Objectives. HPV Classification. The Connection Between Human Papillomavirus and Oropharyngeal Cancer 6/19/2012

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1 The Connection Between Human Papillomavirus and Oropharyngeal Cancer Jennifer L. Cleveland, DDS, MPH Dental Officer/Epidemiologist OSAP Annual Symposium June 23, 2012 Atlanta, GA National Center for Chronic Disease Prevention and Health Promotion Division of Oral Health Objectives Provide an overview of human papillomavirus (HPV ) and the oropharynx Discuss the epidemiology of HPVassociated oropharyngeal squamous cell carcinomas (OPCs) Describe the survival/prognosis of HPVassociated OPCs Summarize available evidence regarding HPV vaccines HPV Classification Over 100 different types of HPV Mucosal HPVs (oral, genital, ~40 types) Cutaneous HPVs (common body warts, ~60 types) High Risk ex: 16, 18 Low and high grade cervical changes; and anogenital and oropharyngeal cancers Low Risk ex: 6, 11 Genital and oral warts, Low grade cervical changes, Respiratory papillomas Common warts (hands, feet ) Adapted from: 1

2 Verruca Vulgaris (wart) Anatomy of Head and Neck Oral Cavity and Oropharynx 2

3 Tonsils 7 HPV-Positive Squamous Cell Carcinoma of the Palatine Tonsil Soft palate Photo Title Myriad Pro, Bold, Back Shadow, of tongue 20pt Caption for photo, references, citations, or credits Myriad Pro, 14pt Screening for Oropharyngeal Cancers Difficult to detect OPCS at early stage No standardized screening tests No oral PAP smear to detect cellular changes No FDA approved test for oral HPV infection No evidence that detection of oral HPV could be used to predict development of OPCs. 3

4 Signs and Symptoms of Oropharyngeal Cancers Persistent sore throat or ear pain Hoarseness or voice changes Pain or difficulty with swallowing Unexplained weight loss A lump in the back of the throat or mouth A lump in the neck HPV oncogenes bind and inactivate Pathogenesis { HPV oncogene E6 HPV oncogene E7 Normal cell growth regulated by tumor P53 Rb suppressor genes { Uncontrolled cell growth 11 Natural History of HPV Infection ~80-85% of people acquire any HPV infection at some point in their lives ~90% infections clear in 1-2 years in healthy individuals Almost all cervical cancers are caused by HPV infections that persist more than 2 years. 4

5 Established Risk Factors for Head and Neck Cancers HPV Tobacco Alcohol Risk Factors for HPV-associated OPCs Associated with lifetime number of vaginal or oral sex partners and open-mouthed kissing Compared with HPV-negative cancers, occur more often: Among white men In a population younger by about 4 years (median age years) In people who may or may not use tobacco or alcohol Evidence of Current and Past HPV Infection Oral HPV DNA in exfoliated cells (e.g., oral rinses) Serum antibodies to HPV proteins (HPV seroprevalence ) which measure cumulative exposure. HPV DNA in oropharyngeal tumors 5

6 Prevalence of HPV in OPCs Almost 65% of all oropharyngeal cancers (OPCs) are HPV-positive; 85-95% of these are high risk HPV-16. Estimates vary widely depending on: Tumor site Detection method Tissue preservation method Geographic region. Sample size Yearly Incidence Counts HPV-associated Cancers, US Male Female Total 11,242 0 Cervix Vulva Vagina Penis Anus Oropharynx Defined by histology and anatomic site; Watson M et al. Cancer Data source: National Program of Cancer Registries (CDC) and SEER (NCI), covering 99% of US population. Average Annual Percentage and Number of Oropharyngeal Cancers Attributable to HPV by Sex U.S., * Site no. % Attributable to HPV** % Range No. attributable to HPV No. Range Female 2, (50-75) 1,500 (1,200-1,800) Male 9, (50-75) 5,900 (4,700-7,000) Total 11,716 7,400 * Watson, MMWR 2012 * *Gillison et al, Cancer

7 Average Annual Number of Oropharyngeal Cancers Attributable to HPV by Site U.S., * Annual No. No. attributable Total Tonsils Base of Other OP Tongue Average Annual Number of Oropharyngeal Cancers Attributable to HPV by Site U.S., * Site Average Annual No. No. attributable to HPV Tonsils 5,077 3,198 Base of tongue 4,536 2,858 Other OP 1,628 1,025 Total 11,241 7,082 Incidence of HPV-associated Cancers of the Oropharynx in the U.S.,

