Abstract
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.
Highlights
Fibrolamellar carcinoma is a rare primary liver carcinoma with distinctive clinical and morphologic characteristics
88 conventional hepatocellular carcinomas were evaluated with PRKACA fluorescent in situ hybridization (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
Data from the SEER database found an average age of 39 years for fibrolamellar carcinoma,[4] which is significantly older than the average age of 27 found in pathologically confirmed cases reported in original studies.[5]
Summary
Fibrolamellar carcinoma is a rare primary liver carcinoma with distinctive clinical and morphologic characteristics. Proper classification of tumors is the foundation on which modern clinical management and therapy is based In this regard, the likelihood of significant advancements in understanding the biology of fibrolamellar carcinoma and developing novel therapies depends in the first place on studying cases that are fibrolamellar carcinomas. A subsequent study found the fusion transcript in only ~ 80% of fibrolamellar carcinomas, but most of the cases in this study did not undergo central pathology review.[8] Recently, a clinical test for fibrolamellar carcinoma has been developed based on fluorescent in situ hybridization (FISH) to detect the PRKACA rearrangement and was positive in all of 26 cases of fibrolamellar carcinoma and in none of the conventional hepatocellular carcinomas.[9]. The second goal was to identify fibrolamellar carcinoma cases with unusual FISH patterns, which may provide novel biological insights and represent interpretative challenges in clinical diagnosis
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