Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of malignancies caused by the traditional risk factors of tobacco, alcohol(Drug information on alcohol), and poor oral hygiene, as well as more recently identified roles of human papillomavirus (HPV) and Epstein-Barr virus (EBV).[1-3] We commend Kim and colleagues on their comprehensive review of the epidemiology of HNSCC. There has been a clear change in the epidemiology of HNSCC which has further accentuated differences in etiology, survival, and demographics among HNSCC patients. We will discuss several important nuances of this changing epidemiology, including the role of tobacco, race, sexual behavior, and gender, as well as HNSCC in nonsmokers and nondrinkers.
As tobacco use has declined over the past several decades,[4,5] so has the number of cancers caused by tobacco and alcohol.[1,6,7] Continued decline in tobacco use and associated HNSCC is not guaranteed, however; in fact, some recent evidence suggests rates of tobacco use in the US may be stabilizing. In contrast, the incidence of HPV-associated HNSCC has increased over the past several decades, although it is unclear what is driving this change. The increasing incidence of HPV-associated HNSCC could be related to changes in oral sexual practices resulting in more oral HPV infection, or it may be explained by increased persistence and progression due to changes in relevant cofactors.
Kim and colleagues noted in their review that HPV-associated HNSCC largely occurs among nonsmokers and nondrinkers. While it is true that HNSCC patients with HPV-associated disease are more likely to be young, white, and lacking a history of tobacco or alcohol use, compared with HNSCC patients not infected with HPV, it is underappreciated that nonsmokers and nondrinkers constitute less than 20% of HPV-associated HNSCC cases.[8-10] Many HPV-associated HNSCCs occur among current and former tobacco and alcohol users, including some individuals with very heavy usage.[8-10] While the proportion of HNSCC patients who are nonsmoker nondrinkers (NSNDs) is higher among HPV-associated HNSCCs,[10,11] this does not suggest that NSNDs are at increased risk of these cancers, but simply that other types of HNSCC are rarer among NSNDs. Indeed, the proportion of HNSCCs caused by HPV in the general population has also increased as tobacco-related cancers have declined.[12-14] Smokers may actually be at increased risk of HPV-associated cancer, as tobacco use is associated with increased oral HPV prevalence[15,16] and persistence, and increased odds of HPV-associated HNSCC in some but not other case control studies.
In the past few decades, survival rates for many cancers have improved, but overall survival rates for HNSCC have remained low. Worldwide 5-year survival for HNSCC remains below 50%. Kim and colleagues mention the increased incidence and decreased survival of HNSCC among African Americans compared with Caucasians. Indeed, median survival for African-American oropharyngeal cancer patients is less than half that observed for Caucasian patients in the same clinical care setting.[6,19] Preliminary evidence suggests that a lower proportion of HNSCC among African Americans are caused by HPV compared with Caucasians.[8,19] As individuals with HPV-associated HNSCCs have substantially improved survival compared with those who have HPV-unassociated HNSCC, the racial differences in HPV etiology may explain some of the heterogeneity in HNSCC survival rates. It is currently unclear, however, whether racial disparities in HNSCC survival are explained solely by the greater proportion of tobacco-related HPV-negative HNSCC among African Americans or whether additional biologic and environmental disparities contribute to the observed survival differences. Additionally, as patients with HPV-associated HNSCC who use tobacco have poorer survival, they are an important group to target in improving patient outcomes.
HPV-associated HNSCC represents an emerging viral cancer, and it is therefore important to understand the associated risk factors. Kim and colleagues noted that sexual behavior is an important risk factor for HPV-associated HNSCC. While we strongly agree that current evidence suggests transmission from oral sex,[8,22,23] that relationship sometimes leads to a mischaracterization of this disease as always being associated with promiscuous behavior. While oral HPV infection is not as ubiquitous as genital HPV infection, risk factors for acquisition and progression to cancer are not yet well understood. Recent studies suggest that more than half of HPV-associated HNSCC patients have had five or fewer lifetime oral sex partners and approximately half did not perform oral sex before they were 20 years of age[8,22,25,26]; that is, many people with HPV-associated HNSCC do not have a high-risk sexual history.
The incidence of HNSCC is two- or three-fold higher among men than women, and interestingly this difference is observed for HPV-associated HNSCC as well as HPV-unassociated HNSCC.[7-10,27] While gender differences in the incidence of HPV-unassociated HNSCC are likely explained by differing rates of tobacco and alcohol use,[1,4] it is less clear why such a strong gender difference is observed for HPV-associated HNSCC. A recent systematic review found similar oral HPV infection prevalence in healthy men and women, suggesting acquisition rates may be similar. If the higher incidence of HPV infection in men is not explained by acquisition differences, then it may be due to differences in HPV persistence and progression in men vs women. Differences in innate immune response by gender have been suggested,[28,29] but their effect on oral HPV infection has not been explored. Efficacy of the prophylactic HPV vaccines against oral HPV infection is not known. Because most HPV-associated HNSCC occurs in men, if these vaccines are proven effective against oral HPV infection, this would need to be factored into considerations for HPV vaccination policy in men.
Financial Disclosure: Dr. D’Souza is a consultant for and has received research funding from Merck Inc, the makers of the Gardasil vaccine. Mr. Beachler has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article