Fibrolamellar Hepatocellular Carcinoma

Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
The American Journal of Gastroenterology (Impact Factor: 9.21). 08/2009; 104(10):2617-24; quiz 2625. DOI: 10.1038/ajg.2009.440
Source: PubMed

ABSTRACT Fibrolamellar hepatocellular carcinoma (FHLCC) generally occurs in young individuals lacking a background of chronic liver disease and other risk factors for hepatocellular carcinoma. The clinical presentations of FLHCC are generally nonspecific, and the alpha-fetoprotein level is typically within the normal range in most cases. Imaging studies have a major role in clinical diagnosis, but pathology is the gold standard in confirming diagnosis. Pathological characteristics of FLHCC include the presence of tumor cells with a deeply eosinophilic cytoplasm and macronucleoli surrounded by abundant fibrous bands. The most effective treatment for FLHCC is aggressive surgical resection. This comprehensive literature review gives a full account of the clinical, pathological, and molecular features of FLHCC.

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    ABSTRACT: 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 genomics 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 genomics 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 400kb deletion, results in a DNAJ1-PRKCA fusion transcript, which leads to increased PKA activity in the index tumor case and other FL-HCC cases compared to normal liver. This PKA fusion protein is oncogenic in HCC cells. The second gene fusion event, a translocation between the CLPTML1 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.
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    ABSTRACT: 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.
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