Cervical cancer screening module 1
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Transcript of Cervical cancer screening module 1
Cervical Cancer Screening Navigating the Jungle
Annekathryn Goodman, MD Division of Gynecologic Oncology Massachusetts General Hospital Harvard Medical School
Cervical Cancer Screening Module I
Background
Epidemiology
Preinvasive disease
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Cervical Cancer Screening Background
Cervical Cancer Statistics
Rationale for screening
The History of Screening
The Consequences of Over-screening
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Background Cervical Cancer Statistics 2012
In the United States 12,170 women diagnosed with invasive cervical cancer
In the United States, 4220 women died from cervical cancer
USA: 6TH MOST COMMON CANCER BLACK AND
LATINA WOMEN
USA: 13TH MOST COMMON CANCER WHITES
In contrast, cervical cancer is the third most common cancer with an estimated 530,000 new cases
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Cervical cancer Incidence among 6 Asian Ethnic
Groups in the United States 1996-2004 Cancer 2010; 116:949-956
Vietnamese women 18.9 /100,000
Korean women 11.9/100,00
Asian Indian/ Pakistani women 4.5/100000
SCC rates increase with age in Vietnamese, Korean, Filipina, and
Chinese women
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Background Cervical Cancer Statistics 2012
In contrast, cervical cancer is the third most common cancer with an estimated 530,000 new cases world - wide
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Cervical Cancer - Globocan 2008 Estimated numbers in
thousands CASES DEATHS
World 530 275
More developed regions 76 32
Less developed regions 453 242
Africa region 75 50
Americas region 80 36
Eastern Mediterranean 18 11
Europe 61 28
Western Pacific 105 46
South East Asia 188 102
USA 11 3
China 75 33
India 134 72
European Union 31 13 Module I
Background Rationale for Screening
Cervical cancer has a long preinvasive phase
There are effective and cheap screening tests for preinvasive and invasive cervical cancer
Cervical cancer can be prevented with adequate screening
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Estimated annual contributions to
squamous cervical cancer screening failures U.S.
% # women Never screened 50% 6,280
>5 yrs since screened 10% 1,260
False Negative Pap 30% 3,770
Errors in follow up 10% 1,260
Total 100% 12,560
Sawaya Obstet Gynecol
1999
660,000 women aged 25-29 are invited for screening in England.
2005-06, only 69.4 per cent did so, - 80 per cent in 1995.
A similar trend has been seen in women aged 30-34.
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The Papanicolaou Smear
Dramatically decreased cervical cancer mortality
Meta-analysis of 94 studies Sensitivity 30-87%
Specificity 86 – 100%
Obstet Gynecol 1995, 86:1017
Annals Intern Med 2000, 132:810
Risks Errors in sampling
Errors in transfer of cells
Errors in interpretation
Errors in evaluation of abnormal results
Background The History of Screening 1941 Introduction of Papanicolau Smear
Introduction of liquid based pap smear techniques (ThinPrep, SurePath)
1988 Bethesda System: standardization of terminology
2001 Revision of Bethesda System
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Background The History of Screening 2012 Lower Anogenital Squamous Terminology Project (LAST): changes in terminology for HPV associated lesions of lower genital tract
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Background The Consequences of Over-Screening
Treatment of lesions that have a high probability of spontaneous regression
Treatment of Teenagers
Long Term Changes to Cervix
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The Consequences of Over-Screening Treatment of lesions that have a high probability of
spontaneous regression
80 percent of low grade lesions will spontaneously regress
63 percent of CIN 2 lesions regress by three years
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The Consequences of Over-Screening Treatment of Teenagers
Scarring of cervix
Cervical stenosis
Shortening of cervix
Traumatic
Dyspareunia
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The Consequences of Over-Screening Long Term Changes to Cervix
Pain
Cervical Stenosis
Infertility
Cervical Incompetence during pregnancy
Inability to perform adequate screening
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The Consequences of Over-Screening Long Term Changes : CERVICAL STENOSIS
The Consequences of Over-Screening Long Term Changes: CERVICAL INCOMPETENCE
LEEP Procedure and Preterm Birth one LEEP: 7.2% preterm deliveries ((between28 and 37 weeks) No LEEP: 4.6% Two LEEPs: preterm risk increases 3x
Obstet Gynecol vol121:1063-1067, 2013
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Cervical Cancer Screening Epidemiology
Human Papillomavirus Infections
Risk factors for cervical cancer
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HPV DEFINITIONS
NON-ENVELOPED VIRUSES
DOUBLE STRANDED, CLOSED CIRCULAR
DNA GENOME - 8 KILOBASES
3 REGIONS TO GENOME
1- UPSTREAMN REGULATORY REGION - REGULATES TRANSCRIPTION AND REPLICATION
2- EARLY REGION: 6 OPEN READING FRAMES - E1, E2, E4, E5, E6, E7
3- LATE REGION: 2 ORFs - VIRAL STRUCTURAL PROTEINS L1, L2
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HPV SUBTYPES
- 45 mucosal/genital subtypes
- high risk : HPV - 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,59,66, 68
- low risk: HPV - 6, 11, 40, 42, 43, 44
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HPV : VIRAL LIFE CYCLE
