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Ki-67 Quantitative Evaluation as a Marker of Cervical Intraepithelial Neoplasia and Human Papillomavirus Infection
  1. Marko Mimica, MD*,
  2. Snježana TomiĆ, MD, PhD,
  3. Goran Kardum, PhD,§,
  4. Irena Drmić Hofman, PhD,,
  5. Vanja Kaliterna, MD** and
  6. Lidija PejkoviĆ, MD††
  1. *Gynenova Policlinic;
  2. Department of Pathology, Split University Hospital and School of Medicine; Departments of
  3. Neuroscience, and
  4. §Scientific Methodology,School of Medicine, University of Split; Departments of
  5. Pathology, and
  6. Biochemistry, Split University Hospital and School of Medicine;
  7. **Educational Public Health Institute of Split and Dalmatia County; and
  8. ††Private Practice, Split, Croatia.
  1. Address correspondence and reprint requests to Marko Mimica, MD, Gynenova Policlinic, Istarska 21, 21000 Split, Croatia. E-mail: marko.mimica1{at}


Objective: To assess the value of Ki-67 quantitative analysis in cervical intraepithelial neoplasia (CIN) in relation to CIN grading and human papillomavirus (HPV) group typing.

Methods: Cervical samples selected retrospectively from 106 cases were analyzed immunohistochemically for Ki-67-positive nuclei in 3 epithelial layers and by polymerase chain reaction for HPV typing.

Results: The proportion of high-risk HPV positivity was 0% in normal controls and 30% in CIN 1, 57% in CIN 2, and 90% in CIN 3 groups, and there was no low-risk HPV finding in CIN 2 and CIN 3 cases (P < 0.001). High-risk HPV-positive cases exhibited significantly more Ki-67-positive nuclei per 100-μm basal membrane, which were more frequent in the middle and upper third layers of the epithelium compared with low-risk HPV and HPV-negative cases (P < 0.001). The differences among the CIN groups in the total number and in the percentages of Ki-67-positive nuclei in the lower, middle, and upper third layers of the epithelium were significant (P < 0.001). With the cutoff value of more than 33% Ki-67-positive nuclei in the middle and the upper third layers of the epithelium, Ki-67 staining demonstrated 98.4% sensitivity (60/61 cases) and 97.8% specificity (44/45 cases) for the detection of CIN 2/CIN 3 in our study group.

Conclusions: The Ki-67 immunostaining proved to be predictive for high-risk HPV infection, and it can differentiate reactive lesions from cervical dysplasias. Ki-67 quantitative analysis in 3 epithelial layers is a sensitive and specific method of differentiation between CIN 1 and CIN 2/CIN 3 grades and can be a valuable adjunctive method for more accurate CIN grading.

  • Cervix
  • CIN
  • Ki-67
  • HPV
  • Immunohistochemistry

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