Lymphoepithelioma-like hepatocellular carcinoma: an uncommon variant of hepatocellular carcinoma with favorable outcome.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is an uncommon variant of HCC with only 22 cases reported in the literature. To better determine the incidence, clinicopathologic features, prognostic significance, and molecular pathogenesis of LEL-HCC, we presented the largest series of LEL-HCC from a 9-year retrospective cohort of patients with HCC undergoing surgical resection. LEL-HCC was identified in 20 patients (4.9%). Compared with patients having HCC without significant tumor-infiltrating lymphocyte (TIL), patients with LEL-HCC had a relatively lower frequency of male sex (P=0.022), tended to present at early-stage disease (80.0% vs. 56.3% as AJCC stage I, P=0.037; 100% vs. 77.3% as BCLC stage 0/A, P=0.010), and all harbored a solitary tumor only (P=0.006). There was no significant difference in the age at presentation, underlying chronic liver disease, cirrhotic background, serum α-fetoprotein level, tumor size, histologic grade, and frequencies of vascular invasion. Most of the TILs in LEL-HCC were cytotoxic T lymphocytes. None of the LEL-HCCs was associated with Epstein-Barr virus. LEL-HCC was associated with better overall (5-y survival: 94.1% vs. 63.9%; P=0.007) and progression-free (5-y survival: 87.8% vs. 46.6%; P=0.002) survivals compared with HCC without significant TIL. The multivariate analysis revealed that LEL-HCC was an independent prognostic factor for overall and progression-free survivals. The adjusted hazard ratio of cancer death and tumor progression for LEL-HCC was 0.12 (P=0.037) and 0.14 (P=0.002), respectively. LEL-HCC did not differ in frequencies of microsatellite instability, BRAF mutation, and DNA hypermethylation. In brief, LEL-HCC is a distinct uncommon variant of HCC characterized by dense cytotoxic T-cell infiltration and favorable prognosis.