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CERVICAL CANCER & OTHER HUMAN CERVICAL CANCER & OTHER HUMAN PAPILLOMAVIRUS- RELATED DISEASESPAPILLOMAVIRUS- RELATED DISEASES
Dr.Ahmed Eltigani Elmahdi HussainDr.Ahmed Eltigani Elmahdi Hussain
Consultant Obstetrician & Gynaecologist, IRELANDConsultant Obstetrician & Gynaecologist, IRELAND
Globocan 2002: ASR (World)
< 1.5
< 0.4
<16.6
< 4.4
Age-adjusted incidence rates per 100,000 women per year
Incidence of Cervical Cancer In Europe
< 7.9
38 countries: European Union except Cyprus (24 countries) + Iceland, Norway, Switzerland, Belarus, Bulgaria, Moldova, Romania, Russian Federation, Ukraine, Albania, Bosnia Herzegovina, Croatia, Macedonia, Serbia and Montenegro.
27 countries: European Union except Cyprus (24 countries) + Iceland, Norway, & Switzerland (3 countries).
EUROPE (38 COUNTRIES): 60,000 new cases per year
EUROPE (27 COUNTRIES): 33,386 new cases per year
* Ovary, Fallopian tube, broad ligament, round ligament, parametrium, and uterine adnexa.
European Union except Cyprus (24 countries) + Iceland, Norway, & Switzerland (3 countries).
Age-standardized (World) incidence & Age-standardized (World) incidence & mortality rates mortality rates
EUROPEEUROPE
Age-standardized (World) incidence & Age-standardized (World) incidence & mortality rates mortality rates
EUROPEEUROPEINCIDENCEINCIDENCEINCIDENCEINCIDENCE MORTALITYMORTALITYMORTALITYMORTALITY
4.9
5.4
7.5
34.0
10.4
0 10 20 30 40
Thyroid
Ovary &…*
Melanoma of skin
Cervix uteri
Breast
Number of cases per 100,000 women per year
1.3
1.3
1.7
2.0
5.7
0 2 4 6
Colon and rectum
Brain, nervous system
Lung
Cervix uteri
Breast
SO
UR
CE
: GLO
BO
CA
N 2
002.
1. Ferlay et al. Globocan 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancer-Base No.5, version 2. Lyon. IARC Press, 2004. 2. Cancer Research UK, Cancer Mortality Figures 2004 http://info.cancerresearchuk.org/images/excel/cs_mort_t6.2.xls
Breakdown of cancers in the young European Breakdown of cancers in the young European female population (15-44 years) in 2002female population (15-44 years) in 2002
21 women die each week
on average in the UK2
Cervical cancer is the second most frequent cancer in Cervical cancer is the second most frequent cancer in young women (15-44 years) in Europeyoung women (15-44 years) in Europe11
National cervical screening programmeNational cervical screening programme
The NHS cervical screening programme is recognised as The NHS cervical screening programme is recognised as world leadingworld leading11
Cervical cancer incidence fell by 42% between 1988 and Cervical cancer incidence fell by 42% between 1988 and
1997 (England and Wales). This fall is believed to be directly 1997 (England and Wales). This fall is believed to be directly
related to an organised cervical screening programmerelated to an organised cervical screening programme22
which was introduced in 1988which was introduced in 1988
1. http://cancerscreening.org.uk/cervical/publications/cervical-annual-review-2004.pdf Accessed 12/10/052. NHS. Cervical Screening pocket guide. 2004.
Clinical studies have shown that in 99.7% of cases, cervical cancer is caused by a virus: human papillomavirus (HPV)1, 2
Mucosal HPV infection can also cause vulval and vaginal pre-cancerous lesions and genital warts3
1. Munoz N. Human papillomavirus and cancer : The epidemiological evidence. J Clin Virol 2000;19:1–5. 2 Walboomers JM, Jacobs MV, Manos MM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–19. 3. Zur Hausen H. Papillomavirus and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2:342-350.
