Bulletin of Experimental Treatments for AIDS, No. 29; June, 1996
Lisa Bardaro, MD

Terminology

Cervical intraepithelial neoplasia (CIN) is now used to describe what was once called dysplasia:

* CIN I = minimal dysplasia * CIN II = moderate dysplasia * CIN III = severe dysplasia or carcinoma in situ

CIN III, severe dysplasia and carcinoma in situ are all different names for the same thing--early cervical cancer. While approximately one-third of all cases of CIN I will resolve in time, the rest will progress. All degrees of CIN, however, require immediate colposcopy.

Medical Historical Background

The Pap smear came into widespread use in the 1960s, although the test was available to women in major urban centers in the 1950s. The advent of the Pap smear revolutionized one aspect of women's healthcare. Widespread availability of this simple, low-cost, easily performed test has saved countless lives. Before the Pap smear came into use, cervical cancer was virtually never diagnosed before a woman had entered the terminal stages, when cancerous growths had become sufficiently large to cause obvious symptoms. A symptom such as bleeding after intercourse might bring a woman in to see her doctor; examination might reveal a large tumor and necrosing (dying) tissue, and ultimately result in a diagnosis of stage IV cancer. (Cervical cancer is classified into 4 stages--see chart of FIGO staging.)

In 1988, a coalition of organizations (the American College of Obstetrics and Gynecology, the American Academy of Family Practice, the American Cancer Society, the National Cancer Institute, the American Medical Association, the American Nursing Association and the American Medical Women's Association) developed a consensus statement regarding cervical Pap smears.

The statement recommended annual Pap smears for all women who were or had been sexually active, or were at least 18 years of age. However, just 1 year later, the United States Preventive Services Task Force issued a very different statement, recommending Pap smears every 1-3 years, depending on risk factors. In addition to HIV infection, other established risk factors for cervical cancer are infection with human papillomavirus (HPV), especially types 16 and 18, immunosuppression due to any cause and cigarette smoking. Current evidence suggests that low dietary levels of folate, vitamin C and beta carotene may also predispose women to cervical neoplasia.

Another crucial question then arises: what is the cost of a Pap smear versus the cost of treating invasive cervical cancer?

Pap Smear and Colposcopy

The Pap smear and colposcopy are the 2 basic tools used for screening and follow-up for CIN. A Pap smear is a simple test performed as part of a regular, simple pelvic examination. Cells are removed from the cervix and vagina with a small flat stick and a cervical brush, and smeared on a glass slide. The slide is sent to a laboratory for analysis. A Pap smear allows a technician to look at cells but not to make a diagnosis, since it only includes cells but not the entire tissue. To make a definitive diagnosis, it is extremely important to be able to view the entire tissue, which is what colposcopy and biopsy allow. Only then can an appropriate treatment plan be devised.

Colposcopy is a diagnostic procedure that entails magnified examination of the vulva, vagina and cervix, with what is essentially a very high-powered microscope. A somewhat involved although not painful procedure, colposcopy must be performed by a trained healthcare provider. Any suspicious areas seen under the lens are biopsied (sampled). A complete colposcopy also entails biopsy of the cervical canal, a procedure known as endocervical curettage (ECC). This step is especially important because many cancers arise from the cervical canal. ECC is contraindicated only during pregnancy.

False-Negative Smears

A very significant issue is the high rate of false-negative Pap smears. A false-negative Pap smear is one that fails to detect existing neoplasia. False-negative Pap smears generally result from either incorrect performance of the Pap smear test (i.e., abnormal cells actually present in the cervix were not gathered, due to poor technique on the part of the health professional) or incorrect reading of the test slide by the laboratory technicians, who view the smear under a microscope. Adequately performed and adequately read smears have a false-negative rate of up to 25%. Clearly, under less than optimal conditions, this rate is even higher. The inherently high rate of false-negative smears must be offset; one of the best ways is to have Pap smears on a regular basis.

Slow and Rapid Disease

Cervical cancer generally takes either a slowly progressive or a rapidly progressive course. The former refers to cases that progress from a normal Pap smear to invasive cervical cancer over a period of about 20 years. The latter describes cases that traverse that journey in 1-3 years, with 10% developing invasive cervical cancer in the first year. While it is generally believed that rapidly progressive disease occurs primarily in high-risk groups, there is no practical way to determine before the development of neoplasia into which group a woman will fall. The strain or type of HPV may be most predictive of the group in which a woman will be classified, but this is of limited utility because 1) tests of HPV type are not routinely performed, except in research settings and 2) typing is not conducted until after the development of neoplasia.

Besides HPV, immunosuppression is also associated with more rapidly progressive disease. Therefore, it is particularly important for women with HIV to have regular Pap smears to diagnose neoplasia early enough for potential cure. Cure rates are high for cervical cancer detected early (stage I and most stage II), but the chance for cure decreases with increasing stage at time of diagnosis.

What Next?

If biopsy reveals CIN I, women should get a repeat Pap smear and colposcopy in 3-6 months. An upcoming trial, AIDS Clinical Trials Group (ACTG) 293, will evaluate a possible treatment regimen for women with HIV and CIN I. Participants will be randomized to receive either oral isotretinoin (Accutane) or observation (no treatment) for 6 months, with an additional follow-up period of 1 year.

If biopsy reports confirm CIN II or CIN III, the next step is a biopsy of the cervix called conization or a cone biopsy, so named because it describes the shape of tissue removed. This can be done by scalpel (cold-knife cone), by laser or, most commonly, by loop electrosurgical excision procedure (LEEP). Essentially, LEEP uses an electric scalpel. The cone biopsy allows a pathologist to stage disease by determining the depth of invasion of cancerous cells. It also can be curative, if all margins of the removed tissue are free of cancer.

Regardless of biopsy results, most authorities recommend cone biopsy or LEEP if:

1) the ECC reveals CIN, 2) any biopsy reveals glandular CIN, or 3) the transformation zone has retracted within the cervical canal and cannot be fully visualized.

Squamous cell cancers account for about 80% of all cases, with the remainder being adenocarcinoma, adenosquamous or undifferentiated cancer.

Staging and Treatment of Cervical Cancer

Treatment of cervical cancer or CIN III depends on the International Federation of Gynecology and Obstetrics (FIGO) stage at the time of diagnosis. This system is used by physicians worldwide to devise treatment plans and to provide consistency in reporting diagnoses to public health authorities.

Four possible FIGO stages are determined by 2 factors: the depth of invasion on the biopsy report and careful pelvic examination. In developed nations, frequently intravenous pyelograms (IVP), computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) can help to define the stage of disease. In general, FIGO stages I and II are treated with radical hysterectomy (removal of the cervix, upper vagina, fallopian tubes, ovaries, pelvic lymph nodes and supporting ligaments). In younger women, the ovaries may be left intact.

After stage II, the cancer cannot be entirely removed by surgery alone. The surrounding abdominal region is now involved, including the lymph nodes and muscles. More advanced stages--stages III-IV, although some physicians recommend the following for stage IIB as well--are treated with radiation therapy using both external beam (a machine is used to radiate the external pelvic region and any other areas where the cancer might be present) and intracavitary radiation (radium pellets are surgically implanted into the tissue of the vagina and cervix). Chemotherapy with anticancer drugs is no longer used to treat cervical cancer.

Cryotherapy and its Legacy

Cryotherapy involves the use of liquid nitrogen to freeze and thereby destroy abnormal tissue. For many years and until recently, cryotherapy was regularly used to treat CIN. Its benefits were ease of use, low cost and the fact that it was a non-surgical approach. Now the bad news: cryotherapy can cause scarring and narrowing of the cervical canal (cervical stenosis). It can also cause the transformation zone (where squamous and columnar tissues meet) to retract upward as it heals, which makes future visualization and biopsy of this area impossible.

However, the worst legacy of this procedure is still more ominous. Cryotherapy can cause normal tissue to heal over a deeper area of neoplasia, causing future Pap smears to appear normal while abnormal tissue continues to grow undetected underneath. For these reasons, gynecological oncologists (specialists in the treatment of reproductive cancers) now recommend against cryotherapy. Women who have been treated with cryotherapy in the past should be examined regularly and carefully.

Previous Hysterectomy

There is no general consensus about the frequency of Pap smears for women who have had hysterectomies for benign conditions. However, women with a history of cervical cancer have a higher rate of subsequent vaginal neoplasia and should have yearly vaginal Pap smears.

Conclusion

When cervical cancer is undiagnosed, untreated or fails to respond to treatment, 95% of women will die within 2 years. Given these facts, and the high rates of cervical neoplasia in women with HIV infection, increasing survival should be the top priority. This author strongly recommends that all women with HIV infection have Pap smears every 6 months.

INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS (FIGO) STAGING OF CERVICAL CANCER

* Stage I -- The cancer is confined to the cervix

- Stage IA -- Microinvasive disease

- Stage IA1 -- Stromal (connective tissue) invasion less than 3 mm

- Stage IA2 -- Stromal invasion 3-5 mm, not in excess of 7 mm in horizontal spread

- Stage IB -- Lesions greater than 7 mm in horizontal spread

* Stage II -- Involvement extends beyond the cervix, including the vagina except for the lowest third, or infiltration of the parametrium (connective tissue near the uterus) but not out to the pelvic sidewall.

- Stage IIA -- Involvement of the upper two-thirds of the vagina, without lateral extension into the parametrium

- Stage IIB -- Lateral extension into the parametrial tissue but not out to the pelvic sidewall

* Stage III -- Involvement of the lowest third of the vagina or the pelvic sidewall or causes hydronephrosis (nonfunctioning kidney)

- Stage IIIA -- Involvement of the lowest third of the vagina

- Stage IIIB -- Involvement of the pelvic sidewall or hydronephrosis

* Stage IV -- Cancer extends beyond the reproductive tract

- Stage IVA -- Involvement of the bladder or rectal mucosa

- Stage IVB -- Distant metastasis (cancer that spreads to other parts of the body away from the original, primary site) or disease outside the true pelvis.

References

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