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Rrisk of infection and hospitalization after transrectal prostate biopsy (TRBx) has been increasing worldwide. Several modified antibiotic regimens have met with variable success in preventing such infections. Transperineal prostate biopsy (TPBx) is increasingly recommended as the preferred alternative due to a potentially lower risk of post-biopsy infections. Aim of this review is to define the magnitude of post-biopsy complications and the effectiveness of preventive strategies, including TPBx approach. We performed a focused review of literature on infectious complications after TRBx and detailed the use of various preventive measures. We summarized the effectiveness of several preventive measures, including TPBx, and outlined the inconsistencies in reported outcomes. We identified potential barriers to the uptake of TPBx, including the gap in knowledge such as lack of high-quality evidence. Several antibiotic prophylaxis protocols, including targeted and augmented, have been utilized for TRBx without demonstrating a clearly superior regimen. Of the non-antibiotic preventive measure, povidone-iodine rectal prep appears to be most effective strategy. Several single-arm cohort studies have reported very low rates of infections after TPBx and demonstrated the feasibility of an office-based procedure. However, barriers to the adoption of TPBx exist including retrospective data, and conflicting results showing minimal reduction in complications with increased burden of resource utilization. Presently, there are no randomized studies comparing the infectious complications after TRBx and TPBx. We discuss the rationale and protocol for a randomized controlled trial to determine the comparative effectiveness of biopsy techniques. TPBx approach has the potential to lower the rate of post-biopsy infections and hospitalizations. However, there are several barriers to widespread adoption of this approach including inconsistencies in reported outcomes and lack of Level-1 evidence. Randomized controlled studies are required to directly compare the infectious complications associated with each biopsy procedure.

Highlights • Clear cell adenocarcinoma of the lower urinary tract is rare and poses diagnostic challenge. • GATA3, which is frequently expressed in urothelial carcinoma, can be expressed in clear cell adenocarcinoma. • ARID1A, PBRM1, ERBB4, and SMARCA4 mutations were identified in the current CASE. • Molecular studies may aid in the diagnosis, and optimal treatment decision-making process.

INTRODUCTION AND OBJECTIVES:Venous thromboembolism (VTE) is a common cause of morbidity and mortality in urologic surgery. Appropriate risk stratification and administration of prophylaxis can help...

INTRODUCTION AND OBJECTIVES:As the Father of Urologic Oncology, Dr. Willett F. Whitmore Jr presided over a dynamic period regarding the diagnosis and treatment of prostate cancer. His commitment to...

Objective: In patients scheduled for radical prostatectomies (RP), preoperative (pre-op) erectile function (EF) characterization may be complicated by social and medical factors. We investigated pre-op use of phosphodiesterase type 5 inhibitor (PDE5i) as a simple metric for predicting long-term postoperative EF. Materials and methods: Electronic medical records (EMRs) for consecutive men who underwent RP between January 2004 and March 2009 at our institution were retrospectively reviewed. Data extracted included demographics, pre-op PDE5i use, cancer treatment details, post-op EF and ED treatment. Predictor variable data were categorical pre-op PDE5i use (pre-op PDE5i use vs. pre-op PDE5i naïve). ANOVA and Chi squared test were used. Results: A total of 250 individuals out of 436 charts met inclusion criteria. Mean follow-up length was 4.2 years (range 2–7). Thirty-seven men (15%) used PDE5i preoperatively. There were no differences in mean age at RP, type of nerve-sparing surgery (NSS), or medical comorbidities between groups. No men with pre-op PDE5i use regained unassisted EF but 37% regained PDE5i-assisted EF after bilateral nerve sparing (BNS). No men with pre-op PDE5i use regained unassisted or PDE5i-assisted EF after unilateral (UNS) or non-nerve-sparing surgery (NNS). Conclusions: Pre-op PDE5i use predicts poor long-term EF outcomes after RP and should be included in pre-op patient counseling.

Background Implant brachytherapy (IBT) is a well-recognized treatment modality for early stage prostate cancer. Rectal ulcer and rectourethral fistula complicating IBT may cause an alteration of the normal anatomic landmarks. In this context, pseudomalignant radiation-induced changes within prostatic epithelium may be misinterpreted as a primary rectal malignancy. Such challenging and misleading findings have not been described, and may not be recognized as such. Materials and methods We present the clinical and pathologic aspects of two patients who underwent IBT for low stage prostate cancer that was complicated by deep rectal ulcer. Both patients underwent extensive palliative surgical resection for disease control. Results The histologic changes in both cases were noteworthy for extensive necrosis and inflammation of the prostate, associated with loss of recto-prostatic anatomical landmarks. Prostatic glands showed striking radiation-induced atypia and pseudomalignant epithelial changes extending to the rectal ulcer bed, with no residual viable tumor. The first patient had undergone a biopsy of the rectal ulcer bed that was misinterpreted as a rectal adenocarcinoma prior to surgery. The similarity between atypical glands of the biopsy and the benign prostatic tissue with radiation-induced atypia in resection specimen confirmed their benign nature. Conclusions Deep rectal ulcer complicating IBT may lead to distortion of the normal recto-prostatic anatomical landmarks, resulting in detection of pseudo-malignant prostatic glands at the ulcer base. Such findings may be mistaken for a primary rectal malignancy in limited biopsy material if not familiar to the pathologist.

