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The American Joint Commission on Cancer (AJCC) identifies five rare variants of prostate adenocarcinoma: mucinous, ductal, signet ring cell, adenosquamous and neuroendocrine including small cell. No prior study has comprehensively detailed incidence and outcomes for all AJCC variants of prostate cancer. We used the Surveillance, Epidemiology and End Results (SEER) program to analyze prostate cancers diagnosed from 1973 to 2008. Cases of mucinous, ductal, signet ring cell, adenosquamous and neuroendocrine carcinoma were identified, along with cases of non-variant adenocarcinoma for comparison. Age-adjusted incidence rates (IRs) and overall survival (OS) were evaluated and stratified by race, age, stage and PSA. All IRs represent the number of cases per million people per year. Each variant is rare, with IRs between 0.03 (adenosquamous) and 0.61 (mucinous). There was a significant difference in incidence between Caucasian and African American patients with mucinous adenocarcinoma. Median OS varied ranged from 10.0 months in neuroendocrine carcinoma to 125.0 months in mucinous adenocarcinoma. In all, 5-year OS ranged from 12.6% in neuroendocrine carcinoma to 75.1% in mucinous adenocarcinoma. There was a significant difference in survival between Caucasian and African American patients for mucinous adenocarcinoma (median survival 144.0 vs 99.0 months, P

The urethra, which carries urine from the urinary bladder to the external urethral orifice for excretion and provides the conduit for semen in males, may be involved by a broad spectrum of both neoplastic and nonneoplastic diseases, which may produce very similar clinical symptoms. This chapter reviews the clinical and pathologic features of urethral diseases organized by clinical setting: urethral stricture, male urethral cancer, female urethral cancer, and female urethral diverticulum.

An important challenge in prostate cancer research is to develop effective predictors of tumor recurrence following surgery to determine whether immediate adjuvant therapy is warranted. To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed, paraffin-embedded radical prostatectomy specimens with known long-term outcomes to perform DASL expression profiling with a custom panel that we designed of 522 prostate cancer–relevant genes. We identified a panel of 10 protein-coding genes and two miRNA genes (RAD23B, FBP1, TNFRSF1A, CCNG2, NOTCH3, ETV1, BID, SIM2, LETMD1, ANXA1, miR-519d, and miR-647) that could be used to separate patients with and without biochemical recurrence (P < 0.001), as well as for the subset of 42 Gleason score 7 patients (P < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of biochemical recurrence for all cases (P = 0.013) and for a subset of 19 Gleason score 7 cases (P = 0.010), both of which were adjusted for relevant clinical information including T-stage, prostate-specific antigen, and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason score 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.

LIV-1, a zinc transporter, is an effector molecule downstream from soluble growth factors. This protein has been shown to promote epithelial-to-mesenchymal transition (EMT) in human pancreatic, breast, and prostate cancer cells. Despite the implication of LIV-1 in cancer growth and metastasis, there has been no study to determine the role of LIV-1 in prostate cancer progression. Moreover, there was no clear delineation of the molecular mechanism underlying LIV-1 function in cancer cells. In the present communication, we found increased LIV-1 expression in benign, PIN, primary and bone metastatic human prostate cancer. We characterized the mechanism by which LIV-1 drives human prostate cancer EMT in an androgen-refractory prostate cancer cells (ARCaP) prostate cancer bone metastasis model. LIV-1, when overexpressed in ARCaP(E) (derivative cells of ARCaP with epithelial phenotype) cells, promoted EMT irreversibly. LIV-1 overexpressed ARCaP(E) cells had elevated levels of HB-EGF and matrix metalloproteinase (MMP) 2 and MMP 9 proteolytic enzyme activities, without affecting intracellular zinc concentration. The activation of MMPs resulted in the shedding of heparin binding-epidermal growth factor (HB-EGF) from ARCaP(E) cells that elicited constitutive epidermal growth factor receptor (EGFR) phosphorylation and its downstream extracellular signal regulated kinase (ERK) signaling. These results suggest that LIV-1 is involved in prostate cancer progression as an intracellular target of growth factor receptor signaling which promoted EMT and cancer metastasis. LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases.

Serum C-reactive protein has been shown to have prognostic value in localized and metastatic renal cell carcinoma. However, the prognostic value of intratumor C-reactive protein remains unknown.A total of 95 patients with resected, clinically localized (T1-T4N0M0) clear cell renal cell carcinoma were followed postoperatively. Intratumor C-reactive protein expression was assessed in surgical specimens using immunohistochemical analysis. Patients were categorized by staining intensity into low risk (staining 0 to 1), intermediate risk (staining 2) and high risk (staining 3) groups. Kaplan-Meier and multivariate Cox regression analyses were used to examine overall survival across patient and disease characteristics. Variables examined in multivariate Cox regression analysis included T stage, Fuhrman nuclear grade, tumor size, preoperative serum C-reactive protein and intratumor C-reactive protein staining.Followup extended up to 46 months with a mean (SD) of 29.8 (11.0) months. Twelve patients (12.6%) died during followup. Of all tumors 49.5%, 25.3% and 25.3% were graded by intratumor C-reactive protein staining as low risk (0 to 1), intermediate risk (2) and high risk (3), respectively. After controlling for variables significant on univariate analysis, patients in the high risk (3) group experienced a 27-fold increased risk of overall mortality compared to those in the low risk (0-1) group (HR 27.767, 95% CI 1.488-518.182). After adjusting for tumor staining, preoperative serum C-reactive protein was not a significant predictor of overall survival (p = 0.741).Intratumor C-reactive protein may be a robust biomarker of prognosis in patients with localized renal cell carcinoma.

