Dual-Phenotype Hepatocellular Carcinoma Exhibits Distinct Clinicopathological Aggressiveness and Poor Prognosis: A Retrospective Cohort Study of 463 Hepatocellular Carcinoma Patients

Objective: To investigate the clinicopathological characteristics and prognostic differences between the dual-phenotype hepatocellular carcinoma (DPHCC) and classical hepatocellular carcinoma (CHCC), and to identify the key prognostic risk factors for DPHCC. Methods : The Clinicopathological data from 463 hepatocellular carcinoma (HCC) patients were retrospectively analyzed. According to the morphology and immunophenotype (co-expression of HCC and intrahepatic cholangiocarcinoma [ICC] markers in > 15% of tumor cells). The cases were divided into two groups: the DPHCC group (93 cases, 20.09%) and the CHCC group (370 cases, 79.91%). Clinicopathological characteristics (microvascular invasion, tumor size, differentiation grade) and survival outcomes (overall survival [OS]; recurrence-free survival[RFS]) were compared between the two groups. Cox regression models were employed to analyze independent prognostic risk factors for DPHCC. Results: The DPHCC group exhibited significantly higher rates of microvascular invasion (MVI) (44.09% vs. 21.08%), tumor size ≥ 3 cm (80.65% vs. 68.92%), multifocality (33.33% vs. 15.14%), poor differentiation (39.78% vs. 21.08%), and necrosis-positivity (76.34% vs. 49.20%), capsular invasion (31.18% vs. 15.95%) compared to the CHCC group (for all, P  < 0.05 ). Survival analysis revealed significantly lower 5-year OS (61.10% vs 80.00%; HR 2.113) and RFS (37.40% vs 55.70%; HR 1.479) rates in the DPHCC group compared to the CHCC group. Multivariate analysis identified tumor size ≥ 3 cm (OS: HR = 3.021), poor differentiation (OS: HR 2.614; RFS: HR 1.927), and cytokeratin 19 (CK19) overexpression (OS: HR 4.903) as independent risk factors for poor prognosis in DPHCC. Additionally, DPHCC patients were significantly younger than CHCC patients (74.19% vs. 57.84% aged < 60 years; P  = 0.003), suggesting a potential association with aberrant differentiation of hepatic progenitor cells. Conclusions: DPHCC represents a distinct HCC subtype characterized by high aggressiveness, poor differentiation, and unfavorable prognosis, influenced by tumor size, differentiation grade, and CK19 expression.. It is recommended that patients diagnosed with this distinct HCC subtype receive intensified postoperative surveillance and personalized treatment strategies targeting the CK19-positive subgroup.