Human papillomavirus infection - the link to cervical cancer & other diseases
HPVHPV It is the most common ST infection among women, an It is the most common ST infection among women, an
estimated 291 million women harbour an HPV worldwide.estimated 291 million women harbour an HPV worldwide.
Indeed all women who are, or have been, sexually active Indeed all women who are, or have been, sexually active are at risk of HPV infection.are at risk of HPV infection.
80% of the infections are thought to be transient, other 80% of the infections are thought to be transient, other lead to CIN, which may or may not then progress to CA.lead to CIN, which may or may not then progress to CA.
Most early lesions will regress spontaneously.Most early lesions will regress spontaneously.
Cervical CA is a late & rare complications of persistent Cervical CA is a late & rare complications of persistent infection and is the end result of a chain of events that take infection and is the end result of a chain of events that take usually in excess of 10 years to unfold usually in excess of 10 years to unfold
Human papillomavirus types 6,11,16 & 18 areHuman papillomavirus types 6,11,16 & 18 arefour common types affecting women’s healthfour common types affecting women’s health
1.Clifford, GM et al. Br J Cancer 2003; 88: 63-73. 2.Daling JR, et al. Gynecol Oncol 2002; 84: 263-270 3.Madeleine et al. J Natl Cancer Inst 1997;89:1516–1523. 4.Clifford GM, et al. Br J Cancer 2003; 89: 101–105 5.Sotlar K, et al. J Clin Microbiol 2004; 42: 3176-3184. 6.van Beurden M, et al. Cancer 1995; 75: 2879-2884. 7.Hording U, et al. Gynecol Oncol 1995; 56: 276–279. 8.Clifford GM, et al. Cancer Epidemiol Biomarkers Prev 2005; 14:1157-1164. 9.von Krogh G. Eur J Dermatol 2001; 11: 598-603. 10.Wieland U, Pfister H. Human Papilloma Virus: A clinical atlas. Ullstein Mosby; 1997. p1-18.
Relationship of HPV infection with genital neoplasiaRelationship of HPV infection with genital neoplasia Cervical cancer- third most common gynaecological malignancyCervical cancer- third most common gynaecological malignancy
All cervical cancers contain HPV DNA- an estimated 99.7% prevalence All cervical cancers contain HPV DNA- an estimated 99.7% prevalence
Significant fraction of vaginal, vulvar, penile and anal cancersSignificant fraction of vaginal, vulvar, penile and anal cancers
Oncogenic HPV types 16 and 18 cumulatively account for ~70% of all Oncogenic HPV types 16 and 18 cumulatively account for ~70% of all cervical cancerscervical cancers
HPV types most commonly results in sub clinical infectionsHPV types most commonly results in sub clinical infections
Most infected women harbour HPV DNA without showing cytological Most infected women harbour HPV DNA without showing cytological or histological changesor histological changes
Risk factorsRisk factors
Sexual activity- number of current and previous partners In men- circumcision reduces risk of the acquisition and
transmission of HPV Use of latex condoms reduces the risk of HPV infection Co infection with Chlamydia trachomatis or Herpes
simplex virus A grater rate and incidence of infection has been observed
imunocompromissed renal transplant patients and HIV infected patients
High parity (5 or more pregnancies) Active and passive cigarette smoking Long term use of oral contraceptives
TransmissionTransmission
HPV is transmitted by genital contact HPV is transmitted by genital contact Virus must have access to the basal epithelial cells, either in Virus must have access to the basal epithelial cells, either in epithelium that is naturally thin & immature: epithelium that is naturally thin & immature: TZ of the cervix TZ of the cervix or the anal vergeor the anal verge microscopic tears or abrasions in the external genital microscopic tears or abrasions in the external genital
skin or the introital or vaginal mucosaskin or the introital or vaginal mucosa
Genital-oral transmission-may be possibleGenital-oral transmission-may be possible
Recurrent papillomatosis in young children can occur from the Recurrent papillomatosis in young children can occur from the transmission of HPV 6 or 11 from a mother to a newborn babytransmission of HPV 6 or 11 from a mother to a newborn baby
Circumcision
Castellsagué et al, NEJM 2002
Male circumcision reduces the risk of Male circumcision reduces the risk of HPV infection in men and of cervical HPV infection in men and of cervical
cancer in the female partnercancer in the female partner
DISEASE CAUSED BY HPV 6/11
Causative agentof genital warts
Causative agentof JORRP
Genital warts
Genital warts, also referred to as Genital warts, also referred to as condyloma acuminata.condyloma acuminata.
