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

Module I

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

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.
%
Never screened
>5 yrs since screened
False Negative Pap
Errors in follow up
Total

50%
10%
30%
10%

# women
6,280
1,260
3,770
1,260
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
Module I

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

Module I

The Consequences of Over-Screening

Treatment of Teenagers
Scarring of cervix

Cervical stenosis
Shortening of cervix

Traumatic
Dyspareunia
Module I

The Consequences of Over-Screening

Long Term Changes to Cervix

Pain

Cervical Stenosis
Infertility

Cervical Incompetence during pregnancy

Inability to perform adequate screening
Module I

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

Module I

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

% HPV -16 & HPV-18

CERVIX

100

70

VAGINA

40

80

VULVA

40

80

PENIS

90

63

ANUS

90

92

ORAL CAVITY 25

95

OROPHARYNX 35

89
Module I

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

Module I

HUMAN
PAPILLOMAVIRUS
TRANSMISSION

Sexual ( incubation period: 3 weeks

to 8 months)
nonsexual (conjunctiva and nose)
vertical (mother - fetus)
laser plume
Module I

Prevalence of High Risk HPV

25
20
15
10
5
0

15-19

20-24

25-29

30-34

Sellors JW CMAJ 2000;163(5)

35-39

40-44

45-49

Module I

Epidemiology
Risk factors for Cervical Cancer
Persistent high risk HPV infections is the
main cause of cervical cancer

Module I

RISK FACTORS - NEW

PERSISTENT HIGH RISK HPV INFECTION
LACK OF PAP SMEAR SCREENING
OTHER UNKNOWN FACTORS
http://jid.oxfordjournals.org/content/191/11/1808.
full

Module I

EPIDEMIOLOGY OF HPV
PREVALENCE:

45 - 50%

LIFETIME RISK:

79 85%

?100%

Module I

Estimated Annual Incidence of Select

HPV-Related Disease in the United States
9730 new cases of cervical cancer1

330,000 new cases of high-grade

cervical dysplasia (CIN 2/3)2

1.4 million new cases of

low-grade cervical dysplasia
(CIN 1)2

Approximately
1 million new cases
of genital warts3
1. American Cancer Society. Cancer Facts & Figures 2005. Atlanta, Ga: ACS; 2005:160. 2. Schiffman M, Solomon D. Arch Pathol Lab Med.
2003;127:946949. 3. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Sex Transm Dis. 2001;28:643647.

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

20-29

1137

92

30-39

6898

190

40-49

8137

135

1.6

50-59

7026

112

60-69

2584

39

1.5

70-79

522

10

>80

92

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

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

Full thickness
dysplastic change

AIN: anal

Carcinoma in situ CIS

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 womans 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

Module I

Preinvasive Disease
Natural History

Module I

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
Module I

Natural History of HPV Infections

Wright and Schiffman (2003) NEJM

Module I

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.