Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects

Abstract Background & Aims Extrahepatic metastasis from hepatocellular carcinoma (HCC) is a catastrophic event, yet organ‐specific pathological characteristics of metastatic HCC remain unclear. We aimed to characterize the pathological aspects of HCC metastases to various organs. Methods We collected intrahepatic HCC (cohort 1, n = 322) and extrahepatic metastatic HCC (cohort 2, n = 130) samples. Clinicopathological evaluation and immunostaining for K19, CD34, αSMA, fibroblast‐associated protein (FAP), CAIX, VEGF, PD‐L1, CD3, CD8, Foxp3, CD163 and epithelial–mesenchymal transition (EMT)‐related markers were performed. Results Independent factors for extrahepatic metastasis included BCLC stage B–C, microvascular invasion (MVI), vessels encapsulating tumour clusters (VETC)‐HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, P < .05 for all). Lung metastases (n = 63) had the highest proportion of VETC‐HCC and macrotrabecular‐massive (MTM)‐HCC. Lymph node metastases (n = 19) showed significantly high rates of EMT‐high features, K19 expression, fibrous tumour stroma with αSMA and FAP expression, high immune cell infiltration, PD‐L1 expression (combined positive score), CD3+, CD8+, Foxp3+ T cell and CD163+ macrophage infiltration (adjusted P < .05 for all). In both cohorts, EMT‐high HCCs showed higher rates of K19 expression, fibrous tumour stroma, high immune cell infiltration, PD‐L1 expression and CD3+ T cell infiltration, whereas EMT‐low HCCs were more frequent among VETC‐HCCs ( P < .05 for all). Overall phenotypic features were not significantly different between paired primary‐metastatic HCCs (n = 32). Conclusions Metastatic HCCs to various organs showed different pathological features. VETC and MTM subtypes were related to lung metastasis, whereas K19 expression, EMT‐high features with fibrous tumour stroma and high immune cell infiltration were related to lymph node metastasis.