Biology of human papillomavirus-related oropharyngeal cancer

Abstract

Recent data show that human papillomavirus-positive oropharyngeal cancer (OPC) has a distinct biological and clinical behavior compared with human papillomavirus-negative OPC. As this subset of head and neck cancer represents an increasing public health concern, a thorough understanding of the causative and mechanistic differences between these diseases and how these distinctions impact clinical treatment is required. In this review, we will summarize recent data in epidemiology, the mechanism of viral carcinogenesis and differences in tumor biology that may provide insights to improve the clinical management of patients with human papillomavirus-positive OPC.

Figure 1

Incidence rates for overall oropharyngeal cancer (OPC), human papillomavirus (HPV)–positive OPC, and HPV-negative (HPV–) OPC between 1988 and 2004 in Hawaii, Iowa, and Los Angeles. (Reprinted with permission from 2008 American Society of Clinical Oncology. All rights reserved.) (Color version of figure is available online.)

Figure 2

Schematic drawings of tonsillar surface. (A) Topography of the human palatine tonsil. The surface epithelium of the palatine tonsil deeply invaginates into lymphoid stroma with blind endings and ramifying crypts (boxed area), which increase the surface area of the tonsil by nearly 700%. Drawing by Max Brödel. (B) The specialized reticulated epithelium lining the tonsillar crypts. The squamous epithelium zones—basal, intermediate, and superficial layers—are interrupted by migrating nonepithelial cells, including lymphocytes and antigen-presenting cells. Loss of structural integrity leaves the basement membrane exposed to deposition of viral particles. Drawing by T. Phelps. (Reprinted with permission from 2009 Annual Reviews. All rights reserved.) (Color version of figure is available online.)

Figure 3

Diagram of cellular deregulation resulting from HPV oncoproteins E6 and E7 in keratinocytes. (A) Ubiquitination by the E6/E6AP ubiquitin ligase complex leads to p53 degradation.^,- (B) Ubiquitination by E7 and the cullin 2 ubiquitin ligase complex leading to pRb degradation.^- (C) Increased expression of p16 as a consequence of positive feedback because of the absence of functional pRb. (Color version of figure is available online.)

Figure 4

Representative cases of HPV-16–positive OPC by in situ hybridization (ISH) and p16 immunohistochemistry (IHC) staining. (A) ISH visualizing multiple punctuated loci per tumor cell nucleus reflecting multiple copies of HPV-16 genome. (B) p16 IHC staining of the corresponding tumor in panel A. (C) ISH visualizing a single-punctuated locus per tumor cell nucleus. (D) p16 IHC staining of the corresponding tumor in panel C. Panel insets demonstrate positive controls performed in all assays derived from cell lines with ~500 (CaSki, inset panel A) or 2 integrated copies of HPV16 (SiHa, inset panel C). (Color version of figure is available online.)