A micropapillary variant of prostatic acinar adenocarcinoma has not been reported in the literature. Herein, we report a case of a 50-year-old patient who presented with an elevated prostate-specific antigen concentration and was subsequently diagnosed with prostatic acinar adenocarcinoma on biopsy. Radical prostatectomy specimen revealed prostatic carcinoma with Gleason score 4 + 5 = 9/10, with micropapillary component constituting 80% of tumor volume. Immunohistochemical studies of the prostate carcinoma showed a homogeneously positive prostate-specific antigen and α-methylacyl-CoA racemase, high-molecular-weight cytokeratin, and p63 protein cocktail pattern of staining in both micropapillary and conventional components. Pelvic lymph nodes were negative for metastatic disease. In contrast to the aggressive behavior of micropapillary carcinomas of other organs, the disease in our patient has thus far followed a more benign course, with low stage on presentation and a 2-year follow-up free of disease. However, prognostic correlation should be established on large series in order to assign this variant to a grade category within the Gleason scheme.

e24151Background: Confirmation of prostate cancer in men with elevated PSA and suspicious digital rectal exams currently requires a core needle biopsy, which is associated with risks such as infect...

5061Background: We hypothesized that sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with clinically advanced CRPC and CRNEPC. Methods: CGP was performed ...

12070Background: Bladder cancer patients are routinely monitored after treatment by cystoscopy due to a high rate of recurrence. In the absence of an accurate non-invasive screening test to monitor...

348 Background: We performed comprehensive genomic profiling (CGP) to learn whether sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with refractory CRPC and CRNEPC. Methods: DNA was extracted from 40 µm of FFPE sections of 2,424CRPC and 143 CRNEPC. CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median ages for all 4 groups was similar (Table). TMPRSS2+( TMP+) CRPC features significantly greater TP53 and PTEN GA and TMPRSS2-( TMP-) CRPC featured higher MYC and ATM GA. Differences in BRCA2 and RB1 GA were not significant in the CRPC group. RB1 GA were more frequent in CRNEPC than CRPC. TP53 GA were higher in TMP+ CRNEPC than in TMP+ CRPC whereas GA in PTEN and MYC were similar in comparative groups. GA in AR and ATM were more frequent in CRPC than CRNEPC. The median TMB was higher in CRNEPC than CRPC and higher in TMP- than TMP+ tumors. TMP- CRPC and TMP- CRNEPC had higher TMB levelsthan TMP+ tumors in both groups. MSI-High status was more frequent in the TMP- CRPC and TMP- CRNEPC groups. Conclusions: For CRPC but not CRNEPC, the frequency of TMP+CRPC cases appears lower in advanced vsearly stage disease (TCGA data). CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMP+ and TMP- CRPC and CRNEC. Thus, when CRPC and CRNEPC areevaluated as to their TMPRSS2:ERG fusion status, significant genomic differences emerge which may impact therapy selection.[Table: see text]

Background: Lymphedema typically affects a whole limb. Rarely, lymphedema can present as a circumscribed plaque or an isolated skin tumor. Objective: To describe the clinical and pathologic characteristics and etiologic factors of localized lymphedema. Methods: Case–control study of skin biopsy and excision specimens histologically diagnosed with lymphedema and presenting as a localized skin tumor identified during a 4-year period. Results: We identified 24 cases of localized lymphedema presenting as solitary large polyps (11), solid or papillomatous plaques (7), pendulous swellings (4), or tumors mimicking sarcoma (2). Patients were 18 females and 6 males with a mean age of 41 years (range 16–74). Anogenital involvement was most frequent (75%) – mostly vulva (58%), followed by eyelid (13%), thigh (8%) and breast (4%). Causative factors included injury due to trauma, surgery or childbirth (54%), chronic inflammatory disease (rosacea, Crohn’s disease) (8%), and bacterial cellulitis (12%). Eighty-five percent of these patients were either overweight (50%) or obese (35%). Compared with a series of 80 patients with diffuse lymphedema, localized lymphedema patients were significantly younger (41 vs. 62 years old, p = 0.0001), had no history of cancer treatment (0% vs. 18%, p = 0.03), and had an injury to the affected site (54% vs. 6%, p = 0.0001). Histologically, all cases exhibited dermal edema, fibroplasia, dilated lymphatic vessels, uniformly distributed stromal cells and varying degrees of papillated epidermal hyperplasia, inflammatory infiltrates and hyperkeratosis. Tumor size significantly and positively correlated with history of cellulitis, obesity, dense inflammatory infiltrates containing abundant plasma cells, and lymphoid follicles (p

To determine the relationship of total PSA (tPSA), percent free PSA (%fPSA), and complexed PSA (cPSA) with prostate cancer detection and the diagnosis of poorly-differentiated cancers in the contemporary era.We retrospectively reviewed the clinical and pathological records of 292 men who met the following inclusion criteria: (1) tPSA 2.5 to 10 ng/ml; (2) initial biopsy only; (3) extended biopsy scheme (or=10 peripheral zone cores); (4) no previous prostate surgeries. The ability of PSA-related markers to detect cancer was determined by area under the receiver operating characteristics curve analysis (AUC-ROC). Various clinically relevant % fPSA cutoffs and cPSA ranges were analyzed to determine the association with poorly-differentiated cancers.Cancer was detected in 126 (43%) men, with mean Gleason score of 7. The cancer detection rates for various cutoffs of tPSA, cPSA and % fPSA were very similar. On ROC analysis for cancer diagnosis, the AUCs for tPSA, % fPSA, and cPSA were 0.53, 0.54, and 0.52, respectively. Men with % fPSA15 were more likely to have poorly-differentiated cancer than those with % fPSAor=15 (66% vs. 41%, P0.005). Similarly, cPSA ranges (2-4, 4.1-6, and6) were associated with the detection of poorly-differentiated cancers (37%, 57%, and 80% P0.003).With the use of extended prostate sampling in the contemporary screening population, the addition of cPSA and % fPSA does not enhance the diagnostic performance of tPSA. However, the significant association between cPSA and poorly-differentiated cancers suggests that this may be a more useful initial test for prostate cancer screening.

