Transcript The Impact Of Screening Of Cancer Cervix On Women’s Health

Cervical Cancer Screening…
An Overview
AMR NADIM, MD
Professor of Obstetrics & Gynecology
Ain Shams Faculty Of Medicine
Cervical Carcinoma
Second in frequency among women cancers.
It is still the most frequent cancer in the developing
countries.
400,000 new cases identified each year
80% of new cases in developing countries
At least 200,000 women die each year
Screening programs reduced the mortality from
cancer cervix in developed countries by 70%.
Incidence And Mortality For Cervical
Cancer Vs Breast Cancer, [United States, 2000]
192,000
200,000
150,000
100,000
40,200
50,000
12,900
4,400
0
Breast
Cervical
New Cases Per Year
Source: American Cancer Society, 2000
Breast
Cervical
Deaths Per Year
HPV infection
Condyloma Accuminata
Exophytic
Frond like surface
Lesion may be single or multiple
Located within or outside the transformation zone
HPV infection
Subclinical HPV
Flat lesions undetectable naked eye
Best assessed after acetic acid application
Shinny, snow-white lesions
Irregular outline
Satellite lesions beyond the transformation zone
Strong or partial uptake of Lugol’s iodine
What Makes the Cervix Vulnerable?
The HPV-cervical cancer link
Human papillomavirus (HPV) is a very
common infection (more than 50% of adults get it,
in most it is a transitory infection).
99.7% of cervical cancer cases are
associated with HPV.
Progression from HPV infection to cancer
usually takes 20-30 years.
E6
E7
P53
RTS
Immortality
Global distribution of HPV types in
cervical cancer
14%
3%
6%
53%
9%
15%
HPV 16
HPV 18
HPV 45
HPV 31
HPV 33
HPV others
Natural History Of Cervical Cancer
HPV
Infection
years
57%
11%
LSIL
HSIL
Invasive
Cancer
35%
1%
Source: PATH, 2001
>10%
Screening…?
Organized identification
High coverage of a target population
Continuous quality assessment.
Feasibility of treatment & follow up
Of a pre - clinical disease state by a test
that is repeated at a given interval
To screen or To screen not ?
Recommended Screening
Cervical Carcinoma
Breast Carcinoma
Colorectal Carcinoma
Not yet , for…
Ovarian Cancer
Bronchogenic
Carcinoma
Skin cancer
Oral Cancer
Prostate Cancer
Cervical Cancer Screening by The Pap
Smear Is one of the very few cost
effective interventions to prevent cancer.
Pre - requisites For Successful Screening
After Wilson and Jugner (1968):
The condition should be an important health problem.
There should be an accepted treatment .
Facilities for treatment and diagnosis should be available.
There should be a recognizable latent or early
symptomatic stage.
There should be a suitable method of examination.
The test should be acceptable to the population.
The natural history of the disease should be adequately
understood
Pre - requisites, cont....
There should be an agreed policy on whom to treat
as patients.
The cost should be economically balanced with the
expenditure of medical care as a whole.
Case finding should be a continuing process.
They apply reasonably well for screening of
Cervical Carcinoma
Effective Screening Program
Should be tailored to suit the principles for national
cancer control programs. We Should NOT copy
other’s programs...
Otherwise
Too much money & effort will be spent with
minimal impact on the incidence & mortality from
the disease.
Cancer Cervix : A Screenable Preventable
Disease
Cancer cervix still represents a problem in the
developing counties: Less than 5% of the
population is screened.
Its natural history is well-known.
Definitive pre-cancerous lesions are identified
and treatment will eradicate the disease.
Screening tools available for more than 60 years
and are subjected to continuous innovations to
increase specificity and sensitivity
Cervical Cancer Is Preventable
Primary prevention
Education to reduce high-risk sexual behavior
Risk assessment
Secondary prevention
Identify and treat precancerous lesions before
they progress to cervical cancer
Incidence and mortality for cervical cancer,
United States, 1973–1997 (SEER)
Number per 100,000 Women
35
30
25
20
15
Incidence
10
Mortality
5
0
'73 '74 '75 '76 '77 '78 '79 '80 '81 '82 '84 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97
Year
Rate is age-adjusted to 1970 U.S. population
Source: Cancer Statistics Review, 1973–1997
Screening Tools for Cancer Cervix
Molecular Biology
Methods
Cytological Methods
•Traditional Pap smear
•Thin layer prep
HPV-DNA genotyping
Visual Inspection Methods
•Unaided Naked Eye visualization
•Acetic Acid enhanced Naked eye Visualization
•Cervicography
•Colposcopy
The Papanicolaou Test
Nicknamed …
Pap Smear
Cytopathology:
Cytopathology is diagnosis of disease in cells.
