Cervical Cancer Screening (PDQ®): Screening - Health Professional Information [NCI] - Description of the Evidence
Noninvasive cervical squamous cell abnormalities are graded histologically as CIN 1, CIN 2, or CIN 3, according to the severity of the cell changes and the percent of the epithelium replaced by abnormal cell growth. CIN 3 is a reasonably reproducible diagnosis and has an approximate 30% risk of developing into invasive cancer over many years if untreated. CIN 2 has poor interobserver reproducibility, and the biologic behavior is variable. CIN 3 is therefore a more rigorous endpoint for clinical trials, while CIN 2 represents the threshold for treatment to provide an additional measure of safety.
Approximately 15 cancer-associated (high-risk or carcinogenic) HPV genotypes cause virtually all cases of cervical cancer and precursor lesions of CIN 2 and CIN 3. However, carcinogenic HPV infections are very common, particularly in young women, and the majority clear on their own within 1 to 2 years. Therefore, the challenge of incorporating HPV testing in cervical screening programs is to balance sensitivity for detection of CIN 2 or CIN 2+ and to minimize the over-referral of women with transient HPV infections and cervical changes that are destined to regress.
The U.S. Food and Drug Administration (FDA) has approved several HPV tests. Most of these tests are based on the detection of DNA from one or more oncogenic types of HPV. One test detects HPV RNA. HPV testing is approved for use in two contexts: (1) as a second (i.e., triage) test following an equivocal cytology result of ASCUS; and (2) for primary screening in conjunction with cervical cytology for women aged 30 years and older..
A large randomized clinical trial, the ASCUS/LSIL Triage Study (ALTS), demonstrated the cost-effectiveness of using HPV testing to clarify the risk of an ASCUS Pap result. ALTS randomly assigned women with ASCUS to one of three management strategies: Immediate colposcopy regardless of enrollment test results, referral to colposcopy if the HPV test was positive or if the enrollment cytology was HSIL, and referral to colposcopy only if the cytology was HSIL. The HPV triage strategy was as sensitive for detection of CIN 2+ as immediate colposcopy, while referring only about half of the women for the procedure. Repeat cytology with referral to colposcopy at the threshold of HSIL was less sensitive for CIN 3+ (60%) compared with HPV triage (92%); however, using a cytologic threshold of ASCUS for referral increased sensitivity but resulted in 72% of women with ASCUS undergoing colposcopy. HPV testing is not recommended for adolescent women with ASCUS because most of these women are HPV positive.[47,48]
HPV DNA testing is generally not appropriate or clinically useful following cytology results of LSIL, which is more severe than ASCUS, and most of these women (84%–96%) are carcinogenic HPV DNA positive. One exception may be to clarify the risk for postmenopausal women with cytologic LSIL, which is an interpretation that can be falsely positive, presumably due to atrophic changes.