Purpose: The nuclear transcription factor nuclear factor-κB (NFκB) and its inhibitor, IκB, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NFκB transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NFκB has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NFκB immunoreactivity in prostate adenocarcinomas (PACs). Experimental Design: Using prostatectomy specimens, we performed immunohistochemical staining for NFκB and IκBα (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence. Results: Forty-nine percent of PACs overexpressed cytoplasmic NFκB, and 63% showed decreased IκB expression. Cytoplasmic NFκB overexpression correlated with advanced tumor stage (P = 0.048), aneuploidy (P = 0.022), and biochemical disease recurrence (P = 0.001). When we compared the means for the NFκB-positive and -negative subgroups, NFκB overexpression correlated with preoperative serum prostate-specific antigen (P = 0.04) and DNA index (P = 0.05). Fifteen percent of PACs expressed nuclear NFκB, which correlated with high tumor grade (P = 0.001) and advanced stage (P = 0.05). Decreased IκBα expression correlated with high tumor grade (P = 0.015). On multivariate analysis, tumor stage (P = 0.043) and NFκB overexpression (P = 0.006) were independent predictors of biochemical recurrence. Conclusion: These results support a role for NFκB pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NFκB blockade in decreasing the rate of disease relapse.

We report a primary peritoneal mullerian adenosarcoma with sarcomatous overgrowth associated with endometriosis in a 50-year-old female. The tumor formed multiple peritoneal masses occupying the pelvis and subdiaphragmatic space. Histologically, the tumor was composed of benign-appearing mullerian glands surrounded by a sarcomatous stroma. In addition, one perisplenic mass was largely devoid of the epithelial component and was of higher grade than the remaining lesions. Multiple foci of endometriosis were associated with the pelvic masses. To our knowledge, primary peritoneal mullerian adenosarcoma with sarcomatous overgrowth associated with endometriosis has not been previously reported.

429 Background: Relapsed and refractory urethral cancer (UrethC) is a rare form of genito-urinary malignancy that includes urothelial carcinoma (UC), squamous cell carcinoma (SCC), adenocarcinoma (AC) and clear cell carcinoma (CCC) subtypes. No standard treatment exists. Methods: DNA was extracted from 40 microns of FFPE specimen from 46 cases of mUrethC. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of >500X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: The clinical features, GA, TMB findings in the mUrethC patients and the subtypes of UrethC are shown in the Table. In comparison with 1,183 similarly profiled UC of the bladder (UCB), all 46 mUrethC and the 21 urothelial mUrethC as a separate group widely differed in GA frequencies. With the exception of similar TP53 GA frequencies, there were significantly lower GA in ERBB2, FGFR1-3 and PIK3CAin the mUrethC cases (p 20 mut/Mb (4%; p=0.0001). Conclusions: CGP of mUrethC reveals distinctive genomic alteration frequencies among the 4 disease subtypes with higher numbers of GA in the AC than in the UC, SCC and CCC. The TMB appears to be lower in mUrethC than classically seen in UCB where checkpoint inhibition is now approved. Further study of this rare form of genitourinary cancer appears warranted. [Table: see text]

350 Background: Small cell neuroendocrine carcinoma of the bladder (SCCB) is rare but aggressive form of genitourinary cancer that can arise de novo or in conjunction with urothelial carcinoma (UCB). Methods: DNA was extracted from 40 microns of FFPE specimen from 29 cases of relapsed, refractory and metastatic SCCB and 1,113 UCB. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of > 503X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: 29 SCCB cases were confirmed on routine histology and featured positive IHC staining for chromogranin, synaptophysin or both. Patients had a mean age of 68.1 years (range 49-90 years) and 25 (86%) were male. At the time of CGP, 3 (10%) SCCB were Stage III and 26 (90%) were stage IV. The primary SCCB was used for sequencing in 14 (48%) of cases and a metastasis sample in 15 (52%). The 29 SCCB featured 2.86 GA/case.The genomics of SCCB differed significantly from UCB (Table). The most frequent clinically relevant GA in SCCB were RICTOR amp (21%) and PIK3CA (10%), BRCA1, HGF, FBXW7 and CCND2 SV (7% each). The relatively high TMB in SCCB (7% TMB > 20 mut/Mb and 28% TMB > 10 mut/Mb) is similar to that seen in UCB. No SCCB cases were MSI-high. ERBB2 and FGFR1 GA frequencies (both 3%) in SCCB were lower than in similarly studied UCB. Conclusions: SCCB differs in genomic landscape from UCB in having higher frequencies of TP53 and RB1 GA and lower frequencies of FGFR3 and ERBB2 GA. However, like UCB, SCCB shares the presence of multiple GA associated with potential responses to targeted therapies and high TMB associated with response to immune checkpoint inhibitor therapy. [Table: see text]

PURPOSE To test whether p34cdc2 overexpression, CD44s downregulation, and HER-2/neu amplification correlate with disease recurrence after radical prostatectomy, and to evaluate a possible biologic association between p34cdc2 and HER-2/neu expression. MATERIALS AND METHODS Immunohistochemical (IHC) detection of both p34cdc2 cyclin-dependent kinase (CDK) and CD44s expression and fluorescence in situ hybridization (FISH)-based analysis of HER-2/neu gene status were performed on formalin-fixed, paraffin-embedded sections of 106 prostatic adenocarcinomas (PACs). Findings were correlated with Gleason grade, pathologic stage, DNA ploidy, and postsurgical biochemical disease recurrence. RESULTS CDK overexpression correlated with tumor grade (P = .001), DNA ploidy (P = .001), pathologic stage (P = .04), and disease recurrence (P = .01). CD44s downregulation correlated with grade (P = .03), ploidy (P = .01), and recurrence (P = .02). HER-2/neu amplification correlated with grade (P = .001), ploidy (P = .001), and recurrence (P = .01). On multivariate analysis, CDK overexpression independently predicted recurrence (P = .001) after prostatectomy. CDK expression correlated with HER-2/neu status with 32 of 65 (49%) tumors that overexpressed CDK and showed concomitant HER-2/neu amplification (P = .04). CONCLUSION This study showed that p34cdc2, CD44s, and HER-2/neu are variably expressed or amplified in prostatic carcinoma and that such alteration may affect tumor behavior. In addition, CDK overexpression and HER-2/neu amplification may be biologically related.

