Cervical Dysplasia

Background

Cervical dysplasia and cancer are associated with human papillomavirus (HPV), a sexually transmitted virus. Carcinogenic strains of HPV, in conjunction with other factors, may cause dysplasia and cancer not only of the cervix, but also of the vulva, vagina, anus, and oropharynx. HIV-infected women have a higher prevalence of HPV infection than do HIV-uninfected women, and a higher prevalence of oncogenic HPV types. They are about 10 times more likely to develop cervical dysplasia, or squamous intraepithelial lesions (SIL), precursors to cervical cancer. Unfortunately, they also have a higher risk of invasive cervical cancer and tend to have more aggressive forms of cervical cancer and poorer responses to treatment. Invasive cervical cancer is an AIDS-defining illness.

The risk of high-grade cervical lesions appears to be higher for women with advanced immunodeficiency than for women with preserved CD4 cell counts. Other risk factors for dysplasia and cervical cancer include African-American ethnicity, a history of smoking, younger age at onset of sexual intercourse, and multiple sex partners. Effective antiretroviral therapy (ART) with immune reconstitution has not been shown to prevent the progression of dysplasia.

Screening for cervical dysplasia and appropriate intervention in women with high-grade dysplasia are effective in preventing cervical cancer. Frequent monitoring and careful follow-up in women with low-grade lesions are essential for preventing progression to invasive disease. Papanicolaou (Pap) testing should be performed routinely for all HIV-infected women, with testing initiated at the time of HIV diagnosis, repeated 6 months after the first test, then performed annually thereafter if the results are normal. (See chapter Initial and Interim Laboratory and Other Tests.)

Risk factors for candidiasis include diabetes mellitus and the use of oral contraceptives, corticosteroids, or antibiotics.

Because the risk of anal dysplasia also is increased among HIV-infected women (in some studies, rates of anal dysplasia were higher than rates of cervical dysplasia), many experts recommend concurrent screening for anal dysplasia. For further information, see chapter Anal Dysplasia.

For information on prevention of HPV infection, see "Prevention," below.

S: Subjective

Patients with cervical dysplasia or early cervical cancer usually are asymptomatic and disease will not be diagnosed unless screening is performed. Genital condylomata (warts) indicate infection with HPV and typically are associated with low-risk types of HPV; however, a mixture of HPV types may be present, and women with genital warts may have concurrent dysplasia.

The classic symptom of early invasive cervical neoplasia is intermittent, painless bleeding between menstrual periods, which may present initially as postcoital spotting. Late symptoms of invasive cervical carcinoma include flank and leg pain, dysuria, hematuria, rectal bleeding, and obstipation.

Ask all female patients about risk factors for, previous history of, and preventive measures against cervical dysplasia and cancer, including the following:

• Genital warts; previous or current HPV infection
• Previous abnormal cervical Pap test result
• Previous abnormal anal Pap test result
• Previous cervical cancer; when and how treated
• Sexual activity before age 20
• History of multiple sex partners
• Cigarette smoking
• CD4 count of <200 cells/µL
• Pregnancy
• Oral contraceptive use
• History of HPV vaccination

O: Objective

Perform a focused examination of the abdomen and pelvis. Examine the external genital and perianal region. Perform speculum and bimanual examinations to evaluate the vagina and cervix. Look for lesions, masses, warts, and cervical inflammation or discharge, as well as exophytic or ulcerative cervical lesions with or without bleeding. Note that simple visual examination may not reveal abnormalities.

A: Assessment

HIV-infected women have an increased risk of cervical dysplasia with progression to cervical cancer. If abnormalities of cervical disease are suspected, an appropriate evaluation should be performed. Because most women with cervical dysplasia have no symptoms, routine screening should be performed for all women.

P: Plan

Screening

Perform Pap screening for all HIV-infected women. The initial test should be conducted at the time of HIV diagnosis, a second (if the first is normal) should be performed 6 months later. Screening should be repeated annually thereafter if all results are normal. (For HIV-uninfected women, recent guidelines from the American Congress of Obstetricians and Gynecologists recommend increasing the screening interval to 3 years if both Pap and HPV test results are negative; this screening strategy has not been shown to be safe and effective for HIV-infected women and is not recommended.) If a Pap result is abnormal, see below. Also consider screening for anal dysplasia with an anal Pap test (see chapter Anal Dysplasia).

Cervical (and anal) cytology is graded using the Bethesda 2001 system (see "References," below), which categorizes disease in increasing order of severity as follows:

• Negative for intraepithelial lesion or malignancy
• Atypical squamous cells of undetermined significance (ASCUS)
• Atypical squamous cells, cannot exclude HSIL (ASC-H)
• Low-grade squamous intraepithelial lesion (LSIL)
• High-grade squamous intraepithelial lesion (HSIL)
• Squamous cell carcinoma (SCC)

Other abnormalities may be noted, including the following:

• Atypical glandular cells (AGCs), including the following subcategories:
  • AGC NOS (includes endocervical, endometrial, or glandular cells not otherwise specified)
  • AGC, favor neoplasia (includes endometrial or glandular cells)
  • AIS (endocervical adenocarcinoma in situ)
• Infectious organisms such as Trichomonas

Evaluation of Cytologic Abnormalities

Atypical squamous cells of undetermined significance

If ASCUS is present without inflammation or suspected neoplastic process, several options for management exist.

