Cervical Cancer Screening Module 1 - from Massachusetts Medical Society. Copyright © 2013. Massachusetts Medical Society, 860 Winter Street, Waltham Woods Corporate Center, Waltham, MA 02451-1411

1. Cervical Cancer Screening
Navigating the Jungle
Annekathryn Goodman, MD
Division of Gynecologic Oncology
Massachusetts General Hospital
Harvard Medical School

2. Cervical Cancer Screening
Module I
Background
Epidemiology
Preinvasive disease
Module I

3. Cervical Cancer Screening
Background
Cervical Cancer Statistics
Rationale for screening
The History of Screening
The Consequences of Over-screening
Module I

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. The Consequences of Over-Screening
Treatment of Teenagers
Scarring of cervix
Cervical stenosis
Shortening of cervix
Traumatic
Dyspareunia
Module I

16. 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

17. The Consequences of Over-Screening
Long Term Changes : CERVICAL STENOSIS

18. 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

19. Cervical Cancer Screening
Epidemiology
Human Papillomavirus Infections
Risk factors for cervical cancer
Module I

20. 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

21. 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

22. 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

23. 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

24. % 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

25. 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

26. HUMAN
PAPILLOMAVIRUS
TRANSMISSION
€ Sexual ( incubation period: 3 weeks
to 8 months)
€ nonsexual (conjunctiva and nose)
€ vertical (mother - fetus)
€ laser plume
Module I

27. 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

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

29. 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

30. EPIDEMIOLOGY OF HPV
PREVALENCE:
45 - 50%
LIFETIME RISK:
79 – 85%
?100%
Module I

31. 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; 2005:1−60. 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.

32. 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

33. 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

34. CERVIX
GREATEST NEOPLASTIC DANGER
HORMONAL MILEAU?
MATURATION CHANGES (SQUAMOUS
METAPLASIA?)
TRAUMA?
COFACTORS?
Module I

35. Cervical Cancer Screening
Preinvasive Disease
Terminology
Review of Lower Genital Tract Anatomy
Natural History
Module I

36. Preinvasive Disease
Terminology
Preinvasive disease is defined as atypical
or neoplastic changes
Old terminology : dysplasia
Current Terminology: Intraepithelial
neoplasia
Module II

37. 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
Full thickness
dysplastic change
AIN: anal
Carcinoma in situ CIS
PIN: penile
Module I

39. 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

40. Preinvasive Disease
Review of Lower Genital Tract Anatomy
Module I

41. Preinvasive Disease
Natural History
Module I

42. 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

43. Natural History of HPV Infections
Wright and Schiffman (2003) NEJM
Module I

44. 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

45. 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.