Exfoliative & Non-Exfoliative - cytology.
Exfoliative: Cell samples are collected from
normally shedding tissues like epithelium. spatula
or brush to enhances collection.
Non-Exfoliative: Cells samples collected by
needles with suction pressure. (FNAC)
Cytology specimen is fixed, stained and
studied under microscope.
What is a Pap Smear?
Screening test for cervical cancer. It is a type
of exfoliative cytology test.
Simple, safe, non-invasive method
Developed by “George Papanicolaou”
Exfoliated cells from cervix are collected
usually enhanced by using a variety of
spatulas or brushes.
The specimen is processed and studied for
morphology.
Who should have PAP test..
Every woman should have an annual Pap
examination when she becomes sexually
active or turns 18 years old [ whichever
comes first].
Defining the target population is important
in any screening program.
What is the best time for PAP:
The best time for a Pap examination is
during the two weeks following the end of
menstrual flow. (Proliferative phase).
Why…?
If menopause, Pap examination can be
scheduled anytime
Take Care...
Use a good sampling device
Do Not use Lubricants while taking the smear.
Do Not be too slow in plating the slide
Sample the endocervical canal and the whole
transformation zone .
Do Not insert the sampling device too deep in
the endocervical canal:
This invites bleeding
It might draw cells different to interpret.
Who are at increased risk of Cervical
Cancer?
Any woman can develop cancer cervix.
Multiple sex partners or a partner who has
had multiple female partners.
Have had genital warts.
Sexual relations before the age of 18.
Previous abnormal pap examination.
Rare in virgins and with use of condoms.
The Target Population
What should happen…
From onset of sexual
activity and throughout
life.
Covering all social
classes.
Covering urban and rural
sectors.
What should be avoided
…
Limiting screening to the
CBP
Limiting screening to a
particular social class or a
particular sector.
It is estimated that less than 5 % of women in the
developing countries are screened. These are essentially
women under 35.
In the States: Unequal Burden of Disease
Never Screened
50
40
Some Screening in the
Last Five Years
Rarely Screened
10
Cervical Cancer Burden
Source: Shingleton et al., 1995(more than 50% of the cases)
IN EGYPT...
Only sporadic attempts of screening.
No nation-wide program
Primary health care providers…?
Lack of screening of the older women : the
priority target group.
Lack of appreciation by the women of the
relevance of the disease
Lack of availability of health care in the rural
areas.
Fatalism
‫الخـــوف من المجـــــهــــول‬
Characteristics of women never or
rarely screened for cervical cancer
Older
Low SES and/or lack of insurance or ability
to pay for screening
Less educated
No regular health care provider
Live in culturally-isolated urban
neighborhoods or hard-to-reach rural areas
Pathology of Cervix:
the uterine cervix is continually being
bombarded by a variety of stress including
mechanical, microbiologic, chemical, and
hormonal insults.
The cervix responds by
Acute or chronic inflammatory reactions
Adaptive proliferative responses like
Hyperplasia, Metaplasia & Dysplasia.
Anaplasia - Benign & Malignant tumors.
Normal Cervix:
Carcinoma Cervix:
Normal Cervix :
SUPER F
INTERM
BASAL
Chronic Cervicitis:
PAP Smear Normal:
Pathogenesis: (non-neoplastic)
1.
2.
3.
4.
Chronic cervicitis
Hyperplasia – Number
Metaplasia – Change to squamous
Dysplasia – no-maturation, disorder
(CIN 1-3, CIS)
Pathogenesis: (Neoplastic)
Malignant (Cervical Cancer)
Invasion & Spreading.
