An analysis of high-risk human papillomavirus DNA-negative cervical precancers in the ASCUS-LSIL Triage Study (ALTS)

Obstet Gynecol. 2008 Apr;111(4):847-56. doi: 10.1097/AOG.0b013e318168460b.


Objective: To describe women diagnosed with cervical intraepithelial neoplasia-grade 3 (CIN-3) diagnosed over the 2-year duration of the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) Triage Study (ALTS) that tested negative for high-risk human papillomavirus (HPV) at enrollment.

Methods: Clinical center pathologists and quality control pathology group reviewed all histology; any CIN-3 diagnosis on biopsy or loop electrosurgical excision procedure (n=621) by at least one pathology review over the duration of ALTS led to inclusion in this analysis. Enrollment cervical specimens were tested for high-risk HPV DNA by two HPV assays; results were combined to minimize simple testing errors. We compared the characteristics of baseline high-risk HPV-negative (n=33) to baseline high-risk HPV-positive (n=588) cumulative diagnosed CIN-3.

Results: High-risk HPV-negative CIN-3 cases were less likely to have a second, confirming diagnosis of CIN-3 (24% compared with 56%) by the other pathology group, were more likely to be diagnosed later in follow-up, and more likely to be referred into ALTS because of an ASCUS Pap test rather than an LSIL Pap. Upon review of case histories of the 33 baseline high-risk HPV-negative CIN-3 (5.3% of all cases), there was evidence that these cases were due to incident (new) cases (n=12, 1.9%), non-high-risk HPV (n=5, 0.8%), misclassified histology (n=8, 1.3%), and false-negative high-risk HPV (n=8, 1.3%).

Conclusion: In any sizeable population, even among women with evidence of cytologic abnormalities, there will be a few cases of cervical precancer that will test high-risk HPV negative for one or more reasons.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Alphapapillomavirus
  • Cervical Intraepithelial Neoplasia / diagnosis*
  • DNA, Viral / analysis
  • Female
  • Humans
  • Precancerous Conditions / diagnosis*
  • Sensitivity and Specificity
  • Uterine Cervical Neoplasms / diagnosis*


  • DNA, Viral