HPV AND CANCERS

DR.DIVYA JAIN

CHOITHRAM HOSPITAL

INDORE

HUMAN PAPILLOMA VIRUS

HUMAN PAPILLOMA VIRUS

• Papovaviridae family

• small DNA-containing virus • double-stranded circular DNA of 7900 base-pairs long

• Non-enveloped virus

• Epitheliotropic (infects epithelial cells)

• Infects only humans.

CLINICAL TYPES

• High Risk Types: Found preferentially in precancerous and

cancerous specimens including 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

lesion including HPV 6,11,42,43,44

HPV TRANSMISSION

• Direct skin-to-skin contact

• Usually, but not always sexual contact

• Infected birth canal

• Fomites (very rare)

RISK FACTORS

• Multiple partners

• Early age at first intercourse (16 years or younger)

• Male partner has (or has had) multiple sex partners

• Smoking: 4 times R.R.

• Immunosuppression: HIV, Rheumatoid Arthritis,

Cancer

• Condoms: not very good at preventing HPV

• Spermide nonoxynol-9: not protective

HPV INFECTIONS: SUMMARY

• Most people are infected by HPV at some time

• Immune system usually clears HPV, but not always

• Persistent low-risk HPV can lead to warts

• Persistent high-risk HPV can lead to pre-cancer

• Long peristence of HPV can lead to cancer.

HPV

MOLECULAR VIROLOGY

• The E4 protein play a role in G2

arrest in HPV-infected cells

• The 3 HPV oncogenes E5, E6,

and E7 promote unrestrained

cellular proliferation to allow for

viral amplification but also

contribute to the initiation and

progression of cancer

HPV DETECTION

Detection of Human Papilloma Virus

Evidence of functioning

Oncoprotein E7

•DNA In-Situ Hybridization

•PCR assay for viral copies

•mRNA of E6, E7

•p16 Immunohistochemistry

Presence of HPV

DNA

BY 2020….

• The annual number of HPV-positive OPSCCs (approximately

8,700 patients) will surpass the annual number of cervical cancers

(approximately 7,700 patients) with the majority occurring among

men (approximately 7,400).

• By 2030, OPSCC will likely constitute a majority (47%) of all H

& N cancers.

Chaturvedi A K et al. JCO 2011

HEAD AND NECK CANCER

• 6th most common cancer worldwide

• More than 600,000 new diagnoses annually

• > 95% are Squamous cell Carcinomas

• In recent years, many studies have shown that some 25% of

Oropharyngeal carcinomas are associated with Oncogenic or

high-risk HPV, already widely implicated in cervical carcinoma

COMMONEST SITE OF INFECTION IN HEAD AND NECK

• The commonest head and neck sites associated

with HPV infection are

• Tonsil,

• Base of tongue,

• Lingual tonsil

• Lateral wall of the oropharynx.

• Patients with potentially HPV related SCCs often do not

have the known risk factors, like smoking, alcohol

consumption or tobacco chewing.

• Research has shown an association between the HPV

related cancers and having a higher number of sexual

partners and an increase in oral sexual behaviour.

• Pts present with a similar signs and symptoms as other

cancer due to other causes.

DISEASE COURSE AND PROGNOSIS..

• On the assumption that HPV-associated H&N cancer is an

entity of its own, clinical studies have increasingly been

published…

• These studies show that patients with HPV-positive

cancers have a much better prognosis.

•Why does HPV

positive oropharyngeal

cancer have a better

prognosis?

WHY HPV +VE PATIENTS DO WELL??

MANAGEMENT

• The standard treatment for oropharyngeal

Squamous cell cancer at present is mainly

dependent on the stage of the disease and patient

and clinician preferences.

• Single-modality treatment, in the form of surgery or

radiotherapy, is usually recommended for early (T1-

T2, N0) disease.

REVIEWING MANAGEMENT STRATEGIES??

HPV-positive Oro pharyngeal

Carcinoma has better prognosis

Better

Survival

Long-term morbidity associated

with current treatment will be

longer lasting

De-escalating

Treatment

Regimens

DEINTENSIFICATION

• Deintensification trials can be done in 2 ways:

1. Deintensification of local therapy via using alternative

chemotherapy, reduced dose radiation or surgery

2. Use of induction therapy to identify good-responding patients

for subsequent dose reduction.

FUTURE

• HPV detection would become a standard prognostication

factor for H & N cancers like ER-PR & PSA.

• We may use significantly different treatments for patients

with HPV-positive as compared with HPV-negative HNC.

CERVICAL CANCER

• 2nd most common cancer in women worldwide

• Most common cause of death in females in

developing countries

• In India,every year 72,000 females die of cervical

cancer

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.

