Elsevier

Human Pathology

Volume 38, Issue 5, May 2007, Pages 696-701
Human Pathology

Original contribution
Prostate-specific membrane antigen expression as a predictor of prostate cancer progression

https://doi.org/10.1016/j.humpath.2006.11.012Get rights and content

Summary

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, because current therapy may lead to overtreatment of men with limited disease. The prostate-specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is highly restricted to the prostate. Previously, studies analyzing the expression of PSMA have found an up-regulation in correlation with prostate cancer, particularly in advanced cancer. This association is ideal for an application as a prognostic marker. In the current study, we characterized PSMA expression in a high-risk cohort and evaluated its potential use as predictive marker of prostate-specific antigen (PSA) recurrence. PSMA expression was analyzed by immunohistochemistry using tissue microarrays composed of tumor samples from 450 patients. Protein intensity was recorded using a semiautomated quantitative microscope system (ACIS II; Clarient Chromavision Medical Systems, San Juan Capistrano, CA). PSMA expression levels differed significantly (P < .001) between benign prostatic tissue, localized prostate cancer, and lymph node metastases. Dividing the cohort into high- and low-PSMA expressing cancers based on the median area of positive staining, we found that high PSMA levels were associated with significant increase of PSA recurrence (P = .004). This was independent of clinical parameters such as lymph node tumor burden (lymph node density, >20%; P < .001), extraprostatic extension (P = .017), seminal vesicle invasion (P < .001), and high Gleason score (8-10, P = .006). In a multivariate model, PSMA expression and metastases to pelvic lymph nodes were significantly associated with time to PSA recurrence (HR, 1.4; 95% confidence interval, 1.1-2.8, P = .017; and hazard ratio, 5; 95% confidence interval, 2.6-9.7, P < .001, respectively). In summary, PSMA is independently associated with PSA recurrence in a high-risk cohort and thus might provide insight into the additional use of adjuvant therapy. Validation on other cohorts is required.

Introduction

A randomized clinical trial comparing watchful waiting with radical prostatectomy demonstrated significant risk reduction in the development of metastatic disease and cancer-specific death in clinically localized prostate cancer. However, this study also suggests that 19 men require surgical treatment to prevent one clinical event [1]. Therefore, molecular biomarker discovery needs to focus on distinguishing aggressive prostate cancer requiring treatment from indolent disease that may be expectantly followed with the option of delayed treatment if needed. Distinct sets of genes and proteins have been identified to be associated with the progression from precursor lesions to localized disease and eventual hormone refractory metastatic disease [2]. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein [3], which is negatively regulated by androgen. PSMA is significantly overexpressed in androgen-independent prostate cancer [4]. Increased PSMA expression in prostate cancer is associated with higher tumor grade [5], [6] and a high risk of disease progression as defined by biochemical recurrence after radical prostatectomy [7].

Introduction of a more widespread prostate-specific antigen (PSA) screening has led to a dramatic increase in the identification of early localized prostate cancer. In areas of the world with less rigorous screening approaches, high-stage and metastatic prostate cancer represents a higher percentage of new cancer cases [8]. In a high-risk cohort with incomplete PSA screening, we analyzed PSMA expression to determine a potential clinical utility in the setting of high-risk prostate cancer treatment.

Section snippets

Patient population and tissue collection

This study included 450 patients with prostate cancer diagnosed at the University of Ulm Hospital, Ulm, Germany, between the years 1986 and 2000. For these men, we compared PSMA expression in different histopathologic categories (including 24 benign, 225 localized prostate cancer, 73 hormone-naïve lymph node metastases, and 128 hormone refractory distant metastases of different organ sites) [8], [9]. Among these, 93 men (63.4 years, 50.4-76.1 years [mean age, range]) who had localized and

Results

As listed in Table 1, the lowest mean z intensity of PSMA expression was found in benign prostate glands (upper third of core in Fig. 1A), followed by localized prostate adenocarcinoma (positive immunoreactive stained acinar cancer glands in lower two thirds of core in Fig. 1A) and hormone refractory distant metastases, and the highest PSMA expression was observed in the category of regional lymph node metastases (Fig. 1B). As demonstrated in Fig. 2, mean PSMA expression was significantly

Discussion

In prostate cancer, Gleason score is still one of the most reliable parameters in predicting progression of disease [14] but, in many studies, fails to predict disease outcome independently [15], [16], [17]. Even nomograms using Gleason score in combination with extent of biopsy core involvement, pretreatment serum PSA levels, and clinical stage fail to adequately identify all patients at risk of developing biochemical recurrence [18]. Thus, molecular prognostic biomarkers independently

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      Prostate-specific membrane antigen (PSMA) is a membrane-bound type II transmembrane glycoprotein that is 100–1000 times upregulated in >90% prostate cancer cells compared with the level in healthy prostatic epithelial cells. The expression level of PSMA is positively correlated with the stage of the disease and Gleason score, making PSMA an attractive target for PCa diagnosis, intraoperative navigation, and therapy21. To date, various probes targeting PSMA have been developed, and several PSMA-PET/CT tracers have been utilized in clinics for identification of PCa pre- or/and post-surgery; whereas, these probes are impractical for real-time intraoperative use22–25.

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    This work was supported by a grant of the Deutsche Forschungsgemeinschaft (German Research Foundation) (DFG number PE1179/1-1, for S. Perner) and a Department of Defense Fellowship Award (PC030214, for M. D. Hofer).

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