The Correlation between Ki67 Proliferative Marker and the Reactivity and Site of Cervical Intraepithelial Lesions

Document Type : Original Article


1 Associated Professor of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

2 Professor of Obstetrics & Gynecology, Faculty of Medicine, Gynecologic Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

3 Resident of Obstetrics and Gynecology, Mashhad University of Medical Sciences, Mashhad, Iran.

4 Medical Student, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

5 Biologist, Mashhad University of Medical Sciences, Mashhad, Iran.


Introduction: Cervical intraepithelial neoplasia and cancerous lesions are spectrum of morphologic changes without having definite boundaries. Immunohystochemical methods and proliferative markers are among the reliable ways in classifying the various lesions of cervical dysplasia. In related literature ki67 proliferative marker is known as a prognostic factor in the progression of cervical cancerous lesions. This research was performed to propound a more detailed classification of CIN using expression of Ki67 proliferative marker.
Methods: In this cross-sectional descriptive-analytical study 42 cervical biopsies (mild dysplasia N=16, moderate dysplasia N=8, severe dysplasia N=10 cervical normal tissue N=8) were selected from Pathology archive of Ghaem Hospital in Mashhad in year 2007, and the expression of Ki67 proliferative marker was analyzed hystochemically in paraffinized slides . Then the relationship between the severity of dysplasia, the location of expression of Ki67, and the reactivity of the cervical dysplasia was examined. Data was analyzed by SPSS11 and using ANOVA tests.
Results: The direct relationship between the severity of dysplasia changes and the site and reactivity of cervical intraepithelial lesions was observed by using the expression of KI67 marker
Conclusion: Evaluating intraepithelial cervical lesions by Immunohistochemistry methods and Ki67 marker is a reliable method for diagnosis and classification of various dysplastic lesions.


1. Wright TC Jr, Denny L, Kuhn L, Pollack A, Lorincz A, HPV DNA testing of self-collected vaginal
samples compared with cytologic screening to detect cervical cancer . JAMA. 2000 Jan 5;283(1):81­6.
2. Saslow D, Runowicz CD , Solomon D, Moscicki AB, Smith RA, Eyre HJ, et al. American Cancer Society 
guideline for the  early detection  of cervical neoplasia  and  cancer. CA Cancer J  Clin  2002 Nov­ Dec;52(6):342­62.
3. Crum CP. Symposium part1: Should  the Bethesda System terminology be  used in diagnostic surgical
pathology?: Point. Int J Gynecol Pathol 2003 Jan;22(1):5­12.
4. Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, Mayrand MH, et al. Overview of human  papillomavirus­based and other novel options for cervical cancer screening in developed and developed 
and developing countries. Vaccine 2008 Aug 19;26(Suppl 10): K29­41.
5. Goel MM, Mehrotra A, Singh U, Gupta HP,Misra JS. MIB­1 and PCNA immunostaining as a diagnostic  adjunct to cervical pap smear. Diagn Gytopathol 2005 Jul;33(1):15­9.
6. Xue Y, Feng Y, Zhu G, Zhang X. Proliferative activity in  cervical intraepithelial neoplasia and  cervical carcinoma. Chin Med J(Engl )1999 Apr;112(4):373­5.
7. Stoler MH, Schiffman  M, Stoler MH,  Schiffman  M; Atypical Squamous Cells of Undetermined 
Significance­Low­grade  Squamous Intraepithelial Lesion  Triage Study (ALTS) Group. Interobserver
reproductbility of cervical cytologic and  histologic interpretations: realistic estimates  from the ASCUS­ 
LSIL Triage Study. JAMA 2001 Mar 21;285(11):1500­5.
8. Meyer JS, Connor RE. In  vitro labeling of solid tissues with tritiated thymidine for autoradiographic  detection of S­phase nuclei. Stain Technol 1977 Jul;52(4):185­95.
9. Tjalma W, Weyler J, Pollefliet C, Bogers  J,  Van  Marck  E,  Van  Dam P, et al. The evaluation  of
proliferative activity in CIN III and microinvasive cervical cancer and its role in recurrence. Eur J Obstet
Gyencol Reprod Biol 2001 Feb:94(2):270­5.
10. Lee KR, Sun D, Crum CP. Endocervical intraepithelial glandular atypia  (dysplasia ): a histopathologic, human papillomavirus, and MIB­1 analysis of 25 cases. Hum Pathol 2000 Jun;31(6):656­64.
11. Wang JL, Zheng BY, Li XD, Angstrom T, Lindstrom MS, Wallin  KL. Predictive  significance  of the  alterations of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen expression in the progression  of cervical cancer. Clin Cancer Res 2004 Apr 1;10(7):2407­14.
12. Cuzick J, Mayrand MH, Ronco G, Snijders P, Wardle J. Chapter 10: New dimensions in cervical cancer screening. Vaccine 2006 Aug 31;24( Suppl 3):S3/90­7.
13. Bar JK, Harlozinska A, Sedlaczek P, Kasiak J, Markowska J. Relations between the expression of p53, c­ erB­2, Ki­67 and HPV infection in cervical carcinomas and cervical dysplasias. Anticancer Res 2001 Mar­ Apr;21(2A):1001­6.
14. Beneder JL, Bender H, Jones  H 3rd, Ngan HY, Pecorelli S. FIGO staging classifications  and clinical
practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology.
Int J Gynecol Obstet 2000 Aug;70(2):209­62.
15. Sanchez­Rosales M, Osorio­Morales S, Diaz­Araujo F. [Evaluation of the inmunohistochemical markers  PCNA and MIB­1 in the diagnosis of low grade lesions of the uterine cervix]. [Article in Spanish]. Invest
Clin 2004 Sep;45(3):213­20.
16. Kuo KT, Chang HC, Hsiao CH, Lin MC. Increased Ki­67 proliferative index and absence of P16INK4 in  CIN­HPV related pathogenic pathways  different from cervical squamous intraepithelial lesion. Br J 
Ophthalmol 2006 Jul;90(7):894­9.
17. al­Saleh W, Delvenne P, van den Brulet FA, Menard S, Boniver J, Castronovot V. Expression of the 67 
KD laminin  receptor in  human cervical preneoplastic and  neoplastic squamous  epithelial lesions: an 
immunohistochemical study. J Pathol 1997 Mar;181(3):287­93.
18. Saha B, Chaiwun B, Tsao–Wei DD, Groshen SL, Naritoku WY, Atkinson  RD, et al. Telomerase and  markers of cellular proliferation  are  associated with the progression  of cervical intraepithelial neoplasia 
lesion. Int J Gyencol Pathol 2007 Jul;26(3):214­22.
19. Pirog EC, Baergen RN, Soslow RA, Tam D, DeMattia AE, Chen YT, et al. Diagnostic accuracy of cervical
low­grade squamous Intraepithelial lesions is  improved  with MIB­1  immunostaining. Am J  Surg Pathol
2002 Jan;26(1):70­5.
20. Erfanian M, Sharifi N, Omidi AA. [P63  and Ki67 expression in trophoblastic disease and sponotaneous  abortion. [Article in Persian]. JRMS 2009 Sept­Oct;l14(5): 23­32.