Correspondence
Human Papillomavirus and Oropharyngeal Cancer
N Engl J Med 2007; 357:1156-1158September 13, 2007
- Article
To the Editor:
The study by D'Souza et al. (May 10 issue)1 on oropharyngeal squamous-cell carcinomas associated with human papillomavirus (HPV) provides important epidemiologic insights into a cancer that is becoming increasingly common in the United States.2 However, the molecular mechanisms of carcinogenesis in HPV-associated oropharyngeal squamous-cell carcinomas remain unclear.
The integration of HPV type 16 (HPV-16) into the host genome is an important mechanism in cervical carcinogenesis,3 but there is no direct evidence that this process occurs in oropharyngeal squamous-cell carcinomas. The authors state that Southern blot, real-time polymerase-chain-reaction (PCR), and fluorescence in situ hybridization analyses4 have established integration sites but that these methods provide only indirect evidence. Direct evidence would require observation of the viral DNA sequence either flanked or attached to one end of human DNA (junction sequences). Mellin et al.5 did not observe this finding in HPV-16–positive tonsillar carcinomas. We previously used restriction-site PCR in more than 100 HPV-16 and HPV-18 cervical cancers to identify many of these junction sequences.6 However, when we used this same technique in 40 oropharyngeal squamous-cell carcinomas that were positive for HPV-16, we did not detect junction sequences (unpublished data). This finding, which suggests a mechanism of carcinogenesis that is distinct from that in cervical cancer, warrants further investigation.
6 ReferencesOdey C. Ukpo, M.S.
Eric J. Moore, M.D.
David I. Smith, Ph.D.
Mayo Clinic, Rochester, MN 55905
oukpo1979@gmail.com 1
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
Full Text | Web of Science | Medline2
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 | Web of Science | Medline3
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 | Web of Science | Medline4
Gillison ML . Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin Oncol 2004;31:744-754
CrossRef | Web of Science | Medline5
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 | Web of Science | Medline6
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 | Web of Science | Medline
To the Editor:
Little is known about the natural history of oral HPV infection.1 In a cohort of 360 healthy students (mean age, 18.7 years), 69% of whom were female,2 we tested oral cytobrush samples for HPV DNA by means of multiplex PCR. Of these students, 20 (5.6%) were positive for HPV. Three years later, 8 of 183 students who were retested (4.4%) were positive, and 1 had persistent infection. Oral HPV infection was unusual, and the persistence of infection was rare.
Of the 183 students who were retested, 28 were sexually inactive, and all these students were HPV-negative. Of the sexually active students, 100% of those who were HPV-positive had had both penetrative and oral–genital sex in the previous 3 years; of those sexually active students who were HPV-negative, 88% had had only penetrative sex and 86% had had only oral–genital sex. These findings support the hypothesis that oral HPV is transmitted through sexual contact and that oral–genital contact is the likely mechanism.
2 ReferencesHilary Williams, M.B., Ch.B., Ph.D.
Bristol Haematology Oncology Centre, Bristol BS2 8ED, United Kingdom
hilary.williams@ubht. nhs. uk Craig D. Higgins, M.Sc.
London School of Hygiene and Tropical Medicine, London WC1E 7HT, United KingdomDorothy H. Crawford, M.D., Ph.D.
University of Edinburgh, Edinburgh EH9 1QH, United Kingdom1
Syrjanen S . Human papillomaviruses in head and neck carcinomas. N Engl J Med 2007;356:1993-1995[Erratum, N Engl J Med 2007;357:313.]
Full Text | Web of Science | Medline2
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 | Web of Science | Medline
To the Editor:
D'Souza et al. report a very high prevalence of HPV involving 72% of oropharyngeal squamous-cell carcinomas. This finding is unlikely to be related to the detection method,1 since in situ hybridization was used, a reliable technique with a test outcome that is often similar to that of viral oncogene transcript analysis.2 We previously reported that in a Dutch cohort, 6 of 37 oropharyngeal carcinomas (16%) contained transcriptionally active HPV.3 This prevalence differs significantly (P<0.001) from that reported by D'Souza et al. A review article also reported a prevalence of HPV in oropharyngeal carcinomas that was much lower than 72%.4 We wonder whether the associations reported by DeSouza et al. can be extrapolated to other populations.
4 ReferencesBoudewijn 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@vumc. nl 1
Syrjanen S . Human papillomaviruses in head and neck carcinomas. N Engl J Med 2007;356:1993-1995[Erratum, N Engl J Med 2007;357:313.]
Full Text | Web of Science | Medline2
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).
3
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
CrossRef | Web of Science | Medline4
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
CrossRef | Web of Science | Medline
Author/Editor Response
The results of in situ hybridization correlate with viral oncogene expression in our laboratory (unpublished data). Therefore, it is unlikely that the high prevalence of HPV in oropharyngeal cancers that we found can be explained by false positive misclassification. However, our study was performed in a hospital and was not population-based. We cannot exclude the possibility that subjects who did not have traditional risk factors were more likely to participate in the study. The HPV prevalence of 72% was similar to the 63% prevalence in cancers of the oropharynx that were collected throughout the United States in a clinical trial conducted by the Eastern Cooperative Oncology Group.1
We acknowledge that the fraction of oropharyngeal cancers caused by HPV in the United States may differ from that in other geographic regions. Cross-sectional prevalence in a population would largely be driven by incidence rates for HPV-positive and HPV-negative squamous-cell cancers of the head and neck. One might reasonably expect that the relative incidence of these two cancers would be driven by local societal mores — for example, the prevalence of alcohol and tobacco use, sexual behaviors, and other cofactors (including diet and oral hygiene) in a population. Incidence rates may also be quite dynamic, because behaviors may change considerably over time. For instance, a significant increase in the prevalence of HPV-associated tonsillar cancer from about 23% in the 1970s to 68% in the period from 2000 through 2002 was reported in Sweden.2 Therefore, geographic variation in the prevalence of HPV in oropharyngeal cancers may be strongly influenced by the region and calendar period sampled.
Although viral integration occurs in the majority of cervical cancers, it is neither necessary for nor specific to invasive carcinoma.3 Increased expression and stability of viral oncogene transcripts occur as a consequence of viral integration. Analogous deregulation of viral oncogene expression may occur in episomal virus through methylation or mutation of the viral upstream regulatory region.3 Although we agree with Ukpo et al. that patterns of in situ hybridization and RT-PCR are indirect measures of integration, analysis of restriction-fragment–length polymorphisms by Southern blot hybridization is a direct measure. Viral integration into the genome of head-and-neck squamous-cell carcinoma has been demonstrated by this method4 and through the cloning of viral-cell genome fusion sites,5 albeit in few cases.
Although oral HPV infection is now recognized as a causative factor 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 understanding of the risk factors for acquisition of oral HPV infection and the factors that affect the duration of infection.
5 ReferencesMaura L. Gillison, M.D., Ph.D.
Johns Hopkins Medical Institutions, Baltimore, MD 21231
gillima@jhmi.edu 1
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 Oncol2007;25-252
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 | Web of Science | Medline3
Pett M ,Coleman N . Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007;212:356-367
CrossRef | Web of Science | Medline4
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
Web of Science | Medline5
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 | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Nadine C. Olthof, Jos M.J.A.A. Straetmans, Robert Snoeck, Frans C.S. Ramaekers, Bernd Kremer, Ernst-Jan M. Speel. (2011) Next-generation treatment strategies for human papillomavirus-related head and neck squamous cell carcinoma: where do we go?. Reviews in Medical Virologyn/a-n/a
CrossRef
