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

Fifteen to twenty percent of all human malignancies are caused by bacterial or viral pathogens. High-risk human papillomavirus (hr-HPV) is a well-established cause of cervical, anogenital, and oropharyngeal cancers, with a strong association between hr-HPV and adenocarcinoma of the cervix. The study explores the hypothesis that hr-HPV plays a similar role in the pathogenesis of esophageal adenocarcinoma, based on similarities in immunology, genetics, and the presence of a transformation zone as a potential predilection site for viral infection. This is particularly important given the exponential rise in esophageal adenocarcinoma (OAC) incidence, which cannot be fully explained by currently understood risk factors such as chronic heartburn and Barrett's esophagus (BO). The review aims to provide evidence supporting a possible causal relationship between hr-HPV and OAC, acknowledging the challenges posed by the multifactorial etiology and long latency of the disease. Understanding this potential link is crucial for developing improved detection and prevention strategies for esophageal cancer.

The review involved a comprehensive search across PubMed, MEDLINE, Scopus, and Google Scholar from 1960 to 2022, yielding 7042 articles. After applying inclusion criteria (English language, full-text availability, relevance to search terms), and excluding studies focused solely on squamous cell carcinoma or lacking OAC-specific data, 108 articles were included. The literature search focused on human papillomavirus, HPV, viruses, viral pathogens, oncogenic viruses, HPV integration, HPV-associated cancers, esophageal adenocarcinoma, esophageal cancer, Barrett's esophagus, Barrett's metaplasia, Barrett's dysplasia, and epidemiology.

This is a narrative review summarizing existing evidence. The authors synthesize data from multiple studies, including their own prior work, examining the association between hr-HPV and esophageal adenocarcinoma. They evaluate the evidence for causality using Koch's postulates and Hill's criteria, considering epidemiological data, molecular studies, and genomic analyses comparing HPV-positive and HPV-negative esophageal adenocarcinomas. Specific analyses include HPV DNA detection by nested PCR, viral oncogene activity assessment via E6/7 mRNA expression and p16INK4A immunohistochemistry, HPV integration analysis, and serological investigation of HPV-related antibodies using multiplex technology. Genomic studies using whole exome sequencing were also reviewed to compare the mutational landscapes of HPV-positive and HPV-negative OAC. The review also addresses the issue of long latency periods, low infection-to-cancer conversion rates, and the involvement of host and environmental cofactors in esophageal carcinogenesis.

Systematic reviews and meta-analyses report HPV DNA prevalence rates in OAC ranging from 13% to 35%. The authors' prior research demonstrated a strong association between transcriptionally active high-risk HPV genotypes (16 and 18) and Barrett's dysplasia (BD) and OAC. In their studies, HPV DNA was detected in 31% of patients, with a significantly higher prevalence in BD (68.6%) and OAC (66.7%) compared to controls (18%). The majority of viral-positive cases were high-risk HPV types. Furthermore, p16INK4A expression was significantly increased in BD and OAC, and E6/E7 mRNA was detected in a significant proportion of BD and OAC patients. A greater viral load and higher frequency of HPV integration were associated with increased disease severity. Whole exome sequencing showed that HPV-positive OAC had fewer somatic mutations and a lower number of cancer driver genes compared to HPV-negative OAC, with a notable absence of TP53 mutations in HPV-positive cases. A study investigating the association between HPV status and survival showed a superior disease-free and overall survival in HPV-positive patients with Barrett's HGD and EAC. However, the review also notes inconsistencies across studies regarding the prognostic impact of HPV status in esophageal squamous cell carcinoma (OSCC). Investigations into HPV presence in esophageal cell lines also demonstrate disruption of the E2 gene and the expression of various viral transcripts, similar to cervical cancer. Serological studies yielded mixed results, with some showing increased prevalence of antibodies to specific HPV proteins in HPV-positive cases, while others found no significant difference or even a negative association between HPV serostatus and OAC.

The findings suggest a probable causal relationship between hr-HPV and a subset of OAC, although further research is needed to definitively establish causality. The observed exponential increase in OAC incidence, despite a reduction in the estimated cancer risk associated with BO, is partially explained by the strong association with hr-HPV. This highlights the importance of considering HPV as a significant risk factor in esophageal carcinogenesis. The distinct genomic and proteomic signatures in HPV-positive OAC compared to HPV-negative OAC indicate that HPV-positive tumors constitute a unique subgroup with potential implications for risk stratification and treatment personalization. Improved survival outcomes observed in HPV-positive patients also suggest potential benefits from targeted therapies or a modified treatment strategy. The inconsistent findings regarding the prognostic impact of HPV in OSCC might be due to differences in study design, sample size, and HPV detection methods.

The review provides accumulating evidence for a probable relationship between hr-HPV and a subgroup of OAC. Further large-scale studies are crucial to confirm these findings and establish a definitive causal link. This research highlights the need for improved risk stratification and tailored treatment strategies based on HPV status. Future research should focus on larger genomic and proteomic studies to elucidate the mechanisms of HPV oncogenesis in esophageal adenocarcinoma, potentially leading to improved detection, prevention (e.g., vaccination), and treatment approaches.

The review is based on a synthesis of existing literature and acknowledges the limitations of some individual studies, including small sample sizes, variations in HPV detection methods, and potential biases. The inconsistencies in findings across studies regarding HPV's prognostic impact on survival in OSCC highlight the need for larger, well-designed prospective studies with standardized methodologies to clarify these discrepancies.