Cervical dysplasia is the term used to describe abnormal cells on the cervix (the head and neck of the uterus). On a Pap smear report, dysplasia is referred to as cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesion (SIL). Cervical dysplasia is usually first discovered by Pap smear, where cells are swabbed from in and around the cervical os (opening of the cervix). Dysplastic changes on Pap smear are rated as "low grade" or "high grade;" high grade lesions are considered precursors to cervical cancer, while the significance of low grade dysplasia has not been established.

Cervical dysplasia and cervical cancer are strongly associated with, and believed to be caused by, specific subtypes of the sexually transmitted virus called HPV (human papillomavirus). Other subtypes of HPV cause genital and anal warts (condyloma acuminata) in men and women. HIV positive women have a high rate of persistent HPV infections, and a higher rate than HIV negative women with the types of HPV that are associated with the development of high grade dysplasia and cervical cancer. In one recent study, persistent HPV infections were found in 24 percent of HIV positive women but in only 4 percent of HIV negative women. Twenty percent of the HIV positive women and 3 percent of the HIV negative women had persistent infection with HPV 16 or HPV 18 viral types, which are most strongly associated with cervical cancer.

Numerous studies have also documented that HIV positive women are more likely than HIV negative women to have cervical dysplasia. A large study comparing HIV positive and HIV negative women with documentation of dysplasia by colposcopy revealed 5 times as many HIV positive as HIV negative women with disease. Studies have observed, too, that the incidence of HPV-related dysplasia increases as immune function declines. Studies of HIVpositive women demonstrate that both rates of HPV infection and disease and of highgrade dysplasia increase as T cell counts decline.

The strong association between HPV infection and cervical dysplasia, the finding that HIV positive women are more likely to have persistent HPV infection of the specific subtypes associated with dysplasia, and that HIV positive women have a much higher incidence of dysplasia, all suggest that HIV-related immunosuppression either increases the risk of persistent HPV infection, or changes the natural history of HPV-related disease.

What, then, is the risk of developing invasive cervical cancer in women with HIV infection and HPV-related cervical dysplasia? The documentation of increased rates of cervical dysplasia prompted the CDC to add invasive cervical cancer to the AIDS surveillance case definition in 1993. However, much remains unknown about the incidence and natural history of this disease in HIV positive women.

Several small studies have found few, if any, cases of invasive cancer in HIV positive women with cervical dysplasia. In contrast, a study of women with invasive cervical cancer found that 19% of the cases in patients under the age of 50 were HIV positive. Other researchers have published case reports of rapidly progressive invasive cervical cancer in women with HIV. The bottom line is that the risk of invasive cervical cancer in HIV positive women with dysplasia may be increased, but the magnitude of the risk has not been adequately defined.

Early Detection and Treatment

Although many questions remain about the risk of cervical cancer in HIV positive women, it is important to remember that cervical cancer is largely a preventable disease. Screening by Pap smear for all sexually active women can identify those with dysplastic precursor lesions so that they can be treated and monitored before more serious disease develops. With the high rates of HPV infection and dysplasia known to exist in the HIV-infected population, screening, early diagnosis, treatment and careful monitoring are crucial. With no medical intervention available to prevent HPV infection and disease, regular Pap smears, lower genital tract inspection, and appropriate colposcopic follow-up and treatment of abnormalities are the best hope for preventing serious disease in women with cervical dysplasia. Colposcopy is performed to evaluate atypical and dysplastic smears.

Unfortunately, at this point there is not a consensus of opinion regarding frequency of Pap smears or the management of abnormal findings in HIV positive women. Many clinicians who care for large numbers of HIV positive women and experts in HIV primary care for women have recommended more aggressive surveillance for genital tract dysplasia than the published recommendations of the federal government's CDC or Agency for Health Care Policy and Research (AHCPR). These recommendations are based on the following facts:

0. Pap smears are about 80% sensitive in detecting abnormalities, meaning the Pap smear may miss 20% of abnormalities. Abnormalities are more common in HIV positive women, thus there is a greater risk that abnormalities will be missed. An undetected abnormality may progress to more serious disease more rapidly in an immunocompromised woman. Therefore, many clinicians feel the appropriate interval for Pap smear testing and genital tract inspection for HIV positive women with previously normal smears is every 6 months.

   AHCPR guidelines: Annual Pap smears for women with normal results, and Pap smears every 6 months for women with a history of HPV or dysplasia. CDC guidelines: Two Pap smears in the first year after HIV diagnosis, then annually if negative. Pap smears every six months optional for high risk women.

