To the Editor: The study by D'Souza et al. (May 10 issue)1 onoropharyngeal squamous-cell carcinomas associated with humanpapillomavirus (HPV) provides important epidemiologic insightsinto a cancer that is becoming increasingly common in the UnitedStates.2 However, the molecular mechanisms of carcinogenesisin HPV-associated oropharyngeal squamous-cell carcinomas remainunclear.
The integration of HPV type 16 (HPV-16) into the host genomeis an important mechanism in cervical carcinogenesis,3 but thereis no direct evidence that this process occurs in oropharyngealsquamous-cell carcinomas. The authors state that Southern blot,real-time polymerase-chain-reaction (PCR), and fluorescencein situ hybridization analyses4 have established integrationsites but that these methods provide only indirect evidence.Direct evidence would require observation of the viral DNA sequenceeither flanked or attached to one end of human DNA (junctionsequences). Mellin et al.5 did not observe this finding in HPV-16–positivetonsillar carcinomas. We previously used restriction-site PCRin more than 100 HPV-16 and HPV-18 cervical cancers to identifymany of these junction sequences.6 However, when we used thissame technique in 40 oropharyngeal squamous-cell carcinomasthat were positive for HPV-16, we did not detect junction sequences(unpublished data). This finding, which suggests a mechanismof carcinogenesis that is distinct from that in cervical cancer,warrants further investigation.
Odey C. Ukpo, M.S. Eric J. Moore, M.D. David I. Smith, Ph.D. Mayo Clinic Rochester, MN 55905 oukpo1979{at}gmail.com
References
D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356:1944-1956. [Free Full Text]
Frisch M, Hjalgrim H, Jaeger AB, Biggar RJ. Changing patterns of tonsillar squamous cell carcinoma in the United States. Cancer Causes Control 2000;11:489-495. [CrossRef][ISI][Medline]
Park JS, Hwang ES, Park SN, et al. Physical status and expression of HPV genes in cervical cancers. Gynecol Oncol 1997;65:121-129. [CrossRef][ISI][Medline]
Gillison ML. Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin Oncol 2004;31:744-754. [CrossRef][ISI][Medline]
Mellin H, Dahlgren L, Munck-Wikland E, et al. Human papillomavirus type 16 is episomal and a high viral load may be correlated to better prognosis in tonsillar cancer. Int J Cancer 2002;102:152-158. [CrossRef][ISI][Medline]
Thorland EC, Myers SL, Gostout BS, Smith DI. Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. Oncogene 2003;22:1225-1237. [CrossRef][ISI][Medline]
To the Editor: Little is known about the natural history oforal HPV infection.1 In a cohort of 360 healthy students (meanage, 18.7 years), 69% of whom were female,2 we tested oral cytobrushsamples for HPV DNA by means of multiplex PCR. Of these students,20 (5.6%) were positive for HPV. Three years later, 8 of 183students who were retested (4.4%) were positive, and 1 had persistentinfection. Oral HPV infection was unusual, and the persistenceof infection was rare.
Of the 183 students who were retested, 28 were sexually inactive,and all these students were HPV-negative. Of the sexually activestudents, 100% of those who were HPV-positive had had both penetrativeand oral–genital sex in the previous 3 years; of thosesexually active students who were HPV-negative, 88% had hadonly penetrative sex and 86% had had only oral–genitalsex. These findings support the hypothesis that oral HPV istransmitted through sexual contact and that oral–genitalcontact is the likely mechanism.
Hilary Williams, M.B., Ch.B., Ph.D. Bristol Haematology Oncology Centre Bristol BS2 8ED, United Kingdom hilary.williams{at}ubht.nhs.uk
Craig D. Higgins, M.Sc. London School of Hygiene and Tropical Medicine London WC1E 7HT, United Kingdom
Dorothy H. Crawford, M.D., Ph.D. University of Edinburgh Edinburgh EH9 1QH, United Kingdom
References
Syrjänen S. Human papillomaviruses in head and neck carcinomas. N Engl J Med 2007;356:1993-1995. [Erratum, N Engl J Med 2007;357:313.] [Free Full Text]
Higgins CD, Swerdlow AJ, Macsween KF, et al. A study of risk factors for acquisition of Epstein-Barr virus and its subtypes. J Infect Dis 2007;195:474-482. [CrossRef][ISI][Medline]
To the Editor: D'Souza et al. report a very high prevalenceof HPV involving 72% of oropharyngeal squamous-cell carcinomas.This finding is unlikely to be related to the detection method,1since in situ hybridization was used, a reliable technique witha test outcome that is often similar to that of viral oncogenetranscript analysis.2 We previously reported that in a Dutchcohort, 6 of 37 oropharyngeal carcinomas (16%) contained transcriptionallyactive HPV.3 This prevalence differs significantly (P<0.001)from that reported by D'Souza et al. A review article also reporteda prevalence of HPV in oropharyngeal carcinomas that was muchlower than 72%.4 We wonder whether the associations reportedby DeSouza et al. can be extrapolated to other populations.
