant metastases postoperatively. The other patients are still being followed-up. Hepatocellular carcinoma is associated with a high rate of mortality because of early invasion, widespread metastasis and lack of effective therapeutic modalities. Accurate diagnosis and staging of these tumours is critical for optimal treatment planning and for determining prognosis.
Ray, K 2017Liver cancer: Nivolumab: checkmate for hepatocellular carcinoma?Nat Rev Gastroenterol Hepatol 14(6): 326.
Rimm, DL, G Han, JM Taube, ES Yi, JA Bridge, DB Flieder, R Homer, WW West, H Wu, AC Roden, J Fujimoto, H Yu, R Anders, A Kowalewski, C Rivard, J Rehman, C Batenchuk, V Burns, FR Hirsch and Wistuba, II 2017A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol 3(8): 1051-1058. IMPORTANCE: Four assays registered with the US Food and Drug Administration (FDA) detect programmed cell death ligand 1 (PD-L1) to enrich for patient response to anti-programmed cell death 1 and anti-PD-L1 therapies. The tests use 4 separate PD-L1 antibodies on 2 separate staining platforms and have their own scoring systems, which raises questions about their similarity and the potential interchangeability of the tests. OBJECTIVE: To compare the performance of 4 PD-L1 platforms, including 2 FDA-cleared assays, 1 test for investigational use only, and 1 laboratory-developed test. DESIGN, SETTING, AND PARTICIPANTS: Four serial histologic sections from 90 archival non-small cell lung cancers from January 1, 2008, to December 31, 2010, were distributed to 3 sites that performed the following immunohistochemical assays: 28-8 antibody on the Dako Link 48 platform, 22c3 antibody on the Dako Link 48 platform, SP142 antibody on the Ventana Benchmark platform, and E1L3N antibody on the Leica Bond platform. The slides were scanned and scored by 13 pathologists who estimated the percentage of malignant and immune cells expressing PD-L1. Statistical analyses were performed from December 1, 2015, to August 30, 2016, to compare antibodies and pathologists' scoring of tumor and immune cells. MAIN OUTCOMES AND MEASURES: Percentages of malignant and immune cells expressing PD-L1. RESULTS: Among the 90 samples, the SP142 assay was an outlier, with a significantly lower mean score of PD-L1 expression in both tumor and immune cells (tumor cells: 22c3, 2.96; 28-8, 3.26; SP142, 1.99; E1L3N, 3.20; overall mean, 2.85; and immune cells: 22c3, 2.15; 28-8, 2.28; SP142, 1.62; E1L3N, 2.28; overall mean, 2.08). Pairwise comparisons showed that the scores from the 28-8 and E1L3N tests were not significantly different but that the 22c3 test showed a slight (mean difference, 0.24-0.30) but statistically significant reduction in labeling of PD-L1 expression in tumor cells. Evaluation of intraclass correlation coefficients (ICCs) between antibodies to quantify interassay variability for PD-L1 expression in tumor cells showed high concordance between antibodies for tumor cell scoring (0.813; 95% CI, 0.815-0.839) and lower levels of concordance for immune cell scoring (0.277; 95% CI, 0.222-0.334). When examining variability between pathologists for any single assay, the concordance between pathologists' scoring for PD-L1 expression in tumor cells ranged from ICCs of 0.832 (95% CI, 0.820-0.844) to 0.882 (95% CI, 0.873-0.891) for each assay, while the ICCs from immune cells for each assay ranged from 0.172 (95% CI, 0.156-0.189) to 0.229 (95% CI, 0.211-0.248). CONCLUSIONS AND RELEVANCE: The assay using the SP142 antibody is an outlier that detected significantly less PD-L1 expression in tumor cells and immune cells. The assay for antibody 22c3 showed slight yet statistically significantly lower staining than either 28-8 or E1L3N, but this significance was detected only when using the mean of 13 pathologists' scores. The pathologists showed excellent concordance when scoring tumor cells stained with any antibody but poor concordance for scoring immune cells stained with any antibody. Thus, for tumor cell assessment of PD-L1, 3 of the 4 tests are concordant and reproducible as read by pathologists.
Roth, GS and T Decaens 2017Liver immunotolerance and hepatocellular carcinoma: Patho-physiological mechanisms and therapeutic perspectives. Eur J Cancer 87: 101-112. At the moment of the diagnosis of hepatocellular carcinoma (HCC), 70% of patients have only access to palliative treatments, with very few therapeutic options. Liver immunology is very specific, and liver immunotolerance is particularly developed because of the constant and massive influx of antigens. Deregulation of hepatic immunotolerance is implicated in chronic liver diseases development and particularly in liver carcinogenesis. For these reasons, HCC may be an excellent candidate for anticancer immunotherapies such as immune checkpoint inhibitors targeting CTLA-4 and PD-L1/PD-1. Nonetheless, because of the specific immune environment of the liver and the frequent association of HCC with hepatocellular insufficiency, the safety and the efficacy of these new treatments have to be properly studied in this situation. Thus, multiple phase II and III studies are in progress studying immune checkpoint inhibitor monotherapies, combination of different immunotherapies or local strategies such as transarterial chemoembolization combined with immune checkpoint inhibitors. Currently, only the final results of the tremelimumab phase II and the Nivolumab phase I/II study (CheckMate-040) are available. The latter is promising but need to be confirmed by the ongoing phase III studies to confirm the place of immunotherapy in the treatment of HCC. With many new molecular targets and therapeutic combination, immunotherapy represents a new hope in treating HCC patients although serious evaluation is still needed to confirm its interest.
Schmid, I and D von Schweinitz 2017Pediatric hepatocellular carcinoma: challenges and solutions.J Hepatocell Carcinoma 4: 15-21. Hepatocellular carcinoma (HCC) is a very rare entity in children, making it nearly impossible to orchestrate Phase II/III studies even as multinational cooperative trials. In contrast to adults, nearly 50% of the children have a response (alpha-fetoprotein decline and/or tumor shrinkage) to chemotherapeutic agents such as cisplatin and doxorubicin (PLADO), demonstrating that HCC in childhood can be chemotherapy sensitive. As a result, the main treatment options in pediatric HCC focus on systemic drug therapies and resection as the central therapy. In nonmetastatic patients with complete resection upfront, the 5-year event-free survival and overall survival has reached 80%-90%. In almost all reported studies, children received adjuvant chemotherapy (mostly PLADO), but it has never been proven that postoperative chemotherapy is superior to observation. No data are available for the effects of sorafenib. The 3-year survival is <20% in children with unresectable HCC independent of the chemotherapy given preoperatively. Currently, PLADO in combination with sorafenib is recommended with the goal of achieving operability status. Alternatively, data are promising for the combination of sorafenib with gemcitabine and oxaliplatin. For children with nonresectable and nonmetastastic liver tumors, it has been shown that the Milan criteria regarding liver transplantation are not applicable - individual decisions have to be made. Transarterial chemoembolization could be offered to patients with chemotherapy-resistant liver tumors for palliative care or potentially to achieve surgical resectability, and therefore cure. Information about the feasibility or effects of new agents or approaches as discussed in adult HCC patients is not available for childhood HCC. Research has to be done for characterizing the molecular and genomic mechanisms of pediatric HCC to support the development of novel therapeutic approaches and the implementation of personalized medicine.
Shah, SS, TT Wu, MS Torbenson and VS Chandan 2017Aberrant CDX2 expression in hepatocellular carcinomas: an important diagnostic pitfall.Hum Pathol 64: 13-18. CDX2 is a sensitive and specific marker of intestinal differentiation. It is routinely used in surgical pathology, as its expression within a tumor favors an origin within the gastrointestinal tract. We had anecdotally encountered occasional hepatocellular carcinomas (HCCs) that were CDX2 positive. CDX2 expression in HCC has not yet been reported, but it has also not been examined in detail. Therefore, we evaluated CDX2 expression in a large number of resected HCCs. Full tumor sections from 172 resected HCCs and 6 resected fibrolamellar carcinomas (FLCs) were stained for CDX2. Nine (5.2%) of 172 HCCs were positive for CDX2, whereas all 6 FLCs were negative. CDX2 expression in HCCs was more commonly seen in poorly differentiated tumors (5 of 16 cases, 31%) than well and moderately differentiated tumors (4 of 156 cases, 2.5%), P = .0004. No other statistically significant correlations were observed (P>.05). Results of our study show that a small subset (5%) of HCCs can be CDX2 positive. Awareness of this phenomenon is important because CDX2 expression in a liver tumor does not completely exclude a diagnosis of HCC.
Sharifnia, T, AL Hong, CA Painter and JS Boehm 2017Emerging opportunities for target discovery in rare cancers. Cell Chem Biol 24(9): 1075-1091. Rare cancers pose unique challenges to research due to their low incidence. Barriers include a scarcity of tissue and experimental models to enable basic research and insufficient patient accrual for clinical studies. Consequently, an understanding of the genetic and cellular features of many rare cancer types and their associated vulnerabilities has been lacking. However, new opportunities are emerging to facilitate discovery of therapeutic targets in rare cancers. Online platforms are allowing patients with rare cancers to organize on an unprecedented scale, tumor genome sequencing is now routinely performed in research and clinical settings, and the efficiency of patient-derived model generation has improved. New CRISPR/Cas9 and small-molecule libraries permit cancer dependency discovery in a rapid and systematic fashion. In parallel, large-scale studies of common cancers now provide reference datasets to help interpret rare cancer profiling data. Together, these advances motivate consideration of new research frameworks to accelerate rare cancer target discovery.
Sia, D, A Villanueva, SL Friedman and JM Llovet 2017Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152(4): 745-761. Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocyte precursor cells (which then become HCC cells that express progenitor cell markers), or to transdifferentiate into biliary-like cells (which give rise to iCCA). Alternatively, progenitor cells also give rise to HCCs and iCCAs with markers of progenitor cells. Advances in genome profiling and next-generation sequencing have led to the classification of HCCs based on molecular features and assigned them to categories such as proliferation-progenitor, proliferation-transforming growth factor beta, and Wnt-catenin beta1. iCCAs have been assigned to categories of proliferation and inflammation. Overall, proliferation subclasses are associated with a more aggressive phenotype and poor outcome of patients, although more specific signatures have refined our prognostic abilities. Analyses of genetic alterations have identified those that might be targeted therapeutically, such as fusions in the FGFR2 gene and mutations in genes encoding isocitrate dehydrogenases (in approximately 60% of iCCAs) or amplifications at 11q13 and 6p21 (in approximately 15% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making.
Sorenson, EC, R Khanin, ZM Bamboat, MJ Cavnar, TS Kim, E Sadot, S Zeng, JB Greer, AM Seifert, NA Cohen, MH Crawley, BL Green, DS Klimstra and RP DeMatteo 2017Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation. PLoS ONE 12(5): e0176562. Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC.
Surjan, RC, ES Dos Santos, T Basseres, FF Makdissi and MA Machado 2017A proposed physiopathological pathway to hyperammonemic encephalopathy in a non-cirrhotic patient with fibrolamellar hepatocellular carcinoma without ornithine transcarbamylase (OTC) mutation. Am J Case Rep 18: 234-241. BACKGROUND Hyperammonemic encephalopathy is a potentially fatal condition that may progress to irreversible neuronal damage and is usually associated with liver failure or portosystemic shunting. However, other less common conditions can lead to hyperammonemia in adults, such as fibrolamellar hepatocellular carcinoma. Clinical awareness of hyperammonemic encephalopathy in patients with normal liver function is paramount to timely diagnosis, but understanding the underlying physiopathology is decisive to initiate adequate treatment for complete recovery. CASE REPORT A 31-year-old male with fibrolamellar carcinoma and peritoneal carcinomatosis presented with rapid onset hyperammonemic encephalopathy. Despite usual treatment for hepatic encephalopathy, his hyperammonemia was aggravated. A physiopathological pathway to encephalopathy resulting from hepatocellular dysfunction or portosystemic shunting was suspected and proper treatment was initiated, which resulted in complete remission of encephalopathy. Thus, we propose there is a physiopathology path to hyperammonemic encephalopathy in non-cirrhotic patients with fibrolamellar carcinoma independent of ornithine transcarbamylase (OTC) mutation. An ornithine metabolism imbalance resulting from overexpression of Aurora Kinase A as a result of a single, recurrent heterozygous deletion on chromosome 19, common to all fibrolamellar carcinomas, can lead to a c-Myc and ornithine decarboxylase overexpression that results in ornithine transcarboxylase dysfunction with urea cycle disorder and subsequent hyperammonemia. CONCLUSIONS The identification of a physiopathological pathway allowed adequate medical treatment and full patient recovery from severe hyperammonemic encephalopathy.
Torbenson, MS 2017Morphologic Subtypes of Hepatocellular Carcinoma.Gastroenterol Clin North Am 46(2): 365-391. Hepatocellular carcinomas can be further divided into distinct subtypes that provide important clinical information and biological insights. These subtypes are distinct from growth patterns and are on based on morphologic and molecular findings. There are 12 reasonably well-defined subtypes as well as 6 provisional subtypes, together making up 35% of all hepatocellular carcinomas. These subtypes are discussed, with an emphasis on their definitions and the key morphologic findings.
Vinayak, R, RJ Cruz, Jr., S Ranganathan, R Mohanka, G Mazariegos, K Soltys, G Bond, S Tadros, A Humar, JW Marsh, RR Selby, J Reyes, Q Sun, K Haberman and R Sindhi 2017Pediatric liver transplantation for hepatocellular cancer and rare liver malignancies: US multicenter and single-center experience (1981-2015).Liver Transpl 23(12): 1577-1588. A tenth of all pediatric liver transplantations (LTs) are performed for unresectable liver malignancies, especially the more common hepatoblastoma (HBL). Less understood are outcomes after LT for the rare hepatocellular carcinoma, nonhepatoblastoma embryonal tumors (EMBs), and slow growing metastatic neuroendocrine tumors of childhood. Pediatric LT is increasingly performed for rare unresectable liver malignancies other than HBL. We performed a retrospective review of outcomes after LT for malignancy in the multicenter US Scientific Registry of Transplant Recipients (SRTR; n = 677; 1987-2015). We then reviewed the Children's Hospital of Pittsburgh (CHP; n = 74; 1981-2014) experience focusing on LT for unresectable hepatocellular cancer (HCC), EMBs, and metastatic liver tumors (METS). HBL was included to provide reference statistics. In the SRTR database, LT for HCC and HBL increased over time (P < 0.001). Compared with other malignancies, the 149 HCC cases received fewer segmental grafts (P < 0.001) and also experienced 10-year patient survival similar to 15,710 adult HCC LT recipients (51.6% versus 49.6%; P = 0.848, not significant [NS], log-rank test). For 22 of 149 cases with incidental HCC, 10-year patient survival was higher than 127 primary HCC cases (85% [95% confidence interval (CI), 70.6%-100%] versus 48.3% [95% CI, 38%-61%]; P = 0.168, NS) and similar to 3392 biliary atresia cases (89.9%; 95% CI, 88.7%-91%). Actuarial 10-year patient survival for 17 EMBs, 10 METS, and 6 leiomyosarcoma patients exceeded 60%. These survival outcomes were similar to those seen for HBL. At CHP, posttransplant recurrence-free and overall survival among 25 HCC, 17 (68%) of whom had preexisting liver disease, was 16/25 or 64%, and 9/25 or 36%, respectively. All 10 patients with incidental HCC and tumor-node-metastasis stage I and II HCC survived recurrence-free. Only vascular invasion predicted poor survival in multivariate analysis (P < 0.0001). A total of 4 of 5 EMB patients (80%) and all patients with METS (neuroendocrine-2, pseudopapillary pancreatic-1) also survived recurrence-free. Among children, LT can be curative for unresectable HCC confined to the liver and without vascular invasion, incidental HCC, embryonal tumors, and metastatic neuroendocrine tumors.
Vishnu, N, AV Kulkarni, S Vidhyalakshmi, S Sambandam, P Garg, V LeelaKrishnan, K Janarthan, G Singh, M Kaur, TV Chitra and BJ John 2017Fibrolamellar variant of hepatocellular carcinoma presenting during pregnancy: management dilemmas. Ann Hepatobiliary Pancreat Surg 21(1): 48-51. The Fibrolamellar variant of Hepatocellular Carcinoma (FLHCC) is a rare form of liver cancer that presents in the 3(rd) decade of life, is rarely associated with cirrhosis or chronic Hepatitis B/C virus infection, and usually presents with normal serum alpha-fetoprotein (AFP) levels. FLHCC presenting during pregnancy is extremely rare, with only 4 cases reported. We present a case of FLHCC in pregnancy and discuss the dilemmas in management. A 26 year-old primigravida, 26 weeks of gestation presented with a month's history of obstructive jaundice secondary. Investigations revealed a mass in the left lateral segment of the liver with extension down the left hepatic duct into the common bile duct. Following an emergency caesarean section at 31 weeks, she underwent a left hepatectomy with extrahepatic bile duct excision. The postoperative course was uneventful. Histopathology showed FLHCC. In conclusion, liver tumors presenting during pregnancy should be managed in a multidisciplinary setup with facilities for neonatal intensive care. Management depends on the presumed pathology, period of gestation and family preferences. Shah, SS, TT Wu, MS Torbenson and VS Chandan (2017).
Wahab, MA, E El Hanafy, A El Nakeeb and MA Ali 2017Clinicopathological features and surgical outcome of patients with fibrolamellar hepatocellular carcinoma (experience with 22 patients over a 15-year period). World J Gastrointest Surg 9(2): 61-67. AIM: To evaluate the clinicopathological features and the surgical outcomes of patients with fibrolamellar hepatocellular carcinoma (FL-HCC) over a 15-year period. METHODS: This is a retrospective study including 22 patients with a pathologic diagnosis of FL-HCC who underwent hepatectomy over a 15-year period. Tumor characteristics, survival and recurrence were evaluated. RESULTS: There were 11 male and 11 female with a median age of 29 years (range from 21 to 58 years). Two (9%) patients had hepatitis C viral infection and only 2 (9%) patients had alpha-fetoprotein level > 200 ng/mL. The median size of the tumors was 12 cm (range from 5-20 cm). Vascular invasion was detected in 5 (23%) patients. Four (18%) patients had lymph node metastases. The median follow up period was 42 mo and the 5-year survival was 65%. Five (23%) patients had a recurrent disease, 4 of them had a second surgery with 36 mo median time interval. Vascular invasion is the only significant negative prognostic factor. CONCLUSION: FL-HCC has a favorable prognosis than common HCC and should be suspected in young patients with non cirrhotic liver. Aggressive surgical resection should be done for all patients. Repeated hepatectomy should be considered for these patients as it has a relatively indolent course.
Xie, G, M Swiderska-Syn, ML Jewell, MV Machado, GA Michelotti, RT Premont and AM Diehl 2017Loss of pericyte smoothened activity in mice with genetic deficiency of leptin. BMC Cell Biol 18(1): 20. BACKGROUND: Obesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation. RESULTS: We found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage. CONCLUSIONS: Leptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage.
Alsina, AE, E Franco, A Nakshabandi, C Albers, N Kemmer, AC Berry and J Finan 2016Successful liver transplantation for hyperammonemic fibrolamellar hepatocellular carcinoma.ACG Case Rep J 3(4): e106.Fibrolamellar hepatocellular carcinoma is a rare hepatocellular tumor usually arising in noninfected and noncirrhotic livers. Only 2 cases accompanied by hyperammonemia due to intrahepatic shunting have been reported. A 23-year-old white woman presented with a 2-week history of nausea, vomiting, generalized weakness, and intermittent right upper quadrant pain. Abdominal computerized tomography revealed a 13 x 9-cm hepatic mass. Core-needle biopsy revealed fibrolamellar hepatocellular carcinoma. She presented with coma due to hyperammonemia levels (peak at 437 mcg/dL) but without metastatic disease. She was urgently transplanted, started on daily sorafenib 8 weeks after transplantation, and was free of disease at 1 year after transplantation
Batra, J, S Tripathi, A Kumar, JM Katz, NJ Cox, RB Lal, S Sambhara and SK Lal 2016Human Heat shock protein 40 (Hsp40/DnaJB1) promotes influenza A virus replication by assisting nuclear import of viral ribonucleoproteins.Sci Rep 6: 19063.A unique feature of influenza A virus (IAV) life cycle is replication of the viral genome in the host cell nucleus. The nuclear import of IAV genome is an indispensable step in establishing virus infection. IAV nucleoprotein (NP) is known to mediate the nuclear import of viral genome via its nuclear localization signals. Here, we demonstrate that cellular heat shock protein 40 (Hsp40/DnaJB1) facilitates the nuclear import of incoming IAV viral ribonucleoproteins (vRNPs) and is important for efficient IAV replication. Hsp40 was found to interact with NP component of IAV RNPs during early stages of infection. This interaction is mediated by the J domain of Hsp40 and N-terminal region of NP. Drug or RNAi mediated inhibition of Hsp40 resulted in reduced nuclear import of IAV RNPs, diminished viral polymerase function and attenuates overall viral replication. Hsp40 was also found to be required for efficient association between NP and importin alpha, which is crucial for IAV RNP nuclear translocation. These studies demonstrate an important role for cellular chaperone Hsp40/DnaJB1 in influenza A virus life cycle by assisting nuclear trafficking of viral ribonucleoproteins.
Bernieh, A, K Adams, X Susan Liu, R Flowers, V Shenoy, M Baliga and I Akhtar 2016Fibrolamellar hepatocellular carcinoma in ascitic fluid: A case report with cytohistological correlation.Diagn Cytopathol 44(9): 757-760.The fibrolamellar variant of hepatocellular carcinoma (FL-HCC) is distinguished from other hepatocellular carcinoma's (HCC) by its unique clinical and pathological features. Cytological features of this tumor on fine needle aspiration have been described earlier. We report a rare case of a 17-year-old African American male with metastatic FL-HCC, diagnosed by body fluid cytology. The patient presented with ascites and computed tomography (CT) scan revealed multiple omental masses and liver lesions. The fluid sample was obtained along with the omental biopsy and was found positive for metastatic fibrolamellar hepatocellular carcinoma. The fluid cytology showed atypical polygonal cells with enlarged nuclei, prominent nucleoli, and abundant granular cytoplasm. Cytomorphologic features of FL-HCC presenting in body fluids have been rarely described before. This case enriches the cytopathology literature by providing awareness of this tumor presenting as metastasis in body fluids, especially in young individuals with liver lesions. Presence of a concurrent biopsy specimen provided cytohistological correlation, as it remains the gold standard for the accuracy and reliability of cytological diagnoses. Diagn. Cytopathol. 2016;44:757-760. (c) 2016 Wiley Periodicals, Inc.
Billingham, L, K Malottki and N Steven 2016Research methods to change clinical practice for patients with rare cancers.Lancet Oncol 17(2): e70-e80.Rare cancers are a growing group as a result of reclassification of common cancers by molecular markers. There is therefore an increasing need to identify methods to assess interventions that are sufficiently robust to potentially affect clinical practice in this setting. Methods advocated for clinical trials in rare diseases are not necessarily applicable in rare cancers. This Series paper describes research methods that are relevant for rare cancers in relation to the range of incidence levels. Strategies that maximise recruitment, minimise sample size, or maximise the usefulness of the evidence could enable the application of conventional clinical trial design to rare cancer populations. Alternative designs that address specific challenges for rare cancers with the aim of potentially changing clinical practice include Bayesian designs, uncontrolled n-of-1 trials, and umbrella and basket trials. Pragmatic solutions must be sought to enable some level of evidence-based health care for patients with rare cancers.
Blay, JY, JM Coindre, F Ducimetiere and I Ray-Coquard 2016The value of research collaborations and consortia in rare cancers.Lancet Oncol 17(2): e62-e69.Rare cancers are defined by an incidence of less than six per 100,000 people per year. They represent roughly 20% of all human cancers and are associated with worse survival than are so-called frequent tumours, because of delays to accurate diagnosis, inadequate treatments, and fewer opportunities to participate in clinical trials (because of a paucity of dedicated trials from both academic and industrial sponsors). In this Series paper, we discuss how these challenges can be addressed by research consortia and suggest the integration of these consortia with reference networks, which gather multidisciplinary expert centres, for management of rare tumours.
Boyd, N, JE Dancey, CB Gilks and DG Huntsman 2016Rare cancers: a sea of opportunity.Lancet Oncol 17(2): e52-e61.Rare cancers, as a collective, account for around a quarter of all cancer diagnoses and deaths. Historically, they have been divided into two groups: cancers defined by their unusual histogenesis (cell of origin or differentiation state)--including chordomas or adult granulosa cell tumours--and histologically defined subtypes of common cancers. Most tumour types in the first group are still clinically and biologically relevant, and have been disproportionately important as sources of insight into cancer biology. By contrast, most of those in the second group have been shown to have neither defining molecular features nor clinical utility. Omics-based analyses have splintered common cancers into a myriad of molecularly, rather than histologically, defined subsets of common cancers, many of which have immediate clinical relevance. Now, almost all rare cancers are either histomolecular entities, which often have pathognomonic mutations, or molecularly defined subsets of more common cancers. The presence of specific genetic variants provides rationale for the testing of targeted drugs in rare cancers. However, in addition to molecular alterations, it is crucial to consider the contributions of both mutation and cell context in the development, biology, and behaviour of these cancers. Patients with rare cancers are disadvantaged because of the challenge of leading clinical trials in this setting due to poor accrual. However, the number of patients with rare cancers will only increase as more molecular subsets of common cancers are identified, necessitating a shift in the focus of clinical trials and research into these cancer types, which, by epidemiological definitions, will become rare tumours.
Carpino, G, A Renzi, A Franchitto, V Cardinale, P Onori, L Reid, D Alvaro and E Gaudio 2016Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration.Stem Cells Int 2016: 3658013.Niches containing stem or progenitor cells are present in different anatomical locations along the human biliary tree and within liver acini. The most primitive stem or progenitors, biliary tree stem or progenitor cells (BTSCs), reside within peribiliary glands located throughout large extrahepatic and intrahepatic bile ducts. BTSCs are multipotent and can differentiate towards hepatic and pancreatic cell fates. These niches' matrix chemistry and other characteristics are undefined. Canals of Hering (bile ductules) are found periportally and contain hepatic stem or progenitor cells (HpSCs), participating in the renewal of small intrahepatic bile ducts and being precursors to hepatocytes and cholangiocytes. The niches also contain precursors to hepatic stellate cells and endothelia, macrophages, and have a matrix chemistry rich in hyaluronans, minimally sulfated proteoglycans, fetal collagens, and laminin. The microenvironment furnishes key signals driving HpSC activation and differentiation. Newly discovered third niches are pericentral within hepatic acini, contain Axin2+ unipotent hepatocytic progenitors linked on their lateral borders to endothelia forming the central vein, and contribute to normal turnover of mature hepatocytes. Their relationship to the other stem or progenitors is undefined. Stem/progenitor niches have important implications in regenerative medicine for the liver and biliary tree and in pathogenic processes leading to diseases of these tissues.
Chapuy, CI, I Sahai, R Sharma, AX Zhu and ON Kozyreva 2016Hyperammonemic encephalopathy associated with fibrolamellar hepatocellular carcinoma: Case report, literature review, and proposed treatment algorithm.Oncologist 21(4): 514-520.We report a case of a 31-year-old man with metastatic fibrolamellar hepatocellular carcinoma (FLHCC) treated with gemcitabine and oxaliplatin complicated by hyperammonemic encephalopathy biochemically consistent with acquired ornithine transcarbamylase deficiency. Awareness of FLHCC-associated hyperammonemic encephalopathy and a pathophysiology-based management approach can optimize patient outcome and prevent serious complications. A discussion of the management, literature review, and proposed treatment algorithm of this rare metabolic complication are presented. IMPLICATIONS FOR PRACTICE: Pathophysiology-guided management of cancer-associated hyperammonemic encephalopathy can improve patient outcome and prevent life-threatening complications. Community and academic oncologists should be aware of this serious metabolic complication of cancer and be familiar with its management.
Diaz Hernandez, HA, IA Gomez Ruiz and A Torre 2016Duodenal recurrence of fibrolamellar carcinoma 12 years after partial hepatectomy and adjuvant chemotherapy.ACG Case Rep J 3(4): e160.Fibrolamellar carcinoma (FLC) has a better prognosis than hepatocellular carcinoma; however, it is a highly recurrent disease. A 17-year-old woman presented with FLC with regional disease at the right lobe of the liver and underwent right hepatic lobe resection plus adjuvant chemotherapy with interferon alpha and adriamycin. She then presented at age 29 years with anemia. Endoscopy revealed an exofitic lesion in the duodenum, which was a recurrence of FLC. The patient underwent duodenal partial resection of a metastatic FLC tumor with disease-free edges and without neural or lymphoid-vascular involvement, a nonreported site of recurrence.
Estrella Diez, E, FJ Alvarez Higueras, G Marin Zafra, A Bas Bernal, C Garre Sanchez, J Egea Valenzuela, DJ Nova Lopez, E Navarro Noguera, G Anton Rodenas and LF Carballo Alvarez 2016Fibrolamellar hepatocellular carcinoma: a rare entity diagnosed by abdominal ultrasound.Rev Esp Enferm Dig 108(8): 494-495.We present the case of a young man with a hepatic mass in which ultrasound gives great and immediate support for diferential diagnosis.
Graham, RP, JJ Garcia, PT Greipp, EG Barr Fritcher, BR Kipp and MS Torbenson 2016FGFR1 and FGFR2 in fibrolamellar carcinoma.Histopathology 68(5): 686-692.AIMS: Fibrolamellar carcinoma is characterized by a recurrent DNAJB1-PRKACA chimeric transcript. The functional properties of the fusion are unknown, but are believed to include PRKACA up-regulation. PRKCA is a subunit of protein kinase A. The downstream targets of protein kinase A are unknown, but may include interactions with fibroblast growth factor receptor (FGFR) pathways. In addition, inhibitors for FGFR proteins have been developed recently. METHODS AND RESULTS: Nineteen histologically confirmed fibrolamellar carcinomas were studied. All showed the characteristic DNAJB1-PRKACA transcript by reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemistry for FGFR1 was negative in 19 of 19 cases using a monoclonal antibody, while a polyclonal antibody showed no expression (n = 11) or weak and focal expression (n = 8). RNAin-situ hybridization was 2+ in two cases, 1+ in four cases and negative in four cases. FGFR1 fluorescence in-situ hybridization (FISH) revealed polysomy of chromosome 8 in 17 of 19 cases. Break-apart FISH for FGFR2 was negative for rearrangements in 12 of 12 informative cases. CONCLUSIONS: Fibrolamellar carcinomas show polysomy of chromosome 8 and the FGFR1 locus, and only modest mRNA expression and weak or absent expression at the protein level. FGFR2 rearrangement was not detected. These data reduce the likelihood that FGFR inhibitors will be effective in the treatment of most fibrolamellar carcinomas.
Graham, RP, LM Terracciano, A Meves, PM Vanderboom, S Dasari, MM Yeh, MS Torbenson and MW Cruise 2016Hepatic adenomas with synchronous or metachronous fibrolamellar carcinomas: both are characterized by LFABP loss.Mod Pathol 29(6): 607-615.Rare hepatic adenomas are associated with synchronous or metachronous fibrolamellar carcinomas. The morphology of these adenomas has not been well described and they have not been subclassifed using the current molecular classification schema. We examined four hepatic adenomas co-occurring with or preceding a diagnosis of fibrolamellar carcinoma in three patients. On histological examination, three of the adenomas showed the typical morphology of HNF1-alpha inactivated adenomas, whereas one showed a myxoid adenoma morphology. All of the adenomas were negative for PRKACA rearrangements by Fluorescence in situ Hybridization (FISH) analysis. All four of the adenomas showed complete loss or significant reduction of liver fatty acid binding protein (LFABP) expression by immunohistochemistry. Interestingly, the fibrolamellar carcinomas in each case also showed loss of LFABP by immunohistochemistry. One of the fibrolamellar carcinomas was negative for PRKACA rearrangements by FISH, whereas the others were positive. To investigate if LFBAP loss is typical of fibrolamellar carcinomas in general, an additional cohort of tumors was studied (n=19). All 19 fibrolamellar carcinomas showed the expected PRKACA rearrangements and immunostains showed loss of LFABP in each case, consistent with HNF1-alpha inactivation. To validate this observation, mass spectrometry-based proteomics was performed on tumor-normal pairs of six fibrolamellar carcinomas and showed an average 10-fold reduction in LFABP protein levels, compared with matched normal liver tissue. In conclusion, hepatic adenomas co-occurring with fibrolamellar carcinomas show LFABP loss and are negative for PRKACA rearrangements, indicating they are genetically distinct lesions. These data also demonstrate that LFABP loss, which characterizes HNF1-alpha inactivation, is a consistent feature of fibrolamellar carcinoma, indicating HNF1-alpha inactivation is an important event in fibrolamellar carcinoma pathogenesis.
Grandhi, MS, AK Kim, SM Ronnekleiv-Kelly, IR Kamel, MA Ghasebeh and TM Pawlik 2016Hepatocellular carcinoma: From diagnosis to treatment.Surg Oncol 25(2): 74-85.Primary liver cancer is the sixth most common cancer overall and the second most common cause of cancer mortality worldwide. Hepatocellular carcinoma accounts for up to 90% of all primary hepatic malignancies and represents a major international health problem. While surgical resection and transplantation are the cornerstone of therapy in early-stage hepatocellular carcinoma, locoregional therapy and sorafenib are beneficial in those with more advanced disease or those who are not surgical candidates. At times, the integration of both surgical and locoregional therapy may be necessary. Hence, hepatocellular carcinoma requires a multidisciplinary approach to determine the most appropriate treatment as well as the timing of various treatments for optimal outcomes.
Griffith, OL, M Griffith, K Krysiak, V Magrini, A Ramu, ZL Skidmore, J Kunisaki, R Austin, S McGrath, J Zhang, R Demeter, T Graves, JM Eldred, J Walker, DE Larson, CA Maher, Y Lin, W Chapman, A Mahadevan, R Miksad, I Nasser, DW Hanto and ER Mardis 2016A genomic case study of mixed fibrolamellar hepatocellular carcinoma.Ann Oncol 27(6): 1148-1154.BACKGROUND: Mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) is a rare liver tumor defined by the presence of both pure FL-HCC and conventional HCC components, represents up to 25% of cases of FL-HCC, and has been associated with worse prognosis. Recent genomic characterization of pure FL-HCC identified a highly recurrent transcript fusion (DNAJB1:PRKACA) not found in conventional HCC. PATIENTS AND METHODS: We performed exome and transcriptome sequencing of a case of mFL-HCC. A novel BAC-capture approach was developed to identify a 400 kb deletion as the underlying genomic mechanism for a DNAJB1:PRKACA fusion in this case. A sensitive Nanostring Elements assay was used to screen for this transcript fusion in a second case of mFL-HCC, 112 additional HCC samples and 44 adjacent non-tumor liver samples. RESULTS: We report the first comprehensive genomic analysis of a case of mFL-HCC. No common HCC-associated mutations were identified. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variants, and high expression of ERBB2 were more consistent with previous reports of pure FL-HCC than conventional HCC. In particular, the DNAJB1:PRKACA fusion transcript specifically associated with pure FL-HCC was detected at very high expression levels. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed our finding that the fusion was detectable in conventional components. An expanded screen identified a third case of fusion-positive HCC, which upon review, also had both conventional and fibrolamellar features. This screen confirmed the absence of the fusion in all conventional HCC and adjacent non-tumor liver samples. CONCLUSION: These results indicate that mFL-HCC is similar to pure FL-HCC at the genomic level and the DNAJB1:PRKACA fusion can be used as a diagnostic tool for both pure and mFL-HCC.
Kassahun, WT 2016Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments.World J Surg Oncol 14(1): 151.Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant liver tumor which is thought to be a variant of conventional hepatocellular carcinoma (HCC). It accounts for a small proportion of HCC cases and occurs in a distinctly different group of patients which are young and usually not in the setting of chronic liver disease. The diagnosis of FL-HCC requires the integration of clinical information, imaging studies, and histology. In terms of the treatment options, the only potentially curative treatment option for patients who have resectable disease is surgery either liver resection (LR) or liver transplantation (LT). When performed in a context of aggressive therapy, long-term outcomes after surgery, particularly liver resection for FL-HCC, were favorable. The clinical outcome of patients with unresectable disease is suboptimal with median survival of less than 12 months. The aim of this review is to update the available evidence on diagnosis, treatment options, outcome predictors, and recent developments of patients with this rare disease and to provide a summarized overview of the available literature.
Khan, SY, S Vasanth, F Kabir, JD Gottsch, AO Khan, R Chaerkady, MC Lee, CC Leitch, Z Ma, J Laux, R Villasmil, SN Khan, S Riazuddin, J Akram, RN Cole, CC Talbot, N Pourmand, NA Zaghloul, JF Hejtmancik and SA Riazuddin 2016FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1.Nat Commun 7: 10953.FOXE3 is a lens-specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole-exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in a mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, here we report DNAJB1 is a transcriptional target of FOXE3 in a novel pathway that is crucial for the development of the anterior segment of the eye.
Kubo, N, K Araki, H Kuwano and K Shirabe 2016Cancer-associated fibroblasts in hepatocellular carcinoma.World J Gastroenterol 22(30): 6841-6850.The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts (CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAFtargeted therapy may be effective for suppression not only of fibrosis but also cancer progression.
LaQuaglia, MJ, JL Grijalva, KA Mueller, AR Perez-Atayde, HB Kim, G Sadri-Vakili and K Vakili 2016YAP subcellular localization and Hippo pathway transcriptome analysis in pediatric hepatocellular carcinoma.Sci Rep 6: 30238.Pediatric hepatocellular carcinoma (HCC) is a rare tumor which is associated with an extremely high mortality rate due to lack of effective chemotherapy. Recently, the Hippo pathway and its transcriptional co-activator Yes-associated protein (YAP) have been shown to play a role in hepatocyte proliferation and development of HCC in animal models. Therefore, we sought to examine the activity of YAP and the expression of Hippo pathway components in tumor and non-neoplastic liver tissue from 7 pediatric patients with moderately differentiated HCC. None of the patients had underlying cirrhosis or viral hepatitis, which is commonly seen in adults with HCC. This highlights a major difference in the pathogenesis of HCC between children and adults. We found a statistically significant increase in YAP nuclear localization in 100% of tumors. YAP target gene (CCNE1, CTGF, Cyr61) mRNA expression was also increased in the tumors that had the most significant increase in YAP nuclear localization. Based on Ki67 co-localization studies YAP nuclear localization was not simply a marker of proliferation. Our results demonstrate a clear increase in YAP activity in moderately differentiated pediatric HCC, providing evidence that it may play an important role in tumor survival and propagation.
