Causal Link of Human Papillomavirus in Barrett Esophagus and Adenocarcinoma: Are We There Yet?

SIMPLE SUMMARY: Esophageal cancer is not an uncommon malignancy in the world with a relatively high mortality. There has been a dramatic upward trajectory (approximately 400%) in the number of patients diagnosed with the glandular form of esophageal cancer (adenocarcinoma) since the 1970’s. It has been thought that this condition is related to chronic heartburn causing Barrett’s esophagus (a pre-cancerous condition), smoking and obesity. Nevertheless, this excess number of esophageal cancers is not entirely explained by these known risk factors despite improved screening, detection and treatment strategies. The discovery of high-risk type human papillomavirus (with an increased cancer potential) being strongly associated with this glandular form of tumor of the esophagus in a subset of patients (approximately 25%) may partially explain this anomaly. This discovery will aid improved detection rates of those with a greater risk of progressing to malignancy and modified treatment strategies including vaccination in the hope of reduced mortality. ABSTRACT: Esophageal cancer is a relatively common malignancy worldwide with a high mortality (5-year survival of <15%). Despite screening, surveillance, improved imaging and treatment, the exponential rise in OAC continues. The strongest risk factors for OAC are chronic heartburn and metaplastic transformation of the lower third of the esophagus (Barrett’s esophagus). The risk profile includes Caucasian race, male gender older age, obesity and smoking. Although the tumor risk in BO has been progressively revised downwards, the exponential rise in OAC remains unchecked. This paradox points to an unidentified missing link. Relatively recently, we provided the world’s initial data for a strong association of biologically relevant hr-HPV with BD and OAC. Since then, systematic reviews and meta-analysis have documented HPV DNA prevalence rates in OAC of between 13 to 35%. In this review, we provide some evidence for a probable causal relationship between hr-HPV and OAC. This is challenging given the multifactorial etiology and long latency. Increasingly, high-risk HPV (hr-HPV) is regarded as a risk factor for OAC. This discovery will aid identification of a sub-group of high-risk progressors to esophageal cancer by surveillance and the development of effective preventive strategies including vaccination.