Submit Your Article CMED MEACR meeting
Home Print this page Email this page Users Online: 514
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 3  |  Page : 114-117  

Changing face of head and neck cancer: Role of human papillomavirus beyond cervical cancer


1 Department of Oral Pathology and Microbiology, Swami Devi Dyal Hospital and Dental College, Panchkula, Haryana, India
2 Department of Oral Medicine and Radiology, Swami Devi Dyal Hospital and Dental College, Panchkula, Haryana, India

Date of Web Publication25-Oct-2012

Correspondence Address:
Harkanwal Preet Singh
Swami Devi Dyal Hospital and Dental College, Panchkula, Haryana
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-0513.102877

Rights and Permissions
  Abstract 

Human papillomaviruses (HPV) have been an area of interest since last two decades because of its potential role in the pathogenesis of malignant tumors. Approximately 35 years ago a role of human papillomaviruses (HPV) in cervical cancer has been postulated. Today it is well established that this very heterogeneous virus family harbours important human carcinogens, causing not only the vast majority of cervical, but also a substantial proportion of other anogenital and head and neck cancers. This review article has attempted to briefly analyze the present state of linking HPV to human cancers and have discussed some emerging developments. We have emphasized on the fact that HPV positive and negative cancer behave differently and should have separate treatment strategy.

Keywords: Cancer, infection, papillomavirus, tobacco


How to cite this article:
Singh HP, Nayar A, Bains SK, Bansal T. Changing face of head and neck cancer: Role of human papillomavirus beyond cervical cancer. Clin Cancer Investig J 2012;1:114-7

How to cite this URL:
Singh HP, Nayar A, Bains SK, Bansal T. Changing face of head and neck cancer: Role of human papillomavirus beyond cervical cancer. Clin Cancer Investig J [serial online] 2012 [cited 2019 Oct 20];1:114-7. Available from: http://www.ccij-online.org/text.asp?2012/1/3/114/102877


  Introduction Top


Head and neck squamous cell cancer (HNSCC) constitute tumors of diverse origin involving oral cavity, oropharynx, hypopharynx, larynx, nasopharynx and sinonasal tract. Smoking and alcohol are the two main causative factors accounting for approximately 80% of oral, oropharyngeal and laryngeal carcinomas. The association between human papilloma virus (HPV) and head and neck squamous cell carcinoma (HNSCC) has been under investigation for at least 20 years. [1],[2]

The morphological similarity of genital and oral HPV associated lesions was one of the early findings that raised the possibility that HPV might be involved in oral and laryngeal squamous cell carcinomas (SCCs). The oral cavity is lined by a mucous membrane consisting of a stratified squamous epithelium and lamina propria made up of dense connective tissue. The squamous epithelium of the gingiva, hard palate and the dorsum of the tongue are completely keratinized with a superficial horny layer, whereas in the lip, cheek, vestibular fornix, alveolar mucosa, floor of mouth and soft palate, the epithelium is non-keratinized. Thus, the histology of oral mucosa resembles that of the uterine cervix, other lower genital tract or skin, depending on the anatomic site. On the basis of these morphological similarities, one can anticipate the presence of both the mucosal and cutaneous human papillomavirus (HPV) types in different squamous cell lesions of the oral mucosa. [3]

Though smoking and alcohol are established factors responsible for head and neck cancer but role of HPV is of recent interest. Despite the fact that HPV in cervical cancer is well documented fact, its role in H and N cancer is controversial and contentious topic. [4] However, a recent meta-analysis has confirmed HPV as an independent risk factor for oral carcinoma. HPV is the most prevalent infection world wide with several new cases diagnosed every year. [5] HPV is now thought to cause 30-65% of head and neck cancers. [6]


  Mode of Oral and Oropharyngeal HPV Infection Top


The infection of HPV 16 is reported in 27% of oral cancer from north India whereas from western part of the country it ranges from 25 to 31%. The reports of HPV prevalence in oral cancer from southern India seems to be highly variable. 34% of invasive laryngeal carcinoma is found to be associated with HPV in India. [8]

Both oral and oropharyngeal HPV infection and oral and oropharyngeal SCC are associated with the practice of orogenital sex and with the high-risk sexual behaviour of cohabiting with many partners, particularly at a younger age. In a study primarily aimed at vulvogenital HPV infection, tobacco smoking and increasing age were found to be risk factors associated with increased frequency of persistent oral HPV infections in women. This appears to be because tobacco-mediated and age-related local genetic and immune dysregulation renders the tissues more susceptible to HPV infection. Although oral and oropharyngeal HPV infections are primarily sexually acquired, mouth to mouth contact between partners and between family members, autoinoculation, and vertical birth-transmission are also routes whereby HPV infection of oral and oropharyngeal sites can be established. [9],[10],[11]


