Oropharyngeal Carcinoma with a Special Focus on HPV-Related Squamous Cell Carcinoma

Abstract

Human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system separates HPV-OPSCC from its HPV-negative counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment deintensification as a means to improve quality of life while maintaining acceptable survival outcomes. Owing to the distinct biology of HPV-OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage, highlighting the need for diagnostic biomarkers to aid in earlier detection. In this review, we highlight important advances in the epidemiology, pathology, diagnosis, and clinical management of HPV-OPSCC and underscore the need for a progressive understanding of the molecular basis of this disease toward early detection and precision care.

Keywords: head and neck squamous cell carcinoma; human papillomavirus; immune escape; nonkeratinizing; oropharynx.

Figure 1

Drawing of tonsil illustrating numerous branching crypts (original drawing by Max Brödel; provided with permission by the Department of Art as Applied to Medicine at The Johns Hopkins Hospital). Inset shows the histologic features of the reticulated epithelium lining the crypts where the basaloid squamous cells are obscured by infiltrating lymphocytes.

Figure 2

Schematic rendition of the tonsillar crypt epithelium highlighting a disrupted basement membrane, a porous epithelial-subepithelial interface, and a thin and disrupted epithelium permitting exposure of the basement membrane to viral particles. Drawing by T. Phelps; reproduced from Reference . Abbreviation: HPV, human papillomavirus.

Figure 3

Various strategies for human papillomavirus (HPV) detection now allow for microscopic visualization of progressive steps in the cellular biology of HPV tumorigenesis from (a) the cellular insertion of HPV DNA (DNA in situ hybridization) to (b) the transcription of viral mRNA (high-risk HPV E6/E7 mRNA in situ hybridization) to (c) the disruption of the normal cellular machinery giving rise to high levels of expression of the cellular protein p16 (p16 immunohistochemistry). All of these steps culminate in (d) the prototypic microscopic appearance of HPV-related oropharyngeal squamous cell carcinoma (routine hematoxylin-eosin histology). Hybridization signals are readily apparent at higher magnification (b, inset). Figure adapted with permission from Reference ; copyright 2012 Wolters Kluwer Health, Inc.

Figure 4

Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas typically arise from the tonsillar crypts and grow beneath the surface epithelium as expanding lobules, often with central necrosis (a). The lobules are composed of nonkeratinized basaloid cells that are surrounded and infiltrated by lymphocytes (a, inset). (b) In the reticulated crypt epithelium, p16 staining is useful in highlighting the distribution of tumor cells in the tonsils.

Figure 5

Morphologic variant forms of human papillomavirus (HPV)-associated oropharyngeal carcinoma include those that take on highly developed basaloid (a), lymphoepithelial (b), and ciliated (c) features. The presence of a high-grade neuroendocrine component (d) is a finding that signals aggressive tumor behavior.