Elsevier

Seminars in Oncology

Volume 31, Issue 6, December 2004, Pages 744-754
Seminars in Oncology

Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity

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There is currently sufficient evidence to conclude that human papillomavirus (HPV) plays a role in the pathogenesis of a distinct subset of head and neck squamous cell cancers (HNSCC), particularly tonsillar cancers. There is a strong and consistent association between high-risk HPV types, specifically HPV16, a known human carcinogen, and these distinctive oropharyngeal cancers with molecular characteristics indicative of viral oncogene function. Risk for HPV-HNSCC is increased by certain sexual behaviors after consideration of alcohol and tobacco exposure, consistent with an extensive literature that has established HPV infection as a sexually transmitted disease. Furthermore, exposure to HPV16 has been associated with increased risk for subsequent development of oropharyngeal cancer. Prophylactic and therapeutic vaccines targeted against the viral capsid components and oncoproteins will provide the ultimate evidence for a role for HPV in HNSCC, if demonstrated to be effective in the prevention or therapy of this disease. It is time for clinician scientists to translate knowledge of this newly recognized disease entity into potential applications for the prevention, detection, and treatment of HPV-HNSCC.

Section snippets

Human papillomavirus in HNSCC

The biologic plausibility of HPV as a carcinogen in human epithelia is well established. HPV, a predominantly sexually transmitted virus, is necessary for the development of cervical cancer and other anogenital tract malignancies. HPVs are DNA viruses with a specific tropism for human epithelia, and more than 120 different HPV types have been isolated. HPVs (eg, HPV6, 11) that induce benign hyperproliferation of the epithelium such as papillomas and warts are categorized as low-risk. High-risk

A distinct molecular entity

Growing distinctions between HPV-HNSCC and HPV-negative HNSCC support the existence of two pathways in the pathogenesis of HNSCC, one driven by alcohol and tobacco and the other by HPV (Fig 1). The molecular abnormalities found in HPV-HNSCC reflect the oncogenic function of viral E6 and E7. As in a majority of other human malignancies, disruption of p53 function, either by mutation of TP53 or through degradation by HPV16 E6, appears to be an important common genetic alteration in HNSCC. In 123

Pathologic and clinical correlates

The establishment of the presence of HPV in some tumors subsequently allowed for the characterization of HPV-HNSCC by comparing pathologic and clinical characteristics of patients with HPV-HNSCC to those with HPV-negative tumors. It is clear from numerous studies that HPV-HNSCC arises predominantly from the lingual and palatine tonsils in the oropharynx.6, 27, 28, 29, 30, 32, 73, 74 In a detailed analysis of 253 patients with HNSCC, a distinct basaloid histopathology was strongly associated

Prognostic significance

Numerous case series have suggested that a diagnosis of HPV-HNSCC may have important prognostic implications (Table 2). The most compelling data have come from analyses of oropharyngeal cancer patients33, 44, 78 and from studies with sufficient sample size to adjust for other prognostic factors.7, 27, 29, 79 Studies that have evaluated disease-specific rather than overall survival make an important contribution, because overall survival can be confounded by the presence of comorbidity

HPV in premalignant lesions

At all anogenital sites where HPV plays an etiologic role, multiple lines of evidence indicate that HPV infection precedes the development of dysplasia. If HPV plays an analogous role in the pathogenesis of oral squamous cell carcinomas, then HPV would be expected to be present in premalignant lesions and to have a clonal relationship with the dysplasia. A distinct form of oral dysplasia, characterized by nuclear koilocytic abnormalities consistent with HPV replication and the specific presence

Risk factors for HPV-HNSCC

The risk factor profiles of HPV-HNSCC patients appear to be distinct from those of patients with HPV-negative HNSCC, particularly with regard to alcohol and tobacco use. The odds ratios from these case-case comparisons are interpreted as the odds of a diagnosis of HPV-HNSCC among individuals with HNSCC and are not estimates of risk for the general population. Patients with HPV-HNSCC are less likely to have a history of tobacco use when compared to patients with HPV-negative tumors,7, 11, 29, 30

How to make the diagnosis of HPV-HNSCC

The diagnosis of HPV-HNSCC should be considered in all squamous cell carcinomas that arise from the lingual and palatine tonsils, particularly in nonsmokers and nondrinkers and in patients with basaloid or poorly differentiated histology and in young patients, including known FA patients. The specific presence of high-risk HPV within tumor cell nuclei can currently be demonstrated by ISH: for example, the GenPoint system (Dako, Carpinteria, CA) can detect one or two copies of integrated HPV16

Therapeutic implications of a diagnosis of HPV-HNSCC

In the future, prophylactic or therapeutic vaccines123, 124 may prevent HPV-associated HNSCC. A prophylactic vaccine composed of HPV16 viral capsid proteins has shown promise for the prevention of persistent cervical HPV16 infection in a randomized controlled trial.125 A reduction in the incidence of oropharyngeal cancer in vaccinated populations would provide definitive evidence for a causal role for the virus in these cancers.

Because the overwhelming majority (90% to 95%) of these tumors is

Acknowledgment

The author thanks David Symer for his assistance in the development of all figures included in this document, as well as comments on the manuscript.

References (128)

  • C.S. Miller et al.

    Human papillomavirus expression in oral mucosa, premalignant conditions, and squamous cell carcinomaA retrospective review of the literature

    Oral Surg Oral Med Oral Pathol Oral Radiol Endod

    (1996)
  • H. Nielsen et al.

    Human papillomavirus in oral premalignant lesions

    Eur J Cancer B Oral Oncol

    (1996)
  • K.R. Shroyer et al.

