A large study that included data from the National Breast and Cervical Cancer Early Detection Program together with modeling found little further mortality reduction from cervical cancer for screening every year as compared with screening every 3 years. A similar modeling study from Australia found no differences between every 2 year and every 3 year screening.
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 an HPV DNA test. One of these tests is Hybrid Capture 2 (HC2), which is designed to detect 13 carcinogenic HPV types. The HPV HC2 test is performed on a cervical sample, using either residual specimen from liquid-based cytology collection or a separately collected cervical specimen. The FDA-approved threshold for a positive result is 1.0 relative light unit compared with a 1 pg/mL HPV DNA positive control, in which interlaboratory reliability and reproducibility are excellent.
A second DNA-based HPV test, Cervista, has been approved by the FDA. The sensitivity and specificity of this test to detect cervical disease has not been published.
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. The ALTS trial used the HC2 test. 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.[53,54]