Download Cervical Cancer Screening

CERVICAL CANCER SCREENING
Caroline Kim, M.D., M.P.H.
WEEK 8: 02/21 – 02/25/05
Learning Objectives:
1. Understand the limitations of screening tests for cervical cancer
2. Be able to identify patients at high risk for cervical cancer so that they can be
screened appropriately
3. Be familiar with the Bethesda System for reading Pap smears
Author’s Note:
Before we get started, keep in mind that no module on cancer screening would be
complete without a discussion of the ideal tools for cancer screening and the ideal cancers
for which we should screen. From Wagner JL. Cost-effectiveness of screening for
common cancers. Cancer and Metastasis Reviews. 1997; 16:281-294, please take a
moment to review Table 1, which has been adapted here.
Table 1: Considerations in Constructing a Cancer Screening Model
Natural history:
-age/stage specific distribution of pre-clinical/precancerous dwelling times
-spontaneous regression probabilities of early or precancerous lesions
-age/stage specific mortality rates from cancer and from all other causes
-age/stage specific quality of life measures
Screening test:
False negative and false positive rates
Positive and negative predictive value (probability that a positive test leads to a diagnosis of
cancer or that a negative test is normal)
Follow-up/surveillance test performance:
Sensitivity and specificity of confirmatory tests
Sensitivity and specificity of periodic surveillance of those identified with early cancer
Effectiveness of early intervention
Medical risks of screening/early intervention
Cost of screening and of diagnostic follow-up of positive screening tests
CASE ONE:
After finishing a three-year stint in a punishing but highly rewarding internal medicine
residency program, you hang your shingle. Among the many projects upon which you
now embark is the selection of equipment for your office.
Questions:
1. What are your options for sampling tools and for specimen collections for Pap
smears? Why is it important to select carefully?
Cervical cancer was once a leading cause of cancer death in this country but because of
cytologic screening and surveillance, cervical cancer is uncommon. Still, there are five
cases per 100,000 women in a disease that is largely curable, so you will want to be
careful in choosing your strategies for testing.
The Papanicolaou smear is the screening test of choice for lower female genital tract
neoplasia. This test relies upon sampling of exfoliated cells from the vagina, cervix, and
upper genital tract, and, in some cases, the peritoneal cavity. In normal hosts, stratified
squamous epithelium lines the vagina and cervix while the endocervix and endometrium
are lined with simple columnar (glandular) epithelium. The transformation zone is an
area of squamous metaplasia between these two types of epithelium. Abnormalities are
detected based upon histologic cell alteration, inflammation, and infection or
colonization with infectious agents.
Depending upon the study that you read, the sensitivity of a Pap smear can be as low as
51%, while specificity is 98%. Considering that you test patients yearly, a negative result
in a very high-risk patient may or may not be reassuring, depending upon how you
crunch those sensitivity/specificity numbers. Also keep in mind that there are many
variables in the proper interpretation of a Pap smear (the patient examiner, the
collecting devices, and the cytologist, among others) and that these variables will affect
your results. In fact, 67% of false negatives in one study were due to the poor quality of
the slides and improper sampling techniques, leading to inadequately preserved cells and
obscuring of the cells by mucus or blood. Clearly, anything that you can do to reduce
error will be helpful.
The following sampling devices are available currently:
a. The Ayre spatula is familiar to all of us but is likely the least effective device for
specimen collection. The plastic spatula is preferable because the wooden
spatula transfers only 20% of the exfoliated cells to the collection medium.
b. Saline-moistened cotton-tipped applicators work better and may be useful for the
pregnant patient whose cervix is vascular and likely to bleed.
c. The broom was created to replace both the cytobrush and the spatula but its
endocervical component is still inadequate.
d. The endocervical brush and broom together is the most effective combination for
non-pregnant women. Despite this, there is still a low transfer to glass-slide rate.
The following preserving devices are available currently:
a. Glass slides that are treated with fixative after sampling and delivered to the
laboratory in cardboard slide holders.
b. Liquid elution of exfoliated cells suspended in a methanol-fixative solution
(ThinPrep). The automated processor separates mucus and debris from the cell
and then filter-collects intact epithelial cells and transfers them to a slide. One
large validated cohort trial looked at the ThinPrep device and found that it was
more sensitive at detecting cervical cancer and significantly more sensitive at
detecting HSIL and CIN compared to more traditional techniques (92.9% and
100% vs. 77.8% and 90% conventional device). Specificity was 85% in this same
study. The other convenience is the ability to perform reflex HPV testing in the
case of an abnormal Pap smear. However, the ThinPrep specifically was found
to be cost effective only if the interval between testing was three years or more.
