The role of human papillomavirus (HPV) in Barrett's esophagus (BE) remains unclear. The few studies that have previously investigated HPV and esophageal adenocarcinoma (EAC) or BE have produced either negative data or positive results of doubtful clinical/etiological significance or have detected only low-risk HPV types. We therefore prospectively determined the prevalence of biologically active HPV in esophageal epithelium of patients representing the Barrett's metaplasia–dysplasia–adenocarcinoma sequence. HPV DNA was estimated by nested PCR and viral transcriptional activity detected by E6/7 oncogene mRNA expression and p16INK4A immunohistochemistry in fresh frozen and paraffin-embedded esophageal biopsies of patients with BE, Barrett's dysplasia (BD), and EAC, as well as controls. Biopsies were obtained from the transformation zone (squamocolumnar junction (SCJ)) and the lesion, or corresponding site in controls, i.e., 2 cm above the gastroesophageal junction (GEJ). Of the 261 patients, 81 were positive for HPV DNA. In controls and BE, the virus was mostly detected at the transformation zone. Compared with controls (18.0%), HPV positivity was significantly more common in BD (68.6%, incidence rate ratio (IRR) 2.94, 95% confidence interval (CI) 1.78–4.85, P<0.001) and EAC (66.7%, IRR 2.87, 95% CI 1.69–4.86, P<0.001), but not in BE (22.1%, IRR 1.06, 95% CI 0.60–1.85, P=0.85). Of the patients, 92.6% were high-risk (HR) HPV, i.e., types 16 and 18. Again, p16INK4A positivity was greatest in BD and EAC and much less in BE patients (44.1%, IRR 17.0 (95% CI 4.86–59.6, P<0.001), 44.4%, 17.0 (95% CI 4.87–59.4, P<0.001), and 10.6%, 3.93 (95% CI 1.01–15.3, P=0.048) respectively). In 66 HPV DNA–positive patients tested for E6/E7 mRNA, none of the control (n=16) or BE (n=13) individuals were positive, whereas 9/22 BD and 9/15 EAC patients demonstrated oncogene expression (P<0.001). When HPV DNA, p16INK4A, and E6/E7 mRNA were all positive, there was a very strong association with disease severity (SCJ: odds ratio (OR) 104, 95% CI 20.3–529, P<0.001; lesion: OR 62.2, 95% CI 12.4–311, P<0.001) than when all were negative. Transcriptionally active HR-HPV was strongly associated with BD and EAC, but was largely biologically irrelevant in BE and controls, suggesting a potential role in esophageal carcinogenesis. These data provide robust justification for further detailed longitudinal, interventional, and molecular studies.

Esophageal adenocarcinoma (EAC) is one of the fastest-growing and deadliest cancers in the Western world,^1,2 although recently the rate of increase has diminished and possibly plateaued in the United States and Sweden.^3,4 Currently, Barrett esophagus (BE) is the only recognized visible precursor lesion for EAC. Intriguingly, these high rates of EAC have occurred against a backdrop of progressive reduction in the risk estimate of malignancy associated with BE.⁵ In this regard, our discovery of a strong association of transcriptionally active high-risk human papillomavirus (HPV) with a subset of Barrett dysplasia (BD) and EAC⁵ may be relevant.

HPV has been identified as the major aetiological factor in cervical carcinogenesis,1 being detected in 90–100% of cervical cancer specimens compared with 20% of controls.2 In addition, the HPV viral genome has been identified in most of the precursor lesions of cervical intraepithelial neoplasia.3 HPVs are epitheliotropic and were thought to preferentially infect squamous epithelia only. However, it is now known that much of the virus is present at the squamo–columnar junction. Moreover, a consistent, strong and robust association between infection by high-risk HPV types and risk of development of adenocarcinoma of the cervix has been demonstrated.4 5