Hybrid lesions of hepatocellular adenoma and focal nodular hyperplasia: a clinicopathological and molecular study of two cases.

Abstract

Aims: Hybrid lesions containing distinct components of hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) within a single nodule are exceptionally rare. This study aimed to investigate the biological nature of these unusual lesions.

Methods and results: The two cases identified to date were examined by histopathological, immunohistochemical and targeted next-generation sequencing analyses. In case 1, the hybrid tumour (6.0 cm) consisted of approximately equal proportions of HNF1α-inactivated HCA and FNH, which were intimately admixed but remained histologically distinct. In case 2, the tumour (9.5 cm) consisted predominantly of HNF1α-inactivated HCA but contained a small peripheral nodule of FNH, resulting in a nodule-in-nodule appearance. The HCA components in both cases showed loss of FABP1 expression, whereas the FNH components retained FABP1 expression and showed a map-like pattern of glutamine synthetase expression. Next-generation sequencing in case 1 demonstrated that the mutations were not shared between the HCA and FNH components, with HNF1A and FLT1 mutations identified only in the HCA component. In case 2, the same HNF1A splice-site mutation was identified in both the HCA and FNH components, but was also present in the non-neoplastic gallbladder, confirming its germline origin. The HCA component, but not the FNH component, additionally harboured somatic mutations in ATM and FAT4.

Conclusion: HCA, particularly the HNF1α-inactivated subtype, rarely coexists with FNH. The distinct molecular and immunohistochemical profiles of the two components support a collision mechanism, indicating that the FNH component represents a separate non-neoplastic lesion and arguing against one component arising from the other.