Genomic Profiling Suggests Combined Hepatocellular Cholangiocarcinoma Cases May Be Genomically Subclassified

Over 70% of combined hepatocellular cholangiocarcinoma (cHCC-CCA) cases may be genomically subclassified during treatment into disease which is more similar to hepatocellular carcinoma (HCC) and disease which is more similar to cholangiocarcinoma (CCA; JCO Prec Onc. 2021 Aug. 19:5, 1285-1296).

“The two most frequent forms of primary liver carcinomas (HCC and CCA) are ontologically, morphologically, and clinically distinct. However, as evoked by its name, cHCC-CCA is a poorly understood, aggressive rare primary liver cancer that exhibits morphologic characteristics of both HCC and CCA. As such, cHCC-CCA is an extremely challenging disease regarding both diagnosis and management,” described lead author Karthikeyan Murugesan, MS, Foundation Medicine Inc, Cambridge, Massachusetts and colleagues.

Due to the rarity of cHCC-CCA (estimates of incidence vary from 0.4% to 5% of primary liver tumors), there are no guidelines for disseminated or recurrent disease; however, there are both numerous trials and consensus guidelines for HCC and CCA.

Differences in the genomic features between CCA and HCC cases allowed the researchers to build a machine learning model that could characterize a primary liver carcinoma as CCA-like or HCC-like without additional clinicopathologic input. The genomic profiles of a high-quality cohort of 4975 CCA, 1470 HCC, and 73 cHCC-CCA cases arising in the course of clinical care were reviewed for genomic alterations (GA) and other characteristics.

Presence of hepatitis B virus (HBV) was determined by the identification of DNA sequences consistent with genomic HBV DNA.

When CCA was compared with HCC, genes were preferentially altered including ARID1A, BAP1, CDKN2A/B, FGFR2, IDH1, KRAS, and PBRM1 in CCA; and CTNNB1, MYC, and TERT in HCC. Genomic HBV was also significantly associated with HCC compared to CCA (10.5% v 1.9%, P = 4.2e–42, odds ratio = 6.14).

Among cHCC-CCA cases, we observed a median of 4 GA per tumor (range 0-14). Frequently altered genes in cHCC-CCA were TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), which may be potentially targetable.