Posted March 1, 2012
Feriyl Bhaijee, MD
The term throat cancer refers to malignancies of the pharynx and larynx. The vast majority of these are squamous cell carcinomas (SCC). Traditional risk factors for throat cancer include tobacco use and alcohol consumption. However, in the oropharynx, particularly the tonsil, human papillomavirus (HPV) infection has emerged as a prominent risk factor. HPV is found in 45% to 95% of oropharyngeal SCC.1,2,3 Unlike tobacco-related throat cancer, which is decreasing in incidence with declining rates of tobacco use, HPV-related oropharyngeal SCC shows increasing incidence in several Western countries.1,3,4,5
The association between oropharyngeal SCC and HPV infection is now well established.6 HPV subtypes are classified as high- or low-risk based on their malignant potential. Only high-risk HPV subtypes (including 16, 18, 31, 33, and 35) have been associated with oropharyngeal SCC of which HPV 16 is the most common subtype identified in HPV-positive cancers.7 High-risk HPVs produce two oncoproteins, E6 and E7, which facilitate viral replication and malignant transformation. HPV E7 protein binds to and degrades the retinoblastoma protein (pRb), which results in upregulation of the p16 protein. HPV-positive tumors frequently show high expression of p16, thus detection of the p16 protein by immunohistochemistry is considered a useful surrogate marker for HPV-positivity.8
HPV-positive oropharyngeal SCC represents a distinct subset of head and neck SCC.6 HPV-positive cancers, especially tonsillar cancers, usually present at a younger age, and often without a prior history of tobacco and alcohol use.9,10 It appears, however, that HPV-associated oropharyngeal SCC is, in some ways, a sexually transmitted disease: factors such as number of sexual partners (including oral sex partners), prior history of genital warts, and HIV infection confer a higher risk of tonsillar and base-of-tongue cancers.
Despite smaller primary tumor sizes at presentation, HPV-positive cancers often present with large, cystic, nodal involvement.6 These lateral cervical metastatic masses may mimic branchial cleft cysts, especially in younger patients. Histologically, HPV-positive tumors are typically nonkeratinizing, and ‘basaloid’ in appearance, in contrast to the keratinizing appearance of HPV-negative SCC.11
Overall, however, HPV-positive oropharyngeal SCC has a better prognosis than HPV-negative cancers, regardless of lymph node involvement, age, gender, clinical stage, tumor differentiation, or treatment strategy.6 Studies show an 80% to 95% two- to three-year overall survival rate for patients with HPV-positive SCC, compared to a 57% to 62% rate for those with HPV-negative cancers.12,13 The pathogenetic mechanisms underlying the association between HPV positivity and improved outcome are not clearly understood and may involve a combination of patient- and tumor- related factors.6 HPV-positive tumors have significantly fewer chromosomal abnormalities than HPV-negative cancers.14
Oropharyngeal SCC is usually treated by surgical resection and adjuvant chemoradiotherapy. Transoral robotic surgery (TORS), an emerging robotic-assisted technology, offers disease control in both HPV-negative and HPV-positive patients with oropharyngeal SCC when followed by appropriate adjuvant therapy.15 The clinical benefits of TORS include avoidance or dose reduction of adjuvant chemoradiotherapy and improved swallow function and cosmetic outcome.16,17 Randomized controlled trials are needed to determine the appropriate role of TORS in clinical management.
The clinical significance of HPV infection in laryngeal SCC is unclear. Meta-analysis suggests that up to 25% of laryngeal SCC contains HPV infection and, as in oropharyngeal SCC, HPV 16 is the most commonly identified subtype.18
In summary, HPV-related oropharyngeal SCC represents a distinct clinicopathologic subtype of head and neck SCC. HPV positivity in oropharyngeal SCC confers a better prognosis than HPV negativity, and HPV status is a robust prognostic indicator for overall survival, treatment response, and tumor control. HPV infection also occurs in laryngeal SCC, but the clinical relevance thereof requires further investigation.
- Hammarstedt L, Lindquist D, Dahlstrand H, et al. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer. 2006;119(11):2620–2623.
- Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol. 2006;24(17):2606–2611.
- Nasman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockhold, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer. 2009;125(2):362–366.
- Ernster JA, Sciotto CG, O’Brien MM, et al. Rising incidence of oropharyngeal cancer and the role of oncogenic human papilloma virus. Laryngoscope. 2007;117(12)21:2115–28.
- Chenevert J, Chiosea S. Incidence of human papillomavirus in oropharyngeal squamous cell carcinomas: now and 50 years ago. Hum Pathol. 2011 Jul 19. [Epub ahead of print].
- Marklund L, Hammarstedt L. Impact of HPV in oropharyngeal cancer. J Oncol. 2011;2011:509036. doi:10.1155/2011/509036.
- Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467–475.
- Klussmann JP, Gultekin E, Weissenborn SJ, et al. Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol. 2003;162(3):747–753.
- Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM. Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer. 2001;92(4):805–813.
- Smith EM, Ritchie JM, Summersgill KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer. 2004;108(5):766–772.
- Wilczynski SP, Lin BTY, Xie Y, Paz IB. Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma. Am J Pathol. 1998;152(1):145–156.
- Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261–269.
- Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. New Engl J Med. 2010;363(1):24–35.
- Braakhuis BJ, Snijders PJ, Keune WJ, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst. 2004;96(13):998–1006.
- Cohen MA, Weinstein GS, O’Malley BW Jr, Feldman M, Quon H. Transoral robotic surgery and human papillomavirus status: oncologic results. Head Neck. 2011;33(4):573–580.
- Weinstein GS, Quon H, O’Malley BW Jr, Kim GG, Cohen MA. Selective neck dissection and deintensified postoperative radiation and chemotherapy for oropharyngeal cancer: a subset analysis of the University of Pennsylvania transoral robotic surgery trial. Laryngoscope. 2010;120(9):1749–1755.
- Arora A, Cunningham A, Chawdhary G, et al. Clinical applications of telerobotic ENT-head and neck surgery. Int J Surg. 2011;9(4):277–284.
- Torrente MC, Rodrigo JP, Haigentz M Jr, et al. Human papillomavirus infections in laryngeal cancer. Head Neck. 2011;33(4):581–586. doi:10.1002/hed.21421.
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