Pap Smear Results:
Existing Screening Guidelines
WHO (1992): Annual Pap tests are often
unnecessary—“it is clear that it is more costeffective to recruit a high proportion of the
population and screen them infrequently,
than to recruit a low proportion and screen
them often.”
Existing Screening Guidelines
(continued)
USPSTF (1996): “There is little evidence
that women who receive annual screening
are at significantly lower risk for invasive
cervical cancer than are women who are
tested every 3–5 years.”
Existing Screening Guidelines
(continued)
ACPM (1996): “Estimates from
mathematical models indicate that regular
triennial screening would achieve 91-96%
of the benefit of annual screening, while
greatly reducing the cost, potential harms,
and inconvenience.”
Existing Screening Guidelines
(continued)
ACOG (2000): “After a woman has had three or more
consecutive, satisfactory, annual cytological
examinations with normal findings, the Pap test may be
performed less frequently on a low-risk woman at the
discretion of her physician.”
ACS (2001): “After three or more consecutive annual
exams with normal findings, the Pap test may be
performed less frequently at the discretion of the
physician.”
The Screening Interval…A Controversy
A negative smear ensures a protective effect of 93%
if repeated yearly and 91 % if repeated at 3 years
interval.
At 10 years interval the protective effect drops
to 64 % …still a 2/3 reduction of the risk.
Screening Interval…Our Policy
Annual Screening of ladies is advocated, we think it
is a way of establishing a multiplicative correction
effect by which the 20% false negative screening
results may be reduced down to 1 % .
“Unsatisfactory smears” are repeated the following
cycle.
“Satisfactory smears but limited by….” are repeated
as soon as the condition is corrected.
If laser or conization were made, the smear is
repeated after 3 months.
Pap Test as a Screening Tool
Sensitivity
Moderate: 51–88%
Specificity
High: 95–98%
Source: Meyers et al., 2000
Brown and Garber, 1999
Given the sensitivity and
specificity of the Pap test,
“...the major barrier to
prevention of cervical
cancer is not the accuracy
of the Pap test, but the
failure to be screened at
all.”
The Fluid - Based Technology
The Thin - Prep
The sample is put into a liquid medium “collection
vial” which is sent to the lab where it is processed
as a thin layer slide.
There is no more:
Air drying artifacts.
Dirty backgrounds.
Spreading errors
Cells left entangled in the sampling device.
The Thin - Prep, cont...
All the cells are examined
Cells are more evenly distributed.
HPV typing & semi quantitative assays .
The Sensitivity & Specificity are increased:
- More detection of SIL, less incidence of
“satisfactory but limited.”
- Eliminating many ASCUS
What We Know About Liquidbased Testing Technologies
More sensitive, but not more specific, than
conventional Pap tests (Austin, 1998)
ACOG did not recommend routine use in
1998:
Cost too high
Insufficient data demonstrating reduction of
disease incidence or cancer survival
Currently silent on the issue
The French Society of Clinical Cytology
Study Group
recently compared the sensitivity, specificity, and
interobserver reliability of conventional Pap tests,
monolayer cytology, and HPV testing in a setting
with "complete independence from the
suppliers."
What the researchers discovered was that results with
the conventional Pap smear
were more often satisfactory according to the Bethesda
system,
more reliable, and
had consistently better sensitivity and specificity than
monolayer cytology.
Coste J, et al; French Society of Clinical Cytology Study Group. 2003
HPV/DNA Testing
Atypical LSIL Triage Study Trials
No benefit for women with LSIL results
Probable benefit for women with ASCUS
results
An Ideal Reporting System…
High degree of sensitivity and specificity.
Reproducible.
Uniform format and standardized nomenclature.
Therapeutic implications are drawn from
diagnostic nomenclature.
Emphasizes that the pap test is a a request for
a medical consultation between the
gynecologist and the cytopathologist.
And So Was Introduced
The Bethesda System…
First issued following a NCI workshop in
1989.
Revised in 1991 and 1993.
Latest revision in October 2001.
The Bethesda System
Confounding terminologies were omitted,
e.g. Smears with evidence of repair or
inflammations are reported as being
“within normal limits”.
The Pap smear is redefined as a medical
consultation
The physician provides
the history
The cytologist provides the diagnosis
And make recommendations regarding follow up
Smear Adequacy
Well preserved
Endovervical cells
present
Satisfactory But limited
by:
Scant cellularity
Obscured by blood or
discharge.
