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

Abstract

BACKGROUND & AIMS\nExtrahepatic 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.\n\n\nMETHODS\nWe 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.\n\n\nRESULTS\nIndependent factors for extrahepatic metastasis included BCLC stage B-C, microvascular invasion (MVI), vessels encapsulating tumor clusters (VETC)-HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, p<0.05 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 tumor 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<0.05 for all). In both cohorts, EMT-high HCCs showed higher rates of K19 expression, fibrous tumor stroma, high immune cell infiltration, PD-L1 expression, and CD3+ T cell infiltration, whereas EMT-low HCCs were more frequent among VETC-HCCs (p<0.05 for all). Overall phenotypic features were not significantly different between paired primary-metastatic HCCs (n=32).\n\n\nCONCLUSIONS\nMetastatic 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 tumor stroma and high immune cell infiltration were related to lymph node metastasis.