Human Papillomavirus Infection Is a Favorable Prognostic Factor for Patients With Stages I to IVA Esophageal Squamous Cell Carcinoma but not Adenocarcinoma.

With its 2 distinct histological subtypes (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]), its increasing incidence in both high- and low-income countries and its elevated 5-year mortality rate, esophageal cancer still represents a significant global health challenge. Although the implication of high-risk human papillomaviruses (HPV) in both anogenital and head and neck carcinogenesis is well-established, the association between these mucosotropic viruses and esophageal cancers has been a subject of debate for nearly 2 decades. In an effort to resolve this unclear situation and advance precision medicine, data from a large cohort of 378 patients diagnosed with locally advanced esophageal carcinoma (SCC [n = 226] and ADC [n = 152]) over a 20-year period were collected and thoroughly characterized (at clinical, histopathological, immunological, and virological levels). In total, about one-third (48/152, 31.58%) of ADC were positive for high-risk HPV DNA, but a transcriptionally active infection was only detected in 17.76% of the samples. Surprisingly, only a minority of malignant cells (typically <20%) showed viral transcripts, and HPV positivity had no prognostic significance for patients with esophageal ADC. Regarding SCC, 12.39% (28/226) of tissue specimens were HPV-positive, with viral/transcriptional activity observed in virtually 100% of neoplastic cells. These HPV-positive neoplasms more frequently exhibited basaloid differentiation and nonaberrant p53 expression and were significantly less associated with tobacco/alcohol use than their virus-negative counterparts. Importantly, uni-multivariate analyses indicated that HPV positivity was a reliable predictor of improved progression-free survival in patients with esophageal SCC. Taken together, our findings indicate that unlike in ADC, where testing for HPV is unnecessary, a dual classification system for esophageal SCC based on HPV status could/should be considered, with potential implications for personalized and optimized treatment strategies.