Identification and relevance of inter-tumour heterogeneity in hepatocellular adenoma according to subtypes and the context.

Abstract

Introduction: Different molecular subtypes of hepatocellular adenoma (HCA) can occur at the same time within the same patient, defining inter-tumour heterogeneity (ITH). We describe a series of HCA-ITH cases, most identified in Bordeaux with additional cases contributed by other international centres.

Methods: ITH-HCA cases were subtyped by immunohistochemistry, confirmed by molecular analysis in most cases. The resulting diagnoses were HNF1A-HCA (H-HCA), inflammatory HCA (IHCA), b-catenin-mutated HCA (b-HCA) involving exon 3 or 7/8, b-catenin-mutated IHCA (b-IHCA) involving exon 3 or 7/8, sonic hedgehog HCA (sh-HCA) and unclassified HCA (UHCA).

Results: We identified 26 patients with ITH-HCA including 17 women; none had underlying liver disease, whereas most men did (8/9). The largest subgroup comprised 22 patients with IHCA combined with another subtype: H-HCA (five patients); H-HCA and b-IHCA-exon 3 borderline (one patient); b-IHCA-exon 3 (six patients); b-HCA and b-IHCA exon 3 (four patients); b-IHCA-exon7/8 (two patients); sh-HCA (three patients); UHCA (one patient). The remaining four patients had sh-HCA combined with UHCA (one patient) or b-IHCA ex3 (one patient), and 2 patients with HNF1A adenomatoses, one with malignant transformation, the other associated with a b-IHCA exon3 progressed to HCC. The largest nodule was a 13 cm IHCA. One of the sh-HCA presented with bleeding.

Conclusion: ITH-HCA covers the whole spectrum of the HCA classification. It is rare but poses significant clinical challenges, particularly in terms of identifying those lesions at risk of malignant transformation (b-HCA or b-IHCA exon 3) or bleeding (sh-HCA). Referral to a special tertiary centre is recommended.