Woman With a Tonsillar Lesion
A previously healthy 39-year-old woman is evaluated for a lesion found by her dentist on her right tonsil. Her medical history is unremarkable, and her only medication is a multivitamin supplement.
HISTORY
The patient is married and has 2 children aged 3 and 7 years. Currently, she uses an intrauterine device for birth control. She works as an office manager. She smoked sporadically in college but has not done so for many years. She enjoys a glass of wine daily.
PHYSICAL EXAMINATION AND
LABORATORY RESULTS
Results of a thorough physical examination and laboratory evaluation are normal. Biopsy of the 1.5-cm tonsillar lesion reveals a well-differentiated squamous cell carcinoma.
Which of the following is the most likely causative factor in this patient’s head and neck squamous cell carcinoma?
A. Alcohol consumption.
B. Tobacco use.
C. A mutated (9p 21-22) p53 gene.
D. Oral human papillomavirus (HPV) infection.
(Answer on next page.)
CORRECT ANSWER: D
This case illustrates the changing epidemiology of head and neck cancers. Although the patient’s history reveals some tobacco and alcohol exposure, her age at diagnosis and the location of the lesion strongly suggest HPV as the primary causative factor in her squamous cell carcinoma of the oropharynx.
Traditionally, head and neck cancer has been strongly associated with tobacco and alcohol use. The risk of head and neck cancer among smokers is 5- to 25-fold higher than among nonsmokers.1 Alcohol consumption is also an independent risk factor and, when coupled with tobacco use, the combination synergistically leads to a higher incidence of head and neck cancers.
A shift in epidemiology and demographics. However, with growing public awareness of the inherent risks associated with cigarette smoking, tobacco consumption has continued to decline. In conjunction with this trend, the age-adjusted incidence rates for head and neck cancers have generally 
also decreased. Interestingly, this trend has not been demonstrated in all cancers of the head and neck. While the decline in smoking prevalence has been mirrored by decreases in the incidence of larynx, oral cavity, and hypopharynx cancers, oropharyngeal cancers have recently increased. Furthermore, the rise in incidence of cancers of the oropharynx seems to be most striking in patients under the age of 45. This observation is especially concerning, given that the median age at diagnosis for all head and neck cancers is in the sixth decade. There is now considerable emerging evidence that HPV infection may account for this increased incidence of oropharyngeal cancers. Thus, the epidemiologic considerations presented here make choice D most likely in this case.
HPV is a DNA virus with a well-documented association with cervical cancer. This virus has multiple subtypes; HPV-16 represents the most malignant strain. HPV incorporates its DNA into the host genome of a squamous epithelial cell. The tumorigenesis associated with HPV infection is mediated through the expression of the E6 and E7 proteins encoded in the HPV DNA. These proteins inactivate the tumor suppressor genes, p53 and pRb, leading to dysregulated cell growth. This mechanism is in contrast to that observed in classic head and neck cancers related to alcohol and
tobacco use, which often involve a mutated p53 gene (choice C).
HPV DNA has been identified in up to 50% of oropharyngeal cancers, while it is relatively uncommon among non-oropharyngeal head and neck cancers.1,2 Of course, many of these patients also have significant smoking and alcohol use histories and, therefore, it has been of interest to define
the interaction between HPV infection and smoking status. This question has been addressed in several studies.
A recently published retrospective analysis of patients with treated oropharyngeal cancers best addressed this issue.2 In this study, adjustments were made for age, race, and stage (tumor size and nodal status), as well as tobacco use. Patients with HPV-positive tumors had significantly improved 3-year overall survival (82.4% vs 57.1%). The HPV-positive patients also had a 58% reduction in the risk of death. Further analysis demonstrated that HPV status was the major determinant in overall survival, allowing patients to be further stratified into low-, intermediate-, or high-risk groups based on smoking status, tumor size, and involvement of locoregional lymph nodes. Several other trials have demonstrated these results as well.3,4
The development of HPV-associated oropharyngeal cancers seems to be related to sexual history, similar to what has been seen with cervical cancers. Several studies have demonstrated that an increased risk of HPV-positive head and neck cancers is associated with increased numbers of both oral and vaginal sex partners, multiple simultaneous partners, genital warts, and a history of same-sex contact. In one representative analysis, men who had ever had oral sex were found to be more than 4 times as likely as those who had not to develop cancer of the base of the tongue.5
Implications for treatment and prevention. The implications of this epidemiologic shift in the development of head and neck cancers are profound. First, from a treatment standpoint, patients with HPV-positive oropharyngeal cancers respond better to therapy and have improved survival. Given that the management of head and neck cancers often requires radiation therapy, chemotherapy, and surgery, knowledge of HPV status may at some point permit treatment to be tailored to each patient, allowing some to avoid the toxicities involved with such intense therapies.
The molecular mechanisms that render HPV-positive head and neck cancers more sensitive to treatment have yet to be established. This represents an active area of research. The discrepancy in survival between patients with HPV-positive and those with HPV-negative oropharyngeal cancers may be explained by additional mutations incurred by increased tobacco exposure in the HPV-negative patients. Understanding these pathways may ultimately lead to less toxic targeted therapies, such as those already used in chronic myelogenous leukemia and breast, lung, and colon cancers.
Second, from a prevention standpoint, the use of vaccines such as those already employed in cervical cancers may lead to a decrease in the incidence of HPV-related head and neck cancers. The use of the vaccine combined with changes in sexual practices may enable us to curtail the rising incidence of HPV-related oropharyngeal cancers.
Outcome of this case. The patient underwent concurrent radiation therapy and chemotherapy with cisplatin. She is currently doing well 1 year after treatment without evidence of residual disease, and her overall prognosis is good.
REFERENCES:
1. Kim L, King T, Agulnik M. Head and neck cancer: changing epidemiology and public health implications. Oncology (Williston Park). 2010;24:915-919.
2. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35.
3. Settle K, Posner MR, Schumaker LM, et al. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila). 2009;9:776-781.
4. Maxwell JH, Kumar B, Feng FY, et al. Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res. 2010;16:1226-1235.
5. Heck JE, Berthiller J, Vaccarella S, et al. Sexual behaviors and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol. 2010;39:166-181.