The American Cancer Society (ACS) recently updated its guideline for the early detection of cervical neoplasia and cancer. The revised guideline was published in the November/December 2002 issue of CA: A Cancer Journal for Clinicians and is also available at CAonline. AmCancer Soc.org/cgi/content/full/52/6/342.

Present Situation

In the past 50 years, mortality from cervical cancer has decreased by more than 70 percent, largely because of the Papanicolaou (Pap) test. Preinvasive cervical lesions now are detected far more often than invasive malignancies. Because DNA from high-risk types of sexually transmitted human papillomavirus (HPV) is present in more than 93 percent of squamous cell cervical cancers, another purpose of screening is to detect and remove HPV-associated high-grade lesions before they become cancers.

The ACS notes that the Pap test is not perfect and that false-negative results cannot be completely eliminated. Various factors, including small lesion size, inaccessible location of the lesion, and failure to sample the lesion, limit test sensitivity for high-grade cervical intraepithelial neoplasia (CIN) to between 70 and 80 percent.

No matter what test is used, the incidence of cervical cancer can be reduced further by increasing screening rates in women who have never been screened or who are screened infrequently. At present, these women account for approximately 60 percent of cervical cancers diagnosed in the United States.

Initiation of Screening

RECOMMENDATION

The ACS recommends that cervical cancer screening begin approximately three years after the onset of vaginal intercourse or no later than 21 years of age. The ACS also emphasizes the importance of providing preventive health care (e.g., health-risk assessment, prevention counseling, screening for and treatment of sexually transmitted diseases [STDs]) to adolescents who may not need cervical cytology.

RATIONALE

Data suggest that the risk of missing an important cervical lesion is small until three to five years after initial HPV exposure. According to the ACS expert panel, an upper age limit of 21 years for initiating screening represents a more practical and realistic age than 25 for compliance and access to patients.

The risk of HPV infection and cervical lesions may be increased in victims of sexual abuse who have had vaginal intercourse, particularly after puberty. When these patients are ready to be screened (i.e., after puberty), they should be tested by a physician who is experienced in working with abused adolescents.

The patient's choice (after counseling) and the physician's discretion should guide the initiation of cytologic screening in young women 21 years and older who have not had vaginal intercourse and have no history of sexual abuse.

Testing in young women with human immunodeficiency virus (HIV) infection or another condition that compromises the immune system (e.g., organ transplantation, chemotherapy, chronic corticosteroid therapy) should be in accordance with U.S. Public Health System guidelines.

Discontinuation of Screening

RECOMMENDATIONS

The ACS recommends that women older than 70 years discuss their need for cervical cancer screening with their physician. Women may choose to discontinue screening after age 70 if they have an intact uterus, three consecutive normal or negative cervical cytologic tests, and no abnormal or positive tests within the previous 10 years. Testing may be stopped in women who have severe comorbid or life-threatening illness.

The ACS recommends cervical cytology in women 70 years and older if screening has not been performed previously or is unlikely to have been performed, or information about previous screening is unavailable. Screening should be continued in women who have a history of cervical cancer, a condition that compromises the immune system (e.g., HIV infection), or in utero exposure to diethylstilbestrol (DES); these women should be screened for as long as their health is reasonably good and they have no life-limiting medical condition. Until more information is available, and at the discretion of the physician, screening should continue in women who have tested positive for HPV DNA.

RATIONALE

The ACS notes that cervical cancer is rare in older screened women in the United States. Most cervical cancers in older women occur in those who have not been screened, have not been screened frequently, or have not had three consecutive normal cytologic tests.

Because of atrophy, cervical stenosis, or other conditions, obtaining satisfactory cervical samples from older women may be difficult. Furthermore, screening in this population has potential harms, such as discomfort during the procedure and the effects of false-positive results (e.g., invasive procedures, discomfort, increased health care costs). The ACS expert panel set the age to discontinue screening at 70 years in an effort to balance the benefits and harms of screening older women.

Screening After Hysterectomy

RECOMMENDATIONS

Screening with vaginal cytology is not indicated in women who have undergone total hysterectomy, including removal of the cervix, for confirmed or documented benign disease. Cervical cancer screening should be continued in women who have had a subtotal hysterectomy.

The ACS recommends screening after hysterectomy in women with a history of CIN2/3, or in whom the absence of CIN2/3 before hysterectomy or an indication for hysterectomy cannot be documented. Screening should be continued until these women have had three documented, consecutive, technically satisfactory normal or negative tests and no abnormal or positive tests in a 10-year period.

Screening also should be done after hysterectomy in women with a history of in utero DES exposure or cervical cancer. These women should be screened for as long as they have reasonably good health and no life-limiting medical condition.

RATIONALE

The ACS notes that cytology tests screen the vaginal cuff in women who have their cervix removed for benign reasons. Vaginal cancer is uncommon; however, the risk of vaginal and cervical cancer is increased in women with a history of in utero DES exposure. Although data are limited, women who have undergone hysterectomy because of cervical intraepithelial lesions also may be at increased risk for vaginal cancer.

