Use of genomic analysis in classifying well-differentiated hepatocellular lesions
Distinguishing focal nodular hyperplasia and hepatocellular adenoma from well-differentiated hepatocellular carcinoma in noncirrhotic liver can be challenging. High-grade dysplastic nodule (HGDN) in cirrhosis can have features that overlap well-differentiated hepatocellular carcinoma. The authors conducted a study to examine the role of genomic analysis in better categorizing well-differentiated hepatocellular lesions (WDHL). Genomic analysis using capture-based next-generation sequencing (NGS) was performed on 23 WDHL that could not be definitively classified based on morphology, reticulin stain, or IHC and that were designated as atypical hepatocellular neoplasms. Staining with glutamine synthetase was classified as diffuse homogeneous (moderate to strong staining in more than 90 percent of tumor cells), diffuse heterogeneous (in 50 to 90 percent), not diffuse (in less than 50 percent), and borderline (not clear if in more or less than 50 percent). The genomic profile provided additional information for the diagnosis or risk assessment, or both, enabling a diagnosis of benign in 15 of 23 (66 percent) cases and hepatocellular carcinoma (HCC) in four of 23 (17 percent) cases, while the diagnosis remained atypical in the remaining four cases. Of the four cases with final HCC diagnoses, findings were suspicious but not diagnostic based on morphology/IHC. Changes such as TERT promoter mutation (n = 2), AXIN mutation (n = 1), CDKN2A loss (n = 2), and copy number alterations (n = 3) helped support the diagnosis of HCC. Of the 15 cases with a final diagnosis of benign, the status of β-catenin activation was unclear based on staining with glutamine synthetase in eight cases, two of which showed CTNNB1 exon 7 mutation, one of which showed CTNNB1 exon 8 mutation, and five of which did not show any evidence of Wnt activation. Focal nodular hyperplasia-like features were seen in two cases, but the genomic changes excluded that condition (CTNNB1 and ARID1A mutation). The final diagnosis was unchanged from the initial diagnosis of atypical hepatocellular neoplasm in four of 23 (17 percent) cases as the molecular findings did not favor a diagnosis of HCC. The authors concluded that genomic changes were helpful in characterizing WDHL, supporting a diagnosis of HCC in 17 percent of cases and clarifying β-catenin activation status in all seven cases with borderline glutamine synthetase staining. Genomic changes are not specific but can provide diagnostic clues in selected challenging cases that cannot be classified based on morphology and IHC. The authors propose that given the significant treatment implications of distinguishing between HCC and benign or premalignant entities, routine use of genomic analysis in diagnostically challenging settings should be considered.
Akarca FG, Grenert JP, Kakar S. Role of genomic analysis in the classification of well differentiated hepatocellular lesions. Hum Pathol. 2025. doi.org/10.1016/j.humpath.2025.105794
Correspondence: Dr. F. G. Akarca at [email protected], or Dr. James P. Grenert at [email protected], or Dr. Sanjay Kakar at [email protected]