They are soft growths that are typically They are soft growths that are typically found on the skin or mucous membranesfound on the skin or mucous membranes
Benign, very rarely become malignant.Benign, very rarely become malignant.
More than 90% of genital wart cases are More than 90% of genital wart cases are caused by HPV types 6 and 11caused by HPV types 6 and 112,2, 33
Genital warts on male subject
Genital warts on
female subject
Prevalence
HPV infection typically asymptomatic in men prevalence rates of HPV in men range 16-45% prevalence is similar in both sexes (both men and
women develop genital warts-1%sexual active adults)
Prevalence
HPV infection most prevalent in young woman and adolescents:
As a result of increased transmission during the early years of sexual activity A lack of previous exposure that might generate a
protective immune response The transformation zone of cervical epithelium undergoes
a process of squamosus metaplasia during puberty that exposes normally protected basal cells to infection
In one study using PCR-based DNA amplification systems to detect HPV DNA 32% of women 16-24 years old tested positive for HPV DNA, compared with 4% of women aged >45 years
In women, peak exposure to human papillomavirus occurs In women, peak exposure to human papillomavirus occurs in late teens and early twenties in late teens and early twenties
Sanofi Pasteur MSD Data on File 2006 06/004
PercentagePercentage of 15 year old girls who have of 15 year old girls who have had sexual intercourse by countryhad sexual intercourse by country
Adapted from Ross J, Godeau E, Dias S. Sexual health. In: Currie et al. Eds. Young people’s health in context. Health behaviour in school-aged children study : international report from the 2001/2002 survey. WHO Europe;2004.p. 153-160.
Estimated HPV DNA prevalence in the world
(Meta-analysis of 67 studies involving 139,777 cytologically normal women)
GLOBAL 10.2% (10.0-10.5)
AFRICA 23.4% (22.0 - 24.8)
AMERICA 12.8% (12.1 - 13.5)
EUROPE 8.2% (7.9 - 8.6)
ASIA 7.6% (7.2 - 8.1)
Which specific HPV Which specific HPV types are important types are important in cervical cancer?in cervical cancer?
•HPV types 16,18,31,33,35,45,52 are HPV types 16,18,31,33,35,45,52 are responsible for >90%of all high grade CIN responsible for >90%of all high grade CIN grades CIN 11-111grades CIN 11-111
•Just 2 types- 16,18 account for >70% of all Just 2 types- 16,18 account for >70% of all cervical cancers.cervical cancers.