  Topographic Representation of HPV Infection in the Head and Neck Region Top


The proportion of OSCCs that are potentially HPV-related (cancers of the tongue base and tonsil, including lingual tonsil and Waldeyer's ring) increased in the USA from 1973 to 2004, perhaps as a result of changing sexual behaviours. [12] The IARC Multicenter Study estimated that 18% of oral and oro-pharyngeal cancers worldwide are HPV associated. [13],[14] There is a general agreement in the current literature as regard the ranking of HPV prevalence according to SCC subsites. HPV infection is most prevalent in OPSCC, followed by Laryngeal SCCs and, finally, by OSCCs, and not detected in tumors from other HN sites. [15] Shiboski et al. (2005) showed, with an analysis of the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) data from 1973-2001, an annual increase in the incidence of oral tongue, palatine tonsil, and base-of-tongue cancers, by 2.1%, 3.9%, and 1.7%, respectively, in 20- to 44-year-old white patients, while the incidence of HNSCC at other sites declined. [16] Postma and Van Heerden have observed a significant association between cervical and oral carcinoma, suggesting that the oral-genital transmitted HPV infection could induce a neoplastic onset, both synchronous and asynchronous, in different mucosal sites. [17]


  Molecular Insight into Role of HPV Genome in Oncogenic Mechanisms of H and N Cancer Top


Human papillomaviruses (HPV) are epitheliotropic viruses present in the skin and mucosa of several animals. In humans, more than 70 types have been described. [19] According to epidemiological case-control studies, 15 high-risk HPV types have been recognized (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), while 3 types have been nominated as probable high-risk (types 26, 53, and 66) and 12 types have been classified as low-risk [Table 1]. [20] Recognized initially as sexually transmitted agents, HPVs are now considered human carcinogens. [21] Functionally high risk HPV infection contributes to carcinogenesis and tumor progression predominantly through the actions of two viral oncogenes, E6 and E7. These oncogenes are consistently expressed in cervical cell lines and in human cancers [Table 2]. [22],[23] Both of these oncogenes interact with and inhibit the activities of critical components of cell cycle regulatory systems, in particular E6 with p53 and E7 with Rb. [22],[23],[24] The E7 protein interacts with pRB and inactivates this cellular protein. [25] As a consequence, E2F transcription factor is released from pRB-E2F complex, leading to transcriptional activation of several genes involved in cell proliferation. [26] Binding of the E6 protein to the p53 promotes the degradation of the latter through a ubiquitin-dependent proteolysis system. Also of significance is that on completion of the degradation of p53 by the ubiquitin-dependent proteolysis system, the E6 protein is free to interact again with remaining p53 molecules, leading to further degradation of the latter. [27] The products of genes E6 and E7 are essential in the process of HPV induced cellular immortalization and transformation. [28],[29] The variants are thought to differ in their biological properties and in their contribution to carcinogenesis. The different type of viruses are characterised by genotypic variations in DNA base sequences of E6 and E7. It is this genotypic variation that permits stratification of virus oncogenic phenotype into high, intermediate and low risk types. E.g. E7 protein of HPV 16 is more oncogenic than E7 protein of HPV 6 [30] [Figure 1].
Figure 1: A model explaining the interaction of HPV E6 and E7 with tumor suppressor genes functioning in cell cycle

Click here to view
Table 1: HPV genotypes and Oncogenic risk[7]

Click here to view
Table 2: Prevalence of HPV genotypes in Squamous cell carcinoma of oral cavity as determined by Polymerase chain reaction[18]

Click here to view



  HPV Positive versus HPV Negative Head and Neck Cancer Top


Interestingly, while patients with HPV-associated head and neck cancers commonly present with more advanced disease, they have significantly improved outcomes compared with stage and comorbidity matched HPV-negative patients. Differences in five year overall survival between HPV-positive and HPV-negative patients exceed 30% in a number of retrospective analyses. This difference is one of the largest yet identified for cancers that arise within the same tissues, have very similar patterns of spread, and have overlapping histology. Interestingly, even within patients with HPV-positive HNSCC, those with a history of significant tobacco/alcohol use show significantly worse outcomes than never smokers; but an outcome that remains better than those with HPV-negative disease. Persons with oropharyngeal SCC in which HPV can be detected intracellularly have a better prognosis than persons with HPV-cytonegative oropharyngeal SCC. [6]

