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;287:2120-

2129.

OPTION ONE OPTION THREE

OPTION TWO

(-) x 2 ASC-US or higher

(+) (+) (-)

(-)CIN (+)CIN

Yes, workup

No, workup began with reflex

began with colposcopy testing

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.

(-) and review of previous results (+)CIN

agrees with ASC-H

(-) and review of previous

results leads to a new interpretation

YES NO NO YES

YES NO

(-)

(-)

(+)

(+)

(+)

NONINVASIVE DISEASE INVASIVE DISEASE OR CIN

UNSATISFACTORY SATISFACTORY

WITH NO LESIONS WITH LESIONS

(-)CIN (+)CIN

(+)CIN (-)CIN

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.

ALL OTHERS

SATISFACTORY UNSATISFACTORY

BIOPSY CONFIRMED NO LESION NO LESION BIOPSY CONFIRMED

CIN OR CIN1 OR CIN1 CIN

REVIEW OF PREVIOUS REVIEW OF PREVIOUS

RESULTS LEADS TO A RESULTS IS NOT POSSIBLE OR

NEW INTERPRETATION UPHOLDS HSIL OR CIN1

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;67:1759-1766.

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.

-----------------------

ASC-US (atypical squamous cells of undetermined significance)

Repeat Pap every 4 to 6 months

Colposcopy

Reflex testing for high risk HPV DNA: preferred method if available

Repeat Pap in 12 months

SEE 2001 Consensus Guidelines for the Management of Women with Cervical Histological Abnormalities (beyond the scope of this module and most internal medicine practices)

Is HPV status known?

Routine care

Repeat Pap in 12 months

Repeat Pap at 6 and 12 months OR HPV DNA testing at 12 months and refer abnormalities back to colposcopy

ASC-H (atypical squamous cells, cannot exclude HSIL)

Colposcopy

SEE 2001 Consensus Guidelines for the Management of Women with Cervical Histological Abnormalities

Refer to Algorithm for new interpretation

Repeat Pap at 6 and 12 months or HPV DNA testing at 12 months

AGC: all undergo colposcopy with endocervical sampling

AGC, endometrial?

Diagnostic cold-knife conization (excisional)

AGC, favor neoplasia?

SEE 2001 Consensus Guidelines for the Management of Women with Cervical Histological Abnormalities

Invasive disease or CIN?

Endocervical sampling

Age >35 or age ................
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