Abstract and Introduction
Background The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case–control studies conducted in regions with differing background risks of esophageal cancer.
Methods We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case–control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided.
Results We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036).
Conclusions We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers.
Cancer of the esophagus was the eighth most frequently occurring type of cancer in 2008, with an estimated 481 400 new diagnoses. In the same year, there were an estimated 406 000 deaths from the disease, making it the sixth most common cancer cause of death. Despite increasing rates of esophageal adenocarcinomas in many Western countries, squamous cell carcinoma of the esophagus remains the dominant histological type of esophageal cancer worldwide and thus is the focus of this study.
Tobacco smoking and alcohol consumption are considered causal for esophageal squamous cell carcinoma, particularly in developed countries, where exposure to both of these factors has been shown to increase the risk greatly, sometimes multiplicatively.[2–4] In certain geographic regions with a high incidence of esophageal squamous cell carcinoma, most notably in developing countries, the risk of esophageal squamous cell carcinoma has been found to be associated with local factors, such as poor socioeconomic conditions;[5,6] diets low in fruits, vegetables, and specific micronutrients such as niacin, vitamins A and C, magnesium, and riboflavin; low serum selenium levels in China; consumption of hot tea in South America (9) and Iran; the use of certain traditional medicinal plants (eg, Solanum nigrum) in Transkei, South Africa; and consumption of specific opiates.[12,13] However, the lack of known prevalent strong risk factors for esophageal squamous cell carcinoma in many high-incidence regions suggests that additional important risk factors are yet to be identified.
One possible risk factor for esophageal squamous cell carcinoma is infection with oncogenic human papillomavirus (HPV) types. HPV type 16 (HPV16) is known to cause the majority of squamous cell carcinomas of the cervix[14–17] and is strongly associated with subgroups of squamous cell carcinomas at other anogenital sites.[18,19]and with cancers of the head and neck, particularly the oropharynx.[20–22] The possibility that HPV might play an etiologic role in the development of esophageal squamous cell carcinoma was first proposed in 1982 by Syrjänen et al..[23,24] based on histological findings that suggested possible associations between HPV and both malignant and benign squamous cell lesions of the esophagus. Since then, although more than 100 studies have investigated the relationship between esophageal squamous cell carcinoma and HPV, the evidence of an association is inconclusive. Arguments in support of an association include 1) the detection of HPV DNA in esophageal squamous cell carcinoma; 2) the histological similarities of the oral and esophageal squamous epithelia; 3) the proximity of the esophagus and oropharynx and their similar neoplastic responses to smoking and alcohol;[26,27] 4) evidence of an association between HPV and bovine esophageal cancer; and 5) in vitro transformation of esophageal epithelial cells by HPV. Arguments against an association between esophageal squamous cell carcinoma and HPV include the inconsistent conclusions among serological studies of HPV and esophageal squamous cell carcinoma and the wide variations in the prevalence of HPV DNA detected in esophageal squamous cell carcinoma tissue among studies.
Serological testing for HPV proteins has been a useful tool for identifying and confirming associations between HPV and various types of squamous cell cancer.[16–22] The presence of circulating antibodies to the HPV late capsid protein L1 is considered a marker of cumulative (lifetime) exposure to HPV and high seropositivity for HPV16 L1 has been shown to be associated with increased risks of cancer of the cervix.[16,19] the oral cavity, and the oropharynx.[20,22] A number of serological studies have examined the association between esophageal squamous cell carcinoma and HPV16 L1 or HPV18 L1 antibodies.[19,31–36] Although all of those studies measured L1 antibodies using similar methods, the definitions of seropositivity varied among the studies, making comparisons of results between studies difficult. Seropositivity for the E6 and E7 proteins of HPV16 and HPV18 have been shown to be moderately sensitive and highly specific markers for HPV-driven carcinomas of the cervix, oropharynx.[20,21] and penis, and thus appear to be useful markers for identifying patients with HPV-positive tumors. However, the statistical power to detect relatively small underlying associations between specific cancer types and seropositivity for E6 or E7 antibodies is limited in case–control studies because invasive HPV-driven carcinomas are rare in the populations from which control subjects are chosen.[17,18,20–22] Thus, it is important to consider the absence of a statistical association between esophageal squamous cell carcinoma and seropositivity to either E6 or E7 for a given HPV type in conjunction with the results for all other serological markers of that HPV type.
The evolution of reliable high-throughput multiplex serological techniques has allowed the simultaneous testing of up to 100 different markers using only 2 μL of serum per sample.[37–39] The aim of this collaboration was to examine the associations between the risk of esophageal squamous cell carcinoma and a number of HPV serological markers measured using this technology in serum from existing case–control studies conducted in regions with differing background risks of esophageal cancer, after adjustment for smoking, alcohol consumption, and other potential confounders. To our knowledge, this is the largest study to examine the relationship between esophageal squamous cell carcinoma and HPV antibodies, the first study to compare HPV E6/E7 seroreactivities of esophageal squamous cell carcinoma case subjects with that of control subjects, and the first study to examine the relationships between esophageal squamous cell carcinoma and antibodies to HPV types other than HPV16, HPV18, HPV33, and HPV73 (a very rare type known to be associated with cervical cancer but not examined in this study).
J Natl Cancer Inst. 2012;104(2):147-158. © 2012 Oxford University Press