Moreover, HPV-positive tumors often present at a higher stage with a small T-size (T1-T2) but frequently there is a large, often cystic, nodal involvement (N+), thus the HPV-positive tumors are often diagnosed in clinical advanced stages, that is, Stages III-IV [Table 3]. [31]
Table 3: Important differences in the Epidemiology, Demographic Background, Molecular etiology and Clinical characteristics of HPV-positive and HPV-negative Head and Neck Squamous cell Carcinoma[32]

Click here to view



  Diagnostic Methods to Detect HPV Infection Top


Until recently, diagnostic laboratory testing for HPV was impossible since the virus does not grow in tissue cultures or in laboratory animals. Currently, with recent technologic advancements in molecular biology techniques for HPV testing, scientists have isolated more than 120 different HPV types. [33],[34],[35],[36]

Light microscopy, Electron microscopy, Non-amplified techniques such as DNA in sit hybridisation Southern and dot blot hybridization, Molecular methods e.g. PCR Probe amplification Signal amplification are currently used in detection of HPV [Table 4].
Table 4: Pros and cons of methods used for detection of HPV[17]

Click here to view



  Conclusion Top


However, role of HPV in Head and Neck cancer is controversial and contentious topic which tends to explain the etiology of head and neck cancer besides the traditional tobacco/alcohol factors. We emphasize on the fact that HPV positive cancers behave differently from HPV negative cancer and need separate treatment strategies. So, in future there is a need to run various clinical trials to differentiate HPV positive and negative cancer.

 
  References Top

1.Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.  Back to cited text no. 1
[PUBMED]    
2.Andrew W, Joseph BS, Sara I. Human papillomavirus and disease mechanisms: Relevance to oral and cervical cancers. Oral Dis 2005;11:350-9.  Back to cited text no. 2
    
3.Papilloma viruses in the causation of human cancers - A brief historical account. Virology 2009;384:260-5.  Back to cited text no. 3
    
4.Syrjanen S. Role of human papillomavirus infection in head and neck cancers. Ann Oncol 2010;21:243-5.  Back to cited text no. 4
    
5.Singh H, Kumar P, Kumar A. Possible role of human papilloma virus in oral diseases- An update. Internet J Infect Dis 2011;9.  Back to cited text no. 5
    
6.Kimple A, Torres AD, Yang RZ, Kimple RJ. HPV-associated head and neck cancer: Molecular and nano-scale markers for prognosis and therapeutic stratification. Sensors (Basel) 2012;12:5159-69.  Back to cited text no. 6
    
7.Chang F, Syrjanen S, Kellokoski J, Syrjanen K. Human papilloma virus infections and their associations with oral disease. J Oral Pathol Med 1991;20:305-10.  Back to cited text no. 7
    
8.Bisht M, Bist SS. Human papilloma virus: A new risk factor in a subset of head and neck cancers. J Can Res Ther 2011;7:251-5.  Back to cited text no. 8
[PUBMED]  Medknow Journal  
9.Feller L, Wood NH, Khammissa R, Lemmer J. Human papillomavirus-mediated carcinogenesis and HPV-associated oral and oropharyngeal squamous cell carcinoma. Part 2: Human papillomavirus associated oral and oropharyngeal squamous cell carcinoma. Head Face Med 2010;6:15.  Back to cited text no. 9
    
10.Kreimer AR, Alberg AJ, Daniel R, Gravitt PE, Viscidi R, Garrett ES, et al. Oral human papillomavirus infection in adults is associated with sexual behaviour and HIV serostatus. J Infect Dis 2004;189:686-98.  Back to cited text no. 10
[PUBMED]    
11.D'Souza G, Fakhry C, Sugar EA, Seaberg EC, Weber K, Minkoff HL: Six-month natural history of oral versus cervical human papillomavirus infection. Int J Cancer 2007;121:143-50.  Back to cited text no. 11
    
12.Chaturvedi KA, Engels EA, Anderson WF, Gillison ML. Incidence Trends for Human Papillomavirus-Related and -Unrelated Oral Squamous Cell Carcinomas in the United States. J Clin Oncol 2008;26:612-9.  Back to cited text no. 12
    
13.Petersen PE. Oral cancer prevention and control-The approach of the World Health Organization. Oral Oncol 2009;45:454-60.  Back to cited text no. 13
[PUBMED]    
14.Herrero R, Castellsagué 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;95:1772-83.  Back to cited text no. 14
    
