Molecular Characteristics of Fibrolamellar Hepatocellular Carcinoma

Abstract

Fibrolamellar hepatocellular carcinoma (FLC) occurs in non-cirrhotic liver and the etiopathogenesis is still obscure. Both hepatocellular and cholangiocellular markers are expressed in the tumor, however, molecular alterations and altered pathways playing role in the tumor pathogenesis are not clearly identified. The purpose of the present study was to compare the expression level of EGFR, syndecan-1 and ß-catenin in FLC, conventional hepatocellular carcinoma (cHCC) and cholangiocellular carcinoma (CCC) and to investigate the possibility of mutation both in EGFR and K-RAS. Eight FLCs were compared with 7 cHCCs, 7 CCCs and 5 normal liver samples. Cytokeratins 7, 8, 18, 19, HepPar1 (HSA), EGFR, syndecan-1 (CD138) and ß-catenin were detected by immunohistochemistry. In addition EGFR, ß-catenin and syndecan-1 were evaluated by digital morphometry and K-RAS, EGFR mutations in FLC cases using paraffin-embedded samples. All FLCs were positive for HepPar1 (HSA) and cytokeratins 7, 8, 18, but negative for cytokeratin 19 by immunohistochemistry. EGFR was significantly overexpressed in all three tumor types, being highest in FLCs (p = 0,0001). EGFR, K-RAS mutation analyses revealed no mutations in exons studied in FLCs. Our findings proved that expression of EGFR is higher in FLC than in other types of primary malignant hepatic tumors and no K-RAS mutation can be detected, so FLC is a good candidate for anti-EGFR treatment.

Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma

“…CK7, HepPar-1) as well as neuroendocrine (e.g. PCSK1, NTS) lineages31112131415. We also have shown that FLCs are remarkably rich in cancer stem cells, unlike HCCs and CCAs, and that their gene expression profile more closely resembles that of primitive biliary tree stem cells than any other lineage stage of the liver16.…”

Unique Genomic Profile of Fibrolamellar Hepatocellular Carcinoma

“…Despite previous attempts to find frequently mutated cancer genes in FLC (i.e. KRAS and EGFR 11 ), none had been reported. By WES, FLC showed 23 damaging mutations, which included the well-known TSG BRCA2 implicated in DNA repair.…”

“…The most relevant findings include molecular alterations of the MAPK/ERK 9 , ErbB 10 and Akt-mTOR 12 signaling pathways, few chromosomal aberrations based on comparative genomic hybridization data 13 , and no mutations in EGFR or KRAS genes 11 . More recently, a DNAJB1-PRKACA fusion protein caused by a deletion at chromosome 19 has been discovered in all 15 FLCs evaluated 14 .…”

Hepatocellular Carcinoma with Both Fibrolamellar and Classical Components: An Unusual Morphological Pattern

“…FLC is a malignant hepatocellular tumor with distinct clinical and pathologic characteristics that differ from classical HCC, predominantly in FLC there is no consistent mutation, and shows fewer chromosomal abnormalities compared with HCC [2]. …”

“…It was first reported as a separate entity by Hugh Edmondson in 1956, who described the typical gross and microscopic features of this neoplasm as “a liver cell carcinoma in which stroma is profuse and the similarity of the cancer cells to normal cells is striking” [1]. Since then, it has been further studied, and its diagnostic criteria have been clearly established, the tumor express characteristics of conventional hepatocellular carcinoma (HCC) including cytokeratin 7 a cholangiocellular marker; however studies suggest that no consistent mutation is known in FLC so far [2]. …”