1. Some women evaluated by colposcopy whose Pap smears showed only "atypia" have been found to have high-grade dysplasia. Therefore "atypical" smears, as well as all those revealing dysplasia, should be evaluated by colposcopy. Colposcopic evaluation of abnormal Pap smears should be performed within six to eight weeks of the abnormal Pap smear findings.

   AHCPR guidelines: Refer all women with abnormal Pap results for colposcopy. CDC guidelines: Annual follow-up for atypical cells of undetermined significance

2. Treatment failure and recurrence of dysplasia in HIV positive women is well documented. HIV positive women who have undergone any treatment for dysplasia in the past year should have a Pap smear three months after treatment and every three months after that for one year. After four negative Pap smears, they can resume a schedule of every six months.

There are a number of methods for destroying or removing dysplasia from the cervix (see box). However, dysplasia can recur after treatment, especially in HIV positive women. One study found that 62% of HIV positive women studied had recurrences of dysplasia three years after treatment. Recurrence was most common in women with advanced HIV disease, with 90% of those treated who had T-cells below 200 recurring by three years after treatment.

This is a discouraging finding for women who must deal with the realities of diagnosis, evaluation, and treatment of dysplasia in the face of concurrent HIV disease. In theory it is possible that highly active antiretroviral therapies will improve local and systemic immune function and treatment success in affected women, but this remains to be seen. In the meantime, HIV-infected women with dysplasia are left to deal with the difficult reality of frequent evaluation and possible frequent repetitions of uncomfortable procedures and treatments in an effort to avoid cervical cancer.

Colposcopy

Colposcopy is a method of examination of the cervix with a microscope that magnifies the cervical surface. Colposcopy is used to identify the site, severity, and extent of abnormal cell growth as well as to aid directed biopsy, plan treatment, and allow the use of conservative methods to treat early lesions. A speculum stays in place during the procedure, and is the same type which is used when you have a routine pelvic exam and Pap smear. The area to be colposcoped is wet with 5% acetic acid (a vinegar), which stains the HPV-affected tissues white, making them more clearly visible. Small samples of abnormal appearing tissue (a biopsy) may then be taken and sent to the lab for analysis. The procedure takes about 10 minutes, and can cause a pressure-type discomfort or menstrual-like cramping briefly. Scant bleeding is normal after the procedure.

Treatment of Cervical Dysplasia

Treatment decisions are based on the grade of dysplasia (low vs. high), the location of the lesion on the cervix, the size of the lesion, whether the entire lesion is visible through the colposcope, and on previous treatment modalities employed. Observation: It can be appropriate to leave low grade dysplastic lesions untreated if they are carefully and regularly evaluated by colposcopy and biopsy. When there are signs of higher grades of dysplasia, aggressive treatment should be offered. Cryotherapy: Tissue destruction by freezing (application of a gas via a low temperature probe, which freezes and destroys the area where it is applied). Done in the clinic or doctor's office. Mild discomfort, with slight spotting and watery vaginal discharge common after treatment. Laser therapy: Tissue destruction by laser (a highly concentrated beam of light energy). Usually done in an outpatient surgical setting. Spotting and vaginal discharge after therapy common. Mildly uncomfortable. Loop excision: Tissue removal by a "loop" of wire adjusted to be just larger than the size and shape of the affected zone of the cervix and the visible lesion. After the loop of tissue is removed, an endocervical curettage is done by scraping cells from inside the cervical canal (which removes tissue that may not be visible through the colposcope). Cramping is common during the procedure, and light bleeding is expected. Can be done in the clinic or office. Cone biopsy: A "cone" of tissue is removed from in and around the cervical os, either by traditional surgery or by laser. Done in a surgical setting with some anesthesia. Light bleeding and discomfort common after the procedure. Isotretinoin: Experimental. An oral drug, used to treat severe acne, which has shown some promise in treating HPV disease in immunocompetent women. Information on its effectiveness in HIV-infected women not yet available (Clinical trial: ACTG 293). 5-Fluorouracil: Experimental. A topical cream being studied for its effectiveness in preventing recurrence of disease in HIV positive women with high grade dysplasia that has been treated with standard therapy (ACTG 200).

Mary Jo Hoytt, NP, MSN is the director of the Women's Health Program, Section of HIV Medicine at St. Vincent's Hospital and Medical Center of New York City.

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