Telomerase adds a hexanucleotide telomeric sequence to the chromosomal ends during replication and is postulated to play a role in cellular senescence and immortalization. Thirty-four human prostate tissues (18 malignant; 16 benign) were analyzed for telomerase activity by a sensitive nonradioactive polymerase chain reaction (PCR)-based method using the TRAP-ezeTM telomerase detection kit (Oncor, Inc., Gaithers-burg, MD). Telomerase activity in the homogenized tissue extracts was correlated with tumor grade, pathologic stage, and DNA ploidy. Specimens that exhibited the 36 bp internal control band and a ladder of products with 6-base increments starting with 50 nucleotides were considered positive. Fourteen (78%) of 18 prostatic adenocarcinomas (PACs) and only 2 (13%) of 16 benign prostate tissues exhibited telomerase activity. Our results indicate that, in contrast to most benign prostate tissues, telomerase activity can be detected in the majority of PACs and appears to be independent of tumor grade, stage, or DNA ploidy. Telomerase expression is occasionally detected in benign prostatic tissues bordering PACs and may result from either the presence of undetected tumor foci in these stored specimens or the proliferative response of the benign elements to adjacent cancer.

BACKGROUND CD44, a transmembrane protein, is associated with cell-cell and cell-matrix interaction and with tumor growth and metastasis. Expression of both standard form and variant isoforms of CD44 protein has been associated with aggressive behavior and metastasis in various tumors, but has not been characterized in prostate adenocarcinoma (PAC). METHODS The expression of CD44 standard (CD44s) and splice variant v3, v4/5, v6, v7/8, and v10 proteins were studied in 109 PACs and correlated with tumor grade, DNA ploidy, and mRNA levels. Monoclonal antibodies against the various CD44 proteins were applied to microwave irradiated, formalin fixed, paraffin embedded sections. The DNA content of the tumors was evaluated by the Feulgen method with the CAS200 Image Analyzer. Total RNA exhibiting 18s and 28s bands was derived from two benign prostatic tissues and 5 PACs exhibiting decreased levels of CD44 protein by immunohistochemistry. The RNA was analyzed with reverse transcriptase polymerase chain reaction using CD44 specific primers. RESULTS The basal cells of the benign prostatic acini revealed uniform membranous staining for CD44s, v3, and v6 in 95–97% of cases. Similar staining was observed for v4/5, v7/8, and v10 in 40%, 30%, and 2% of cases, respectively. Secretory epithelial cells of the benign prostatic acini showed predominant expression of CD44s (97% of cases). Staining for CD44 variant proteins (v3, v4/5, v6, v7/8, and v10) in this location ranged from 9–22% of cases. Approximately 70% of the PACs showed significant loss of CD44s expression, which correlated with high tumor grade (Gleason ≥ 7) (P = 0.01) and aneuploid status (P = 0.002). In 93–98% of the PACs, there was a complete lack of membranous expression for all CD44 variant isoforms. The metastatic PACs did not show preferential expression of either the standard form or any variant isoform. The cDNA from the normal prostates yielded a prominent CD44 standard form polymerase chain reaction product at 482 base pair (bp) and variant isoforms at ˜650 and 850 bp. No CD44 products could be amplified from the subset of five PAC cDNAs, even when present at four-fold excess. CONCLUSIONS PACs exhibit down-regulation of CD44 protein expression, which correlates with high tumor grade and aneuploidy. v6 and v3 isoforms were preferentially expressed in the basal cells of benign prostatic acini. Based on a subset of cases, loss of CD44 protein expression is associated with decreased abundance of CD44 mRNA. Cancer 1996;78:1461-9.

Purpose: We assessed the staging accuracy of endo-rectal coil magnetic resonance imaging (MRI) in patients with clinically localized prostate cancer.Materials and Methods: In a prospective study 56 consecutive patients underwent endo-rectal coil MRI before scheduled surgery. The ability of MRI to identify tumor involvement of the periprostatic soft tissue, seminal vesicles and pelvic lymph nodes was assessed by comparison with final pathological stage.Results: Specificity of MRI was relatively high (84 percent for periprostatic soft tissue, 93 percent for seminal vesicles and 91 percent for pelvic lymph nodes) and sensitivity was low (22, 23 and 0 percent, respectively). Accuracy was 64 percent for identification of periprostatic soft tissue invasion, 77 percent for seminal vesicle invasion and 86 percent for pelvic lymph node metastases. Had we excluded from surgery patients with MRI evidence of extraprostatic disease our organ confined disease rate would have improved by 16.6 percent. However, t...

E-cadherin (E-CD) is a cell-adhesion molecule that has been associated with invasion and metastasis in a wide variety of human neoplasms. We have recently shown that, although decreased E-CD expression is associated with increased bladder-wall invasion and higher tumor grade of infiltrating transitional cell carcinomas (TCC), E-CD expression in the exophytic portion of pure papillary and papillary-infiltrating TCC is increased over that of normal transitional cells. To evaluate whether E-CD levels could serve as a diagnostic adjunct in urinary cytology specimens, we stained 40 alcohol-fixed bladder-washing cytospin preparations with an avidin-biotin-peroxidase method using a monoclonal antibody to E-CD (Sigma Chemical Co., St. Louis, MO). E-CD expression level was defined as a high-intensity or low-intensity staining increase over background squamous cell staining for the transitional cells in 21 biopsy-proven transitional cell carcinomas with papillary components, and in 19 benign or reactive control specimens. Twenty-one of 21 TCC (100%) showed an increased E-CD level over background, with 13 low-intensity and 8 highintensity cases. Ten of 19 benign cases (53%) showed increased E-CD staining over background, with 8 low-intensity and 2 highintensity cases. This difference between malignant and benign specimens was statistically significant (chi-square test. P approximately 0.001). We conclude that increased E-CD expression in the papillary components of TCC can be identified in urinary cytology specimens, may reflect the physical and chemical structural makeup of papillary architecture, and warrants further study as a diagnostic adjunct in the interpretation of urine cytology specimens.

