Transforming human papillomavirus infection and the esophageal transformation zone: prime time for total excision/ablative therapy?

High-risk human papillomavirus (hr-HPV) infection is causal for almost all cervical malignancy (both squamous and adenocarcinoma), 90% of anal neoplasia, 70% of penile tumors, and 25% of head and neck cancers. The shared immunogenetics of cervical and esophageal malignancy suggests that HPV infection could well be a common denominator in the etiology of both cancers. In this regard, we have demonstrated that transcriptionally active hr-HPV (genotypes 16 and 18) is strongly associated with Barrett's dysplasia and esophageal adenocarcinoma. Increasing hr-HPV viral load and integration status has been linked with greater disease severity along the Barrett metaplasia-dysplasia-adenocarcinoma sequence as has been demonstrated in cervical intraepithelial neoplasia and cancer. HPV infections in both the cervix and esophagus are both focal, i.e., present in greater quantities at the squamocolumnar junction (SCJ). HPV affinity is to junctional tissue, as basal cells are particularly accessible at the squamocolumnar transformation zone and especially susceptible to this viral infection. We have postulated that progressive acid damage to the esophagus increases the likelihood of mucosal breaks enabling the virus to enter the basal layer of the transformation zone. The SCJ is the transformation zone of the esophagus and is strikingly similar to the transition zone (ectoendocervical SCJ) of the uterine cervix where almost all high-grade cervical lesions and cancers arise including 80% of adenocarcinomas. These transition zone cells exhibit features of squamous epithelium as well as glandular cells, which have been described in both Barrett's esophagus and cervical mucosa. Barrett's esophagus (BE) is derived from a discrete population of embryonic cells residing at the SCJ. There is loss of SCJ immune-phenotype following excision without regeneration at other junctional sites. Prevention of cervical cancer in up to 80-95% of patients with screen-detected CIN is dependent on the excision/ablation of the entire transformation zone. The persistence of hr-HPV 16/18 following eradication of CIN is a significant risk factor for recurrence. Similarly, we have demonstrated that persistent hr-HPV infection 16/18 and p53 overexpression are associated with treatment failure after endoscopic ablation of BD/EAC. Thus, we believe that excision/ablation of the SCJ in patients with BD/intramucosal EAC should be performed to reduce the potential malignant risk. We propose to test this hypothesis by a multicenter randomized controlled trial whereby patients (both HPV positive and those which are virus negative) will be allocated into two arms: complete excision of the SCJ via endoscopic mucosal resection (EMR) in addition to radiofrequency ablation (RFA) ± EMR of BD/intramucosal EAC (experimental arm) versus current standard of care (RFA ± EMR) of said lesions. Treatment efficacy in both groups will be evaluated by comparing disease elimination, regression/progression, and recurrence (if any). All patients would be entered into an intensive endoscopic surveillance protocol (biannually) for at least 2 years with lesional/neosquamous biopsies to compare the recurrence rate of both dysplasia/neoplasia in both arms. Viral (HPV DNA/p16INK4A/E6/E7 mRNA) and host biomarkers (e.g., p53) will be analyzed both at baseline and posttreatment intervals. A positive study would initiate development of tools best suited for SCJ destruction.