Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance

  • The ASCUS-LSIL Triage Study (ALTS)* Group


      Objective: This study was undertaken to compare alternative strategies for the initial management of a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS). Study Design: A total of 3488 women with a community-based ASCUS interpretation were randomly assigned to immediate colposcopy, triage that was based on enrollment HPV DNA testing and liquid-based cytology at a colposcopy referral threshold of high-grade squamous intraepithelial lesion (HSIL), or conservative management based on repeat cytology at a referral threshold of HSIL. All arms included 2 years of semiannual follow-up and colposcopy at exit. Loop electrosurgical excision procedure was offered to women with histologic diagnoses of cervical intraepithelial neoplasia (CIN) grade 2 or 3 at any visit or persistent CIN grade 1 at exit. The study end point was 2-year cumulative diagnosis of CIN grade 3. Results: The 2-year cumulative diagnosis of CIN grade 3 was 8% to 9% in all study arms. The immediate colposcopy strategy yielded 53.6% sensitivity for cumulative cases of CIN grade 3 diagnosed over 2 years. The human papillomavirus (HPV) triage strategy referred 55.6% of women and detected 72.3% of cumulative cases of CIN grade 3. A conservative management strategy of repeat cytology at the HSIL threshold referred 12.3% of women while detecting 54.6% of cumulative CIN grade 3. To compare triage tests, we re-estimated the performance of HPV and cytology in successfully referring women with underlying CIN grade 3 (ie, ignoring the insensitivity we discovered in colposcopically directed biopsies). A single enrollment HPV test identified 92.4% of the women diagnosed with CIN grade 3. Serial cytology, even at an ASCUS threshold, would have required two visits to achieve similar sensitivity (95.4%) and would have referred 67.1% to colposcopy. Conclusion: HPV triage is at least as sensitive as immediate colposcopy for detecting CIN grade 3 and refers about half as many women to colposcopy. Follow-up that used repeat cytology is sensitive at an ASCUS referral threshold but requires two follow-up visits and ultimately more colposcopic examinations than HPV triage. (Am J Obstet Gynecol 2003;188:1383-92.)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Broder S.
        Rapid communication.
        JAMA. 1992; 267: 1892
        • Kurman RJ
        • Henson DE
        • Herbst AL
        • Noller KL
        • Schiffman ME.
        Interim guidelines for management of abnormal cervical cytology: the 1992 National Cancer Institute Workshop.
        JAMA. 1994; 271: 1866-1869
        • ASCUS-LSIL Triage Study ALTS Group
        A randomized trial on the management of LSIL cytology interpretations.
        Am J Obstet Gynecol. 2003; 188: 1393-1400
        • Cox JT
        • Schiffman M
        • Solomon D
        • ASCUS LSIL Triage Study Group
        Prospective follow-up suggest similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy.
        Am J Obstet Gynecol. 2003; 188: 1406-1412
        • Guido R
        • Schiffman M
        • Solomon D
        • Burke L
        • ASCUS LSIL Triage Study Group
        Postcolposcopy management strategies for patients referred with low-grade squamous intraepithelial lesions or human papillomavirus DNA-positive atypical squamous cells of undetermined significance: a two-year prospective study.
        Am J Obstet Gynecol. 2003; 188: 1401-1405
        • Schiffman M
        • Adrianza ME
        • ALTS Group
        The ASCUS-LSIL Triage Study (ALTS): design, methods, and characteristics of trial participants.
        Acta Cytol. 2000; 44: 726-742
        • Wright Jr, TC
        • Cox JT
        • Massad LS
        • Twiggs LB
        • Wilkinson EJ
        • 2001 ASCCP-Sponsored Consensus Conference
        2001 Consensus guidelines for the management of women with cervical cytological abnormalities.
        JAMA. 2002; 287: 2120-2129
        • Frable WJ.
        ASCUS! ASCUS! Down the rabbit hole.
        Cancer Cytopathol. 1999; 87 ([editorial]): 319-321
        • Jones DE
        • Creasman WT
        • Combroski RA
        • Lentz SS
        • Waeltz JL.
        Evaluation of the atypical Pap smear.
        Am J Obstet Gynecol. 1987; 157: 544-549
        • Koss LG.
        The Papanicolaou test for cervical cancer detection: a triumph and a tragedy.
        JAMA. 1989; 261: 737-743
        • Bosch FX
        • Manos MM
        • Munoz N
        • Sherman M
        • Jansen AM
        • Peto J
        • et al.
        Prevalence of human papillomavirus in cervical cancer: a worldwide perspective: International Biological Study on Cervical Cancer (IBSCC) Study Group.
        J Natl Cancer Inst. 1995; 87: 796-802
        • National Cancer Institute Workshop
        The 1988 Bethesda System for reporting cervical/vaginal cytologic diagnoses.
        JAMA. 1988; 262: 931-934
        • Solomon D
        • Davey D
        • Kurman R
        • Moriarty A
        • O'Connor D
        • Prey M
        • et al.
        The 2001 Bethesda System terminology for reporting results of cervical cytology.
        JAMA. 2002; 287: 2114-2119
        • Wright Jr, TC
        • Lorincz AT
        • Ferris DG
        • Rickart RM
        • Ferenczy A
        • Mielzynska I
        • et al.
        Reflex HPV DNA testing in women with abnormal Papanicolaou smears.
        Am J Obstet Gynecol. 1998; 178: 962-966
        • Manos MM
        • Kinney WK
        • Hurley LB
        • Sherman ME
        • Shieh-Ngai J
        • Kurman RJ
        • et al.
        Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results.
        JAMA. 1999; 281: 1605-1610
        • Bergeron C
        • Jeannel D
        • Poveda J
        • Cassonnet P
        • Orth G.
        Human papillomavirus testing in women with mild cytologic atypia.
        Obstet Gynecol. 2000; 95: 821-827
        • Lin CT
        • Tseng CJ
        • Lai CH
        • Hsueh S
        • Huang HJ
        • Law KS.
        High-risk HPV DNA detection by Hybrid Capture II: an adjunctive test for mildly abnormal cytologic smears in women τ or + 50 years of age.
        J Reprod Med. 2000; 45: 345-350
        • Shlay JC
        • Dunn T
        • Byers T
        • Baron AE
        • Douglas Jr., JM
        Prediction of cervical intraepithelial neoplasia grade 2-3 using risk assessment and human papillomavirus testing in women with atypia on Papanicolaou smears.
        Obstet Gynecol. 2000; 96: 410-416
        • Solomon D
        • Schiffman M
        • Tarone R
        • ALTS Study group
        Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial.
        J Natl Cancer Inst. 2001; 93: 293-299
        • Stoler MH
        • Schiffman M
        • ALTS group
        Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates for the ASCUS-LSIL Triage Study.
        JAMA. 2001; 285: 1500-1505
        • Eskridge C
        • Begneaud WP
        • Landwehr C.
        Cervicography combined with repeat Papanicolaou test as triage for low-grade cytologic abnormalities.
        Obstet Gynecol. 1998; 92: 351-355
        • Kim JJ
        • Wright TC
        • Goldie SJ.
        Cost-effectiveness of alternative triage strategies for atypical squamous cells of undetermined significance.
        JAMA. 2002; 287: 2382-2390