Triage
Primary Screening

Non-invasive cervical squamous cell abnormalities are graded histologically as cervical intraepithelial neoplasia (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.[1] CIN 2 has poor interobserver reproducibility,[2] and the biologic behavior is variable.[3] CIN 3 is therefore a more rigorous endpoint for clinical trials, while CIN 2 represents the threshold for treatment in order to provide an additional measure of safety.

Approximately 15 cancer-associated (high-risk or carcinogenic) human papillomavirus (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.

Currently, the only U.S. Food and Drug Administration (FDA) approved HPV DNA test is Hybrid Capture 2 (HC2), 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.[4]

HC2 is approved for use in two contexts: (1) as a second (i.e., triage) test following an equivocal cytology result of atypical squamous cells of undetermined significance (ASCUS); and (2) for primary screening in conjunction with cervical cytology for women aged 30 years and older.[5]

A large randomized clinical trial, the ASCUS/Low-Grade Squamous Intraepithelial Lesions (LSIL) Triage Study (ALTS) demonstrated the cost effectiveness of using HPV testing to clarify the risk of an ASCUS Papanicolaou (Pap) result.[6] 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 the enrollment cytology was high-grade squamous intraepithelial lesions (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.[7] HPV testing is not recommended in adolescent women with ASCUS as the majority of such women are HPV positive.[8,9]

HPV DNA testing is generally not appropriate or clinically useful following cytology results of LSIL, which is more severe than ASCUS, and the vast majority of such women (84%–96%) are carcinogenic HPV DNA positive.[10] 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.[11]

Testing for HPV DNA as a primary screening test has been FDA approved only in conjunction with cervical cytology and only in women aged 30 years and older. Women who are negative by cytology and HPV testing are at extremely low risk of CIN 3 or cancer (CIN 3+) and therefore may be screened less often. Screening more frequently than every three years would not improve sensitivity significantly, but would increase costs and overtreatment.[12,13]

Numerous studies have demonstrated that, compared with cytology, HPV DNA testing is more sensitive for identifying women who have CIN 2+ (range of sensitivities 84%–97%).[14-20] In one randomized trial using both Pap and HPV testing in random order among women aged 30 to 69 years, sensitivity of HPV was 95% compared with 55% for Pap cytology. The combination of HPV and cytology had 100% sensitivity and a referral rate of 7.9%.[15]

The lower specificity of HPV DNA testing compared with cytology is a consideration. Among women older than 30 years, cytology had a specificity of 97% compared with 94% for HPV testing.[15] The specificity of HPV DNA testing would likely be even lower among women younger than 30 years who have more transient HPV infection that is of little consequence. Thus, detecting such women would potentially increase the number of follow-up diagnostic workups. Potential approaches to minimize over-referral with HPV DNA testing and improve specificity, include: (1) triage HPV positive results with cytology;[20] or another more specific molecular assay;[21] and (2) trigger further workup only after two sequential positive HPV test results as it is the persistence of carcinogenic HPV that confers the greatest risk of CIN 2/3.[22,23]

A study using data from a population-based randomized trial of cervical screening among women aged 32 to 38 years, compared 11 different screening strategies using HPV DNA testing and cytology. The strategy of initial screening with an HPV DNA test and a triage of HPV-positive results with cytology, and subsequent repeat HPV DNA testing after 1 year for women who were HPV-positive but cytology-negative, increased the sensitivity for detection of CIN 3+ by 30% compared with cytology alone, and increased the total number of screening tests performed by only 12%.[24]

References

1. McCredie MR, Sharples KJ, Paul C, et al.: Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol 9 (5): 425-34, 2008.  [PUBMED Abstract]
   
   
2. Stoler MH, Schiffman M; Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group.: Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 285 (11): 1500-5, 2001.  [PUBMED Abstract]
   
   
3. Castle PE, Schiffman M, Wheeler CM, et al.: Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol 113 (1): 18-25, 2009.  [PUBMED Abstract]
   
   
4. Carozzi FM, Del Mistro A, Confortini M, et al.: Reproducibility of HPV DNA Testing by Hybrid Capture 2 in a Screening Setting. Am J Clin Pathol 124 (5): 716-21, 2005.  [PUBMED Abstract]
   
   
5. New Device Approval: Digene Hybrid Capture 2 High-Risk HPV DNA Test - P890064 S009 A004 . Rockville, Md: U.S. Food and Drug Administration, Center for Devices and Radiological Health, 2003. Available Online. Last accessed February 10, 2009. 
   