Reflex HPV testing. The sensitivity/specificity for HSIL is 82%/78% respectively
and for LSIL is 66%/91% respectively.
c. AutoCyte. The brush tip is placed into the vial and is sent with the sample.
CASE ONE CONTINUED:
How fortunate that your gynecologic equipment is ready to go! Among your first patients
is a 31-year-old woman, Connie Loma, who is in good health. She has never had a Pap
smear before, although she has tested HIV negative on various occasions and denies ever
being exposed to or having acquired a sexually transmitted disease. She has had multiple
sexual partners and has never been pregnant. She smokes one pack per day of tobacco and
does not drink alcohol. This is the first time she’s seen a doctor in seven years. Because
your practice is not busy, you suggest that she should have a Pap smear performed during
her visit. While she is not opposed to this idea, she is nearing the end of her period and still
is having some occasional spotting of blood.
2. What are her risks for cervical cancer? Should she have been screened by now?
Should you proceed with the Pap smear?
Risks for cervical cancer include the early onset of intercourse and greater number of
lifetime partners. By far the most important factor, however, is infection with oncogenic
strains of human papilloma virus. 100% of squamous cell cervical cancer and 75-95% of
high grade CIN have detectable HPV DNA. Cigarette smoking, additionally, increases
the risk 2 to 4 fold. Immune function, genetic polymorphisms, and nutritional status
likely have some effect as well. In HIV positive women, cervical cancer follows a more
aggressive and invasive course. In contrast, in young healthy women, HPV and resultant
lesions often regress spontaneously.
Of the 50 million women who undergo Pap testing in the United States annually, 3.5
million (7%) have an abnormal result requiring additional evaluation. If Ms. Loma were
to have cervical cancer, she would have a 92% chance of surviving five years if the lesion
was caught early and was still localized; in contrast, if she had distant disease, she would
only have a 13% chance of five-year survival. Over the years, the introduction of
screening has decreased rates of cervical cancer by 60-90% and mortality from cervical
cancer by 20-60%.
Ideally, Ms. Loma should have been screened within three years of the onset of sexual
activity. Although the alternative start date of screening is the age of 21, there is little
value in screening women who have never had sexual intercourse. Having said this, it is
important to realize that by the age of 25, most high-risk adolescents have had at least
seven sexual partners and may not give an accurate history to their health care provider.
It is clear that Ms. Loma should have been tested years ago. Although she is near the end
of her period, she is at high risk and you may lose her to follow-up if you don’t test her
now. The use of liquid collection devices has made it easier to separate blood from
endothelial cells and avert sampling errors. Though a sub optimal exam, it’s likely
necessary in this patient.
CASE ONE CONTINUED:
Because you’re such a great doctor, you develop a wonderful patient-doctor relationship
with Ms. Loma. You ultimately perform a gynecologic exam and send the Pap smear for
evaluation. A week later, you get the results. The specimen is satisfactory for evaluation,
but there is an absence of the endocervical zone component.
3. What are the different categories of reporting according to the 2001 Bethesda
System? What does this particular statement mean? What do you need to do next?
What are the algorithms for managing the other results?
The categories of reporting according to the 2001 Bethesda System have been included in
Box 2 in this module. The terms are aimed at guiding therapy through actual laboratory
and clinical experience and leaves a blank space for “educational notes and
suggestions” that are a rough consultation from the pathologist. Categories are based
upon results that hold clinical significance and, thus, give clinicians the ability to triage
reports and arrange for appropriate step-wise follow-up in a more timely fashion.
Resultant algorithms aim to minimize the false negative rate and are based upon the
probability that a person presenting with a specific lesion will already have, or will go on
to have, a high grade lesion or invasive cancer.
The notation that Ms. Loma’s result has been given is not required reporting, but it is
recommended that laboratories include this notation. The lack of transformation zone
suggests that sampling quality may be sub optimal, but is still satisfactory for evaluation
(8000-12,000 well-visualized squamous cells). One need not repeat the smear based
upon these results, but one may be less confident of the sensitivity of the results.
Before going on to review the attached algorithms for each particular interpretation, a
brief mention of “Other: Endometrial cells in a woman >40 years old” is warranted. In
short, cells in a woman younger than 40 are not significant. However, in a woman 40 or
older, the significance of benign-appearing endometrial cells in the Pap specimen is
unknown.
