HPV, Barrett's Dysplasia, and Esophageal Adenocarcinoma
HPV, Barrett's Dysplasia, and Esophageal Adenocarcinoma
Objectives: 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.
Methods: 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).
Results: 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.
Conclusions: 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.
Barrett's esophagus (BE) is a condition in which the distal third of the normal stratified squamous epithelium is replaced by specialized intestinal metaplasia. BE is the most important and recognizable known precursor lesion for esophageal adenocarcinoma (EAC), which has increased in incidence by 600% in the United States between 1975 and 2001. It has been proposed that a metaplasia–dysplasia–cancer sequence exists, whereby patients with BE (no dysplasia) undergo dysplastic transformation (low- and high-grade dysplasia) before cancer development. Our understanding of the known and unknown risk factors and molecular aberrations that are involved in the Barrett's metaplasia–dysplasia–carcinoma sequence is incomplete. Interactions with as yet unidentified risk factors including viruses cannot be excluded. It is therefore of interest to note that human papillomavirus (HPV) DNA has been reported in up to 66% of esophageal squamous cell carcinoma specimens, with significant geographical and racial variations. An association between HPV infection and oropharyngeal cancers has been demonstrated and the dramatic rise in head and neck cancers in the United States, Sweden, and Australia has been attributed to this virus. HPV infection is thought to be related to orogenital sexual transmission that potentially exposes the upper gastrointestinal (GI) tract to this infectious agent.
The few studies that have previously investigated HPV and EAC or BE have produced either negative data or positive results of doubtful clinical/etiological significance or have detected only low-risk HPV types without seeking evidence of viral integration or replication.
Our objective, therefore, was to determine whether the prevalence of HPV DNA in esophageal epithelium, assessed using nested PCR, was increased in patients with Barrett's metaplasia/dysplasia and/or those with EAC compared with controls with or without gastroesophageal reflux disease (GERD) symptoms and without changes of BE. Additionally, we investigated if there was an increasing detection rate of transcriptionally active virus, measured by p16INK4A immunohistochemistry (IHC) and E6/E7 mRNA reverse transcriptase–PCR (RT–PCR), in esophageal tissue of patients representing the Barrett's metaplasia–dysplasia–adenocarcinoma sequence. A secondary objective was whether the detection rate of the virus (if present) was different between the transformation zone (squamocolumnar junction (SCJ)) and adjacent esophageal epithelium.
Abstract and Introduction
Abstract
Objectives: 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.
Methods: 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).
Results: 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.
Conclusions: 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.
Introduction
Barrett's esophagus (BE) is a condition in which the distal third of the normal stratified squamous epithelium is replaced by specialized intestinal metaplasia. BE is the most important and recognizable known precursor lesion for esophageal adenocarcinoma (EAC), which has increased in incidence by 600% in the United States between 1975 and 2001. It has been proposed that a metaplasia–dysplasia–cancer sequence exists, whereby patients with BE (no dysplasia) undergo dysplastic transformation (low- and high-grade dysplasia) before cancer development. Our understanding of the known and unknown risk factors and molecular aberrations that are involved in the Barrett's metaplasia–dysplasia–carcinoma sequence is incomplete. Interactions with as yet unidentified risk factors including viruses cannot be excluded. It is therefore of interest to note that human papillomavirus (HPV) DNA has been reported in up to 66% of esophageal squamous cell carcinoma specimens, with significant geographical and racial variations. An association between HPV infection and oropharyngeal cancers has been demonstrated and the dramatic rise in head and neck cancers in the United States, Sweden, and Australia has been attributed to this virus. HPV infection is thought to be related to orogenital sexual transmission that potentially exposes the upper gastrointestinal (GI) tract to this infectious agent.
The few studies that have previously investigated HPV and EAC or BE have produced either negative data or positive results of doubtful clinical/etiological significance or have detected only low-risk HPV types without seeking evidence of viral integration or replication.
Our objective, therefore, was to determine whether the prevalence of HPV DNA in esophageal epithelium, assessed using nested PCR, was increased in patients with Barrett's metaplasia/dysplasia and/or those with EAC compared with controls with or without gastroesophageal reflux disease (GERD) symptoms and without changes of BE. Additionally, we investigated if there was an increasing detection rate of transcriptionally active virus, measured by p16INK4A immunohistochemistry (IHC) and E6/E7 mRNA reverse transcriptase–PCR (RT–PCR), in esophageal tissue of patients representing the Barrett's metaplasia–dysplasia–adenocarcinoma sequence. A secondary objective was whether the detection rate of the virus (if present) was different between the transformation zone (squamocolumnar junction (SCJ)) and adjacent esophageal epithelium.
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