Evaluation of p16INK4a, minichromosome maintenance protein 2, DNA topoisomerase IIα, ProEX C, and p16INK4a/ProEX C in cervical squamous intraepithelial lesions

Shi, Jianhui; Liu, Haiyan; Wilkerson, Myra L.; Huang, Yajue; Meschter, Steven; Dupree, William B.; Schuerch, Conrad; Lin, Fan

doi:10.1016/j.humpath.2007.01.025

Cited by 70 publications

(54 citation statements)

References 26 publications

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“…Interestingly, the ProEx C signal intensity in these occasional LSIL cases was typically stronger than with p16 and MiB-1 ( Figure 3b), corroborating the results of a recent study. 10 Focusing on the detection of LSIL, Shi et al, explored the role of the same biomarkers as in this study and found that compared with MiB-1 (85.3%) and p16 (76.5%) ProEx C not only had a higher sensitivity (94.1%), but also showed a stronger and more diffuse nuclear staining for LSIL cases. In the present study, we observed a larger number of cells stained by ProEx C in comparison with MiB-1 in both HSIL and LSIL cases (Figure 3).…”

Section: Discussionmentioning

confidence: 64%

“…6,[12][13][14][15] ProEx C has been proposed as a marker with a potential to detect HSIL in cervical biopsy specimens 10 and liquid-based cervical cytology. 16,17 To date, only one other study has investigated the sensitivity and specificity of ProEx C in histopathological specimens.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 To date, only one other study has investigated the sensitivity and specificity of ProEx C in histopathological specimens. 10 As mentioned above, the authors focused on LSILs, and included a limited sample of HSILs (14 cases) and benign squamous mucosa (14 cases). They found a sensitivity of 78.6% for HSIL detection; the specificity in their series was 100% for HSILs.…”

Section: Discussionmentioning

confidence: 99%

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Biomarker (ProEx C, p16INK4A, and MiB-1) distinction of high-grade squamous intraepithelial lesion from its mimics

et al. 2008

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Topoisomerase IIa and minichromosome maintenance protein 2 are proteins associated with aberrant S-phase induction. The current study evaluated the performance of these biomarkers (ProExt C; TriPath Oncology, Burlington, NC) compared with p16INK4A and MiB-1 in distinguishing high-grade squamous intraepithelial lesions (HSILs) from HSIL mimics. We collected archival cervical biopsy, cone, and curettage specimens from 96 cases in which the differential diagnosis of HSIL vs reactive epithelial changes was considered. Hematoxylinand eosin-stained slides were reviewed independently by three pathologists and scored for the presence or absence of SIL. Immunostains for ProEx C, p16, and MiB-1 were available for 95, 96, and 59 samples, respectively, and classified blinded to histological interpretation. Strong nuclear and cytoplasmic staining for p16 and staining for MiB-1 and ProEx C that extended beyond the lower one-third of the epithelium were scored as positive. v 2 -tests and receiver operating characteristic analysis were conducted to statistically compare biomarker immunostaining performance against majority histological interpretation of SIL. Agreement between pathologists was also assessed by the j-statistic. Inter-observer agreement ranged from fair to moderate (j ¼ 0.37-0.57). All three biomarkers correlated strongly with the majority diagnosis of SIL (Po0.001). Positive staining for ProEx C, p16, and MiB-1 was observed in 87% (N ¼ 52/60), 84% (N ¼ 51/61), and 94% (34/36), respectively, of SIL and negative in 71% (N ¼ 25/35), 63% (N ¼ 22/35), and 52% (N ¼ 12/23), respectively, of majority diagnoses of NoSIL. The combination of p16/ProEx C predicted more SIL (92%, N ¼ 33/36) and NoSIL (61%, N ¼ 14/23) than p16 plus MiB-1 (94%, N ¼ 34/36 and 43%, N ¼ 10/23), although this difference was not statistically significant. ProEx C appears to provide an equivalent level of sensitivity and a higher level of specificity for HSIL alone or in conjunction with p16. Its principal value may be in providing a lower false positive rate for NoSIL relative to MiB-1.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Biomarker (ProEx C, p16INK4A, and MiB-1) distinction of high-grade squamous intraepithelial lesion from its mimics

et al. 2008

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“…P16 INK4a (p16) is a kind of anti-oncogene and considered as a preferable substitute marker for Hr-HPV infection [1][2][3][4][5][6][7][8][9][10][12][13][14][15][16][17][18]. As a cyclin-dependent kinase inhibitor, p16 competes with cyclin D1 to combine with CDK4/6 and specifically suppresses the activity of CDK4, inhibiting the CDK-induced phosphorylation of pRb and arresting the cell transition from G1 phase to S phase, thereby playing a role in feedback control of mitosis.…”

Section: Introductionmentioning

confidence: 99%

A cocktail of MCM2 and TOP2A, p16 INK4a and Ki-67 as biomarkers for the improved diagnosis of cervical intraepithelial lesion