   
6. Kulasingam SL, Kim JJ, Lawrence WF, et al.: Cost-effectiveness analysis based on the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion Triage Study (ALTS). J Natl Cancer Inst 98 (2): 92-100, 2006.  [PUBMED Abstract]
   
   
7. ASCUS-LSIL Traige Study (ALTS) Group.: Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 188 (6): 1383-92, 2003.  [PUBMED Abstract]
   
   
8. Wright TC Jr, Massad LS, Dunton CJ, et al.: 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 197 (4): 346-55, 2007.  [PUBMED Abstract]
   
   
9. Sherman ME, Schiffman M, Cox JT, et al.: Effects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst 94 (2): 102-7, 2002.  [PUBMED Abstract]
   
   
10. ASCUS-LSIL Traige Study (ALTS) Group.: A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol 188 (6): 1393-400, 2003.  [PUBMED Abstract]
    
    
11. Zuna RE, Wang SS, Rosenthal DL, et al.: Determinants of human papillomavirus-negative, low-grade squamous intraepithelial lesions in the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions triage study (ALTS). Cancer 105 (5): 253-62, 2005.  [PUBMED Abstract]
    
    
12. Saslow D, Runowicz CD, Solomon D, et al.: American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 52 (6): 342-62, 2002 Nov-Dec.  [PUBMED Abstract]
    
    
13. Goldie SJ, Kim JJ, Wright TC: Cost-effectiveness of human papillomavirus DNA testing for cervical cancer screening in women aged 30 years or more. Obstet Gynecol 103 (4): 619-31, 2004.  [PUBMED Abstract]
    
    
14. Arbyn M, Sasieni P, Meijer CJ, et al.: Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine 24 (Suppl 3): S3/78-89, 2006.  [PUBMED Abstract]
    
    
15. Mayrand MH, Duarte-Franco E, Rodrigues I, et al.: Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 357 (16): 1579-88, 2007.  [PUBMED Abstract]
    
    
16. Naucler P, Ryd W, Törnberg S, et al.: Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 357 (16): 1589-97, 2007.  [PUBMED Abstract]
    
    
17. Bulkmans NW, Berkhof J, Rozendaal L, et al.: Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 370 (9601): 1764-72, 2007.  [PUBMED Abstract]
    
    
18. Cuzick J, Szarewski A, Cubie H, et al.: Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet 362 (9399): 1871-6, 2003.  [PUBMED Abstract]
    
    
19. Hartmann KE, Hall SA, Nanda K, et al.: Screening for Cervical Cancer. Rockville, Md: Agency for Health Research and Quality, 2002. Available online. Last accessed February 12, 2009. 
    
    
20. Cuzick J, Clavel C, Petry KU, et al.: Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 119 (5): 1095-101, 2006.  [PUBMED Abstract]
    
    
21. Carozzi F, Confortini M, Dalla Palma P, et al.: Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 9 (10): 937-45, 2008.  [PUBMED Abstract]
    
    
22. Koshiol J, Lindsay L, Pimenta JM, et al.: Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis. Am J Epidemiol 168 (2): 123-37, 2008.  [PUBMED Abstract]
    
    
23. Castle PE: Invited commentary: is monitoring of human papillomavirus infection for viral persistence ready for use in cervical cancer screening? Am J Epidemiol 168 (2): 138-44; discussion 145-8, 2008.  [PUBMED Abstract]
    
    
24. Naucler P, Ryd W, Törnberg S, et al.: Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst 101 (2): 88-99, 2009.  [PUBMED Abstract]
    
    

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