•HPV 16 alone is responsible for 52% of all HPV 16 alone is responsible for 52% of all cervical cancers)cervical cancers)
HPV PREVALENCE IN THE CERVIX BY HPV PREVALENCE IN THE CERVIX BY CYTOLOGICAL / HISTOLOGICAL DIAGNOSISCYTOLOGICAL / HISTOLOGICAL DIAGNOSISHPV PREVALENCE IN THE CERVIX BY HPV PREVALENCE IN THE CERVIX BY CYTOLOGICAL / HISTOLOGICAL DIAGNOSISCYTOLOGICAL / HISTOLOGICAL DIAGNOSIS
WOMEN WITH N. CYTOLOGY 9-10 % (2-3%)
PRE-INVASIVE LESIONS 80-90 % (50%)
CERVICAL CANCER 95-100 % (70%)
DIAGNOSIS HPV-DNA HPV 16/18
DE SANJOSE ET AL IN PREPARATION;DE SANJOSE ET AL IN PREPARATION;CLIFFORD ET AL 2003; CLIFFORD ET AL 2003;
MUÑOZ ET AL 2003MUÑOZ ET AL 2003
Cervical Intraepithelial neoplasia (CIN1) 1
Vulval Intraepithelial neoplasia (VIN)4
Cervical Intraepithelial neoplasia (CIN 2/3)2,3
Genital warts 6,7
Vaginal Intraepithelial neoplasia (ValN)5
1.Clifford GM etal. Cancer Epidemiol Biomarkers Prev 2005; 14:1157 – 1164 2. Clifford GM, Smith JS, Aguado T et al. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: A meta-analysis. Br J Cancer 2003; 89: 101–105 3. Sotlar K, Diemer D, Dethleffs A et al. Detection and typing of human papillomavirus by E6 nested multiplex PCR. J Clin Microbiol 2004; 42: 3176-3184. 4.Madeleine MM, Daling JR, Carter JJ et al. Cofactors with human papillomavirus in a population-based study of vulvar cancer.J Natl Cancer Inst 1997;89:1516–1523. 5. Daling JR, Madeleine MM, Schwartz SM et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002; 84: 263-270.6.Von Krogh G. Eur J Dermatol 2001;11:598-603. 7. Wieland U., Pfister H. In:Gross, Barrasso eds Human papillomavirus: A clinical atlas.Ullstein Mosby; 1997.p1-18
Common human papillomavirus types affecting Common human papillomavirus types affecting women’s healthwomen’s health
1.Munoz et al. Int J Cancer 2004;111: 278-285.2.Clifford, G. M et al. British Journal of Cancer, 88, 63-73. 20033.Von Krogh G. Eur J Dermatol 2001;11:598–603.4. Wieland U,& Pfister H. Human Papilloma Virus Infection, A Clinical Atlas. Gross/Barrasso; 2005.
Oncogenic (High risk)
There are seven genotypes that account for 85-90% of cervical cancers worldwide1
Types 16 & 18 account for ~75% of cervical cancers in Europe2
Non-oncogenic (Low risk)
Types 6 & 11 account for 90% of genital warts3,4
Images courtesy of Dr J. Monsonego
Genital Warts
Cervical Lesions
Infection with human papillomavirus can lead to genital warts Infection with human papillomavirus can lead to genital warts
4,174 people in Ireland were diagnosed in 2004 with genital warts which is an increase of 4.8% compared with 20031
??????The economic burden of HPV infectionThe economic burden of HPV infection??????
Cervical cancer screeningCervical cancer screening
Follow- up of abnormal Pap test resultsFollow- up of abnormal Pap test results
Treatment of invasive cancerTreatment of invasive cancer
Only 10% is attributed to the treatment of invasive cervical cancerOnly 10% is attributed to the treatment of invasive cervical cancer
Other 90% is for cervical cancer preventionOther 90% is for cervical cancer prevention
Diagnosis and treatment of genital warts alone also very expensiveDiagnosis and treatment of genital warts alone also very expensive
Cervical cancer screening programs are not accessible to women Cervical cancer screening programs are not accessible to women of all social and ethnic backgroundsof all social and ethnic backgrounds
UK burden of disease – cervical cancer
17.9%
7.3%
CC Cases*
Management of abnormal findings
CC Screening
Hospital days for existing cervical cancer cases
New cervical cancer cases
£104.3 million
£34.5 million
£33.3 million
£13.5 million
56.2%
18.6%
25.2%
*No data for NIBrown RE et al. Curr Med Res Opin 2006; 22 : 663–670
Total estimated cost of cervical cancer from screening to Total estimated cost of cervical cancer from screening to management of the disease in the UK in 2003 is around management of the disease in the UK in 2003 is around £185.6 million£185.6 million
Estimated cost of disease management
The Solution!!!!!! The Solution!!!!!! The Vaccine ?????The Vaccine ?????
