Role of apoptotic index, mitotic index and MIB-1 antibody expression as biomarkers in preneoplastic and neoplastic lesions of uterine cervix

Rashmi Chauhan, Nidhi Verma, S. P. Sharma, Ruchika Bhargava, Preeti Singh


Background: In India, cervical cancer ranks as the 2nd most frequent cancer among women. This study was carried out to study the role of apoptotic index (AI), mitotic index (MI) and MIB-1 labelling index (LI) as biomarkers in preneoplastic and neoplastic lesions of uterine cervix.

Methods: Total of 90 cases was studied, over a period of two years, in the Department of Pathology as well as Obstetrics and Gynaecology, LLRM Medical College and associated SVBP Hospital, Meerut, India. Apoptotic Index and Mitotic Index were calculated on H & E stained sections in all the 90 cases while ki-67 immunostaining was done only on 44.44% (40/90) cases.

Results: Apoptotic Index, Mitotic Index and MIB-1 expression were found to increase as the grade of lesion increased from cervical dysplasia to invasive cervical carcinoma. In CIN-I, MIB-1 positive cells were confined to lower one-third of ectocervix and full thickness was involved in CIN-III.

Conclusion: We found proliferative indices (Mitotic index and MIB-1 labelling index) and Apoptotic index useful in determining the grading of dysplasia and cervical carcinoma.Key words: Cervical dysplasia, Cervical carcinoma, Apoptotic index, Mitotic index, MIB-1 Labelling index


Cervical dysplasia, Cervical carcinoma, Apoptotic index, Mitotic index, MIB-1 Labelling index

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GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012.

Bruni L, Barrionuevo-Rosas L, Albero G, Aldea M, Serrano B, Valencia S, et al. ICO Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in India. Summary Report. 2015.

Martin CM, O’Leary JJ. Histology of cervical intraepithelial neoplasia and the role of biomarkers. Best Pract Res Clin Obstet Gynaecol. 2011;25:605-15.

Dascau V, Furau G, Furau C, Paiusan L, Radu A, Stanescu C. Cervical intraepithelial neoplasia in the “dr. Salvator vuia” clinical obstetrics and gynecology hospital-araa during the 2000-2009 period. Maedica (Buchar). 2012;7:138-42.

Creagh T, Bridger JE, Kupek E, Fish DE, Martin-Bates E, Wilkins MJ. Pathologist variation in reporting cervical borderline epithelial abnormalities and cervical intraepithelial neoplasia. J Clin Pathol. 1995;48:59-60.

Chen EY, Tran A, Raho CJ, Birch CM, Crum CP, Hirsch MS. Histological ‘progression’ from low (LSIL) to high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance review. Mod Pathol. 2010;23:1045-51.

van Diest PJ, Brugal G, Baak JPA. Proliferation markers in tumours: interpretation and clinical value. J Clin Pathol. 1998;51:716-24.

Panjkovic M, Ivkovic-Kapicl T. Ki-67 expression in squamous intraepithelial lesions of the uterine cervix. Arch Oncol. 2006;14(1-2):23-5.

Yim EK, Park JS. Biomarkers in cervical cancer. Biomarker Insights. 2006;2:215-25.

Goel MM, Mehrotra A, Singh U, Gupta HP, Misra JC. MIB-1 and PCNA immunostaining as a diagnostic adjunct to cervical pap smear. Diagn Cytopathol. 2005;33:15-9.

Dlamini Z, Mbita Z, Zungu M. Genealogy, expression and molecular mechanisms in apoptosis. Pharmacol Ther. 2004;101:1-15.

Soini Y, Paakko P, Lehto VP. Histopathological evaluation of apoptosis in cancer. Am J Pathol. 1998;153:1041-53.

Mysorekar VV, David S and Rao SG. Proliferative and Apoptotic Indices in Squamous Epithelial Lesions of the Cervix. Bahrain Medical Bulletin. 2008;30:156-9.

Bhardwaj S, Wani FA. Evaluating the Importance of Apoptotic Index, Mitotic Index and Turnover Index in Premalignant and Malignant Lesions of Cervix. Open Journal of Pathology. 2015;5:29-37.