National screening programs resulting in an increased detection rate of prostatic adenocarcinoma have prompted the search for new methods of predicting disease outcome that can be applied to the initial narrow bore needle biopsy specimens. Cathepsin D, a lysosomal aspartyl protease and autocrine mitogen, has been studied in a wide variety of human neoplasms as an invasion and metastasis marker. Prostatic carcinoma needle biopsy tumor cell cathepsin D content was measured in 61 men using a semiquantitative image analysis assisted immunohistochemical procedure. Results were compared with preoperative serum prostatic specific antigen levels, tumor grade, DNA ploidy status, pathologic stage after radical prostatectomy and disease recurrence during a median 2.6 year follow-up. Biopsy cathepsin D levels significantly correlated with tumor grade ( P = .022) and DNA ploidy status ( P = .028) by logistic regression analysis. Post-prostatectomy pathologic stage and disease recurrence did not correlate with tumor cathepsin D levels. Final prostatectomy grade and DNA ploidy status independently predicted metastasis and post-operative disease recurrence ( P < .001). Although this study did not find independent prognostic status for cathepsin D in prostate cancer, the correlation with tumor grade and DNA ploidy status is noteworthy and the inter-relationship of outcome variables may prove of interest and warrant further evaluation of this potential predictor or CO-predictor of disease outcome.

187 Background: Neuroendocrine carcinoma of the prostate (NCAP) is an aggressive high grade malignancy that often presents as metastatic disease. Current treatments of this tumor have only modest benefit leading investigators to query whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 37 consecutive cases of relapsed/metastatic NCAP. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 583X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the men in this study was 65.1 years (range 43 to 83 years). All (100%) cases were positive for neuroendocrine markers on immunohistochemical staining and were Stage IV at the time of CGP. Samples used for sequencing were obtained from the primary tumor in 9 (24%) of NCAP and from metastatic sites in 28 (76%) of NCAP (12 liver, 6 LN, 2 each from bladder, pelvis and soft tissue, and 1 each from rectum, bone, urethra and ureter. There were 213 total GA (5.8 GA/sample) and 47 CRGA (1.3 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (68%) and RB1 (51%). TMPRSS:ERG fusions were identified in 32% of cases whereas AR was altered in 8% (1 mutation and 2 amplifications). The most frequent CRGA involved PTEN (32%), BRCA2 (14%), FGFR1 (5%), PIK3CA (5%) and AKT2 (3%). No alterations in BRAF were identified. Clinical responses to MTOR inhibitors in patients with MTOR pathway alterations will be presented. Conclusions: NCAP has distinctive genomic alterations from classic acinar CAP including reduced frequencies of alterations in TMPRSS:ERG and AR and frequent RB1 mutations. Multiple alterations in the MTOR pathway identified in this infrequent tumor type suggest that these patients may be candidates for MTOR inhibitors and other targeted therapies.

4522Background: Upper tract urothelial carcinoma (UTUC) is generally thought to have a more aggressive clinical phenotype as compared to urothelial carcinoma of the bladder (UCB). We interrogated g...

Background. DNA ploidy determination of carcinomas in radical prostatectomy specimens has shown significant correlation with patient outcome, but the predictive value of ploidy status of cancers obtained by transrectal ultrasound-guided needle biopsies has not been studied extensively. Methods. Eighty-nine paired needle biopsy specimens (NBX) and radical prostatectomy (RPX) specimens from patients with early clinical stage (A2-B2) prostate cancer were evaluated for DNA content by image analysis of Feulgen stained tissue sections. Findings were compared with Gleason grading on the same specimens by univariate and multivariate analyses for prediction of local tumor invasion, metastasis, disease recurrence, and serum prostate specific antigen concentration during a 0.9-6.0 year clinical follow-up period. Results. There was excellent correlation of ploidy status between NBX and RPX specimens (P < 0.0001); NBX and RPX grades did not correlate. On RPX specimens, aneuploid status correlated with high tumor grade (P < 0.0005). Aneuploidy in NBX specimens was associated with a twofold higher rate of extracapsular spread (ECS) (P = 0.04). Aneuploid NBX tumors featured a ten fold greater frequency of metastasis than did diploid NBX tumors (P < 0.005). Radical prostatectomy grade correlated with ECS (P < 0.001) and presence of metastatic disease (P = 0.04). On multivariate logistic regression analysis, aneuploidy in both NBX and RPX specimens was the most significant variable and independently predicted the presence of metastasis (P = 0.006 for NBX; P = 0.028 for RPX). Tumor grade of NBX and RPX specimens did not independently predict metastatic disease or disease recurrence, but RPX grade was associated independently with ECS (P = 0.005). Aneuploid NBX tumors recurred after RPX three times more often than did diploid cases, which was significant on univariate (P < 0.001) and multivariate (P = 0.018) analyses using the Cox proportional hazards model. There was no correlation with NBX or RPX Gleason score and disease recurrence. Preoperative serum PSA concentration did not correlate with tumor grade or ploidy status, but on multivariate analysis, when paired with ploidy status, independently contributed to the propensity for ECS, metastasis, and disease recurrence. Conclusions. DNA content analysis of early clinical stage prostate carcinoma needle biopsy specimens by im age analysis directly correlates with radical prostatectomy specimen ploidy status and is associated independently, with the presence of metastasis, postprostatectomy disease recurrence, and ECS. Needle biopsy tumor grading did not correlate with prostatectomy grade and did not predict disease outcome accurately.