Poor preservation
No sufficient clinical data.
Unsatisfactory for Diagnosis
Poor preparation.
Obscured by blood or inflammation or
discharge.
Scanty cellularity.
Unlabeled slides
Negative for Intraepithelial Lesion
OR Malignancy
Reactive changes associated
with:
Inflammation
Radiation
IUD
Organisms:
Fungal
Bacterial
Protozoal
HSV
Atrophy
Glandular status post
Hysterectomy
Epithelial Cell Abnormalities
Squamous cells
Glandular cells
Atypical GUS
Atypical squamous cells
Of undetermined
significance: ASC-US
Can not exclude HSIL:
ASC-H
LSIL
HSIL
Squamous cell carcinoma
Endocervical
Endometrial
Other
Atypical
Endocervical cells, favor
neoplastic
Glandular cells, favor
neoplastic
Endocervical Adenocarc. In
situ
Adenocarcinoma
ASC-US
Nuclear enlargement
2-3 X.
Variation in size and
shape.
Mild Hyperchromasia.
Limited irregularity.
ASCUS-H
Favoring a SIL:
Hyperchromasia
Nuclear irregularities
Marked pleomorphism
Several clusters
involved
LSIL
Nuclear enlargement
X3.
Hyperchromasia.
Optically clear
cytoplamic halo.
Nuclear irregularities.
HSIL
Marked increase in
the N/C ratio.
Hyperchromasia.
Irregular nuclear
outine.
The Bethesda System, TBS
Making a uniform Terminology.
Eliminating the Papanicolaou classes.
Including statement on the adequacy of the
specimen.
To highlight that cytological examination is a
medical consultation between clinician and
cytologist
To provide a frame work dealing with
reparative atypia
“Satisfactory for Evaluation ,
But Limited By…”
Lack of clinical Information.
Lack of endocervical component.
Partially obscured by blood or
inflammatory background : 50-75% of
the slide.
ASCUS
X1000
HSIL X400
LSIL
Koilocytes
LSIL
LSIL
Mild dysplasia+ HPV
HSIL
Perinuclear cytoplasm clearing
ASCUS-H
LSIL
HSIL
HSIL X1000
Chlamydia inclusion
body
Quality Control & Computer
Assisted Rescreening Strategies
Random rescreening by senior cytologists of slides
that were originally classified as negative.
Directed rescreening for slides of known patients
at risk.
The auto Pap 300 QC system
The Pap Net system
End Of The
First Part
Visualizing the Cervix
Unaided Naked eye examination
Acetic acid-enhanced Naked eye
examination (VIA)
Cervicography
Colposcopy
Potential Alternatives to Pap Smears:
Applicability in Low-Resource Settings
1
•Visual Inspection
Yes
Yes
Yes
Yes
Yes
•Automated Pap Smear
Yes
Yes
No
No
No
•HPV/DNA Test
Yes
Yes
No
No
No
•Cervicography
Yes
Yes
No
No
No
•Polar Probe/ Spectroscopic
Yes
Yes
No
No
No
Visual inspection of the cervix using acetic acid (VIA) and with magnification (VIAM).
Source: PATH 1997.
Acetic Acid –enhanced
Visual Inspection of the Cervix “VIA”
1. Acetic acid coagulates mucus, which becomes easier to
remove.
-allows a better view of the cervix
2. Acetic acid constricts the superficial vessels and blows up
the columnar papillae so that they become pale.
allows a better view of the squamocolumnar junction
3. Acetic acid causes dehydration of the cells and coagulation
of cellular proteins, thereby reducing the transparency of
the epithelium
allows a better recognition of dysplastic epithelium
Abnormalities Seen After Acetic
Acid
Aceto-white
Margins and surface
White gland openings
Mosaic & punctation
Abnormal vessels
What May Be Acetowhite
NOT All acetowhite lesions are cancer
Any of these epithelial changes can become
acetowhite
Healing or regenerating epithelium
Congenital transformation zone
Inflammation
Immature squamous metaplasia
HPV infection
SIL
Adenocarcinoma
Invasive squamous cell carcinoma
VIA: Conclusions
Alternative to cytology or HPV testing
Effective in identifying precancerous disease
Identify cancers
Effective in ruling out disease
Specificity of VIA is likely to depend on:
training intervention
presence of STDs in population screened
importance placed on picking up diseased cases
Positive predictive value of VIA can be increased
through sequential or risk-based triage screening
The Alternative…Downstaging !!!