Latysheva, NS and MM Babu 2016Discovering and understanding oncogenic gene fusions through data intensive computational approaches.Nucleic Acids Res 44(10): 4487-4503.Although gene fusions have been recognized as important drivers of cancer for decades, our understanding of the prevalence and function of gene fusions has been revolutionized by the rise of next-generation sequencing, advances in bioinformatics theory and an increasing capacity for large-scale computational biology. The computational work on gene fusions has been vastly diverse, and the present state of the literature is fragmented. It will be fruitful to merge three camps of gene fusion bioinformatics that appear to rarely cross over: (i) data-intensive computational work characterizing the molecular biology of gene fusions; (ii) development research on fusion detection tools, candidate fusion prioritization algorithms and dedicated fusion databases and (iii) clinical research that seeks to either therapeutically target fusion transcripts and proteins or leverages advances in detection tools to perform large-scale surveys of gene fusion landscapes in specific cancer types. In this review, we unify these different-yet highly complementary and symbiotic-approaches with the view that increased synergy will catalyze advancements in gene fusion identification, characterization and significance evaluation.
Liu, L, SS Shah, BV Naini, S French, TT Wu, MS Torbenson and VS Chandan 2016Immunostains used to subtype hepatic adenomas do not distinguish hepatic adenomas from hepatocellular carcinomas.Am J Surg Pathol 40(8): 1062-1069.Immunostains are used to subtype hepatic adenomas to stratify for the risk of malignant transformation. The most common panel of immunostains used for this purpose includes liver fatty acid-binding protein (LFABP), serum amyloid A (SAA) protein, C-reactive protein (CRP), and glutamine synthetase (GS). Importantly, some pathologists use these stains in an attempt to distinguish hepatocellular carcinomas (HCC) from hepatic adenomas. However, there are limited data on the performance of these stains in HCCs. To investigate the staining characteristics of HCCs, we studied 159 HCCs (92 well-differentiated, 67 moderately differentiated, and 7 poorly differentiated) and 7 fibrolamellar carcinomas for the expression of LFABP, SAA, CRP, and GS. All of the stains were positive in at least a subset of HCCs: SAA was positive in 27 of 159 (17%), CRP in 86 of 159 (54%), and GS in 23 of 47 (49%) cases; LFABP showed loss of staining in 36 of 159 (23%) cases. Fibrolamellar carcinomas were consistently CRP positive (7 of 7 cases) and frequently showed loss of LFABP (4 of 7 cases). There was no association between expression of SAA, CRP, and GS as well as loss of LFABP expression and other clinicopathologic features. HCCs with loss of LFABP were more frequently associated with negative GS expression (11 of 14 cases, P=0.02). These data show that immunostains used to subtype hepatic adenomas are not useful for distinguishing HCCs from hepatic adenomas and should be used only after a diagnosis of hepatic adenoma has been made using other criteria.
Lu, J, Y Xia, K Chen, Y Zheng, J Wang, W Lu, Q Yin, F Wang, Y Zhou and C Guo 2016Oncogenic role of the Notch pathway in primary liver cancer.Oncol Lett 12(1): 3-10.Primary liver cancer, which includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and fibrolamellar HCC, is one of the most common malignancies and the third leading cause of cancer-associated mortality, worldwide. Despite the development of novel therapies, the prognosis of liver cancer patients remains extremely poor. Thus, investigation of the genetic background and molecular mechanisms underlying the development and progression of this disease has gained significant attention. The Notch signaling pathway is a crucial determinant of cell fate during development and disease in several organs. In the liver, Notch signaling is involved in biliary tree development and tubulogenesis, and is also significant in the development of HCC and ICC. These findings suggest that the modulation of Notch pathway activity may have therapeutic relevance. The present review summarizes Notch signaling during HCC and ICC development and discusses the findings of recent studies regarding Notch expression, which reveal novel insights into its function in liver cancer progression.
Nguyen, BD 2016EDUCATION AND IMAGING. Hepatobiliary and Pancreatic: Post-transplant recurrence of fibrolamellar hepatocellular carcinoma in lung and pancreas.J Gastroenterol Hepatol 31(2): 286.
Reid, LM 2016Stem progenitor cells and reprogramming (plasticity) mechanisms in liver, biliary tree, and pancreas. Hepatology 64(1): 4-7
Reid, LM and P Sethupathy 2016The DNAJB1-PRKACA chimera: Candidate biomarker and therapeutic target for fibrolamellar carcinomas.Hepatology 63(2): 662-664.
Riggle, KM, KJ Riehle, HL Kenerson, R Turnham, MK Homma, M Kazami, B Samelson, R Bauer, GS McKnight, JD Scott and RS Yeung 2016Enhanced cAMP-stimulated protein kinase A activity in human fibrolamellar hepatocellular carcinoma.Pediatr Res 80(1): 110-118.BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) affects children without underlying liver disease. A consistent mutation in FL-HCCs leads to fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PRKACA). We sought to characterize the resultant chimeric protein and its effects in FL-HCC. METHODS: The expression pattern and subcellular localization of protein kinase A (PKA) subunits in FL-HCCs were compared to paired normal livers by quantitative polymerase chain reaction (qPCR), immunoblotting, and immunofluorescence. PKA activity was measured by radioactive kinase assay, and we determined whether the FL-HCC mutation is present in other primary liver tumors. RESULTS: The fusion transcript and chimeric protein were detected exclusively in FL-HCCs. DNAJB1-PRKACA was expressed 10-fold higher than the wild-type PRKACA transcript, resulting in overexpression of the mutant protein in tumors. Consequently, FL-HCCs possess elevated cAMP-stimulated PKA activity compared to normal livers, despite similar Kms between the mutant and wild-type kinases. CONCLUSION: FL-HCCs in children and young adults uniquely overexpress DNAJB1-PRKACA, which results in elevated cAMP-dependent PKA activity. These data suggest that aberrant PKA signaling contributes to liver tumorigenesis.
Riggle, KM, R Turnham, JD Scott, RS Yeung and KJ Riehle 2016Fibrolamellar hepatocellular carcinoma: mechanistic distinction from adult hepatocellular carcinoma.Pediatr Blood Cancer 63(7): 1163-1167.Fibrolamellar hepatocellular carcinoma (FL-HCC) has historically been classified as a rare subtype of HCC. However, unlike "classic" HCC, it occurs in children and young adults without underlying liver disease. The recent discovery of a deletion mutation in all FL-HCCs represented a major advancement in understanding the pathogenesis of this disease. This deletion results in the fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PKA, PRKACA), and overexpression of PRKACA and enhanced cAMP-dependent PKA activity. This review summarizes recent advancements in FL-HCC pathogenesis and characteristics of the HSP40-PKA C protein.
Ryerson, AB, CR Eheman, SF Altekruse, JW Ward, A Jemal, RL Sherman, SJ Henley, D Holtzman, A Lake, AM Noone, RN Anderson, J Ma, KN Ly, KA Cronin, L Penberthy and BA Kohler 2016Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer.Cancer 122(9): 1312-1337.BACKGROUND: Annual updates on cancer occurrence and trends in the United States are provided through an ongoing collaboration among the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR). This annual report highlights the increasing burden of liver and intrahepatic bile duct (liver) cancers. METHODS: Cancer incidence data were obtained from the CDC, NCI, and NAACCR; data about cancer deaths were obtained from the CDC's National Center for Health Statistics (NCHS). Annual percent changes in incidence and death rates (age-adjusted to the 2000 US Standard Population) for all cancers combined and for the leading cancers among men and women were estimated by joinpoint analysis of long-term trends (incidence for 1992-2012 and mortality for 1975-2012) and short-term trends (2008-2012). In-depth analysis of liver cancer incidence included an age-period-cohort analysis and an incidence-based estimation of person-years of life lost because of the disease. By using NCHS multiple causes of death data, hepatitis C virus (HCV) and liver cancer-associated death rates were examined from 1999 through 2013. RESULTS: Among men and women of all major racial and ethnic groups, death rates continued to decline for all cancers combined and for most cancer sites; the overall cancer death rate (for both sexes combined) decreased by 1.5% per year from 2003 to 2012. Overall, incidence rates decreased among men and remained stable among women from 2003 to 2012. Among both men and women, deaths from liver cancer increased at the highest rate of all cancer sites, and liver cancer incidence rates increased sharply, second only to thyroid cancer. Men had more than twice the incidence rate of liver cancer than women, and rates increased with age for both sexes. Among non-Hispanic (NH) white, NH black, and Hispanic men and women, liver cancer incidence rates were higher for persons born after the 1938 to 1947 birth cohort. In contrast, there was a minimal birth cohort effect for NH Asian and Pacific Islanders (APIs). NH black men and Hispanic men had the lowest median age at death (60 and 62 years, respectively) and the highest average person-years of life lost per death (21 and 20 years, respectively) from liver cancer. HCV and liver cancer-associated death rates were highest among decedents who were born during 1945 through 1965. CONCLUSIONS: Overall, cancer incidence and mortality declined among men; and, although cancer incidence was stable among women, mortality declined. The burden of liver cancer is growing and is not equally distributed throughout the population. Efforts to vaccinate populations that are vulnerable to hepatitis B virus (HBV) infection and to identify and treat those living with HCV or HBV infection, metabolic conditions, alcoholic liver disease, or other causes of cirrhosis can be effective in reducing the incidence and mortality of liver cancer. Cancer 2016;122:1312-1337. (c) 2016 American Cancer Society.
Safwan, M, M Vij, G Narasimhan, N Shanmugam and M Rela 2016Caroli's Syndrome with Incidental Fibrolamellar Carcinoma on Liver Explant.Indian J Pediatr 83(1): 85-86.
Simon, S 2016DNAJB1-PRKACA - A novel PKa fusion protein that drives fibrolamellar hepatocellular carcinoma.FASEB Journal 30(S1): 510.512-510.512.Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver tumor that usually occurs in adolescents and young adults. Characterized by hepatocytes with deeply eosinophilic, granular cytoplasm interspersed with fibrous bands, FLHCC is without signs of cirrhosis as in Hepatocellular Carcinoma. To characterize its molecular pathogenesis, we performed RNA-seq and whole genome sequencing of FLHCC paired with normal liver from the same patient. The majority of the DNA was unremarkable with few recurrent mutations or structural variants such as amplifications or inversions. The exception was a heterogeneous deletion of ~400 kB in one copy of chromosome 19. This produced a chimeric transcript and a fusion between the heat shock protein DNAJB1 and the catalytic subunit of protein kinase A (PRKACA) which retained full enzymatic activity. This chimera has been found in every patient (n>200). Differential expression analysis of RNA-seq revealed many changes in the gene expression in FLHCC. These were generally consistent between patients with FLHCC and different from HCC samples from the TCGA or published reports of other cancers. Some of the observed changes can directly be linked to increased activity of PRKACA. Other changes involve pathways known to participate in the initiation and progression of other cancers, which, along with an increase of PRKACA activity, represent targets for therapeutic intervention. Several of these targets are now being explored in cellular models, genetic, and PDX mouse models, as well as clinical trials.
Swiderska-Syn, M, G Xie, GA Michelotti, ML Jewell, RT Premont, WK Syn and AM Diehl 2016Hedgehog regulates yes-associated protein 1 in regenerating mouse liver.Hepatology 64(1): 232-244.Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes-associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated, but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. In cultured hepatic stellate cells (HSCs), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1- and Hedgehog-regulated genes that enable HSC to become myofibroblasts (MFs). In mice, disrupting Hedgehog signaling in MFs inhibited liver regeneration after partial hepactectomy (PH). Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma-derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up-regulating Yap1- and Hedgehog-regulated transcription factors that normally promote their proliferation. CONCLUSIONS: Morphogenic signaling in HSCs is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment post-PH. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer.
Turnham, RE and JD Scott 2016Protein kinase A catalytic subunit isoform PRKACA; History, function and physiology.Gene 577(2): 101-108.Our appreciation of the scope and influence of second messenger signaling has its origins in pioneering work on the cAMP-dependent protein kinase. Also called protein kinase A (PKA), this holoenzyme exists as a tetramer comprised of a regulatory (R) subunit dimer and two catalytic (C) subunits. Upon binding of two molecules of the second messenger cAMP to each R subunit, a conformational change in the PKA holoenzyme occurs to release the C subunits. These active kinases phosphorylate downstream targets to propagate cAMP responsive cell signaling events. This article focuses on the discovery, structure, cellular location and physiological effects of the catalytic subunit alpha of protein kinase A (encoded by the gene PRKACA). We also explore the potential role of this essential gene as a molecular mediator of certain disease states.
Yamashita, S, JN Vauthey, AO Kaseb, TA Aloia, C Conrad, MM Hassan, G Passot, KP Raghav, MA Shama and YS Chun 2016Prognosis of fibrolamellar carcinoma compared to non-cirrhotic conventional hepatocellular carcinoma.J Gastrointest Surg 20(10): 1725-1731.BACKGROUND: Fibrolamellar carcinoma (FLC) and conventional hepatocellular carcinoma (HCC) share the same American Joint Committee on Cancer (AJCC) staging. The worse survival with HCC is attributed to the underlying cirrhosis.The aim of this study was to compare stage-matched prognosis after resection of FLC and non-cirrhotic HCC. METHODS: Outcomes after resection of 65 consecutive patients with FLC and 158 non-cirrhotic patients with HCC were compared. Patients were staged according to the 7th edition AJCC staging. RESULTS: The AJCC stage distributions for FLC and HCC demonstrated a predominance of stage IV disease in FLC and stage I in HCC (FLC stage I-23 %, II-15 %, III-15 %, IV-46 % vs. HCC stage I-42 %, II-32 %, III-20 %, IV-6 %, p < 0.001). Among stage IV FLC patients, 81 % had isolated nodal metastases, which did not affect overall survival (OS) or recurrence-free survival (RFS). In FLC, OS was significantly affected by the number of tumors and vascular invasion (p < 0.05). Recurrent disease developed in 56 (86 %) FLC patients and was treated with repeat surgical resection in 25 (45 %) patients. Vascular invasion was associated with recurrent FLC, with 3-year RFS rates of 9 % and 35 %, with and without vascular invasion (p = 0.034). With respect to RFS, the AJCC staging did not stratify FLC patients, compared to non-cirrhotic HCC. CONCLUSIONS: When compared to non-cirrhotic HCC, patients with FLC are not adequately stratified by AJCC staging with respect to RFS. Our results support classifying lymph node metastases in FLC as regional disease, rather than systemic disease. Important prognostic factors in FLC are the number of tumors and vascular invasion.
Abou-Alfa, GK, RJ Mayer, D Cosgrove, M Capanu, MA Choti, CE Atreya, C Ang, RK Kelley, RK Do, JD Gordan, AX Zhu, M Ly, P Nolan, L Lubin, JJ Harding, L Saltz and AP Venook 2015Randomized phase II study of everolimus (E), leuprolide + letrozole (LL), and E + LL (ELL) in patients (pts) with unresectable fibrolamellar carcinoma (FLC). J Clin Oncol 33(15_suppl): e15149-e15149.Background: FLC, a rare primary liver malignancy affecting adolescents and young adults without an underlying history of chronic liver disease, presently lacks a proven standard of care. FLC is associated with elevated serum estrogen levels, aromatase overexpression, pregnancy, and oral contraceptive use, as well as male gynecomastia that may regress following tumor resection. Upregulation of PI3K/Akt/mTOR signaling has also been linked with FLC. Methods: Pts with FLC histologic diagnosis, ECOG 0-2, and adequate bone marrow, renal, and hepatic function were randomized to receive E, LL, or ELL; upon disease progression, pts receiving E or LL alone were additionally treated with LL or E respectively. The primary study endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints: median PFS, median overall survival (OS), response rate by RECIST 1.1, rate of conversion to resectable status, and safety. An extensive profile of correlative tissue and serum biomarkers was performed and will be reported at a later time. PFS6 was assessed using a Simon’s minimax two-stage design, hypothesizing an improvement in PFS6 from 40% to 64% for each arm. Results: 28 pts were enrolled since July 2013: Female=14, median age 23 years (range 15-49), ECOG 1 (0-1). An unplanned analysis was performed due to perceived concern of lack of efficacy. Stable disease was reported in 6 pts (21%). Grade 3 and 4 adverse events noted in ? 10% of patients were: nausea (11%), vomiting (11%), anemia (11%), elevated AST (32%), ALT (36%), and alkaline phosphatase (14%). There were 4 deaths on study, 3 due to progression of disease and one due to liver failure related to disease progression. Conclusions: At the time of this unplanned analysis, the absence of events of PFS6 and low probability for extending PFS6 with adding more subjects led to the study being halted. The study proves the ability to accrue to clinical trials of rare malignancies such as FLC. The outcomes presented herein also establish historical references for future studies. Plans for evaluating other novel therapeutic approaches are underway. Clinical trial information: NCT01642186. E LL ELL PFS6 0% 0% 0% Median PFS (months) 2.7 2.7 2.8 Median OS (months) 12.5 NR 7.4
Andersen, JB 2015Fibrolamellar hepatocellular carcinoma: a rare but distinct type of liver cancer. Gastroenterology 148(4): 707-710.
Bhagat, M, S Kembhavi and SS Qureshi 2015Fibrolamellar hepatocellular carcinoma with extensive vascular thrombosis. J Cancer Res Ther 11(2): 493-494.
Castro-Villabon, D, LE Barrera-Herrera, PA Rodriguez-Urrego, R Hudacko, A Vera, J Alvarez, R Andrade and R Lopez 2015Hepatocellular carcinoma with both fibrolamellar and classical components: an unusual morphological pattern. Case Rep Pathol 2015: 609780.Fibrolamellar carcinoma (FLC) is an uncommon form of primary liver malignancy with unique clinical, histological, and biological characteristics. It is usually seen in young adults without underlying liver disease. Histologically, it shows large cells with abundant eosinophilic cytoplasm, large vesicular nuclei, prominent nucleoli, and lamellar type fibrosis. In contrast, classical hepatocellular carcinoma (HCC) is typically present in elderly male patients with cirrhosis. It is the most common histological subtype, and it is characterized by its resemblance to the normal liver, both in its growth pattern and its cytology. The unusual case of a liver carcinoma that presented with histological features of both FLC and classical HCC is herein reported. This was the case of a 37-year-old female complaining of diffuse abdominal discomfort and epigastric pain for two months. She was referred to us for further management after she was diagnosed with HCC in a noncirrhotic liver. She underwent a left-sided hepatectomy. A yellow nodular mass with well-defined borders and a necrotic center was present in the resection specimen. The morphological features and immunohistochemical studies were consistent with a diagnosis of FLC mixed with classical HCC. The patient was followed up for five months, and no signs of recurrence were evident.
Chagas, AL, L Kikuchi, P Herman, RS Alencar, CM Tani, MA Diniz, V Pugliese, S Rocha Mde, LA D'Albuquerque, FJ Carrilho and VA Alves 2015Clinical and pathological evaluation of fibrolamellar hepatocellular carcinoma: a single center study of 21 cases. Clinics (Sao Paulo) 70(3): 207-213.OBJECTIVES: Fibrolamellar hepatocellular carcinoma is a rare primary malignant liver tumor that differs from conventional hepatocellular carcinoma in several aspects. The aim of this study was to describe the clinical, surgical and histopathological features of fibrolamellar hepatocellular carcinoma and to analyze the factors associated with survival. METHODS: We identified 21 patients with histopathologically diagnosed fibrolamellar hepatocellular carcinoma over a 22-year period. Clinical information was collected from medical records and biopsies, and surgical specimens were reviewed. RESULTS: The median age at diagnosis was 20 years. Most patients were female (67%) and did not have associated chronic liver disease. Most patients had a single nodule, and the median tumor size was 120 mm. Vascular invasion was present in 31% of patients, and extra-hepatic metastases were present in 53%. Fourteen patients underwent surgery as the first-line therapy, three received chemotherapy, and four received palliative care. Eighteen patients had "pure fibrolamellar hepatocellular carcinoma," whereas three had a distinct area of conventional hepatocellular carcinoma and were classified as having "mixed fibrolamellar hepatocellular carcinoma." The median overall survival was 36 months. The presence of "mixed fibrolamellar hepatocellular carcinoma" and macrovascular invasion were predictors of poor survival. Vascular invasion was associated with an increased risk of recurrence in patients who underwent surgery. CONCLUSION: Fibrolamellar hepatocellular carcinoma was more common in young female patients without chronic liver disease. Surgery was the first therapeutic option to achieve disease control, even in advanced cases. Vascular invasion was a risk factor for tumor recurrence. The presence of macrovascular invasion and areas of conventional hepatocellular carcinoma were directly related to poor survival.
Cheung, J, C Ginter, M Cassidy, MC Franklin, MJ Rudolph, N Robine, RB Darnell and WA Hendrickson 2015Structural insights into mis-regulation of protein kinase A in human tumors. Proc Natl Acad Sci U S A 112(5): 1374-1379.The extensively studied cAMP-dependent protein kinase A (PKA) is involved in the regulation of critical cell processes, including metabolism, gene expression, and cell proliferation; consequentially, mis-regulation of PKA signaling is implicated in tumorigenesis. Recent genomic studies have identified recurrent mutations in the catalytic subunit of PKA in tumors associated with Cushing's syndrome, a kidney disorder leading to excessive cortisol production, and also in tumors associated with fibrolamellar hepatocellular carcinoma (FL-HCC), a rare liver cancer. Expression of a L205R point mutant and a DnaJ-PKA fusion protein were found to be linked to Cushing's syndrome and FL-HCC, respectively. Here we reveal contrasting mechanisms for increased PKA signaling at the molecular level through structural determination and biochemical characterization of the aberrant enzymes. In the Cushing's syndrome disorder, we find that the L205R mutation abolishes regulatory-subunit binding, leading to constitutive, cAMP-independent signaling. In FL-HCC, the DnaJ-PKA chimera remains under regulatory subunit control; however, its overexpression from the DnaJ promoter leads to enhanced cAMP-dependent signaling. Our findings provide a structural understanding of the two distinct disease mechanisms and they offer a basis for designing effective drugs for their treatment.
Cornella, H, C Alsinet, S Sayols, Z Zhang, K Hao, L Cabellos, Y Hoshida, A Villanueva, S Thung, SC Ward, L Rodriguez-Carunchio, M Vila-Casadesus, S Imbeaud, A Lachenmayer, A Quaglia, DM Nagorney, B Minguez, F Carrilho, LR Roberts, S Waxman, V Mazzaferro, M Schwartz, M Esteller, ND Heaton, J Zucman-Rossi and JM Llovet 2015Unique genomic profile of fibrolamellar hepatocellular carcinoma. Gastroenterology 148(4): 806-818 e810.BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. METHODS: By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. RESULTS: Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. CONCLUSIONS: In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time.
Cui, X, HK Choi, YS Choi, SY Park, GJ Sung, YH Lee, J Lee, WJ Jun, K Kim, KC Choi and HG Yoon 2015DNAJB1 destabilizes PDCD5 to suppress p53-mediated apoptosis. Cancer Lett 357(1): 307-315.Although PDCD5 promotes p53-mediated apoptosis in various cancers, little is known about PDCD5 regulation. We recently found that DNAJB1 interacts with PDCD5 and induces the ubiquitin-dependent proteasomal degradation of PDCD5, thereby inhibiting p53-mediated apoptosis. To investigate these novel roles for PDCD5 and DNAJB1, we performed DNAJB1 mapping with PDCD5. PDCD5 specifically binds to the DNAJB1-D5 domain (Delta180-210), which was found to be essential for the stabilization of PDCD5. Further study showed that DNAJB1 post-translationally regulates PDCD5 stability. DNAJB1 ubiquitinated PDCD5 via a ubiquitin-mediated pathway. In human lung A549 cancer cells, DNAJB1 promoted the ubiquitination and degradation of PDCD5 and inhibited p53 activation. However, DNAJB1 knockdown in A549 cells increased the etoposide-induced activation of the p53-mediated apoptosis pathway and repressed cancer cell growth. Because this function was p53 dependent, DNAJB1 depletion increased the expression of p53-targeted apoptosis genes. In conclusion, we screened a novel PDCD5-associating protein, DNAJB1, by yeast two-hybrid screening and provided evidences that DNAJB1 targets PDCD5 to suppress p53-dependent apoptosis of cancer cells. Thus, we identified DNAJB1 as a negative regulator of PDCD5-mediated apoptosis and found that the apoptosis network of PDCD5 regulates cancer cell death.
Darcy, DG, R Chiaroni-Clarke, JM Murphy, JN Honeyman, U Bhanot, MP LaQuaglia and SM Simon 2015The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients. Oncotarget 6(2): 755-770.Fibrolamellar hepatocellular carcinoma is a rare, malignant liver tumor that often arises in the otherwise normal liver of adolescents and young adults. Previous studies have focused on biomarkers and comparisons to traditional hepatocellular carcinoma, and have yielded little data on the underlying pathophysiology. We performed whole genome sequencing on paired tumor and normal samples from 10 patients to identify recurrent mutations and structural variations that could predispose to oncogenesis. There are relatively few coding, somatic mutations in this cancer, putting it on the low end of the mutational spectrum. Aside from a previously described heterozygous deletion on chromosome 19 that encodes for a functional, chimeric protein, there were no other recurrent structural variations that contribute to the tumor genotype. The lack of a second-hit mutation in the genomic landscape of fibrolamellar hepatocellular carcinoma makes the DNAJB1-PRKACA fusion protein the best target for diagnostic and therapeutic advancements. The mutations, altered pathways and structural variants that characterized fibrolamellar hepatocellular carcinoma were distinct from those in hepatocellular carcinoma, further defining it as a distinct carcinoma.
Darcy, DG, MM Malek, R Kobos, DS Klimstra, R DeMatteo and MP La Quaglia 2015Prognostic factors in fibrolamellar hepatocellular carcinoma in young people. J Pediatr Surg 50(1): 153-156.BACKGROUND/PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) arises in pediatric/adolescent patients without cirrhosis. We retrospectively evaluated the impact of resection, nodal status, metastasis, and PRETEXT stage on overall survival (OS). METHODS: With IRB approval, we reviewed records of 25 consecutive pediatric patients with FL-HCC treated at our institution from 1981 to 2011. We evaluated associations between OS and PRETEXT stage, nodal involvement, metastasis, and complete resection. RESULTS: Median age at diagnosis was 17.1years (range, 11.6-20.5). Median follow-up was 2.74years (range, 5-9.5). Five (28%) patients had PRETEXT stage 1 disease, 10 (56%) had stage 2, 2 (11%) had stage 3, and 2 (11%) had stage 4 disease. On presentation, 17 (68%) patients had N1 disease, and 7 (28%) had parenchymal metastases. Complete resection was achieved in 17 (80.9%) of 21 patients who underwent resection. Five-year OS was 42.6%. Survival was positively associated with complete resection (P =0.003), negative regional lymph nodes (P =0.044), and lower PRETEXT stage (P <0.001), with a trend for metastatic disease (P =0.05). CONCLUSIONS: In young patients with FL-HCC, lower PRETEXT stage and complete resection correlated with prolonged survival, while metastatic disease and positive lymph node status were associated with poor prognosis. Thus, we recommend complete resection and regional lymphadenectomy whenever possible.
Graham, RP, L Jin, DL Knutson, SM Kloft-Nelson, PT Greipp, N Waldburger, S Roessler, T Longerich, LR Roberts, AM Oliveira, KC Halling, P Schirmacher and MS Torbenson 2015DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol 28(6): 822-829.Fibrolamellar carcinoma is a distinct subtype of hepatocellular carcinoma that predominantly affects young patients without underlying cirrhosis. A recurrent DNAJB1-PRKACA fusion has recently been reported in fibrolamellar carcinomas. To determine the specificity of this fusion and to develop routinely available clinical methods of detection, we developed an RT-PCR assay for paraffin-embedded tissues and a FISH probe for detection of the rearrangements of the PRKACA locus. We also developed an RNA in situ hybridization assay to assess expression levels of the total chimeric transcript and wild-type transcripts. A total of 106 primary liver tumors were studied by RT-PCR, including 26 fibrolamellar carcinomas (4 of which were metastases to the abdominal wall or lymph nodes), 25 conventional hepatocellular carcinomas, 25 cholangiocarcinomas, 25 hepatic adenomas, and 5 hepatoblastomas. RT-PCR was successful in 92% of tested fibrolamellar carcinoma cases (24 out of 26) and the DNAJB1-PRKACA fusion transcript was found in all fibrolamellar carcinomas but not in other tumor types. FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas, which can closely mimic fibrolamellar carcinoma. Rearrangements of the PRKACA locus was seen in all 19 fibrolamellar carcinoma specimens, but in none of the scirrhous hepatocellular carcinomas. Finally, a RNA in situ hybridization strategy was positive in 7 out of 7 successfully hybridized cases, and showed mRNA over-expression in all of the fibrolamellar carcinomas. In addition, the stromal cells embedded in the characteristic intratumoral fibrosis of fibrolamellar carcinomas and the background liver tissues were negative for the DNAJB1-PRKACA fusion by all tested methods. In conclusion, detection of DNAJB1-PRKACA is a very sensitive and specific finding in support of the diagnosis of fibrolamellar carcinoma.
Hirschey, MD, RJ DeBerardinis, AME Diehl, JE Drew, C Frezza, MF Green, LW Jones, YH Ko, A Le, MA Lea, JW Locasale, VD Longo, CA Lyssiotis, E McDonnell, M Mehrmohamadi, G Michelotti, V Muralidhar, MP Murphy, PL Pedersen, B Poore, L Raffaghello, JC Rathmell, S Sivanand, MG Vander Heiden, KE Wellen and T Target Validation 2015Dysregulated metabolism contributes to oncogenesis.Semin Cancer Biol 35 Suppl: S129-S150.Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review "Hallmarks of Cancer", where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it.
Jernigan, PL, K Wima, DJ Hanseman, RS Hoehn, SA Ahmad, SA Shah and DE Abbott 2015Natural history and treatment trends in hepatocellular carcinoma subtypes: Insights from a national cancer registry. J Surg Oncol 112(8): 872-876.BACKGROUND: Histopathologic advancements have identified several rare subtypes of hepatocellular carcinoma (HCC), but the clinical significance of these distinctions is incompletely understood. Our aim was to investigate pathologic and treatment differences between HCC variants. METHODS: The American College of Surgeons National Cancer Data Base (1998-2011) was queried to identify 784 patients with surgical management of six rare HCC subtypes: fibrolamellar (FL, n = 206), scirrhous (SC, n = 29), spindle cell (SP, n = 20), clear cell (CC, n = 169), mixed type (M, n = 291), and trabecular (T, n = 69). We examined associations between demographic, tumor and treatment-specific variables, and overall survival (OS). RESULTS: Patients with FL-HCC were younger than other variants (median age 27 vs. 54-61, P < 0.001), more commonly female (56.3%, P < 0.001), and less likely to receive a transplant (3.66%, P < 0.001). Patients with FL- and Sp-HCC presented more frequently with larger tumors (>5 cm, P < 0.001) and node-positive disease (P < 0.001). Better OS was associated with lower pathologic stage, node-negative disease, FL-HCC, and liver transplant. Adjuvant therapy (11% of patients) was not associated with better OS. CONCLUSIONS: This largest series of recognized HCC variants demonstrates distinct differences in presentation, treatment, and prognosis. These findings can provide a valuable reference for clinicians and patients who encounter these rare clinical entities.
Kelly, D, K Sharif, RM Brown and B Morland 2015Hepatocellular carcinoma in children. Clin Liver Dis 19(2): 433-447.Liver tumors are relatively rare in childhood, but may be associated with a range of diagnostic, genetic, therapeutic, and surgical challenges sufficient to tax even the most experienced clinician. This article outlines the epidemiology, etiology, pathologic condition, initial workup, and management of hepatocellular carcinoma in children and adolescents.
Lafaro, KJ and TM Pawlik 2015Fibrolamellar hepatocellular carcinoma: current clinical perspectives. J Hepatocell Carcinoma 2: 151-157.Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC), which comprises approximately 1%-9% of all HCCs. Although FLC is a variant of HCC, it is distinct from HCC in that it most often affects younger patients (10-35 years of age) with no underlying liver disease. FLC often presents with vague abdominal pain, nausea, abdominal fullness, malaise, and weight loss. Surgery is the current mainstay of treatment for FLC and remains the only potentially curative option. While FLCs are considered less responsive to chemotherapy than their classic HCC counterparts, there have been suggestions that multimodality treatments may be effective, especially in advanced cases. Further research is necessary to determine effective systemic therapies as an adjunct to surgery for FLC.
Limaiem, F, S Bouraoui, M Sboui, S Bouslama, A Lahmar and S Mzabi 2015Fibrolamellar carcinoma versus scirrhous hepatocellular carcinoma : diagnostic usefulness of CD68. Acta Gastroenterol Belg 78(4): 393-398.BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of hepatocellular carcinoma that commonly affects young individuals without a prior history of liver disease. The principal differential diagnosis is conventional hepatocellular carcinoma especially the scirrhous variant. Despite their distinctive appearance, recent studies have demonstrated a lack of consistency in how FL-HCC are diagnosed by pathologists. AIM: To investigate the diagnostic utility of CD68 in differentiating between FL-HCC and scirrhous hepatocellular carcinoma. PATIENTS AND METHODS: In our retrospective study, we reviewed four cases of FL-HCC that were diagnosed at the pathology department of Mongi Slim hospital over a thirteen-year period (2002-2014). Relevant clinical information and microscopic slides were available in all cases and were retrospectively reviewed. Immunohistochemical analysis was performed using the avidin-biotin complex technique with antibodies against CD68 and CK7. RESULTS: Our study group included one man and three women (sex ratio M/F=0.33) aged between 23 and 34 years (mean=28 years). All cases arose in non-cirrhotic liver. Immunohistochemically, all cases were positive for CK7 and for CD68 (n=4). CONCLUSIONS: CD68 immunostaining is a sensitive marker for FL-HCC that may be of use in routine diagnostic surgical pathology. Lack of CD68 staining should suggest caution in making a diagnosis of FL-HCC.
Malouf, GG, T Tahara, V Paradis, M Fabre, C Guettier, J Yamazaki, H Long, Y Lu, NJ Raynal, J Jelinek, R Mouawad, D Khayat, L Brugieres, E Raymond and JP Issa 2015Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features. Epigenetics 10(9): 872-881.With the goal of studying epigenetic alterations in fibrolamellar hepatocellular carcinoma (FLC) and establish an associated DNA methylation signature, we analyzed LINE-1 methylation in a cohort of FLC and performed next-generation sequencing of DNA methylation in a training set of pure-FLCs and non-cirrhotic hepatocellular carcinomas (nc-HCC). DNA methylation was correlated with gene expression. Furthermore, we established and validated an epigenetic signature differentiating pure-FLC from other HCCs. LINE-1 methylation correlated with shorter recurrence-free survival and overall survival in resected pure-FLC patients. Unsupervised clustering using CG sites located in islands distinguished pure-FLC from nc-HCC. Major DNA methylation changes occurred outside promoters, mainly in gene bodies and intergenic regions located in the vicinity of liver developmental genes (i.e., SMARCA4 and RXRA). Partially methylated domains were more prone to DNA methylation changes. Furthermore, we identified several putative tumor suppressor genes (e.g., DLEU7) and oncogenes (e.g., DUSP4). While approximately 70% of identified gene promoters gaining methylation were marked by bivalent histone marks (H3K4me3/H3K27me3) in embryonic stem cells, approximately 70% of those losing methylation were marked by H3K4me3. Finally, we established a pure FLC DNA methylation signature and validated it in an independent dataset. Our analysis reveals a distinct epigenetic signature of pure FLC as compared to nc-HCC, with DNA methylation changes occurring in the vicinity of liver developmental genes. These data suggest new options for targeting FLC based on cancer epigenome aberrations.
Meyerowitz, JG, WA Weiss and WC Gustafson 2015A new angle on kinase inhibitor design: Prioritizing amphosteric activity above kinase inhibition. Mol Cell Oncol 2(2): e975641.The MYCN oncoprotein has remained an elusive target for decades. We recently reported a new class of kinase inhibitors designed to disrupt the conformation of Aurora kinase A enough to block its kinase-independent interaction with MYCN, resulting in potent degradation of MYCN. These studies provide proof-of-principle for a new method of targeting enzyme activity-independent functions of kinases and other enzymes.
Mittal, PK, CC Moreno, B Kalb, A Mittal, JC Camacho, K Maddu, HD Kitajima, BC Quigley, N Kokabi and WC Small 2015Primary biliary tract malignancies: MRI spectrum and mimics with histopathological correlation. Abdom Imaging 40(6): 1520-1557.Contrast-enhanced magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRCP), due to their excellent soft tissue contrasts, have become first-line noninvasive tests in the characterization and detection of both hepatic and pancreaticobiliary pathologies. MRCP is also helpful in detecting the level and cause of obstruction in patients presenting with jaundice. Cholangiocarcinoma (CCA) is the most common primary malignant tumor arising from the bile duct epithelium, with extrahepatic tumors presenting more often than with intrahepatic ones. However, the diagnosis and management of CCA is made more complex by a variety of malignant and benign conditions that resemble CCA, including hepatocellular carcinoma variants such as the fibrolamellar variant of hepatocellular carcinoma, cholangiocellular carcinoma, biliary metastases, hepatic inflammatory pseudotumor, lymphoepithelioma-like carcinoma, confluent fibrosis, primary sclerosis cholangitis, and the secondary sclerosing cholangitis complex. Consequently, knowledge of the underlying risk factors and imaging characteristics of these conditions is important in differentiating between neoplastic and non-neoplastic conditions in order to reach a definite diagnosis. Endoscopic retrograde cholangiopancreatography should be reserved for those patients who require intervention or biopsy for histopathological diagnosis.
Moody, SE, AC Schinzel, S Singh, F Izzo, MR Strickland, L Luo, SR Thomas, JS Boehm, SY Kim, ZC Wang and WC Hahn 2015PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling.Oncogene 34(16): 2061-2071.Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, the BCl-2-associated death promoter, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.
Oikawa, T, E Wauthier, TA Dinh, SR Selitsky, A Reyna-Neyra, G Carpino, R Levine, V Cardinale, D Klimstra, E Gaudio, D Alvaro, N Carrasco, P Sethupathy and LM Reid 2015Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells.Nat Commun 6: 8070.The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells--newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies.