To determine whether p53 immunoreactivity correlates with the Gleason tumor grade in primary adenocarcinoma of the prostate we analyzed 107 consecutive surgical specimens (78 radical prostatectomies and 29 transurethral resections). A hematoxylin-eosin-stained slide from a representative block of each tumor was examined, and primary and secondary Gleason scores were assigned in each case. Additional paraffin sections from the same block were stained immunohistochemically for p53 expression using the monoclonal antibody clone DO-1, a mouse IgG2a directed against a denaturation-resistant epitope of p53. Four of 54 (7.4%) low-grade tumors (combined Gleason score of 6 and below) and 11 of 53 (20.8%) high-grade tumors (combined Gleason score of 7 and above) revealed strong nuclear positivity for p53. When evaluated using only the primary Gleason score, none of 23 (0%) Gleason grade 2 tumors and 15 of 84 (17.9%) Gleason grade 3 or higher tumors were positive. These data demonstrate a positive association between p53 immunoreactivity and higher Gleason grade tumors (P = .04 for the combined score, P = .02 for primary score only). In addition, we noted occasional p53-positive nuclei in basal cells of benign glandular acini in regions flanking tumor. Focally positive nuclear staining also was demonstrated in basal cells from nine of 25 prostate glands exhibiting benign prostatic hyperplasia with no tumor. These results suggest that p53 overexpression might be associated with the known proliferative capacity of basal cells in benign hyperplastic prostate glands, and that mutations of p53 might play a role in the pathogenesis of a subset of high-grade prostate adenocarcinomas.

True carcinosarcoma of the prostate is a rare neoplasm, with only 9 cases well documented by immunocytochemistry and ultrastructural examination. We report a case of an unresectable pelvic tumor studied at autopsy. The primary prostatic neoplasm and pulmonary metastases were composed of well differentiated adenocarcinoma admixed with foci of leiomyosarcoma and osteosarcoma. The sarcomatous components showed reactivity with vimentin and desmin, did not express prostatic acid phosphatase (PAP) and prostate specific antigen (PSA), and contained myofilaments on electron microscopic examination. Positive staining of the carcinomatous component for PAP and PSA was noted. These findings confirm the mixed epithelial and mesenchymal components in primary and metastatic sites, and support the diagnosis of true prostatic carcinosarcoma.

Objectives Extended biopsy schemes are now the standard of care for detection of prostate cancer. Submitting biopsy cores individually raises the cost of pathologic evaluation significantly while important prognostic information is lost when the samples are bundled into fewer containers. We devised a protocol for bundling biopsy cores to reduce the cost while maintaining our ability to identify important biopsy features. Materials and Methods Four hundred fifty-two consecutive men underwent a prostate biopsy using our prospectively designed protocol. The lateral peripheral cores were marked with India ink and combined with cores from the corresponding sextant site into one container (maximum containers = 6). Prognostic information from each core was recorded. Cost analysis was based on the reimbursement rates for variable number of containers. Results Tissue-labeling protocol did not increase the procedure time or introduce any tissue artifacts. Cancer was detected in 177 (39%) men with mean Gleason score of 7. A single core with cancer was noted in 28%, and cancer in ≤25% of the core was found in 41%. Thirteen of 64 (20%) men undergoing radical prostatectomy had extracapsular extension (ECE) and 10 (15%) had a positive surgical margin. The location of ECE on prostatectomy specimen correlated with a positive biopsy site in 9 (70%) patients. The cost of histopathologic evaluation is based on number of individually labeled specimen containers. By reducing the number of specimen containers from 12 to 6, the potential savings may be in hundreds of million per year. Conclusions This simple tissue-labeling protocol facilitates extended prostate biopsies in a cost-effective manner, while maintaining our ability to glean important prognostic information from each core.

Claudins, members of a large family of adherent junction proteins, regulate the integrity and function of tight junctions and influence tumorigenesis. Recent studies have shown that altered levels of the different claudins may be related to invasion and progression of carcinoma cells in several primary neoplasms. However, there is no reported study documenting the pattern of claudin expression in prostatic adenocarcinomas (PACs). Formalin-fixed paraffin-embedded sections from 141 PACs were immunostained by manual and automated methods on the Xmatrx (BioGenex, San Ramon, CA) using antihuman claudin-1, -3, -4, -5, and -7 antibodies (Zymed, San Francisco, CA). Membranous immunoreactivity for each protein was semiquantitatively scored in both the tumor and adjacent benign epithelium in each case. Results were correlated with clinicopathologic variables. Variable membranous positivity was noted in the adjacent benign glands for all 5 proteins in all cases. PACs showed variable membranous positivity ranging from decreased, similar to, and increased in relation to the adjacent benign epithelium for all claudins. Decreased expression of claudin-1 correlated with high tumor grade (P = .001) and biochemical disease recurrence (P = .01), whereas decreased claudin-7 correlated with high tumor grade (P < .0001). In contrast, expression of claudin-3 correlated with advanced stage tumors (P = .03) and recurrence (P = .02), and expression of claudin-4 correlated with advanced stage (P = .02). On multivariate analysis, advanced stage (P = .026) and decreased claudin-1 protein expression (P = .005) independently predicted disease recurrence. Immunohistochemical expression and prognostic significance of claudins are variable in PACs, with decreased expression of claudin-1 emerging as an independent prognostic variable warranting further study.