Yang

Zhu²,

Liou³

et al. 2013

pjp

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The purpose of this paper was to explore the immunohistochemistry (IHC) results for a cocktail of minichromosome maintenance protein 2 (MCM2) and topoisomerase IIα (TOP2A), p16 INK4a and Ki-67 as biomarkers for the diagnosis of cervical intraepithelial neoplasia (CIN), improving the routine interpretation of cervical histopathology. 133 cases of CIN were collected from the archival data. All routine hematoxylin and eosin (HE)-stained slides of the subjects were re-examined independently by three senior pathologists, to provide a "consensus diagnosis". Immunohistochemistry for the three biomarkers was performed, and the results were reviewed independently of the corresponding archival diagnosis to make a "diagnosis assisted by IHC" by the original pathological practitioners. The diagnosis accordance rate of the archival original diagnosis with the "consensus diagnosis" and the "diagnosis assisted by IHC" with the "consensus diagnosis" were verified by Fisher's exact test. The results showed that raw agreement between the original HE diagnosis and the "consensus diagnosis" was 88.55%, and raw agreement between the "diagnosis assisted by IHC" and the "consensus diagnosis" was 95.78%. The latter was significantly higher than the former (Fisher's exact test, p = 0.023). In conclusion, the three biomarkers had a high degree of sensitivity and specificity, and appear to be a useful and reliable diagnostic adjunct to improve the routine diagnosis, and reduce inter-observer variability in cervical biopsy specimens.

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“…Its expression is directly associated with the action of the HPV oncogene, as continuous expression of E7 is necessary to maintain a malignant phenotype in HPV-associated cancer (26). Several studies have shown that positive p16 immunostaining is significantly associated with CIN2/3 or carcinoma (27)(28)(29)(30)(31)(32)(33)(34). Although varying efficacy of p16 immunostaining in CIN2-3 or carcinoma has Table IV.…”

Section: Discussionmentioning

confidence: 99%

Cervical intraepithelial neoplasia in pregnancy: Interference of pregnancy status with p16 and Ki-67 protein expression

et al. 2016

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Abstract. To date, there are evidence-based guidelines available for cervical dysplasia diagnosed in pregnancy. Certain functional biomarkers have proven useful in the prediction of regressing and non-regressing cervical intraepithelial neoplasia (CIN) lesions in non-pregnant women. In the present study, Ki-67 and p16 immunostaining were evaluated in different grades of CIN lesions diagnosed in pregnant or non-pregnant women with the aim to identify any differences in order to better understand the behavior of CIN in pregnancy. The current retrospective case-control study included 17 pregnant patients that conceived naturally with first-time onset of CIN occurring at no later than 16 gestational weeks. The control group included 17 non-pregnant patients matched for age, parity and number of previous sexual partners. Exclusion criteria included previous cervical treatment, immunocompromised status, chronic hepatitis B and/or C and cigarette smoking. p16 and Ki-67 protein expression were respectively detected using the CINtec Histology kit and monoclonal antibodies against Ki-67. p16 and Ki-67 staining were analyzed using a classification system based on the distribution of positivity on a semi-quantitative three point-scale. p16 and Ki-67 immune reactivity correlated positively with the grade of epithelial dysplasia in the total cohort of pregnant and non-pregnant patients; expression increased linearly from CIN1 to CIN3. Furthermore, the association between p16 immunostaining and CIN grade was significant in non-pregnant patients but not in pregnant patients. In pregnant patients, positivity for Ki-67 was less intense than in non-pregnant patients. These results appear to suggest that pregnancy status interferes with the expression of cellular proteins involved in cell-cycle regulation and the carcinogenic process induced by high-risk human papilloma virus, exhibiting increased variability in their staining. IntroductionThe results of Pap tests performed during routine screenings at the beginning of prenatal care are abnormal in 8-12% of cases (1). Overall, the prevalence of abnormal cervical cytology in pregnancy is similar to that of age-matched, non-pregnant women (2). The incidence of cervical intraepithelial neoplasia (CIN) in pregnancy varies among different patient populations, as it does in non-pregnant women, but when age-matched, the risk of CIN is not higher than that among women who are not pregnant, ranging between 3.4 and 10.0% (3). The management of pregnant women with abnormal cytology depends on the degree of cytological abnormality, the outcome of colposcopy, and, when necessary, directed biopsy. Since, the only diagnosis that may alter management in pregnancy is invasive cancer, the management of pregnant women with abnormal cervical cytology or biopsy-proven CIN is generally more conservative compared with management of similar cytology and histology in non-pregnant women. However, management guidelines for cervical dysplasia are not well defined and are based on data collected from non-pregn...

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Evaluation of p16INK4a, minichromosome maintenance protein 2, DNA topoisomerase IIα, ProEX C, and p16INK4a/ProEX C in cervical squamous intraepithelial lesions

Cited by 70 publications

References 26 publications

Biomarker (ProEx C, p16INK4A, and MiB-1) distinction of high-grade squamous intraepithelial lesion from its mimics

Biomarker (ProEx C, p16INK4A, and MiB-1) distinction of high-grade squamous intraepithelial lesion from its mimics

A cocktail of MCM2 and TOP2A, p16 INK4a and Ki-67 as biomarkers for the improved diagnosis of cervical intraepithelial lesion

Cervical intraepithelial neoplasia in pregnancy: Interference of pregnancy status with p16 and Ki-67 protein expression

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