VOLUME 24 ⅐ NUMBER 17 ⅐ JUNE 10 2006 JOURNAL OF CLINICAL ONCOLOGY REVIEW ARTICLE Clinical Implications of Human Papillomavirus in Head and Neck Cancers Carole Fakhry and Maura L. Gillison From the Departments of Viral Oncol- ABSTRACT ogy, Aerodigestive Malignancy, and Cancer Prevention and Control, The Human papillomavirus (HPV) is now recognized to play a role in the pathogenesis of a subset of head and neck Sidney Kimmel Comprehensive Cancer squamous cell carcinomas (HNSCCs), particularly those that arise from the lingual and palatine tonsils within Center at Johns Hopkins; and the the oropharynx. High-risk HPV16 is identified in the overwhelming majority of HPV-positive tumors, which have Departments of Epidemiology and molecular-genetic alterations indicative of viral oncogene function. Measures of HPV exposure, including Molecular Microbiology and Immunol- sexual behaviors, seropositivity to HPV16, and oral, high-risk HPV infection, are associated with increased risk ogy, The Johns Hopkins Bloomberg for oropharyngeal cancer. HPV infection may be altering the demographics of HNSCC patients, as these School of Public Health, Baltimore, MD. patients tend to be younger, nonsmokers, and nondrinkers. There is sufficient evidence to conclude that a Submitted February 9, 2006; accepted diagnosis of HPV-positive HNSCC has significant prognostic implications; these patients have at least half the February 27, 2006. risk of death from HNSCC when compared with the HPV-negative patient. The HPV etiology of these tumors Supported in part by National Institute may have future clinical implications for the diagnosis, therapy, screening, and prevention of HNSCC. for Dental and Craniofacial Research Grant No. DE016631-02. J Clin Oncol 24:2606-2611. © 2006 by American Society of Clinical Oncology Authors’ disclosures of potential con- flicts of interest and author contribu- cer, in HNSCC, HPV appears to play a pathogenic tions are found at the end of this INTRODUCTION 1,2,6,11-18 article. role for only a subset. It is clear that contin- Address reprint requests to Maura L. Oral human papillomavirus (HPV) infection, like ued expression of the viral oncogenes is necessary for Gillison, MD, PhD, Cancer Research alcohol and tobacco, is now recognized to play a role histopathologic progression and the malignant phe- Building I, Room G91, 1650 Orleans St, in the pathogenesis of head and neck squamous cell notype of an HPV-associated tumor19-22: HPVs are Baltimore, MD 21231; e-mail: gillima@ 1-7 jhmi.edu. carcinomas (HNSCC). HPVs are DNA viruses not known to work by a hit-and-run mechanism. with a specific tropism for squamous epithelia, and Therefore, demonstration of HPV genomic DNA in © 2006 by American Society of Clinical Oncology more than 120 different HPV types have been iso- tumors is essential for HPV to play a role in the lated to date. Low-risk HPVs, such as HPV6 and -11, 23 0732-183X/06/2417-2606/$20.00 pathogenesis of a tumor. In a recent meta-analysis, induce benign hyperproliferations of the epithelium HPV genomic DNA was detected in approximately DOI: 10.1200/JCO.2006.06.1291 such as papillomas or warts. By contrast, high-risk, 26% of all HNSCC by sensitive polymerase chain oncogenic types (eg, HPV16, -18, -31, -33, -35) are reaction (PCR) -based methods.24 However, data defined by their strong epidemiologic association are most strong and consistent for HPV presence in 8 with cervical cancer. The prototypic high-risk types oropharyngeal cancers. In the majority of studies, -16 and -18 are capable of transforming epithelial 50% or more of oropharyngeal tumors contained cells derived from both the genital and upper respi- the HPV genome.1,2,11,15,17,18,25-30 In a recent multi- 9 ratory tracts. The transforming potential of high- national study conducted by the International risk HPVs is largely a result of the function of two Agency for Research on Cancer (IARC), only 18% of viral oncoproteins, E6 and E7, which functionally oropharyngeal tumors were HPV positive, indicat- inactivate two human tumor-suppressor pro- ing that this proportion likely varies by geography.31 teins, p53 and pRb, respectively.10 Expression of Regardless of the study population, high-risk high-risk HPV E6 and E7 results in cellular pro- HPV16 accounts for the overwhelming majority liferation, loss of cell cycle regulation, impaired (90% to 95%) of HPV-positive tumors, whereas cellular differentiation, increased frequency of other high-risk types -31, -33, and -35 account for spontaneous and mutagen-induced mutations, the minority.24,31 For oropharyngeal tumors, viral and chromosomal instability.10 HPV DNA has been specifically localized to tumor cell nuclei,2,6 is frequently integrated,2,4,6,32-36 and HPV DNA PRESENCE AND EXPRESSION IN is transcriptionally active.2,4,5,11,27,32,34,37 Further- OROPHARYNGEAL CANCERS more, HPV is present in high copy number in tumor cell nuclei of in situ, invasive, and metastatic disease Infection by a high-risk HPV type is now known to and absent in adjacent normal tissue.38 These data be necessary, although insufficient, for the develop- indicate that HPV infection is specific to tumor cell ment of cervical cancer. In contrast to cervical can- nuclei and that infection precedes histopathologic 2606 Information downloaded from www.jco.org and provided by NIH LIBRARY on June 12, 2006 from 156.40.204.91. Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved. HPV in Head and Neck progression of the tumor. Equivalent data are not available for risk of cancer is currently unclear, with some studies suggesting a non-oropharyngeal tumors. For instance, HPV has not been synergistic effect with tobacco1 or alcohol,53 whereas others have shown to have an etiologic association with oral tongue cancers found no such synergy.31,53 diagnosed at any age. Although HPV can infect the epithelium of Numerous case-control studies of cervical cancer patients have the upper aerodigestive tract in general, the tonsil appears uniquely indicated that HPV infection is predominantly sexually transmitted.54 susceptible to transformation by the virus. As for the transforma- Certain sexual behaviors, such as a high number of sexual partners, are tion zone of the cervix, the reason for this anatomic site specificity associated with increased risk of cervical cancer because they serve as for transformation is unknown. surrogate markers for the probability that an individual has been A role for HPV in oropharyngeal tumors is further substantiated exposed to HPV. Consistent with this literature, several case-control by distinct molecular genetic alterations in HPV-positive versus HPV- studies have reported certain sexual behaviors to elevate risk of negative tumors. As for many cancers, inactivation of the p53 and pRb HNSCC.1,55 Risk factors among men include young age at first inter- pathways is a common event in the molecular progression of HNSCC. course, number of sexual partners, and a history of genital warts.1 Risk However, inactivation occurs by different mechanisms in HPV- is elevated among women with a high number of sexual partners.56 positive and -negative tumors. In HPV-positive HNSCC, genetic Furthermore, specific sexual behaviors have bee more strongly associ- alterations are reflective of viral oncogene function. For instance, ated with risk of an HPV-positive tumor, including a history of per- HPV-positive tumors tend to have wild-type p53, because p53 is forming oral sex and oral-anal contact.17,31,57 functionally inactivated by viral E6 oncoprotein.2,4,6,11,18,35,39,40 By Direct measures of HPV exposure and infection have also been contrast, HPV-negative tumors have specific p53 mutations demon- associated with risk of oral cancers. Seropositivity to the HPV16 viral strated to be induced by carcinogens in tobacco smoke.2,4,6,11,18,35,39,40 capsid protein confers a two- to three-fold increase in risk for As another example, pRb function is inactivated by viral E7 protein in HNSCC.1,7,31 In case-control studies, the presence of an oncogenic, the HPV-positive tumor, but in HPV-negative tumors, the pRb path- oral HPV infection has been associated with a six-fold increase in risk way is altered by other mechanisms, including amplification of cyclin for oral cancer.57-59 Risk estimates are stronger when restricted to D and inactivation of p16.3,4,6,27,29,38 More complex differences in oropharyngeal cancer. In a recent study conducted in Sweden,59 oral regions of chromosomal loss and gain have been demonstrated in infection by a high-risk HPV type was demonstrated to dramatically HPV-positive versus -negative tumors through techniques such as elevate odds for oropharyngeal cancer (odds ratio, 230; 95% CI, 44 to comparative genomic hybridization41 and microsatellite analysis.42 1,200), after adjustment for alcohol and tobacco. In a nested case- control study conducted in Norway,7 HPV16-seropositive individuals had a greater than 14-fold increase in risk of subsequent oropharyn- CLINICAL CHARACTERISTICS OF THE HPV-POSITIVE PATIENT geal cancer when compared with seronegative individuals. This study was particularly important because it demonstrated that HPV expo- In addition to molecular-genetic distinctions, HPV affects the demo- sure preceded development of clinical disease. graphics, clinical presentation, and histopathology of the HNSCC Although natural history studies have not been conducted, it is patient. Patients with HPV-positive HNSCC tend to be younger by presumed that oral HPV infection precedes development of an HPV- approximately 5 years, on average, when compared with HPV- positive HNSCC. Therefore, risk factors for oral HPV infection are negative HNSCC patients.28,30,43-45 With regard to sex, men appear to likely, by extension, to be risk factors for HPV-positive HNSCC. Oral be at equal risk to women.