Park, SY, HK Choi, JS Seo, JY Yoo, JW Jeong, Y Choi, KC Choi and HG Yoon 2015DNAJB1 negatively regulates MIG6 to promote epidermal growth factor receptor signaling.Biochim Biophys Acta 1853(10 Pt A): 2722-2730.Mitogen-inducible gene 6 (MIG6) is a tumor suppressor implicated in the development of human cancers; however, the regulatory mechanisms of MIG6 remain unknown. Here, using a yeast two-hybrid screen, we identified DnaJ homolog subfamily B member I (DNAJB1) as a novel MIG6-interacting protein. We found that DNAJB1 binds to and decreases MIG6 protein, but not mRNA, levels. DNAJB1 overexpression dosage-dependently decreased MIG6 protein levels. Conversely, DNAJB1 knockdown increased MIG6 protein levels. DNAJB1 destabilizes MIG6 by enhancing K48-linked ubiquitination of MIG6. However, knocking-down of DNAJB1 reduced the ubiquitination of MIG6. DNAJB1 positively regulates the epidermal growth factor receptors (EGFR) signaling pathway via destabilization of MIG6; however, DNAJB1 knockdown diminishes activation of EGFR signaling as well as elevation of MIG6. Importantly, the increased levels of MIG6 by DNAJB1 knockdown greatly enhanced the gefitinib sensitivity in A549 cells. Thus, our study provides a new molecular mechanism to regulate EGFR signaling through modulation of MIG6 by DNAJB1 as a negative regulator.
Patman, G 2015Liver cancer: A model of fibrolamellar carcinoma.Nat Rev Gastroenterol Hepatol 12(12): 672.
Riehle, KJ, MM Yeh, JJ Yu, HL Kenerson, WP Harris, JO Park and RS Yeung 2015mTORC1 and FGFR1 signaling in fibrolamellar hepatocellular carcinoma.Mod Pathol 28(1): 103-110.Fibrolamellar hepatocellular carcinoma, or fibrolamellar carcinoma, is a rare form of primary liver cancer that afflicts healthy young men and women without underlying liver disease. There are currently no effective treatments for fibrolamellar carcinoma other than resection or transplantation. In this study, we sought evidence of mechanistic target of rapamycin complex 1 (mTORC1) activation in fibrolamellar carcinoma, based on anecdotal reports of tumor response to rapamycin analogs. Using a tissue microarray of 89 primary liver tumors, including a subset of 10 fibrolamellar carcinomas, we assessed the expression of phosphorylated S6 ribosomal protein (P-S6), a downstream target of mTORC1, along with fibroblast growth factor receptor 1 (FGFR1). These results were extended and confirmed using an additional 13 fibrolamellar carcinomas, whose medical records were reviewed. In contrast to weak staining in normal livers, all fibrolamellar carcinomas on the tissue microarray showed strong immunostaining for FGFR1 and P-S6, whereas only 13% of non-fibrolamellar hepatocellular carcinomas had concurrent activation of FGFR1 and mTORC1 signaling (P<0.05). When individual samples were stratified according to staining intensity (scale 0-4), the average score in fibrolamellar carcinomas was 2.46 for FGFR1 and 3.77 for P-S6, compared with 0 and 0, respectively, in non-tumor liver. Immunoblot analyses of fibrolamellar carcinomas revealed high mTORC1 activities relative to AKT activities accompanied by reduced TSC2 expression, which was not observed in non-fibrolamellar hepatocellular carcinomas. Our findings provide evidence for mTORC1 activation and FGFR1 overexpression in human fibrolamellar carcinoma, and support the use of FGFR1 inhibitors and rapamycin analogs in the treatment of patients with unresectable fibrolamellar carcinoma.
Sergi, CM 2015Hepatocellular carcinoma, fibrolamellar variant: Diagnostic pathologic criteria and molecular pathology update. A primer.Diagnostics (Basel) 6(1).Fibrolamellar hepatocellular carcinoma (FL-HCC) is generally a fairly rare event in routine pathology practice. This variant of hepatocellular carcinoma (HCC) is peculiarly intriguing and,in addition, poorly understood. Young people or children are often the target individuals with this type of cancer. Previously, I highlighted some pathology aspects of FL-HCC, but in this review, the distinctive clinico-pathologic features of FL-HCC and the diagnostic pathologic criteria of FL-HCC are fractionally reviewed and expanded upon. Further, molecular genetics update data with reference to this specific tumor are particularly highlighted as a primer for general pathologists and pediatric histopathologists. FL-HCC may present with metastases, and regional lymph nodes may be sites of metastatic spread. However, peritoneal and pulmonary metastatic foci have also been reported. To the best of our knowledge, FL-HCC was initially considered having an indolent course, but survival outcomes have recently been updated reconsidering the prognosis of this tumor. Patients seem to respond well to surgical resection, but recurrences are common. Thus, alternative therapies, such as chemotherapy and radiation, are ongoing. Overall, it seems that this aspect has not been well-studied for this variant of HCC and should be considered as target for future clinical trials. Remarkably, FL-HCC data seem to point to a liver neoplasm of uncertain origin and unveiled outcome. A functional chimeric transcript incorporating DNAJB1 and PRKACA was recently added to FL-HCC. This sensational result may give remarkable insights into the understanding of this rare disease and potentially provide the basis for its specific diagnostic marker. Detection of DNAJB1-PRKACA seems to be, indeed, a very sensitive and specific finding in supporting the diagnosis of FL-HCC. In a quite diffuse opinion, prognosis of this tumor should be reconsidered following the potentially mandatory application of new molecular biological tools.
Simon, EP, CA Freije, BA Farber, G Lalazar, DG Darcy, JN Honeyman, R Chiaroni-Clarke, BD Dill, H Molina, UK Bhanot, MP La Quaglia, BR Rosenberg and SM Simon 2015Transcriptomic characterization of fibrolamellar hepatocellular carcinoma.Proc Natl Acad Sci U S A 112(44): E5916-5925.Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of approximately 400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change >/= 1, false discovery rate
Villa, NA, R Pannala, DO Faigel, DJ Haakinson, N Katariya, R Ramanathan, D Jaroszewski, TK Lidner and T Byrne 2015Metastatic Fibrolamellar Hepatocellular Carcinoma to the Pancreas.Case Rep Gastroenterol 9(2): 266-271.Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of hepatocellular carcinoma, usually presenting in the younger population (<40 years) without underlying liver disease. Although it has a better prognosis than hepatocellular carcinoma, it has a high rate of recurrence months to years after primary resection. While sites of recurrence usually involve the liver, regional lymph nodes, peritoneum, and lung, metastasis to the pancreas is extremely rare, with only 2 other cases reported in the literature. We present the case of a 46-year-old patient with metastatic FL-HCC to the pancreas 30 years after diagnosis and 26 years since his last resected liver recurrence.
Weledji, EP, DS Nsagha, G Enoworock and M Mouladje 2015Familial hepatocellular carcinoma in an endemic area: two case reports.BMC Res Notes 8: 415.BACKGROUND: Hepatocellular carcinoma (HCC) usually affects patients aged 50-70 years but earlier onset (25-40 years) may occur in hepatitis B endemic areas. 70-90% of HCC develop on a background of cirrhosis. However, hepatitis B virus is directly oncogenic and can cause HCC in the absence of cirrhosis. This may represent a major cause of death from late diagnosis in resource-limited areas. CASE PRESENTATION: We report a black African family in which clinical diagnosis of HCC was made on two male siblings in the south west region of Cameroon. CONCLUSIONS: The highest risk for HCC may occur in families in which a hereditary component may be acting in concert with hepatitis B virus. In all cases of HCC, it is important to screen all first degree relatives to detect early and asymptomatic disease.
Xu, L, FK Hazard, AF Zmoos, N Jahchan, H Chaib, PM Garfin, A Rangaswami, MP Snyder and J Sage 2015Genomic analysis of fibrolamellar hepatocellular carcinoma.Hum Mol Genet 24(1): 50-63.Pediatric tumors are relatively infrequent, but are often associated with significant lethality and lifelong morbidity. A major goal of pediatric cancer research has been to identify key drivers of tumorigenesis to eventually develop targeted therapies to enhance cure rate and minimize acute and long-term toxic effects. Here, we used genomic approaches to identify biomarkers and candidate drivers for fibrolamellar hepatocellular carcinoma (FL-HCC), a very rare subtype of pediatric liver cancer for which limited therapeutic options exist. In-depth genomic analyses of one tumor followed by immunohistochemistry validation on seven other tumors showed expression of neuroendocrine markers in FL-HCC. DNA and RNA sequencing data further showed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. The first, a 400 kb deletion, results in a DNAJB1-PRKCA fusion transcript, which leads to increased cAMP-dependent protein kinase (PKA) activity in the index tumor case and other FL-HCC cases compared with normal liver. This PKA fusion protein is oncogenic in HCC cells. The second gene fusion event, a translocation between the CLPTM1L and GLIS3 genes, generates a transcript whose product also promotes cancer phenotypes in HCC cell lines. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.
Zhou, S, DM Parham, E Yung, P Pattengale and L Wang 2015Quantification of glypican 3, beta-catenin and claudin-1 protein expression in hepatoblastoma and paediatric hepatocellular carcinoma by colour deconvolution.Histopathology 67(6): 905-913.AIMS: To identify an immunohistochemical panel for paediatric malignant epithelial liver tumours. METHODS AND RESULTS: Forty-five hepatoblastomas (HBs), 13 paediatric hepatocellular carcinomas (HCCs) and two hepatocellular malignant neoplasms not otherwise specified (NOS) were chosen for immunohistochemical staining of glypican 3 (GPC3), beta-catenin, claudin-1, delta-like protein (DLK), and forkhead box protein G1 (FOXG1). Immunostaining was quantitatively analysed with NIH imagej software coupled with colour deconvolution. Different subtypes of HB and HCC showed distinct staining patterns of GPC3, beta-catenin, and claudin-1. Moreover, GPC3, beta-catenin and claudin-1 all showed higher expression in classic HCC and embryonal HB than in fetal HB; GPC3 showed complete negativity in small-cell undifferentiated (SCU) HB and fibrolamellar HCC (FLC); beta-catenin showed the strongest expression in SCU HB but the weakest expression in FLC. A panel of these three immunomarkers was useful for the diagnosis of hepatocellular malignant neoplasms NOS. The expression of DLK and FOXG1 was inconstant among fetal and embryonal HB and classic HCC. CONCLUSIONS: A panel of GPC3, beta-catenin and claudin-1 is helpful for differentiating HB subtypes and distinguishing HB from HCC.
Allan, BJ, B Wang, JS Davis, PP Parikh, EA Perez, HL Neville and JE Sola 2014A review of 218 pediatric cases of hepatocellular carcinoma. J Pediatr Surg 49(1): 166-171; discussion 171. PURPOSE: This study evaluates the incidence trends and clinical outcomes of children with hepatocellular carcinoma (HCC) and assesses factors predictive of patient survival. METHODS: The Surveillance, Epidemiology, and End Results registry was queried from 1973 to 2009 for all patients between ages 0 and 19 with primary HCC. Demographics, tumor histology, surgical intervention, and patient survival were collected. RESULTS: Overall, 218 patients were identified. The annual age-adjusted incidence was 0.05 cases per 100,000 in 2009. Fibrolamellar subtype tumors were exclusive to children >5years old and exhibited greater survival compared to non-fibrolamellar subtype (57% vs. 28%, respectively, p=0.002). Tumor extirpation for patients with resectable disease significantly improved overall survival at 5years compared to no surgery (60% vs. 0%, respectively, p<0.0001). Overall 5-, 10- and 20-year survival for the entire cohort was 24%, 23%, and 8%, respectively. Independent prognostic factors of lower mortality according to multivariate analysis were surgical resection (hazard ratio (HR)=0.18), non-Hispanic ethnicity (HR=0.52), and local disease at presentation (HR=0.46). CONCLUSION: Over the past four decades, the incidence of HCC has remained relatively stable. Children of Hispanic ethnicity have high mortality rates. However, HCC resection for curative intent significantly improves outcomes.
Canberk, S, VA LiVolsi and Z Baloch 2014Oncocytic lesions of the neuroendocrine system. Adv Anat Pathol 21(2): 69-82. This paper reviews the pathologic features of lesions which are oncocytic and involve classic endocrine organs. The history of the oncocytic cell, its morphologic and ultrastructural features, and important immunohistochemical findings are reviewed. Oncocytic proliferations including non-neoplastic and neoplastic of the thyroid, parathyroid, adrenal (both cortex and medulla), and pituitary are described. Their clinical relevance, functional capacity and capability, and where appropriate, prognostic implications are discussed. Important and relevant molecular biological information is included where appropriate.
Do, RK, A McErlean, CS Ang, RP DeMatteo and GK Abou-Alfa 2014CT and MRI of primary and metastatic fibrolamellar carcinoma: a case series of 37 patients. Br J Radiol 87(1040): 20140024. OBJECTIVE: Fibrolamellar carcinoma (FLC) is a rare disease, with limited radiographic reported information. We assessed the imaging patterns of primary and metastatic FLC. METHODS: CT and MR examinations of patients with FLC were retrospectively reviewed. Imaging features were assessed for primary and recurrent liver tumours, including dimension, enhancement characteristics, and presence or absence of central scars. Locations of nodal and extranodal metastases were also recorded. RESULTS: Of 37 patients (18 males and 19 females; average age, 23.5 years) with FLC, 24 had imaging of their primary tumour; 13 had metastases at presentation and 7 developed metastases on follow-up. The remaining 13 patients had follow-up imaging of metastatic disease. Primary FLC had a mean diameter >11 cm, with central scars in ten (46%) patients. Most tumours enhanced heterogeneously (96%) and showed arterial enhancement (81%). On MRI, 62% of FLCs were hypointense on T1 weighted imaging and 54% were hyperintense on T2 weighted imaging. 13 patients (54%) had nodal metastases at presentation, mostly in the upper abdomen (92%) and commonly in the chest (38%). Extrahepatic metastases were most frequently pulmonary or peritoneal. Predominantly small and homogeneous intrahepatic recurrences were detected on follow-up in 15 patients. CONCLUSION: FLC often presents as a large hepatic tumour with nodal and distant metastases. Thoracic adenopathy and lung metastases were frequently found in our series, suggesting the need for pre-operative and follow-up chest imaging. ADVANCES IN KNOWLEDGE: Thoracic nodal and lung metastases are common in FLC; therefore, dedicated chest imaging should be part of the evaluation of a patient with FLC.
Fakih, M 2014A case of fibrolamellar cancer with a palliative response and minor radiographic regression with erlotinib and bevacizumab combination therapy. Am J Ther 21(6): e207-210. Fibrolamellar cancer (FLC) is a rare primary hepatic malignancy with no established standard systemic treatments. Case reports and subgroup analyses from larger liver cancer studies suggest possible activity for fluoropyrimidines, platinum agents, and interferon-alpha. However, randomized studies are lacking, and the merits of any particular regimen in FLC are still largely unsubstantiated. We report the outcome of a case of metastatic FLC with previous progressive disease on 5-FU plus interferon-alpha and FOLFOX regimens that was treated with bevacizumab and erlotinib. The patient derived a prompt palliative response with complete resolution of cancer-related pain 2 weeks after initiation of erlotinib. Computed tomography after 2 months of treatment showed disease regression in distant lymphadenopathy. Molecular testing failed to confirm any evidence of epidermal growth factor receptor (EGFR) mutation, whereas immunohistochemistry showed 2 to 3+ staining for EGFR expression. To our knowledge, this is the first case report of a clinical benefit for FLC in association with erlotinib and bevacizumab treatment. FLC overexpresses EGFR in comparison to hepatocellular cancer, suggesting that EGFR targeting may be an interesting therapeutic approach in this rare malignancy.
Ganeshan, D, J Szklaruk, V Kundra, A Kaseb, A Rashid and KM Elsayes 2014Imaging features of fibrolamellar hepatocellular carcinoma. AJR Am J Roentgenol 202(3): 544-552. OBJECTIVE: Fibrolamellar hepatocellular carcinoma (HCC) is a rare primary liver tumor, which significantly differs from conventional HCC. This article reviews the molecular cytogenetics, pathology, imaging features, and management of this relatively rare tumor. CONCLUSION: Fibrolamellar HCC predominantly occurs in young patients without underlying hepatitis or cirrhosis. Serum alpha-fetoproteins are not elevated in most cases, and hence imaging plays an important role in diagnosis, staging, and surveillance.
Groeschl, RT, JT Miura, RK Wong, M Bloomston, ML Lidsky, BM Clary, RC Martin, G Belli, JF Buell and TC Gamblin 2014Multi-institutional analysis of recurrence and survival after hepatectomy for fibrolamellar carcinoma. J Surg Oncol 110(4): 412-415. BACKGROUND AND OBJECTIVES: Fibrolamellar carcinoma (FLC) presents in young, otherwise-healthy individuals. This study examined recurrence and survival characteristics after surgical resection for FLC by utilizing an international multi-institutional database. METHODS: Consecutive patients undergoing hepatectomy for FLC from six institutions (1993-2010) were reviewed retrospectively. Survival was studied with life tables and Cox regression models. RESULTS: Thirty-five patients (13 female, 37%) were included (median age: 32 years). R0 resection was achieved in all curative-intent operations (n = 30), and palliative operations were performed for five patients. Crude 30-day morbidity and mortality rates were 22% and 3%, respectively. For curative-intent surgery, overall and recurrence-free survivals at 5 years were 62% and 45%, respectively. In patients who achieved a 4-year disease-free interval after surgery, none subsequently developed recurrence. In multivariate models, presence of extrahepatic disease was the only factor that independently predicted overall (hazard ratio [HR]: 5.58, 95% confidence interval [CI]: 1.38-22.55, P = 0.016) and recurrence-free survival (HR: 5.64, 95% CI: 1.48-21.49, P = 0.011). CONCLUSIONS: Patients with surgically amenable FLC had encouraging long-term survival. Recurrence-free survival to 4 years suggested possible freedom from disease thereafter. Recurrent resectable disease was associated with an excellent prognosis, and repeat surgery should be strongly considered.
Herman, P, AL Chagas, MV Perini, FF Coelho, GM Fonseca, VA Alves, FJ Carrilho and I Cecconello 2014Surgical treatment of fibrolamellar hepatocellular carcinoma: an underestimated malignant tumor? Hepatobiliary Pancreat Dis Int 13(6): 618-621. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare disease with an indolent behavior. Its prognosis is better than that of patients with hepatocellular carcinoma. The authors present their experience with resection of FLHCC. METHODS: Twenty-one patients with FLHCC were treated at our institution between 1990 and 2012. Of these patients, 14 were subjected to resection of the tumor. Patient demographics, medical history, results of imaging studies and laboratory tests, surgical data, and pathologic findings were evaluated. RESULTS: The median age of the patients at the diagnosis of the tumor was 20 years and 14 patients were female. None of the patients had tumor-associated chronic liver disease or cirrhosis. The mean tumor size was 12.8 cm (range 6-19) and 18 patients had a single liver nodule. Fourteen patients were subjected to hepatectomy and six of them had lymph node metastases resected. Pathologic evaluation revealed that 5 (35.7%) patients had major vascular invasion. Tumor recurrence was seen in 8 patients (66.7%), during a follow-up. The median survival time for patients who were subjected to resection was 36 months. The 5-year overall survival rate and disease free survival rate were 28.0% and 8.5%, respectively. Univariate analysis showed that vascular invasion was the only variable associated with the disease free survival rate. CONCLUSIONS: Despite an aggressive treatment, patients with FLHCC presented unexpected low survival rates. It seems that an underestimated malignant behavior is attributed to this disease, and that the forms of adjuvant treatment should be urgently evaluated.
Honeyman, JN, EP Simon, N Robine, R Chiaroni-Clarke, DG Darcy, Lim, II, CE Gleason, JM Murphy, BR Rosenberg, L Teegan, CN Takacs, S Botero, R Belote, S Germer, AK Emde, V Vacic, U Bhanot, MP LaQuaglia and SM Simon 2014Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343(6174): 1010-1014. Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. We identified a chimeric transcript that is expressed in FL-HCC but not in adjacent normal liver and that arises as the result of a ~400-kilobase deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis.
Jardim, DL, JJ Wheler, K Hess, AM Tsimberidou, R Zinner, F Janku, V Subbiah, A Naing, SA Piha-Paul, SN Westin, S Roy-Chowdhuri, F Meric-Bernstam and DS Hong 2014FBXW7 mutations in patients with advanced cancers: clinical and molecular characteristics and outcomes with mTOR inhibitors. PLoS ONE 9(2): e89388. PURPOSE: FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. Clinicopathologic characteristics of cancer patients with FBXW7 mutations and their responses to mTOR inhibitors remain unknown. METHODS: Using multiplex gene panels we evaluated how the FBXW7 mutation affected the cancer phenotype of patients referred to a phase I clinic starting January 2012. Whenever possible patients positive for FBXW7 mutation were treated with regimens containing an mTOR inhibitors and their outcomes were reviewed. RESULTS: FBXW7 mutations were detected in 17 of 418 patients (4.0%). Among tumor types with more than 10 patients tested, FBXW7 mutations occurred in colorectal cancer (7/49; 14.3%), squamous cell cancer of head and neck (2/18; 11.1%), liver (1/13; 7.7%), and ovarian cancers (1/40; 2.5%). No one clinical, pathological or demographic feature was characteristic of the FBXW7-mutated patient population. The mutation occurred in isolation in only 2/17 (12%) patients, and KRAS was frequently found as a concomitant mutation, especially in patients with colorectal cancer (6/7; 86%). Ten patients were treated on a protocol containing an mTOR inhibitor, with a median time to treatment failure of 2.8 months (range, 1.3-6.8). One patient with liver cancer (fibrolamellar subtype) continues to have a prolonged stable disease for 6.8+ months. CONCLUSION: In patients with advanced cancers, somatic mutations in FBXW7 usually occur with other simultaneous molecular aberrations, which can contribute to limited therapeutic efficacy of mTOR inhibitors.
Kanterman, J, M Sade-Feldman, M Biton, E Ish-Shalom, A Lasry, A Goldshtein, A Hubert and M Baniyash 2014Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes. Cancer Res 74(21): 6022-6035. Colorectal cancer is associated with chronic inflammation and immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Although chemotherapy reduces tumor burden at early stages, it tends to have limited effect on a progressive disease, possibly due to adverse effects on the immune system in dictating disease outcome. Here, we show that patients with advanced colorectal cancer display enhanced MDSC levels and reduced CD247 expression and that some conventional colorectal cancer chemotherapy supports the immunosuppressive tumor microenvironment. A FOLFOX combined therapy reduced immunosuppression, whereas a FOLFIRI combined therapy enhanced immunosuppression. Mechanistic studies in a colorectal cancer mouse model revealed that FOLFIRI-like therapy including the drugs CPT11 and 5-fluorouracil (5FU) damaged host immunocompetence in a manner that limits treatment outcomes. CPT11 blocked MDSC apoptosis and myeloid cell differentiation, increasing MDSC immunosuppressive features and mouse mortality. In contrast, 5FU promoted immune recovery and tumor regression. Thus, CPT11 exhibited detrimental immunoregulatory effects that offset 5FU benefits when administered in combination. Our results highlight the importance of developing therapeutic regimens that can target both the immune system and tumor towards improved personalized treatments for colorectal cancer.
Kostenko, S, KL Jensen and U Moens 2014Phosphorylation of heat shock protein 40 (Hsp40/DnaJB1) by mitogen-activated protein kinase-activated protein kinase 5 (MK5/PRAK). Int J Biochem Cell Biol 47: 29-37. Heat shock protein 40 (Hsp40) acts as a co-chaperone with Hsp70 to promote protein folding, protein transport and degradation. The human Hsp40 family contains more than 40 members, some of which can exist as phosphoproteins in the cell. However, little is known about the protein kinases responsible for their phosphorylation and the functional relevance of this post-translational modification remains elusive. Here we show that Hsp40/DnaJB1 is an in vitro and in vivo substrate for the mitogen-activated protein kinase-activated protein kinase 5 (MK5). MK5 and Hsp40/DnaJB1 form complexes in cells and this interaction is accomplished by the C-terminal regions of both proteins. MK5 can phosphorylate Hsp40/DnaJB1 at several residues in vitro. Studies with specific phosphoantibodies indicate that MK5 phosphorylates Hsp40/DnaJB1 in vivo at Ser-149 or/and Ser-151 and Ser-171 in the C-terminal domain of Hsp40/DnaJB1. MK5 modestly stimulates the ATP hydrolyse activity of Hsp40/Hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by Hsp40/DnaJB1.
Lamouille, S, J Xu and R Derynck 2014Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15(3): 178-196. The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-beta (TGFbeta) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.
Lim, II, BA Farber and MP LaQuaglia 2014Advances in fibrolamellar hepatocellular carcinoma: a review. Eur J Pediatr Surg 24(6): 461-466. Fibrolamellar hepatocellular carcinoma is a rare primary liver tumor that often arises in the absence of cirrhosis or viral hepatitis. Compared with hepatocellular carcinoma, patients are typically younger with less comorbidities. Diagnosis is often multimodal and requires a high level of suspicion, as traditional liver pathology markers, such as serum alpha fetoprotein and transaminases, are often normal. Overall, patients respond well to surgical resection but recurrences are frequent, and alternative therapies, such as chemotherapy and radiation, are not well studied. Currently, there are no established chemotherapy regimens; there are only limited case reports of select agents, such as 5-fluorouracil with interferon-alpha and gemcitabine with oxaliplatin, used with varying degrees of success. Because little is known about this rare tumor, the development of serum markers and alternative therapies continues to be a challenge. A major advancement in the understanding of this rare disease is the discovery of a functional chimeric transcript incorporating DNAJB1 and PRKACA. This finding may finally provide the basis for specific diagnostic markers and chemotherapies that patients with this disease have long needed. Here, we present advances in the surgical treatment of fibrolamellar hepatocellular carcinoma, as well as recent data on its tumor biology and pathogenesis.
Malouf, GG, S Job, V Paradis, M Fabre, L Brugieres, P Saintigny, L Vescovo, J Belghiti, S Branchereau, S Faivre, A de Reynies and E Raymond 2014Transcriptional profiling of pure fibrolamellar hepatocellular carcinoma reveals an endocrine signature. Hepatology 59(6): 2228-2237. UNLABELLED: Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of liver cancer occurring mostly in children and young adults. We have shown that FLC comprises two separate entities: pure (p-FLC) and mixed-FLC (m-FLC), differing in clinical presentation and course. We show that p-FLCs have a distinct gene expression signature different from that of m-FLCs, which have a signature similar to that of classical hepatocellular carcinomas. We found p-FLC profiles to be unique among 263 profiles related to diverse tumoral and nontumoral liver samples. We identified two distinct molecular subgroups of p-FLCs with different outcomes. Pathway analysis of p-FLCs revealed ERBB2 overexpression and an up-regulation of glycolysis, possibly leading to compensatory mitochondrial hyperplasia and oncocytic differentiation. Four of the sixteen genes most significantly overexpressed in p-FLCs were neuroendocrine genes: prohormone convertase 1 (PCSK1); neurotensin; delta/notch-like EGF repeat containing; and calcitonin. PCSK1 overexpression was validated by immunohistochemistry, yielding specific, diffuse staining of the protein throughout the cytoplasm, possibly corresponding to a functional form of this convertase. CONCLUSION: p-FLCs have a unique transcriptomic signature characterized by the strong expression of specific neuroendocrine genes, suggesting that these tumors may have a cellular origin different from that of HCC. Our data have implications for the use of genomic profiling for diagnosis and selection of targeted therapies in patients with p-FLC.
Mayo, SC, MN Mavros, H Nathan, D Cosgrove, JM Herman, I Kamel, RA Anders and TM Pawlik 2014Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma: a national perspective. J Am Coll Surg 218(2): 196-205. BACKGROUND: Surgery remains the only potentially curative option for patients with hepatocellular carcinoma (HCC) and fibrolamellar carcinoma (FLC). We sought to investigate the differences over time in surgically managed FLC compared with conventional HCC using population-based data. STUDY DESIGN: Using SEER data, we identified 7,225 patients with surgically managed FLC or HCC from 1986 to 2008. We examined differences in clinicopathologic and surgical factors associated with long-term survival. RESULTS: Of the 7,225 patients, the majority had HCC (n = 7,135; 99%) vs FLC (n = 90; 1%). Patients with FLC were younger (25 years vs 59 years) and more often were women (44% vs 27%) than patients with HCC (both p < 0.001). Regional disease was more common among patients with FLC (42.2%) vs patients with HCC (22.1%) (p < 0.001). More than one-third of patients with FLC (36.9%) were operatively managed with a hemihepatectomy compared with patients with HCC, who were more often managed with a liver transplant (p < 0.001). On univariable analysis, there was a marked difference in overall survival, with patients with FLC surviving a median of 75 months vs 43 months for HCC (hazard ratio [HR]: 0.59; p = 0.001). There was a marked difference in survival when patients were stratified by localized (FLC, 78 months vs HCC, 49 months; p = 0.012) vs regional disease (FLC, 46 months vs HCC, 23 months; p = 0.002. CONCLUSIONS: Patients with FLC have many clinicopathologic features that are different from those of patients with HCC, including younger age and female sex. Despite a higher likelihood of advanced disease at the time of diagnosis, surgically treated FLC patients had better long-term outcomes than patients with conventional HCC.
Njei, B, VR Konjeti and I Ditah 2014Prognosis of patients with fibrolamellar hepatocellular carcinoma versus conventional hepatocellular carcinoma: A systematic review and meta-analysis. Gastrointest Cancer Res 7(2): 49-54. BACKGROUND: Emerging data suggest that the fibrolamellar variant of hepatocellular carcinoma (FL-HCC) differs in clinical course and prognosis from conventional (nonfibrolamellar) HCC (NFL-HCC). Although FL-HCC is believed to have a better prognosis than NFL-HCC, data comparing the prognoses of the two types of HCC remain lacking. The aim of this systematic review was to compare the prognosis of FL- vs. NFL-HCC. METHODS: Two of the authors independently conducted a comprehensive search of the Cochrane Library, PubMed, Scopus, and published proceedings from major hepatology and gastrointestinal meetings from January 1980 to October 2013. Outcomes of interest were mean overall survival (OS) and 5-year survival. The analyses were performed with a fixed- or random-effects model, as appropriate. The Begg's and Egger's tests with visual inspection of the funnel plot were used to assess for population bias. All analyses were performed with RevMan 5.1 (Cochrane IMS). RESULTS: Seventeen studies involving 368 patients with FL-HCC and 9877 patients with NFL-HCC were included in the analysis. There was an overall statistically significant increase in the 5-year survival for the FL-HCC vs. the NFL-HCC patients (RR, 2.09; 95% CI, 1.38-3.16). In a subgroup analysis limited to noncirrhotic patients, there was no significant difference in 5-year survival in the FL-HCC group compared to that in the NFL-HCC group (RR, 1.69; 95% CI, 0.69-4.17). A significant increase in mean OS was reported in patients with FL-HCC compared with the survival time of those with NFL-HCC (84.9 +/- 15.8 vs. 42.9 +/- 6.5 months) undergoing partial hepatectomy, but there was no difference in patients undergoing liver transplantation (51.4 +/- 14.4 vs. 47.5 +/- 5.5 months). CONCLUSION: Patients with FL-HCC treated with hepatic resection had significantly higher 5-year survival rates than did those with NFL-HCC. However, survival was similar for both FL-HCC and conventional HCC in noncirrhotic patients. There seems to be no difference in survival outcomes for FL- and NFL-HCC when transplantation is used as the therapeutic option.
Okur, A, EP Eser, G Yilmaz, A Dalgic, UO Akdemir, A Oguz, C Karadeniz, G Akyol, B Demirogullari, O Boyunaga and FG Pinarli 2014Successful multimodal treatment for aggressive metastatic and recurrent fibrolamellar hepatocellular carcinoma in a child. J Pediatr Hematol Oncol 36(5): e328-332. Fibrolamellar variant of hepatocellular carcinoma (FLHCC) does not have a favorable prognosis than conventional HCC, and there is no difference regarding the response to chemotherapy and the degree of surgical resectability. FLHCC commonly recurs after complete surgical resection, and there is a high rate of lymph node metastases. Herein, we report a 12-year-old girl with metastatic FLHCC with multiple recurrences aggressively treated with surgery, chemotherapy, and antiangiogenic agents. She is in complete remission after 4 years and 2 months after the diagnosis of metastatic FLHCC. The standard treatment of FLHCC is excision of the primary tumor and its metastases. Chemotherapy for FLHCC is controversial, and it has been suggested that cytoreductive chemotherapy was ineffective and adjuvant chemotherapy did not improve survival. Our patient with multiple recurrences was successfully treated with surgery, first-line chemotherapy with cisplatin and doxorubicin, second-line chemotherapy with 5-fluorouracil/interferon-alpha combination, and adjuvant antiangiogenic agents like cyclophosphamide and thalidomide. As FLHCC patients have no underlying liver disease, they can tolerate higher doses of chemotherapy compared with conventional HCC patients. We support the use of repeated aggressive surgery with adjuvant chemotherapy and antiangiogenic therapy, which provided complete remission in our patient with metastatic and recurrent FLHCC.
Qi, M, J Zhang, W Zeng and X Chen 2014DNAJB1 stabilizes MDM2 and contributes to cancer cell proliferation in a p53-dependent manner. Biochim Biophys Acta 1839(1): 62-69. Both MDM2 and MDMX regulate p53, but these proteins play different roles in this process. To clarify the difference, we performed a yeast 2 hybrid (Y2H) screen using the MDM2 acidic domain as bait. DNAJB1 was found to specifically bind to MDM2, but not MDMX, in vitro and in vivo. Further investigation revealed that DNAJB1 stabilizes MDM2 at the post-translational level. The C-terminus of DNAJB1 is essential for its interaction with MDM2 and for MDM2 accumulation. MDM2 was degraded faster by a ubiquitin-mediated pathway when DNAJB1 was depleted. DNAJB1 inhibited the MDM2-mediated ubiquitination and degradation of p53 and contributed to p53 activation in cancer cells. Depletion of DNAJB1 in cancer cells inhibited activity of the p53 pathway, enhanced the activity of the Rb/E2F pathway, and promoted cancer cell growth in vitro and in vivo. This function was p53 dependent, and either human papillomavirus (HPV) E6 protein or siRNA against p53 was able to block the contribution caused by DNAJB1 depletion. In this study, we discovered a new MDM2 interacting protein, DNAJB1, and provided evidence to support its p53-dependent tumor suppressor function.
Qu, S, K Wang, H Xue, Y Wang, R Wu, C Liu, AC Gao, PW Gout, CC Collins and Y Wang 2014Enhanced anticancer activity of a combination of docetaxel and Aneustat (OMN54) in a patient-derived, advanced prostate cancer tissue xenograft model. Mol Oncol 8(2): 311-322. The current first-line treatment for advanced metastatic prostate cancer, i.e. docetaxel-based therapy, is only marginally effective. The aim of the present study was to determine whether such therapy can be improved by combining docetaxel with Aneustat (OMN54), a multivalent botanical drug candidate shown to have anti-prostate cancer activity in preliminary in vitro experiments, which is currently undergoing a Phase-I Clinical Trial. Human metastatic, androgen-independent C4-2 prostate cancer cells and NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, alone and in combination. In vitro, Aneustat markedly inhibited C4-2 cell replication in a dose-dependent manner. When Aneustat was combined with docetaxel, the growth inhibitions of the drugs were essentially additive. In vivo, however, the combination of docetaxel and Aneustat enhanced anti-tumor activity synergistically and very markedly, without inducing major host toxicity. Complete growth inhibition and shrinkage of the xenografts could be obtained with the combined drugs as distinct from the drugs on their own. Analysis of the gene expression of the xenografts using microarray indicated that docetaxel + Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the single drugs. Our findings, obtained with a highly clinically relevant prostate cancer model, suggest, for the first time, that docetaxel-based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat.
Rich, BS, JN Honeyman, DG Darcy, PT Smith, AR Williams, Lim, II, LK Johnson, M Gonen, JS Simon, MP LaQuaglia and SM Simon 2014Endogenous antibodies for tumor detection. Sci Rep 4: 5088. The study of cancer immunology has provided diagnostic and therapeutic instruments through serum autoantibody biomarkers and exogenous monoclonal antibodies. While some endogenous antibodies are found within or surrounding transformed tissue, the extent to which this exists has not been entirely characterized. We find that in transgenic and xenograft mouse models of cancer, endogenous gamma immunoglobulin (IgG) is present at higher concentration in malignantly transformed organs compared to non-transformed organs in the same mouse or organs of cognate wild-type mice. The enrichment of endogenous antibodies within the malignant tissue provides a potential means of identifying and tracking malignant cells in vivo as they mutate and diversify. Exploiting these antibodies for diagnostic and therapeutic purposes is possible through the use of agents that bind endogenous antibodies.
Rosa, M and A Mohammadi 2014Cytologic features of fibrolamellar carcinoma with mucin production: a rare variant of combined hepatocellular-cholangiocarcinoma. Diagn Cytopathol 42(5): 431-435. Fibrolamellar carcinoma (FC) is an uncommon tumor that usually arises in non-cirrhotic livers of adolescents or young adults. It differs clinically from hepatocellular carcinoma in its better prognosis and lack of gender predilection. Cytologically, the tumor is composed of large polygonal cells with abundant cytoplasm, pleomorphic nuclei, and prominent large nucleoli. A variant of FC with mucinous differentiation has been previously described. These tumors have been regarded as combined hepatocellular cholangiocarcinomas. Herein, we report the case of a 44-year-old Asian female with a large liver mass present for approximately two years. Core needle biopsy with imprint cytology demonstrated FC with areas of intracellular mucin. To our knowledge, cytological features of this rare tumor have not been described before.
Simonsen, K, A Rode, A Nicoll, G Villadsen, U Espelund, L Lim, P Angus, N Arachchi, H Vilstrup, E Nexo and H Gronbaek 2014Vitamin B(1)(2) and its binding proteins in hepatocellular carcinoma and chronic liver diseases. Scand J Gastroenterol 49(9): 1096-1102. BACKGROUND: The vitamin B12 (B12)-binding protein haptocorrin (HC) has proven to be a potentially useful biomarker in patients with fibrolamellar hepatocellular carcinoma (HCC). Little is known concerning the level of HC and other B12-related proteins in patients with HCC as compared to patients with other chronic liver diseases (CLDs) and healthy controls. We hypothesized that HC could be a biomarker of HCC. AIMS: To investigate levels of HC and B12-related proteins in HCC compared to CLDs and healthy controls. METHODS: We investigated two patient populations: A cross-sectional cohort of HCC patients (n = 130), CLD patients (n = 102) and healthy controls (n = 46) and a cohort of 38 HCC patients studied at baseline and 1, 4, and 12 weeks following ablative treatment. Patients were evaluated by standard biochemistry, Child-Pugh-score and Barcelona Clinic Liver Cancer (BCLC) classification. We analyzed total B12 by routine methods and HC, transcobalamin (TC), B12 saturated TC (holoTC), and the soluble cell surface receptor for holoTC (sCD320) by in-house enzyme-linked immunosorbent assay. RESULTS: HC showed higher median (range) levels for both HCC (590 [290-5860]) and CLD patients (620 [310-4010]) compared to controls (460 [250-2020]) (p < 0.01). Total B12, TC, holoTC, and sCD320 showed elevated levels in both HCC and CLD compared to controls. Only holoTC changed following treatment, without a concurrent change in TC. CONCLUSION: B12 and B12-related proteins (total B12, HC, TC, holoTC, and sCD320) show elevations in both HCC and CLD patients compared to controls, suggesting a relation to CLD in general rather than to primary liver cancer. Thus, HC is not useful as a biomarker for HCC.
