Ronald J. Cohen

Gene Expression Patterns in Renal Cell Carcinoma Assessed by Complementary DNA Microarray

Renal cell carcinoma comprises several histological types with different clinical behavior. Accurate pathological characterization is important in the clinical management of these tumors. We describe gene expression profiles in 41 renal tumors determined by using DNA microarrays containing 22,648 unique cDNAs representing 17,083 different UniGene Clusters, including 7230 characterized human genes. Differences in the patterns of gene expression among the different tumor types were readily apparent; hierarchical cluster analysis of the tumor samples segregated histologically distinct tumor types solely based on their gene expression patterns. Conventional renal cell carcinomas with clear cells showed a highly distinctive pattern of gene expression. Papillary carcinomas formed a tightly clustered group, as did tumors arising from the distal nephron and the normal kidney samples. Surprisingly, conventional renal cell carcinomas with granular cytoplasm were heterogeneous, and did not resemble any of the conventional carcinomas with clear cytoplasm in their pattern of gene expression. Characterization of renal cell carcinomas based on gene expression patterns provides a revised classification of these tumors and has the potential to supply significant biological and clinical insights.

The value of preoperative needle core biopsy for diagnosing benign lesions among small, incidentally detected renal masses.

PURPOSE We determined the safety and accuracy of preoperative needle core biopsy for diagnosing benign lesions among small incidental asymptomatic renal masses. MATERIALS AND METHODS Between February 2000 and December 2007 we received a total of 235 preoperative core biopsies from 222 less than 5 cm incidental renal masses. Biopsy results were correlated with surgical specimen final pathology findings or with patient followup if surgery was avoided. RESULTS Of the 235 biopsies 184 (78%) were diagnostic, whereas 51 (22%) were nondiagnostic due to insufficient material or contents of only normal, inflammatory, fibrotic or necrotic tissue, or blood clot. Diagnostic biopsies revealed 138 malignant (75%) and 46 benign (25%) lesions. Of these patients 108 (59%) underwent renal surgery, which showed a 100% biopsy accuracy rate for distinguishing malignant from benign lesions and a 98% rate for determining histological tumor type. Followup with radiological imaging was performed for 59 lesions in patients with nondiagnostic biopsies or benign masses and for 16 low grade malignant tumors in elderly patients. Lesions remained stable in 61 cases, showed minor size changes in 9 and resolved in 5. No patient has shown symptoms or required renal surgery to date. Significant biopsy related complications were noted in only 2 patients (0.9%). CONCLUSIONS We found that needle core biopsy was a safe and accurate technique for distinguishing between malignant and benign tumors in small asymptomatic incidentally detected renal masses. Biopsy of small tumors is associated with a relatively high rate of technical biopsy failure, although this may be addressed by adopting improved biopsy techniques, as discussed.

Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer.

Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying prostate-specific deletion of the phosphatase tensin homolog tumor suppressor (Pten(pc-/-)), also exhibit high levels of TRAP-1. Expression of TRAP-1 in nontransformed prostatic epithelial BPH-1 cells inhibited cell death, whereas silencing of TRAP-1 in androgen-independent PC3 or DU145 prostate cancer cells by small interfering RNA enhanced apoptosis. Targeting TRAP-1 with a novel class of mitochondria-directed Hsp90 inhibitors, ie, Gamitrinibs, caused rapid and complete killing of androgen-dependent or -independent prostate cancer, but not BPH-1 cells, whereas reintroduction of TRAP-1 in BPH-1 cells conferred sensitivity to Gamitrinib-induced cell death. These data identify TRAP-1 as a novel mitochondrial survival factor differentially expressed in localized and metastatic prostate cancer compared with normal prostate. Targeting this pathway with Gamitrinibs could be explored as novel molecular therapy in patients with advanced prostate cancer.

A Proposal on the Identification, Histologic Reporting, and Implications of Intraductal Prostatic Carcinoma

CONTEXT Prostatic adenocarcinoma growing within acinar-ductal spaces (intraductal carcinoma) in contrast to high-grade prostatic intraepithelial neoplasia (HG-PIN) impacts negatively on patient outcome. There is currently no generally accepted definition of this lesion nor is it classified in the current prostate cancer grading system (Gleason). OBJECTIVE To define intraductal carcinoma of the prostate (IDC-P) with major and minor diagnostic criteria that clearly separate it from HG-PIN. The implications of such a lesion are discussed with proposals to incorporate this entity into the Gleason grading system. DATA SOURCES We reviewed all published data referring to intraductal spread of prostate carcinoma. Articles discussing endometrial, endometrioid, and ductal carcinoma are included. CONCLUSIONS Intraductal carcinoma of the prostate as defined by major criteria that include enlarged gland structures, neoplastic cells spanning the gland lumen, central comedonecrosis, and further supported by minor diagnostic criteria including molecular biological markers, separate this entity from HG-PIN. Despite its perimeter basal cells, IDC-P should be interpreted as biologically equivalent to Gleason pattern 4 or 5 adenocarcinoma. Several hypotheses are proposed as to the evolution of IDC-P, which is almost always a late event in prostate carcinoma progression. Diagnosis of IDC-P on needle biopsy should prompt therapeutic intervention rather than surveillance or repeat biopsy, as is the case for HG-PIN.

Distinction Between Intraductal Carcinoma of the Prostate (IDC-P), High-Grade Dysplasia (PIN), and Invasive Prostatic Adenocarcinoma, Using Molecular Markers of Cancer Progression

Prostate ducts and acini whose lumens are filled with malignant cells represent a well‐recognized histological pattern recently termed intraductal carcinoma of the prostate (IDC‐P). These tumors are often associated with rapid disease progression, and most recur after radical surgery. Controversy exists as to whether IDC‐P should be recognized as a separate entity, an extension of high‐grade dysplasia (PIN) or invasive carcinoma as described by the Gleason grading system. This study investigates the use of molecular markers in defining the position of IDC‐P in the evolutionary hierarchy of prostate cancer progression.