8 Annual Percentage Change in OPC, Defined by histology and anatomic site; Watson M et al. Cancer Data source: National Program of Cancer Registries (CDC) and SEER (NCI), covering 89% of US population. Annual Percentage Change in OPC by Sex and Race/Ethnicity, Defined by histology and anatomic site; Watson M et al. Cancer Data source: National Program of Cancer Registries (CDC) and SEER (NCI), covering 89% of US population. Incidence Rates for HPV-related and Unrelated Sites Unrelated Related Charturvedi AK et al. J Clin Oncology 2/1/2008 8

9 HPV and Rising OPC Incidence in the U.S. 271 OPCs collected by 3 cancer registries in Incidence of HPV-positive OPCs increased by 225% during incidence of HPV-negative cancers declined by 50%. Should recent trends continue, the annual number of HPV-positive OPCs among men will surpass that of cervical cancers among women by the year Source: Chaturvedi A et al., J Clin Oncology 2011 Prognosis HPV-positive OPCs have improved prognosis/outcomes relative to HPV-negative OPCs. HPV-positive tumors have higher survival rates, respond better to radiation and chemotherapy treatment, and are less likely to recur than HPV-negative ones. Median survival in OPC patients with HPV is 131 months; without it, 20 months. (REF!) HPV +/ tumor status may drive treatment decisions. Reasons for Improved Outcomes Among HPV-positive OPCs Greater sensitivity of HPV-positive tumors to treatment with radiation and chemotherapy Enhanced immune response after radiotherapy Patients are younger with fewer comorbities and lack a history of tobacco and alcohol use. 9

10 Is HPV a Driver or a Passenger? Source: Evans MF, Head Neck Pathology, 2011 Differences in HPV-Positive OPCs by Race/Ethnicity HPV-positive oropharyngeal cancers occur more often in whites and are associated with improved outcomes Settle, 2009 Median overall survival: 70.6 months for whites vs months for blacks HPV positivity in OPC patients nearly 9-fold higher in whites than blacks Vaccines FDA Approval Gardasil Cervarix 4 Types HPV 6,11,16,18 2 Types HPV 16,18 Females and Males Females 30 10

11 ACIP Recommendations for HPV Vaccine in the United States Quadrivalent vaccine Routine, females 11 or 12 yrs* Catch-up, yrs Quadrivalent or Bivalent vaccine Routine, females 11 or 12 yrs* Catch-up, yrs Quadrivalent vaccine May be given, males 9-26 yrs June October Quadrivalent (HPV 6,11,16,18) vaccine; Bivalent (HPV 16,18) vaccine; ACIP: Advisory Committee on Immunization Practices * Can be given starting at 9 years of age Potential for HPV Vaccines to Prevent Oral HPV Infection Effectiveness to prevent oral HPV infection is unknown. High prevalence of HPV-16 in OPCs suggests HPV vaccination may have a major impact on incidence of OPCs. Periodic surveillance in HPV-associated OPCs will be important to monitor the impact of HPV vaccines. Clinical Implications Tobacco Cessation Most HNSCCs (75%) caused by tobacco and alcohol use Expand efforts for tobacco cessation, particularly among black males and females Dentists should be aware that younger patients with no tobacco or alcohol use may develop HPV-associated OPCs 11

12 Conclusions Rates of HPV-positive OPCs are increasing in young, white males. HPV-positive OPCs are diagnosed later but have better prognosis than HPV-negative cancers. Potential for number of HPV-positive OPCs among men to surpass that of cervical cancers among women by the year HPV vaccines may greatly affect the US public health by preventing non-cervical cancers, such as OPCs. Future Research Questions Is persistence of oral HPV infections a risk factor for oropharyngeal cancers? If so, what is the time period between persistent infection and OPC? Does a precancerous state exist for OPC? Does HPV cause cancers in other regions of the head and neck? Will HPV vaccines protect against oral HPV infections? Breaking News! 12

13 The Association of HPV-Positive OPCs and Cervical Cancers, women were diagnosed with HPVassociated OPC; of these, 20 had cervical cancer Risk of cervical cancer in OPC patients was >25 times that of the general population Suggests frequent coinfection of oropharyngeal and genital tissues Coinfection through sexual behaviors Genetic susceptibility to the oncogenic effects of HPV Shared risk factors, e.g., smoking Biron et al. J Otolaryng Head & Neck Surg, February,

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