Stransky, N, E Cerami, S Schalm, JL Kim and C Lengauer 2014The landscape of kinase fusions in cancer. Nat Commun 5: 4846.Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been characterized as extensively. Here we develop heuristics for reliably detecting gene fusion events in RNA-seq data and apply them to nearly 7,000 samples from The Cancer Genome Atlas. We thereby are able to discover several novel and recurrent fusions involving kinases. These findings have immediate clinical implications and expand the therapeutic options for cancer patients, as approved or exploratory drugs exist for many of these kinases.
Wolosz, D, A Walczak, GM Wilczynski, G Szparecki, E Wilczek and B Gornicka 2014Deleted in liver cancer 1 expression and localization in hepatocellular carcinoma tissue sections. Oncol Lett 8(2): 785-788.The deleted in liver cancer (DLC) protein family is composed of proteins that are hypothesized to function predominantly by regulating the activity of the small GTPases. The aim of the present study was to determine the expression and exact localization of DLC1 in hepatocellular carcinoma (HCC) tissue sections. In two types of HCC tissues, typical and fibrolamellar, immunohistochemical and immunofluorescent analysis were performed to assess DLC1 immunoreactivity. Additionally, the DLC1 gene status was determined by the fluorescence in situ hybridization. According to the observations, DLC1 is often lost in cancer cells; however, it can remain within the stromal component of tumor sections. The DLC1 immunoreactivity was particularly noticeable within the capsules surrounding the tumor masses. It was found that the DLC1 gene was deleted in 52% of HCC cases. In addition, the hemizygous deletion was observed to be independent of the HCC subtype. The results indicate that although the loss of DLC1 is a common step during hepatocarcinogenesis, this protein may be present in the tumor microenvironment.
Ang, CS, RK Do, A Shamseddine, EM O'Reilly, A Haydar, A Al-Olayan, W Faraj, F Boulos, M Naghy, D Makanjoula, H Farran, H Sibai, D Wehbe, DP Kelsen and GK Abou-Alfa 2013A young woman with liver cancer. Gastrointest Cancer Res 6(1): 17-21.
Ang, CS, RK Kelley, MA Choti, DP Cosgrove, JF Chou, D Klimstra, MS Torbenson, L Ferrell, TM Pawlik, Y Fong, EM O'Reilly, J Ma, J McGuire, GP Vallarapu, A Griffin, F Stipa, M Capanu, RP Dematteo, AP Venook and GK Abou-Alfa 2013Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: data from the fibrolamellar carcinoma consortium. Gastrointest Cancer Res 6(1): 3-9. BACKGROUND: Fibrolamellar carcinoma is a rare and poorly understood malignancy that affects the young in the absence of underlying liver disease. Despite reported small review series, the literature lacks large retrospective studies that may help in understanding this disease. METHODS: Medical record review was undertaken for all patients histopathologically diagnosed with fibrolamellar carcinoma, seen at Memorial Sloan-Kettering Cancer Center, the University of California San Francisco, and Johns Hopkins Hospital from 1986 to 2011. Demographic, clinical, pathologic, and treatment data were recorded. Overall survival was estimated by using Kaplan-Meier methods. The impact of different clinicopathologic variables on survival was assessed with Cox regression models. RESULTS: Ninety-five patients were identified. Median age was 22 years, 86% were Caucasian, and 50% presented with stage IV disease. There were more females than males (58% vs. 42%). Seventy-seven percent of the patients underwent surgical resection and/or liver transplantation; of these 31.5% received perioperative therapy. Patients with unresectable disease, including 8 patients treated in clinical trials, were treated with chemotherapy, occasionally given with interferon or biologic agents. Ten patients received sorafenib, and 7 received best supportive care. Median survival was 6.7 years. Factors significantly associated with poor survival were female sex, advanced stage, lymph node metastases, macrovascular invasion, and unresectable disease. CONCLUSIONS: The clinicopathologic characteristics and survival outcomes from this dataset are consistent with those reported in the literature. Surgical resection and disease extent were confirmed as important predictors of survival. The possibility of a negative association between female sex and prognosis could represent a clue as to future therapeutic strategies.
Eggert, T, KA McGlynn, A Duffy, MP Manns, TF Greten and SF Altekruse 2013Fibrolamellar hepatocellular carcinoma in the USA, 2000-2010: A detailed report on frequency, treatment and outcome based on the Surveillance, Epidemiology, and End Results database. United European Gastroenterol J 1(5): 351-357. OBJECTIVE: Epidemiological and clinical information on fibrolamellar hepatocellular carcinoma (fHCC) is scarce. We performed a Surveillance, Epidemiology and End Results (SEER) database analysis with the aim of collecting information to better understand the biology and clinical aspects of this rare disease. DESIGN: Incidence trends, race- and age-specific rates, tumor size, first course surgery and five-year relative survival of 191 US cases (SEER) diagnosed with fHCC during 2000-2010 were compared to cases with hepatocellular carcinoma (HCC), HCC-not otherwise specified (HCC-NOS) and other HCC-types. RESULTS: While HCC-NOS incidence rates increased by 5.2% annually from 2000-2008 (p < 0.05) before leveling, the 1.3% change in fHCC incidence was not statistically significant. The rates of fHCC were similar across ethnic groups while HCC-NOS incidence rates were higher among non-whites. Although 16% of fHCC patients had primary tumors
Eggert, T, KA McGlynn, A Duffy, MP Manns, TF Greten and SF Altekruse 2013Epidemiology of fibrolamellar hepatocellular carcinoma in the USA, 2000-10. Gut 62(11): 1667-1668.
Ghiringhelli, F, M Bruchard and L Apetoh 2013Immune effects of 5-fluorouracil: Ambivalence matters. Oncoimmunology 2(3): e23139. Cytotoxic anticancer drugs can promote antitumor immune responses. The anticancer activity of 5-fluorouracil (5FU) relies on the restoration of T-cell immunity following the elimination of myeloid-derived suppressor cells (MDSCs). We have recently discovered that the 5FU-driven activation of the NLRP3 inflammasome in MDSCs promotes tumor angiogenesis by eliciting TH17 responses that compromise anticancer immunity. This underscores the need to combine 5-FU with NLRP3 inhibitors to prevent tumor progression.
Kaseb, AO, M Shama, IH Sahin, A Nooka, HM Hassabo, JN Vauthey, T Aloia, JL Abbruzzese, IM Subbiah, F Janku, S Curley and MM Hassan 2013Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma. Oncology 85(4): 197-203. OBJECTIVE: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of HCC. We report an analysis of the clinicopathologic features, treatment outcomes, and prognostic indicators of 94 cases. METHODS: We retrospectively collected clinicopathologic and treatment outcome data from 94 FLHCC patients (48 males and 46 females). Median overall survival (OS) and recurrence-free survival (RFS) were calculated using Kaplan-Meier curves, and survival rates were compared by the log-rank test. The Cox proportional hazard model was used for univariate and multivariate estimation of hazard risk ratios and 95% confidence intervals (CI) for factors that correlated with survival and disease recurrence after resection. RESULTS: Median age was 23 years (14-75); median OS was 57.2 months (95% CI, 36.4-77.9), and median RFS was 13.9 months (95% CI, 8.8-18.9). White race, female gender, early tumor stage, and tumor resection including metastasectomy were positively associated with longer OS, while female gender was the only significant positive predictor of longer RFS. Finally, the 5-fluorouracil-interferon combination was the most frequently used systemic therapy. CONCLUSIONS: Our analyses indicate that surgical approaches including metastasectomy as the first-line treatment in FLHCC correlated with better outcome. Multimodality approaches, including neoadjuvant and adjuvant therapies, prolonged patient survival.
Oikawa, T, A Kamiya, M Zeniya, H Chikada, AD Hyuck, Y Yamazaki, E Wauthier, H Tajiri, LD Miller, XW Wang, LM Reid and H Nakauchi 2013Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers. Hepatology 57(4): 1469-1483. UNLABELLED: Liver cancers, including hepatocellular carcinomas (HCCs), cholangiocarcinomas (CCs), and fibrolamellar HCCs (FL-HCCs) are among the most common cancers worldwide and are associated with a poor prognosis. Investigations of genes important in liver cancers have focused on Sal-like protein 4 (SALL4), a member of a family of zinc finger transcription factors. It is a regulator of embryogenesis, organogenesis, pluripotency, can elicit reprogramming of somatic cells, and is a marker of stem cells. We found it expressed in normal murine hepatoblasts, normal human hepatic stem cells, hepatoblasts and biliary tree stem cells, but not in mature parenchymal cells of liver or biliary tree. It was strongly expressed in surgical specimens of human HCCs, CCs, a combined hepatocellular and cholangiocarcinoma, a FL-HCC, and in derivative, transplantable tumor lines in immune-compromised hosts. Bioinformatics analyses indicated that elevated expression of SALL4 in tumors is associated with poor survival of HCC patients. Experimental manipulation of SALL4's expression results in changes in proliferation versus differentiation in human HCC cell lines in vitro and in vivo in immune-compromised hosts. Virus-mediated gene transfer of SALL4 was used for gain- and loss-of-function analyses in the cell lines. Significant growth inhibition in vitro and in vivo, accompanied by an increase in differentiation occurred with down-regulation of SALL4. Overexpression of SALL4 resulted in increased cell proliferation in vitro, correlating with an increase in expression of cytokeratin19 (CK19), epithelial cell adhesion molecules (EpCAM), and adenosine triphosphate (ATP)-binding cassette-G2 (ABCG2). CONCLUSION: SALL4's expression is an indicator of stem cells, a prognostic marker in liver cancers, correlates with cell and tumor growth, with resistance to 5-FU, and its suppression results in differentiation and slowed tumor growth. SALL4 is a novel therapeutic target for liver cancers.
Patonai, A, B Erdelyi-Belle, A Korompay, A Somoracz, P Torzsok, I Kovalszky, T Barbai, E Raso, G Lotz, Z Schaff and A Kiss 2013Molecular characteristics of fibrolamellar hepatocellular carcinoma. Pathol Oncol Res 19(1): 63-70. Fibrolamellar hepatocellular carcinoma (FLC) occurs in non-cirrhotic liver and the etiopathogenesis is still obscure. Both hepatocellular and cholangiocellular markers are expressed in the tumor, however, molecular alterations and altered pathways playing role in the tumor pathogenesis are not clearly identified. The purpose of the present study was to compare the expression level of EGFR, syndecan-1 and ss-catenin in FLC, conventional hepatocellular carcinoma (cHCC) and cholangiocellular carcinoma (CCC) and to investigate the possibility of mutation both in EGFR and K-RAS. Eight FLCs were compared with 7 cHCCs, 7 CCCs and 5 normal liver samples. Cytokeratins 7, 8, 18, 19, HepPar1 (HSA), EGFR, syndecan-1 (CD138) and ss-catenin were detected by immunohistochemistry. In addition EGFR, ss-catenin and syndecan-1 were evaluated by digital morphometry and K-RAS, EGFR mutations in FLC cases using paraffin-embedded samples. All FLCs were positive for HepPar1 (HSA) and cytokeratins 7, 8, 18, but negative for cytokeratin 19 by immunohistochemistry. EGFR was significantly overexpressed in all three tumor types, being highest in FLCs (p = 0,0001). EGFR, K-RAS mutation analyses revealed no mutations in exons studied in FLCs. Our findings proved that expression of EGFR is higher in FLC than in other types of primary malignant hepatic tumors and no K-RAS mutation can be detected, so FLC is a good candidate for anti-EGFR treatment.
Peacock, JG, JA Call and KR Olivier 2013Radiotherapy for metastatic fibrolamellar hepatocellular carcinoma. Rare Tumors 5(3): e28. Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC) that commonly affects young individuals without a prior history of liver disease. FLHCC commonly results in a better prognosis than HCC; however, the risk of recurrence and metastatic disease is high. FLHCC is typically treated by primary resection of the tumor with 50-75% cure rates. The use of radiation therapy in FLHCC has not been assessed on its own, and may show some success in a very few reported combination therapy cases. We report on the successful use of radiation therapy in a case of metastatic FLHCC to the lung following primary and secondary resections. Our treatment of the large, metastatic, pulmonary FLHCC tumor with 40 Gy in 10 fractions resulted in an 85.9% tumor volume decrease over six months. This suggests FLHCC may be a radiosensitive tumor and radiotherapy may be valuable in unresectable or metastatic tumors.
Subbiah, IM, V Subbiah, A Naing, S Fu, AO Kaseb, GS Falchook, D Tan, CE Herzog, F Janku and R Kurzrock 2013Targeted therapies in early-phase trials for the treatment of advanced fibrolamellar hepatocellular carcinoma. Journal of Clinical Oncology 31(4_suppl): 232-232. 232 Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary liver malignancy, affecting young adults w/o chronic liver disease. Limited data exists on the novel therapeutics for this disease. Methods: Given its rarity, we evaluated the characteristics, outcomes and performed molecular analysis for targetable pathways in patients with FLHCC enrolled on phase I trials with an emphasis on targeted therapies. Results: Ten FLHCC patients (8 female, 2 male; median age 23yrs) were evaluated in the Phase I Clinic. Eight had recurrence from prior resections. Eight patients enrolled on a phase I trial. Pt #7 (58F w recurrence post-resection), received sunitinib (inhibitor of PDGFR, VEGFR, FLT3, RET) with valproic acid (HDAC inhibitor) and had a 41% decrease per RECIST for 16.5 months without any high-grade toxicities. Pt #5 (24F) had a 22% decrease for 5.4 months pazopanib (inhibitor of VEGFR, PDGFR, FGFR, cKIT) and vorinostat (HDAC inhibitor). Pt #8 remains on study with bevacizumab+sorafenib now for 5 months with 9% decrease. Pt #1 received a novel proteosome inhibitor with stable disease >9 months while pts #3, #5, and #7 received HDAC inhibitors vorinostat and valproic acid. Analysis for molecular aberrations and next generation sequencing are in progress with preliminary data showing the activation of the PI3K/AKT/mTOR signaling pathway. Conclusions: This work is the first such to report on the use of targeted therapies in advanced FLHCC. Overall pts tolerate targeted therapy with early data showing clinical efficacy and biologic activity of multikinase inhibitors, specifically sunitinib and pazopanib, in combination with HDAC inhibitors, valproic acid and vorinostat. Li et al report morphoproteomic analysis showing high expression of phosphorylated (p)-NF-?Bp65 (at serine 536, a putative site of activation) in FLHCC in comparison to normal liver (p < 0.001) in 7 of 8 (88%) tested FL-HCC samples, signifying the constitutive activation of the NF-?B pathway and the therapeutic potential of proteosome inhibitors and HDAC inhibitors. Given the lack of consensus on treatment of unresectable FLHCC, this analysis presents seminal data on targeted agents for these patients.
Weeda, VB, M Murawski, AJ McCabe, R Maibach, L Brugieres, D Roebuck, M Fabre, A Zimmermann, JB Otte, M Sullivan, G Perilongo, M Childs, P Brock, J Zsiros, J Plaschkes, P Czauderna and DC Aronson 2013Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer 49(12): 2698-2704. PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. PATIENTS AND METHODS: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. RESULTS: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. CONCLUSIONS: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.
Berger, C, P Dimant, L Hermida, F Paulin, M Pereyra and M Tejo 2012[Hyperammonemic encephalopathy and fibrolamellar hepatocellular carcinoma]. Medicina (B Aires) 72(5): 425-427. We present the case of a young woman, 22 years old, with an aggressive form of fibrolamellar hepatocellular carcinoma. She began with the signs and symptoms of a hyperammonemic encephalopathy, an uncommon form of presentation. Fibrolamellar carcinoma is a rare liver tumor, which affects young patients without previous liver disease. Its etiology is unknown, and it has been considered as a tumor with a better prognosis than the classic hepatocellular carcinoma.
Gras, P, S Truant, V Boige, L Ladrat, P Rougier, FR Pruvot and M Hebbar 2012Prolonged Complete Response after GEMOX Chemotherapy in a Patient with Advanced Fibrolamellar Hepatocellular Carcinoma. Case Rep Oncol 5(1): 169-172. The only currently validated treatment for advanced hepatocellular carcinoma (HCC) is sorafenib. However, sorafenib has been mainly studied in patients with HCC developed in cirrhotic liver. Chemotherapy might be more suitable for patients with HCC in non-cirrhotic liver. We report the case of a young woman with fibrolamellar HCC in a non-cirrhotic liver, with histologically proven metastatic ganglionary relapse after surgical resection of the primary tumour. Chemotherapy with gemcitabine and oxaliplatin (GEMOX regimen) achieved a complete response without relapse five years after discontinuation of chemotherapy. This exceptional case raises the question of clinical trials specifically designed for patients with HCC in non-cirrhotic liver.
Hashash, JG, K Thudi and SM Malik 2012An 18-year-old woman with a 15-cm liver mass and an ammonia level of 342. Gastroenterology 143(5): 1157-1402.
Honeyman, JN and MP La Quaglia 2012Malignant liver tumors. Semin Pediatr Surg 21(3): 245-254. Malignant tumors of the liver comprise a relatively small fraction of the total number of pediatric malignancies. However, these tumors can be a significant cause of morbidity and mortality, and there have been significant therapeutic gains during the past few decades through advances in systemic therapy and surgical treatment. Even in patients with advanced local disease, complete resection is now a possibility because of improvements in liver transplantation techniques. In this review, we will discuss the staging and treatment of common malignant tumors of the liver.
Kakkar, V, LC Prins and HH Kampinga 2012DNAJ proteins and protein aggregation diseases. Curr Top Med Chem 12(22): 2479-2490. Many neurodegenerative diseases are late onset diseases, associated with aggregation of proteins, implying that aged cells are more susceptible to proteotoxic stress. It is known that with aging, there is a decline in the functionality of chaperone networks and on the other hand, accumulation of damaged proteins occurs. Together, this has a cumulative effects on cellular protein homeostasis. Several studies have revealed that availability of DNAJ proteins, the co-chaperones to the Hsp70 machine, could be a rate-limiting factor in handling diseased proteins within the cell. In this review,we highlight how DNAJ proteins can affect aggregation of disease-causing proteins, if and how this depends on their function as Hsp70 co-chaperones, and how much this depends on the type of protein causing the disease. Finally, we will discuss the five known degenerative diseases that are linked to mutations in individual DNAJ members and what mechanism may underlie these DNAJ chaperonopathies.
Ko, YH, HA Verhoeven, MJ Lee, DJ Corbin, TJ Vogl and PL Pedersen 2012A translational study case reportJ Bioenerg Biomembr 44(1): 163-170 The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells' energy metabolism, both its high glycolysis ("Warburg Effect") and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an "Energy Blocker", is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP's discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83-91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269-275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the Department of Biological Chemistry at Johns Hopkins University, School of Medicine was taken effectively to bedside treatment at Johann Wolfgang Goethe University Frankfurt/Main Hospital, Germany. The results obtained hold promise for 3BP as a future cancer therapeutic without apparent cyto-toxicity when formulated properly.
Malouf, GG, L Brugieres, MC Le Deley, S Faivre, M Fabre, V Paradis, I Aerts, C Le Tourneau, C Dreyer, S Branchereau, J Belghiti and E Raymond 2012Pure and mixed fibrolamellar hepatocellular carcinomas differ in natural history and prognosis after complete surgical resection. Cancer 118(20): 4981-4990. BACKGROUND: The purpose of the current study was to describe pure and mixed fibrolamellar hepatocellular carcinoma (FL-HCC). METHODS: Consecutive patients with pure and mixed FL-HCC were identified from a central pathological review using Edmondson's criteria. Clinical, pathological, and epigenetic characteristics of patients who underwent curative surgery were evaluated. Overall and disease-free survival as well as patterns of disease recurrence were examined. Methylation levels of L1 retrotransposon (LINE-1) repetitive elements and Ras association domain family 1A gene (RASSF1) promoter were also assessed using pyrosequencing. RESULTS: Forty of 53 patients with a median age of 22 years (range, 9 years-;65 years) met the criteria for analysis. Central pathological review found that 30 patients (75%) had pure and 10 patients (25%) had mixed FL-HCC. Pure FL-HCC typically occurred in patients aged < 30 years. These patients often presented with lymph node metastasis at the time of diagnosis and frequently experienced extrahepatic recurrences (n = 16). Conversely, mixed FL-HCC appeared to resemble to classic HCC, occurring in patients aged > 40 years and frequently involving the liver as the primary site of disease recurrence. With a median follow-up of 7.8 years, the median overall survival from the time of diagnosis in all patients was 6.4 years (range, 3.2 years-12 years). Multivariate analysis found that the risk of death was increased in patients with higher American Joint Committee on Cancer disease stages (P = .003) and those with mixed FL-HCC (P = .03). Methylation analysis of LINE-1 repetitive elements and RASSF1 promoter revealed different methylation levels between pure and mixed FL-HCC, suggesting a different epigenetic background. CONCLUSIONS: Pure and mixed FL-HCC display distinct clinical presentations and epigenetic backgrounds leading to different prognoses and as such may be regarded as separate clinical entities.
Mavros, MN, SC Mayo, O Hyder and TM Pawlik 2012A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. J Am Coll Surg 215(6): 820-830. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver tumor presenting earlier in life than nonfibrolamellar hepatocellular carcinoma (NFL-HCC), with distinct epidemiologic and clinical characteristics. Although FLC is believed to have a better prognosis than NFL-HCC, data on treatment and prognosis are scarce. We performed a systematic review to investigate treatment options and clinical outcomes of patients with FLC. STUDY DESIGN: The study is a systematic review of the literature and pooled analysis of individual patient data. RESULTS: A total of 35 series were analyzed, reporting on 575 patients (52% female, elevated alpha-fetoprotein in 10%, cirrhosis in 3%, hepatitis B in 2%), most of whom were treated with partial hepatectomy (55%) or orthotopic liver transplantation (23%). Nineteen studies provided data on 206 individual patients with a median age of 21 years and tumor size of 12 cm. Median overall survival (OS) was 39 months; 1-year, 3-year, and 5-year OS rates were 85%, 53%, and 44%, respectively. For patients treated with liver resection, median OS was 18.5 years and 1-year, 3-year, and 5-year OS were 93%, 80%, and 70%, respectively. Based on data from 15 studies, FLC appeared to follow a relatively indolent course compared with NFL-HCC. CONCLUSIONS: Patients with FLC treated with partial hepatectomy have excellent long-term survival, with 5-year overall survival reaching 70%. Patients fared worse with the use of other therapeutic options including chemotherapy, intra-arterial therapy, and transplantation, although data directly comparing resection vs transplantation were limited.
Nault, JC, M Fabre, G Couchy, C Pilati, E Jeannot, J Tran Van Nhieu, MC Saint-Paul, A De Muret, MJ Redon, C Buffet, S Salenave, C Balabaud, S Prevot, P Labrune, P Bioulac-Sage, JY Scoazec, P Chanson and J Zucman-Rossi 2012GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. J Hepatol 56(1): 184-191. BACKGROUND & AIMS: Mosaic G-protein alpha-subunit (GNAS)-activating mutations are responsible for the McCune-Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis. METHODS: GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines. RESULTS: A somatic GNAS-activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A, CTNNB1, and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS-mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS-mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation. CONCLUSIONS: We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS-activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.
Niederle, IM, MA Worns, S Koch, M Nguyen-Tat, C Duber, G Otto, M Schuchmann, PR Galle and A Weinmann 2012Clinicopathologic features and prognosis of young patients with hepatocellular carcinoma in a large German cohort. J Clin Gastroenterol 46(9): 775-778. GOALS AND BACKGROUND: Hepatocellular carcinoma in non-hepatitis B virus endemic areas is rare in patients younger than 40 years of age. The aim of this study was to characterize young patients in a large German cohort in comparison with older patients with regard to underlying liver disease, clinical management, and survival. STUDY: We analyzed the clinical data and medical records of 1108 consecutive patients with confirmed hepatocellular carcinoma. Twenty-five patients (2%) were younger than 40 years of age. We compared this subgroup with patients older than 40 years of age. RESULTS: Underlying chronic liver disease was less common in young patients and detectable in only 56% of patients. Fibrolamellar carcinoma was more frequent in young versus old patients (20% vs. 0.7%; P<0.001). There was a trend toward more potentially curative treatment options in young patients, and overall survival was longer in the young group compared with older patients (56.0 vs. 15.2 mo; P=0.048). CONCLUSIONS: This western cohort of young patients is distinctly different from described Asian cohorts, especially with regard to a lower rate of underlying liver disease and particularly hepatitis B virus. Young patients had a better overall survival than older patients.
Torbenson, M 2012Fibrolamellar carcinoma: 2012 update. Scientifica (Cairo) 2012: 743790. Fibrolamellar carcinomas are a unique type of primary liver cancer. They occur most commonly in children and young adults. Their etiology remains a mystery, as they are not associated with chronic liver disease. Fibrolamellar carcinomas are not indolent tumors, but have an overall better prognosis than typical hepatocellular carcinomas, in part because of the younger age at presentation and the lack of cirrhosis. The most important prognostic feature is whether the tumor is resectable. Histologically, the tumor is made up of large cells that contain abundant mitochondria. The nuclei of the tumor cells have prominent nucleoli. The tumor cells induce the formation of extensive intratumoral fibrosis, which often grows in parallel, or lamellar bands. The tumor cells clearly show hepatocellular features but are also unique in showing both biliary and neuroendocrine differentiation. The uniqueness of fibrolamellar carcinoma extends to their molecular findings. While the genetic abnormalities that lead to fibrolamellar carcinomas are not yet known, studies have shown that they lack mutations in the genes most commonly mutated in typical hepatocellular carcinoma (TP53 and CTNNB1). In this paper, the clinical, pathological, and basic science literature on fibrolamellar carcinoma is comprehensively reviewed. Key areas of needed research are also discussed.
Choi, SS, A Omenetti, WK Syn and AM Diehl 2011The role of Hedgehog signaling in fibrogenic liver repair. Int J Biochem Cell Biol 43(2): 238-244. Repair of adult liver, like many tissues, involves the coordinated response of a number of different cell types. In adult livers, fibroblastic cells, ductular cells, inflammatory cells, and progenitor cells contribute to this process. Our studies demonstrate that the fates of such cells are dictated, at least in part, by Hedgehog, a fetal morphogenic pathway that was once thought to be active mainly during embryogenesis. Studies of injured adult human and rodent livers demonstrate that injury-related activation of the Hedgehog pathway modulates several important aspects of repair, including the growth of hepatic progenitor populations, hepatic accumulation of myofibroblasts, repair-related inflammatory responses, vascular remodeling, liver fibrosis and hepatocarcinogenesis. These findings identify the Hedgehog pathway as a potentially important target for biomarker development and therapeutic manipulation, and emphasize the need for further research to advance knowledge about how this pathway is regulated by and interacts with other signals that regulate adult liver repair.
Fleming, CM 2011The epidemiology of cirrhosis and abnormal liver function in the general population of the UK. Faculty of Medicine and Health Sciences, School of Community Health Sciences. Nottingham, United Kingdom, University of Nottingham. Ph.D.: 397.Liver disease is a serious problem both in the UK and globally. While the
incidence and mortality from several chronic diseases are decreasing,
mortality from liver disease is increasing. As well as the medical sequelae for
an individual with liver disease, in the UK the increase in chronic liver disease
poses particular problems with respect to increasing hospital admissions,
mortality and significant costs to the public both in terms of treatment and in
loss of productivity. The increase in society of several risk factors for chronic
liver disease, notably alcohol intake, obesity and type 2 diabetes, mean that
these problems are likely to increase in the future.

Despite these apparent problems there are surprisingly few reliable sources of
data on the occurrence of chronic liver disease (cirrhosis) in the general
population of the UK and the rate and consequence of disease progression
particularly among ambulatory patients. Nor are their robust estimates of the
prevalence of abnormal liver function tests (which may represent undiagnosed
liver disease) and their associations with mortality.

This thesis utilises two distinct datasets to examine separate areas of interest
in the epidemiology of liver disease in the UK. The first three studies
contained within this thesis are concerned with the epidemiology of cirrhosis in
the general population of the UK. The second group of three studies focuses
on the prevalence of elevated liver function tests in a population of older
people in the UK, the demographic, clinical and lifestyle factors associated
with such and the mortality following an elevated liver function test.
Gasparre, G, G Romeo, M Rugolo and AM Porcelli 2011Learning from oncocytic tumors: Why choose inefficient mitochondria? Biochim Biophys Acta 1807(6): 633-642. A prominent role for mitochondrial genes and metabolism has been recently characterized in oncocytic transformation of cancer cells. From mitochondrial ultrastructure alterations to respiratory complexes disruption and mutations within mitochondrial genes, oncocytic tumors present with a plethora of features that have helped understand the role that these organelles and their fundamental metabolic functions may play in cancer development. The history of this under-diagnosed subset of tumors and the bioenergetic implications of their mitochondrial derangement are discussed in this review along with the opportunities that oncocytic tumors offer to draw general conclusions on the involvement of mitochondria in cancer.
Guaraldi, F, G Zang, AP Dackiw and P Caturegli 2011Oncocytic mania: a review of oncocytic lesions throughout the body. J Endocrinol Invest 34(5): 383-394. Oncocytic lesions are characterized pathologically by an abundance of oncocytes, that is by enlarged, eosinophilic, and finely granular cells enriched in mitochondria. They can arise in numerous organs and tissues, often in endocrine glands, and have been associated with hyperplasia, autoimmunity, and neoplasia. The causes and mechanisms that transform a normal cell into an oncocyte remain to be elucidated. Aim of this article is to review the most common oncocytic lesions, highlighting their key pathological features and clinical significance.
Lepreux, S, P Bioulac-Sage and E Chevet 2011Differential expression of the anterior gradient protein-2 is a conserved feature during morphogenesis and carcinogenesis of the biliary tree. Liver Int 31(3): 322-328. BACKGROUND: The anterior gradient protein-2 (AGR2) is overexpressed in numerous tumours such as breast, prostate or pancreas carcinomas and recently reported in fibrolamellar hepatocellular carcinoma (HCC). AIMS: In the present study, we further describe AGR2 expression patterns all along the adult and fetal biliary tree and in cholangiocarcinomas. METHODS: Immunohistochemistry using anti-AGR2 antibodies was performed in adult and fetal livers, gallbladders as well as cholangiocarcinomas and HCCs. RESULTS: In adult and fetal liver, the tall epithelial cells covering the large bile ducts as well as gallbladder epithelial cells showed strong AGR2 staining. Hilar and extrahepatic cholangiocarcinomas, and a subset of intrahepatic cholangiocarcinomas, which displayed a morphological mucus-excreting feature, also displayed AGR2 expression. In contrast, AGR2 expression was not detected in typical HCCs. CONCLUSION: Our study shows that the differential expression of AGR2 is a phenotypic feature of the cholangiocytes covering different segments of the biliary tree. This pattern of expression is conserved during fetal and adult life, as well as during biliary carcinogenesis.
Li, M, H Zhao, X Zhang, LD Wood, RA Anders, MA Choti, TM Pawlik, HD Daniel, R Kannangai, GJ Offerhaus, VE Velculescu, L Wang, S Zhou, B Vogelstein, RH Hruban, N Papadopoulos, J Cai, MS Torbenson and KW Kinzler 2011Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 43(9): 828-829. Through exomic sequencing of ten hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype.
Lildballe, DL, KQ Nguyen, SS Poulsen, HO Nielsen and E Nexo 2011Haptocorrin as marker of disease progression in fibrolamellar hepatocellular carcinoma. Eur J Surg Oncol 37(1): 72-79. AIMS: No valid markers are routinely available to follow disease progression in patients with fibrolamellar hepatocellular carcinoma (FLHCC). We report data suggesting that the vitamin B12 binding protein haptocorrin (HC) may prove a suitable marker. METHODS: We monitored a 15-year-old boy diagnosed to have FLHCC by measuring the common markers alanine aminotransaminase, alkaline phosphatase, lactate dehydrogenase, and bilirubin, as well as vitamin B12 (B12), and the forms of the B12 binding proteins. Tumour biopsies were examined immunohistologically. DNA and RNA were extracted from tumour and normal tissue and examined for content of HC DNA and mRNA. RESULTS: The only markers indicative of disease progression were HC and (B12), levels of which were markedly elevated to 84 (11) nmol/L at the time of diagnosis and returned to values within the reference interval (0.43 (0.33) nmol/L) after an apparently radical removal of the tumour. The disappearance rate of HC followed a biphasic curve, the unsaturated protein displaying a half-life of 2.8 days and B12 and saturated HC one of 13 days. Before each diagnosed relapse, an increased concentration of HC was observed. We found a strong immunoreaction against HC in tumour tissue and a high mRNA expression of HC supporting the notion that HC was tumour derived. CONCLUSIONS: Plasma HC proved to be a useful tumour marker in a patient with FLHCC, and we suggest the use of this protein as a marker of disease progression in these patients.
Muramori, K, S Taguchi, T Taguchi, K Kohashi, K Furuya, K Tokuda and E Ishii 2011High aromatase activity and overexpression of epidermal growth factor receptor in fibrolamellar hepatocellular carcinoma in a child. J Pediatr Hematol Oncol 33(5): e195-197. An 11-year-old boy was admitted with a liver tumor and underwent right trisegmentectomy for a diagnosis of fibrolamellar hepatocellular carcinoma. He had suffered from bilateral gynecomastia for a year, which improved after complete resection of the tumor. The tumor cells had significant aromatase activity (8.03 pmol/g/h) and contained high levels of estradiol (82.1 pg/mL), which contributed to gynecomastia. Furthermore, overexpression of epidermal growth factor receptor was determined in the tumor cells, which suggests that antitumor strategies using epidermal growth factor receptor antagonists may be effective.
Patonai, A, B Erdelyi-Belle, A Korompay, A Somoracz, BK Straub, P Schirmacher, I Kovalszky, G Lotz, A Kiss and Z Schaff 2011Claudins and tricellulin in fibrolamellar hepatocellular carcinoma. Virchows Arch 458(6): 679-688. Fibrolamellar hepatocellular carcinoma is a subtype of hepatocellular carcinoma occurring in non-cirrhotic liver at a younger age. The tumor expresses both hepatocellular and cholangiocellular markers. Previously, our group described overexpression of tight junction protein claudin 4 in cholangiocellular carcinoma in contrast to hepatocellular carcinoma. In the present study, tight junction protein expressions were studied to possibly clarify bipotential lineage of fibrolamellar hepatocellular carcinoma. Eleven fibrolamellar hepatocellular carcinomas were compared with seven "conventional" hepatocellular carcinomas, seven cholangiocellular carcinomas, and five normal liver samples. By immunohistochemistry, all fibrolamellar hepatocellular carcinomas were positive for HepPar1 and cytokeratins 7, 8, and 18, but negative for cytokeratin 19. Glypican-3 gave weak staining in two cases. Expression of claudin 1 was lower, while that of claudin 2 was higher in fibrolamellar hepatocellular carcinomas than in other tumors. Claudins 3, 4, and 7 were not detectable in fibrolamellar hepatocellular carcinomas as in the majority of "conventional" hepatocellular carcinomas, contrary to high expression observed in cholangiocellular carcinomas. Focal or diffuse claudin 5 expression was detected in nine of 11 fibrolamellar hepatocellular carcinomas contrary to other tumors. Tricellulin was significantly downregulated in all tumors compared with normal liver. Our findings showed claudins to exhibit specific expression patterns in fibrolamellar hepatocellular carcinomas not observed in other primary liver tumors, with unique claudin 5 expression and pattern features similar to common hepatocellular carcinoma, but different from cholangiocellular carcinoma. This is the first report describing the loss of tricellulin expression in human hepatic tumors.
Ross, HM, HD Daniel, P Vivekanandan, R Kannangai, MM Yeh, TT Wu, HR Makhlouf and M Torbenson 2011Fibrolamellar carcinomas are positive for CD68. Mod Pathol 24(3): 390-395. Fibrolamellar carcinomas are a unique type of liver carcinoma that arise in non-cirrhotic livers of young individuals. Despite their distinctive appearance, recent studies have demonstrated a lack of consistency in how fibrolamellar carcinomas are diagnosed by pathologists. As a potential aide in diagnosis, we investigated the staining properties of CD68. The CD68 gene encodes for a transmembrane glycoprotein located within lysosomes and endosomes. Macrophages as well as other cell types rich in lysosomes/endosomes are CD68 positive. Cases of fibrolamellar carcinoma were collected from four academic centers. Control groups included hepatocellular carcinomas arising in both non-cirrhotic livers and cirrhotic livers. A group of cholangiocarcinomas were also stained. CD68 immunostaining was scored for both intensity and distribution on a scale of 0 to 3+. Twenty-three primary fibrolamellar carcinomas and 9 metastases (total of 24 individuals) were immunostained and showed a distinctive granular, dot-like or stippled pattern of cytoplasmic staining in nearly all cases (31/32), with a median distribution and intensity score of 3+. In control hepatocellular carcinomas that arose in non-cirrhotic livers, 10/39 showed CD68 staining with a median distribution and intensity score of 2+. In hepatocellular carcinomas arising in cirrhotic livers, 3/27 cases showed CD68 positivity, all with stippled dot-like cytoplasmic staining similar to that of fibrolamellar carcinomas. All five cholangiocarcinomas were negative. Overall, CD68 positivity was strongly associated with fibrolamellar carcinomas, P<0.001 and had a sensitivity of 96%, a specificity of 80%, and a negative predictive value of 98%. In sum, tumor positivity for CD68 staining was highly sensitive for fibrolamellar carcinoma and a lack of CD68 staining should suggest caution in making a diagnosis of fibrolamellar carcinoma.
