Central histopathological review of a European hepatocellular carcinoma cohort: impact of the WHO 2019 classification on histological diagnosis and TNM staging

The World Health Organization (WHO) 2019 classification of hepatocellular carcinoma (HCC) introduces new histological subtypes aiding morphomolecular classification. We aimed to reclassify and restage archival HCC following central pathology review and evaluate the frequency of new subtypes in a large European HCC cohort. All histological material of 100 curative liver resection specimens for HCC from 100 patients (80 male, median age 72, IQR: 61.5-76.5 years, BCLC stage 0-C) operated from 2001 to 2018 was centrally reviewed. All cases were reclassified according to WHO 2019 and restaged according to TNM 2017 system. Thirty-five HCCs (35%) were classified into new subtypes: 15 macrotrabecular-massive (15%), 7 steatohepatitic (7%), 4 scirrhous (4%), 3 fibrolamellar (3%), 2 chromophobe (2%), 2 lymphocyte-rich (2%), 1 clear cell (1%), and 1 neutrophil-rich (1%). Histological grade changed in 45% HCCs (p < 0.001). TNM stage was modified from 1 to 2 in 22/100 HCCs (p < 0.001). The main histological pattern was solid (52%), pseudoglandular (17%), trabecular (16%), and macrotrabecular (15%). Microvascular invasion was detected in 64% HCCs. The non-neoplastic liver parenchyma showed steatosis (40%), steatohepatitis (19%), and/or chronic inflammation (71%). Fibrosis was staged as F0 35%, F1 17%, F2 13%, F3 11%, or F4 24%. Central histopathology review according to WHO 2019 and TNM 2017 modified histological grading in approximately half and staging in one quarter of resected HCCs, respectively, with clinical implications. One-third of HCCs were reclassified into new histological subtypes, some with known molecular background, prognostic and/or predictive impact, important for patient management.