High-risk human papilloma virus (HPV; genotypes 16 and 18) has been strongly associated in previous research with a subset of Barrett’s dysplasia and esophageal adenocarcinoma (EAC). This prompted my colleagues and I to ponder whether HPV status of Barrett’s high-grade dysplasia (HGD) and EAC influence survival as they do in viral positive head and neck cancers.

We, therefore, sought to determine the prognostic significance of esophageal tumor HPV status and associated viral transcriptional markers indicating biological activity (E6/E7 mRNA and p16INK4A). Sequencing of the TP53 gene was also undertaken. In this retrospective case-control study, we evaluated pre-treatment biopsies from patients with HGD and EAC who underwent endotherapy and/or esophagectomy. Participants were enrolled from secondary and tertiary referral centers between December 2002 and November 2017.

Among 142 patients with HGD and EAC, 37 were HPV positive and 105 HPV negative. Patients who were HPV positive mostly had high p16INK4A expression, low p53 expression, wild-type TP53, and early T stage tumors. HPV positivity and associated viral transcriptional markers were associated with a significantly improved disease-free survival compared with viral negativity. Recurrence and progression were reduced in the HPV-positive cohort as were distant metastasis and death from EAC. Mean overall survival was also significantly improved in the HPV-positive group compared with the HPV-negative cohort.

HPV-positive HGD/EAC is a distinct biological entity with a favorable prognosis when compared with viral-negative esophageal tumors. If confirmed in larger cohorts with more advanced disease, our findings present an opportunity for treatment de-escalation in the hope of reducing toxicity without deleteriously affecting survival. Future research would include other HPV-related biomarkers and survival, genomics, and therapeutic studies, including vaccination.