Sterrenberg, JN, GL Blatch and AL Edkins 2011Human DNAJ in cancer and stem cells. Cancer Lett 312(2): 129-142. The heat shock protein 40kDa (HSP40/DNAJ) co-chaperones constitute the largest and most diverse sub-group of the heat shock protein (HSP) family. DNAJ are widely accepted as regulators of HSP70 function, but also have roles as co-chaperones for the HSP90 chaperone machine, and a growing number of biological functions that may be independent of either of these chaperones. The DNAJ proteins are differentially expressed in human tissues and demonstrate the capacity to function to both promote and suppress cancer development by acting as chaperones for tumour suppressors or oncoproteins. We review the current literature on the function and expression of DNAJ in cancer, stem cells and cancer stem cells. Combining data from gene expression, proteomics and studies in other systems, we propose that DNAJ will be key regulators of cancer, stem cell and possibly cancer stem cell function. The diversity of DNAJ and their assorted roles in a range of biological functions means that selected DNAJ, provided there is limited redundancy and that a specific link to malignancy can be established, may yet provide an attractive target for specific and selective drug design for the development of anti-cancer treatments.
Tang, KH, S Ma, TK Lee, YP Chan, PS Kwan, CM Tong, IO Ng, K Man, KF To, PB Lai, CM Lo, XY Guan and KW Chan 2011CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth and self-renewal through neurotensin / IL-8 / CXCL1 signaling. Hepatology. A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133(+) liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133(+) cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133(+) liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis and initiate tumors. In further support of these observations, IL-8 repression in CD133(+) liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133(+) liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the MAPK pathway. Enhanced IL-8 secretion by CD133(+) liver TICs can in turn activate an IL-8-dependent feedback loop that signals through MAPK pathway. Further to its role as a liver TIC marker, CD133 also plays a functional part in regulating tumorigenesis of liver TICs via regulating NTS, IL-8, CXCL1 and MAPK signaling. CD133(+) liver TICs promote angiogenesis, tumorigenesis and self-renewal through NTS-induced activation of the IL-8 signaling cascade. (HEPATOLOGY 2011.).
Taylor, SL and S Haque 2011Hepatobiliary pathology. Curr Opin Gastroenterol 27(3): 248-255.PURPOSE OF REVIEW: Recent studies pertaining to the histopathology of the liver and biliary tract are reviewed. RECENT FINDINGS: Several studies are reviewed which describe the histologic features and clinical behavior of 'plasma cell hepatitis' in the posttransplant setting. Cytokeratin 7, EMA, and CD68 were found to be useful immunohistochemical stains in fibrolamellar hepatocellular carcinoma and may aid in the distinction between this variant and classic hepatocellular carcinoma. Arginase-1, another immunohistochemical stain, was found to have improved sensitivity over HepPar-1 in the diagnosis of classic hepatocellular carcinoma. Metabolic syndrome is common in children with nonalcoholic fatty liver disease and may be an indicator of more severe disease activity and fibrosis. Histologic features were described that may aid in the distinction between the steroid-responsive IgG4-associated cholangitis and the steroid-nonresponsive primary sclerosing cholangitis. In addition, immunohistochemical stains for IgM and IgG may be helpful in distinguishing between autoimmune liver diseases, with primary biliary cirrhosis and its antimitochondrial-negative variant, autoimmune cholangitis, being the two autoimmune liver diseases with a predominance of IgM-positive plasma cells. SUMMARY: Several informative studies pertaining to hepatobiliary pathology were published this year, with topics including posttransplant plasma cell hepatitis, familial hemophagocytic lymphohistiocytosis, pediatric nonalcoholic fatty liver disease, and the use of immunohistochemical stains specific for various immunoglobulin subtypes.
Ward, SC and S Waxman 2011Fibrolamellar carcinoma: a review with focus on genetics and comparison to other malignant primary liver tumors. Semin Liver Dis 31(1): 61-70. Fibrolamellar carcinoma is a rare primary malignant liver neoplasm that usually affects adolescents and young adults with no underlying liver disease. Morphologically, the tumor cells resemble oncocytic hepatocytes arranged in cords with a stroma of lamellated collagen fibers. Immunohistochemical studies have found that fibrolamellar carcinomas express markers associated with both biliary (CK7 and epithelial membrane antigen) and hepatocytic (heppar-1and glypican-3) differentiation, as well as markers associated with hepatic progenitor cells (CK19 and EpCAM) and stem cells (CD133 and CD44). Genetic studies show fewer alterations compared with classic hepatocellular carcinoma. Pooled data from comparative genomic hybridization studies show that fibrolamellar carcinomas have fewer and less frequent genomic alterations when compared with classic hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma. Of the alterations seen in fibrolamellar carcinoma, the most frequent are gains in 1q and 8q (also frequently seen in other hepatic tumors) and loss of 18q. Fibrolamellar carcinoma also has less frequent methylation of tumor suppressor promoters compared with hepatocellular carcinoma and minimal alterations in mitochondrial DNA. Fibrolamellar carcinoma is associated with better survival than hepatocellular carcinoma and cholangiocarcinoma, presumably due to the young age of the patients and the lack of cirrhosis. These features make more aggressive surgical therapy possible. There is currently very little information on the effectiveness of chemotherapy for fibrolamellar carcinoma.
Watahiki, A, Y Wang, J Morris, K Dennis, HM O'Dwyer, M Gleave, PW Gout and Y Wang 2011MicroRNAs associated with metastatic prostate cancer. PLoS ONE 6(9): e24950. OBJECTIVE: Metastasis is the most common cause of death of prostate cancer patients. Identification of specific metastasis biomarkers and novel therapeutic targets is considered essential for improved prognosis and management of the disease. MicroRNAs (miRNAs) form a class of non-coding small RNA molecules considered to be key regulators of gene expression. Their dysregulation has been shown to play a role in cancer onset, progression and metastasis, and miRNAs represent a promising new class of cancer biomarkers. The objective of this study was to identify down- and up-regulated miRNAs in prostate cancer that could provide potential biomarkers and/or therapeutic targets for prostate cancer metastasis. METHODS: Next generation sequencing technology was applied to identify differentially expressed miRNAs in a transplantable metastatic versus a non-metastatic prostate cancer xenograft line, both derived from one patient's primary cancer. The xenografts were developed via subrenal capsule grafting of cancer tissue into NOD/SCID mice, a methodology that tends to preserve properties of the original cancers (e.g., tumor heterogeneity, genetic profiles). RESULTS: Differentially expressed known miRNAs, isomiRs and 36 novel miRNAs were identified. A number of these miRNAs (21/104) have previously been reported to show similar down- or up-regulation in prostate cancers relative to normal prostate tissue, and some of them (e.g., miR-16, miR-34a, miR-126*, miR-145, miR-205) have been linked to prostate cancer metastasis, supporting the validity of the analytical approach. CONCLUSIONS: The use of metastatic and non-metastatic prostate cancer subrenal capsule xenografts derived from one patient's cancer makes it likely that the differentially expressed miRNAs identified in this study include potential biomarkers and/or therapeutic targets for human prostate cancer metastasis.
Abdul-Al, HM, G Wang, HR Makhlouf and ZD Goodman 2010Fibrolamellar hepatocellular carcinoma: an immunohistochemical comparison with conventional hepatocellular carcinoma. Int J Surg Pathol 18(5): 313-318. The fibrolamellar variant of hepatocellular carcinoma (FLC) differs from conventional hepatocellular carcinoma (HCC) in some clinical and pathological features. The authors investigated possible differences in reactivity between FLCs and HCCs using glypican-3 (GPC3), an oncofetal protein, and survivin, an antiapoptotic protein. They also compared staining of FLC and HCC with antibodies to cytokeratins 7 (CK7) and 19 (CK19) and CD34. GPC3 was significantly more often and more strongly expressed in HCCs (72%) than in FLCs (17%). Survivin nuclear translocation in tumor cells did not differ between HCCs (10%) and FLCs (9%). There was more abundant expression of CK7 in FLCs (92%) than in HCCs (33%), whereas CK19 was more often found in HCCs (20%) than in FLCs (5%). All tumors had CD34-positive sinusoids. This study shows that FLCs and HCCs differ in the expression of GPC3, CK7, and CK19 and that there is a lack of difference as regards survivin and CD34.
Bosman, FT, F Carneiro, RH Hruban and ND Theise 2010WHO Classification of Tumors of the Digestive System. Lyon, France, International Agency for Research on Cancer.
Dhingra, S, W Li, D Tan, M Zenali, H Zhang and RE Brown 2010Cell cycle biology of fibrolamellar hepatocellular carcinoma. Int J Clin Exp Pathol 3(8): 792-797. CONTEXT: fibrolamellar hepatocellular carcinoma (FLHCC) has a better prognosis than conventional hepatocellular carcinoma. Nevertheless, FLHCC has a propensity to recur with limited responsiveness to chemotherapy. OBJECTIVE: The purpose of this study was to provide insight into the cell cycle biology of FLHCC, as it relates to FLHCC's relatively indolent nature and lack of chemoresponsiveness. DESIGN: in seven cases of FLHCC, we assessed: 1. immunoexpression of protein analytes indicating cell cycle progression including Ki-67 (G1, S, G2 and M phases) and S-phase kinase-associated protein (Skp) 2 along with the mitotic index (MI); 2.immunoreactivity for cyclin-dependent kinase inhibitors of cell cycle progression from G1 to S phase, p27Kip1 and p16INK4. RESULTS: the mean percentage of Ki-67 nuclear positivity in neoplastic hepatocytes ranged from 1.0% to 29.7%. Nuclear Skp2 immunoexpression was not observed in any of the cases. The mitotic index was very low (0-1 mitotic figure / 10 high-power fields). All cases showed moderate to strong nuclear p16INK4 positivity (diffuse in five and focal in two). Contras-tively, the adjacent non-neoplastic hepatocytes expressed only mild (2 cases) to no (3 cases) p16INK4. CONCLUSION: our analysis has revealed that cell cycle arrest in FLHCC occurs in G0G1 phase and is associated with overexpression of the cell cycle regulator, p16INK4 in tumoral cell nuclei compared with non-neoplastic hepatocytes. In conjunction with our previous immunohistochemical demonstration of a constitutively activated nuclear factor (NF)-kappaB pathway and stemness characteristics of FLHCC with limited differentiation, this cell cycle arrest elucidates the biology of FLHCC's indolent nature and relative chemoresistance.
Trankenschuh, W, F Puls, M Christgen, C Albat, A Heim, J Poczkaj, P Fleming, H Kreipe and U Lehmann 2010Frequent and distinct aberrations of DNA methylation patterns in fibrolamellar carcinoma of the liver. PLoS ONE 5(10): e13688. BACKGROUND: Gene silencing due to aberrant DNA methylation is a frequent event in hepatocellular carcinoma (HCC) and also in hepatocellular adenoma (HCA). However, very little is known about epigenetic defects in fibrolamellar carcinoma (FLC), a rare variant of hepatocellular carcinoma that displays distinct clinical and morphological features. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the methylation status of the APC, CDH1, cyclinD2, GSTpi1, hsa-mir-9-1, hsa-mir-9-2, and RASSF1A gene in a series of 15 FLC and paired normal liver tissue specimens by quantitative high-resolution pyrosequencing. Results were compared with common HCC arising in non-cirrhotic liver (n = 10). Frequent aberrant hypermethylation was found for the cyclinD2 (19%) and the RASSF1A (38%) gene as well as for the microRNA genes mir-9-1 (13%) and mir-9-2 (33%). In contrast to common HCC the APC and CDH1 (E-cadherin) genes were found devoid of any DNA methylation in FLC, whereas the GSTpi1 gene showed comparable DNA methylation in tumor and surrounding tissue at a moderate level. Changes in global DNA methylation level were measured by analyzing methylation status of the highly repetitive LINE-1 sequences. No evidence of global hypomethylation could be found in FLCs, whereas HCCs without cirrhosis showed a significant reduction in global methylation level as described previously. CONCLUSIONS: FLCs display frequent and distinct gene-specific hypermethylation in the absence of significant global hypomethylation indicating that these two epigenetic aberrations are induced by different pathways and that full-blown malignancy can develop in the absence of global loss of DNA methylation. Only quantitative DNA methylation detection methodology was able to identify these differences.
Vincent, J, G Mignot, F Chalmin, S Ladoire, M Bruchard, A Chevriaux, F Martin, L Apetoh, C Rebe and F Ghiringhelli 20105-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70(8): 3052-3061. Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumor bed during tumor growth. They contribute to the immune tolerance of cancer notably by inhibiting the function of CD8(+) T cells. Thus, their elimination may hamper tumor growth by enhancing antitumor T-cell functions. We have previously reported that some anticancer agents relied on T cell-dependent anticancer responses to achieve maximal efficacy. However, the effect of anticancer agents on MDSC has remained largely unexplored. In this study, we observed that gemcitabine and 5-fluorouracil (5FU) were selectively cytotoxic on MDSC. In vivo, the treatment of tumor-bearing mice with 5FU led to a major decrease in the number of MDSC in the spleens and tumor beds of animals whereas no significant effect on T cells, natural killer cells, dendritic cells, or B cells was noted. Interestingly, 5FU showed a stronger efficacy over gemcitabine to deplete MDSC and selectively induced MDSC apoptotic cell death in vitro and in vivo. The elimination of MDSC by 5FU increased IFN-gamma production by tumor-specific CD8(+) T cells infiltrating the tumor and promoted T cell-dependent antitumor responses in vivo. Altogether, these findings suggest that the antitumor effect of 5FU is mediated, at least in part, by its selective cytotoxic action on MDSC.
Vivekanandan, P, H Daniel, MM Yeh and M Torbenson 2010Mitochondrial mutations in hepatocellular carcinomas and fibrolamellar carcinomas. Mod Pathol 23(6): 790-798. Mitochondrial mutations are well documented in hepatocellular carcinoma, but their role in carcinogenesis remains unclear. To clarify their significance, a comprehensive analysis was performed of hepatocellular carcinomas (N=24), including quantifying the total mitochondrial DNA levels, quantifying the levels of mitochondrial DNA with the common deletion, and complete sequencing of the mitochondrial control region. In addition, these studies were expanded and reinforced by analysis of fibrolamellar carcinomas (N=15), a unique type of liver carcinoma that has increased numbers of mitochondria on electron microscopy. Overall, approximately 50% of hepatocellular carcinomas had lower levels of total mitochondrial DNA than paired non-neoplastic tissues. Interestingly, despite their increased numbers of mitochondria, primary fibrolamellar carcinomas had lower levels of total mitochondrial DNA. In contrast, metastatic fibrolamellar carcinomas had greatly increased mitochondrial DNA levels. Overall, deletions in the control region were associated with lower total DNA levels in typical hepatocellular carcinoma, but somatic single base pair mutations were not. In fact, almost all single base pair mutations were either reversions to the wild-type sequence or known population polymorphisms, strongly suggesting they are not directly oncogenic. Complete sequencing of the entire mitochondrial genome in fibrolamellar carcinomas identified several somatic mutations, but no consistent pattern of mutations was found. Overall, the levels of the common deletion were highest in tissues with lower total mitochondrial DNA. In conclusion, control region deletions, but not somatic mutations, may influence total DNA copy numbers. Somatic control region mutations in hepatocellular carcinoma are not directly oncogenic but instead may be adaptive.
Ward, SC, J Huang, SK Tickoo, SN Thung, M Ladanyi and DS Klimstra 2010Fibrolamellar carcinoma of the liver exhibits immunohistochemical evidence of both hepatocyte and bile duct differentiation. Mod Pathol 23(9): 1180-1190. Fibrolamellar carcinoma is a rare malignant primary liver neoplasm with characteristic histological features that typically arises in young patients without viral hepatitis or cirrhosis. Previous studies on this entity have been limited by small numbers of patients. In contrast to classical hepatocellular carcinoma, individual cases of fibrolamellar carcinoma have been reported to express cytokeratin 7. In addition, ultrastructural and serological studies have suggested that fibrolamellar carcinoma may show neuroendocrine differentiation. The cellular differentiation of fibrolamellar carcinoma has not been studied and little is reported about its immunohistochemical profile. We studied 26 cases of fibrolamellar carcinoma and 62 cases of classical hepatocellular carcinoma by immunohistochemistry for HepPar1, glypican-3, pCEA, CD10, alpha-fetoprotein, cytokeratin 20, neuroendocrine markers, and surrogate markers for biliary differentiation (cytokeratin 7, cytokeratin 19, epithelial membrane antigen, EpCAM, mCEA, B72.3, and CA19.9). In situ hybridization for albumin mRNA was also performed. Tumor cells of fibrolamellar carcinoma and hepatocellular carcinoma showed positive signals for albumin mRNA by in situ hybridization in all cases. Both tumor types stained uniformly positively with HepPar1 and most showed a canalicular staining pattern for pCEA, confirming their hepatocellular differentiation. In addition, 39% of hepatocellular carcinoma cases and 59% of fibrolamellar carcinoma cases were positive for glypican-3. All 22 fibrolamellar carcinoma cases tested showed positive staining for cytokeratin 7 and epithelial membrane antigen, whereas less than one-third of hepatocellular carcinoma cases were positive for these markers (P<0.0001). Further, 36% of fibrolamellar carcinoma cases showed staining for B72.3, cytokeratin 19, EpCAM, or mCEA. Minimal evidence of neuroendocrine differentiation in either tumor was found with any of the usual immunohistochemical markers used for this purpose. Therefore, cytokeratin 7 and epithelial membrane antigen may be useful to differentiate between fibrolamellar carcinoma and hepatocellular carcinoma. On the basis of immunohistochemistry, fibrolamellar carcinoma seems to show both hepatocellular and bile duct differentiation.
Zenali, MJ, D Tan, W Li, S Dhingra and RE Brown 2010Stemness characteristics of fibrolamellar hepatocellular carcinoma: immunohistochemical analysis with comparisons to conventional hepatocellular carcinoma. Ann Clin Lab Sci 40(2): 126-134. The involvement of cancer stem cells (CSC) in tumorigenesis has been studied in several malignancies, but their presence in fibrolamellar hepatocellular carcinoma (FLHCC) has not previously been evaluated. General characteristics of "stemness" include the expression of putative stem cell antigens, reduced cell cycle progression, and limited functional differentiation or dedifferentiation under the influence of the microenvironment. Immunohistochemical probes applied to 8 archival cases of FLHCC vis-a-vis contiguous non-neoplastic parenchyma, which was present in 5 cases, revealed such stemness characteristics by showing: (a) stem cell antigens, with moderate to intense expression of CD133 in the cytoplasm (6 of 8 FLHCC cases and comprising >40% of the tumoral areas) and of CD44 on the plasmalemmal aspect (7 of 8 FLHCC cases and comprising 50 to 95% of the tumor cells), vs foci of such overexpressions in only 1 of 5 of the contiguous liver parenchyma (p = 0.053 and p = 0.015, respectively); (b) limited G1 to S phase progression ( <1 % of tumor cells with nuclear S phase kinase-associated protein [Skp]2 expression); and (c) dedifferentiation or reduced functional differentiation in the form of minimal to absent expression of a differentiation-associated marker, peroxisomal proliferator-activator receptor (PPAR)-gamma in tumoral nuclei and loss of plasmalemmal expression of beta-catenin in 6 of 8 FLHCC cases vs expression of these proteins in the non-neoplastic, differentiated hepatocytes in 5 of 5 and 4 of 5 cases, respectively, in contiguous liver parenchyma (p <0.01 and p = 0.053, respectively). In contrast, only 1 of 11 cases of well-differentiated, conventional hepatocellular carcinoma (HCC) showed mild to moderate expression of CD133 in the cytoplasm, but with the majority (8 of 11) showing occasional nuclear expression. Similarly, only 3 of 11 cases of conventional HCC expressed plasmalemmal CD44. Notably, 11 of 11 cases of conventional HCC expressed beta-catenin on the plasmalemmal aspect of the tumor cells, and 3 of 11 showed nuclear translocation. These findings in conventional HCC were significantly different from those in FLHCC (p = 0.003, 0.009, and 0.0005, respectively). This study provides evidence of stemness in FLHCC and discusses the implications of stemness in the histogenesis of FLHCC vs conventional, well-differentiated HCC.
Bhaijee, F, ML Locketz and JE Krige 2009Fibrolamellar hepatocellular carcinoma at a tertiary centre in South Africa: a case series. S Afr J Surg 47(4): 108-111. BACKGROUND: Fibrolamellar carcinoma (FLC) is an uncommon malignant tumour of hepatocyte origin that differs from hepatocellular carcinoma (HCC) in aetiology, demographics, condition of the affected liver, and tumour markers. Controversy exists whether FLC demonstrates a more favourable prognosis than typical HCC. A review of existing literature reveals a dearth of FLC data from the African continent. METHODS: We utilised the prospective liver resection database at Groote Schuur Hospital to identify all patients who underwent surgery for FLC between 1990 and 2008. RESULTS: Seven patients (median age 21 years, range 19 - 42, 5 men, 2 women) underwent surgery for FLC. No patient had underlying liver disease or an elevated alpha fetoprotein (AFP) at either initial presentation or recurrence. Six patients had a solitary tumour at diagnosis (mean largest diameter = 12cm), and underwent left hepatectomy (N=2), right hepatectomy (N=1), extended right hepatectomy (N=1), right hepatectomy (N=1), extended right hepatectomy (N=1), and segmentectomies (N=2). Three patients underwent a portal lymphadenectomy for regional lymphatic tumour involvement. One patient with advanced extrahepatic portal nodal metastasis was unresectable. No peri-operative deaths occurred. Recurrence occurred post resection in all 6 patients. Median overall survival was 60 months, and overall 5-year survival was 4 out of 7 (57%). Post-resection survival (N=6) was 61 months, with a 5-year survival rate of 4 out of 6 (67%). The patient with unresectable disease survived 38 months after tumour embolisation with Lipiodol. CONCLUSION: Our series suggests that despite (i) a high resection rate of solitary lesions with clear tumour resection margins, and (ii) absence of underlying liver disease, FLC has a high recurrence rate with an ultimately poor clinical outcome. These findings concur with recent international experience of FLC. experience of FLC.
Cieply, B, G Zeng, T Proverbs-Singh, DA Geller and SP Monga 2009Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology 49(3): 821-831. UNLABELLED: Wnt/beta-catenin signaling plays an important role in liver development and regeneration. Its aberrant activation, however, is observed in a subset of primary hepatocellular cancers (HCCs). In the current study, we compare and contrast the tumor characteristics of HCC in the presence or absence of mutations in the beta-catenin gene (CTNNB1). Frozen HCCs (n = 32), including five fibrolamellar (FL) variants, and control livers (n = 3) from Health Sciences Tissue Bank and Department of Surgery at the University of Pittsburgh Medical Center, were examined for mutations in CTNNB1, protein levels of beta-catenin, tyrosine-654-phosphorylated-beta-catenin (Y654-beta-catenin), and glutamine synthetase (GS). Missense mutations in the exon-3 of CTNNB1were identified in 9/32 HCCs. Total beta-catenin levels were higher than controls in most tumors; however, GS was exclusively increased in HCCs with mutations. Phenotypically, greater percentages of mutated HCCs showed macrovascular and microvascular invasion. Also, the tumor size was greater than double in mutated HCCs. High levels of total beta-catenin protein were observed in multinodular tumors independent of beta-catenin mutations. In addition, significant cases with mutations showed absence of cirrhosis. Finally, the highest levels of Y654-beta-catenin were exclusively observed in fibrolamellar (FL)-HCC cases. CONCLUSION: Thus, HCCs that harbor missense mutations in exon-3 of CTNNB1 exhibit, histologically, a more aggressive phenotype. Also, CTNNB1 mutations might lead to HCC in the absence of cirrhosis. Finally, FL-HCC cases display a unique up-regulation of tyrosine-phosphorylated-beta-catenin, suggesting robust receptor tyrosine kinase signaling in this tumor type.
Gulati, G and RK Saran 2009Fine needle aspiration cytology of fibrolamellar hepatocellular carcinoma: recognizing the oncocytic hepatocyte. Indian J Pathol Microbiol 52(2): 288-289.
Li, W, D Tan, MJ Zenali and RE Brown 2009Constitutive activation of nuclear factor-kappa B (NF-kB) signaling pathway in fibrolamellar hepatocellular carcinoma. Int J Clin Exp Pathol 3(3): 238-243. Fibrolamellar hepatocellular carcinoma (FLHCC) is an aggressive neoplasm due to high frequency of recurrence after surgical resection and resistance to chemotherapy and radiation therapy. Activation of transcription factor NF-kB signaling pathway has been recognized for involvement in progression of various malignant neoplasms. The role of NF-kB pathway in FLHCC has not been studied to date. Formalin-fixed, paraffin-embedded tissue sections of 8 FLHCC, 10 normal liver tissues (NLT) were evaluated immunohistochemically for the expression of p-NF-kBp65 using phosphospecific antibody directed against phosphorylated (p)-NF-kBp65 (Ser 536). The level of p-NF-kBp65 (Ser 536) expression was categorized into four grades: 0 (background), 1+ (weak), 2+ (moderate), or 3+ (strong) based on intensity of intranuclear staining, and was further assessed using two scales: high expression (2+ or 3+) and low expression (0 or 1+). Only high expression of p-NF-kBp65 (Ser 536) in cells with nuclear translocation was considered as constitutive NF-kB activation. High expression of p-NF-kBp65 (Ser 536) was found in 88 % (7/8) of FLHCC tissue. In contrast, only 10 % (1/10) of NLT showed high expression for p-NF-kBp65 (Ser 536). The differences in p-NF-kBp65 nuclear expression between FLHCC tissue and NLT were significant (P < 0.001). There was no significant correlation between the expression of intranuclear p-NF-kBp65 and the stage of FLHCC. Constitutive NF-kB activation was observed in FLHCC. The findings suggest that NF-kB activation is involved in the tumorigenesis of FLHCC and may represent novel targets for therapeutic intervention to FLHCC.
Malouf, G, B Falissard, D Azoulay, F Callea, LD Ferrell, ZD Goodman, Y Hayashi, HC Hsu, SG Hubscher, M Kojiro, IO Ng, AC Paterson, M Reynes, ES Zafrani and JF Emile 2009Is histological diagnosis of primary liver carcinomas with fibrous stroma reproducible among experts? J Clin Pathol 62(6): 519-524. AIMS: In the era of targeted therapeutics, histological typing of hepatobiliary carcinomas has major clinical implications. Little is known about the reproducibility of the pathological diagnosis of primary liver carcinomas. Therefore, this study aimed to evaluate the worldwide variation in the pathological expert diagnoses of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis. METHODS: A single set of slides was selected from 25 tumours, and this set was reviewed independently by 12 pathologists who have worldwide expertise in liver tumours. Reproducibility of the diagnoses was evaluated by Light's kappa, and diagnoses were clustered by multidimensional scaling. Immunohistochemistry was performed after histological review. RESULTS: The interobserver reproducibility for diagnosis of hepatocellular carcinoma subtypes and cholangiocarcinomas was poor (kappa 0.23-0.52), even when the experts considered that the diagnosis required no additional stains or clinical information. Interestingly, multidimensional scaling revealed three main clusters of tumours: hepatocellular carcinoma with no other specifications (n = 13), fibrolamellar hepatocellular carcinoma (n = 3) and cholangiocarcinoma (n = 9). Using immunohistochemistry, these histological clusters correlated with expression of anti-hepatocyte and anti-cytokeratin 19 (p<0.001). CONCLUSIONS: The results demonstrate the poor reproducibility among experts of the pathological diagnosis of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis, and highlight that the systematic use of immunohistochemistry may improve the diagnostic accuracy.
Maniaci, V, BR Davidson, K Rolles, AP Dhillon, A Hackshaw, RH Begent and T Meyer 2009Fibrolamellar hepatocellular carcinoma: prolonged survival with multimodality therapy. Eur J Surg Oncol 35(6): 617-621. AIM: We report the clinical outcome for a series of ten patients with fibrolamellar hepatocellular treated with resection followed by close surveillance and aggressive management of relapse. METHODS: The case notes for all patients treated at this institution since 1982 were reviewed and details of initial stage and management were extracted along with investigations and treatment of relapse. Time to relapse, overall survival and post-relapse survival were analysed. RESULTS: Relapse occurred in all ten cases at a median of 2.2 (95% CI 0.9-2.7) years but, with a combination of re-resection, systemic chemotherapy and radiotherapy, the overall median survival was 9.3 (95% CI 3.0-18.5) years. One patient was disease free eight years after two resections for recurrent disease. Two of nine patients had a partial response to cisplatin and fluorouracil while three had stable disease. FDG-PET was positive for recurrence in three of four cases of relapse, and in one case detected recurrence in advance of CT. CONCLUSION: The early detection of relapse combined with multimodality therapy results in prolonged survival. Further improvements in systemic therapy are required to improve the prognosis in this disease.
Sethi, S, N Tageja, J Singh, H Arabi, M Dave, A Badheka and S Revankar 2009Hyperammonemic encephalopathy: a rare presentation of fibrolamellar hepatocellular carcinoma. Am J Med Sci 338(6): 522-524. Fibrolamellar carcinoma (FLC) is a rare malignant hepatocellular tumor of unknown etiology, arising almost exclusively from noninfected, noncirrhotic liver of young adults. FLC has traditionally been considered to have better survival than hepatocellular carcinoma; however, this notion might be highly erroneous. Patients with metastatic disease at presentation have a dismal prognosis with 5-year survival of only 15%. We describe a case of highly aggressive metastatic FLC that presented as hyperammonemic encephalopathy, which has never been previously reported in the literature.
Thirabanjasak, D, D Sosothikul, A Mahayosnond and PS Thorner 2009Fibrolamellar carcinoma presenting as a pancreatic mass: case report and review of the literature. J Pediatr Hematol Oncol 31(5): 370-372. Fibrolamellar carcinoma is a subtype of hepatocellular carcinoma with distinct clinicopathologic features including presentation at a younger age. Although early studies suggested that fibrolamellar carcinoma had a better prognosis than conventional hepatocellular carcinoma, most later studies have found no difference. Patients often have lymph node metastases at presentation in addition to the hepatic primary. We describe an unusual case in a Thai boy who presented with a pancreatic mass that was clinically suspected to be a primary pancreatic tumor, but on biopsy was found to be metastatic fibrolamellar carcinoma. To our knowledge, this manner of presentation has not been previously reported for fibrolamellar carcinoma, nor has metastatic spread to the pancreas.
Vivekanandan, P, ST Micchelli and M Torbenson 2009Anterior gradient-2 is overexpressed by fibrolamellar carcinomas. Hum Pathol 40(3): 293-299. Anterior gradient-2 expression is critical in normal embryonic development. Aberrant expression of anterior gradient-2 in adult tissues has been linked to breast, prostate, esophageal, and pancreatic carcinoma. To define the role of anterior gradient-2 in primary hepatocellular neoplasms, we used tissue microarrays and examined protein expression in typical hepatocellular carcinomas (n = 44), fibrolamellar carcinomas (n = 12), and hepatic adenomas (n = 9). In nonneoplastic liver tissues, anterior gradient-2 was expressed in the septal-sized bile ducts and weakly in zone 3 hepatocytes in 11 (18%) of 61 cases. In tumors, anterior gradient-2 was overexpressed by only 1 (2%) of 44 hepatocellular carcinomas. In contrast, 6 (75%) of 8 fibrolamellar and 3 (75%) of 4 metastatic fibrolamellar carcinomas were positive. All 9 hepatic adenomas were negative. Further analysis of mRNA in fibrolamellar carcinomas identified 2 novel splice variants, but expression levels were very low. Sequencing of the anterior gradient-2 gene in fibrolamellar carcinomas identified several polymorphisms (refSNP Ids: rs6842, rs8071, rs1051905) but no mutations. In conclusion, anterior gradient-2 is overexpressed in the majority of fibrolamellar carcinomas but is only rarely overexpressed in hepatocellular carcinomas.
Fujii, T, Y Zen, K Harada, H Niwa, S Masuda, Y Kaizaki, K Watanabe, A Kawashima and Y Nakanuma 2008Participation of liver cancer stem/progenitor cells in tumorigenesis of scirrhous hepatocellular carcinoma--human and cell culture study. Hum Pathol 39(8): 1185-1196. Cancer stem cells reportedly participate in the tumorigenesis of some neoplasms. Scirrhous hepatocellular carcinoma is a variant of hepatocellular carcinoma with abundant fibrous stroma. Herein, we clinicopathologically examined scirrhous (29 cases) and conventional (50 cases) hepatocellular carcinoma with reference to cancer stem cells. Scirrhous hepatocellular carcinoma was classifiable into 3 types based on small neoplastic cells at the periphery of tumor cell nests. Of 29 cases of scirrhous hepatocellular carcinoma, 21 contained small neoplastic cells. Immunohistochemically, those cells were positive for cytokeratin 7 and ATP-binding cassette transporter G2. In 11 cases, those small tumor cells were also positive for cytokeratin 19, neural cell adhesion molecule, and epithelial cell adhesion molecule (type 1), whereas 10 cases did not show such additional expression (type 2). The remaining 8 tumors did not contain small tumor cells with stem cell features (type 3). In the central parts of tumor nests, carcinoma cells got hepatocellular markers and lost expression of neural cell adhesion molecule, and epithelial cell adhesion molecule, suggesting hepatocellular maturation. Transforming growth factor beta1, a fibrogenic cytokine, was also detected in those small tumor cells. Culture cells extracted as "side population" from hepatocellular carcinoma cell lines (HuH7 and PLC5) expressed more intensely cytokeratins 7 and 19, neural cell adhesion molecule, epithelial cell adhesion molecule, and transforming growth factor beta1 than did non-side population cells. Small tumor cells with stem cell features in scirrhous hepatocellular carcinoma may correspond to side population of culture cells and might be involved in fibrogenesis of scirrhous hepatocellular carcinoma.
Moore, SW, A Davidson, GP Hadley, M Kruger, J Poole, D Stones, L Wainwright and G Wessels 2008Malignant liver tumors in South African children: a national audit. World J Surg 32(7): 1389-1395. BACKGROUND: Malignant liver tumors (mostly hepatoblastoma [HB] and hepatocellular carcinoma [HCC]) are uncommon, representing 0.5%-2% of childhood malignancies worldwide. The pattern of liver tumors appears to differ in Southern Africa as a result of infectious factors (e.g., hepatitis B/retroviral disease (HIV). This study aimed to assess recent changes in the prevalence and surgical management of liver tumors in South African children. METHODS: Data were obtained from the tumor registry and pediatric oncology units in South African hospitals to audit and review the epidemiology, treatment, and outcome of malignant hepatic tumors in South African children. RESULTS: Malignant primary hepatic tumors were reported in 274 children (ages 0-14 years) from 1988 through June 2006. Of these 134 (48%) had HB; 77 (27%) had HCC (9 [3%] fibrolamellar subtype); 38 (13%), vascular tumors; and 17 (6%), liver sarcomas. In a further 8 patients (3%) other tumors included lymphoma and endodermal sinus tumor. Vascular tumors included hemangioendotheliomas (12), and there were 5 malignant tumors in children with HIV, including 1 angiosarcoma and 13 Kaposi sarcoma-like tumors. Hepatoblastoma occurred at a mean age of 1.47 years, and none were encountered in patients > 4 years of age. Hepatocellular carcinoma mostly occurred in the older patients (mean age: 10.48 years), but 6% presented in patients < 8 years of age (10 months, 2, 2.6, 5, 5, and 6 years). Hepatic sarcoma occurred at a mean age of 7.66 years and had a female predominance (M:F ratio: 0.4). The relative HCC prevalence (male predominant: hepatitis B related) was reflected in the low HB:HCC (1.67) ratio. However, a significant decrease in HCC was attributed to the effect of hepatitis B inoculation. There appeared to be an increase in the incidence of vascular tumors, presumably the result of an increase in Kaposi-like sarcoma in retrovirus-positive patients. The surgical resection rate was low because most patients presented late, with advanced disease. Survival was 11% and 52% for HB and HCC, respectively, and was related to chemotherapeutic response and complete surgical resection. CONCLUSIONS: Liver tumors appear to have a different epidemiological pattern in South Africa. The observed increased HCC prevalence appears to be decreasing with hepatitis B vaccination. Retroviral disease does not yet appear to have a major influence on the distribution of liver tumors in South Africa, although it possibly affects the vascular tumor prevalence.
Vivekanandan, P and M Torbenson 2008Epigenetic instability is rare in fibrolamellar carcinomas but common in viral-associated hepatocellular carcinomas. Mod Pathol 21(6): 670-675. Fibrolamellar carcinomas have a unique predilection for younger individuals and arise in livers without recognizable liver disease. In contrast to typical hepatocellular carcinomas, fibrolamellar carcinomas show few chromosomal changes and lack mutation in key genes such as TP53 and CTNNB1. Epigenetic instability, manifesting as methylation of important tumor suppressor gene promoters, has not been investigated in fibrolamellar carcinomas. Thus, the methylation status of 11 tumor suppressor gene promoters was investigated using methylation-specific PCR: RASSF1, CDH1, CDKN2B, HPP1, CDKN2A, GSTP1, P16, RARA, FLJ13081, SOCS1, and TP53. Nine fibrolamellar carcinomas were studied including primary tumors (N=5) and metastatic deposits (N=4) along with control groups of typical hepatocellular carcinoma arising in livers with (N=21) and without cirrhosis (N=10). In fibrolamellar carcinomas, RASSF1A and CDH1 (e-cadherin) were the most commonly methylated genes with 80-100% of tumors methylated. However, overall fibrolamellar carcinomas showed low levels of methylation with no differences between fibrolamellar carcinomas and their paired normal livers. However, fibrolamellar carcinomas showed significantly less methylation than hepatocellular carcinomas that arose in the background of viral cirrhosis. Overall, methylation was most strongly linked to viral cirrhosis. In conclusion, fibrolamellar carcinoma shows low levels of methylation. In contrast, higher levels of promoter methylation are associated with hepatocellular carcinomas that arise in the setting of viral induced cirrhosis.
