Olaf Bettendorf

Chromosomal imbalances, loss of heterozygosity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate

Recent studies have shown that intraductal prostate carcinoma (IDC‐P) should be considered as a separate lesion distinct from prostatic intraepithelial neoplasia (PIN). The purpose of the present study was to analyze the genetic relationship between benign prostatic tissue, PIN, invasive cancer, IDC‐P, and extracapsular tumor tissue to get further information about the role of IDC‐P in the development of prostate cancer. One hundred five radical prostatectomy specimens were investigated immunohistochemically, 77 cases were analyzed by PCR for LOH of the tumor suppressor genes TP53 and RB1, and 11 cases of IDC‐P and 10 cases of PIN were investigated using comparative genomic hybridization (CGH). At CGH analysis, IDC‐P showed several chromosomal imbalances in contrast to PIN, where no changes were found. We could demonstrate a significant increase of LOH for TP53 or RB1 from benign tissue to PIN. LOH of both TP53 and RB1 were frequently found in IDC‐P (52%), followed by extracapsular tumor tissue (44%), invasive cancer (24%), PIN (19%), and benign prostatic tissue (17%). Increased immunohistochemical expression was found in invasive cancer for TP53, RB1, and for PTEN. Decreased expression could be demonstrated in extracapsular tumor tissue and in IDC‐P. Our results indicate that IDC‐P in general follows the genetic pathway from normal epithelium over PIN lesion. IDC‐P represents a separate prostatic lesion and should be graded as a poorly differentiated carcinoma.

Duodenal duplication cyst mimicking pancreatic cyst in a patient with pancreatitis.

Pancreatic pseudocyst is a common complication of pancreatitis that often confounds patient management. Reported here is a case of an enteric duplication cyst within the duodenal wall of a 16-year-old boy that lead to recurrent episodes of pancreatitis because of intermittent obstruction of both the bile duct and the pancreatic duct. The cyst was the cause and not the result of pancreatic inflammation.

CMDX©-based single source information system for simplified quality management and clinical research in prostate cancer

BackgroundHistopathological evaluation of prostatectomy specimens is crucial to decision-making and prediction of patient outcomes in prostate cancer (PCa). Topographical information regarding PCa extension and positive surgical margins (PSM) is essential for clinical routines, quality assessment, and research. However, local hospital information systems (HIS) often do not support the documentation of such information. Therefore, we investigated the feasibility of integrating a cMDX-based pathology report including topographical information into the clinical routine with the aims of obtaining data, performing analysis and generating heat maps in a timely manner, while avoiding data redundancy.MethodsWe analyzed the workflow of the histopathological evaluation documentation process. We then developed a concept for a pathology report based on a cMDX data model facilitating the topographical documentation of PCa and PSM; the cMDX SSIS is implemented within the HIS of University Hospital Muenster. We then generated a heat map of PCa extension and PSM using the data. Data quality was assessed by measuring the data completeness of reports for all cases, as well as the source-to-database error. We also conducted a prospective study to compare our proposed method with recent retrospective and paper-based studies according to the time required for data analysis.ResultsWe identified 30 input fields that were applied to the cMDX-based data model and the electronic report was integrated into the clinical workflow. Between 2010 and 2011, a total of 259 reports were generated with 100% data completeness and a source-to-database error of 10.3 per 10,000 fields. These reports were directly reused for data analysis, and a heat map based on the data was generated. PCa was mostly localized in the peripheral zone of the prostate. The mean relative tumor volume was 16.6%. The most PSM were localized in the apical region of the prostate. In the retrospective study, 1623 paper-based reports were transferred to cMDX reports; this process took 15 ± 2 minutes per report. In a paper-based study, the analysis data preparation required 45 ± 5 minutes per report.ConclusionscMDX SSIS can be integrated into the local HIS and provides clinical routine data and timely heat maps for quality assessment and research purposes.

The presence of positive surgical margins in patients with organ-confined prostate cancer results in biochemical recurrence at a similar rate to that in patients with extracapsular extension and PSA≤10 ng/ml

