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