Kannangai, R, P Vivekanandan, F Martinez-Murillo, M Choti and M Torbenson 2007Fibrolamellar carcinomas show overexpression of genes in the RAS, MAPK, PIK3, and xenobiotic degradation pathways. Hum Pathol 38(4): 639-644. Fibrolamellar carcinomas (FLC) are a rare type of primary hepatocellular carcinoma found in younger individuals. FLC are known to have relatively few consistent chromosomal alterations, although a gain of chromosome 1q has been reported. The gene expression of 4 FLC (2 primary FLC and 2 metastatic deposits) were studied using Affymetrix DNA microarray technology (Santa Clara, CA). Selected genes were confirmed by real-time polymerase chain reaction. Relatively few genes were significantly overexpressed-447 genes, case 1; 1298 genes, case 2-corresponding to approximately 0.8% and 2.3%, respectively, of the 56000 transcripts present in the arrays. Of these, 155 genes were overexpressed simultaneously by both tumors. The number of significantly overexpressed genes more than doubled in the 2 metastatic deposits (2777 and 2855 genes compared with 1298 in the primary tumor). Proteins involved in the RAS, MAPK, PIK3, and xenobiotic degradation pathways were commonly overexpressed. Because chromosome 1q is thought to contain an important oncogene, additional attention was focused on this region. Of 114 total genes found overexpressed in common among all primary and metastatic tumors, 11 of 114 genes were located on chromosome 1q: ARF1, CD46, CNIH4, ENSA, FH, NICE-3, PSMB4, RGS2, RGS5, TIMM17A, and UFC1. Primary FLC show overexpression of genes involved in the RAS, MAPK, PIK3, and xenobiotic degradation pathways. Eleven common genes were consistently overexpressed on chromosome 1q among all tumors and metastases and warrant further study as potential oncogenes.
Torbenson, M 2007Review of the clinicopathologic features of fibrolamellar carcinoma. Adv Anat Pathol 14(3): 217-223. Since its first description 50 years ago, fibrolamellar carcinomas (FLCs) have been recognized as a unique type of primary liver cancer. FLCs occur principally in children and young adults and are not associated with chronic liver disease. Their etiology is unknown. The tumor is made up of large polygonal cells containing abundant eosinophilic cytoplasm, large vesiculated nuclei, and large nucleoli, with tumor cells that are embedded in lamellar bands of fibrosis. Although rare, the most common variant of FLC shows areas of glandular type differentiation with mucin production. The uniqueness of FLC extends to their molecular findings, as they show no evidence for involvement by many of the major pathways and genes that are dysregulated in typical hepatocellular carcinoma, including alpha-fetoprotein, TP53 mutations, and beta catenin mutations. FLCs are not indolent tumors, but have an overall better prognosis than hepatocellular carcinomas of the usual sort because of the younger age at presentation and lack of cirrhosis. The most important prognostic feature is resectability. Although their morphologic appearance on routine stains is well defined, their etiology is still unknown and much of their molecular biology remains poorly described and awaits future investigation.
Buckley, AF, LJ Burgart and S Kakar 2006Epidermal growth factor receptor expression and gene copy number in fibrolamellar hepatocellular carcinoma. Hum Pathol 37(4): 410-414. Increased expression of epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase, is associated with tumor progression in many carcinomas. Epidermal growth factor receptor inhibitors have shown promise in treating some of these tumors. Fibrolamellar hepatocellular carcinoma (FL-HCC) is an aggressive neoplasm that occurs in young patients with no history of cirrhosis. This study examines the expression and gene copy number of EGFR in FL-HCC. Formalin-fixed, paraffin-embedded FL-HCC (n = 13) sections were stained with a monoclonal antibody against EGFR. Fluorescence in situ hybridization analysis was performed using probes against EGFR gene and centromeric region of chromosome 7 (CEP 7). Epidermal growth factor receptor and CEP 7 signals were counted in 50 tumor nuclei per case as well as 300 normal hepatocyte nuclei. The EGFR to CEP 7 signal ratio was calculated for each case. Most (92%, 12/13) of FL-HCC showed strong and diffuse staining with anti-EGFR antibody. Fluorescence in situ hybridization was informative in 11 cases, 10 of which showed extra EGFR gene copy numbers (mean, 3.69; range, 3.13-5.0). Epidermal growth factor receptor was overexpressed in all these cases. The mean number of EGFR signals per cell in FL-HCC was double that of normal hepatocytes (3.69 versus 1.80); the mean EGFR/CEP 7 ratio in tumor cells was 1.05. In conclusion, EGFR is strongly overexpressed on the cell membrane in nearly all cases of FL-HCC. Similar gains of chromosome 7 are observed, indicating that the extra EGFR gene copies are due to polysomy rather than gene amplification. The strong expression of EGFR in FL-HCC tumors suggests that they may respond to treatment with EGFR antagonists.
Qiu, XB, YM Shao, S Miao and L Wang 2006The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cell Mol Life Sci 63(22): 2560-2570. DnaJ/Hsp40 (heat shock protein 40) proteins have been preserved throughout evolution and are important for protein translation, folding, unfolding, translocation, and degradation, primarily by stimulating the ATPase activity of chaperone proteins, Hsp70s. Because the ATP hydrolysis is essential for the activity of Hsp70s, DnaJ/Hsp40 proteins actually determine the activity of Hsp70s by stabilizing their interaction with substrate proteins. DnaJ/Hsp40 proteins all contain the J domain through which they bind to Hsp70s and can be categorized into three groups, depending on the presence of other domains. Six DnaJ homologs have been identified in Escherichia coli and 22 in Saccharomyces cerevisiae. Genome-wide analysis has revealed 41 DnaJ/Hsp40 family members (or putative members) in humans. While 34 contain the typical J domains, 7 bear partially conserved J-like domains, but are still suggested to function as DnaJ/ Hsp40 proteins. DnaJA2b, DnaJB1b, DnaJC2, DnaJC20, and DnaJC21 are named for the first time in this review; all other human DnaJ proteins were dubbed according to their gene names, e.g. DnaJA1 is the human protein named after its gene DNAJA1. This review highlights the progress in studying the domains in DnaJ/Hsp40 proteins, introduces the mechanisms by which they interact with Hsp70s, and stresses their functional diversity.
Sicklick, JK, SS Choi, M Bustamante, SJ McCall, EH Perez, J Huang, YX Li, M Rojkind and AM Diehl 2006Evidence for epithelial-mesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol 291(4): G575-583. Both myofibroblastic hepatic stellate cells (HSC) and hepatic epithelial progenitors accumulate in damaged livers. In some injured organs, the ability to distinguish between fibroblastic and epithelial cells is sometimes difficult because cells undergo epithelial-mesenchymal transitions (EMT). During EMT, cells coexpress epithelial and mesenchymal cell markers. To determine whether EMT occurs in adult liver cells, we analyzed the expression profile of primary HSC, two HSC lines, and hepatic epithelial progenitors. As expected, all HSC expressed HSC markers. Surprisingly, these markers were also expressed by epithelial progenitors. In addition, one HSC line expressed typical epithelial progenitor mRNAs, and these epithelial markers were inducible in the second HSC line. In normal and damaged livers, small ductular-type cells stained positive for an HSC marker. In conclusion, HSC and hepatic epithelial progenitors both coexpress epithelial and mesenchymal markers, providing evidence that EMT occurs in adult liver cells.
Sicklick, JK, YX Li, A Melhem, E Schmelzer, M Zdanowicz, J Huang, M Caballero, JH Fair, JW Ludlow, RE McClelland, LM Reid and AM Diehl 2006Hedgehog signaling maintains resident hepatic progenitors throughout life. Am J Physiol Gastrointest Liver Physiol 290(5): 859-870. Hedgehog signaling through its receptor, Patched, activates transcription of genes, including Patched, that regulate the fate of various progenitors. Although Hedgehog signaling is required for endodermal commitment and hepatogenesis, the possibility that it regulates liver turnover in adults had not been considered because mature liver epithelial cells lack Hedgehog signaling. Herein, we show that this pathway is essential throughout life for maintaining hepatic progenitors. Patched-expressing cells have been identified among endodermally lineage-restricted, murine embryonic stem cells as well as in livers of fetal and adult Ptc-lacZ mice. An adult-derived, murine hepatic progenitor cell line expresses Patched, and Hedgehog-responsive cells exist in stem cell compartments of fetal and adult human livers. In both species, manipulation of Hedgehog activity influences hepatic progenitor cell survival. Therefore, Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and may be a new therapeutic target in patients with liver damage.
Stiller, CA, J Pritchard and E Steliarova-Foucher 2006Liver cancer in European children: incidence and survival, 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer 42(13): 2115-2123. Data on 849 children diagnosed with malignant hepatic tumours (International Classification of Childhood Cancer, Group VII) before the age of 15 years during 1978-1997 in Europe were extracted from the ACCIS database. Age-standardised incidence during 1988-1997 was 1.5 per million overall, 1.2 per million for hepatoblastoma and 0.2 per million for hepatic carcinoma. Over 90% of cases of hepatoblastoma occurred before age 5 years, whereas hepatic carcinoma had a fairly flat age distribution. Both tumours had an incidence in boys of 1.5-1.6 times that in girls. There were no significant time trends in incidence during 1978-1997. Five-year survival from hepatoblastoma diagnosed during 1988-1997 was 63% overall, and ranged from 52% in Eastern Europe to 84% in the North. Survival from hepatic carcinoma was much lower (37%). Between 1978-1982 and 1993-1997, 5-year survival (95% confidence interval (95% CI)) increased from 28% (95% CI 18-39) to 66% (95% CI 55-74) for hepatoblastoma and from 17% (95% CI 6-33) to 50% (95% CI 26-70) for hepatic carcinoma. These increases reflect the impact of advances in treatment of childhood liver cancer at a population level.
Stipa, F, SS Yoon, KH Liau, Y Fong, WR Jarnagin, M D'Angelica, G Abou-Alfa, LH Blumgart and RP DeMatteo 2006Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer 106(6): 1331-1338. BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of hepatocellular carcinoma, has distinct pathologic features, and typically occurs in young patients without underlying hepatitis or cirrhosis. METHODS: Forty-one patients with the pathologic diagnosis of FL-HCC evaluated at our institution between 1986 and 2003 were identified from a prospective database. RESULTS: Median age of all patients was 27 years. None of these patients had underlying hepatitis or cirrhosis, and only 3 (7%) patients had an alpha-fetoprotein level > 200 ng/mL. Twenty-eight patients with primary disease underwent complete gross resection, and 13 patients were unresectable. In patients treated with resection, median tumor size was 9 cm (range, 3-17), 9 (36%) had vascular invasion, and 14 (50%) had lymph node metastases. There were no perioperative deaths. With a median follow-up of 34 months, 5-year overall survival for resected patients was 76%. However, 5-year recurrence-free survival was only 18%, and of the 9 resected patients with more than 5 years of follow-up, 7 had recurrences. Lymph node metastasis was the only significant negative prognostic factor. Seventeen (61%) patients underwent a second operation for recurrent disease. Median survival for unresected patients with FL-HCC was only 12 months, and no patient survived beyond 5 years. CONCLUSIONS: FL-HCC occurs in a distinctly different population of patients than common HCC, and patients with FL-HCC generally fare better after complete resection. These tumors have a relatively indolent tumor biology, and late recurrences are common. Repeat resections for recurrence should be considered given the lack of other effective treatment options.
Klein, WM, EP Molmenti, PM Colombani, DS Grover, KB Schwarz, J Boitnott and MS Torbenson 2005Primary liver carcinoma arising in people younger than 30 years. Am J Clin Pathol 124(4): 512-518. Primary liver carcinomas in children and young adults are uncommon and poorly described. We examined primary liver carcinomas in people younger than 30 years and performed immunostains for markers of biliary (cytokeratin [CK] 7, CK19, CD56) and hepatocellular (HepPar) differentiation. We found 23 primary liver carcinomas were found: 13 hepatocellular carcinomas (HCCs), 9 fibrolamellar carcinomas (FLCs), and 1 cholangiocarcinoma. Most HCCs showed compact (n = 7) or trabecular (n = 4) growth patterns. The Edmondson grades were as follows: 1, 3 tumors; 2, 8 tumors; and 3, 2 tumors). All HCCs and FLCs were HepPar(+). All FLCs and 7 of 9 HCCs were CK7(+). In contrast, a control group of 65 adult HCCs showed less CK7 positivity (24 [37%]; P = .03). CK19 was positive in 2 HCCs and CD56 in 1 HCC. No chronic background liver disease was seen, although 3 cases showed foci of altered hepatocytes. HCCs are the most common primary liver carcinoma in children and young adults followed by FLCs. They are morphologically similar to adult HCC, but more likely to be CK7(+).
Moreno-Luna, LE, O Arrieta, J Garcia-Leiva, B Martinez, A Torre, M Uribe and E Leon-Rodriguez 2005Clinical and pathologic factors associated with survival in young adult patients with fibrolamellar hepatocarcinoma. BMC Cancer 5: 142. BACKGROUND: Fibrolamellar Carcinoma (FLC), a subtype of hepatocellular carcinoma (HCC), is a rare primary hepatic malignancy. Several aspects of the clinic features and epidemiology of FLC remain unclear because most of the literature on FLC consists of case reports and small cases series with limited information on factors that affect survival. METHODS: We did a retrospective analysis of the clinical and histological characteristics of FLC. We also determined the rate of cellular proliferation in biopsies of these tumors. We assessed whether these variables were associated with survival. RESULTS: We found 15 patients with FLC out of 174 patients with HCC (8.6%). Between patients with these neoplasms, we found statistically significant survival, age at onset, level of alpha fetoprotein, and an earlier stage of the disease. The 1, 3 and 5 year survival in patients with FLC was of 66, 40 and 26% respectively. The factors associated with a higher survival in patients with FLC were age more than 23 years, feasibility of surgical resection, free surgical borders, absence of thrombosis or invasion to hepatic vessels and the absence of alterations in liver enzymes. The size of the tumor, gender, cellular proliferation and atypia did not affect the prognosis. CONCLUSION: We concluded that FLC patients diagnosed before 23 years of age have worse prognosis than those diagnosed after age 23. Other factors associated with worse prognosis in this study are: lack of surgical treatment, presence of positive surgical margins, vascular invasion, and altered hepatic enzymes.
Tanaka, K, T Honna, Y Kitano, T Kuroda, K Tanaka, N Morikawa, H Matsuda, N Kawashima, K Matsuoka and J Miyauchi 2005Combined fibrolamellar carcinoma and cholangiocarcinoma exhibiting biphenotypic antigen expression: a case report. J Clin Pathol 58(8): 884-887. Fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC), very rarely occurs in association with cholangiocarcinoma (CC). This report describes the first case of FLC coexisting with CC (FLC-CC) from Japan. Although the major part of the tumour located in the right lobe of the liver showed the typical features of FLC, CC was admixed with the FLC, not only in the primary hepatic tumour, but also in the lymph node metastases. Immunohistochemical analysis revealed that, although carcinoembryonic antigen (CEA), which can be detected with monoclonal antibodies in the cytoplasm and the cell surface of CC cells but not HCC cells, was expressed in only the CC cells in the primary tumour, it was expressed extensively in the cytoplasm of both CC and FLC cells in the metastatic and recurrent tumours. Furthermore, Hep Par 1, a hepatocyte specific antigen, was also expressed in both the FLC and CC cells. These findings suggest that, in this case, both FLC and CC were possibly derived from the same cancer stem cell with the capacity to differentiate into both hepatocytes and bile duct epithelium, and that both the cellular components, therefore, exhibited biphenotypic antigen expression.
El-Serag, HB and JA Davila 2004Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology 39(3): 798-803. There have been no population-based studies of the epidemiology and prognosis of patients with fibrolamellar carcinoma (FLC). We conducted a retrospective cohort study using information collected by population-based registries of the Surveillance, Epidemiology, and End Results (SEER) program. The demographic features, stage at diagnosis, and type of therapy, as well as age-adjusted incidence rates and observed and relative survival rates were compared between persons with FLC and those with hepatocellular carcinoma (HCC) diagnosed between 1986 and 1999. A multivariate Cox proportional hazards model was constructed to examine the effect of histology (FLC vs. HCC) on the risk of mortality. There were 68 microscopically confirmed cases of FLC and 7,896 cases of HCC. FLC constituted 0.85% of all cases of primary liver cancer and 13.4% of all cases below the age of 40. Compared to HCC, patients with FLC were more likely to be younger (mean age 39 vs. 65), female (51.5% vs. 26.3%), and white (85.3% vs. 56.9%). A greater proportion of case with FLC had localized disease (41.2% vs. 30.9%), or received potentially curative therapy (resection, transplantation), compared to cases with HCC. The age-adjusted incidence rate for FLC was 0.02 per 100,000; No significant differences in age-adjusted incidence rates were observed by gender or race. The 1- and 5-year observed and relative survival rates were significantly longer in patients with FLC than HCC. The 5-year relative survival rate was 31.8% (95% CI, 20.5%-43.1%) for FLC, compared with 6.8% (95% CI, 6.3 %-7.4 %) for HCC. Adjusting for differences in age, gender, race, stage of disease, receipt of resection or transplantation, and time of diagnosis, FLC was independently associated with a 46% reduction in risk of mortality within 5 years compared with HCC. In conclusion, in a population-based study, we observed remarkable differences in the epidemiology and prognosis of FLC compared to HCC.
Sahin, F, R Kannangai, O Adegbola, J Wang, G Su and M Torbenson 2004mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 10(24): 8421-8425. PURPOSE: mTOR and P70 S6 kinase (S6K) play a key role in regulating protein translation. The role of mTOR and S6K in hepatocellular carcinoma has not been investigated, but this pathway is of particular interest because an effective inhibitor, rapamycin, is available. This study was undertaken to determine the prevalence and clinicopathological correlates of mTOR pathway activation in hepatocellular carcinoma and to determine whether rapamycin inhibits the pathway in cell culture. EXPERIMENTAL DESIGN: Total and phosphorylated mTOR and S6K protein expression were studied by immunohistochemistry in hepatocellular carcinomas (n = 73), fibrolamellar carcinomas (n = 13), and hepatic adenomas (n = 15). Results were correlated with tumor growth pattern as defined by the WHO (trabecular, pseudoglandular/acinar, compact, and scirrhous), tumor size, Ki-67 proliferation index, and the modified Edmondson nuclear grade, which has a scale of 1 to 4. HepG2 and Hep3B cell lines were treated with rapamycin to see the effect on proliferation and S6K phosphorylation. RESULTS: Increased expression of total mTOR was seen in 5% of hepatocellular carcinoma, whereas overexpression of phospho-mTOR was evident in 15% of hepatocellular carcinoma. Phospho-mTOR positivity correlated with increased expression of total S6K, which was found in 45% of cases. Total S6K overexpression was positively correlated with tumor nuclear grade, inversely with tumor size, and was unassociated with the proliferation index or WHO growth pattern. Rapamycin treatment of HepG2 and Hep3B cell lines markedly inhibited cell proliferation and reduced S6K phosphorylation in both cell lines. CONCLUSIONS: The mTOR pathway is activated in a subset of hepatocellular carcinoma. Rapamycin can inhibit proliferation of neoplastic hepatocytes in cell culture.
Terracciano, LM, L Tornillo, P Avoledo, D Von Schweinitz, T Kuhne and E Bruder 2004Fibrolamellar hepatocellular carcinoma occurring 5 years after hepatocellular adenoma in a 14-year-old girl: a case report with comparative genomic hybridization analysis. Arch Pathol Lab Med 128(2): 222-226. An unusual case of fibrolamellar carcinoma of the liver developed 5 years after removal of a hepatocellular adenoma in a 14-year-old girl belonging to a family with Carney syndrome. Both tumors were studied by light and electron microscopy, flow cytometry, and comparative genomic hybridization. The first tumor, removed at the age of 9, was a bulky well-circumscribed liver mass composed of large eosinophilic cells with a focal pseudoglandular pattern but without cytologic atypia or sclerosis. A diagnosis of hepatocellular adenoma was rendered. Five years later, another hepatic tumor was removed from the right lobe. Microscopic examination revealed polygonal cells, each with a large amount of eosinophilic cytoplasm and a round nucleus with a conspicuous nucleolus. These cells were arranged in nests and strands and separated by bands of dense fibrous tissue, leading to a diagnosis of fibrolamellar carcinoma. Comparative genomic hybridization analysis revealed no genetic alteration in the adenoma; however, several chromosomal aberrations (loss of chromosome regions 1p and 4p and gains of chromosome regions 6q, 13q, and Xq) were detected in the fibrolamellar carcinoma. To our knowledge, this is the first report of an association between hepatocellular adenoma and fibrolamellar carcinoma.
Katzenstein, HM, MD Krailo, MH Malogolowkin, JA Ortega, W Qu, EC Douglass, JH Feusner, M Reynolds, JJ Quinn, K Newman, MJ Finegold, JE Haas, MG Sensel, RP Castleberry and LC Bowman 2003Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 97(8): 2006-2012. BACKGROUND: Children with hepatocellular carcinoma (HCC) were treated on a prospective, randomized trial and were then analyzed to determine whether children with the fibrolamellar (FL) histologic variant of HCC have a more favorable presentation, increased surgical resectability, greater response to therapy, and improved outcome compared with children who have typical HCC. METHODS: Forty-six patients were enrolled on Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group Study 8945/Children's Cancer Group Study 8881) between August 1989 and December 1992. After undergoing initial surgery or biopsy, children with Stage I HCC (n = 8 patients), Stage III HCC (n = 25 patients), and Stage IV HCC (n = 13 patients) were assigned randomly, regardless of histology, to receive treatment either with cisplatin, vincristine, and fluorouracil (n = 20 patients) or with cisplatin and continuous-infusion doxorubicin (n = 26 patients). RESULTS: Ten of 46 patients (22%) had the fibrolamellar variant of HCC (FL-HCC). For the entire cohort, the estimated 5-year event free survival (EFS) rate (+/- standard deviation) was 17% +/- 6%. There was no difference in outcome among patients who were treated with either regimen. The 5-year EFS rate for patients with FL-HCC was no different the rate for patients with typical HCC (30% +/- 15% vs. 14% +/- 6%, respectively; P = 0.18), although the median survival was longer in patients with FL-HCC. There was no difference in the number of patients with advanced-stage disease, the incidence of surgical resectability at diagnosis, or the response to treatment between patients with FL-HCC and patients with typical HCC. CONCLUSIONS: Children with FL-HCC do not have a favorable prognosis and do not respond any differently to current therapeutic regimens than patients with typical HCC. Children with initially resectable HCC have a good prognosis irrespective of histologic subtype, whereas outcomes are poor uniformly for children with advanced-stage disease. The use of novel chemotherapeutic agents and the incorporation of other treatment modalities are indicated to improve the dismal survival of pediatric patients with all histologic variants of advanced-stage HCC.
Patt, YZ, MM Hassan, RD Lozano, TD Brown, JN Vauthey, SA Curley and LM Ellis 2003Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol 21(3): 421-427. PURPOSE: Because cirrhosis is extremely common in hepatocellular carcinoma (HCC) in the United States, and it precludes the use of several chemotherapy agents, this phase II trial of fluorouracil (FU) and recombinant interferon alfa-2b (rIFNalpha2b) in HCC was launched with the assumption that it could be tolerated by cirrhotics. PATIENTS AND METHODS: Forty-three patients with HCC (34), and fibrolamellar HCC (FLHCC; nine) were treated with continuous intravenous (IV) FU (200 mg/m2/d x 21 every 28 days) and subcutaneous (SC) rIFNalpha2b (4 million U/m2) three times weekly. Survival was determined in all 43 patients, and response could be assessed in 28 HCC and 8 FLHCC patients. RESULTS: The median ages of the patients were 63.5 and 19 years among HCC and FLHCC patients, respectively. Liver cirrhosis was present among 71% of HCC patients but among none of the FLHCC patients. Nine of 36 (25%; four of 28 [14%] HCC patients; five of eight [62.5%] FLHCC patients) patients in which a response could be assessed had a complete response (CR; one patient with FLHCC and no patients with HCC) or partial response (PR; eight patients [four HCC and four FLHCC patients]). Four HCC patients underwent resection, and two had a histologic CR; one HCC patient with a PR underwent orthotopic liver transplantation. One FLHCC patient also underwent resection without clear margins. Overall median survival was 19.5 months (95% confidence interval [CI], 11.2 to 27.8 months); median survival was 15.5 months (95% CI, 8.5 to 22.5 months) among HCC patients, and that of FLHCC patients was 23.1 months (95% CI, 10.3 to 35.9 months). Overall grade 3 or 4 toxicity included stomatitis (32.6%), fatigue (4.7%), and hematologic toxicity (9.3%). CONCLUSION: Continuous IV FU and thrice-weekly SC rIFNalpha2b are an effective treatment, especially for FLHCC, and may have a neoadjuvant role in this disease. This regimen has activity in HCC and can be tolerated even by cirrhotic patients.
Schoedel, KE, VZ Tyner, TH Kim, GK Michalopoulos and WM Mars 2003HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver. Mod Pathol 16(1): 14-21. Fibrolamellar variant is an uncommon subcategory of hepatocellular carcinoma with a better prognostic outcome. Proteinases and growth factors that are involved in the remodeling of extracellular matrix may influence the behavior of cancers. To determine whether these factors contribute to the distinct etiologies of fibrolamellar hepatocellular carcinoma and traditional hepatocellular carcinoma, we assayed hepatocyte growth factor, the hepatocyte growth factor receptor, and two hepatocyte growth factor activators, hepatocyte growth factor activator and urokinase-type plasminogen activator, in hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cirrhotic liver and normal liver. In addition, we examined the urokinase-type plasminogen activator receptor, the type 1 plasminogen activator inhibitor, plasmin, fibrinogen, and the type IV matrix metalloproteinases. Eighteen hepatocellular carcinomas and 11 fibrolamellar hepatocellular carcinomas were obtained as paraffin embedded sections from the University of Pittsburgh Department of Pathology. Frozen tissues from a subset of cases (9 hepatocellular carcinomas, 4 fibrolamellar hepatocellular carcinomas, 12 cirrhotic livers and 2 normal livers) were also available for analysis. Antibodies against urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, hepatocyte growth factor and hepatocyte growth factor receptor were used to analyze immunoperoxidase stained slides from the paraffin blocks. Western blot analyses using antibodies against hepatocyte growth factor, hepatocyte growth factor receptor, phosphotyrosine, hepatocyte growth factor activator, urokinase-type plasminogen activator receptor, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, fibrinogen and plasmin were performed on membrane-enriched fractions from the frozen tissue, as was collagen zymography for matrix metalloproteinase-2 and matrix metalloproteinase-9. The most notable findings are as follows: hepatocyte growth factor activator was only detected in malignant tissue but not cirrhotic liver or normal liver. Although hepatocyte growth factor was detected in most samples, it was significantly elevated in 5/9 hepatocellular carcinomas. Furthermore, 8/9 fibrolamellar hepatocellular carcinomas demonstrated hepatocyte growth factor receptor levels similar to normal, whereas 8/9 hepatocellular carcinomas and 11/12 cirrhotic livers exhibited either an increase or decrease. In contrast, active matrix metalloproteinase-2, which was absent in normal liver, was elevated in fibrolamellar hepatocellular carcinoma as compared to cirrhotic liver and conventional hepatocellular carcinoma. Surprisingly, 10/12 cirrhotic livers and 2/4 fibrolamellar hepatocellular carcinomas but only 1/9 hepatocellular carcinomas were enriched for plasmin. The combined data suggest that the hepatocyte growth factor and plasmin systems tend to be operative in hepatocellular carcinoma and cirrhotic liver, more than fibrolamellar hepatocellular carcinoma. Furthermore, matrix turnover appears to be a more prominent feature of fibrolamellar hepatocellular carcinoma. These findings provide insight into the behavioral differences between hepatocellular carcinoma and the fibrolamellar variant.
Arista-Nasr, J, L Gutierrez-Villalobos, J Nuncio, H Maldonaldo and L Bornstein-Quevedo 2002Fibrolamellar hepatocellular carcinoma in mexican patients. Pathol Oncol Res 8(2): 133-137. UNLABELLED: The aim of this report is to describe the frequency, clinical, and morphologic characteristics of fibrolamellar hepatocellular carcinoma in Mexican patients. Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma. Although this tumor appears to be predominant among the Caucasian population of the U.S, FLHCC has been described in many other countries. The frequency and characteristics of FLHCC in Latin American population is almost unknown. The clinico-pathologic characteristics of seven (5.8%) Mexican patients with FLHCC, obtained among 121 hepato-cellular carcinomas are described. The frequency of these tumors was compared with the frequency reported in other geographic areas in the international literature between 1980 and 1999. There were four women and three men. Two patients had taken oral contraceptives for six months and a year prior to diagnosis; another patient had positive serology for the hepatitis B virus. Common symptoms included a palpable mass, abdominal pain and weight loss; two patients presented jaundice. In two patients the tumor had been removed eight and three years previously, and they were readmitted when FLHCC recurred. In three patients the diagnosis was suspected in radiological studies (computed tomography and/or magnetic resonance). Laboratory tests were non-specific. In four patients, resection of the tumor was performed, and in the remaining three the neoplasm was diagnosed by percutaneous hepatic biopsy. Two patients had died of disease at the time of the study, and another was alive with recurrent disease. CONCLUSIONS: fibrolamellar hepatocarcinoma is an uncommon, but not an exceptional neoplasm in our population and represents 5.8% of all hepatocarcinomas reviewed.
Dadke, D, P Jaganath, S Krishnamurthy and S Chiplunkar 2002The detection of HBV antigens and HBx-transcripts in an Indian fibrolamellar carcinoma patient: a case study. Liver 22(1): 87-91. Fibrolamellar carcinoma (FLC) of the liver is a rare variant of hepatocellular carcinoma (HCC). Here we report the case of a 12-year-old Indian male with typical FLC with no apparent hepatitis B virus (HBV) infection and a non-cirrhotic liver. The patient, though seronegative for HBsAg, showed expression of HBcAg in both the liver and tumour tissue. RT-PCR analysis revealed the presence of full-length HBx-transcripts in both liver/tumour tissue, along with truncated HBx-transcripts only in the tumour tissue. The lymphocytes in both peripheral and liver/tumour compartments showed a proliferative response to either/or HBcAg and HBxAg, which could be further augmented on addition of rIL-2. This is the first study to show not only the presence of HBcAg in the liver/tumour tissue but also prior exposure of the FLC patient's lymphocytes to HBV antigens. Also, the presence of the full-length and truncated HBx-transcripts in the tumour tissue, a proposed tumorigenic marker for hepatocarcinogenesis in chronic HBV patients, suggests an oncogenic role of HBV in this rare variant of HCC.
Sarode, VR, R Castellani and A Post 2002Fine-needle aspiration cytology and differential diagnoses of fibrolamellar hepatocellular carcinoma metastatic to the mediastinum: case report. Diagn Cytopathol 26(2): 95-98. We report a case of fibrolamellar hepatocellular carcinoma (FL-HCC) that metastasized to the posterior mediastinum. The diagnosis was made on fine-needle aspiration biopsy (FNAB). The cytologic features were characterized by the presence of large, dishesive, polygonal cells with granular cytoplasm and well-defined cell outlines resembling oncocytes. Groups of neoplastic hepatocytes containing bile pigment were also noted. The diagnosis of FL-HCC in a metastatic site can pose diagnostic challenges on FNAB. The cytologic features overlap with a variety of tumors that have oncocytic features and also with melanoma and paraganglioma. Recognition of specific cytologic features of FL-HCC can facilitate accurate diagnosis in a metastatic site. The cytologic findings and differential diagnoses of FL-HCC that metastasized to the posterior mediastinum are discussed.
Cheuk, W and JK Chan 2001Clear cell variant of fibrolamellar carcinoma of the liver. Arch Pathol Lab Med 125(9): 1235-1238. Fibrolamellar carcinoma of the liver is a distinctive variant of hepatocellular carcinoma characterized histologically by trabeculae of oncocytic cells with intervening lamellae of collagen fibers. We describe a case with a prominent component of clear cells, a feature not previously recognized in this tumor type. The patient was a 59-year-old woman incidentally found to have a solitary liver tumor, measuring 5 cm. Pathologic examination revealed a circumscribed, firm, tan tumor with peculiar concentric streaks. Oncocytic cells and clear cells were arranged in trabeculae separated by lamellae of collagen or sinusoids. The clear cells possessed abundant finely reticulated clear cytoplasm, which was highlighted by trichrome stain and immunostaining with antimitochondria antibody. Ultrastructurally, the cytoplasm of the clear cells was packed with empty membrane-bound vesicles that occasionally contained short cristae. The features suggested that the clear cell change resulted from ballooning and rarefactive changes of mitochondria. Clear cell fibrolamellar carcinoma should not be confused with conventional clear cell hepatocellular carcinoma, since the former is associated with a more favorable prognosis.
Dominguez-Malagon, H and S Gaytan-Graham 2001Hepatocellular carcinoma: an update. Ultrastruct Pathol 25(6): 497-516. Hepatocellular carcinoma (HCC) is the most common malignant tumor of males in the world, with an incidence of 1,000,000 new cases a year. It is endemic in Southeast Asia and Sub-Saharan Africa. Risk factors include chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), Aflatoxin B1 uptake, hemochromatosis, and alpha1 -antitripsin deficiency. Epidemiological studies provide evidence for the association of HCC with HBV infection. The incidence of HCC is high in regions hyperendemic for HBV. Chronic carrier state and maternal-infant transmission are important factors in the development of HCC. Evidence of direct oncogenic effect of H BV is well established, HCCs contain viral DNA sequences integrated into hepatocyte DNA that act as random insertional mutagens, and these sites are near genes involved in the control of proliferation and differentiation. The mechanism of hepatitis C virus in hepatocarcinogenesis is still imprecise but a high percentage of cases are related to this virus. Chronic alcohol consumption and cirrhosis are cofactors that increase the development of HCC in patients with chronic viral infection. In experimental carcinogenesis a multipotential element called oval cell proliferates in the early stages. The cellular events are accompanied by increased expression of several growth factors that enhance the survival of carcinogen-activated cells by suppressing apoptosis and increasing elements entering the cell cycle. Hepatic carcinogenesis is a complex process associated with accumulation of genetic and epigenetic changes that run through steps of initiation, promotion and progression. Activation of oncogenes of the "ras" family and others has been detected during chemically-induced HCC in rodents, but there is little evidence of such activation in human tumors. The role of tumor supressor genes such as retinoblastoma (RB) and P53 genes has been documented. Aflatoxin B1 that contaminates foods in endemic areas has a clear role in hepatocarcinogenesis. Metabolites of this toxin promote apurinic sites and G to T mutations in chromosomal DNA, the third base of codon 249 of the P53 gene is preferentially targeted to form aducts with aflatoxin B1, and this mutation has been specifically identified in HBV infection. Histological and cytological criteria for the diagnosis of HCC are well established and are based in architectural and cytological changes. An important issue is the diagnosis of liver "nodules" detected by image, from which small biopsies or aspiration material is obtained. Special studies such as reticulin, CD34, cytokeratin profile, and MOC-31 can be very useful for the differential diagnosis of primary and metastatic tumors. Telomerase activity has been found in HCC and negative in pericancerous tissue. It is more pronounced in poorly differentiated tumors and correlates with factors of clinical importance, such as prognosis and recurrences. Cells of well-differentiated HCC have an ultrastructural appearance similar to normal hepatocytes. During the process of dedifferentiation, there is progressive loss of organization of intracellular organelles. The cell cohesion is lost, intercellular gaps with microvilli appear, the sinusoids become capillarized, and reparative changes are seen in the spaces of Disse. A variety of inclusions, such as Mallory bodies, granular material, secondary lysosomes, and Dubin-Johnson pigment, have been described. Fibrolamellar carcinoma has a characteristic histological picture and ultrastructurally oncocytic features. Neuroendocrine granules and combination of HCC with bile duct carcinoma are seen by electron microscopy.
Sirivatanauksorn, Y, V Sirivatanauksorn, NR Lemoine, RC Williamson and BR Davidson 2001Genomic homogeneity in fibrolamellar carcinomas. Gut 49(1): 82-86. BACKGROUND: Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC) with distinctive clinical and histological features. To date there have been few studies on the genotypic aspects of FLC and no previous attempts have been made to use the arbitrarily primed-polymerase chain reaction (AP-PCR) technique to detect genetic alterations in this disease. AIM: The aim of this study was to assess the degree of genomic heterogeneity of FLC using the AP-PCR technique. METHODS: A total of 50 tissue samples of primary and metastatic FLCs from seven patients were microdissected. AP-PCR amplification of each genomic DNA sample was carried out using two arbitrary primers. RESULTS: DNA fingerprints of the primary FLCs and all their metastatic lesions (both synchronous and metachronous disease) were identical in an individual patient. The fingerprints were different between tumours of different patients. No evidence of intratumour heterogeneity was observed. CONCLUSIONS: Such genomic homogeneity in FLCs may explain their indolent growth. The absence of clonal evolution, which is present in other tumours (particularly HCCs), may explain the distinct behaviour in this tumour. The tumorigenic pathway and degree of somatic genomic changes in this disease may be less complex than in HCC.
Bralet, MP, JM Regimbeau, P Pineau, S Dubois, G Loas, F Degos, D Valla, J Belghiti, C Degott and B Terris 2000Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases. Hepatology 32(2): 200-204. Hepatocellular carcinoma (HCC) occurring in nonfibrotic liver represents a rare, ill-defined subgroup of HCC without cirrhosis in which mechanisms of hepatocarcinogenesis remain unclear. The aim of our study was to assess epidemiological factors and detailed histopathologic changes in the nontumoral liver of patients developing such tumors. Of 330 HCCs resected in our institution between 1985 and 1998, we retrospectively analyzed 80 cases (53 men, 27 women; mean age, 51 +/- 16 years) in which the nontumoral liver showed no (n = 28) or minimal (n = 52) portal fibrosis without any septal fibrosis. In the group with no portal fibrosis there was no male predominance, and patients were significantly younger (44 +/- 19 years vs. 54 +/- 14 years) than those with minimal portal fibrosis. Sixty-seven tumors were typical HCCs, 8 were of fibrolamellar type, and 5 were hepatocholangiocarcinomas. Mean tumor size was 10 +/- 5 cm. Risk factors for HCC development were found in 30 patients: hepatitis B (n = 17) or C (n = 2) virus infections, alcohol consumption (n = 11), and hemochromatosis (n = 1). In the nontumoral liver, periportal and lobular necrosis, mild portal inflammation, steatosis, and iron overload were present in 15%, 57%, 52%, and 54% of cases, respectively. Liver cell changes were noted in 6%. This study emphasizes the need for strict criteria to classify HCC without cirrhosis. HCC in nonfibrotic liver is a distinct subgroup in which nontumoral liver shows nonspecific minimal changes without regeneration or premalignant lesion. Etiologic factors are often unidentified, although presence of HBV infection in 21% suggests a direct oncogenic role of this virus.
