The European Association for the Study of the Liver (EASL) convened an international, multidisciplinary panel to evaluate and summarize current knowledge on rare primary liver cancers. The resulting paper focused in three major rare liver cancers, combined hepatocellular–cholangiocarcinoma (cHCC‑CCA), fibrolamellar carcinoma (FLC), and hepatic epithelioid hemangioendothelioma (HEHE), as well as several ultra‑rare varieties. Due to their low incidence, these cancers lack robust clinical data, are frequently misdiagnosed, and are often excluded from major clinical trials.
Across all these rare cancers, microscopic examination of the tissue is essential for diagnosis because imaging is rarely definitive. In addition, surgery remains the only consistently curative option across most rare PLCs. Significant gaps also exist in systemic therapy evidence, with most data coming from small, retrospective cohorts. The paper highlights the need for coordinated international research and biobanking to improve diagnosis, management, and therapeutic development.
Below are the effort’s key findings for each type of cancer:
Combined Hepatocellular–Cholangiocarcinoma (cHCC‑CCA)
A rare tumor (1–5% of primary liver cancers) with both hepatocellular and bile‑duct differentiation. Diagnosis can only be made when a tissue sample shows both parts of the tumor under the microscope, since imaging is unreliable and the cancer often mimics HCC.
Key Points
- Occurs in patients with or without cirrhosis; only ~50% have underlying liver disease.
- Mutational profile includes alterations common to hepatocellular carcinoma (TERT, CTNNB1) and cholangiocarcinoma (KRAS, IDH1, FGFR2).
- Surgical resection is the only curative therapy, though outcomes are generally poorer than those of HCC.
- Transplantation remains controversial with mixed results.
- Locoregional therapies (transarterial chemoembolization (TACE), transarterial radio embolization (TARE)) can offer disease control in unresectable cases.
- No standard systemic therapy exists; patients often receive HCC‑ or CCA‑based regimens pending results from ongoing phase II trials.
Fibrolamellar Carcinoma (FLC)
A rare liver cancer of adolescents and young adults without liver disease. FLC has distinct pathology containing fibrous bands and tumor cells with abundant pink, granular cytoplasm when stained.
Key Points
- Accounts for approximately 1% of primary liver cancers, typically affecting patients aged 20–30 years.
- Defined by a characteristic DNAJB1‑PRKACA fusion, which is considered to confirm diagnosis in a liver tumor.
- Levels of alpha fetoprotein (AFP) are usually normal; imaging may resemble focal nodular hyperplasia, requiring biopsy for diagnosis.
- Surgical resection with lymphadenectomy (lymph node removal) is the only curative treatment, achieving ~70% 5‑year survival when complete resection is possible.
- Recurrence rates remain very high (40–100%).
- Limited systemic therapy evidence exists:
- Best historical activity: 5‑FU + interferon (25–62% response).
- Targeted therapies (mTOR inhibitors, aurora kinase inhibitors) show minimal benefit.
- Immunotherapy has inconsistent effectiveness, though combinations such as nivolumab + lenvatinib show early promise.
- New approaches under investigation include DNAJB1‑PRKACA–directed vaccines and BCL‑XL targeted therapeutics.
Hepatic Epithelioid Hemangioendothelioma (HEHE)
A rare vascular cancer with variable behavior—from indolent to aggressive—often presenting with multiple tumors in the same area.
Key Points
- Occurs most frequently in young to middle‑aged women.
- Nearly all cases have CAMTA1‑WWTR1 fusions, which are diagnostic.
- Surgery or liver transplantation are potentially curative; transplantation is viable even with limited disease outside of the liver.
- Locoregional therapies (TACE, ablation) are used for downstaging the disease or palliation.
- No consensus exists on systemic therapy; sirolimus and other targeted agents are under investigation, and surveillance is appropriate in selected cases.
Other Ultra‑Rare Primary Liver Cancers
The paper also summarizes diseases including hepatic angiosarcoma, hepatocellular carcinoma arising in adenoma, mucinous cystic neoplasms, primary hepatic neuroendocrine tumors, carcinosarcoma, squamous cell carcinoma, leiomyosarcoma, and embryonal sarcoma. Treatment is usually surgical when feasible, with poor outcomes in aggressive forms like angiosarcoma.