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Both Cell Proliferation and Apoptosis Increase with Lesion Grade in Cervical Neoplasia but Do Not Correlate with Human Papillomavirus Type¹

Department of Pathology, Division of Gynecological Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Recent molecular studies suggest that the expression of high-risk but not low-risk human papillomavirus (HPV) oncoproteins E6 and E7 can significantly alter normal cell cycle regulation. The alterations in cell cycle regulation may be reflected by changes in the balance between cell growth and cell loss through apoptosis in cell populations expressing E6 and/or E7. We evaluated the kinetic indices of cell proliferation and apoptosis in a histopathological spectrum of cervical neoplasia and compared low-versus high-risk HPV-associated lesions. The cell proliferation index, as determined by detection of the nuclear antigen Ki67, increased with increasing lesion grade. Apoptotic cells were identified with terminal deoxynucleotidyl transferase-labeling of the 3'-hydroxyl ends of DNA nucleosomes. No apoptosis was observed in normal epithelium, and only occasional apoptotic cells were seen in low-grade lesions. However, there was a low but measurable apoptotic index in the higher grade lesions, which increased with lesion grade. There was no significant difference in the proliferative and apoptotic indices in similar grade lesions when stratified into low- versus high-risk HPV types. These findings suggest that apoptosis in HPV-infected lesions correlates with proliferative activity rather than HPV type.

¹ Supported by funds from the Stetler Research Fund for Women Physicians (to C. I.), the Richard W. TeLinde Endowment, Grant 3223 from The Council for Tobacco Research (to K. R. C.), and Grant CA 64466 from the NIH (to K. R. C.). L. H. is a recipient of a Passano Physician Scientist Award.

² To whom requests for reprints should be addressed, at Department of Pathology, The Johns Hopkins University School of Medicine, Ross Research Building, Room 656, 720 Rutland Avenue, Baltimore, MD 21205. Phone: (410) 550-5160; Fax: (410) 614-3548.

Received 11/28/95. Accepted 1/ 2/96.

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