    Detection of human papillomavirus DNA by in situ DNA hybridization and polymerase chain reaction in premalignant and malignant oral lesions

    Oral Surg Oral Med Oral Pathol

    (1991)
  • F. Elamin et al.

    Prevalence of human papillomavirus infection in premalignant and malignant lesions of the oral cavity in U.K. subjectsA novel method of detection

    Oral Oncol

    (1998)
  • J. D’Costa et al.

    Detection of HPV-16 genome in human oral cancers and potentially malignant lesions from India

    Oral Oncol

    (1998)
  • M. Bouda et al.

    “High risk” HPV types are frequently detected in potentially malignant and malignant oral lesions, but not in normal oral mucosa

    Mod Pathol

    (2000)
  • M. Sugiyama et al.

    Detection of human papillomavirus-16 and HPV-18 DNA in normal, dysplastic, and malignant oral epithelium

    Oral Surg Oral Med Oral Pathol Oral Radiol Endod

    (2003)
  • S. Franceschi et al.

    Human papillomavirus and cancers of the upper aerodigestive tractA review of epidemiological and experimental evidence

    Cancer Epidemiol Biomarkers Prev

    (1996)
  • G. Niedobitek et al.

    Detection of human papillomavirus type 16 DNA in carcinomas of the palatine tonsil

    J Clin Pathol

    (1990)
  • P.J. Snijders et al.

    Prevalence and expression of human papillomavirus in tonsillar carcinomas, indicating a possible viral etiology

    Int J Cancer

    (1992)
  • S.M. Schwartz et al.

    Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection

    J Natl Cancer Inst

    (1998)
  • M.L. Gillison et al.

    Evidence for a causal association between human papillomavirus and a subset of head and neck cancers

    J Natl Cancer Inst

    (2000)
  • T. Andl et al.

    Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control

    Cancer Res

    (1998)
  • T. Wiest et al.

    Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control

    Oncogene

    (2002)
  • V.M. van Houten et al.

    Biological evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell carcinomas

    Int J Cancer

    (2001)
  • H.C. Hafkamp et al.

    A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5–8

    Int J Cancer

    (2003)
  • J. Mork et al.

    Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck

    N Engl J Med

    (2001)
  • M. Frisch et al.

    Changing patterns of tonsillar squamous cell carcinoma in the United States

    Cancer Causes Control

    (2000)
  • J.H. Gagnon et al.

    The sexual scripting of oral genital contacts

    Arch Sex Behav

    (1987)
  • B.A. Evans et al.

    Trends in female sexual behaviour and sexually transmitted diseases in London, 1982–1992

    Genitourin Med

    (1995)
  • N. Munoz et al.

    Epidemiologic classification of human papillomavirus types associated with cervical cancer

    N Engl J Med

    (2003)
  • J.K. McDougall

    Immortalization and transformation of human cells by human papillomavirus

    Curr Top Microbiol Immunol

    (1994)
  • E. Schwarz et al.

    Structure and transcription of human papillomavirus sequences in cervical carcinoma cells

    Nature

    (1985)
  • P.M. Howley

    Role of the human papillomaviruses in human cancer

    Cancer Res

    (1991)
  • T. Crook et al.

    Continued expression of HPV-16 E7 protein is required for maintenance of the transformed phenotype of cells co-transformed by HPV-16 plus EJ-ras

    EMBO J

    (1989)
  • V. Balz et al.

    Is the p53 inactivation frequency in squamous cell carcinomas of the head and neck underestimated? Analysis of p53 exons 2–11 and human papillomavirus 16/18 E6 transcripts in 123 unselected tumor specimens

    Cancer Res

    (2003)
  • J. Pintos et al.

    Human papillomavirus and prognoses of patients with cancers of the upper aerodigestive tract

    Cancer

    (1999)
  • P.J. Snijders et al.

    Prevalence of mucosotropic human papillomaviruses in squamous-cell carcinoma of the head and neck

    Int J Cancer

    (1996)
  • M. Brandwein et al.

    HPV detection using “hot start” polymerase chain reaction in patients with oral cancerA clinicopathological study of 64 patients

    Mod Pathol

    (1994)
  • I.B. Paz et al.

    Human papillomavirus (HPV) in head and neck cancerAn association of HPV 16 with squamous cell carcinoma of Waldeyer’s tonsillar ring

    Cancer

    (1997)
  • P. Fouret et al.

    Human papillomavirus in head and neck squamous cell carcinomas in nonsmokers

    Arch Otolaryngol Head Neck Surg

    (1997)
  • J.M. Ritchie et al.

    Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx

    Int J Cancer

    (2003)
  • D.J. Haraf et al.

    Human papilloma virus and p53 in head and neck cancerClinical correlates and survival

    Clin Cancer Res

    (1996)
  • S.P. Wilczynski et al.

    Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma

    Am J Pathol

    (1998)
  • M. Gillison et al.

    Evidence for a causal association between human papillomavirus and a subset of head and neck cancers

    J Natl Cancer Inst

    (2000)
  • H. Mellin et al.

    Human papillomavirus (HPV) DNA in tonsillar cancerClinical correlates, risk of relapse, and survival

    Int J Cancer

    (2000)
  • S.E. Strome et al.

    Squamous cell carcinoma of the tonsilsA molecular analysis of HPV associations

    Clin Cancer Res

    (2002)
  • R. Herrero et al.

    Human papillomavirus and oral cancer

    J Natl Cancer Inst

    (2003)
  • H. Mellin 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)
  • J.P. Klussmann et al.

    Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas

    Cancer

    (2001)
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    Supported by grants from the NIADR (DE13121). M.L.G. is a Damon Runyon-Lilly Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation.

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