Patterns of Differentiation and Proliferation in Intraductal Carcinoma of the Prostate: Significance for Cancer Progression

Cribriform prostatic intraepithelial neoplasia (C‐PIN) identifies a unique histological pattern: dysplastic cells line ductal/acinar walls but also span across gland lumens. C‐PIN is distinct from other forms of dysplasia; it is seldom seen except within invasive cancer, it is more frequent in larger/higher‐grade cancers; and it appears to contribute independently to aggressive behavior. Hence, C‐PIN may represent a separate, more aggressive entity: intraductal carcinoma of the prostate (IDC‐P). Here, support for that distinction stems from a histologic/biologic subclassification of IDC‐P, whose elements are linked to features of invasive cancer.

Direct Visualization of Propionibacterium acnes in Prostate Tissue by Multicolor Fluorescent In Situ Hybridization Assay

ABSTRACT Prostate tissues from patients with prostate cancer and benign prostatic hyperplasia (BPH) frequently contain histological inflammation, and a proportion of these patients show evidence of Propionibacterium acnes infection in the prostate gland. We developed a multicolor fluorescent in situ hybridization (FISH) assay targeting P. acnes 23S rRNA along with a 14-kb region of the P. acnes genome. This assay was used to analyze prostate tissues from patients with prostate cancer and BPH. P. acnes infection of the prostate gland was demonstrated in prostatic tissue in 5 of 10 randomly selected prostate cancer patients. FISH analysis and confocal laser microscopy imaging revealed intracellular localization and stromal biofilm-like aggregates as common forms of P. acnes infection in prostate tissues from both prostate cancer and BPH patients. A sequential analysis of prostate tissue from individual patients suggested that P. acnes can persist for up to 6 years in the prostate gland. These results indicate that P. acnes can establish a persistent infection in the prostate gland. Further study is needed to clarify the link between this bacterium and prostatic inflammation which may contribute to the development of BPH and prostate cancer.

Central Zone Carcinoma of the Prostate Gland: A Distinct Tumor Type With Poor Prognostic Features

PURPOSE The central zone of the prostate gland is a region rarely associated with carcinoma. To our knowledge central zone tumors have not previously been compared to carcinoma originating in the peripheral or transition zone of the prostate gland. MATERIALS AND METHODS All 2,010 radical prostatectomy cases seen at our institution from October 1998 to December 2006 were reviewed to identify tumor zonal origin. Central zone carcinoma was characterized and compared with tumors of other zones. RESULTS Zonal origin was determined in a total of 2,494 tumors in 1,703 cases. Of the tumors 63 (2.5%) were of central zone origin with 59 of the 63 representing the index or main tumor. Comparative analysis of a defined subset of 726 cases showed that central zone cancers were significantly more aggressive than peripheral or transition zone cancers with a far greater risk of extracapsular extension, seminal vesicle invasion and positive surgical margins. Escape from the gland was often via the ejaculatory ducts and seminal vesicles. Kaplan-Meier analysis confirmed that the probability of post-prostatectomy biochemical failure was double that of tumors of the other zones with a far more rapid rate of failure. Multivariate Cox regression analysis identified Gleason grade, positive margins, extracapsular extension, tumor volume and preoperative serum prostate specific antigen as the major contributors to this poor prognosis, rather than specific zonal origin. CONCLUSIONS To our knowledge this study provides the first characterization and comparative analysis of central zone carcinoma, identifying these tumors as a rare but highly aggressive form of prostate carcinoma with a distinct route of spread from the gland that contrasts with tumors of other zones. Preoperative identification is currently hampered by the avoidance of biopsy targeting the central zone. However, if recognized preoperatively, aggressive intervention may possibly improve the currently bleak outlook.

Transition zone carcinoma of the prostate gland: a common indolent tumour type that occasionally manifests aggressive behaviour

Aims: Tumours arising in the transition zone (TZ) of the prostate gland are often well differentiated and considered clinically unimportant. We have observed examples of high‐grade TZ cancers that prompted this study. Methods: Review of 654 radical prostatectomy specimens previously assessed by systematic whole organ histology identified 187 (29%) TZ cancers of which 76 (11.6%) represented the index (main) tumour. These were compared with a volume‐matched group of 76 peripheral zone (PZ) carcinomas. Results: Fifty‐nine of 76 TZ index carcinomas had additional minor tumours mainly located in the PZ. Compared to PZ tumours of similar size, TZ tumours had significantly lower Gleason scores, less Gleason grade 4/5 and lower rates of capsular penetration and positive surgical margins. However, within this TZ tumour group, seven carcinomas had a major Gleason grade 4 or 5 component with high rates of capsular penetration (57%) and positive surgical margins (43%). Positive anterior and bladder neck margins were more common in TZ carcinoma than peripheral tumours and transperineal biopsy was the method of choice for TZ cancer diagnosis. Conclusions: A subset of TZ carcinoma characterised by high tumour grade has a significant risk of extraprostatic spread, margin positivity and possible biochemical failure. We recommend transperineal prostate biopsy for TZ tumour diagnosis and histological sampling of the anterior TZ at radical prostatectomy, even if macroscopically normal, to detect patients at risk from aggressive TZ carcinoma.

Percutaneous core biopsy of small renal mass lesions: a diagnostic tool to better stratify patients for surgical intervention.

Study Type – Prognosis (case series)