Human Papillomavirus and Oropharyngeal Cancer

Pradit Rushatamukayanunt MD, PhDDivision of Head Neck and Breast Surgery

Department of SurgeryFaculty of Medicine Siriraj Hospital

Mahidol University

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

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

Changing Trend of Tobacco Use and Epidemiology of HNC

Giovino GA et al., Am J Prev Med, 33: s318-s326, 2007

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

Global Trend for Oropharyngeal and Oral carcinoma among men

Chaturvedi AK, J Clin Oncol 2013

Among men, OPSCCsignificantly increased inmany developed countries

e.g. United States, Canada United Kingdom, Japan, the Netherlands, Denmark, Australia, Slovakia, Brazil

Incidence Trend of HNSCC in Thailand

Chaturvedi et al, J Clin Oncol 2013

Male Female

Incidence Trend of Oropharyngeal and Oral cavity SCC in Men and Women in Thailand

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)

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

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

HPV Structure

L2

L1E6 E7 E1

E2 E5

E4

Oncogenic

Viral Replication

Assembly and

Release

Capsid proteins

(Zur Hausen, Nat Rev Cancer 2002)

Carcinogenic Effect caused by Oncoprotein E7

(Syrjänen S, Head and Neck Pathology 2012)

Carcinogenic Effect caused by Oncoprotein E6

(Syrjänen S, Head and Neck Pathology 2012)

HPV Pathogenesis

(Syrjänen S, Head and Neck Pathology 2012)

Clinical Types of HPV Infection

High Risk Types: found preferentially in precancerous and cancerous specimensincluding HPV 16,18,31,33,34,35,39,45,51,52,56,58,59,66,68,70

Low Risk Types: detected in wart and non-malignant lesionincluding HPV 6,11,42,43,44

(Syrjänen S, Head and Neck Pathology 2012)

Risk of HPV Infection

Oro-genital contact>1 partner

Young age of 1st Sexual IntercourseHistory of genital wart

Less oro-genital contactPartner 1-2

1st Sexual Intercourse 20.9 yrLack of history STD

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

Different Clinical and Biological Features of HPV-negative and HPV-positive Cases

HPV Positive: p16↑, p53 wt

Biological Features of HPV-negative and HPV-positive

HPV Positive: p16↓, p53 wt

(Leemans CR et al, Nat Rev Cancer 2011)

p16 ↑, wt p53

p16 ↓, mutant p53

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

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

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

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)

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

p-16 Immunohistochemistry

(Rushatamukayanunt et al, APJCP 2014)

HPV as a prognostic marker

Ang KK, Sem in Rad Oncol2012

Interaction between HPV and Tobacco Consumption

(Ang KK, NEJM 2010)

HPV-ISH vs p16 status and survival

(Ang KK, NEJM 2010)

Ang KK, Sem in Rad Oncol2012

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

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

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

Future Trend

• Actual HPV prevalence in various geographic regions

• Suitable method of HPV detectionsingle or combined method

• Additional effects of EGFR status and TP53 mutation on therapeutic response