Cervical Dysplasia

Background

Precancerous lesions and cancer of the cervix 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 intraepithelial neoplasia (CIN), 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 and cervical cancer 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 CIN.

Screening for cervical cancer and appropriate intervention in women with high-grade CIN (CIN 3) 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. For all HIV-infected women (if they have had sex partners), including adolescents and young women, Papanicolaou (Pap) testing should be performed routinely. An initial test should be done 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.)

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 and some guidelines 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 CIN 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 CIN 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 throughout life if all results are normal. (For HIV-uninfected adolescents and young women, recent guidelines recommend beginning cervical screening at age 21; for HIV-infected young women, guidelines suggest screening beginning within 1 year of first sexual activity, given the risk of progression of cervical abnormalities.) 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 usually 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 not otherwise specified (AGC NOS) (includes endocervical, endometrial, or glandular cells)
    • 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 repeat the Pap test in 6-12 months. If repeat Pap is reported at greater than ASCUS, the woman should be referred for colposcopy.
  • There are limited and conflicting data to support the use of HPV DNA testing as part of the management of HIV-infected women with ASCUS. Current OI guidelines (see "References," below) emphasize that HPV testing alone is not recommended.

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 CIN. Consult with an HIV-experienced gynecologist, oncologist, or other dysplasia specialist. High-grade lesions in women with satisfactory colposcopy are typically treated with ablation (e.g., cryo-therapy, electrocautery, laser vaporization) or excision (e.g., loop electrosurgical excision [LEEP], laser or cold-knife conization). For women with unsatisfactory colposcopy, excisional methods are recommended.

Prevention

Latex or plastic barriers may block transmission of HPV in areas covered by these barriers and have been shown to reduce the risk of infection with oncogenic HPV. Although infection may occur through bodily contact outside the area covered by the barriers, the use of condoms is recommended to prevent transmission or acquisition of HPV (as well as HIV and other STDs).

Two vaccines have been approved by the U.S. Food and Drug Administration for the prevention of certain HPV strains; these are recommended for HIV-infected women and girls 9-26 years of age. They have been shown to reduce rates of cervical dysplasia; the quadrivalent vaccine also has been shown to protect against vulvar, vaginal, and anal dysplasia (as well as anogenital warts) related to the covered HPV types.

  • Quadrivalent (Gardasil): includes HPV types 16 and 18 (which cause nearly 70% of cervical cancer, as well as vaginal, vulvar, and anal cancer), and types 6 and 11 (which cause most anogenital warts
  • Bivalent (Cervarix): includes HPV types 16 and 18

The quadrivalent vaccine also is recommended for use with males aged 9-26 for prevention of genital warts and anal intraepithelial neoplasia.

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. For optimal protection, these vaccines should be given before the individual is exposed to HPV through sexual activity. They are likely to be less effective in older adolescents and adults who already may have been infected with one or more of the covered HPV types. There are few data on the use of the vaccines in persons older than 26, and they are not approved for this group. Importantly, women who have been vaccinated should continue to be screened for cervical cancer as described above; vaccination does not protect women perfectly from all oncogenic HPV viruses.

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

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly