Intratumoral Granulomas in Hepatocellular Carcinoma: Clinicopathologic Associations, Prognostic Significance, and Diagnostic Pitfalls.

Intratumoral granulomas (ITGs) are rarely described in hepatocellular carcinoma (HCC) and may obscure malignancy in limited biopsy specimens. We retrospectively reviewed 614 HCCs diagnosed from 2010 to 2023 to identify tumors with ITG and compared clinicopathologic features and overall survival with HCCs lacking ITG. ITG was identified in 32/614 cases (5.2%). All granulomas were non-necrotizing; 3/32 cases also had granulomas in background liver. No patient had sarcoidosis, primary biliary cholangitis, or documented infection. Patients with ITG were predominantly male (23/32, 71.9%), with a mean age of 67.5 years. Metabolic dysfunction-associated steatotic liver disease (MASLD) was the most common underlying liver disease (13/32, 40.6%). Compared with HCCs without ITG, HCCs with ITG were significantly associated with MASLD (13/32, 40.6% vs 98/582, 16.8%; P = 0.0072), steatohepatitic subtype (22/32, 68.8% vs 119/576, 20.7%; P < 0.0001), intratumoral lymphocytic inflammation (26/28, 92.9% vs 366/572, 64.0%; P = 0.0001), and at least moderate peritumoral inflammation (11/18, 61.1% vs 60/255, 23.5%; P = 0.003). Granuloma-associated inflammation was T-cell predominant and enriched for CD4-positive T cells. In univariable analysis, patients with ITG had improved overall survival (P = 0.004); however, the association was attenuated and did not reach statistical significance after adjustment for age, tumor size, stage, and MASLD etiology (HR 0.52, 95% CI 0.20-1.11; P = 0.098). Among stage II tumors, patients with ITG had borderline improved survival (P = 0.05). Prominent ITG may mask HCC in biopsy specimens. These findings support ITG as an uncommon but recognizable HCC-associated tumor microenvironment enriched in MASLD-related steatohepatitic HCC.