Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy

Fibrolamellar hepatocellular carcinoma is a rare and unique subtype of primary liver cancer that predominantly affects adolescents and young adults who do not have underlying liver disease or cirrhosis. Representing less than five percent of all liver tumors, it poses significant diagnostic and therapeutic challenges due to its uncommon occurrence, vague clinical symptoms, and absence of standardized treatment protocols. This review summarizes the current understanding of the disease, covering its epidemiology, clinical presentation, imaging characteristics, histopathologic features, molecular biology, and treatment approaches. Patients often present with nonspecific abdominal symptoms, and typical tumor markers, such as alpha-fetoprotein, are usually absent. Imaging may show a central scar and calcifications, while histology reveals large eosinophilic tumor cells separated by fibrous bands. A defining molecular hallmark is the <i>DNAJB1</i>-<i>PRKACA</i> fusion gene, found in the majority of cases. Surgical resection remains the primary curative treatment for localized disease, although recurrence rates are high. Liver transplantation may be an option for selected patients with non-resectable, liver-confined tumors. Treatment options for advanced disease are limited, with some benefit observed from chemotherapy and targeted agents. Recent developments in molecular therapies and immunotherapy offer promise, but further research and clinical trial participation are essential to improve outcomes in this challenging malignancy.