Evaluation of Ki67, p16 and CK17 Markers in Differentiating Cervical Intraepithelial Neoplasia and Benign Lesions

Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
Iranian Journal of Medical Sciences 03/2013; 38(1):15-21.
Source: PubMed

ABSTRACT Background: Cervical intraepithelial neoplasia (CIN) is a premalignant lesion capable of progressing to cervical cancer. Despite the existing well-defined criteria, the histomorphologic diagnosis is subject to high rates of discordance among pathologists. The aim of this study was to evaluate Ki-67 (MIB-1), CK17 and p16 INK4a (p16) markers by immunohistochemical methods in differentiating CIN from benign cervical lesions.

Methods: The present study reviewed and re-classified 77 cervical biopsies, originally diagnosed as 31 non-CIN, and 46 CIN, as 54 non-CIN, and 23 CIN based on at least two similar diagnoses. Immunostaining by Ki67, p16 and CK17 markers was performed on all cases and the results were compared with pervious and consensus diagnosis.

Results: The overall agreement between pervious and consensus diagnosis was 67.5% (Kappa=0.39, P<0.001). The sensitivity and specificity of Ki67 immunostaining were 95.6% and 85.1% respectively, while for p16 the corresponding values were 91.3% and 98.1%. The overall agreement, for both p16 and Ki67, with consensus diagnosis were significant (P<0.001). The sensitivity and specificity of CK17 negative staining in CIN detection were 39.1% and 40.7% respectively.

Conclusion: Ki67 and p16 markers are recommended as complementary tests for differentiating between dysplastic and non-dysplastic lesions. CK17 does not discriminate between immature metaplasia with and without dysplasia.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cervical cancer is the third most commonly diagnosed cancer worldwide and the fourth leading cause of cancer-related mortality in females worldwide, accounting for 10-15% of cancer-related mortalities. Cytological screening and DNA testing for high-risk human papillomavirus (HPV) types have markedly decreased the rates of cervical cancer in developed countries, however, for vulnerable populations without access to health care, cervical cancer remains a considerable problem. Chemotherapeutic agents such as cisplatin (DDP) are considered as first-line treatment for cervical carcinoma. Although initially patients often exhibit high responsiveness, the majority eventually develop DDP resistance. However, the mechanisms underlying this process remain unclear. Furthermore, patients with metastatic cancer and those exhibiting persistent or recurrent disease after platinum-based chemoradiotherapy have limited options and thus, non-platinum combination chemotherapy has been proposed as a strategy to circumvent platinum resistance, however, novel therapeutic strategies are required. In the present study, P16 expression was analyzed by quantitative-polymerase chain reaction and western blot analysis in SiHa and SiHa-DDP cells and the interaction between P16 and CDK4 was detected via co-immunoprecipitation. In addition, the proliferation and apoptosis rates of P16 knockdown SiHa-DDP cells were measured by MTT assay and Annexin V flow cytometry and the subsequent changes in cyclin D1 and pRb expression were analyzed by western blot analysis. In this study, a high level of P16(INK4A) expression and its enhanced interaction with cyclin-dependent kinase-4 in cervical carcinoma DDP-resistance cells (SiHa-DDP) was identified, which was associated with the inactivation of phosphorylated retinoblastoma protein (pRb). Knockdown of P16(INK4A) significantly induced cellular growth, when compared with the control cells, via the upregulation of pRb, and also promoted apoptosis following treatment with DDP. The results of this study indicated, for the first time, that P16(INK4A) is required for DDP resistance in cervical carcinoma SiHa cells and, thus, these results may lead to the development of novel strategies for the treatment of chemoresistant cervical carcinoma.
    Oncology letters 03/2015; 9(3):1104-1108. DOI:10.3892/ol.2014.2814 · 0.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Breast cancer is the most common malignancy and the leading cause of cancer death in women worldwide; however, early diagnosis has been difficult due to its complex pathological structure. This study evaluated the value of morphological examination in conjunction with dynamic contrast-enhanced MRI (DCE-MRI) for more precise diagnosis of breast cancer, as well as their correlation with angiogenesis and proliferation biomarkers. Material and Methods DCE-MRI parameters (including Ktrans: volume transfer coefficient reflecting vascular permeability, Kep: flux rate constant, Ve: extracellular volume ratio reflecting vascular permeability, and ADC: apparent diffusion coefficient) were obtained from 124 patients with breast cancer (124 lesions). Microvessel density (MVD) was evaluated by the immunohistochemical analysis of tumor vessels for CD31 and CD105 expression. The proliferation was assessed by analyzing Ki67. Results Ktrans values were in the order of: malignant lesions > benign lesions > normal glands. Similar results were observed for Kep. The opposite changes were seen with Ve. Ktrans and Kep values were significantly higher in invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS) than in mammary ductal dysplasia (MDD; ANOVA followed by Dunnett's test). In sharp contrast, ADC values were lower in IDC and DCIS than in MDD, and Ve was not significantly different among the three groups. The data from MIP (maximum intensity projection) showed that benign breast lesions had no or only one blood vessel, whereas malignant lesions had two or more blood vessels. In addition, expression of CD105 and Ki67, the commonly recognized markers for angiogenesis and proliferation, respectively, were closely correlated with MRI parameters as revealed by Pearson analysis. Conclusions Determination of Ktrans, Kep and ADC values permits estimation of tumor angiogenesis and proliferation in breast cancer and DCE-MRI parameters can be used as imaging biomarkers to predict patient prognosis and the biologic aggressiveness of the tumor.
    Medical science monitor: international medical journal of experimental and clinical research 01/2015; 21:376-82. DOI:10.12659/MSM.892534 · 1.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Cervical intraepithelial neoplasias (CIN) represent precursor lesions of cervical cancer. These neoplastic lesions are traditionally subdivided into three categories CIN 1, CIN 2, and CIN 3, using microscopical criteria. The relation between grades of cervical intraepithelial neoplasia (CIN) and its fractal dimension was investigated to establish a basis for an objective diagnosis using the method proposed. Methods Classical evaluation of the tissue samples was performed by an experienced gynecologic pathologist. Tissue samples were scanned and saved as digital images using Aperio scanner and software. After image segmentation the box counting method as well as multifractal methods were applied to determine the relation between fractal dimension and grades of CIN. A total of 46 images were used to compare the pathologist's neoplasia grades with the predicted groups obtained by fractal methods. Results Significant or highly significant differences between all grades of CIN could be found. The confusion matrix, comparing between pathologist's grading and predicted group by fractal methods showed a match of 87.1%. Multifractal spectra were able to differentiate between normal epithelium and low grade as well as high grade neoplasia. Conclusion Fractal dimension can be considered to be an objective parameter to grade cervical intraepithelial neoplasia.
    PLoS ONE 10/2014; 9(10):e108457. DOI:10.1371/journal.pone.0108457 · 3.53 Impact Factor

Full-text (3 Sources)

Available from
May 28, 2014