Markers of differentiation and prognosis in prostate cancer : A morphological and immunohistochemical study

Prostate cancer (PCa) is the most common malignancy in men worldwide. The disease shows a wide range of patient outcome between indolent and highly aggressive tumor behavior. Prognostic factors are needed to stratify PCa patients in different prognostic groups for treatment decision and to predict outcome. Today serum prostate specific antigen (PSA), TNM staging and histomorphological prognostic factors such as the Gleason score (GS) are used in clinical practice for prediction of prognosis. Despite its powerful prognostic power, the utility of GS has decreased in the last decades due to a grade and stage shift. Efforts have been made to develop the GS and modified systems such as percent Gleason grade 4/5 (%GG4/5) and modified Gleason score (mGS) have been suggested. Almost monthly new potential biomarkers for PCa are reported but most of them will have only very limited clinical impact. To be useful, a marker must provide prognostic information, which is independent from that of established prognostic factors, its reproducibility must be satisfactory and the information obtained clinically relevant. The interobserver reproducibility of the conventional GS, %GG4/5 and mGS was analyzed among four uropathologists. The overall reproducibility of %GG4/5 and mGS was at least as good as that of the GS. However, clustering of mGS in odd scores was found and severe disagreement was more common than with GS. The ability of prostate needle biopsies to correctly predict %GG4/5 in prostatectomy specimens was found to be almost as good as for GS. We investigated the expression of pancreatic duodenal homeobox-1 (PDX-1) and heat shock proteins (HSP) 27, 60 and 70 in prostate tissue. Tissue microarrays (TMA) were constructed for analysis of prognostic value (289 PCas, median follow-up 48.9 months), expression in benign tissues, high-grade PIN, primary PCa and lymph node metastases. Two independent observers evaluated intensity and extent of immunohistochemical staining. HSP 27 and 60, but not PDX-1 and HSP 70, correlated with biochemical recurrence. In a multivariate analysis including histological prognostic factors HSP 60 was an independent predictor of recurrence. PDX-1 was overexpressed in cancer vs. benign tissue, but also in atrophy and high-grade PIN. PDX-1 decreased with higher Gleason pattern and in metastases. There was only slight interobserver agreement for extent of immunoreactivity of PDX-1 and HSPs but moderate to substantial agreement for intensity of the staining. Thus, the question was raised whether staining extent should be estimated on TMA. Presence of PDX-1 protein in benign and malignant prostatic tissue was confirmed by Western blot. In conclusion we suggest that HSP 27 and HSP 60 are predictors of biochemical recurrence after radical prostatectomy and PDX-1 is of potential interest in the pathogenesis of PCa. ISBN 978-91-7357-542-3 To my parents Helga and Jochen Glaessgen, my wife Daria Glaessgen and our children Ioana and Felix LIST OF PUBLICATIONS I. Glaessgen A, Hamberg H, Pihl CG, Sundelin B, Nilsson B, Egevad L. Interobserver reproducibility of percent Gleason grade 4/5 in total prostatectomy specimens. Journal of Urology 2002; 168(5): 2006-10 II. Glaessgen A, Hamberg H, Pihl CG, Sundelin B, Nilsson B, Egevad L. Interobserver reproducibility of percent Gleason grade 4/5 in prostate biopsies. Journal of Urology 2004; 171(2 Pt 1): 664-7 III. Glaessgen A, Hamberg H, Pihl CG, Sundelin B, Nilsson B, Egevad L. Interobserver reproducibility of modified Gleason score in radical prostatectomy specimens. Virchows Archives 2004; 445(1): 17-21 IV. Glaessgen A, Busch C, Norberg M, Haggman M, Nilsson B, Egevad L. Prediction of percent Gleason grade 4/5 by multiple core biopsies. Scandinavian Journal of Urology and Nephrology 2006; 40(6): 465-71 V. Jonmarker S, Glaessgen A, Culp W.D, Pisa P, Lewensohn R, Ekman P, Valdman A, Egevad L. Expression of PDX-1 in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic tissue. Acta Pathologica, Microbiologica et Immunologica Scandinavica, in press VI. Glaessgen A, Jonmarker S, Anna Lindberg, Nilsson B, Lewensohn R, Ekman P, Valdman A, Egevad L. Heat shock proteins 27, 60 and 70 as prognostic markers of prostate cancer. Acta Pathologica, Microbiologica et Immunologica Scandinavica, submitted