Wilkens, L, M Bredt, P Flemming, S Kubicka, J Klempnauer and H Kreipe 2000Cytogenetic aberrations in primary and recurrent fibrolamellar hepatocellular carcinoma detected by comparative genomic hybridization. Am J Clin Pathol 114(6): 867-874. Fibrolamellar hepatocellular carcinoma (FLC) is a rare entity of hepatocellular carcinoma (HCC) not yet analyzed cytogenetically. By using comparative genomic hybridization (CGH), we looked for chromosome changes in 2 primary FLCs and a recurrent FLC with and without metastases. CGH revealed an amplification of 1q in 1 primary FLC. The other primary FLC and a metastasis revealed no changes. The recurrent FLC showed 18 aberrations, including 1q+, 2p+, 3p+, 3q+, 4p+, 4q+, 5p+, 5q+, 6q+, 8p+, 8q+, 9q+, 12p+, 12q+, 18p+, 18q+, Xp+, and Xq+. In 2 metastases, 9 and 10 aberrations were seen, including 1q+, 3p-, 3q-, 4q+, 5p+, 5q+, 8q+, 10p+, 10q+, Xp+, and Xq+. In 9 cases of other entities of HCC, a mean of 10.2 aberrations per case were detectable affecting 1q (7 cases), 4q (5), 5q (4), 6q (5), 8p (5), 8q (5), 9p (4), 9q (5), 16q (4), 17p (5), and 17q (4). Chromosomes 2p, 2q, 3p, 3q, 4p, 5p, 6p, 7p, 7q, 10q, 11p, 11q, 12p, 12q, 13q, 14q, 16p, 18p, 18q, 20p, 20q, and 21q were altered in up to 3 samples. Our findings indicate striking differences in the number of chromosomal imbalances in primary FLC and recurrent FLC, whereas imbalances seen in the recurrent FLC and the other entities of HCC were similar in number and chromosomes involved. It may be speculated that these aberrations represent secondary events based on a genetic instability and do not mirror the primary alterations in these carcinomas.
Epstein, BE, TF Pajak, TL Haulk, JM Herpst, SE Order and RA Abrams 1999Metastatic nonresectable fibrolamellar hepatoma: prognostic features and natural history. Am J Clin Oncol 22(1): 22-28. Fibrolamellar hepatoma has a clinical course distinct from that of typical histologic hepatocellular carcinoma. The clinical behavior and prognostic features of nonresectable metastatic fibrolamellar hepatoma have not previously been fully addressed and are the focus of this report. Retrospective chart review of all patients (n = 17) with nonresectable metastatic fibrolamellar hepatoma referred to the Johns Hopkins Oncology Center from 1985 through 1990 was carried out. All patients had hepatic parenchymal involvement and regional node metastases at the time of referral. Metastases were limited to regional nodes in four patients. The remaining patients had lung metastases (n = 4), peritoneal metastases (n = 5), or both (n = 4). To assess the impact of the fibrolamellar variant, characteristic-matched control patients with typical histologic hepatocellular carcinoma were obtained from the Radiation Therapy Oncology Group database. Actuarial median survival from treatment was 14 months in the patients with fibrolamellar hepatoma and 7.7 months in the patients with hepatocellular carcinoma (p < 0.001). Karnofsky performance status and hepatic tumor volume at time of referral were important prognostic features. Multimodality treatment included radiation therapy and radiolabelled antibody, cisplatin-based chemotherapy, or both; results are discussed. Thirteen patients died, nine of liver failure, three of metastatic disease, and one of sepsis. Fibrolamellar histologic type, liver function tests, tumor volume, and patient performance status were significant predictors of survival. The cause of death in fibrolamellar hepatoma differs considerably from that observed in typical histologic hepatocellular carcinoma in the United States. The techniques of treatment of this uncommon disease were modeled after advances in the multimodality treatment of hepatocellular carcinoma and are discussed. Median survival was 14 months in patients with metastatic nonresectable fibrolamellar hepatoma.
Herrmann, G 1999Immunohistochemical study of HBV antigens in 338 liver cell carcinomas. Z Gastroenterol 37(5): 329-342. Tumor tissue (n = 338) and liver parenchyma (n = 276) from patients of Asian (n = 31) and European descent (n = 307) with hepatocellular carcinoma (HCC, n = 299), cholangiocellular carcinoma (CCC, n = 16) and combined HCC/CCC (n = 23) were screened with immunohistochemical methods for HBV antigens (HBs, preS1, preS2, HBc, HBe and HBx). Of the HCC cases nine were of the fibrolamellar type (FLC). All cases of HCC/CCC and CCC were from Western European patients. HBV antigens could be demonstrated more frequently in HCC cases of Asian descent (59.09% in liver parenchyma and 66.67% in tumor tissue) compared to Western European HCC cases (23.11% and 30.77%; chi-square test, p = 0.0003 and p = 0.0001, respectively), HCC/CCC (26.32% and 30.43%), CCC (7.14% and 20%) and FLC (0% and 25%). Results for HBx were not considered here due to questionnable HBV specificity of the antibodies employed. Immunohistochemical detection mainly HBs, whereas HBc, HBe and preS antigens played only a minor part. Comparing the results obtained with a rabbit and a goat polyclonal HBs antibody and a cocktail of seven monoclonal HBs antibodies showed statistically significant superior sensitivity for the goat antibody. Reactivity of tumor tissue for HBc and/or HBe as observed in twelve cases is suggestive of virus replication within tumor tissue. These data plus the demonstration of HBV antigens within so-called proliferated bile ducts, which represent metaplastic hepatocytes, underscore the nature of CCC as malignant counterpart of proliferated bile ducts. Consequently, it is proposed to divide the entity liver cell carcinoma (LCC) into the subcategories HCC and CCC in contrast to adenocarcinomas arising from bile ducts or peribiliary glands. In conclusion, HBV seems to play a part in the pathogenesis of LCC in Asian and in Western European patients. Further factors like HCV and other chronic inflammatory processes may be employed here.
Ichikawa, T, MP Federle, L Grazioli, J Madariaga, M Nalesnik and W Marsh 1999Fibrolamellar hepatocellular carcinoma: imaging and pathologic findings in 31 recent cases. Radiology 213(2): 352-361. PURPOSE: To review characteristic findings of fibrolamellar hepatocellular carcinoma (HCC) at computed tomography (CT) and magnetic resonance (MR) imaging. MATERIALS AND METHODS: The authors retrospectively reviewed the clinical, pathologic, and preoperative imaging findings in 31 patients with histologically proved fibrolamellar HCC. Dynamic contrast material-enhanced CT of the liver was performed in 31 patients, helical multiphase CT in 21, and MR imaging in 11. Complete resection was performed in 17 patients, and imaging-pathologic correlation was performed. RESULTS: Large tumors (mean diameter, 13 cm) were depicted at CT and MR in all cases. At CT, the margins of the tumors were well defined in 24 (77%) of 31 cases calcifications were depicted in 21 (68%), a central scar in 22 (71%), and abdominal lymphadenopathy in 20 (65%). In 20 (80%) of 25 cases with hepatic arterial phase CT images, all tumors were heterogeneous and depicted areas of hypervascularity. At MR imaging, tumors were hypointense to liver on T1-weighted images (n = 11) and hyperintense to liver on T2-weighted images (n = 10). Calcification was not depicted on MR images, but a central scar was depicted as hypointense to surrounding tumor in nine cases. CONCLUSION: CT and MR images demonstrate characteristic features that may allow confident diagnosis of fibrolamellar HCC.
Stenram, U, B Ohlsson and KG Tranberg 1999Immunohistochemical expression of metallothionein in resected hepatic primary tumors and colorectal carcinoma metastases. Apmis 107(4): 420-424. Metallothionein is a protein with affinity for metals and is present in several tumors. We examined its immunohistochemical expression in 37 resected primary liver tumors and 117 colorectal metastases. The reaction was intense in the two fibrolamellar hepatocellular carcinomas and in many of the hepatocytes of the pseudotumor case of focal nodular hyperplasia. The reaction was low or moderate in 5 of 17 ordinary hepatocellular carcinomas and in 4 of 14 cholangiocellular carcinomas. There was no reaction in one case each of spindle cell hepatocellular carcinoma, oncocytic adenoma and hemangioendothelial sarcoma. In the metastases, the reaction was low or moderate in 14 cases and negative in 103. Surrounding hepatocytes and stromal cells were more or less positive in all cases.
Terris, B, P Pineau, L Bregeaud, D Valla, J Belghiti, P Tiollais, C Degott and A Dejean 1999Close correlation between beta-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene 18(47): 6583-6588. Several lines of evidence indicate that beta-catenin acquires oncogenic activity when its intracellular concentration increases as a result of either mutation in the beta-catenin gene itself or inactivation of the adenomatous polyposis coli (APC) gene. In an attempt to elucidate the molecular mechanisms underlying hepatocellular carcinogenesis, we have studied the frequency of beta-catenin gene alterations in exon 3, a region known to represent a mutation hot spot, and its inappropriate protein expression by immunohistochemistry in 73 hepatocellular carcinomas (HCCs). The results were correlated with different clinical and pathological data, particularly with the presence or not of an associated cirrhosis. Fourteen (19%) HCCs showed beta-catenin gene alterations with missense mutations in nine cases and interstitial deletions in five cases. These genetic alterations were present in both cirrhotic and non-cirrhotic groups. By contrast, we did not find any beta-catenin gene alterations in the nine fibromellar carcinomas we examined. Nuclear accumulation of the protein was observed in 18 of them (25%). Remarkably, these included ten of the 14 tumors harboring somatic mutations in the beta-catenin gene (P < 0.001). Our results indicate that accumulation of beta-catenin resulting from genetic mutations is a frequent event in non-fibrolamellar type hepatocellular carcinoma. The close association between increased beta-catenin protein stability and mutation indicates that immunohistochemistry may be a powerful method for the detection of the mutated protein in future clinical practice.
Agarwal, VR, K Takayama, JJ Van Wyk, H Sasano, ER Simpson and SE Bulun 1998Molecular basis of severe gynecomastia associated with aromatase expression in a fibrolamellar hepatocellular carcinoma. J Clin Endocrinol Metab 83(5): 1797-1800. This report represents the first study in the literature linking development of severe gynecomastia, in a 17 1/2-yr-old boy, to high levels of aromatase expression in a large fibrolamellar hepatocellular carcinoma, which gave rise to extremely elevated serum levels of estrone (1200 pg/mL) and estradiol-17 beta (312 pg/mL) that suppressed FSH and LH (1.3 and 2.8 IU/L, respectively), and consequently testosterone (1.53 ng/mL). After removal of a 1.5-kg hepatocellular carcinoma, gynecomastia partially regressed, and essentially, normal hormone levels were restored (estradiol-17 beta, < 50 pg/mL; estrone, 74 pg/mL; testosterone, 6.85 ng/mL; and FSH/LH, 6.3/3.7 mIU/mL). Conversion of C19 steroids to estrogens occurs in a number of human tissues and is catalyzed by aromatase P450 (P450arom), the product of the CYP19 gene in a number of human tissues. Tissue-specific promoters are used to regulate P450arom gene transcription in adult human tissues, e.g. promoters I.4 and I.3 in adipose fibroblasts, and promoter II in the gonads. Human fetal liver uses promoter I.4 to express markedly high levels of P450arom, whereas hepatic P450arom expression normally becomes undetectable in postnatal life. Using immunohistochemistry, diffuse intracytoplasmic aromatase expression was detected in the liver cancer cells from this severely feminized boy. Northern analysis indicated the presence of P450arom transcripts in total RNA from the hepatocellular cancer but not in the adjacent liver nor in disease-free adult liver samples. Promoter use for aromatase expression was determined by a specific RT-PCR method. Promoters I.3 and II were used for P450arom gene expression in the hepatocellular cancer tissue. Because aromatase is not expressed in the disease-free adult liver, the presence of extremely high levels of aromatase expression in this fibrolamellar hepatocellular carcinoma tissue is intriguing, particularly because there is preferential use of the proximally located P450arom promoters I.3 and II by the tumor, instead of the much more distally located fetal liver-type promoter I.4.
Cheetham, ME and AJ Caplan 1998Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chaperones 3(1): 28-36. This report represents the first study in the literature linking development of severe gynecomastia, in a 17 1/2-yr-old boy, to high levels of aromatase expression in a large fibrolamellar hepatocellular carcinoma, which gave rise to extremely elevated serum levels of estrone (1200 pg/mL) and estradiol-17 beta (312 pg/mL) that suppressed FSH and LH (1.3 and 2.8 IU/L, respectively), and consequently testosterone (1.53 ng/mL). After removal of a 1.5-kg hepatocellular carcinoma, gynecomastia partially regressed, and essentially, normal hormone levels were restored (estradiol-17 beta, < 50 pg/mL; estrone, 74 pg/mL; testosterone, 6.85 ng/mL; and FSH/LH, 6.3/3.7 mIU/mL). Conversion of C19 steroids to estrogens occurs in a number of human tissues and is catalyzed by aromatase P450 (P450arom), the product of the CYP19 gene in a number of human tissues. Tissue-specific promoters are used to regulate P450arom gene transcription in adult human tissues, e.g. promoters I.4 and I.3 in adipose fibroblasts, and promoter II in the gonads. Human fetal liver uses promoter I.4 to express markedly high levels of P450arom, whereas hepatic P450arom expression normally becomes undetectable in postnatal life. Using immunohistochemistry, diffuse intracytoplasmic aromatase expression was detected in the liver cancer cells from this severely feminized boy. Northern analysis indicated the presence of P450arom transcripts in total RNA from the hepatocellular cancer but not in the adjacent liver nor in disease-free adult liver samples. Promoter use for aromatase expression was determined by a specific RT-PCR method. Promoters I.3 and II were used for P450arom gene expression in the hepatocellular cancer tissue. Because aromatase is not expressed in the disease-free adult liver, the presence of extremely high levels of aromatase expression in this fibrolamellar hepatocellular carcinoma tissue is intriguing, particularly because there is preferential use of the proximally located P450arom promoters I.3 and II by the tumor, instead of the much more distally located fetal liver-type promoter I.4.
Gruner, BA, TS DeNapoli, W Andrews, G Tomlinson, L Bowman and SD Weitman 1998Hepatocellular carcinoma in children associated with Gardner syndrome or familial adenomatous polyposis. J Pediatr Hematol Oncol 20(3): 274-278. PURPOSE: Gardner syndrome, a variant of familial adenomatous polyposis, is characterized by colonic polyps that undergo malignant change and benign and malignant extracolonic lesions. Tumors frequently associated with Gardner syndrome include carcinoma of the ampulla of Vater, papillary carcinoma of the thyroid, and, in children, hepatoblastoma. The childhood malignancies often precede the appearance of other manifestations by several years. PATIENTS AND METHODS: Two patients are described. Gardner syndrome was diagnosed in a 15-year-old girl with fibrolamellar hepatocellular carcinoma after desmoid tumors and colonic polyposis developed. Classic hepatocellular carcinoma was also diagnosed in a 9 1/2-year-old boy with familial adenomatous polyposis. RESULTS: In patient 1, the diagnosis of fibrolamellar hepatocellular carcinoma preceded the diagnosis of Gardner syndrome by almost 2 years. The diagnosis was confirmed by identifying a germline mutation of the adenomatous polyposis coli (APC) gene. This is the first patient reported with fibrolamellar hepatocellular carcinoma associated with Gardner syndrome. Patient 2 had a strong family history of familial adenomatous polyposis but no manifestations of Gardner syndrome. He was not tested for the APC mutation. The current literature and previously reported cases of hepatocellular carcinoma in patients with Gardner syndrome or familial adenomatous polyposis are reviewed. CONCLUSIONS: Because hepatocellular carcinoma is uncommon in the pediatric and adolescent population, it is important to consider the possibility of Gardner syndrome or familial adenomatous polyposis in these patients.
Honda, K, E Sbisa, A Tullo, PA Papeo, C Saccone, S Poole, M Pignatelli, RR Mitry, S Ding, A Isla, A Davies and NA Habib 1998p53 mutation is a poor prognostic indicator for survival in patients with hepatocellular carcinoma undergoing surgical tumour ablation. Br J Cancer 77(5): 776-782. Forty-two patients with hepatocellular carcinoma (HCC) were resected and their tumours were analysed for p53 mutations by GC-clamped denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP) and gene sequencing. All the exons have been analysed in this study. Eight of 12 HCCs with cirrhosis due to viral hepatitis and the two patients with sarcomatoid changes displayed p53 mutations. In contrast, no mutation was observed in the fibrolamellar variant (n = 9), non-cirrhotics (n = 13) and alcoholic cirrhosis (n = 6). The mutations observed were in exons 5-8. Two mutations were observed in codons 136 and 213 as well as a T insertion between residues 156 and 157 (exon 5) and these are reported for the first time in HCC. Likewise, the silent mutation polymorphism in codon 213 was noticed in 3 of the 42 patients. Survival analysis of these patients after surgery showed the mean and median survival in patients with wild-type p53 to be 60 and 43 months respectively. In the group with p53 mutations, the mean and median survival was 15 and 12 months. The difference was statistically significant (P= 0.003).
Tallini, G 1998Oncocytic tumours. Virchows Arch 433(1): 5-12. Oncocytic tumours represent a distinctive set of lesions with distinctive granular cytoplasmic eosinophilia of the neoplastic cells. These cells are called oncocytes because of the "swollen" appearance they have as the result of a striking accumulation of mitochondria. Although generally uncommon, oncocytic tumours are by no means rare and have been reported, with different frequencies, in virtually every organ. A variety of biochemical and molecular changes have been identified, and the aberrant biogenesis of mitochondria in oncocytic cells bears intriguing similarities to that of a group of degenerative disorders known as mitochondrial encephalomyopathies. Although the relationship between the accumulation of mitochondria and the occurrence of tumours is unknown, investigation into the cellular alterations of oncocytes may further our knowledge of a variety of important biological processes such as proliferation, energy production and ageing.
Hany, MA, DR Betts, M Schmugge, E Schonle, FK Niggli, M Zachmann and HJ Pluss 1997A childhood fibrolamellar hepatocellular carcinoma with increased aromatase activity and a near triploid karyotype. Med Pediatr Oncol 28(2): 136-138. We report a 15-year-old boy with hepatocellular carcinoma (HCC) of the fibrolamellar type. He presented with advanced disease and a non-resectable tumor. Clinical features included marked gynecomastia which had been present for 3 years, failure to enter puberty, and failure to thrive. These features might have been due to a high aromatase activity of the tumor. The course of the illness suggested that the tumor had been present for at least 3 years prior to diagnosis. At diagnosis the patient had multiple metastases which included infiltrated ascites. Cytogenetic analysis of the ascites revealed a near triploid karyotype with cell-to-cell variation and an abnormality of chromosome 1 q. This to our knowledge is the first karyotype report of fibrolamellar HCC in a child.
Hemming, AW, B Langer, P Sheiner, PD Greig and BR Taylor 1997Aggressive surgical management of fibrolamellar hepatocellular carcinoma. J Gastrointest Surg 1(4): 342-346. Fibrolamellar hepatocellular carcinoma (FLHC) is recognized as a distinct clinicopathologic variant of hepatocellular carcinoma. Ten consecutive patients with FLHC undergoing operative management at our institution were reviewed. At the initial presentation seven patients had stage II disease (pT2N0M0), whereas three patients were in stage III (pT2N0M0 or pT3N0M0). Initial procedures included formal right or left hepatectomy in four patients, right or left trisegmentectomy in two patients, left lateral segmentectomy or nonanatomic resection in three patients, and in one patient considered for liver transplantation, only exploration with biopsy of positive nodes was performed. Four stage II patients required a second procedure for resection of recurrent disease from 8 months to 6 years after the initial resection and one patient required a third procedure after 13 years. Reoperations included hepatic re-resection, resection of extrahepatic disease, and liver transplantation. Overall 5- and 10-year Kaplan-Meier survival was 70%. There were no deaths among stage II patients (follow-up 96 to 180 months). All stage III patients (i.e., lymph node involvement, vascular invasion, or multiple tumors) died within 5 years. Patients with stage II disease had better survival than patients with stage III disease (P = 0.011, log-rank test). Aggressive treatment of FLHC including reoperation and liver transplantation is justified, especially in patients with stage II disease.
Orsatti, G, P Hytiroglou, SN Thung, KG Ishak and F Paronetto 1997Lamellar fibrosis in the fibrolamellar variant of hepatocellular carcinoma: a role for transforming growth factor beta. Liver 17(3): 152-156. Transforming growth factor-beta (TGF-beta) is a pluripotent regulatory molecule, found in at least five different isoforms. It is produced in many different organs. In the liver, TGF-beta is expressed in non-parenchymal cells, but not in hepatocytes. This growth factor is known to induce fibrosis in the course of a variety of pathologic processes. Recently, TGF-beta has also been identified in hepatocellular carcinoma (HCC) cells, and the suggestion has been made that this growth factor may play a role in hepatocarcinogenesis. In this study, we report the findings of immunohistochemical stains for TGF-beta, performed on paraffin sections of 14 human HCCs of the usual type and 11 examples of the fibrolamellar variant (FLC). TGF-beta was detected in tumor cells of 3 HCCs (21%) and 9 FLCs (82%). Compared with the HCCs, the FLCs displayed a more diffuse and intense staining pattern for TGF-beta. Our findings suggest that lamellar fibrosis, which is a histologic hallmark of FLC, may be due to the action of TGF-beta produced by tumor cells.
Bower, M, ES Newlands and N Habib 1996Fibrolamellar hepatocellular carcinoma responsive to platinum-based combination chemotherapy. Clin Oncol (R Coll Radiol) 8(5): 331-333. A patient with advanced unresectable fibrolamellar hepatocellular carcinoma is reported, who was treated with cisplatinum, epirubicin and 5-fluorouracil combination chemotherapy. Tumour regression was achieved, enabling major debulking surgery to be performed. The patient remains in clinical remission 11 months after completing therapy.
Kaczynski, J, B Gustavsson, G Hansson and S Wallerstedt 1996Fibrolamellar hepatic carcinoma in an area with a low incidence of primary liver cancer: a retrospective study. Eur J Surg 162(5): 367-371. OBJECTIVE: To assess the incidence and prognosis of fibrolamellar hepatic carcinoma in a defined population. DESIGN: Retrospective study of histological slides. SETTING: University hospital, Sweden. SUBJECTS: The 532 patients (out of a total of 711 who were treated at the university hospital during a 22 year period 1 January 1958-31 December 1979) whose primary hepatocellular carcinoma was confirmed on review of the histological slides. MAIN OUTCOME MEASURES: Incidence and prognosis of fibrolamellar hepatic carcinoma. RESULTS: Two patients (women aged 22 and 46) were found to have fibrolamellar tumours and in both they were advanced and the patients died 2 weeks and 9 months, respectively, after exploratory laparotomy. If these are taken as a proportion of the 18 patients who were under the age of 50 at the time of diagnosis then the incidence of the fibrolamellar type of hepatocellular carcinoma is 11%. Since then (in 1993) we have come across one further case, a woman of 39 who was well 22 months after operation though she had metastatic disease. CONCLUSIONS: The fibrolamellar type of hepatocellular carcinoma is rare, and all three of our cases were young women (under the age of 50). It seems to have a slightly better prognosis than other types of primary hepatic tumours.
Lowichik, A, NR Schneider, V Tonk, MQ Ansari and CF Timmons 1996Report of a complex karyotype in recurrent metastatic fibrolamellar hepatocellular carcinoma and a review of hepatocellular carcinoma cytogenetics. Cancer Genet Cytogenet 88(2): 170-174. Metastatic fibrolamellar hepatocellular carcinoma (HCC) was detected in the abdominal lymph nodes of an adolescent male after resection of the primary tumor. No dividing cells were isolated from attempted cytogenetic studies of the primary tumor. However, cytogenetic analysis of lymph node metastases detected 9 and 12 months after partial hepatectomy revealed abnormal hypertriploid karyotypes, with a suggestion of clonal evolution: 62-92 < 3n >,XX, -Y, +3, +6, +6, +7, +7, +8, +10, +13, +15, +16, +20, -21, -22, +mar1 x 2, +mar[cp6]/46,XY[8] and 78 < 3n >,XX, -Y,der(1)t(1;1)(p36.1;q21), +4, +6, +6, +7, +7,i(8)(q10), +10, +15, +20, -21, -22, +mar1 x 2, +mar2[3]/46, XY[17], respectively. Karyotypes of this variant of HCC have not been reported previously. The cytogenetics of HCC are reviewed.
Scoazec, JY, JF Flejou, A D'Errico, M Fiorentino, A Zamparelli, AF Bringuier, G Feldmann and WF Grigioni 1996Fibrolamellar carcinoma of the liver: composition of the extracellular matrix and expression of cell-matrix and cell-cell adhesion molecules. Hepatology 24(5): 1128-1136. We have analyzed the composition of the tumor stroma and the expression of cell-matrix and cell-cell adhesion molecules in 11 cases of fibrolamellar carcinoma of the liver (FLC), in comparison with 34 cases of hepatocellular carcinoma and 8 cases of focal nodular hyperplasia. Fibrolamellar carcinoma was characterized by the presence of large amounts of tenascin in tumor stroma and by the scarce expression of basement membrane components at the contact of neoplastic clusters. Like normal hepatocytes, neoplastic cells constantly expressed the alpha1 integrin chain, lacked the beta4 integrin chain, and coexpressed E-cadherin and the hepatocyte N-related cadherin. Abnormalities in the expression of cell adhesion molecules, including altered cadherin expression, alphaV integrin chain induction, and CD44 expression, were detected in the majority of cases. The composition of the tumor stroma and the pattern of expression of cell adhesion molecules in fibrolamellar carcinoma were reminiscent of those observed in grade III and grade IV hepatocellular carcinomas. Our results therefore show that, despite its slow local growth and good prognosis, fibrolamellar carcinoma expresses many characteristics usually associated with clinically aggressive malignancies. Further studies are needed to identify the factors responsible for the apparent dissociation between clinical behavior and biological characteristics in this tumor.
Stevens, WR, CD Johnson, DH Stephens and DM Nagorney 1995Fibrolamellar hepatocellular carcinoma: stage at presentation and results of aggressive surgical management. AJR Am J Roentgenol 164(5): 1153-1158. OBJECTIVE: The purpose of this study was to report the stage of fibrolamellar carcinoma at presentation and the imaging findings of postoperative recurrent tumor in an aggressively managed population and to assess the implications of those findings relative to the patients' management. MATERIALS AND METHODS: Imaging studies in 10 patients with pathologically proved fibrolamellar carcinoma were reviewed. Preoperative studies included CT (n = 10), sonography (n = 8), and MR imaging (n = 2). Postoperative studies included CT (n = 9), sonography (n = 4), and MR imaging (n = 1). Imaging findings were correlated with clinical and surgical follow-up data. Patients were followed up for 2-75 months (median, 26 months). RESULTS: At presentation, seven (70%) of 10 patients had metastatic lymphadenopathy. Seven patients (70%), including four with lymph node metastasis, had tumor resections with intent to cure. Postoperative imaging studies revealed recurrent tumor in all seven of these patients, including six patients (86%) who had intrahepatic recurrence with or without lymph node metastasis after 6-18 months, and one patient (14%) who had distant metastases 66 months postoperatively. Recurrent lesions were subsequently resected in three (43%) of seven patients, who were disease-free at a mean of 8 months after their second resection. Five patients died after 9 months mean survival, and two patients were alive with residual tumor after 3 months mean follow-up. CONCLUSION: Fibrolamellar carcinomas are often of advanced stage at diagnosis. Recurrence after resection with intent to cure is common. Early and frequent follow-up imaging is necessary for optimizing surgical management in patients with fibrolamellar carcinoma.
Yuan, CY, CC Yuan, GF Shiou, CH Tseng and MT Yau 1995Fibrolamellar variant of hepatocellular carcinoma--report of a Chinese patient. Hepatogastroenterology 42(2): 182-184. Fibrolamellar hepatocellular carcinoma is rare. By chance, a Chinese woman detected a mass in the right upper quadrant of the abdomen. Ultrasonography, computed tomography and magnetic resonance imaging revealed a solid tumor with a central fibrous scar locating at the posterior inferior subsegment of the right hepatic lobe. The tumor was successfully resected and histopathological examination revealed a fibrolamellar hepatocellular carcinoma. Our case shows that fibrolamellar hepatocellular carcinoma may also occur in Chinese as well as in Japanese and Westerners.
Cyr, DM, T Langer and MG Douglas 1994DnaJ-like proteins: molecular chaperones and specific regulators of Hsp70. Trends Biochem Sci 19(4): 176-181. The folding of proteins and the assembly of protein complexes within subcompartments of the eukaryotic cell is catalysed by different members of the Hsp70 protein family. The chaperone function of Hsp70 proteins in these events is regulated by members of the DnaJ-like protein family, which occurs through direct interaction of different Hsp70 and DnaJ-like protein pairs that appear to be specifically adapted to each other. This review highlights the diversity of functions of DnaJ-like proteins by using specific examples of DnaJ-Hsp70 interactions with polypeptides in yeast protein-biogenesis pathways.
Ehrenfried, JA, Z Zhou, JC Thompson and BM Evers 1994Expression of the neurotensin gene in fetal human liver and fibrolamellar carcinoma. Ann Surg 220(4): 484-489; discussion 489-491. OBJECTIVE: This study determined whether the neurotensin gene (NT/N) is expressed in the normal adult liver and focal nodular hyperplasia (FNH) and confirmed NT/N expression in fibrolamellar carcinoma; whether NT/N or the neurotensin receptor is expressed in the fetal liver; and whether hepatic resection leads to expression of NT/N. SUMMARY BACKGROUND DATA: Neurotensin (NT), a gut tridecapeptide localized in the gastrointestinal tract of the adult to the small bowel, is an important hormone-regulating gut motility, secretion, and mucosal growth. Expression of the NT/N gene has been identified in fibrolamellar carcinomas, but NT/N is not known to be expressed in the normal liver. METHODS: Sensitive ribonuclease (RNase) protection assays were used to determine whether NT/N is expressed in fibrolamellar carcinoma, FNH, or healthy fetal and adult livers. The authors also determined whether the receptor for NT was present in the fetal liver and whether liver resection and subsequent regeneration could lead to re-expression of NT/N in the rat. RESULTS: Neurotensin is expressed in fibrolamellar carcinoma and in the fetal human liver, but not in the adult liver or the samples of FNH. In addition, the authors were not able to detect expression of the NT receptor in the fetal liver and did not identify NT/N gene activation in the regenerating liver of the rat. CONCLUSIONS: The NT/N gene will be a useful molecular marker to differentiate fibrolamellar carcinoma from other liver tumors. The finding of NT/N expression in the fetal liver suggests a stem cell descendant that is common to both the liver and gut. The absence of NT/N expression in the regenerating liver suggests that NT does not play a role in this rapid growth process.
Orsatti, G, PD Greenberg, DB Rolfes, KG Ishak and F Paronetto 1994DNA ploidy of fibrolamellar hepatocellular carcinoma by image analysis. Hum Pathol 25(9): 936-939. Twelve cases of fibrolamellar hepatocellular carcinoma (FLC) were evaluated for DNA ploidy by means of image analysis of Feulgen-stained tissue sections. All of the tumors showed a nondiploid DNA distribution (six aneuploid and six tetraploid); no diploid pattern was found. The nuclear area of the tumors (53.8 microns 2 +/- 18.0; mean +/- standard deviation) was significantly larger than that of the surrounding noncancerous livers (33.2 +/- 4.7; P < .0001). These findings suggest that DNA content in fibrolamellar carcinoma (FLC) is not directly related to the clinical behavior and that other factors may be responsible for the better prognosis of this variant of HCC.
Caplan, AJ, DM Cyr and MG Douglas 1993Eukaryotic homologues of Escherichia coli dnaJ: a diverse protein family that functions with hsp70 stress proteins. Mol Biol Cell 4(6): 555-563.
Ding, SF, JD Delhanty, L Bowles, JS Dooley, CB Wood and NA Habib 1993Infrequent chromosome allele loss in fibrolamellar carcinoma. Br J Cancer 67(2): 244-246. As yet, there is no reported study of chromosome allele loss in fibrolamellar carcinoma (FLC), a distinct, rare variant of hepatocellular carcinoma (HCC). We searched for evidence of allele loss in FLC using 18 DNA probes for 10 chromosomes and compared the pattern of loss with our series of HCC. Two of the probes, lambda MS32 (1q42-43) and cMS621 (5p) showed allele losses in one tumour, while other probes showed no loss. The frequency of allele loss in FLC was much lower than in HCC, which may be associated with their different prognoses.
Silver, PA and JC Way 1993Eukaryotic DnaJ homologs and the specificity of Hsp70 activity. Cell 74(1): 5-6.
Wennerberg, AE, MA Nalesnik and WB Coleman 1993Hepatocyte paraffin 1: a monoclonal antibody that reacts with hepatocytes and can be used for differential diagnosis of hepatic tumors. Am J Pathol 143(4): 1050-1054. Hepatocyte paraffin 1 is a monoclonal antibody that has been developed specifically to react with hepatocytes in routine formalin-fixed and paraffin-embedded surgical pathology tissues. It results in a distinct, granular cytoplasmic staining of hepatocytes but fails to react with bile ducts and nonparenchymal liver cells. The antibody decorates a majority of hepatocellular carcinomas, including fibrolamellar variants. It fails to react with a wide variety of other adult malignancies, with the exception of focal staining in a few gastrointestinal malignancies, including a subpopulation of gastric carcinomas.
Zhao, M, JA Laissue and A Zimmermann 1993Neuroendocrine differentiation in hepatocellular carcinomas (HCCs): immunohistochemical reactivity is related to distinct tumor cell types, but not to tumor grade. We have analyzed neuroendocrine differentiation (ND) in hepatocellular carcinomas (HCCs) of fifty patients. It turned out that ND is frequent in HCCs, and that it is not restricted to fibrolamellar hepatocellular carcinoma (FL-HCC). Multiexpression is seen in a quarter of the cases, and marker coexpression may occur within the same tumor cell. ND predominates in trabecular and mixed HCCs, but does not appear to be related to grade. Most positive cases showed a hepatocyte-like cell morphology, frequently associated with bile formation. It thus appears that the HCC cell type most likely to show ND is a hepatocyte-like one, i.e. differentiated cell, frequently polarized and producing bile, rather than a small and poorly-differentiated cell. Possible pathogenic mechanisms leading to ND in HCCs are briefly discussed.
Nerlich, AG, S Majewski, N Hunzelmann, RE Brenner, B Wiebecke, PK Muller, T Kreig and K Remberger 1992Excessive collagen formation in fibrolamellar carcinoma of the liver: a morphological and biochemical study. Mod Pathol 5(5): 580-585. We have studied the excessive deposition of extracellular matrix in a patient with fibrolamellar carcinoma of the liver. The collagen matrix was predominantly composed of collagens I, III, and V. Since specific mRNAs for collagens I and III were detected by in situ hybridization, we also provide evidence that the fibroblastoid stromal cells were the major source of this collagen. Occasionally, also tumor cells could be shown to express collagen III-mRNA. Furthermore, some tumor cells showed positive signals for TGF-beta 1, while isolated stromal cells expressed interleukin-6. This cytokine expression may probably be related to the altered control of collagen gene expression.
Pi, ZM1992"[20 rare primary hepatic malignant tumors]Zhonghua Zhong Liu Za Zhi 14(3): 210-212.We collected 20 primary liver malignant tumors other than hepatocellular carcinoma from 1968 to 1990; sarcomas from mesenchymal tissue (hepatic leiomyosarcoma, hepatic fibrosarcoma, Kupffer cell sarcoma, hepatic lymphatic sarcoma), two subtypes of hepatocellular carcinoma (fibrolamellar carcinoma and clear cell carcinoma), hepatic carcinoid, squamous carcinoma, etc. Analysis with review of literature is given.
Iwatsuki, S, TE Starzl, DG Sheahan, I Yokoyama, AJ Demetris, S Todo, AG Tzakis, DH Van Thiel, B Carr, R Selby and et al. 1991Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 214(3): 221-228; discussion 228-229. During the 10-year period (1980 to 1989), 76 patients with hepatocellular carcinoma (HCC) were treated by subtotal hepatic resection (HX) and 105 patients by orthotopic liver transplantation (TX) under cyclosporine-steroid therapy. Overall 1- to 5-year survival rates of the HX group were 71.1%, 55.0%, 47.2%, 37.2%, and 32.9%, respectively, and those of the TX group were 65.7%, 49.0%, 39.2%, 35.6%, and 35.6%, respectively. The survival rates after HX and after TX correlated well with pTNM stages and were similar in each stage between the two groups. However, when HCC was associated with cirrhosis of the liver, the survival rates after TX were significantly better than those after HX at each stage of pTNM classification. The tumor-recurrence rate was high both after HX (50%) and TX (43%), particularly in advanced stages of pTNM classification (60% or more). Twelve patients after HX and 13 patients after TX lived more than 5 years during this 10-year period. Fibrolamellar HCC and early stages of HCC were highly represented among the long-term survivors. Further improvement in survival rates depends on nonsurgical anti-cancer therapy before and/or after surgical removal of HCC.
Read, D, A Shulkes, R Fernley and R Simpson 1991Characterization of neurotensin(6-13) from an hepatic fibrolamellar carcinoma. Peptides 12(4): 887-892. Neurotensin(6-13) has been isolated and sequenced as the major form of neurotensin-like immunoreactivity (NTLI) in a human hepatic fibrolamellar carcinoma. Circulating NTLI in the patient, especially C-terminal, was very high. In additional studies, NT(6-13) was synthesized and compared with the purified tumor NTLI by HPLC analysis and by testing stability in plasma in vitro. These methods confirmed that the tumor NTLI was identical to NT(6-13). Since the metabolic clearance rate of synthetic NT(6-13) in sheep was 30-fold higher than NT(1-13), it suggests that the elevated plasma levels are the result of impaired clearance and/or markedly elevated production.
Altmann, HW 1990Some histological remarks on the fibrolamellar carcinoma of the liver. Pathol Res Pract 186(1): 63-69. Investigations on five fibrolamellar carcinomas of the liver suggest that this tumor originates from purely epithelial proliferations, while the ensuing fibrous growth leading to lamellar formations is but a secondary event. Nevertheless, progressing fibrosis has a considerable influence on cell shape as the surrounded cell complexes are quasi immured, and their supply and transport procedures impaired. Its influence further evokes a compensatory increase of mitochondria so that, in advanced cases, these cells may be mistaken for genuine oncocytes, although the appraisal of an oncocytic tumor is not confirmed. At this point only, increased amount of fibrinogen-containing (endoplasmic) vacuoles and PAS positive globuli are interpreted as phenomena of cellular retention, and so is the accumulation of unexcretable copper. Ultimately, this fibrous incarceration will cause cell death, destruction and depletion resulting in abundant scarring especially in the center of the focus, without, however, signalling any close relationship with focal nodular hyperplasia. Excess fiber formation exerts a proliferation-inhibiting effect resulting in slower growth and consequently, in the more favorable prognosis of this tumor of distinctive and well-characterized morphology.