GardasilGardasil
CervarixCervarix
VaccinesVaccines
2 multivalent VLP vaccines: Bivalent HPV 16 and 18 VLP- reduce cervical cancer
rates(CERVARIX) Quadrivalent HPV vaccine includes most common HPV
disease causing types- 6,11,16,18- reduce the incidence of external genital warts in addition to preventing cervical cancer(GARDASIL)
In the per-protocol cohort, the vaccine was 89% effective in preventing persistent infection and 100% effective in preventing clinical disease (CIN 1/2/3) associated with the 4 HPV types
Vaccines- prepared from Vaccines- prepared from exogenously exogenously expressed HPV major L1 capsid proteins expressed HPV major L1 capsid proteins VLPs VLPs (virus-like particles)(virus-like particles) and have been and have been induce HPV type-specific antibody responsesinduce HPV type-specific antibody responses
VLPs:VLPs:
• Do not contain genetic materialDo not contain genetic material •Are not infectiousAre not infectious •Have no oncogenic potentialHave no oncogenic potential
* CIN = Cervical intraepithelial neoplasia** World Health Organisation*** Food and Drug Administration US
Proven efficacy in the prevention of cervical Proven efficacy in the prevention of cervical cancer against a truly predictive clinical endpointcancer against a truly predictive clinical endpoint
0 years 10 + years
1. Adapted from Franco EL, Harper DM. Vaccine 2005; 23:2388-94 2. Sanofi Pasteur MSD Data on File 06/008
2
Rationale for designing a quadrivalent HPV vaccineRationale for designing a quadrivalent HPV vaccine
1. Clifford, G. M et al. British Journal of Cancer, 88, 63-73. 20032. Von Krogh G. Eur J Dermat. 2001;11: 598-603. 3. Koutsky L. Am J Med. 1997; 102: 3-8.
Reason for choice of the human papillomavirus typesReason for choice of the human papillomavirus types
Anticipated benefits
41
HPV vaccines for prevention of infectionHPV vaccines for prevention of infection
Reduce the incidence of the majority of Reduce the incidence of the majority of HPV- associated diseasesHPV- associated diseases
Vaccine induced immunity may reduce Vaccine induced immunity may reduce both horizontal (person-to-person) and both horizontal (person-to-person) and vertical (mother-to-newborn) vertical (mother-to-newborn) transmissiontransmission
HPV VACCINEHPV VACCINE
The vaccine was shown to be 100% effective in the The vaccine was shown to be 100% effective in the short term at preventing type-specific short term at preventing type-specific premalignant disease of the cervix. premalignant disease of the cervix.
The potential of such a vaccine to reduce the The potential of such a vaccine to reduce the worldwide incidence of cervical cancer is worldwide incidence of cervical cancer is immediately apparent. immediately apparent.