As you review the algorithms presented in the flow sheets in this module, keep in mind
that a gynecologist will likely be making the upper-level triaging decisions. However,
it’s important for you to help your patient keep track of her follow-up.
CASE ONE CONTINUED:
For several years now, you have run a highly successful practice, and Ms. Loma has
continued to seek health care from you. Her third Pap smear result is negative. “No
offense, Doc, but I hate these exams. Could we wait a while before you send another Pap
smear off?”
4. Can you? On what data do you base your answers?
Trend studies indicate that after Pap smear screening began, fewer people died of
cervical cancer. Furthermore, case-control studies have found that women who have
never been screened for cervical cancer are at increased risk for developing invasive
cancer. But when to start screening? When to stop? How often?
Many of the current recommendations for cancer screening stem not only from “best
practices” for health but also from an actuarial point of view. Legislative decisions on
Medicare and Medicaid coverage for services and insurers’ decisions about preventive
services are driven in large part by studies on cost-effectiveness and thresholds by which
experts judge a health care service affordable and, even, worth the cost.
One unit for measuring this is the quality-adjusted life year (QALY). An intervention that
restores someone somewhere halfway between perfect health and death yields 0.5 QALYs
while perfect health yields 1 QALY. Costs include basic items such as the price of a
diagnostic or therapeutic procedure and also some intangibles, such as the opportunity
cost of spending time in a doctor’s office instead of going to work. What are the
benefits? In other words, what is the value of a life? Again, one model might look at
how much someone is willing to pay to receive a year’s worth of life.
One classic model of cost-effectiveness analysis was a study by Eddy that looked
specifically at cervical cancer screening. Eddy estimated that 5-year screening intervals
would deliver an additional year of life at a cost of $375 in 1987. Screening yearly cost
$1,715 per life.
So based upon cost-effectiveness analysis and the rapidity with which a cervical lesion
might become invasive, there are some guidelines that you can follow in taking care of
Ms. Loma.
USPSTF: “…no direct evidence that annual screening achieves better outcomes than
screening every three years…. Because sensitivity of a single Pap test for high-grade
lesions may only be 60 to 80 percent, most organizations…recommend… annual
smears…until a specified number (usually two or three) are cytologically normal before
lengthening the screening interval.”
ACS: lengthen the interval after age 30.
ACOG: ongoing annual screening if there are additional risk factors (HPV or other
STDs, history of cervical cancer, or high risk sexual behavior)
CASE ONE CONTINUED:
As you reach your twilight years, Ms. Loma has aged gracefully. After her 70th birthday,
she wants to kick the Pap habit permanently.
5. What do you say?
Less than 1 in 1000 women age >60 with normal baseline Pap smears will develop CIN 3
or cancer. This means that these women will disproportionately bear the burden of
having false-positive results. However, women being screened for the first time had rates
of 2.3/1000 for ages 50-64 and 1.7 per 1000 for 65 and over.
USPSTF: stop screening women over the age of 65 if they have had adequate recent
screening with normal Pap smears and are not otherwise at high risk.
ACS: women age >70 with three consecutive normal Pap smears and no abnormals in
10 years may choose to stop.
ACOG: limited studies on older women make it difficult to set an upper age limit.
Also, one final note: while the yield is very low in women after hysterectomy, screening
may be continued in women with a history of invasive cervical cancer or DES exposure.
Algorithms
Adapted from Wright TC, Cox JT, Massad LS, et al. 2001 Consensus guidelines for the
management of women with cervical cytological abnormalities. JAMA. 2002;287:21202129.
ASC-US (atypical squamous cells of
undetermined significance)
OPTION ONE
OPTION THREE
Repeat Pap every 4 to 6
months
(-) x 2
Reflex testing for high risk
HPV DNA: preferred method
if available
OPTION TWO
ASC-US or higher
(+)
Colposcopy
(+)
(-)
Routine care
(-)CIN
Repeat Pap in 12
months
(+)CIN
Is HPV status known?