The detection of the disease at an
earlier stage when still curable…
Just
Insert a speculum and look at the
cervix
Warning signs of early cervical
cancer
1. Yellowish and friable epithelium
2. Abnormal contour
3. Ulceration
4. Atypical vessels
5. Very severe colposcopic atypia
6. Large, significant lesion
7. Canal lesion, going out of range
8. Perimenopausal and post radiation
Mimics of cervical cancer
1. Severe cervicitis e.g., herpes, syphilis
2. Benign ulceration e.g., trauma
3. Foreign body reaction
4. Granulomatous cervical conditions
5. Granuloma inguinale
6. Lymphogranuloma venereum
7. Schistosomiasis
8. Cervical condylomata
Cololposcopy aids differentiation.
Histology is the gold standard
What May Be Acetowhite
NOT All acetowhite lesions are cancer
Any of these epithelial changes can become
acetowhite
Healing or regenerating epithelium
Congenital transformation zone
Inflammation
Immature squamous metaplasia
HPV infection
SIL
Adenocarcinoma
Invasive squamous cell carcinoma
Visualizing the Cervix
Unaided Naked eye examination
Acetic acid-enhanced Naked eye examination (VIA)
Visual Inspection with Lugol’s Iodine (VILI)
Cervicography
Colposcopy
Potential Alternatives to Pap Smears:
Applicability in Low-Resource Settings
1
•Visual Inspection
Yes
Yes
Yes
Yes
Yes
•Automated Pap Smear
Yes
Yes
No
No
No
•HPV/DNA Test
Yes
Yes
No
No
No
•Cervicography
Yes
Yes
No
No
No
•Polar Probe/ Spectroscopic
Yes
Yes
No
No
No
Visual inspection of the cervix using acetic acid (VIA) and with magnification (VIAM).
Source: PATH 1997.
Acetic Acid –enhanced
Visual Inspection of the Cervix “VIA”
1. Acetic acid coagulates mucus, which becomes easier to
remove.
-allows a better view of the cervix
2. Acetic acid constricts the superficial vessels and blows up
the columnar papillae so that they become pale.
allows a better view of the squamocolumnar junction
3. Acetic acid causes dehydration of the cells and coagulation
of cellular proteins, thereby reducing the transparency of
the epithelium
allows a better recognition of dysplastic epithelium
Abnormalities Seen After Acetic
Acid
Aceto-white
Margins and surface
White gland openings
Mosaic & punctation
Abnormal vessels
What May Be Acetowhite
NOT All acetowhite lesions are cancer
Any of these epithelial changes can become
acetowhite
Healing or regenerating epithelium
Congenital transformation zone
Inflammation
Immature squamous metaplasia
HPV infection
SIL
Adenocarcinoma
Invasive squamous cell carcinoma
Colposcopy
Visual inspection of
the cervix through a
set of magnifying
lenses after adding
acetic acid and
Lugol’s iodine
Indications
Grossly visible or palpable abnormality of the cervix ??
Abnormal cervical cytology
Positive screening test for cervical neoplasia such as
spectroscopy, cervicography, speculoscopy
Cervical cytology unsatisfactory due to unexplained
inflammation
History of in-utero diethylstilbestrol (DES) exposure
Unexplained cervico-vaginal discharge
Unexplained abnormal lower genital tract bleeding
History of lower genital tract neoplasia (cervical, vaginal,
vulvar)
Post-treatment surveillance
Colposcopic signs.
Diagnostic between non significant TZ(NS) and
highly significant (HS)
NS
-Acetic acid
-Limits
-Perilesional reaction
-Situation
not visible
precise
absent
generally near ectopy
HS
visible
imprecise
present
rarely associated to
ectopy
-Surface
flat
coarse
-Epithelial trauma
no ulcerations
erosions, ulcerations
-Visual density
stronger in periphery stronger near SCJ
-Vascularization
normal vessels
atypical vessels
-Glandular openings absent
present and often
Keratinized
A Lesion = A Biopsy
Modified Reid Colposcopic Scoring
-2
0
1
2
3
Topography
Away
ext.os
Reaches
ext.os
Endocerv.
