Correspondence to: Philip E. Castle, PhD, MPH, Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Blvd., MSC 7234, Bethesda, MD 20892-7234 (e-mail: castlep{at}mail.nih.gov)
I read with interest the article by Smith et al. (1) reporting an association between human papillomavirus (HPV) and head and neck squamous-cell carcinoma (HNSCC). Their study is consistent with two previous reports of the association of HPV with HNSCCs and especially with tonsillar and oropharyngeal cancers (2,3). These three studies suggest that approximately 25% of tonsillar and oropharyngeal cancers are linked with HPV-induced carcinogenesis. In addition, all three studies found a preponderance (i.e., 85% or more) of HNSCCs with HPV type 16 (HPV16) DNA, the type that causes approximately 50% of cervical cancers. These data are consistent with an etiologic role for HPV in the development of a subset of HNSCCs and the notion that HPV16 is uniquely oncogenic.
However, Smith et al. (1) state that "HPV testing of an oral rinse may be predictive of HPV-related head and neck cancers." Such a statement warrants caution. Although oral HPV DNA was strongly associated with having HNSCC compared with HPV DNAnegative control subjects (odds ratio [OR] = 11.5, 95% confidence interval [CI] = 5.2 to 25.7), the association was substantially less than the more than 100-fold (odds ratio) associations between HPV DNA in exfoliated cervical cells and cervical cancer. This order-of-magnitude difference in strength of the association is partly the result of the non-HPV etiology of HNSCCs but also of the weak concordance between oral HPV status and HPV positivity of the tumor ( = 0.40, 95% CI = 0.23 to 0.57). Oral HPV testing by Smith et al. (1) was more accurate for that detection of HNSCC than that previously observed (2). Combining data from these two studies (Table 1),
was 0.33 (95% CI = 0.18 to 0.47). Unlike HPV testing of exfoliated cervical specimens that can be highly concordant with biopsy HPV DNA (due to the proximity of the sampling to the tumor), oral HPV DNA status may reflect an exposure to HPV that is often unrelated to having a cancer in other anatomic locations of the head and neck. A recent study found that the prevalence of HPV DNA in oral rinses was significantly higher than that in transepithelial brush biopsy specimens of the tonsillar region (4), suggesting that oral HPV DNA status poorly reflects HPV status elsewhere. Thus, the combination of high prevalence of oral HPV DNA in non-case subjects and poor agreement of oral HPV DNA status in case subjects will limit the usefulness of oral HPV DNA testing for HPV-related HNSCCs, except possibly among patients, such as Fanconi anemia patients, who have a predilection for these malignancies and who are uniquely susceptible to HPV-induced carcinogenesis and are at a high risk of an HPV16-induced HNSCC (5).
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Finally, although screening and/or early detection of HPV16-induced HNSCC may remain intractable for the near future, this cancer may be preventable by vaccination with HPV16 L1 viruslike particle vaccines, which have shown 100% prophylactic efficacy for cervical HPV16 infections (7). Whether these vaccines will similarly prevent HPV16 infections of the head and neck remains unknown. Targeted vaccination of high-risk populations such as Fanconi anemia patients may address the prophylactic potential of these vaccines for preventing HPV infections of the head and neck, confirm the causal link between HPV16 infection and HNSCC, and provide a much needed intervention for these patients.
REFERENCES
1 Smith EM, Ritchie JM, Summersgill KF, Hoffman HT, Wang DH, Haugen TH, et al. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst 2004;96:44955.
2 Herrero R, Castellsague X, Pawlita M, Lissowska J, Kee F, Balaram P, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003;95:177283.
3 Gillison ML, Shah KV. Human papillomavirus-associated head and neck squamous cell carcinoma: mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers. Curr Opin Oncol 2001;13:1838.[CrossRef][ISI][Medline]
4 Kreimer AR, Alberg AJ, Daniel R, Gravitt PE, Viscidi R, Garrett ES, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 2004;189:68698.[CrossRef][ISI][Medline]
5 Kutler DI, Wreesmann VB, Goberdhan A, Ben Porat L, Satagopan J, Ngai I, et al. Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst 2003;95:171821.
6 Wadsworth JT, Somers KD, Cazares LH, Malik G, Adam BL, Stack BC Jr, et al. Serum protein profiles to identify head and neck cancer. Clin Cancer Res 2004;10:162532.
7 Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:164551.
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