title: Role of the Biomarker p16 in Downgrading -IN 2 Diagnoses and Predicting Higher-grade Lesions.
abstract: 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.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Kruti P
authors.initials: KP
authors.lastname: Maniar
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sanchez
authors.forename: Ajit
authors.initials: A
authors.lastname: Paintal
authors.forename: Demirkan B
authors.initials: DB
authors.lastname: Gursel
authors.forename: Ritu
authors.initials: R
authors.lastname: Nayar
mesh_terms: D000328:Adult; D000368:Aged; D001005:Anus Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000628:therapy / Q000821:virology; D014408:Biomarkers, Tumor / Q000032:analysis*; D001706:Biopsy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D015588:Observer Variation; D030361:Papillomavirus Infections / Q000821:virology; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D065310:Squamous Intraepithelial Lesions of the Cervix / Q000378:metabolism* / Q000473:pathology / Q000628:therapy / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000628:therapy / Q000821:virology; D014625:Vaginal Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000628:therapy / Q000821:virology; D014846:Vulvar Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000628:therapy / Q000821:virology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000737:chemistry* / Q000473:pathology / Q000628:therapy / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16