Oropharyngeal cancers Pradit Rushatamukayanunt, MD

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