Data for this review were identified by searches of Medline, Current Contents, PubMed, and references from relevant articles, with the search terms “head and neck squamous cell cancer”, “oropharynx”, “HPV16”, and “p16”. Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English and French between January, 1980, and November, 2009, were included.
ReviewHPV-associated head and neck cancer: a virus-related cancer epidemic
Introduction
Cancers of the head and neck arise from mucosa lining the oral cavity, oropharynx, hypopharynx, larynx, sinonasal tract, and nasophaynx. By far the most common histological type is squamous cell carcinoma, and grade can vary from well-differentiated keratinising to undifferentiated non-keratinising. An increase in incidence of oropharyngeal squamous cell carcinoma—specifically in the tonsil and tongue base—has been seen in the USA, most notably in individuals aged 40–55 years. Patients with oropharyngeal cancer are mainly white men. Unlike most tobacco-related head and neck tumours, patients with oropharyngeal carcinoma usually do not have a history of tobacco or alcohol use. Instead, their tumours are positive for oncogenic forms of the human papillomavirus (HPV), particularly 16 type. About 60% of oropharyngeal squamous cell cancers in the USA are positive for HPV 16. HPV-associated head and neck squamous cell carcinoma seems to be a distinct clinical entity, and this malignant disease has a better prognosis than HPV-negative tumours, due in part to increased sensitivity of cancers to chemotherapy and radiation therapy. Although HPV is now recognised as a causative agent for a subset of oropharyngeal squamous cell carcinomas, the biology and natural history of oropharyngeal HPV infection and the best clinical management of patients with HPV-related head and neck squamous cell tumours is not well understood.
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Epidemiology and risk factors
Head and neck cancer is the sixth most common cancer worldwide, with an estimated annual burden of 563 826 incident cases (including 274 850 oral cavity cancers, 159 363 laryngeal cancers, and 52 100 oropharyngeal cancers) and 301 408 deaths.1 Although HPV has been long known to be an important cause of anogenital cancer, only in recent times has it been recognised as a cause of a subset of head and neck squamous cell carcinomas.2 More than 100 different types of HPV exist,3 and at least 15
Biology and clinical presentation
HPV-associated head and neck squamous cell carcinoma arises most commonly in the lingual and palatine tonsils.35 HPV targets preferentially the highly specialised reticulated epithelium that lines tonsillar crypts; however, the intrinsic properties of this epithelium that render it vulnerable to HPV infection are not yet recognised.36 Once the virus integrates its DNA genome within the host cell nucleus, it dysregulates expression of the oncoproteins E6 and E7.37 The E6 protein induces
Pathological diagnosis
HPV detection may ultimately serve a more comprehensive role than mere prognostication. Detection of HPV is emerging as a valid biomarker for discerning the presence and progress of disease encompassing all aspects of patients' care, from early cancer detection,41 to more accurate tumour staging (eg, localisation of tumour origin),42, 43 to selection of patients most likely to benefit from specific treatments,44 to post-treatment tumour surveillance.45, 46 Consequently, there is a pressing need
Management
The standard of care for locally advanced (T3–T4 or N2–N3) oropharyngeal cancer is either surgery and adjuvant radiotherapy with or without concurrent cisplatin, as indicated, or more usually, concurrent chemoradiation for preservation of speech and swallowing function, which is especially applicable to management of disease at the base of the tongue or tonsil. This approach became the standard of care after publication of a multicentre, randomised controlled trial of 226 patients with stage
Future direction of treatment
On the basis of prospective and retrospective analyses of data from clinical trials, HPV-positive oropharyngeal cancer is recognised as a distinct subset of head and neck squamous cell carcinoma with a favourable outcome. In future clinical trials, researchers will, at the very least, need to stratify for HPV status. An opportunity now exists to investigate less intense treatment strategies that do not compromise survival outcomes but lower the risk of potentially debilitating late effects. For
Concluding remarks
In summary, tumour HPV status is a prognostic factor for overall survival and progression-free survival and might also be a predictive marker of response to treatment. The method of in-situ hybridisation provides a feasible approach for implementation in most diagnostic pathology laboratories, and immunohistochemical staining for P16 could be useful as a surrogate marker for HPV status. Seemingly, locoregional recurrence—but not the rate of distant disease—is diminished in patients with
Search strategy and selection criteria
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