THEORETICAL IMPACT OF A VACCINE INCLUDING HPV Types 6, 11, 16 & 18THEORETICAL IMPACT OF A VACCINE INCLUDING HPV Types 6, 11, 16 & 18
67-71%
52-60%
~35%
~20-30%
ASCUS: Atypical Squamous Cell of Undetermined SignificanceL/HSIL: Low/High Grade Squamous Intraepithelial LesionICC: Invasive Cervical Cancer
ICC
ASCUS
LSIL
HSIL
POTENTIAL
REDUCTION
Months
Years
Decade(s)
Potential benefits of HPV vaccinesPotential benefits of HPV vaccines
Vaccination of 12-year-old girls with an HPV 16/18 Vaccination of 12-year-old girls with an HPV 16/18 vaccine would reduce the number of cervical vaccine would reduce the number of cervical cancer cases by >95%cancer cases by >95%
Vaccination both men and women was predicted to Vaccination both men and women was predicted to be more beneficial than vaccinating only womenbe more beneficial than vaccinating only women
Vaccines effectively reduce the incidence of HPV-Vaccines effectively reduce the incidence of HPV-associated clinical disease will also reduce the associated clinical disease will also reduce the psychological morbidity associated with diagnosis psychological morbidity associated with diagnosis and treatmentand treatment
INDICATION OF VACCINEINDICATION OF VACCINE
Prevention of:Prevention of:
high-grade cervical dysplasia (CIN 2/3)high-grade cervical dysplasia (CIN 2/3)
cervical carcinomacervical carcinoma
high-grade vulvar dysplastic lesions (VIN 2/3)high-grade vulvar dysplastic lesions (VIN 2/3)
external genital warts (condyloma acuminataexternal genital warts (condyloma acuminata)
….causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18 causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18
in adult females 16 to 26 years of age and , 9- to 15-year old children and in adult females 16 to 26 years of age and , 9- to 15-year old children and
adolescentsadolescents
Dosage and administrationDosage and administration
Primary vaccination series consist of 3 separate 0.5 ml doses, Primary vaccination series consist of 3 separate 0.5 ml doses, administrated IM injectionsadministrated IM injections
Following schedule : 0-2-6 monthFollowing schedule : 0-2-6 month
Alternative schedule: 0-1-3 monthAlternative schedule: 0-1-3 month
All 3 doses should be given within a 1 year periodAll 3 doses should be given within a 1 year period
The need for booster dose has not been establishedThe need for booster dose has not been established
Pregnancy- insufficient data- vaccinations should be postponed Pregnancy- insufficient data- vaccinations should be postponed until after completion of pregnancyuntil after completion of pregnancy
Can be given breast feeding womenCan be given breast feeding women
VaccineVaccine Generally well-toleratedGenerally well-tolerated
Most commonly reported adverse events were Most commonly reported adverse events were
injection site reactions and mild feverinjection site reactions and mild fever
Fever >38.9°C (oral temperature) within 5 days of a Fever >38.9°C (oral temperature) within 5 days of a
vaccination visit, was reported in 1.5% of the vaccination visit, was reported in 1.5% of the
GARDASILGARDASIL®® vaccinated population (n=6,040) compared vaccinated population (n=6,040) compared
to 1.1% in the placebo population (n=3,981)to 1.1% in the placebo population (n=3,981)11
Sanofi Pasteur MSD Data on File 2006 06/007
SUMMARYSUMMARY
HPV is an important health problem in Europe & HPV is an important health problem in Europe & worldwideworldwide
HPV is a common virus HPV is a common virus (approximately 290 millions women are harboring HPV DNA, of
whom 105 millions are positive for HPV 16/18) An estimated 80% of sexually active women will be exposed to HPV in An estimated 80% of sexually active women will be exposed to HPV in
their lifetimetheir lifetime HPV types 16 & 18 have been found in > 75% cases of cervical cancerHPV types 16 & 18 have been found in > 75% cases of cervical cancer HPV is casually related to:HPV is casually related to:
Benign conditions: genital warts, CIN1, RRP, Pre-malignant conditions: CIN2/3, CIS, VaIN, VIN, AIN, PIN Malignant conditions: cervix, vulva, vagina, penis, anus, tonsil and
oropharynx
benefits of the HPV vaccinebenefits of the HPV vaccine
Before cervical cancer occursBefore cervical cancer occurs
The vaccine can prevent high-grade cervical dysplasia (CIN 2/3)The vaccine can prevent high-grade cervical dysplasia (CIN 2/3)
The vaccine has demonstrated efficacy against low-grade cervical The vaccine has demonstrated efficacy against low-grade cervical
dysplasia (CIN 1)dysplasia (CIN 1)
Beyond the cervixBeyond the cervix
The vaccine can prevent vulval pre-cancers and reduces the The vaccine can prevent vulval pre-cancers and reduces the
incidence of vaginal pre-cancers compared with placebo (0 vs 5 incidence of vaginal pre-cancers compared with placebo (0 vs 5
women)women)
The vaccine can prevent external genital warts The vaccine can prevent external genital warts
SummarySummary
THANK YOUTHANK YOU