The Case for HPV
HPV is a DNA virus comprising more than 100 genotypes that specifically target the basal layer of squamous epithelial cells. Almost all invasive cancers of the cervix and most other anogenital tract cancers contain oncogenic HPV viruses. The basic molecular mechanisms by which oncogenic HPV proteins E6 and E7 disrupt cell-cycle control and stimulate viral replication through their respective effects on p53 and Rb tumor suppressor genes have been well-studied and accepted in the carcinogenesis of cervical and other anogenital tract cancers.[6-8]
The involvement of HPV in oral and oropharyngeal carcinogenesis was first proposed in 1983, based on characteristic HPV morphological and immunohistochemical properties seen on oral squamous cell carcinoma biopsies.[7,25] HPV, particularly HPV 16, is now regarded as an independent risk factor for a subset of HNSCCs. There is consistent evidence that oncogenic HPV DNA is contained in approximately 50% of oropharyngeal cancers and in a high proportion of oropharyngeal cancers in nonsmokers and nondrinkers.[2,6,8,26,27]
Although HPV DNA in HNSCC is not exclusively found in nonsmokers, many studies have shown that HPV-positive tumors in nonsmokers tend to be localized to the oropharynx. At the molecular level, there is further support for the claim that HPV increases the risk for HNSCC, independent of and in a manner different from the carcinogenic effects of tobacco and alcohol(Drug information on alcohol). The genetic and transcriptional development of HNSCC related to tobacco and alcohol has been well studied and established. In HNSCC caused by these two traditionally major risk factors, p53 is commonly mutated and the chromosome band 9p21-22 is lost early in carcinogenesis, resulting in loss of the tumor suppressor gene, p16. In contrast, HPV-positive HNSCC has decreased expression of wild-type p53, due to inactivation/degradation by HPV viral protein E6, and these tumors do not show p16 depletion. In fact, p16 overexpression has been identified as a marker for transcriptionally active HPV, which the cervical cancer literature has established as being necessary for HPV to induce carcinogenesis.
There is a correlation between HPV-associated anogenital cancers and HNSCC. Several studies have examined the incidence of second cancers after an initial diagnosis of cervical or other anogenital cancers, and have subsequently demonstrated an increased risk of HNSCC, as well as additional anogenital cancers. A population-based SEER study found that the lifetime risk of second primary cancer in the head and neck in patients with cervical cancer was higher than in the general population, with a standardized incidence ratio (SIR) of 1.7, suggesting a role of HPV. The Swedish Family Cancer Database followed 135,386 women from 1958 to 1996 who were initially diagnosed with cervical carcinoma, for the occurrence of second primary cancers in the upper aerodigestive tract, as well as first primary cancers among their husbands. This study revealed that female patients with cervical cancer had elevated risks for second cancers in the upper aerodigestive tract; for patients with in situ disease, the overall SIR was 1.68 (1.10–2.43), compared with females with invasive cervical cancer, who had an overall SIR of 2.45 (1.05–4.98). Husbands of cervical cancer patients also had elevated SIRs of cancers of the upper aerodigestive tract, suggesting an association with HPV.
When considering the distinct risk factors for HPV-positive HNSCC, HPV seems to meet most of the criteria for disease causation: strength and consistency; numerous basic scientific and epidemiologic data supporting HPV as a cause of HNSCC; biological plausibility, with the model of HPV tumorigenesis in the head and neck derived from well-established models of cervical cancer; and a temporal relationship.
Unlike HPV-negative HNSCC, the major risk factors for HPV-positive cancers are not tobacco and alcohol; risk appears to be related to sexual history. The risk for HPV-positive HNSCC has been shown by numerous studies to increase with increasing numbers of oral and vaginal sexual partners, multiple simultaneous partners, earlier age of first intercourse, a history of genital warts, and in men a history of same-sex contact.[31-33] In an international pooled analysis, risk for base of tongue cancer was greater among men who ever had oral sex, (odds ratio [OR] = 4.32), had two simultaneous partners in comparison to only one (OR = 2.02), and had a history of same-sex contact (OR = 8.89). Consequently, changing sexual practices, such as more frequent oral sex among adolescents and young adults, may be contributing to this upward trend in HPV-associated oropharyngeal cancers.
