Elsevier

The Lancet Oncology

Volume 11, Issue 8, August 2010, Pages 781-789
The Lancet Oncology

Review
HPV-associated head and neck cancer: a virus-related cancer epidemic

https://doi.org/10.1016/S1470-2045(10)70017-6Get rights and content

Summary

A rise in incidence of oropharyngeal squamous cell cancer—specifically of the lingual and palatine tonsils—in white men younger than age 50 years who have no history of alcohol or tobacco use has been recorded over the past decade. This malignant disease is associated with human papillomavirus (HPV) 16 infection. The biology of HPV-positive oropharyngeal cancer is distinct with P53 degradation, retinoblastoma RB pathway inactivation, and P16 upregulation. By contrast, tobacco-related oropharyngeal cancer is characterised by TP53 mutation and downregulation of CDKN2A (encoding P16). The best method to detect virus in tumour is controversial, and both in-situ hybridisation and PCR are commonly used; P16 immunohistochemistry could serve as a potential surrogate marker. HPV-positive oropharyngeal cancer seems to be more responsive to chemotherapy and radiation than HPV-negative disease. HPV 16 is a prognostic marker for enhanced overall and disease-free survival, but its use as a predictive marker has not yet been proven. Many questions about the natural history of oral HPV infection remain under investigation. For example, why does the increase in HPV-related oropharyngeal cancer dominate in men? What is the potential of HPV vaccines for primary prevention? Could an accurate method to detect HPV in tumour be developed? Which treatment strategies reduce toxic effects without compromising survival? Our aim with this review is to highlight current understanding of the epidemiology, biology, detection, and management of HPV-related oropharyngeal head and neck squamous cell carcinoma, and to describe unresolved issues.

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.

Section snippets

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

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.

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