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Cervical Cancer Screening Guidelines—a 2008 Update

The “2006 Consensus Guidelines for the Management of Women with Abnormal Cervical Cancer Screening Tests,” developed by the American Society for Colposcopy and Cervical Pathology, were published in 2007. Clinicians who screen women for cervical cancer and its precursors should implement these practice guidelines, and pathologists should consider making follow-up recommendations based on these guidelines in their reports.

Over the past six years, new diagnostic tests and strategies have emerged to detect cervical cancer. These result from a better understanding of the role human papillomavirus (HPV) infection plays in the etiology of cervical cancer and its precursors (CIN 2/3). While high-risk HPV infection is the causative agent of 95 percent of cervical carcinomas worldwide, most high-risk and low-risk HPV infections are transient and regress spontaneously. A high rate of transient high-risk HPV infection is particularly common in women under age 30; this prevalence drops markedly in women over age 30. Thus, cervical cancer is an unusual complication of persistent infection by a high-risk HPV type.

The widespread use of thin-layer, liquid-based cytology (which has greater sensitivity than the conventional Pap smear) has facilitated the implementation of these strategies, because “high-risk” HPV DNA testing can be performed on the same liquid-based specimen collected for the Pap test. As a consequence, high-risk HPV testing can be conveniently added to cytology screening to achieve a sensitivity of 95 percent (compared to 50 to 55 percent for cytology alone). It is important to note that the FDA has approved the Digene hc2 High-Risk HPV DNA Test only as an adjunct to the Pap test—and only in specified patient populations. The FDA advises that the HPV DNA test should not be used as the sole basis for clinical assessment and treatment.

The 2001 Bethesda System terminology should be used for cytology classification. This is now the standard of practice, and use of earlier systems is not acceptable. CIN (Cervical Intraepithelial Neoplasia) 1 and 2/3 is the histological grading system for precursor lesions. CIN 1 is not a precancer; it is evidence of active HPV infection. Most of these lesions are transient and spontaneously regress. CIN 2/3 lesions are precancers associated with persistent infection by high-risk HPV; they have a higher risk of progression and require treatment.

The entire 2006 Consensus Guidelines should be reviewed, because only the major points are summarized here:

1. Acceptable management of women over age 20 with a cytology diagnosis of ASC-US (atypical squamous cells – of undetermined significance) is testing for high-risk HPV DNA or repeat Pap testing at six and 12 months or colposcopy. If the Pap test was liquid based or if a sample for HPV testing was co-collected, reflex testing for high-risk HPV is the preferred approach.
   
   If the HPV test is negative, follow up with repeat cytologic testing at 12 months (the risk for CIN 2/3 is 6 to 12 percent). If the HPV test is positive, colposcopy is recommended. If a colposcopic-directed biopsy does not show CIN 2/3, follow up with either high-risk HPV testing at 12 months or cytologic testing at six and 12 months.
   
   
2. Reflex HPV testing is not an effective triage method for women with a Pap test diagnosis of ASC-H (atypical squamous cells – cannot exclude HSIL) or LSIL (low-grade squamous intraepithelial lesion). This is because of the high prevalence of high-risk HPV in this population (reflex testing for HPV is acceptable for postmenopausal women with LSIL).
   
   
3. All women with HPV-positive ASC-US or LSIL or ASC-H should receive colposcopy (roughly 12 to 16 percent with HPV-positive ASC-US or LSIL and 55 to 65 percent with ASC-H will have CIN 2/3 on biopsy). If biopsy negative for CIN 2/3 or biopsy positive for CIN 1, they may be followed with HPV testing at 12 months until there is one negative or with Pap testing at six and 12 months until there are two negatives—and then returned to routine cytologic screening. If high-risk HPV is detected or if a Pap test shows ASC-US or worse, colposcopy is recommended.
   
   
4. All women with HSIL (high-grade squamous intraepithelial lesion) should receive either loop electrosurgical excision (LEEP) or colposcopy with endocervical assessment. If CIN 2/3 is not identified, either a diagnostic excisional procedure or colposcopy and cytology at six and 12 months is acceptable. Biopsy-proven CIN 2/3 should be treated. HPV testing at six and 12 months is recommended for the follow-up of treated CIN 2/3.
   
   
5. During pregnancy, only cervical cancers are treated. Colposcopy is deferred for pregnant women with a cytology diagnosis of LSIL. Colposcopy may be performed on pregnant women with a cytology diagnosis of HSIL, but only to rule out invasive cancer, and treatment for CIN 2/3 is deferred to the postpartum period.
   
   
6. Adolescents and women under 21 have a very high incidence of HPV infection, abnormal Pap tests, and CIN 1 lesions. The infections are usually transient, and most lesions are of little clinical significance and spontaneously regress. HPV testing and treatment of CIN 1 is not indicated in this age group.
   
   For ASC-US and LSIL, annual Pap testing is recommended. At the 12-month follow-up, adolescents with HSIL or greater are referred to colposcopy. At the 24-month follow-up, those with ASC-US or greater should be referred to colposcopy.
   
   
7. For women 30 years of age and older, HPV DNA testing combined with a Pap test is FDA approved for cervical cancer screening. The negative predictive value is 99 to 100 percent. When both the HPV and Pap tests are negative, repeat testing is recommended in three years. If the HPV test is positive and the Pap test is negative, retest with cytology and HPV testing in 12 months (60 percent of these patients become HPV negative during this time interval). If both tests are negative, re-screen in three years. If persistently HPV positive, colposcopy is recommended.
   
   
8. The conventional Pap test is not effective in detecting cervical adenocarcinoma. The abnormal cells are often interpreted as atypical glandular cells or reactive endocervical cells.
   
   When atypical glandular cells (AGCs) or adenocarcinoma-in-situ (AIS) is found on a Pap test, colposcopy with endocervical sampling is recommended. If not already performed, HPV testing should be done at the time of colposcopy. If the patient is 35 or older, endometrial sampling should also be performed. CIN is the most common histologic finding when AGCs are found on the Pap test.
   
   If cervical AIS is found, LEEP is an acceptable alternative to a cold knife cone. With either technique, the objective is an intact specimen with interpretable margins.
   
   If AIS or CIN 2/3 is not found, follow up with a repeat Pap test and HPV testing at six months if HPV positive or at 12 months if HPV negative. Referral to colposcopy is recommended for those who test positive for HPV or have ASC-US or greater. If both tests are negative, return to routine cytologic testing.

Appendix:

A. The American Cancer Society Cervical Cancer Screening Guidelines:

B. Cervical Biopsy Alert to Clinicians

A single Pap test has a high false-negative rate (circa 55 percent). Therefore, when collecting the Pap test specimen, if the clinician sees a cervical abnormality (ulceration, induration, a visible or elevated lesion, bleeding), it should be biopsied. In a patient with cervical cancer and a false-negative Pap test, the failure to biopsy a cervical abnormality may be below the standard of practice and constitute negligence.

C. Clinical Laboratory Improvement Amendments (CLIA)

CLIA compliance is part of the cytology standard of practice. Assure laboratory compliance with the regulations published in the CLIA modifications of January 2003. These can be found on the Department of Health and Human Services Web site at www.phppo.cdc.gov/clia/pdf/CMS-2226-F.pdf.