Role of the biomarker p16 in downgrading-IN 2 diagnoses and predicting higher-grade lesions

Kruti P. Maniar*, Beatriz Sanchez, Ajit Paintal, Demirkan B. Gursel, Ritu Nayar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


In 2012, the College of American Pathologists and American Society for Colposcopy and Cervical Pathology published the "LAST" recommendations for histopathology reporting of human papilloma virus-related squamous lesions of the lower anogenital tract, including the use of a 2-tier nomenclature (low-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion [LSIL/HSIL]) and expanded use of the biomarker p16 to classify equivocal lesions as either precancer (HSIL) or low-grade lesions (LSIL)/non-human papilloma virus changes. We aimed to determine (1) the frequency with which the poorly reproducible diagnosis of intermediate-grade (-IN 2) lesion in the lower anogenital tract would be downgraded on the basis of p16 results, and (2) whether p16 status was predictive of subsequent higher-grade lesions. A total of 200 specimens diagnosed as an intermediate-grade (-IN 2) lesion of the cervix (168), vagina (2), vulva (2), and anus (28) were reviewed and immunostained for p16. Slides were independently reviewed by 2 pathologists, with discrepant p16 interpretations adjudicated by a third pathologist. Of the 200 cases, 32% were negative for p16. Among the 166 patients with subsequent pathology (including 131 excisions), 26.2% of p16-positive cases versus 4.4% of p16-negative cases were associated with a subsequent diagnosis of HSIL (-IN 3) or worse (P=0.002). Reproducibility of the biopsy diagnosis was fair, with no significant difference with the addition of p16 or using 2 versus 3 tiers. In 11.5% of cases, there was discordance in p16 interpretation (κ 0.735, good agreement). The results indicate that using the Lower Anogenital Squamous Terminology recommendations would result in approximately one third of equivocal (-IN 2) diagnoses being downgraded to LSIL over 1 year in a busy academic practice. The significant association of p16 expression with a higher risk for HSIL on a subsequent specimen suggests that use of p16 to adjudicate equivocal (-IN 2) diagnoses in lower anogenital tract specimens as either LSIL or HSIL would likely predict lesion grade more accurately and avoid unnecessary excisional procedures.

Original languageEnglish (US)
Pages (from-to)1708-1718
Number of pages11
JournalAmerican Journal of Surgical Pathology
Issue number12
StatePublished - Dec 1 2015


  • AIN 2
  • CIN 2
  • Lower Anogenital Squamous Terminology (LAST) project
  • VAIN 2
  • VIN 2
  • intraepithelial neoplasia
  • p16ink4

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine


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