HCC

Introduction Fibrolamellar carcinoma (FLC) is a rare and biologically distinct primary liver cancer that predominantly affects adolescents and young adults without cirrhosis or other chronic liver disease. Unlike conventional hepatocellular carcinoma, FLC usually presents with normal or minimally elevated alpha-fetoprotein and often behaves aggressively despite occurring in otherwise healthy livers. A major advance in the field was the discovery of the DNAJB1::PRKACA fusion, which is now recognized as the central molecular driver in nearly all classical cases and has fundamentally changed the diagnostic and therapeutic framework of this disease. Because FLC responds poorly to treatments borrowed from conventional HCC or hepatoblastoma, this guideline is important in establishing a disease-specific approach to diagnosis, surgery, locoregional therapy, systemic treatment, and supportive care. Key Takeaways FLC should no longer be viewed as a subtype of conventional hepatocellular carcinoma, because it is a biologically separate disease with a different molecular driver, clinical pattern, and treatment response. The diagnosis of FLC requires three essential components: a primary liver tumor, characteristic histology, and molecular confirmation of DNAJB1::PRKACA fusion or, in very rare cases, PRKAR1A loss. Histology alone is not sufficient for diagnosis, because some conventional HCCs, especially scirrhous tumors, can mimic fibrolamellar morphology. Core needle biopsy is preferred over fine needle aspiration because preservation of fibrotic architecture is important for accurate diagnosis. The DNAJB1::PRKACA fusion is the defining molecular hallmark of classical FLC and should be actively tested for using targeted RNA-based assays, RT-PCR, or FISH. FLC usually affects adolescents and young adults with noncirrhotic livers and normal or minimally elevated AFP, and this clinical profile strongly supports the diagnosis. A large liver mass with a central scar on imaging is suggestive of FLC, but this finding is not specific and should never be used alone to make the diagnosis. FLC has a striking tendency to spread to regional lymph nodes, peritoneum, and lungs, making nodal assessment much more important than in conventional HCC. Baseline ancillary work-up should include broad NGS testing, HER2 immunohistochemistry, and serum ammonia measurement, because these may influence therapeutic planning and supportive care. Hyperammonemia and hyperammonemic encephalopathy are clinically important complications in FLC and may occur independently of liver failure. Surgery remains the cornerstone of treatment because FLC is only modestly responsive to systemic therapy and many patients tolerate aggressive liver surgery due to preserved underlying liver function. Patients with apparently classic and easily resectable FLC may occasionally proceed directly to surgery without preoperative biopsy when imaging and clinical context are highly convincing. Routine regional lymph node sampling or lymphadenectomy is strongly recommended even when imaging does not clearly show nodal disease, because occult nodal spread is common. Repeat surgery for recurrence, including metastasectomy and staged resection, can meaningfully prolong survival and is an accepted strategy in selected patients. Debulking surgery may still be worthwhile in advanced disease, including selected patients with lymph node, peritoneal, lung, brain, or bone metastases, especially when disease biology is indolent. Liver transplantation should be considered in patients with unresectable disease confined to the liver, even when the tumor does not fit traditional Milan criteria. Locoregional therapies such as Y-90 radioembolization, TACE, and SBRT are recommended both for palliation and as bridges to definitive surgery or control of unresectable disease. For advanced unresectable disease, the guideline supports GEMOX, GEMOX plus lenvatinib, or ipilimumab plus nivolumab as the most favored first-line systemic options based on available evidence and expert consensus. Clinical trial participation should be offered whenever possible because no universal standard systemic regimen exists and several promising fusion-directed or immunotherapy-based strategies are under active investigation. FLC care must include psychosocial, palliative, and multidisciplinary support, because this disease affects adolescents and young adults during a highly vulnerable stage of life and often imposes major emotional, social, fertility, and financial burdens. Conclusion This guideline is highly important because it formally establishes FLC as a unique liver cancer that requires its own diagnostic criteria and treatment strategy. The most practice-changing message is that molecular confirmation of the DNAJB1::PRKACA fusion, aggressive surgery with nodal assessment, and thoughtful use of systemic and locoregional therapies should define modern management. At present, surgery remains central, but the future of FLC care is clearly moving toward fusion-directed immunotherapy, biologically informed clinical trials, and more personalized multimodality treatment.