As outlined by Leslie Kim and colleagues in this issue of ONCOLOGY,[1] almost 650,000 new cases of head and neck cancer are identified and approximately 350,000 individuals die from this disease worldwide each year. Most cancers of the head and neck are squamous cell carcinomas and originate from one of five major sites: oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx. Traditionally, tobacco smoking and alcohol(Drug information on alcohol) consumption have been considered to be the main risk factors for head and neck squamous cell carcinoma (HNSCC) and, thus far, most prevention strategies and public health messages have focused on these two factors. However, as described in the review by Kim et al., there is increasing evidence that, independent of tobacco and alcohol exposure, oral human papillomavirus (HPV) infection is a major risk factor for a specific subset of HNSCCs. We agree with the authors that this is an important public health concern, especially given the increasing prevalence of HPV infection in the US and Western Europe and our limited knowledge about the natural history of oral HPV infection. Here we summarize the role of HPV in HNSCC and discuss clinical implications.
HPV and HNSCC
Human papillomaviruses are small, double-stranded DNA viruses that specifically target proliferating epithelial cells. More than 100 different HPVs have been described, which are commonly classified based on type of epithelial cells infected (cutaneous, mucosal) and on their oncogenic potential (low risk, high risk). HPV genomes encode two regulatory proteins (E1 and E2), three oncoproteins (E5, E6, and E7), and two capsid proteins (L1 and L2).[2] The E5 protein is thought to play an important role in the early stages of infection and has been shown to promote cell proliferation by binding to the epidermal growth factor receptor.[3] However, the E5 coding sequence is often deleted when the viral DNA integrates into the host genome, and the E6 and E7 oncoproteins of high-risk HPVs are considered to play a more significant role in carcinogenesis. E6 and E7 induce the degradation of the tumor suppressors p53 (leads to loss of cell cycle arrest and apoptosis in response to DNA damage, resulting in genomic instability) and pRb (resulting in deregulation of the G1/S cell cycle checkpoint), respectively.[2] Integration of HPV DNA into the host genome disrupts the expression of the E2 protein, resulting in the continuous expression of E6 and E7 and, consequently, disruption of the p53 and pRb pathways. While expression of E6 and E7 alone is not sufficient for cancer development, unfortunately, the additional molecular alterations needed are not yet known. Identification of these other required events may result in new screening methods and targeted treatment approaches for HPV-associated HNSCCs.
Approximately 25% of all HNSCCs worldwide contain HPV DNA.[4,5] The prevalence is highest among patients with oropharyngeal squamous cell carcinoma. HPV16 and HPV18, two high-risk HPVs that are also observed in cervical cancer, together account for almost all HPV types in HNSCC, with HPV16 being the most common type.[4,5] Patients with HPV-related HNSCC are characterized by moderate smoking and alcohol use, certain sexual behaviors, and younger age (5–10 years) compared with patients who have HPV-unrelated HNSCC.[6] Regarding specific molecular characteristics, nearly all HPV-related HNSCCs express the oncoproteins E6 and E7, lack p53 mutations, and express p16. Compared with HPV-negative tumors, oropharyngeal squamous cell carcinomas caused by HPV are associated with a better survival regardless of treatment strategy.[5,7,8] The specific cause of the higher rates of response to chemotherapy and radiation therapy among patients with HPV-positive tumors is not known, but the different molecular profiles likely play a role. Expression of the E6 and E7 oncoproteins may make HPV-positive HNSCCs more immunogenic than HPV-negative HNSCCs; anti-E6 and anti-E7 antibodies are found in the majority of HPV-positive cases.[9] Interestingly, data recently reported by Ang et al. suggest that tobacco smoking negatively affects the prognosis of both HPV-positive and HPV-negative HNSCCs.[8]
Risk Factors
The annual incidence rates of potentially HPV-associated cancers of the tongue and tonsils increased significantly in the US from 1998 through 2003, while incidence rates of HNSCC at other sites decreased or remained stable.[10] Similar changes in incidence rates have been observed in Western Europe.[11] Moreover, oral HPV16 infection has been associated with an almost 15-fold increased risk of oropharyngeal cancer.[12] Thus, oral HPV infection is an important health concern.
Oral HPV infection is likely sexually acquired. An increased number of oral sex partners has been found to be associated with oral HPV infection and with HPV16-positive oropharyngeal cancer.[6,12,13] Additionally, Rintala et al. observed that among married couples, persons whose spouse had persistent oral HPV infection were at a 10-fold higher risk of acquiring persistent oral HPV infection.[14] Unfortunately, little is yet known about the natural history of oral HPV infection and the factors that influence the incidence and persistence of infection, and this greatly hampers development of effective prevention strategies and public health campaigns. Not everyone who is exposed to HPV gets an HPV infection, and not everyone with an oral HPV infection develops HNSCC. This suggests that additional factors, including genetic variation in genes involved in, for instance, clearance of HPV infection, may play an important role. Identification of those factors may enable the identification of high-risk populations that would benefit most from targeted prevention and intervention approaches.
Conclusion
An association with HPV should be suspected in all oropharyngeal squamous cell carcinoma cases, particularly those originating from the base of the tongue and tonsils; in immunosuppressed HNSCC patients; and in cases with no or little-to-moderate exposure to tobacco and alcohol. HPV-positive HNSCCs and HPV-negative HNSCCs are distinct entities; they have different risk profiles and molecular profiles, and they respond differently to treatment. Therefore, their prevention and treatment may benefit from separate approaches. Antismoking campaigns and smoking-cessation programs have been successful in the prevention of HPV-unrelated HNSCC.[1] The incidence of HPV-positive HNSCC may be reduced through enhanced public knowledge of the potential routes of HPV transmission, and by the prophylactic HPV vaccines currently widely available in the US for cervical cancer prevention (and which are now recommended for males to prevent genital warts).
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