Objectives To determine whether improved prostate sampling by the extended biopsy scheme also improves the accuracy of the biopsy Gleason score (bGS). Because most prostate cancer cases are now detected at an early stage with a low prostate-specific antigen level, the bGS may be the most important factor in therapeutic decision-making. Sextant biopsy schemes had poor correlation with prostatectomy Gleason scores. Extended prostate biopsies have replaced the sextant scheme because of the former’s greater cancer detection rate. Methods We identified 426 patients whose biopsy and prostatectomy specimens were reviewed at our center. To minimize the effect of stage migration, all patients before 1997 were excluded. Of the 426 included patients, 221 men had undergone sextant biopsy and 205 men extended biopsy before prostatectomy. The rate of grading concordance and the effect of different variables on the concordance rate was determined. Results The overall accuracy of the extended and sextant schemes was 68% and 48% (P

High grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) in the sextant biopsy had been associated with a high risk of prostate cancer. We determined whether the extended biopsy schemes used in the contemporary era have altered the prognostic value of these lesions at repeat biopsies.From 1998 to 2003, 105 of 1,188 men had at least 1 repeat extended biopsy due to the presence of HGPIN (33 men) or ASAP (72 men) in a previous extended biopsy. Median biopsy interval for HGPIN and ASAP was 15 and 10 weeks (p0.05), respectively. Differences in cancer detection rates were analyzed using the Pearson chi-square test.In the HGPIN group only 1 of 22 (4.5%) men had cancer on 1st repeat biopsy and 0 of 11 men had cancer on 2nd repeat biopsy. In men with ASAP 19 of 53 (36%, p0.005) had cancer on 1st repeat biopsy, and 3 of 19 (16%) had cancer on 2nd repeat biopsy. Cancer was confined to a single core in 16 of 22 (73%) men. Median Gleason score was 6. Patient age, digital rectal examination status, prostate specific antigen, free prostate specific antigen, number of cores and biopsy interval were not independent predictors of cancer in men with ASAP.HGPIN found in the contemporary extended biopsy does not warrant repeat biopsy. ASAP continues to be associated with a high risk of cancer and requires at least 1 repeat biopsy using the extended biopsy scheme.

The ability of traditional and newer molecular-based prognostic factors to predict the outcome of prostate cancer is of considerable interest to urologists, pathologists, and patients. In this review, a series of traditional and newer molecular-based prognostic factors are considered, including those that have achieved widespread use, newer tests that are beginning to be used in clinical practice, and emerging molecular markers that have yet to be widely validated in the published literature or clinical trials.

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading the structural support network for normal and malignant cells, promoting neoplastic cell invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) maintain connective tissue integrity by modulating MMP activity. Formalin-fixed paraffin-embedded tissue sections from 138 prostatic adenocarcinomas (PACs) were immunostained by a combined automated/manual method using monoclonal antibodies against MMP2 and TIMP2. Immunoreactivity was semiquantitatively scored based on stain intensity and distribution, and results were correlated with Gleason grade, pathologic stage, ploidy status, and disease recurrence. One hundred five of 138 (76%) and 113/138 (82%) PACs expressed MMP2 and TIMP2, respectively. Co-expression was observed in 94/138 (68%) of PACs (P = .01), correlated with advanced tumor stage (P = .05), and tended to be associated with disease recurrent cases (P = .07). TIMP2 expression individually correlated with advanced tumor stage (P = .04) and reached near significance with disease recurrence (P = .06). MMP2 expression was also more frequent in recurrent PACs, although this value did not reach statistical significance (P = .07). However, on multivariate analysis, only pathologic stage (P = .009) and ploidy status (P = .03) independently predicted disease recurrence. In conclusion, MMP2 and TIMP2 are co-expressed in a majority of PACs and correlate with prognostic variables. Interestingly, contrary to the previously documented anti-tumor effects of TIMPs, TIMP2 expression appears to have a tumor-promoting role in PACs and warrants further investigation.

We developed a neural network to identify patients with bladder cancer more effectively than hematuria and cytology. The algorithm is based on combined urine levels of nuclear matrix protein-22, monocyte chemoattractant protein-1 and urinary intercellular adhesion molecule-1.A randomized double-blinded study of voided urine from 253 patients undergoing outpatient cystoscopy was performed. Of the patients 27 had bladder cancer on biopsy and 5 had muscle invasion. Urine tumor markers were measured using sandwich-enzyme-linked immunosorbent assay kits. Urine from patients with bladder cancer on cystoscopy was compared to urine from controls with negative cystoscopy results. An algorithm was created with 3 sets of cutoff values modeled to be 100% sensitive for superficial bladder cancer, 100% specific for superficial cancer and 100% specific for muscle invasive cancer, respectively. We compared our model to hematuria and cytology.For the hematuria dipstick test sensitivity, specificity, positive and negative predictive values were 92.6%, 51.8%, 18.7% and 98.2%, respectively. For atypical cytology sensitivity, specificity, positive and negative predictive values were 66.7%, 81%, 29.5% and 95.3%, respectively. For the sensitive model set sensitivity, specificity, positive and negative predictive values were 100%, 75.7%, 32.9% and 100%, respectively. For the specific model set sensitivity, specificity, positive and negative predictive values were 22.2%, 100%, 100% and 91.5%, respectively. For the muscle invasive model set sensitivity, specificity, positive and negative predictive values were 80%, 100%, 100% and 99.6%, respectively. The standard bladder tumor evaluation of 253 patients costs 61,054 US dollars but 36,450 US dollars using our model.Our algorithm is superior to conventional screening tests for bladder cancer. The model identifies patients who require cystoscopy, those with bladder cancer and those with muscle invasive disease. It provides possible savings over current screening methods. The potential loss of other information by not performing cystoscopy was not evaluated in our study.

In this review, a series of relatively well-documented ancillary biomarkers and emerging molecular assays are evaluated for their relative ability to predict prognosis in prostate cancer. Prognostic factors that have achieved widespread use and classified as Category I by the College of American Pathologists Solid Tumor Prognostic Factor Consensus Conference are compared with newer tests that are beginning to be used in clinical practice (Category II) and emerging molecular-based assays that have yet to be widely validated in the published literature or clinical trials (Category III).