Mehrotra A, Goel MM. Assessment of monoclonal antibody MIB-1 labelling indices in cervical intraepithelial lesions of the uterine cervix in paraffin section. J Obstet Gynecol India. 2008;58.

Ancuta E, Ancuta C, Cozma LG, Lordache C, Anghelache-Lupascu I, Anton E, et al. Tumor biomarkers in cervical cancers: focus on Ki-67 proliferation factor and E- cadherin expression. Rom J Morphol Embryol. 2009;50:413-8.

Lane DP. p53, Guardian of the Genome. Nature 1992;358:15-6.

Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710-5.

Nam JH, Kim JH, Huh J, KOH CW, NA JH, et al. Correlation of lesion grade in cervical neoplasia with cell proliferation and apoptosis. Int J Gynecol Cancer. 1998;8.

Sagol O, Yorukoglu K, Sagol S, Koyuncuoglu M, Uslu T. Apoptotic and Mitotic Index in Squamous Cell Carcinomas and Premalignant Lesions of the Uterine Cervix. International Journal of Surgical Pathology. 1999;7:155-60.

Gupta K, Alam K, Maheshwari V, Khan R, Sharma R. Apoptotic index and MIB-1 antibody expression in premalignant and malignant lesions of uterine cervix. Gynecol Obstet. 2013;3:173.

Dey P, Das R, Sabuddin. Correlations between Apoptotic and Proliferative Indices in Cervical Intraepithelial Neoplasia and Carcinoma. Indian Journal of Pathology & Microbiology. 2000;43:271-5.

Sansanwal P, Sankala M, Singh G, Kathuria M. Immunohistochemical detection of proliferative tumor cells in cervical cancer using monoclonal antibody ki-67. Int J Health Sci Res. 2015;5(6):166-71.

McCluggage WG, Buhidma M, Tang L, Maxwell P, Bharucha H. Monoclonal antibody MIB-1 in the assessment of cervical squamous intraepithelial lesions. Int J Gynecol Pathol. 1996;15(2):131-6.

Payne S, Kernohan NM, Walker F. Proliferation in the normal cervix and preinvasive cervical lesions. J. Clin. Pathol. 1996;49:667-71.

Bulten J, Vanderlaak JA, Gemmink JH, Pahlplatz MM, Dewilde PC, Hanselaar AG. MIB-1, a promising marker for the classification of cervical intraepithelial neoplasia. J Pathol. 1996;178:268-73.

ter Harmsel B, Kuijpers J, Smedts F, Jeunink M, Trimbos B, Ramaekers F. Progressing Imbalance between Proliferation and Apoptosis with Increasing Severity of Cervical Intraepithelial Neoplasia. Int J Gynecol Pathol. 1997;16:205-11.

Conesa-Zamora P, Domenech-Peris A, Orantes-Casado FJ, Ortiz-Reina S, Sahuquillo-Frias L, et al. Effect of human papilloma virus on cell cycle- Related proteins p16, Ki-67, Cyclin D1, p53 and ProEx C in precursor lesions of cervical carcinoma: a tissue microarray study. Am J Clin Pathol. 2009;132:378-90.

Srivastava S. P16INK4A and MIB-1: An immunohistochemical expression in preneoplasia and neoplasia of the cervix. Indian J Pathol Microbiol. 2010;53:518-24.

Pahuja S, Choudhury M, Gupta U. Proliferative Activity in Squamous Intraepithelial and Invasive Lesions of Cervix: Analysis by AgNOR Staining. Indian J Pathol Microbiol. 2003;46:573-5.

Carreras R, Alameda F, Mancebo G, García-Moreno P, Mariñoso MLM, Costa C, et al. A study of Ki-67, c-erbB2 and cyclin D-1 expression in CIN-I, CIN-III and squamous cell carcinoma of the cervix. Histol Histopathol. 2007;22:587-92.

Munhoz NG, Rodrigues DA, Pedregosa JF, Rodrigues JO, Junqueira MSG, Yonamine PTK, et al. The use of molecular markers (p16, Ki-67 and E-Cadherin) in uterine cervical biopsies. The Open Pathology Journal. 2009;3:10-7.