No, workup
began with colposcopy
Repeat Pap in 12
months
Yes, workup
began with reflex
testing
SEE 2001 Consensus Guidelines for the
Management of Women with Cervical Histological
Abnormalities (beyond the scope of this module
and most internal medicine practices)
Repeat Pap at 6 and 12 months OR HPV DNA
testing at 12 months and refer abnormalities
back to colposcopy
Special circumstances: postmenopausal women without contraindications to estrogen and with cytological or clinical
evidence of atrophy may receive a course of intravaginal estrogen and have a repeat Pap one week later. A negative
result should be repeated in 4 to 6 months. Immunosuppressed women should be referred to colposcopy irrespective
of level of immunosuppression.
ASC-H (atypical squamous cells, cannot exclude HSIL)
Colposcopy
(-) and review of previous results
agrees with ASC-H
Repeat Pap at 6 and 12
months or HPV DNA testing at
12 months
(+)CIN
(-) and review of previous
results leads to a new interpretation
Refer to Algorithm for new interpretation
SEE 2001 Consensus Guidelines for
the Management of Women with
Cervical Histological Abnormalities
AGC: all undergo colposcopy with
endocervical sampling
AGC, endometrial?
YES
AGC, favor neoplasia?
NO
NO
Age >35 or age <35
and unexplained
vaginal bleeding?
YES
Endocervical
sampling
Invasive disease or CIN?
YES
Diagnostic cold-knife
conization
(excisional)
SEE 2001 Consensus
Guidelines for the
Management of Women
with Cervical Histological
Abnormalities
NO
(-)
(+)
Repeat Pap every 4 to 6
(+)
months until 4 negative
results
(-)
Routine care
(+)
Colposcopy
AIS: all undergo colposcopy with
endocervical sampling
NONINVASIVE DISEASE
Diagnostic cold-knife
conization (excisional)
INVASIVE DISEASE OR CIN
SEE 2001 Consensus
Guidelines for the Management
of Women with Cervical
Histological Abnormalities
LSIL: all undergo colposcopy
UNSATISFACTORY
SATISFACTORY
WITH NO LESIONS
(-)CIN
Endocervical sampling
if not pregnant
(+)CIN
WITH LESIONS
(-)CIN
SEE 2001 Consensus
Guidelines for the
Management of Women with
Cervical Histological
Abnormalities
(+)CIN
SEE 2001 Consensus
Guidelines for the
Management of Women
with Cervical Histological
Abnormalities
Repeat Pap at 6 and 12
months OR HPV DNA
testing at 12 months
Special Circumstances: Postmenopausal women or adolescents may not need immediate colposcopy but may have
either repeat Pap at 6 and 12 months or HPV DNA at 12 months. Postmenopausal women with no contraindications to
estrogen and with cytological or clinical evidence of atrophy may receive a course of intravaginal estrogen and have a
repeat Pap one week later. A negative result should be repeated in 4 to 6 months. Pregnant women should be
evaluated by clinicians experienced in the evaluation of colposcopic changes induced by pregnancy. Unless invasive
cancer is identified, treatment is not acceptable.
HSIL: all undergo colposcopy with endocervical sampling
ALL OTHERS
Not pregnant and older
or at risk for loss to
followup: LEEP
SATISFACTORY
BIOPSY CONFIRMED
NO LESION
CIN
OR CIN1
SEE 2001
Consensus
Guidelines for
the
Management
of Women with
Cervical
Histological
Abnormalities
REVIEW OF PREVIOUS
RESULTS LEADS TO A
NEW INTERPRETATION
Refer to
Algorithm for
new
interpretation
UNSATISFACTORY
NO LESION
BIOPSY CONFIRMED
OR CIN1
CIN
REVIEW OF PREVIOUS
RESULTS IS NOT POSSIBLE OR
UPHOLDS HSIL OR CIN1
Diagnostic
cold-knife
conization
(excisional)
Special Circumstances: see above for pregnant women. Young women of reproductive age with HSIL but not
CIN2,3 may be observed with colposcopy at 4 to 6 month intervals for one year if colposcopy findings are satisfactory,
endocervical sampling is negative, and patient accepts the risks.
References:
1. U.S. Preventive Services Task Force. Screening for cervical cancer:
Recommendations and rationale. American Family Physician. 2003;67:17591766.
2. Box 2 from Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System:
Terminology for reporting results of cervical cytology. JAMA. 2002;287:2116.
Additional References:
1. Eddy DM. The frequency of cervical cancer screening. Comparison of a
mathematical model with empirical data. Cancer. 1987; 60:1117-22, 1987.
2. Wagner, J.L. Cost effectiveness of screening for common cancers. Cancer and
Metastasis Reviews. 1997; 16: 281-94.