Boudewijn J. Braakhuis, Ph.D. Peter J. Snijders, Ph.D. C.René Leemans, M.D., Ph.D. VU University Medical Center 1081 HV Amsterdam, the Netherlands bjm.braakhuis{at}vumc.nl
References
Syrjänen S. Human papillomaviruses in head and neck carcinomas. N Engl J Med 2007;356:1993-1995. [Erratum, N Engl J Med 2007;357:313.] [Free Full Text]
Smeets SJ, Hesselink AT, Speel E-JM et al. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer (in press).
Braakhuis BJM, Snijders PJF, Keune W-JH, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst 2004;96:998-1006. [Free Full Text]
Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467-475. [Free Full Text]
The author replies: The results of in situ hybridization correlatewith viral oncogene expression in our laboratory (unpublisheddata). Therefore, it is unlikely that the high prevalence ofHPV in oropharyngeal cancers that we found can be explainedby false positive misclassification. However, our study wasperformed in a hospital and was not population-based. We cannotexclude the possibility that subjects who did not have traditionalrisk factors were more likely to participate in the study. TheHPV prevalence of 72% was similar to the 63% prevalence in cancersof the oropharynx that were collected throughout the UnitedStates in a clinical trial conducted by the Eastern CooperativeOncology Group.1
We acknowledge that the fraction of oropharyngeal cancers causedby HPV in the United States may differ from that in other geographicregions. Cross-sectional prevalence in a population would largelybe driven by incidence rates for HPV-positive and HPV-negativesquamous-cell cancers of the head and neck. One might reasonablyexpect that the relative incidence of these two cancers wouldbe driven by local societal mores — for example, the prevalenceof alcohol and tobacco use, sexual behaviors, and other cofactors(including diet and oral hygiene) in a population. Incidencerates may also be quite dynamic, because behaviors may changeconsiderably over time. For instance, a significant increasein the prevalence of HPV-associated tonsillar cancer from about23% in the 1970s to 68% in the period from 2000 through 2002was reported in Sweden.2 Therefore, geographic variation inthe prevalence of HPV in oropharyngeal cancers may be stronglyinfluenced by the region and calendar period sampled.
Although viral integration occurs in the majority of cervicalcancers, it is neither necessary for nor specific to invasivecarcinoma.3 Increased expression and stability of viral oncogenetranscripts occur as a consequence of viral integration. Analogousderegulation of viral oncogene expression may occur in episomalvirus through methylation or mutation of the viral upstreamregulatory region.3 Although we agree with Ukpo et al. thatpatterns of in situ hybridization and RT-PCR are indirect measuresof integration, analysis of restriction-fragment–lengthpolymorphisms by Southern blot hybridization is a direct measure.Viral integration into the genome of head-and-neck squamous-cellcarcinoma has been demonstrated by this method4 and throughthe cloning of viral-cell genome fusion sites,5 albeit in fewcases.
Although oral HPV infection is now recognized as a causativefactor for a subgroup of head-and-neck squamous-cell carcinomas,little is known about the natural history of oral HPV infection.Natural-history studies are needed to gain a better understandingof the risk factors for acquisition of oral HPV infection andthe factors that affect the duration of infection.
Maura L. Gillison, M.D., Ph.D. Johns Hopkins Medical Institutions Baltimore, MD 21231 gillima{at}jhmi.edu
References
Fakhry C, Westra WH, Li S, et al. Prognostic significance of human papillomavirus (HPV) tumor status for patients with head and neck squamous cell carcinoma (HNSCC) in a prospective, multi-center phase II clinical trial. J Clin Oncol 2007;:25-25.
Hammarstedt L, Lindquist D, Dahlstrand H, et al. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer 2006;119:2620-2623. [CrossRef][ISI][Medline]
Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007;212:356-367. [CrossRef][Medline]
Steenbergen RD, Hermsen MA, Walboomers JM, et al. Integrated human papillomavirus type 16 and loss of heterozygosity at 11q22 and 18q21 in an oral carcinoma and its derivative cell line. Cancer Res 1995;55:5465-5471. [Free Full Text]
Ragin CC, Reshmi SC, Gollin SM. Mapping and analysis of HPV16 integration sites in a head and neck cancer cell line. Int J Cancer 2004;110:701-709. [CrossRef][ISI][Medline]
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