Hepatocellular carcinoma: Clinicopathologic associations amidst marked phenotypic heterogeneity

•HCC is characterized by marked phenotypic and molecular heterogeneity.•Clinico-morphologic phenotypes and associations have immense relevance for molecular targeted therapy.•There is paucity of published literature on critical analysis morphological heterogeneity in HCC.•This is a retrospective cross sectional study of 217 HCC explants, resections, tumour biopsies.•None of the previous studies have performed in depth systematic analysis of heterogeneity, dominance and associations. Hepatocellular carcinoma (HCC) is characterized by marked phenotypic and molecular heterogeneity. Clinico-morphologic phenotypes and associations are important surrogate markers of molecular aberrations; therefore have immense relevance for targeted therapy. There is paucity of published literature on critical analysis of HCC heterogeneity and morphological alliance. Aims: To assess the heterogeneity and dominance of histomorphological features, and to explore clinicopathological associations in HCC. Retrospective cross-sectional study of 217 HCC tissue specimens was performed for the assessment of prevalence of major histological patterns, cytological features, and clinicopathological correlation. Homogeneous architecture with a single dominant histological pattern was a rarity. Single pattern constituting ≥50 % of the tumour was found in less than 1/5th of the cases. Macrotrabecular HCC represented 9.2 % of cases. The simultaneous presence of 2–3 patterns or atypical variants and/ or cytological characteristics was recorded in 25 % and 30 % respectively. Significant clinicopathological associations: Pseudoglandular with microtrabecular pattern-cholestasis, showed better differentiation and early-stage; macrotrabecular pattern frequently occurred with pleomorphic giant cells, higher tumour stage, higher AFP levels; solid pattern often showed clear cells. Noticeable mutual exclusions were MD bodies with microtrabecular and pseudoglandular patterns; Compact pattern with neutrophilic clusters and cholestasis. Larger tumours were significantly more heterogeneous; however, heterogeneity did not correlate with outcome HCC displays immense heterogeneity with an amalgamation of different histomorphological patterns and features; nevertheless, there are certain reproducible associations and omissions. Tumor biopsies agree fairly well with large specimens. Characterization of phenotypic heterogeneity, dominance, associations, and exclusions in individual patients provides vital informat