PURPOSES We investigated whether patients with organ-confined prostate cancer (PCa) and positive surgical margins (SMs) had a similar biochemical recurrence (BCR) risk compared with patients with pT3a and preoperative prostate-specific antigen (PSA) levels ≤ 10ng/ml. Furthermore, we examined the effects of incorporating SM status, Gleason score (Gls), and preoperative PSA level into the discrimination accuracy of the current tumor node metastasis-staging system. MATERIALS AND METHODS We analyzed 863 PCa patients treated with radical prostatectomy from 1999 to 2008. Only individuals with pT2N0 or pT3N0, without neoadjuvant or adjuvant therapy, were included. We performed chi-square automatic interaction detection analysis to generate a classification model for predicting BCR by analyzing interactions between age at surgery, SM status, Gls, PSA, and tumor stage, tumor volume and relative tumor volume. Cox regression analyses tested the relationship between SM status and BCR rate after stratification according to T-stage and the novel classification. The predictive and discrimination accuracy of the current T-stage and of the classification model was quantified with time-dependent receiver operating characteristics and integrated discrimination improvement. The topographical association between extracapsular extension of PCa and positive SM was analyzed in patients with pT3aR1 using a computational reconstruction diagram of the prostate. RESULTS The chi-square automatic interaction detection analysis found interactions among pT Stage, SM status, PSA and Gls and generated a classification model for BCR prediction: pT2R0, pT2R1, pT3a PSA ≤ 10 ng/ml, pT3a PSA>10 ng/ml and pT3b. Men with pT2R1 had a shorter time to BCR compared with men with pT3a-PSA ≤ 10 ng/ml (P<0.0001). Gls≥7a was correlated with a poorer BCR rate than Gls≤7a in men with pT2R1 or pT3a PSA ≤ 10 ng/ml (P = 0.012). The rank order (highest to lowest) for the risk of developing BCR was pT3b>pT2R1/pT3a-PSA>10 ng/ml>pT2R1/pT3a PSA ≤ 10 ng/ml>pT2R0 (P<0.0001). Discrimination accuracy gains were observed when PCa was stratified according to the novel classification (P<0.0001). A topographical association between extracapsular extension and positive SM was found in patients with pT3aR1 (P = 0.01). CONCLUSION Patients with pT2R1 develop a similar BCR risk to that of patients with pT3a PSA ≤ 10 ng/ml. Gls≥7b is associated with a high BCR risk in these patient groups. Including SM status, PSA, and Gls in pT stage appears to improve prognostic stratification in patients with PCa.

High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and topographical distribution in 1,374 prostatectomy specimens: Existence of HGPIN near prostate cancer†‡

High‐grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor of prostate cancer (PCa). This study evaluated whether HGPIN was located close to PCa in whole radical prostatectomy specimens (RPSs).

Preoperative prostate-specific antigen isoform p2PSA≤22.5 pg/ml predicts advanced prostate cancer in patients undergoing radical prostatectomy

BACKGROUND The prediction value of prostate-specific antigen (PSA) isoform [-2]proPSA (p2PSA) for detecting advanced prostate cancer (PCa) remains unclear. Our objective was to evaluate the additional clinical utility of p2PSA compared with total PSA (tPSA), free PSA (fPSA), and preoperative Gleason score (Gls) in predicting locally advanced PCa (pT3/T4) with high-accuracy discrimination. The aim was to develop a novel classification based on p2PSA and preoperative Gls for predicting advanced PCa. MATERIALS AND METHODS In 208 consecutive men diagnosed with clinically localized PCa who underwent radical prostatectomy, we determined the predictive and discriminatory accuracy of serum tPSA, fPSA, percentage of fPSA to tPSA, p2PSA, p2PSA density, percentage of p2PSA to fPSA, and the Prostate Health Index. The cutoff level of p2PSA with best accuracy was estimated. The novel classification was developed by analyzing the interaction between p2PSA and Gls in predicting pathologic outcomes using a chi-square automatic interaction detection analysis. Decision curve analysis was applied to test the clinical consequences of using the novel classification. RESULTS On univariate analyses, p2PSA, p2PSA density, percentage of p2PSA to fPSA, and Prostate Health Index were accurate but were not independent predictors by multivariate analysis. The p2PSA cutoff level of 22.5 pg/ml showed the best accuracy level for predicting and discriminating advanced diseases (area under the curve [AUC] = 0.725, sensitivity = 51.4%, specificity = 81.8%). By chi-square automatic interaction detection, univariate and multivariate analysis, a p2PSA level > 22.5 pg/ml was significantly associated with an increased frequency and risk of advanced disease. In patients with a p2PSA level ≤ 22.5 pg/ml, 91.8% of Gleason sum 6 PCa was organ confined. The combination of p2PSA and Gls enhanced slightly but significantly the predictive and discriminatory accuracy for advanced disease (0.6%-3.6%). CONCLUSIONS The p2PSA cutoff level of 22.5 pg/ml can accurately discriminate between organ-confined and advanced PCa. The additional use of p2PSA enhanced slightly the predictive accuracy for advanced PCa (pT3/pT4) and has limited additional predictive value in identifying aggressive PCa (Gls > 7a).

Prostate cancers detected on repeat prostate biopsies show spatial distributions that differ from those detected on the initial biopsies

To evaluate the spatial distribution of prostate cancer detected at a single positive biopsy (PBx) and a repeat PBx (rPBx).

Tumor percentage but not number of tumor foci predicts disease-free survival after radical prostatectomy especially in high-risk patients.