One of the most significant clinical implications of distinguishing HPV-positive HNSCC is that it appears to be associated with a better prognosis and have distinct molecular characteristics. These cases are also associated with unique risk factor profiles, when compared with HPV-negative cancers. Studies have shown that patients with HPV-positive oropharyngeal cancer are more responsive to treatment and have better rates of survival than those with HPV-negative oropharyngeal cancer.[7,26]
In a study by Weinberger et al., p16 overexpression in oropharyngeal SCC was associated with a 5-year overall survival (OS) rate of 79% compared with a 5-year OS of 20% in patients with HPV-negative tumors and 18% in patients with HPV-positive tumors but normal expression of p16. A second study found that, compared with patients who had HPV-negative tumors, patients with HPV-positive tumors had higher response rates to induction chemotherapy and combined concomitant chemoradiotherapy. Patients with HPV-positive tumors had improved survival, with a 2-year OS of 95%, compared with 62% for their HPV-negative counterparts. While the mechanism of improved survival in HPV-associated HNSCC is still unclear and needs further research, the ability to distinguish patients with HPV-positive tumors appears to have significant clinical implications, in terms of better tailoring their treatments and informing them of their prognosis.
Future Public Health Implications and Conclusions
Despite the impressive public health advances in tobacco control made over the last 30 years, the overwhelming majority of HNSCCs are still attributed to tobacco and alcohol use. Efforts must also be devoted to targeting the disparities in HNSCC: persons with lower socioeconomic status and lower levels of education, and racial and ethnic groups such as African-Americans, Native Americans, and Alaskan Natives, are particularly at risk for HNSCC, largely because of their greater consumption of tobacco and alcohol. It appears, however, that there is an emerging epidemic of HNSCC which is largely affecting younger persons who are nonsmokers and nondrinkers. The risk to HNSCC epidemiology is that whatever gains are made in preventing individuals from becoming new smokers, or in helping current smokers to quit, may become lost in the increasing numbers of oropharyngeal cancers caused by HPV.
Some preventive strategies against HPV-associated HNSCC can be modeled after those used against cervical cancer, the incidence of which has long been in decline in the United States. In terms of primary disease prevention, in 2006, the Food and Drug Administration approved a vaccine against HPV types 6, 11, 16, and 18 for adolescent girls and young women 9–26 years old. In late 2009 the vaccine was also approved for boys and men 9–26 years of age, for the prevention of genital warts.[39,40] Although the vaccination will undeniably decrease the incidence of cervical carcinoma in females, its impact on oropharyngeal cancer incidence is unclear. The vaccine was also only recently approved for males, a population which some studies suggest has a greater proportion of nonsmokers with oropharyngeal cancers, compared with females, and therefore carries more of the HPV burden than females.[6,41] Although the vaccination appears promising, especially given that it targets HPV 16, it remains to be seen whether its use will have an effect on the incidence of HNSCC, particularly in the younger adult population.
Although oral sexual practices are on the rise among adolescents and young adults, there is very little discourse in the medical literature regarding efforts to address sexual behavior as a form of primary prevention, therefore health education is warranted regarding risk factors for HPV contraction and ways to decrease transmission. In a recent US study by Cermak et al., women reported that their physicians were not educating them about HPV testing, risk factors for contracting HPV, and preventive measures against HPV. Given the association between increasing oral sexual practices and increased risk for HNSCC, health education specialists should use appropriate strategies to not only to educate young people about HPV and its association with anogenital cancer, but also about HPV and the risk of HNSCC.
Success in reducing the incidence of cervical cancer in the United States has been primarily in secondary prevention of disease. Widespread use of the Papanicolau screening test has proven to be a cost-effective method of identifying and treating premalignant cervical lesions in the entire female population. In contrast, effective screening for oropharyngeal premalignancies is limited, although theoretically possible given the unique molecular markers associated with HPV infection. A recent study evaluated salivary rinsing as a potential screening test, not for primary detection, but rather for recurrence of HPV-positive tumors after treatment. In this study, polymerase chain reaction (PCR) detection of HPV E6/E7 viral protein numbers by PCR had a sensitivity of 50% and a specificity of 100% for detection of cancer recurrence. While the study population was small, the findings suggest that quantitative measurement of salivary HPV-16 DNA may be promising for surveillance and early detection of recurrence, although its effectiveness in early detection of premalignant lesions remains to be seen.
Capturing the true epidemiology of head and neck cancers is difficult, owing to the relatively small number and heterogeneity of the cancers. This leads to limited medical literature. Unlike breast or colorectal cancers, however, a great majority of head and neck cancers are the result of exposures to important public health risks—tobacco, alcohol, and the human papillomavirus—and are thus preventable. Given that head and neck cancers can affect some of life’s most critical functions, including speech, communication, swallowing, eating, and cosmesis, more implications for prevention need to be addressed.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products of providers of any service mentioned in this article.