CK7-positive hepatocellular carcinoma represents a distinct subtype: a retrospective cohort study.
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BACKGROUND: Hepatocellular carcinoma (HCC) remains a common and highly lethal malignancy worldwide, with a substantial and persistent disease burden. Although systemic therapies have advanced in recent years, overall prognosis is still far from satisfactory, reflecting the pronounced heterogeneity of HCC and the incomplete understanding of its key molecular drivers. Cytokeratin 7 (CK7), a marker related to biliary epithelium and hepatic progenitor–cell lineage, is routinely applied in diagnostic pathology and contributes to phenotypic classification of liver tumors. In particular, CK19-positive HCC has been recognized as a distinct subtype characterized by more aggressive behavior, higher risks of early recurrence and metastasis, and unfavorable survival outcomes. Ki-67 (Ki67), a widely used indicator of proliferative activity, has likewise been associated with tumor progression and poor prognosis in HCC. Against this background, we sought to delineate the clinicopathological features and outcomes of CK7-positive HCC using readily available clinical data, and to examine these patterns in relation to CK19 and Ki67 expression, thereby generating clinically grounded clues for mechanistic inference and future precision-oriented research. METHODS: This single-center retrospective cohort study included patients who underwent hepatectomy at Guangxi Medical University Cancer Hospital between 2014 and 2021 and had postoperative pathological confirmation of HCC. Among 1,992 eligible cases, 1,668 patients with complete CK7/CK19/Ki-67 immunohistochemical data and key clinicopathological variables constituted the complete-case analysis cohort. Data were extracted on demographics; exposure-related factors (e.g., alcohol use and consumption of raw fish dishes- used here as a proxy for potential biliary/parasitic exposure); liver function and cirrhosis-associated variables (Child–Pugh class, phenotypes suggestive of portal hypertension, splenomegaly, etc.); tumor burden and stage (maximum tumor diameter, tumor number, and BCLC stage); pathological features of invasiveness (including microvascular invasion and the presence of portal vein and/or bile duct tumor thrombus); and follow-up outcomes, including overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). Immunohistochemical staining for CK7, CK19, and Ki67 was dichotomized as negative/positive according to prespecified cutoffs. Continuous variables were compared using Student’s t test or Welch’s t test for approximately normally distributed data, and the Wilcoxon rank-sum test otherwise. Categorical variables were analyzed with the chi-square test or Fisher’s exact test, as appropriate. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported for binary outcomes. Survival was assessed using Kaplan–Meier estimates and log-rank tests; Cox proportional hazards models were fitted for univariable and multivariable analyses, with adjustment for clinically relevant confounders (including age, Child–Pugh class, and portal hypertension), and hazard ratios (HRs) with 95% CIs were reported. RESULTS: Among the 1,668 patients included in the complete-case analysis, positivity rates for CK7, CK19, and Ki-67 were 19.8%, 23.6%, and 81.8%, respectively. CK7 positivity was associated with a history of alcohol use (OR 1.73, 95% CI 1.35–2.21; P < 0.001) and consumption of raw fish dishes (OR 1.52, 95% CI 1.18–1.97; P = 0.001), and was inversely associated with HBsAg positivity (OR 0.70, 95% CI 0.50–0.98; P = 0.044). Clinically, CK7-positive tumors were characterized by lower AFP levels (P < 0.001), modestly higher triglyceride and total bilirubin levels (P = 0.033 and P = 0.029), and a tendency toward smaller maximum tumor diameter (P = 0.001; P < 0.001 in the single-tumor subset), whereas the proportion of multifocal disease did not differ (P = 0.762). In outcome analyses, CK7 positivity was not associated with recurrence-free survival (RFS), distant metastasis–free survival (DMFS), or overall survival (OS) (RFS HR 1.04; DMFS HR 0.97; OS HR 1.01; all P > 0.05). In contrast, CK19 positivity was enriched among patients with anti-HCV positivity (OR 2.93, 95% CI 1.24–6.96; P = 0.018) and was linked to more advanced stage and invasive features, including portal vein tumor thrombus (PVTT), microvascular invasion (MVI), and metastasis, and consistently predicted poorer RFS/DMFS/OS. Similarly, Ki-67 positivity was significantly associated with adverse tumor biology and inferior survival outcomes. CONCLUSION: Using routinely available clinical data, we provide a panoramic characterization of HCC spanning putative exposures, phenotypic stratification, tumor aggressiveness, and clinical outcomes. CK7-positive HCC displayed a clinicopathological and prognostic profile distinct from the CK19-positive subtype, suggesting that CK7 expression may denote a biologically discrete subset with a different etiologic trajectory. These findings offer a clinically grounded rationale for mechanistic studies and the development of subtype-tailored intervention strategies.