p16/ki‐67 dual‐stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology

Abstract

BACKGROUND:The objective of this study was to analyze the diagnostic performance of a newly established immunocytochemical dual‐stain protocol, which simultaneously detects p16INK4a and Ki‐67 expression in cervical cytology samples, for identifying high‐grade cervical intraepithelial neoplasia (CIN2+) in women with Papanicolaou (Pap) cytology results categorized as atypical squamous cells of undetermined significance (ASCUS) or low‐grade squamous intraepithelial lesions (LSIL).METHODS:Residual liquid‐based cytology material from 776 retrospectively collected ASCUS/LSIL cases that were available from a recent study evaluating p16 cytology and HPV testing were subjected to p16/Ki‐67 dual staining. The presence of 1 or more double‐immunoreactive cell(s) was regarded as a positive test outcome, irrespective of morphology. Test results were correlated to histology follow‐up.RESULTS:Sensitivity of p16/Ki‐67 dual‐stain cytology for biopsy‐confirmed CIN2+ was 92.2% (ASCUS) and 94.2% (LSIL), while specificity rates were 80.6% (ASCUS) and 68.0% (LSIL), respectively. Similar sensitivity/specificity profiles were found for both age groups of women aged <30 years versus women aged ≥30 years. Dual‐stain cytology showed comparable sensitivity, but significantly higher specificity, when compared with human papillomavirus (HPV) testing.CONCLUSIONS:The results of this study show that p16/Ki‐67 dual‐stain cytology provided a high sensitivity for the detection of underlying CIN2+ in women with ASCUS or LSIL Pap cytology results, comparable to the rates previously reported for HPV testing and p16 single‐stain cytology. However, the specificity of this morphology‐independent interpretation of p16/Ki‐67 dual‐stain cytology testing was further improved compared with the earlier p16 single‐stain cytology approach, which required morphology interpretation, and it is significantly higher when compared with HPV testing. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.

p16/Ki-67 Dual-Stained Cytology Testing May Predict Postpartum Outcome in Patients with Abnormal Papanicolaou Cytology during Pregnancy

“…All cases of CIN2 or CIN3 that were histologically confirmed postpartum were identified by a positive dual-stained cytology result, while the test had a high specificity using the same CIN2+ threshold. These results are in accordance with previous studies, which have shown that dual-stained cytology combines both high sensitivity and high specificity for the detection of underlying high-grade cervical intraepithelial neoplasia [8,10,11,14]. …”

“…Several recent studies have shown that p16/Ki-67 positivity is strongly associated with the presence of transforming HPV infections and histologic abnormalities [8,9,10,11,12,13,14]. To date, there are no data on the efficiency of this new diagnostic tool in prenatal care.…”

Human Papillomavirus Laboratory Testing: the Changing Paradigm

“…Similarly, studies that evaluated immunostaining for p16 tumor suppressor protein as a surrogate biomarker for the presence of highrisk HPV in cytology smears that had subsequent CIN 2ϩ or CIN 3ϩ biopsy results have shown that performance characteristics were not sufficient to add value as a triage test (87,(114)(115)(116). Other biomarkers, such Ki-67 to detect deregulated cell cycle proliferation, dual staining for Ki-67 plus p16, and BD ProEx C (Becton, Dickinson and Company, Franklin Lakes, NJ) to detect aberrant S-phase induction, genes with aberrant DNA methylation, and chromosomal aberrations in the telomerase RNA gene have not proven useful, or there is insufficient evidence related to the clinical value of the test (117)(118)(119)(120)(121)(122)(123). Further, the leading medical professional societies have not recommended these tests in their cervical cancer screening guidelines.…”

Immunomarkers in Gynecologic Cytology: The Search for the Ideal ‘Biomolecular Papanicolaou Test’

“…MIB-1 complements p16 INK4A in the analysis of histological sections by differentiating SIL from atrophic epithelium with atypia [24]. Its complementary role to p16 INK4A in cytology has also been tested [16,30,33,35,36] and is discussed below.…”

“…The authors found the combination of p16 INK4a and MIB-1 useful for the management of women with equivocal cytology. Evidence from these studies resulted in the development of an ICC dual-stain protocol, which simultaneously detects p16 INK4A and Ki-67 expression in cervical cytology samples [36,65]. The p16 INK4A /Ki-67 dual stain was tested on ASC-US/LSIL cases for HSIL identification, and immunostain positivity was scored independently of the interpretation of cytomorphological abnormalities.…”