15.Pannone G, Santoro A, Papagerakis S, Muzio LL, Rosa GD, Bufo P. The role of human papillomavirus in the pathogenesis of head and neck squamous cell carcinoma: An overview. Infect Agents Cancer 2011;6:4.  Back to cited text no. 15
    
16.Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer 2005;103:1843-9.  Back to cited text no. 16
    
17.Postma TC, Van Heerden WF. Is the human papillomavirus a mutual aetiological agent in oral and cervical squamous cell carcinoma? Anticancer Res 2003;23:3509-12.  Back to cited text no. 17
[PUBMED]    
18.Percoco GP, Ramirez JL. High risk human papillomavirus in oral squamous carcinoma: Evidence of risk factors in a Venezuelan rural population. Preliminary report. J Oral Patho Med 2001;30:355-61.  Back to cited text no. 18
    
19.Zur Hausen H. Papilloma virus infections - A major cause of human cancers. Biochem Biophys Acta 1996;1288:55-78.  Back to cited text no. 19
[PUBMED]    
20.Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsaque X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27.  Back to cited text no. 20
    
21.Munoz N. Human papilloma virus and cancer: The epidemiological evidence. J Clin Virol 2000;19:1-5.  Back to cited text no. 21
    
22.Milde LK, Reithdorf S, Loning T. Association of human papilloma virus infection with carcinoma of the cervix uteri and its precursor lesions: Theoretical and practical implications. Virchows Arch 2000;437:227-33.  Back to cited text no. 22
    
23.McMurray HR, Nguyen D, Westbrook TF, McAnce DJ. Biology of human papilloma viruses. Int J Exp Pathol 2001;82:15-33.  Back to cited text no. 23
[PUBMED]    
24.Philips AC, Voudsen KH. Human papilloma virus and cancer: The viral transforming genes. Cancer Surv 1999;33:55-74.  Back to cited text no. 24
    
25.Dyson N, Howley PM, Munger K, Harlow E. The HPV 16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989;242:934-7.  Back to cited text no. 25
    
26.Sellers WR, Kaelin WG. Role of Rb protein in the pathogenesis of human cancer. J Clin Oncol 1997;15:3301-12.  Back to cited text no. 26
    
27.Scheffner M. Ubiquitin. E6-AP and their role in p53 inactivation. Pharmacol Ther 1998;78:129-39.  Back to cited text no. 27
[PUBMED]    
28.Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6 and E7 genes of the human papilloma virus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 1989;63:4417-21.  Back to cited text no. 28
    
29.Villa LL, Schlegel R. Differences in transformation activity between HPV-18 and HPV-16 map to the viral LCR-E6-E7 region. Virology 1991;181:374-7.  Back to cited text no. 29
    
30.Tang WK. Oncogenic human papilloma virus infection: Epidemiology in local high risk women. Hong Kong Dermatol Venerol Bull 2002;10:160-3.  Back to cited text no. 30
    
31.Marklund L, Hammarstedt L. Impact of HPV in Oropharyngeal Cancer. J Oncol 2011;2011:509036.  Back to cited text no. 31
    
32.Joseph BS, Pai SI. Human Papillomavirus and the Shifting Trends in Head and Neck Cancer. Am Soc Clin Oncol 2011;2:212-6.  Back to cited text no. 32
    
33.Scully C, Prime S. Papilloma viruses: Their possible role in oral disease. Oral Surf Oral Med Oral Pathol 1985;60:166-74.  Back to cited text no. 33
    
34.Chang F, Syrjanen, Kellokoski J, Syrjanen K. Human papilloma virus infections and their associations with oral disease, J Oral Pathol Med 1991;20:305-10.  Back to cited text no. 34
    
35.Coutlee F, Danielle R, Alex F, Eduardo F. The laboratory diagnosis of genital human papilloma virus infections. Cab J infect Dis Med Microbiol 2005;16:83-91.  Back to cited text no. 35
    
36.Malloy C, Sherris MS, Herdman C. HPV DNA testing: Technical and Programmatic issues for Cervical cancer Prevention in low Resource settings. Path December 2000;1:1-27.  Back to cited text no. 36
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
   
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Mode of Oral and...
Topographic Repr...
Molecular Insigh...
HPV Positive ver...
Diagnostic Metho...
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1956    
    Printed93    
    Emailed0    
    PDF Downloaded188    
    Comments [Add]    

Recommend this journal