But
accessible
Endocx. Not
accessible
Aceto-whiteness
-Chronology
-Aspect
None
or
trans.
Precoc. &
prolonged
Weak
Late &
Lasting
Shining
/transparent
Precocious
& Lasting
Dull and
opaque
Limits
Well
Flou
defined
Elevated
Edematous
& vasculari.
Vascular Pattern
Not
fragile
Iodine
+ve
-ve
Fragile
Benign Lesions
Pitfalls of Colposcopy
False SCJ caused by abrasion.
The SCJ is identified by being the lower limit of
the columnar epithelium and not the upper limit of
the squamous epithelium.
The SCJ up in the canal.
The Previously Treated Cervix.
Glandular Lesions.
Missing Vaginal lesions.
Atypical transformation zone
1. Acetowhite epithelium
2. Vascular structure
a. Mosaic pattern
b. Punctation
c. Abnormal vessels
3. Leukoplakia
Acetowhiteness
1. SIL
…dehydration of nuclear dense lesion
2. HPV
…keratin swelling in HPV infected cells
3. Immature squamous metaplasia
4. Healing/regenerating epithelium
5. Congenital transformation zone
6. Inflammation
7. Adednocarcinomas
Invasive squamous carcinoma
Vascular structure
Mosaic pattern (cobblestone-like
appearance).
thick whitish areas of small fields
polygonal or oval in shape
surrounded by reddish borders (fine blood vessels)
iodine negative
Vascular structure
Punctation
… a series of fine red dots on a whitish
background.
Punctate vessels
… dilated, elongated, often slightly twisted and
irregular terminal vessels of the hairpin type.
Cervicography: This is NOT Colposcopy
High-quality colposcopic-type photography of the
cervix
Cervicoscope
- Hand-held camera with a macrolens and a ring-flash
Cervicogram
- 35-mm photo slide is taken
Principles
Recognition of lesions by means suitable
magnification and illumination
Fix up the problems of colposcopy
1. a less expensive form
2. noninvasive method
3. do not require expert skill
Procedures of cervicography
A) Taking a 35-mm cervicogram
(1) Insert speculum and open as wide as possible
… expose an entire cervix and upper vagina
(2) Apply first application of 5% acetic acid by dabbing
… cleanse the cervix of blood and mucus
(3) View the cervix through the cervicoscope
… allows time to begin taking epithelial change
(4) Apply second application of acetic acid.
(5) Take two cervicogram pictures
B) Developing the images
C) Interpreting a magnified image that was projected on the screen
(1) Negative if no definitive lesions are visible
(2) Atypical if there was evidence of acetowhite lesion of doubtful
significance
(3) Positive if there was evidence of a minor or major-grade lesion or
cancer
Why is cervicography needed?
1.Screening
- the pap smear alone is not sensitive enough
- broadened cytology criteria decreases specificity
- triage of increased numbers of atypical smears
2.Documentation
- Evaluation and follow-up
- Research
- Teaching
Multimodal Spectroscopy
Recent FIGO Recommendations For the Management of
Abnormal Smear
( Benedet,2000)
Persistent inflam., persistent ASCUS, LSIL, HSIL, AGCUS,Invasive
Colposcopy ± Biopsy
Normal or LSIL
LLETZ
6 mo smear x 2
TT
Normal
Annual screening
HSIL
Persistent
Invasive
Appropriate
LLETZ
Large Loop Excision of the Transformation Zone
Coming to an end…
Cervical cancer is a preventable disease.
It is even curable if caught at an early stage.
Cervical screening is one of the most successful
public health measures ever introduced for the
prevention of cancer.
Successful screening strategy should be
coupled with an effective treating policy to
eradicate pre-malignant lesions
Still, many of the world's, most vulnerable
women are not being screened.
It is the implementation of comprehensive,
organized, and quality cervical screening
programs that demand our energies and
attention as health professionals,
policymakers, governments, and citizens.