Ruffin, MT1990Fibrolamellar hepatoma. Am J Gastroenterol 85(5): 577-581. Primary hepatocellular carcinoma (HCC) has a high incidence rate worldwide with an extremely grave prognosis, but, fortunately, accounts for only 2% of all cancers in the United States. Yet, a unique subset of HCC fibrolamellar hepatocellular carcinoma (FLHC) is reported only from the United States. Five cases of FLHC from the University of Minnesota's 17 years of experience are reported and compared with the literature reports for FLHC, as well as contrasted to reports of HCC. The review of the literature is addressed for data evaluating FLHC as a distinct entity from HCC.
Van Eyken, P, R Sciot, P Brock, M Casteels-Van Daele, FC Ramaekers and VJ Desmet 1990Abundant expression of cytokeratin 7 in fibrolamellar carcinoma of the liver. Histopathology 17(2): 101-107. Two cases of fibrolamellar carcinoma of the liver, one with lymph node metastasis are reported. Using immunohistochemistry as well as one- and two-dimensional gel electrophoresis and Western blotting, tumour cells of both primary lesions and of the metastasis were found to express cytokeratin polypeptides 8 and 18 and, surprisingly, cytokeratin 7. A small number of cells also expressed cytokeratin 19. This is the first detailed analysis of the cytokeratin expression of fibrolamellar carcinoma, and is also the first to present biochemical evidence that, contrary to what has been suggested, hepatocellular carcinomas do not always preserve the pattern of cytokeratin expression of normal hepatocytes.
Haas, JE, KA Muczynski, M Krailo, A Ablin, V Land, TJ Vietti and GD Hammond 1989Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 64(5): 1082-1095. To determine the relationship between outcome and histologic type, the authors examined data from 168 cases of hepatoblastoma (HB) and 28 cases of hepatocarcinoma (HC) accrued from children over a 14-year period. After adjustment for stage of disease, there was no significant difference in median survival between HB and HC. Mitotic activity was associated with poor prognosis. Necrosis or vascular invasion did not influence prognosis. In 55 cases of completely resected HB, pure fetal histologic type (PFH) was associated with improved survival when compared with all other histologic patterns of HB (92% versus 57% 24 months' survival; P = 0.02). A prognostic effect of PFH was not demonstrable in incompletely resected HB, but the absence of mitoses and the presence of differentiated mesenchymal elements improved survival. The fibrolamellar pattern of HC demonstrated survival similar to that of the typical pattern of HC. The authors conclude that features consistent with differentiation in HB convey improved prognosis for survival. These observations may be important in designing future therapy for children with hepatic tumors.
Kwee, HG 1989Fibrolamellar hepatocellular carcinoma. Am Fam Physician 40(2): 175-177. Fibrolamellar hepatocellular carcinoma is a primary malignant tumor of the liver that usually affects adolescents and young adults. If detected early, this cancer is frequently resectable, with a much longer survival time than in classic hepatocellular carcinoma. Fibrolamellar hepatocellular carcinoma has distinct radiographic and pathologic features. Serum unsaturated vitamin B12 binding capacity and plasma neurotensin may be used as tumor markers.
Berman, MA, JA Burnham and DG Sheahan 1988Fibrolamellar carcinoma of the liver: an immunohistochemical study of nineteen cases and a review of the literature. Hum Pathol 19(7): 784-794. Hepatocellular carcinoma (HCC) is a rapidly fatal neoplasm of high worldwide prevalence. Fibromellar carcinoma (FLC), a variant of HCC, lacks the dismal prognosis of "ordinary" HCC (O-HCC) and is characterized by a diagnostic histologic appearance. The current study analyzes the clinical characteristics, immunohistochemistry, and treatment of nineteen cases of FLC. These data, together with a detailed review of the literature, further characterize this unique variant. FLC affects younger patients and lacks the male predominance of O-HCC. Also, FLC lacks specific association with cirrhosis, hepatitis B virus infection, use of oral contraceptives, and alcohol abuse, all of which are implicated in other hepatic tumors. This, along with differences in serum tumor marker prevalence (AFP, B12 binding protein) suggests that its pathogenesis differs from that of O-HCC. Despite these differences, FLC shares a common differentiation with O-HCC. The increased amounts in FLC of stainable alpha-1-antitrypsin, fibrinogen, and C-reactive protein, all of which are acute phase reactants and normal hepatocyte products, implies better differentiation of FLC cells. Finally, the better prognosis of FLC is supported by this study, since only two of the 19 patients died because of tumor. This contrasts with the reported survival of patients with O-HCC, usually measured in weeks. Hepatic transplantation may hold promise for future patients with "surgically unresectable" FLC as procedure-related complications are overcome.
Kohno, H, N Nagasue, H Taniura, T Nakamura and S Nagaoka 1988Fibrolamellar carcinoma of the liver--a case report from Japan and a review of the literature. HPB Surg 1(1): 77-80. The first Japanese case of fibrolamellar carcinoma (FLC) of the liver is described. The 17-year-old Japanese male affected died of the disease 25 months after palliative operation. The diagnosis of FLC had not been confirmed before autopsy. Pre-operative diagnosis of FLC is important to surgeons. According to the literature, FLC is rare in Asia. The endemic discrepancy may suggest that the carcinogenic factors are different from those of general hepatocellular carcinoma.
McCloskey, JJ, EL Germain-Lee, JA Perman, LP Plotnick and AH Janoski 1988Gynecomastia as a presenting sign of fibrolamellar carcinoma of the liver. Pediatrics 82(3): 379-382.
O'Grady, JG, RJ Polson, K Rolles, RY Calne and R Williams 1988Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg 207(4): 373-379. Ninety-three patients with malignant disease underwent orthotopic liver transplantation between May 1968 and April 1987 in the Cambridge/King's College Hospital program. Of 50 patients with primary hepatocellular carcinoma (HCC) (19 with cirrhosis, 31 without cirrhosis, including 7 with fibrolamellar variant), 37 (74%) survived for more than 3 months, and in this group evidence of tumor recurrence was obtained in 24 (64.9%), the longest survivor being 11.8 years post-transplant, and three survived for more than 5 years. Although there is no correlation between the frequency of tumor recurrence and underlying cirrhosis, or histologic type (except fibrolamellar variant), it was observed earlier in those with moderate/poorly differentiated tumors and also when prednisolone and azathioprine was used for immunosuppression. Tumor recurred in all but two of those with peripheral or central cholangiocarcinoma (one alive at 6.1 years) with median survival times of 34 weeks and 56 weeks for the central and peripheral types, respectively. Among the unusual primary tumors, one with epithelioid haemangioendothelioma developed tumor recurrence at 2 years, one of two patients with apudoma is tumor-free at 2.2 years, and the one patient with bile-duct papillary cystadenocarcinoma is alive at 1.7 years. For the secondary hepatic malignancy group, survival times were shorter with little palliation except for two patients with carcinoid syndrome who were free of associated symptoms at 6 and 10 months. Despite the overall high frequency of tumor recurrence in most categories of hepatic malignancy, liver transplantation gave worthwhile survival with a number of patients cured and in the others considerable palliation of symptoms.
Ruffin, MT1988Fibrolamellar hepatocellular carcinoma. Ann Intern Med 109(7): 596-597.
Vecchio, FM 1988Fibrolamellar carcinoma of the liver: a distinct entity within the hepatocellular tumors. A review. Appl Pathol 6(2): 139-148. Fibrolamellar carcinoma (FLC) of the liver is a clinicopathologic type of hepatocellular carcinoma (HCC) with a favorable prognosis with long-term survival. At variance with the usual HCC, FLC occurs predominantly in young people, both male and female, usually without preexisting liver disease. The distinctive pathologic features of FLC are presented and reviewed. Both gross and microscopic findings suggest that FLC is the malignant counterpart of focal nodular hyperplasia that may arise from preexisting focal nodular hyperplasia. The storage of copper and fibrinogen inside tumor cells is a peculiarity of FLC, and it appears to be in a close relationship with the oncocytic appearance of FLC cells having a deeply eosinophilic, finely granular, mitochondrion-rich cytoplasm. All other immunohistological and ultrastructural findings strongly support the high degree of differentiation of FLC.
Salisbury, JR and BC Portmann1987Oncocytic liver cell adenoma.Histopathology 11(5): 533-539.A 46-year-old woman underwent right hepatic lobectomy for the removal of a solitary liver tumour from a non-cirrhotic liver. The macroscopic and light microscopic features were those of a liver cell adenoma but the cells appeared oncocytic. Electron microscopy confirmed the numerous mitochondria characteristic of oncocytes. The difficulty of distinguishing oncocytic liver cell adenoma from fibrolamellar hepatocellular carcinoma is discussed.
Buamah, PK, P McArdle, M Bennett, OF James and R Lendrum 1986A pleomorphic hepatocellular carcinoma with biochemical features of fibrolamellar hepatocellular carcinoma. J Surg Oncol 32(2): 93-95. A case of pleomorphic hepatocellular carcinoma with biochemical characteristics similar to those of fibrolamellar carcinoma is described. During chemotherapy there was a marked disorder of vitamin B12 metabolism.
Huber, M, J Meier, P Meier and M Schmid 1986[Fibrolamellar hepatoma]. Schweiz Med Wochenschr 116(34): 1154-1158. Unlike hepatocellular hepatoma (HCC), the so-called fibrolamellar hepatoma (FLH) is found almost exclusively in the non-cirrhotic, non-infected liver. Patient characteristics and the course of the disease in FLH differ markedly from HCC. FLH represents only a small portion of hepatomas in general (approx. 2%), but accounts for over 40% of hepatomas in young adults. We present the case of a 38-year-old woman showing the typical histological findings of polygonal eosinophilic tumor cells and characteristic lamellar bundles of fibrous stroma, which led to the diagnosis of FLH. The approx. 140 cases of FLH published in the world literature are also presented and discussed. The usefulness of additional examinations (neurotensin, vitamin B12 binding capacity and copper stains) is mentioned. The difficulty in diagnosing FLH lies in its histological differentiation from focal nodular hyperplasia. When diagnosed early, however, FLH is characterized by good resectability with a chance of cure or at least a markedly better survival rate than HCC.
Payne, CM, RB Nagle, SH Paplanus and AR Graham 1986Fibrolamellar carcinoma of liver: a primary malignant oncocytic carcinoid? Ultrastruct Pathol 10(6): 539-552. Immunohistochemical and ultrastructural findings in two cases of fibrolamellar carcinoma of the liver and two cases of hepatocellular carcinoma of the common histologic type are described. Ultrastructural examination of both cases of fibrolamellar carcinoma revealed the presence of neurosecretory (NS) granules which were sparse in some cells and abundant in others. Many of the tumor cells had a distinct oncocytic appearance with abundant mitochondria. A portion of the glutaraldehyde-fixed neoplasm was processed for the uranaffin reaction (an ultrastructural cytochemical stain specific for the NS granules of neuroendocrine tissue). Abundant uranaffin-positive granules were found in the neoplastic cells of both cases of fibrolamellar carcinoma, whereas no uranaffin-positive granules were found in hepatocellular carcinoma of the common histologic type. There was no statistical difference in the mean diameter of the uranaffin-positive granules measured from both cases. Immunohistochemistry revealed the presence of neuron-specific enolase (NSE) and serotonin in one of the two cases of fibrolamellar carcinoma and no NSE staining in two cases of hepatocellular carcinoma of the common histologic type. These findings suggest that some liver tumors presenting histologically as fibrolamellar carcinoma may be neuroendocrine in nature.
Soreide, O, A Czerniak, H Bradpiece, S Bloom and L Blumgart 1986Characteristics of fibrolamellar hepatocellular carcinoma. A study of nine cases and a review of the literature. Am J Surg 151(4): 518-523. Clinical and laboratory data for nine patients with hepatocellular fibrolamellar carcinoma treated at our institution have been summarized with emphasis on the relevance of plasma neurotensin levels as a tumor marker. The mean age of the patients was 22 years. Seven underwent hepatic resection, and two of these had later surgical removal of recurrent disease. Plasma neurotensin levels were initially elevated in five of the seven patients in whom it was measured. Neurotensin levels were within normal limits in three of four patients with recurrent disease, but were elevated in one patient who also had elevated plasma neurotensin levels preoperatively. In addition, a review of 80 patients reported since 1980 was performed. The mean age of these patients was 23 years, and only 6 percent were older than 50. The male to female ratio was 3:4. Eight percent were positive for hepatitis B antigen and 11 percent had elevated alpha-fetoprotein levels. Four percent had cirrhosis of the liver. The resectability rate was 58 percent. Five year survival for patients who underwent hepatic resection was 56 percent. Patients treated nonsurgically had a median survival of 13 months, and none of these patients lived for 5 years. Fibrolamellar hepatoma seems to be a distinct clinical entity that mainly occurs in young patients. The prognosis in patients treated with a curative resection is good. Plasma neurotensin levels may be of value as a tumor marker, but further studies are necessary to substantiate this theory.
Starzl, TE, S Iwatsuki, BW Shaw, Jr., MA Nalesnik, DC Farhi and DH Van Thiel 1986Treatment of fibrolamellar hepatoma with partial or total hepatectomy and transplantation of the liver. Surg Gynecol Obstet 162(2): 145-148.Fourteen patients with fibrolamellar hepatoma were treated with radical excision. In eight, a subtotal hepatic resection was performed from 16 months to more than 16 years ago. None of the patients have died and recurrences have been seen in only one patient. Six other patients had total hepatectomy and hepatic replacement. Two of these six patients have died of metastases and a third is living with recurrent tumor. This experience has justified the continuing use of quite aggressive extirpative procedures for the treatment of fibrolamellar hepatoma.
Vecchio, FM, F Federico and MA Dina 1986Copper and hepatocellular carcinoma.Digestion 35(2): 109-114The presence of copper and copper-binding protein (CBP) within tumor cells was searched by histochemical methods (rhodanine, rubeanic acid and Shikata's orcein) in a group of 39 autopsies, all consecutive cases of hepatocellular carcinoma (HCC) associated with cirrhosis (HCC + C). In 2 cases, fibrolamellar carcinoma (FLC) not associated with cirrhosis was observed at surgery. Considerable amounts of copper and CBP were found within tumor cells only in the 2 FLC cases and in 1 HCC + C case, in a portion of the tumor showing FLC-like features. Copper-positive tumor cells had an oncocytic appearance, which was confirmed by ultrastructural examination. In 64% of the HCC + C cases (25 out of 39), copper and CBP deposits were found in nonneoplastic hepatocytes mainly distributed along the periphery of cirrhotic nodules. The present study indicates that the storage of copper inside tumor cells is a peculiarity of the FLC type of HCC with a close relationship to the oncocytic nature of neoplastic hepatocytes. The significance of copper deposits in nonneoplastic cirrhotic hepatocytes remains a matter for further investigations.
Xu, YH and RL Peters1986Mitochondrial abnormalities in hepatocytes adjacent to fibrolamellar hepatocellular carcinoma.J Tongji Med Univ 6(1): 26-30.
Caballero, T, J Aneiros, J Lopez-Caballero, M Gomez-Morales and F Nogales 1985Fibrolamellar hepatocellular carcinoma. An immunohistochemical and ultrastructural study. Histopathology 9(4): 445-456. Two cases of fibrolamellar carcinoma of the liver are reported in young female patients of 12 and 21 years of age. Small amounts of perinuclear alpha-fetoprotein were found, unrelated to hyaline globules, as well as alpha 1-antitrypsin in a periglobular fashion in isolated cells. Ferritin was present in a large number of cells. Ultrastructurally, the well differentiated nature of the neoplasm was substantiated by previously unreported findings such as intercellular lumina analogous to bile canaliculi and peroxisome-like bodies containing a central crystalloid. Filamentous material resembling Mallory's type of hyaline was also found. We conclude that both immunohistochemical and ultrastructural features reflect a high degree of differentiation.
Friedman, AC, JE Lichtenstein, Z Goodman, EK Fishman, SS Siegelman and AH Dachman 1985Fibrolamellar hepatocellular carcinomaRadiology 157(3): 583-587.Fibrolamellar hepatocellular carcinoma (HCC) has recently been separated as a distinct clinicopathologic entity with a better prognosis than the usual HCC associated with cirrhosis. The mean age of our 17 patients was 20 years. Alpha fetoprotein levels were normal, and none of the risk factors for HCC was present. Distinctive histologic features included deeply eosinophilic polygonal hepatocytes and abundant fibrous stroma. Calcification was present on plain films of five of 13 cases. Sonography usually showed a homogeneous, echogenic mass. Computed tomography (CT) demonstrated small, central calcification in four of ten cases. A central echodensity, hypodense on CT scans, was seen in two cases and corresponded to a central scar. By combining clinical and laboratory data with radiologic tests, a correct diagnosis can often be suggested before biopsy is performed.
Goodman, ZD, KG Ishak, JM Langloss, IA Sesterhenn and L Rabin 1985Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study. Cancer 55(1): 124-135. Combined hepatocellular-cholangiocarcinoma is a rare form of primary liver cancer showing features of both hepatocellular and biliary epithelial differentiation. In a review of 24 cases of this tumor, three histologic types were encountered. Four cases were Type I or "collision tumors," apparently a coincidental occurrence of both hepatocellular carcinoma and cholangiocarcinoma in the same patient. Twelve cases were Type II or "transitional tumors," in which there were areas of intermediate differentiation and an identifiable transition between hepatocellular carcinoma and cholangiocarcinoma. Eight cases were Type III or "fibrolamellar tumors" which resembled the fibrolamellar variant of hepatocellular carcinoma but which also contained mucin-producing pseudoglands. Type III tumors differ from other combined tumors, occurring at a younger age, in the absence of cirrhosis, and having a slightly longer survival. Immunohistochemical (immunoperoxidase) staining for intracellular antigens showed that alpha-fetoprotein is a fairly specific, although insensitive, marker of hepatocellular differentiation in primary liver cancers, being present in 50% of typical hepatocellular carcinomas and in hepatocellular areas in 29% of combined tumors, but in no cholangiocarcinomas or cholangiocellular areas of combined tumors. Keratin is a good marker of biliary epithelial differentiation, being found in 90% of cholangiocarcinomas and in 52% of combined hepatocellular cholangiocarcinomas, but in no hepatocellular carcinomas. Alpha-1-antitrypsin, fibrinogen, IgG, and carcinoembryonic antigen may be found in both hepatocellular carcinoma, cholangiocarcinoma, and in combined tumors; these antigens are therefore of limited use in differential diagnosis.
Iwatsuki, S, RD Gordon, BW Shaw, Jr. and TE Starzl 1985Role of liver transplantation in cancer therapy. Ann Surg 202(4): 401-407. Fifty-four patients underwent total hepatectomy and liver replacement in the presence of a primary liver malignancy. In 13 recipients in whom the hepatic tumors were incidental to some other endstage liver disease, recurrence was not seen and 12 of the 13 patients are alive after 4 months to 15 1/2 years. In contrast, tumors recurred in 3 of every 4 patients who received liver replacement primarily because of hepatic malignancies that could not be resected by conventional techniques of subtotal hepatectomy and who lived for at least 2 months after transplantation. The most encouraging results were in patients with the fibrolamellar hepatocellular carcinomas that grow slowly and metastasize late, but even with this lesion, the recurrence rate was 57%. In future trials, additional effective anticancer therapy will be needed to improve the results of liver transplantation for primary liver malignancy, but what an improved strategy should be has not yet been defined.
Suen, KC, JF Magee, LS Halparin, NH Chan and CA Greene 1985Fine needle aspiration cytology of fibrolamellar hepatocellular carcinoma. Acta Cytol 29(5): 867-872. The major cytologic features seen in fine needle aspirates from two cases of fibrolamellar hepatocellular carcinoma were: liver-like tumor cells, characterized by plump, polygonal forms with eosinophilic, granular cytoplasm; large oval nuclei with extremely prominent solitary nucleoli; and parallel bands of fibrous tissue and fibrocytes seen within the tumor fragments. Other helpful features included intracytoplasmic hyaline globules and well-delineated pale bodies. Clinically, the tumors occurred in young patients with noncirrhotic livers and ran a more favorable course than do other types of hepatocellular carcinoma.
Teitelbaum, DH, S Tuttle, LC Carey and KP Clausen 1985Fibrolamellar carcinoma of the liver. Review of three cases and the presentation of a characteristic set of tumor markers defining this tumor. Ann Surg 202(1): 36-41. This study demonstrates the unique clinical and histologic aspects of fibrolamellar hepatic carcinoma, a rare variant of hepatocellular carcinoma. Three cases are reviewed and an extensive study of immunologic and intracellular substances defining this tumor is presented. Length of survival was considerably longer than typical hepatoma. The cause of death generally is due to a lack of control of the primary tumor. Successful treatment appears to relate to the ability to perform a total excision of the primary hepatic tumor. Chemotherapy should be used only in the presence of metastatic disease. Surgical resection of metastatic disease, unlike the usual hepatocarcinoma, may have some beneficial use. Fibrinogen was found in all tumors. It is possible that this tumor produces fibrinogen to create its unique histologic appearance. Carcinoembryonic antigen is described for the first time in this tumor. Both deposits of alpha-1 antitrypsin and copper were found in most of the tissues studied. The presence and amounts of these substances differ markedly from the common type of hepatoma. This unique composition of intracellular components may both facilitate histologic diagnosis, particularly if the amount of tissue is limited, and give further insight into the etiology of this tumor.
van Tonder, S, MC Kew, J Hodkinson, J Metz and F Fernandes-Costa 1985Serum vitamin B12 binders in South African blacks with hepatocellular carcinoma. Cancer 56(4): 789-792. Sera from 242 South African blacks with hepatocellular carcinoma were assayed for unsaturated vitamin B12 binding capacity (UBBC) and vitamin B12 activity. Six patients were younger than 20 years of age, and 24% were younger than 30 years of age. Eighty-four percent of the patients had a slightly raised UBBC and 86% had a slightly elevated vitamin B12 value, but in no patient was an exceptionally high UBBC present. Serum UBBC and vitamin B12 were not higher in younger patients, and raised UBBC values were not related to serum alpha-fetoprotein values. Serum UBBC and vitamin B12 concentrations were not significantly different in patients with and without coexisting cirrhosis. In none of the patients with a UBBC above 3000 pg/ml was the fibrolamellar variant of hepatocellular carcinoma present. The authors conclude that South African blacks with hepatocellular carcinoma do not secrete an abnormal vitamin B12 binding protein.
Collier, NA, K Weinbren, SR Bloom, YC Lee, HJ Hodgson and LH Blumgart 1984Neurotensin secretion by fibrolamellar carcinoma of the liver. Lancet 1(8376): 538-540. Serum neurotensin concentrations were supranormal in 5 out of 20 patients with carcinoma of the liver. Liver specimens from 4 of these 5 patients demonstrated features typical of fibrolamellar carcinoma. Neurotensin may be suitable as a tumour marker for fibrolamellar carcinoma and may be useful for the detection of recurrences after treatment.
Giacomantonio, M, SH Ein, K Mancer and CA Stephens 1984Thirty years of experience with pediatric primary malignant liver tumors. J Pediatr Surg 19(5): 523-526. Since 1950, 48 infants and children from 10 weeks to 16 years of age presented with primary hepatic malignancy. Signs and symptoms ranged from asymptomatic to those of malignant disease. All patients had a palpable abdominal mass. Jaundice was seen in five patients, four of whom had preexisting cirrhosis. Three male children had evidence of precocious puberty. Whereas liver function tests were usually normal, alpha-fetoprotein levels, when elevated, proved useful diagnostically and as a tumor marker in follow-up. Hepatic angiography and computed tomography (CT) scans have provided the most valuable preoperative assessment of hepatic architecture. Sixteen infants and children underwent resection for cure. Eleven of these patients are alive and disease free 6 months to 23 years later. Six additional patients had incomplete resection with subsequent radiotherapy and/or chemotherapy; only one such patient is disease-free past 3 years. Twenty-six tumors could only be biopsied; most of these patients died within 12 months regardless of what treatment they received. The histology was hepatoblastoma in 39 patients, hepatocellular carcinoma in 4, fibrolamellar carcinoma in 4, and malignant mesenchymal tumor (mesenchymoma) in 1. The patients with hepatocellular carcinoma and mesenchymoma all died. Three of four patients with fibrolamellar carcinoma are alive and disease-free following resection up to 3 years; this histology seems favorable. The other survivors had hepatoblastoma. The role of adjunctive chemotherapy and/or radiotherapy has not yet been determined.
Sumithran, E1984Fibrolamellar carcinoma of the liver. Am J Clin Pathol 82(5): 633-634.
Vecchio, FM, A Fabiano, G Ghirlanda, R Manna and G Massi1984Fibrolamellar carcinoma of the liver: the malignant counterpart of focal nodular hyperplasia with oncocytic change. Am J Clin Pathol 81(4): 521-526. A case of fibrolamellar carcinoma (FLC) in a noncirrhotic liver of a 20-year-old man is described. Gross features and the presence, among the tumor cells, of bile ducts, of thick-walled blood vessels and nerves, and, ultrastructurally, of myofibroblast-like cells are the most significant findings, suggesting that FLC is the malignant counterpart of focal nodular hyperplasia with oncocytic change. Histochemical and immunohistochemical methods demonstrate the presence inside the oncocytic tumor cells of copper, copper-binding protein, and alpha 1 antitrypsin. The pathogenesis and the significance of these findings then are discussed and related to the restricted capacity of oncocytic cells to fulfill normal cellular function.
An, T, N Ghatak, R Kastner, S Kay and HM Lee1983Hyaline globules and intracellular lumina in a hepatocellular carcinoma.Am J Clin Pathol 79(3):392-396
Farhi, DC, RH Shikes, PJ Murari and SG Silverberg 1983Hepatocellular carcinoma in young people. Cancer 52(8): 1516-1525. The clinical and pathologic features of 23 cases of hepatocellular carcinoma occurring in patients younger than age 35 years (mean age, 17.4 years) were analyzed. Ten of these (43%) were the fibrolamellar oncocytic variant (FLO), characterized by large polygonal neoplastic hepatocytes and lamellar bundles of collagen. The remainder (non-FLO) showed the usual wide range of gross and histologic patterns typical of hepatocellular carcinoma in older age groups. Overall, hepatocellular carcinoma was more common in females than in males. The FLO variant was characterized by a longer duration of symptoms prior to diagnosis, increased frequency of resectability of the tumor, and infrequency of mitoses. Of particular importance is the fact that 5 of 10 patients with the FLO variant are alive and clinically free of disease 1 1/2 to 8 years postoperatively, while none of the 13 patients with non-FLO hepatocellular carcinoma is alive and free of disease. There was no significant difference between the two groups in mean age at diagnosis, presence of single versus multiple hepatic tumors, vascular invasion, or tumor necrosis. Although cirrhosis was present in three non-FLO patients and none of the FLO patients, the difference was not statistically significant. The prognosis of hepatocellular carcinoma in young patients does not appear to differ from that in older patients, with the exception of the fibrolamellar oncocytic variant, a variant which is common in younger patients.
Lack, EE, C Neave and GF Vawter 1983Hepatocellular carcinoma. Review of 32 cases in childhood and adolescence. Cancer 52(8): 1510-1515. The clinical and pathologic features of 32 children and adolescents with hepatocellular carcinoma (HCC) are reviewed. Their average age at diagnosis was 9.7 years (range, 5 months to 21 years) and there was a slight predilection for males in a ratio of 1.7 to one. Of eight patients with associated or underlying abnormalities, five had cirrhosis, two had an antecedent (or coexisting) tumor fulfilling pathologic criteria for hepatic adenoma, and one developed HCC ten years after nephrectomy and radiation therapy for a Wilms' tumor. Our data reaffirm the high mortality associated with HCC (91%). Three of five tumors classified as fibrolamellar type were amenable to surgical resection while only 15% of the remaining HCC were operable. The average duration of disease for patients with conventional HCC was 4.2 months, while those with the fibrolamellar variant had a more lingering course (average, 28.5 months). Available data indicate that the fibrolamellar variant should be distinguished from HCC with more conventional histology because of greater resectability and improved overall survival.
Lefkowitch, JH, R Muschel, JB Price, C Marboe and S Braunhut 1983Copper and copper-binding protein in fibrolamellar liver cell carcinoma. Cancer 51(1): 97-100. Analysis of tissue from a recent case of fibrolamellar liver cell carcinoma by several staining and spectrophotometric methods demonstrated elevated copper and copper-binding protein (CBP) in malignant hepatocytes. Production of CBP has not previously been described for this or any other type of hepatocellular carcinoma. Identification of CBP in liver cell carcinoma adds further evidence that this protein is a normal synthetic product of liver cells which may reappear in chronic cholestasis or hepatic malignancy. The mechanism of disturbed copper homeostasis in this case is uncertain.
Malt, RA, JJ Galdabini and BW Jeppsson 1983Abnormal sex-steroid milieu in young adults with hepatocellular carcinoma. World J Surg 7(2): 247-252. Analysis of 7 patients 20-30 years of age treated for hepatic cell carcinoma during the past 15 years at Massachusetts General Hospital indicated that 5 had an androgenous or exogenous disturbance of gonadal function. The 2 men in this series were taking methyltestosterone. Of the women, 2 had been taking oral contraceptives (OCs) for long durations, 1 had Stein-Leventhal syndrome, and 1 was infertile for 18 months. 3 of the 4 women with altered reproductive function had fibrolamellar carcinomas. These cases suggest that abnormalties of hypophyseal-gonadal endocrine metabolism can predispose to the development of hepatic cell carcinoma. Cessation of methyltestosterone or OC use and major hepatectomy apparently cured 3 of these patients. Although the data are consistent with a role for sex steroids in some cases of hepatic carcinogenesis, a case-control study would be needed to eliminate chance occurrence of fibrolamellar-variant cancer in the age group most likely to be using OCs. It is likely that hepatic carcinogenesis is a complex process involving genetic susceptibility, drug potency, regenerative urges, and the cooperation of promoters and co-carcinogens.
Mierau, GW and EN Orsini, Jr. 1983Diagnosis of human tumors. Case 2: Pancreatoblastoma mimicking fibrolamellar hepatocarcinoma. Ultrastruct Pathol 5(4): 281-284.
Mierau, GW and EN Orsini, Jr. 1983Diagnosis of human tumors. Case 1: Hepatocarcinoma, fibrolamellar type. Ultrastruct Pathol 5(4): 273-279.
Schiff, L 1983Hepatic neoplasia: selected clinical aspects. Semin Roentgenol 18(2): 71-74. Benign liver tumors are relatively uncommon and, even when large enough to be symptomatic, they usually remain undiagnosed prior to exploratory laparotomy. Hemangiomas constitute the majority of benign hepatic neoplasms and are 9 times as frequent in females as in males. Most are asymptomatic but abdominal swelling, a mass, or symptoms due to compression of adjacent organs may occur and abdominal hemorrhage is reported in 4.5% of patients. Hepatic hemangioma may produce a large arteriovenous communication serious enough to cause heart failure. Recently an increased frequency of liver tumors, mostly adenomas, has been noted in women taking oral contraceptives (OCs); the cause has been attributed to estrogens. The exact incidence is unknown but believed to be low. It is most common in women in their late 20s who have been on OCs for 7 years or more. The tumor occasionally completely regresses on withdrawal of the OCs. The tumor may be discovered incidentally at laparotomy or may manifest inself by pain, a palpable mass, or catastrophic hemoperitoneum. Hepatic adenoma is usually a solitary lesion and infrequently degenerates into malignancy. Differential diagnosis includes chronic gall bladder disease and peptic ulcer. Focal nodular hyperplasia (FNH) is apparently much less frequently related to OC use and is less likely to bleed seriously than adenoma. Hepatic chemistry is usually normal in adenoma and FNH, but slight increases in serum bilirubin, serum alkaline phosphatase, and serum transaminase may occur. Primary liver cancer (hepatocellular carcinoma or hepatoma) is mostly a disease of males and in the US and Western Europe seldom develops before age 40. Fibrolamellar carcinoma, which characteristically develops in adolescents and young adults, occurs with equal sex incidence. Doubt has been expressed about its relationship to OCs. In the US about 75% of primary hepatocellular carcinomas are associated with cirrhosis, and about 5% of cirrhosis cases develop primary liver cancer. Clinical manifestations of hepatoma have been divided into 5 groups: frank cancer (62.7%), acute abdominal cancer (8%), febrile cancer (8%), occult cancer (16%), and metastatic cancer (5%). Detection of large amounts of alpha fetoprotein has proven useful in diagnosis of hepatocellular carcinoma, but values may be negative in OC users. It has been estimated that 1/3 to 1/2 of all malignant tumors eventually metastasize to the liver.
Sheppard, KJ, DA Bradbury, JM Davies and DR Ryrie 1983High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. Br Med J (Clin Res Ed) 286(6358): 57.
Farhi, DC, RH Shikes and SG Silverberg1982Ultrastructure of fibrolamellar oncocytic hepatomaCancer 50(4): 702-709
Goodman, ZD and KG Ishak 1982Hepatocellular carcinoma in women: probable lack of etiologic association with oral contraceptive steroids. Hepatology 2(4): 440-444. To investigate the possibility of an association between oral contraceptive steroids (CS) and hepatocellular carcinoma (HCC), we reviewed 128 cases of HCC in women collected between 1953 and 1980. There were 48 cases under the age of 40, and 13 of these (27%) had used CS. However, 62% of HCC associated with CS and 58% of HCC in women under 40 not using CS were classified histologically as "fibrolamellar" carcinoma. This subtype of HCC occurs predominantly in young people, both male and female. The apparent increase in HCC in young women can be explained by the presence of cases of fibrolamellar carcinoma in this age group, an the apparent association with CS is probably coincidental.
Paradinas, FJ, WM Melia, ML Wilkinson, B Portmann, PJ Johnson, IM Murray-Lyon and R Williams 1982High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. Br Med J (Clin Res Ed) 285(6345): 840-842. Ten (9.3%) of 107 patients with hepatocellular carcinoma had considerably increased serum unsaturated vitamin B12 binding capacity. All 10 were young (mean 12 years), had no serum alpha-fetoprotein, and no underlying cirrhosis; all had a longer survival compared with patients without increased serum unsaturated vitamin B12 binding capacity in the study. Seven of the 10 patients had fibrolamellar hepatocellular carcinoma, a recently recognised histological variant, which was found in only one young patient without increased serum unsaturated vitamin B12 binding capacity and no alpha-fetoprotein among the remaining 97. This high degree of correlation between increased serum unsaturated vitamin B12 binding capacity and fibrolamellar hepatocellular carcinoma has not been reported before. Increased serum unsaturated vitamin B12 binding capacity may be of considerable help in diagnosis, prognosis, and monitoring treatment of this well-defined group of patients with hepatocellular carcinoma but no alpha-fetoprotein.
Wong, LK, DP Link, CF Frey, RH Ruebner, H Tesluk and NR Pimstone 1982Fibrolamellar hepatocarcinoma: radiology, management, and pathology.AJR Am J Roentgenol 139(1): 172-175
Govindarajan, S, M Ashcavai and RL Peters 1981alpha-1-Antitrypsin phenotypes in hepatocellular carcinoma. Hepatology 1(6): 628-631. alpha-1-Antitrypsin deficiency due to homozygous Pi ZZ state is reported to be associated with cirrhosis and hepatocellular carcinoma (HCC); however, the role of heterozygous Pi Z state is not definitely known. In order to investigate the possible association, we studied the phenotypic distribution of alpha-1-antitrypsin variants (Pi) in 124 cases of HCC. Two thousand ten normal American Red Cross blood donors were studied as controls. Twelve patients with HCC had aberrant phenotypes, an incidence of 9.67% as compared to 8.36% among normal controls. Nine of 12 patients with HCC with aberrant Pi type had cirrhosis; 5 of the 9 had cirrhosis due to hepatitis B virus; 2 of the 9 had alcoholic liver disease with cirrhosis, and 2 had cryptogenic cirrhosis. The three patients with HCC arising in noncirrhotic livers who also had aberrant Pi phenotypes, had a relatively rare variety of HCC called fibrolamellar type. Z gene was found in five patients: all five were MZ. Incidence of MZ phenotype in HCC was similar to that of the normal control population (4.0% in HCC and 2.9% in the controls). However, 3 of 5 MZ were associated with fibrolamellar HCC. Another aberrant phenotype found among the patients with HCC was MF (fast moving) which occurred with an incidence of 2.41% as compared to none in the control group. In conclusion, we found no significant increase in the incidence of Z gene among 124 patients with HCC as compared to the normal population.
Berman, MM, NP Libbey and JH Foster 1980Hepatocellular carcinoma. Polygonal cell type with fibrous stroma--an atypical variant with a favorable prognosis. Cancer 46(6): 1448-1455. Hepatocellular carcinoma, even when treated with operative resection, is generally regarded as uniformly fatal. Isolated reports of an unusual histologic variant characterized by polyglonal cells with a fibrous stroma (PCFS) suggest a more favorable outcome. Twelve cases of PCFS, representing the largest reported group, are presented. The mean age of the patients at the time of onset was 23.1 years and the male to female ratio was 1:2. Successful operative resection of the primary neoplasm and metastatic foci has resulted in a significant percentage of long-term survivors with a mean survival time of 68 months and two- and five-year survival rates of 82% and 63%, respectively. The variant shows cytologic similarity to differentiated hepatocellular carcinoma with a unique stromal appearance suggesting a pattern of fibrosis associated with focal nodular hyperplasia. Focal nodular hyperplasia is noted occasionally in the liver adjacent to PCFS. The possibility that PCFS represents an intermediate stage between focal nodular hyperplasia and the more malignant variants of hepatocellular carcinoma is discussed.
Craig, JR, RL Peters, HA Edmondson and M Omata 1980Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 46(2): 372-379. Clinical and pathologic features of 23 patients with a distinctive histologic and clinical variant of hepatocellular carcinoma are summarized. The variant pattern of hepatocellular carcinoma is most common in the age group 5--35 years and occurs equally in either sex. The distinctive histologic features include 1) deeply eosinophilic neoplastic hepatocytes, many of which contain intracytoplasmic hyaline globules and distinct pale bodies and 2) fibrosis arranged in a lamellar fashion around the neoplastic hepatocytes. The histologic and gross features of the tumor have been confused both with focal nodular hyperplasia and with hepatocellular adenoma. The average survival of 32 months and the high operability rate of 48% far exceed the survival or operability for ordinary hepatocellular carcinoma. Thus, this tumor type must be recognized and considered separately when evaluating therapeutic results in large series of patients with hepatocellular carcinoma.
Edmondson, HA 1956Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood.AMA J Dis Child 91(2): 168-186