OBJECTIVE To evaluate the predictive value of tumor volume (TV), tumor percentage (TP), and number of tumor foci (NF) in patients with prostate cancer. The prognostic relevance of TV, TP, and NF as predictors of biochemical recurrence (BCR) following radical prostatectomy (RPE) is controversial. PATIENTS AND METHODS The cohort consisted of 758 referred subjects who underwent RPE between 2000 and 2005 at the University of Muenster. The mean time of follow-up was 62 months. TV, TP, and NF were estimated visually with the assistance of a pathologic mapping grid for embedded whole-mount RPE specimens. In addition, TV and TP were assessed in a categorized fashion by using quartiles as cutoff points. Subgroup analyses for high- and low-risk patients using univariate and multivariate Cox proportional hazard analyses for BCR were performed. RESULTS TV, TP, and NF were strongly related to tumor stage, Gleason score, surgical margin status, and preoperative prostate-specific antigen (PSA). In univariate analysis, all pathologic parameters including TV, TP, and NF were predictive for BCR. In multivariate analysis, only TP, tumor stage, and PSA level were independent predictors. In subgroup analysis, TP was an independent predictor for BCR in the high-risk group but not in the low-risk group. CONCLUSIONS TP, but not TV or NF, was found to be an independent predictor for BCR in patients after RPE. TP seems to be more relevant in high-risk patients (i.e., any of the following: > pT2, Gleason score > 6, or PSA > 20 ng/ml).

Analysis of topographical distribution of prostate cancer and related pathological findings in prostatectomy specimens using cMDX document architecture

INTRODUCTION Understanding the topographical distribution of prostate cancer (PCa) foci is necessary to optimize the biopsy strategy. This study was done to develop a technical approach that facilitates the analysis of the topographical distribution of PCa foci and related pathological findings (i.e., Gleason score and foci dimensions) in prostatectomy specimens. MATERIAL & METHODS The topographical distribution of PCa foci and related pathologic evaluations were documented using the cMDX documentation system. The project was performed in three steps. First, we analyzed the document architecture of cMDX, including textual and graphical information. Second, we developed a data model supporting the topographic analysis of PCa foci and related pathologic parameters. Finally, we retrospectively evaluated the analysis model in 168 consecutive prostatectomy specimens of men diagnosed with PCa who underwent total prostate removal. The distribution of PCa foci were analyzed and visualized in a heat map. The color depth of the heat map was reduced to 6 colors representing the PCa foci frequencies, using an image posterization effect. We randomly defined 9 regions in which the frequency of PCa foci and related pathologic findings were estimated. RESULTS Evaluation of the spatial distribution of tumor foci according to Gleason score was enabled by using a filter function for the score, as defined by the user. PCa foci with Gleason score (Gls) 6 were identified in 67.3% of the patients, of which 55 (48.2%) also had PCa foci with Gls between 7 and 10. Of 1173 PCa foci, 557 had Gls 6, whereas 616 PCa foci had Gls>6. PCa foci with Gls 6 were mostly concentrated in the posterior part of the peripheral zone of the prostate, whereas PCa foci with Gls>6 extended toward the basal and anterior parts of the prostate. The mean size of PCa foci with Gls 6 was significantly lower than that of PCa with Gls>6 (P<0.0001). CONCLUSION The cMDX-based technical approach facilitates analysis of the topographical distribution of PCa foci and related pathologic findings in prostatectomy specimens.

Preoperative Serum Prostate-Specific Antigen Levels Vary According to the Topographical Distribution of Prostate Cancer in Prostatectomy Specimens

OBJECTIVE To evaluate whether the spatial distribution of prostate cancer (PCa) influences the concentration of prostate-specific antigen (PSA). METHODS An observational prospective study was performed in 775 consecutive men with preoperative PSA levels ≤20 ng/mL who underwent radical prostatectomy for organ-confined PCa. We evaluated prostate specimens using a cMDX-based map model of the prostate and determined the prostate volume, number of cancer foci, relative tumor volume, Gleason score, zone of origin, localization, and pathologic stage after stratification according to PSA levels categorized into 3 groups: <4 ng/mL, 4-10 ng/mL, and 10.1-20 ng/mL. The distribution of 5254 PCa foci was analyzed after stratification according to PSA levels and visualized on heat maps. A logistic regression analysis was performed to assess the odds ratios of PSA levels for the presence of PCa in 16 regions. RESULTS PCa with PSA <4 ng/mL was predominantly localized to the apical part and the peripheral zone of the prostate. PCa with a PSA level 10.1-20 ng/mL (16.4% of cases) was observed more frequently in the anterior part and the base of the prostate than PCa with a PSA level <4 or 4-10 ng/mL (6% and 10%, respectively). CONCLUSION Preoperative PSA levels vary according to the spatial distribution of PCa in radical prostatectomy specimens. The probability of anterior PCa is increased with higher PSA serum levels. Regions of interest harboring the PCa can be defined according to preoperative PSA and prostate volume. These findings are useful to optimize the focal therapy or to adjust the radiation fields.