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

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.