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Oropharyngeal cancers and HPV
- 1. Human Papillomavirus and Oropharyngeal Cancer Pradit Rushatamukayanunt MD, PhD Division of Head Neck and Breast Surgery Department of Surgery Faculty of Medicine Siriraj Hospital Mahidol University
- 2. Head and Neck Cancer • 6th most common cancer worldwide • > 95% caused by Squamous cell Carcinoma • HNSCC - oral cavity, oropharynx, larynx or hypopharynx • Known risk factors including tobacco, alcohol and betel nut
- 3. Changing Trend of Tobacco Use • Reduction in tobacco use in the USA • In 1965: > 50% of male and 0.25% of female • In 2006: < 25% of male and 20% of female • Numbers of head and neck cancer patient should be decreased ? Giovino GA et al., Am J Prev Med, 33: s318-s326, 2007
- 4. Changing Trend of Tobacco Use and Epidemiology of HNC Giovino GA et al., Am J Prev Med, 33: s318-s326, 2007
- 5. Changing Epidemiology of Head and Neck Cancer • ↑ Incidence of tongue and pharynx in the past two decades • SEER Data (1973-2001) showed ↑ annual incidence of Oropharyngeal carcinomas 0.8% Oropharyngeal subsites: Base of tongue ↑1.27% Tonsillar carcinoma ↑0.6% Chaturvedi AK, J Clin Oncol 2008
- 6. Global Trend for Oropharyngeal and Oral carcinoma among men Chaturvedi AK, J Clin Oncol 2013 Among men, OPSCC significantly increased in many developed countries e.g. United States, Canada United Kingdom, Japan, the Netherlands, Denmark, Australia, Slovakia, Brazil
- 7. Incidence Trend of HNSCC in Thailand Incidence Trend of Oropharyngeal and Oral cavity SCC in Men and Women in Thailand Chaturvedi et al, J Clin Oncol 2013 Male Female
- 8. HPV as a Risk Factor in Oropharyngeal carcinoma • Odds ratio for Oropharyngeal CA in seropositive HPV16 was more than 14 (Mork J, NEJM 2001) • HPV-associated oropharyngeal carcinoma in the USA = 60-70% (D’Souza et al NEJM 2007) (Fakhry C J Nat Can Inst 2008) (Chaturvedi AK J Clin Oncol 2011) • HPV-associated OPSCC in Central Europe and Central America = 10% (Ribeiro KB , Int J Epidemiol 2011) • HPV 38-56% in North America, North and West Europe, Australia and Japan • HPV 13-17% in other parts of the world (de Martel C , Lancet Oncol 2012)
- 9. HPV and HNSCC in Thailand Siriraj Hospital Experiences • Two PCR-based studies • Prevalence of HPV positive = 27.3% (HPV11 = 50%, HPV16 = 33%, HPV26 = 17 ) Relatively low HPV detection • Small population • Methods of detection • Different types of HPV • Lifestyle and behaviour
- 10. Professor Harald Zur Hausen Prince Mahidol Award 2005 Nobel Prize 2008 The First one who demonstrated HPV-DNA sequences in cervical cancer biopsies and cervical cancer cell lines
- 11. HPV Structure L2 L1 E6 E7 E1 E2 E5 E4 Oncogenic Viral Replication Assembly and Release Capsid proteins (Zur Hausen, Nat Rev Cancer 2002)
- 12. Carcinogenic Effect caused by Oncoprotein E7 (Syrjänen S, Head and Neck Pathology 2012)
- 13. Carcinogenic Effect caused by Oncoprotein E6 (Syrjänen S, Head and Neck Pathology 2012)
- 14. HPV Pathogenesis (Syrjänen S, Head and Neck Pathology 2012)
- 15. Clinical Types of HPV Infection High Risk Types: found preferentially in precancerous and cancerous specimens including HPV 16,18,31,33,34,35,39,45,51,52,56,5 8,59,66,68,70 Low Risk Types: detected in wart and non-malignant lesion including HPV 6,11,42,43,44 (Syrjänen S, Head and Neck Pathology 2012)
- 16. Risk of HPV Infection Oro-genital contact >1 partner Young age of 1st Sexual Intercourse History of genital wart Less oro-genital contact Partner 1-2 1st Sexual Intercourse 20.9 yr Lack of history STD
