Abstract The cell kinetic of prostatic intraepithelial neoplasia (PIN) is poorly understood. Herein we report the kinetic pattern of PIN, both not associated (primary) and associated (secondary) with coexistent invasive car- cinoma (PCa). Surgical specimens collected in 20 cases of primary PIN, 20 of secondary PIN and 20 of PCa were studied by MIB-1 immunostaining, in situ end- labeling (ISEL) and DNA histogram analysis, and the cell density in each case was estimated using the formula N=(nπ/4) 2 . Fifty high-power fields (HPF), or the com- plete lesion if smaller, were screened in each lesion, and both mean and standard deviation were recorded. Statis- tical differences were studied by means of Fisher’s exact test. ISEL indices were significantly (P<0.0001) lower in PCa (0.1±0.3) than in primary PIN (0.5±0.3), while the MIB-I indices were similar in both conditions (P=0.56). Statistically significant differences were also detected for both MIB-1 and ISEL indices when secondary PIN (MIB-1 1.9±0.7, ISEL 3.7±3.3) was compared with primary PIN (MIB-1 2.5±2.1, ISEL 0.5±0.3) and PCa (P<0.0001). In terms of cellularity, primary PIN (26.3±7.1) revealed scores significantly lower (P<0.0001) than those recorded in PCa (39.0±8.8) and secondary PIN (32.9±14.3). In conclusion, early prostatic tumor is mainly defined by down-regulated apoptosis rather than by increased proliferation. Secondary PIN displays unique kinetic features suggesting an evolved stage of primary PIN. Key words Prostatic intraepithelial neoplasm · Precancerous lesion · Intraductal extension · Cell kinetics · DNA-ploidy Introduction Currently, high-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of invasive prostatic carcinoma (PCa) [2, 3] and has been reported both as an isolated finding (primary PIN) and coexisting with inva- sive adenocarcinomas (secondary PIN) [4, 22]. The normal cellular turnover is maintained by a strict balance between proliferation and apoptosis [27, 43], studied by several techniques including immunohisto- chemistry, in situ end-labeling (ISEL) of fragmented DNA, and DNA-ploidy analysis. Controversial results have been reported on cell kinetics in PIN because of the heterogeneity of cases (especially regarding total andro- gen ablation) [32, 34, 35] and the diversity of techniques and quantification methods for both proliferating cells [23, 33, 45] and apoptotic cells [18, 31–34, 47]. Addi- tionally, no attempts to differentiate primary from sec- ondary PIN have been published. Therefore, the biologi- cal significance of both types of PIN remains unknown, and their potential implications for therapeutic approach- es need to be determined. The purpose of this study was to characterize the ki- netic features of both primary and secondary PIN in a se- ries of surgical specimens. Combined quantitative ana- lyses of proliferation and apoptosis markers on tissue sections were performed. Ultimately, those parameters were to help define the kinetic of tumor progression in PCa. This work was presented in part in abstract form at the XXIIth In- ternational Congress of the International Academy of Pathology, Nice 1998 M. Koch · S.J. Diaz-Cano Department of Pathology, GSF-München, Munich, Germany M. de Miguel Department of Pathology, University Hospital “Virgen Macarena”, Seville, Spain H. Höfler Department of Pathology, Technical University, Munich, Germany S.J. Diaz-Cano Department of Pathology, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, London, UK S.J. Diaz-Cano ( ✉ ) Department of Morbid Anatomy and Histopathology, The Royal London Hospital, Whitechapel, London E1 1BB, UK e-mail: s.j.diaz-cano@mds.qmw.ac.uk Tel.: +44-171-3777348, Fax: +44-171-3777030 Virchows Arch (2000) 436:413–420 © Springer-Verlag 2000 ORIGINAL ARTICLE Michael Koch · Manuel de Miguel · Heinz Höfler Salvador J. Diaz-Cano Kinetic profiles of intraepithelial and invasive prostatic neoplasias: the key role of down-regulated apoptosis in tumor progression Received: 7 July 1999 / Accepted: 18 November 1999