Natural History of HPV & Cervical Cancer

Normal

CervixHPV

InfectionPre-cancer Cancer

InfectionProgression Invasion

RegressionClearance

Persistence

CIN: PRE-CANCEROUS WARNING

• Cervical intraepithelial neoplasia(CIN) observed in disease progression

• New, abnormal, disorganized growth of cervix epithelium

STAGES OF CIN

1. CIN I

• Number & depth of abnormal cells

is low

2. CIN II

• Abnormal cell growth penetrates

about ½ the thickness of cervical

epithelium

3. CIN III

• “carcinoma in-situ”

• Abnormal cell growth penetrates

entire thickness of cervical epithelium

4. Invasive Cervical Cancer

• Abnormal cell growth penetrates

beyond cervical epithelium

STAGES OF CIN: HISTOLOGY

NORMAL CIN I CIN II CIN III

Furumoto et al., 2002.

CERVICAL CANCER COFACTORS

• HPV is NOT sufficient cause for cervical cancer

• Combination of HPV & 1 or more cofactors increase

risk of cancer progression

• HYGIENE

• PARITY

• HORMONAL CONTRACEPTIVES

• SMOKING

PREVENTION BETTER THAN CURE

• PRIMARY PREVENTION-Vaccination against HPV

• SECONDARY PREVENTION-Screening for

precancerous changes (and treatment if problems

found)

HISTORY OF THE CONVENTIONAL

PAP SMEAR• Developed by Dr. George N. Papanicolaou

in 1940’s

• Most common cancer screening test

• Key part of annual gynecologic examination

• Has greatly reduced cervical cancer

mortality .

CERVICAL CANCER SCREENING GUIDELINES

• First screen 3 years after first intercourse or by age 21

• Screen annually with regular Paps or every 3 years with

liquid-based tests

• After three normal tests, can go to every 5 years

• Stop at 65-70 years with history of negative tests

• Still need annual check-ups

Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2016; 102:417-27.

HPV VACCINE

VACCINATION WITH GARDASIL OR CERVARIX?

VACCINE MOA

• Both the vaccine provide protection against HPV 16 & HPV 18.

• They make use of virus-like particles composed of the major

capsid protein L1 of the targeted HPV subtypes.

GARDASIL® should be administered intramuscularly as 3 separate

0.5-mL doses according to the schedule of 0,2,6 month for females

aged 9 through 26 years.

Care must be taken not to inject intravenously as it can lead to

syncopal attack.

Efficacy is of 5 to 10 yrs.

No booster dose has been recommended.

DOSAGE

Indian and United States

Organizations

IAP – Indian Academy of Pediatrics

FOFSI - The Federation of Obstetric & Gynaecological

Societies of India

AAP = American Academy of Pediatrics

ACHA = American College Health Association

ACOG = American College of Obstetricians and

Gynecologists

AAFP = American Academy of Physicians

SAM = Society for Adolescent Medicine

Recommendations IAP FOGSI ACOG AAFP SAM ACHA AAP

Routine vaccination in females 11-12

years old & catch-up vaccination in 13-26

year olds

√ √ √ √ √ √ √

Females 9-10 years old may be

vaccinated√ √ √ √ √ √ √

Vaccinate regardless of previous HPV

infection or abnormal Pap test results√ √ √ √ √ √ √

Continue Pap testing after vaccination √ √ √ √ √ √ √

Recommendations by US based organizations are only for Gardsil as it is

the only USFDA approved HPV vaccine1. http://www.acog.org/from_home/publications/press_releases/nr08-08-06.cfm, visited on7th March 2008 2.

American Academy of Family Physicians. Practice guidelines: ACIP releases recommendations on quadrivalent

human papillomavirus vaccine. Am Fam Physician. 2007;75(9). Available at:

http://www.aafp.org/afp/20070501/practice.html. Accessed May 30, 2007. 3. Society for Adolescent Medicine.

Human papillomavirus (HPV) vaccine: a position statement of the Society for Adolescent Medicine. Available at:

http://www.adolescenthea lth.org/positionstatement_HPV_vaccine.pdf. Accessed May 16, 2007. 4. American College

Health Association (ACHA). Vaccine Preventable Diseases Committee. Recommendations for institutional

prematriculation immunizations. August 2006. Available at: http://www.acha.org/info_resources/guidelines.cfm.

Accessed May 16, 2007. 5. PEDIATRICS Volume 120, Number 3, September 2007 6. INDIAN PEDIATRICS:

VOLUME 45--AUGUST 17, 2008 7. The Federation of Obstetric & Gynaecological Societies of India (FOGSI).

Recommendations for Vaccination against Human Papilloma Virus (HPV) Infection For the prevention of Cervical

Cancer. Available at http://www.fogsi.org/hiv_vaccine.html. accessed on 20th Feb 20009

HPV VACCINE – IN H&N CANCER???

• HPV-16 is responsible for only 50-60% of cervical

cancers

• In HPV + oropharyngeal cancer, HPV-16 subtype is

present in 94% of these cancers

• Theoretically, HPV vaccine should be even more

effective in head and neck cancer .

• No clinical data available for humans.

• Should boys be vaccinated?

• Can vaccine be given to pregnant women

/lactating mother?

• Can vaccine be given after development of

cancer?

THANK YOU…..