DNA ploidy analysis of prostate needle biopsy specimens was performed to determine whether ploidy status could predict tumor grade shifting at radical prostatectomy. The paired needle biopsy and radical prostatectomy specimens from 111 randomly selected men with prostate cancer were obtained from the surgical pathology files of the Albany Medical Center Hospital. The original tumor grades were assigned by a staff of 12 surgical pathologists according to the Gleason system. Tumors with original Gleason scoresor = 6 were classified as low grade, and tumors with scores ofor = 7 were considered high grade. DNA ploidy analysis was performed on the needle biopsy specimens using the CAS 200 image analyzer (Becton Dickinson Immunocytometry Systems, Mountain View, CA, USA) on Feulgen stained 5-microm tissue sections. There were 88 diploid and 23 nondiploid cases. Thirty-eight of 111 (34%) of cases had grade shifting from needle biopsy to radical prostatectomy specimens. Of 89 low-grade needle biopsy cases, 28 (31%) were upgraded at radical prostatectomy. Of 22 high-grade needle biopsy cases, 10 (45%) were downgraded to low grade at radical prostatectomy. Of the 28 low-grade needle biopsy specimens that were upgraded at radical prostatectomy, 19 (68%) featured an aneuploid histogram and 9 (32%) were diploid. Nineteen of 28 (68%) of aneuploid low-grade tumors on needle biopsy became high-grade at radical prostatectomy. Nine of 10 (90%) diploid high-grade tumors at needle biopsy became low-grade at radical prostatectomy. Of the 38 cases in which ploidy and grade were incongruous, 28 (74%) had grade shifting. In a multivariate regression analysis, a high-grade Gleason score on radical prostatectomy specimens correlated significantly with needle biopsy ploidy (p = 0.0001) but not with needle biopsy grade (p = 0.15). The sensitivity of the needle biopsy grade in the detection of high-grade tumors on radical prostatectomy was 30%, and the specificity was 86%. The sensitivity of ploidy status in the prediction of high grade at radical prostatectomy was 78%, and the specificity was 96%. With a prostate-specific antigen (PSA) level of0.4 ng/ml as the indicator of post-radical prostatectomy disease recurrence on a subset of 106 patients, on univariate analysis, disease recurrence was predicted by needle biopsy ploidy (p = 0.001) and radical prostatectomy grade (p = 0.04) but not by needle biopsy grade (p = 0.39). On multivariate analysis, needle biopsy DNA ploidy status independently predicted disease recurrence (p = 0.002), whereas needle biopsy and prostatectomy grade did not. These results indicate that DNA ploidy analysis of needle biopsy specimens of prostate cancer predicts grade shifting, that it is a more sensitive and specific indicator of final tumor grade at radical prostatectomy than is the original needle biopsy grade, and that ploidy status independently predicts postoperative disease recurrence.

Postoperative ileus is a concern among surgical patients. Epidural anesthesia nd analgesia with local anesthetics can decrease the duration of ileus. Significant systemic absorption of local anesthesia occurs during epidural use. ln this study, we examined whether many of the beneficial effects on bowel function seen with epidural lidocaine are also present when the drug is given parenterally. Forty patients undergoing radical retropubic prostatectomy were studied with one half of the patients receiving a lidoCaine bolus (1.5 mg/kg) and infusion (3 mg/min, unless weight

HER-2/neu expression has been established as a prognostic factor in breast and other cancers. In prostate cancer (PC), a similar predictive role has been hindered by variable immunohistochemical (IHC) results. The authors studied DNA amplification of the HER-2/neu gene on 4-microm sections obtained from 62 formalin-fixed, paraffin-embedded PCs by fluorescence in situ hybridization (FISH). The results were compared with HER-2/neu protein expression as determined by IHC and correlated by logistic regression analysis with Gleason tumor grade, DNA ploidy, serum prostate specific antigen (PSA), and pathological stage. The HER-2/neu gene was localized using the Oncor (Gaithersburg, MD) digoxigenin-labeled unique sequence probe. Amplified PCs had at least 20 malignant cells, with 5 or more copies of the sequence. Amplification of HER-2/neu correlated with Gleason score (P = .0001). The mean Gleason score of unamplified tumors was 5.7 and that of amplified tumors was 7.5. Nondiploid tumors had a significantly greater rate of HER-2/neu amplification compared with diploid tumors (P = .0003). Of the 62 cases evaluated by IHC and FISH, 18 cases (29%) were overexpressed by IHC, and 27 cases (44%) were amplified by FISH. A trend for similar HER-2/neu status in each PC by the two methods did not reach statistical significance (P = .23). HER-2/neu amplification by FISH was associated with advanced pathological stage; however, this relationship reached only near-statistical significance (P = .06). There was no correlation of HER-2/neu amplification by FISH with patient age or preoperative serum PSA levels. The authors conclude that HER-2/neu gene amplification status can be determined by FISH on archival prostate cancer specimens, significantly correlates with high tumor grade and nondiploid DNA content, and is more frequently encountered in tumors with advanced pathological stage. Also, FISH is more sensitive than IHC for detection of abnormalities in the HER-2/neu gene, and further studies should be undertaken to determine whether a FISH-based HER-2/neu detection method may prove of importance in the prediction of prognosis and planning of therapy in prostate cancer patients.

Recent evidence suggests that the tumor suppressor protein, p53, protects somatic cells against the accumulation of genomic mutations. The genomes of cells lacking normal p53 function may become hypermutable, a condition that might result in the accumulation of multiple genetic alterations as the affected cells proliferate. Such cells may then become more susceptible to malignant transformation. We hypothesized that some high-grade prostate cancers might arise from foci of morphologically benign cells that had previously sustained p53 lesions. As an initial test of this hypothesis, we employed a microdissection technique to isolate morphologically benign cells within hyperplastic glands located near foci of high-grade adenocarcinoma. Genomic DNA from these cells was subjected to polymerase chain reaction amplification and single-stranded conformational polymorphism analysis for detecting alterations in the p53 locus. With use of this approach, gross alterations in the p53 locus were demonstrated in benign cells in 1 of 20 (5%) specimens harboring high-grade malignancy (Gleason grade 7 or higher). Thus, in some cases, hyperplastic prostatic epithelium harbors preneoplastic genetic alterations that could possibly give rise to high-grade malignancies.