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

Module I

Cervical Cancer Screening Background

Cervical Cancer Statistics

Rationale for screening

The History of Screening

The Consequences of Over-screening

Module I

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

Module I

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

Module I

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

Module I

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.

Module I

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

Module I

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

Module I

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

Module I

Cervical Cancer Screening Epidemiology

Human Papillomavirus Infections

Risk factors for cervical cancer

Module I

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

Module I

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

Module I

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

Module I

% 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?

Module I

Cervical Cancer Screening Preinvasive Disease

Terminology

Review of Lower Genital Tract Anatomy

Natural History

Module I

Preinvasive Disease Terminology

Preinvasive disease is defined as atypical or neoplastic changes

Old terminology : dysplasia

Current Terminology: Intraepithelial neoplasia

Module II

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

Module I

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

Module I

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)

Module I

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.