The Controversial Link Between Human Papillomavirus Infection and Esophageal Health: An Exploratory Translational Study

Evidence on the contribution of human papillomaviruses (HPVs) to the development of esophageal papillomas is still controversial. Esophageal papillomatosis (EP) is considered an exceedingly rare, but distinct entity within esophageal proliferations, with about 57 cases published so far. Tissues derived from an EP case and from non-EP esophageal papillomas were investigated for the presence of HPVs and virus-positive specimens were subsequently analyzed for transcriptional activity and surrogate markers of infection. Low-risk type HPV6 DNA was detected in a subset of the esophageal papillomatous tissues, including EP, and a variant isolate belonging to lineage A. In the EP tissue, the abundant expression of the viral E6/E7 mRNA and the presence of HPV6-specific E1^E4 transcripts, the latter indicative of productive viral infection, were detected. An analysis of HPV-specific neutralizing antibodies in sera obtained from the EP case during natural infection as well as after HPV vaccination revealed that, despite extensive manifestation, HPV6-specific antibodies were absent during natural infection and only elicited after repeated HPV immunizations. Although limited by a small sample size, this exploratory study suggests a possible involvement of HPV6 in the development of EP. Furthermore, this study may contribute to the evidence distinguishing EP from less extensive forms of non-EP esophageal squamous papillomas.