INFECTION LIMITED TO EPITHELIAL CELLS
COMPLETION OF LIFE CYCLE REQUIRES
EPITHELIAL DIFFERENTIATION
STRATIFIED SQUAMOUS EPITHELIUM:
BASAL/PARBASAL, MIDZONE, SUPERFICIAL
HPV INFECTS BASAL CELLS
VIRAL SHEDDING FROM SUPERFICIAL LAYER
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VIRAL INDUCED ONCOGENESIS
VIRUS DOES NOT COMPLETE NORMAL LIFE CYCLE
INFECTION PERSISTS OVER TIME
E6/E7 MEDIATED DEGRADATION OF P53 & RB1
VIRAL DNA MAY INTEGRATE INTO HOST GENOME
INCREASED GENOMIC INSTABILITY
GAIN OF CHR 3q IN CX CA
METHYLATION OF HPV DNA
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% OF CANCERS
ATTRIBUTABLE TO HPV CANCER SITE % HPV
CERVIX 100
VAGINA 40
VULVA 40
PENIS 90
ANUS 90
ORAL CAVITY 25
OROPHARYNX 35
% HPV -16 & HPV-18
70
80
80
63
92
95
89
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Epidemiology Human Papillomavirus Infections
Almost all cases of cervical cancer are caused by Human Papillomavirus (HPV) infection
However most HPV infections resolve within a few months to years
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HUMAN
PAPILLOMAVIRUS TRANSMISSION
€ Sexual ( incubation period: 3 weeks to 8 months)
€ nonsexual (conjunctiva and nose)
€ vertical (mother - fetus)
€ laser plume
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Prevalence of High Risk HPV
0
5
10
15
20
25
15-19 20-24 25-29 30-34 35-39 40-44 45-49
Sellors JW CMAJ 2000;163(5) Module I
Epidemiology Risk factors for Cervical Cancer
Persistent high risk HPV infections is the main cause of cervical cancer
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RISK FACTORS - NEW PERSISTENT HIGH RISK HPV INFECTION
LACK OF PAP SMEAR SCREENING
OTHER UNKNOWN FACTORS
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http://jid.oxfordjournals.org/content/191/11/1808.full
EPIDEMIOLOGY OF HPV
PREVALENCE: 45 - 50%
LIFETIME RISK: 79 – 85% ?100%
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Estimated Annual Incidence of Select
HPV-Related Disease in the United States
Approximately
1 million new cases
of genital warts3
1.4 million new cases of
low-grade cervical dysplasia
(CIN 1)2
330,000 new cases of high-grade
cervical dysplasia (CIN 2/3)2
9730 new cases of cervical cancer1
1. American Cancer Society. Cancer Facts & Figures 2005. Atlanta, Ga: ACS; 2005:1−60. 2. Schiffman M, Solomon D. Arch Pathol Lab Med.
2003;127:946–949. 3. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Sex Transm Dis. 2001;28:643–647.
AGE SPECIFIC RATES OF HPV + HR WITH NORMAL
CYTOLOGY Bansal et al Gyn Onc 115:257; 2009
Age group Total # tested # positive for hr HPV
% positive
10-19 162 13 8
20-29 1137 92 8
30-39 6898 190 3
40-49 8137 135 1.6
50-59 7026 112 4
60-69 2584 39 1.5
70-79 522 10 2
>80 92 4 4
RISK FACTORS (OLD)
MULTIPLE SEXUAL PARTNERS
EARLY AGE OF FIRST INTERCOURSE
POVERTY
HORMONAL ENVIRONMENT (OCP USE?)
TOBACCO USE
IMMUNE SUPPRESSION
HIGH RISK MALE PARTNER
LACK OF PAP SMEAR
CERVIX GREATEST NEOPLASTIC DANGER
HORMONAL MILEAU?
MATURATION CHANGES (SQUAMOUS
METAPLASIA?)
TRAUMA?
COFACTORS?
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Cervical Cancer Screening Preinvasive Disease
Terminology
Review of Lower Genital Tract Anatomy
Natural History
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Preinvasive Disease Terminology
Preinvasive disease is defined as atypical or neoplastic changes
Old terminology : dysplasia
Current Terminology: Intraepithelial neoplasia
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Preinvasive Disease Terminology (see also Module II)
dysplasia Intraepithelial neoplasia
definitions Terminology by area of lower gential tract
mild I Lower 1/3 of epithelium is dysplastic
CIN: cervical intraepithelial neoplasia
moderate II Lower 2/3 is dysplastic
VAIN: vaginal
severe III Full thickness dysplasitc change
VIN: vulvar
Carcinoma in situ CIS Full thickness dysplastic change
AIN: anal
PIN: penile
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Preinvasive Disease Review of Lower Genital tract Anatomy Stratified squamous epithelium lines the vagina and exocervix
The endocervix is lined by columnar glandular epithelium
The boundary between the squamous and columnar epithelium is called the squamocolumnar junction. (SCJ)
The SCJ migrates from far out on the exocervix to the endocervical canal over a woman’s lifetime.
The boundary between the old SCJ and the current SCJ is called the transition zone
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Preinvasive Disease Review of Lower Genital Tract Anatomy
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Preinvasive Disease Natural History
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HPV(HIGH RISK) NATURAL HISTORY
3-8 MONTH INCUBATION PERIOD
80% CLEARED IN 12 MONTHS
95% CLEARED BY THREE YEARS
LESS THAN 1% OF ALL HPV HIGH RISK
INFECTIONS LEAD TO INVASIVE
CANCER
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Wright and Schiffman (2003) NEJM
Natural History of HPV Infections
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Natural History of HPV in
Young Women RESULTS
• cumulative risk of HPV was 44%
• HPV 16 most common subtype
• 28/2011 developed HSIL
greatest risk for HSIL was 6-12 months after detection
of HPV 16
(Lancet 2001; 357:1831)
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CERVICAL CANCER SCREENING
MODULE I CONCLUSIONS
-Cervical cancer risk varies around the world. There are disparities in risk within the United States.
-HPV infection is associated with all cervical neoplasia and the majority of lower genital tract neoplasia.
-The natural history of most HPV infections: resolution within three years.