Cytology every four to six months is recommended when CIN2/3 was the reason for hysterectomy. Screening may be discontinued if three documented, consecutive, technically satisfactory vaginal cytology tests are normal or negative and no cytology tests are abnormal or positive within 18 to 24 months after the hysterectomy.

In women with a history of CIN2/3 in whom CIN2/3 was not the reason for hysterectomy, screening should continue until three vaginal cytology tests are normal or negative and no cytology tests are abnormal or positive within a 10-year period.

Screening Interval

RECOMMENDATIONS

The ACS recommends that once cervical cancer screening has been initiated, it should be performed annually with conventional cytology or every two years with liquid-based cytology. When women reach 30 years of age and have had three consecutive, technically satisfactory normal or negative test results, they may be screened every two to three years unless they have a history of in utero DES exposure or have HIV infection or another condition that compromises the immune system.

RATIONALE

Screening intervals remain a controversial issue. The ACS notes that the difference in absolute risk of an important lesion progressing to invasive disease is small when comparing one-, two-, and three-year screening intervals with conventional cervical cytology. For screening intervals longer than three years, the risk is considered to be unacceptably high. Preliminary data suggest that a shorter screening interval may be more beneficial in younger women than in those older than 30 years.

When determining the timing of repeat screening in women with a previous normal or negative result, the physician should consider specimen adequacy and quality indicators. An annual repeat screening test may be considered if there are partially obscuring factors or if endocervical cells or transformation zone elements are not present in the sample. Women with a recent abnormal result would be classified as being under surveillance.

Sensitivity in detecting nonsquamous cell carcinomas may be increased through use of the endocervical brush and new technologies (e.g., liquid-based cytology).

Liquid-Based Pap Technology

RECOMMENDATION

Liquid-based cytology performed every two years may be used as an alternative to conventional Pap tests. Testing can be done every two to three years in women 30 years and older who have had three consecutive normal or negative cytology results, unless they have a history of in utero DES exposure, have HIV infection, or are otherwise immunocompromised.

RATIONALE

The U.S. Food and Drug Administration (FDA) has labeled two liquid-based Pap tests as being at least as accurate as Pap smears in detecting cervical precancerous lesions and cancers. The ACS reports that most studies have demonstrated improved sensitivity with liquid-based cytology.

Advantages of liquid-based cytology over conventional smears include decreased artifact, improved specimen adequacy, improved cellular sampling, and availability of residual material for ancillary testing (e.g., for oncogenic HPV DNA).

The recommendation on screening interval was based on modeling, as well as expert opinion based on existing data. At present, no data support a specific screening interval for liquid-based cytology.

HPV DNA Testing with Cytology

PRELIMINARY RECOMMENDATION

The FDA has not approved HPV DNA testing with cytology for primary cervical cancer screening. The ACS guideline review panel found this testing to be promising, based on a review of available data. If this technology is approved, consideration could be given to performing conventional or liquid-based cytology in combination with high-risk HPV DNA testing every three years in women 30 years and older. This testing would be an alternative to the use of conventional cervical cytology alone. The combined testing should not be done more often than every three years.

The ACS notes the critical need for counseling and education about HPV infection. If combined testing is approved, a guideline would be needed for the management of women with a normal or negative cytology test and a positive high-risk HPV DNA result.

RATIONALE

The ACS reports that recent interest in HPV DNA testing for cervical cancer screening is based on the premise that standardized molecular testing of exfoliated cervical cells for the causative agent of cervical cancer could have acceptable diagnostic performance while being more reproducible and more easily adapted for clinical practice than conventional cytology.

The one HPV DNA test currently approved by the FDA detects 13 HPV types that have been associated with cancer of the cervix. The ACS notes that the high negative predictive value resulting from concomitant screening with cytology and HPV DNA could safely permit increasing screening intervals to lower costs. Restricting HPV DNA to women 30 years and older reduces colposcopy referrals caused by transient lesions.

Additional Recommendations

Other statements from the ACS expert panel are as follows:

• Women, particularly teenagers and young women, need to be educated about the difference between a Pap test and a pelvic examination. Regular health visits, including gynecologic care and STD screening and prevention, are important in women who may not need cervical cytology.

• Pelvic examinations do not detect cervical cancer; however, pelvic and rectal examinations can help identify other cancers and gynecologic conditions.

• Given the self-limited nature of low-grade squamous intraepithelial lesions in adolescents, referral for colposcopy may be less necessary than in adult women.

• Adolescents should not be excluded from health insurance coverage because of false-positive cervical cytology tests or mild cytologic abnormalities.

• Physicians should confirm health insurance coverage before they order liquid-based cytology, HPV DNA tests, or triage for patients with atypical squamous cells of undetermined significance (ASCUS).