What is the value of proliferation markers in the normal and neoplastic cervix?

Markers of cellular proliferation have been widely applied in cervical disease and include techniques which are applicable to routinely processed tissue including standard hematoxylin and eosin sections, and sections labelled with antibodies to Ki-67 and PCNA proteins. Flow cytometry and in vivo techniques including labelling with Bromodeoxyuridine (BrdU) and radiolabelled thymidine require more specialized facilities. Increases in the mitotic index and the Ki-67 and PCNA labelling indices, the incidence of aneuploidy together with increases in in vivo labelling with BrdU and radiolabelled thymidine have been demonstrated as the grade of cervical intraepithelial neoplasia (CIN) increases. With respect to invasive tumours increases in these parameters are associated with increased tumour size, stage and improved survival after radiotherapy. At present the major practical application of these markers appears to be in distinguishing between postmenopausal atrophy and CIN lesions on histological sections and, in combination with the Papnet system, in identifying high grade dyskaryosis on blood stained cervical smears. Future development may permit the identification of those patients whose CIN lesion will progress, and who require treatment, to be distinguished from those whose lesions will stay static or regress and who can be followed up cytologically. This promises a more rational use of health care resources. Most of the studies to date have been on small numbers of cases. Meta-analysis of existing studies and large, possibly multicentric, prospective studies are needed to elucidate the value of these markers.