- 17. Different Clinical and Biological Features of HPV-negative and HPV-positive Cases Feature HPV-negative HPV-positive Age Above 60 years Middle-aged Risk factors Tobacco +/- alcohol Sexual behaviour Field cancerization yes Unknown Predilection site None Oropharynx T stage Higher T Stage Lower T Stage Nodal status Lower Higher TP53 mutations Frequent Infrequent
- 18. HPV Positive: p16↑, p53 wt Biological Features of HPV-negative and HPV-positive HPV Positive: p16↓, p53 wt p16 ↑, wt p53 (Leemans CR et al, Nat Rev Cancer 2011) p16 ↓, mutant p53
- 19. Pathological Diagnosis Typical morphology 1. Arise from the tonsillar crypts 2. Unassociated with dysplasia of the surface epithelium 3. Exhibit lobular growth 4. Permeated by infiltrating lymphocytes 5. Lack significant keratinization 6. Demonstrate a prominent “basaloid” morphology Westra WH, Head and Neck Pathology 2009
- 20. Detection of HumanPapillomaVirus Presence of HPV DNA Evidence of functioning Oncoprotein E7 DNA In-Situ Hibridization PCR assay for viral copies mRNA of E6, E7 p16 Immunohistochemistry
- 21. HPV Detection • Polymerase chain reaction • High sensitivity • Prone to cross contaminate • Unable to distinguish episomal vs integrated form • Best fit for frozen specimen • Prone to error when analyze in FFPE specimen • More widely available but not for some pathological lab
- 22. HPV Detection • In situ hybridization • High specificity • Localize HPV DNA within the tumor cell nuclei • Discriminate between integrated and episomal infection • Limited to a few specialist centers (Syrjänen S, Head and Neck Pathology 2002)
- 23. Detection of Functional Oncoproteins • p-16 Immunohistochemistry (Rushatamukayanunt et al,APJCP 2014) • Surrogate of functional downstream effect of Rb gene inactivation by E7 oncoprotein • Sensitivity 100% • Specificity 79% • Applicable for FFPE specimens Smeets Sj et al, Int J Cancer 2007
- 24. p-16 Immunohistochemistry (Rushatamukayanunt et al, APJCP 2014)
- 25. HPV as a prognostic marker Ang KK, Sem in Rad Oncol2012
- 26. Interaction between HPV and Tobacco Consumption (Ang KK, NEJM 2010)
- 27. HPV-ISH vs p16 status and survival (Ang KK, NEJM 2010)
- 28. Ang KK, Sem in Rad Oncol2012
- 29. Application of Knowledge HPV-positive Oropharyngeal Carcinoma has better prognosis Better Survival Long-term morbidity associated with current treatment will be longer lasting De-escalating Treatment Regimens
- 30. De-escalating Treatment Intensity • Potential to reduce • Gastric tube dependence • Osteoradionecrosis • Dysphagia • Xerostomia • Dental decay • Hypothyroidism • Carotid stenosis • De-escalating Strategies • Cetuximab as alternative to Cisplatin when given concurrently with radiation • Reduction of radiation dose when combines with chemotherapy as primary treatment • Reduction of adjuvant chemotherapy or radiotherapy dose following primary surgery
- 31. Conclusion • HPV-positive tumour is important prognostic marker in Oropharyngeal carcinoma • HPV detection should be considered in patient with middle-aged group, low tumour stage with high nodal status • p16-IHC is the most practical method to determine HPV status • Positive-HPV status is prognostic factor of better survival
- 32. Future Trend • Actual HPV prevalence in various geographic regions • Suitable method of HPV detection single or combined method • Additional effects of EGFR status and TP53 mutation on therapeutic response