• Most experts recommend that all women with ASCUS be referred for colposcopy and directed biopsy, regardless of their degree of immunodeficiency. If the biopsy result shows no dysplasia (and the examination is adequate), the patient should be monitored by annual Pap tests.
• As an alternative, patients who are considered reliable for follow-up may be monitored closely with repeat Pap tests every 4-6 months for 2 years until three consecutive results have been negative. If a follow-up test shows ASCUS (or higher-grade abnormalities), colposcopy with directed biopsy should be performed. If the biopsy result does not show dysplasia, the patient should be monitored as usual with Pap tests at 6 months and 12 months.
• There are limited and conflicting data to support utilizing HPV DNA testing as part of the management of HIV-infected women with ASCUS. By this strategy, colposcopic examination is performed if HPV DNA testing shows an oncogenic HPV type. This approach is recommended by American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines but is not favored by most experts on HPV infection in HIV-infected persons.

Atypical squamous cells, cannot exclude HSIL

Women with abnormalities suggestive of high-grade dysplasia should be referred for colposcopy.

Low-grade squamous intraepithelial lesion

Women with LSIL should be referred for colposcopy and directed biopsy.

High-grade squamous intraepithelial lesion or squamous cell carcinoma

Women with HSIL are at high risk of high-grade intraepithelial neoplasia or cervical cancer and should undergo colposcopy with endocervical assessment and directed biopsy as soon as possible. Refer to an oncology specialist for treatment.

Atypical glandular cells

Because of the high rate of significant lesions in patients with AGS, colposcopy with endocervical sampling is recommended for all subcategories, including AIS. In women over age 35, endometrial sampling is recommended in addition to colposcopy and endocervical sampling. Refer to an appropriate specialist for evaluation.

Treatment

The optimal management of precancerous cervical lesions has not been identified clearly for all classes of SIL. Consult with an HIV-experienced gynecologist, oncologist, or other dysplasia specialist.

Prevention

Latex or plastic barriers may block transmission of HPV in areas covered by these barriers, but infection may occur through bodily contact outside the area covered by the barriers. Nonetheless, their use is recommended to prevent transmission or acquisition of HPV.

Two vaccines have been approved by the U.S. Food and Drug Administration for the prevention of certain HPV strains in women:

• Gardasil: includes HPV types 16 and 18 (which cause about 70% of cervical cancer, as well as vaginal and vulvar cancer), and types 6 and 11 (which cause most anogenital warts); approved for females of age 9-26
• Cervarix: includes HPV types 16 and 18; approved for females of age 10-25

Gardasil also has been approved for use with males of age 9-26 for prevention of genital warts; no data are available to evaluate efficacy in preventing cervical dysplasia or cancer in female partners.

These vaccines are not effective against HPV types other than those covered by the vaccine, and they may not be protective against a covered type to which a patient has been exposed previously.

The HPV vaccines have not been thoroughly studied in HIV-infected persons and thus are not specifically recommended for such patients; studies to evaluate efficacy, safety, immunogenicity, and tolerability are under way. The vaccines are not contraindicated for HIV-infected persons, and many clinicians do provide them. There are no data on the efficacy of the vaccines in preventing anal HPV; studies are under way.

Patient Education

• Recommend the use of latex or polyurethane male or female condoms for vaginal or anal intercourse and plastic or latex barriers for oral sex to reduce the risk of transmitting HPV (the usual cause of cervical cancer) to partners. Barriers also reduce the risk of exposure to other sexually transmitted pathogens.
• Patients who smoke should be advised to quit. Cigarette smoking appears to heighten the risk of cervical cancer and makes HPV more difficult to treat. Discuss options for smoking cessation (see chapter Smoking Cessation), and refer patients to the American Lung Association if local programs are available.
• Emphasize the importance of keeping follow-up appointments for Pap screening or colposcopy to allow early detection of precancerous lesions and appropriate monitoring of abnormalities.
• For women with dysplasia who require treatment, emphasize that early treatment is essential for managing the disease and preventing the development of cancer. Advise patients to keep all medical appointments.

References

• Aberg JA, Kaplan JE, Libman H, et al.; HIV Medicine Association of the Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2009 Sep 1;49(5):651-81.
• Abularach S, Anderson J. Gynecological Problems. In: Anderson JR, ed. A Guide to the Clinical Care of Women with HIV. Rockville, MD: Health Services and Resources Administration; 2005.
• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.
• Ellerbrock TV, Chiasson MA, Bush TJ, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA. 2000 Feb 23;283(8):1031-7.
• Massad LS, Ahdieh L, Benning L, et al. Evolution of cervical abnormalities among women with HIV-1: evidence from surveillance cytology in the women's interagency HIV study. J Acquir Immune Defic Syndr. 2001 Aug 15;27(5):432-42.
• Solomon D, Davey D, Kruman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002 Apr 24;287(16):2114-9.
• Wright TC, Massad LS, Dunton CJ, et al.; 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 Consensus Guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. J Low Genit Tract Dis. 2007 Oct;11(4):223-39.