C-reactive protein is produced in response to cytokines such as interleukin (IL)-6. It is known that increased plasma IL-6 levels induce increased hepatic and intratumoral production of C-reactive protein. Cyclooxygenase enzyme-2 is induced by various stimuli, including inflammation and various growth factors. Expression of these two markers has not been well studied in clear cell renal cell carcinoma. The objective of this study is to correlate the expression of C-reactive protein and cyclooxygenase enzyme-2 in clear cell renal cell carcinoma with pathologic parameters. A search of the surgical pathology and consultation files at our institution was performed for nephrectomy specimens with clear cell renal cell carcinoma from 2007 to 2008. Immunohistochemical stains for C-reactive protein and cyclooxygenase enzyme-2 were performed. Staining intensity was graded as 0, 1+, 2+, and 3+. The staining intensity was then correlated with pathologic stage and Fuhrman nuclear grade for each case. A total of 110 cases were identified. Strong expression of C-reactive protein was associated with higher Fuhrman nuclear grade and pathologic stage, and the strength of correlation was statistically significant (p = 0.01 and p = 0.001), respectively. However, cyclooxygenase enzyme-2 expression did not show statistically significant correlation with both pathologic stage and Fuhrman nuclear grade (p = 0.1 and p = 0.15), respectively. To our knowledge, this is the largest study to date correlating the expression of both C-reactive protein and cyclooxygenase enzyme-2 in tissue with pathologic parameters in patients with clear cell renal cell carcinoma, which could have significant prognostic and therapeutic implications.

C-reactive protein (CRP) is an acute-phase reactant that can increase dramatically in response to a variety of pathologic states. Elevated pre- and postoperative CRP levels have been associated with an increased tumor burden and metastasis in kidney cancer. We report on a case that serves to highlight a potentially novel use for CRP monitoring in the postoperative management of renal cell carcinoma. Recently, we treated a patient who presented with a localized renal cell carcinoma and an elevated preoperative CRP level. Surgical pathology demonstrated negative surgical margins and absence of nodal metastasis. Postoperatively, the patient's serum CRP levels remained relatively low, consistent with his continued negative staging on CT scans. However, at 6 months postoperatively, the patient's CRP level increased 13-fold. His subsequent CT scan revealed "multiple pulmonary nodules consistent with progression of metastatic disease." This case demonstrates the potential for monitoring CRP in addition to, or instead of, standard restaging imaging.

Urothelial carcinoma of the bladder with prostatic stromal invasion is included in stage pT4a of the new 2010 American Joint Committee on Cancer/Tumor-Node-Metastasis classification. Despite being a strong indicator of poor prognosis, there have been few large studies investigating the impact of extent of prostatic stromal invasion on patient outcome. A search of the surgical pathology and expert consultation files at our institution was made for cystoprostatectomy specimens diagnosed as urothelial carcinoma with prostatic stromal invasion from 2002 to 2009. Cases were further stratified as follows: group 1--focal prostatic stromal invasion and group 2--extensive prostatic stromal invasion. Only patients who had surgery as monotherapy and those with available follow-up information were selected for this study. Thirty-five cases of urothelial carcinoma with prostatic stromal invasion and follow-up information were identified. Mean patient age was 70 years (range, 44-88 years). Of these 35 patients, 15 (43%) had focal prostatic stromal invasion and 20 (57%) had extensive prostatic stromal invasion. Angiolymphatic invasion was identified in 93% of group 1 cases and 79% of group 2 cases. Positive margins were identified in 50% of group 1 cases and 45% of group 2 cases. Incidence of nodal metastasis was 64% for group 1 and 60% for group 2. Four (27%) of 15 cases in group 1 and 6 (30%) of 20 cases in group 2 had various histologic variants identified. In group 1, there were 2 cases of urothelial carcinoma with micropapillary features and urothelial carcinoma with focal squamous differentiation. In group 2, there were 3 cases of urothelial carcinoma with focal squamous differentiation, 2 cases of urothelial carcinoma with focal sarcomatoid differentiation, and 1 case of urothelial carcinoma with focal micropapillary features. One- and 3-year overall survival for group 1 was 53% and 27%, respectively. One- and 3-year overall survival for group 2 was 47% and 12%, respectively. Mean survival was 17.4 and 16.3 months for groups 1 and 2, respectively. Overall survival curves did not show a statistically significant difference between the 2 groups from initial diagnosis (P = .889) and radical cystoprostatectomy (P = .369). Our study suggests that extent of prostatic stromal invasion by urothelial carcinoma of the bladder as an independent factor does not impact overall patient survival. Other well-known prognostic factors including positive margin status, presence of aggressive histologic variants of urothelial carcinoma, angiolymphatic invasion, and distant metastasis likely play more critical roles in predicting outcome in male patients who have urothelial carcinoma with prostatic stromal invasion.

BackgroundMyeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family, which inhibits cell apoptosis by sequestering pro-apoptotic proteins Bim and Bid. Mcl-1 overexpression has been associated with progression in leukemia and some solid tumors including prostate cancer (PCa). However, the regulatory mechanism for Mcl-1 expression in PCa cells remains elusive.ResultsImmunohistochemical analyses revealed that Mcl-1 expression was elevated in PCa specimens with high Gleason grades and further significantly increased in bone metastasis, suggesting a pivotal role of Mcl-1 in PCa metastasis. We further found that vascular endothelial growth factor (VEGF) is a novel regulator of Mcl-1 expression in PCa cells. Inhibition of endogenous Mcl-1 induced apoptosis, indicating that Mcl-1 is an important survival factor in PCa cells. Neuropilin-1 (NRP1), the "co-receptor" for VEGF165isoform, was found to be highly expressed in PCa cells, and indispensible in the regulation of Mcl-1. Intriguingly, VEGF165promoted physical interaction between NRP1 and hepatocyte growth factor (HGF) receptor c-MET, and facilitated c-MET phosphorylationviaa NRP1-dependent mechanism. VEGF165induction of Mcl-1 may involve rapid activation of Src kinases and signal transducers and activators of transcription 3 (Stat3). Importantly, NRP1 overexpression and c-MET activation were positively associated with progression and bone metastasis in human PCa specimens and xenograft tissues.ConclusionsThis study demonstrated that Mcl-1 overexpression is associated with PCa bone metastasis. Activation of VEGF165-NRP1-c-MET signaling could confer PCa cells survival advantages by up-regulating Mcl-1, contributing to PCa progression.

Preoperative C-reactive protein (CRP) predicts metastasis and mortality in localized renal cell carcinoma (RCC). However, the predictive potential of after resection of localized RCC remains unclear. Therefore, we assessed the absolute ability of postoperative CRP to predict metastases and mortality as a continuous variable.Patients with clinically localized (T1-T3N0M0) clear-cell RCC were followed for 1 year postoperatively. Metastases were identified radiologically and mortality by death certificate. Univariate and multivariate binary logistic regression analyses examined 1 year relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics.Of the 110 patients in this study, 16.4% developed metastases and 6.4% died. Mean (SD) postoperative CRP for patients who did and did not develop metastases were 69.06 (73.55) mg/L and 5.27 (7.80), respectively. Mean (SD) postoperative CRP for patients who did and did not die were 89.31 (69.51) mg/L and 10.88 (30.32), respectively. In multivariate analysis, T-stage (OR: 12.452, 95% CI: 2.889-53.660) and postoperative CRP ((B: .080, SE: .025; P.001) were significant predictors of RFS. T-Stage (OR: 11.715; 95% CI: 1.102-124.519) and postoperative CRP (B: .017; SE: .007; P.001) were also significant predictors of OS. After adjusting for postoperative CRP, preoperative CRP was not predictive of these outcomes.Postoperative, not preoperative, CRP is the better predictor of metastasis and mortality following nephrectomy for localized RCC. Clinicians should consider absolute postoperative CRP to identify high-risk patients for closer surveillance or additional therapy. Predictive algorithms should consider incorporating postoperative CRP as a continuous variable to maximize predictive ability.

Tumors of the urinary bladder may have a variety of histological patterns. Tumors with either glandular or villous features, such as villous adenomas, in situ adenocarcinomas, invasive adenocarcinomas, and variants of urothelial carcinoma such as micropapillary carcinomas have been described. However, urothelial carcinomas with both villous and glandular features have not been well characterized. We identified 14 cases of urothelial carcinoma with villoglandular differentiation. These cases were defined as having villoglandular features if they contained superficial finger-like processes lined by epithelium having true glandular lumina. Mean patient age at presentation was 70 years (range: 46–84 years) with a male predominance (5:1). A total of 3 cases (21%) were non-invasive, five cases (36%) had lamina propria invasion, five cases (36%) had muscularis propria invasion and one case (7%) had extravesicular extension. A concurrent high-grade papillary urothelial carcinoma component was identified in 11 cases (79%), micropapillary component in 5 (36%) cases, in-situ urothelial carcinoma component in 3 cases (21%), plasmacytoid component in 3 cases (21%), invasive adenocarcinoma in 2 cases, sarcomatoid carcinoma component in one case (14%), and small-cell carcinoma component in 1 case (7%). Cystitis cystica et glandularis was present in 3 cases (21%). Angiolymphatic invasion was identified in 3 cases (21%). Histologically, the villoglandular components were composed of finger-like processes lined by glands intimately admixed with high-grade urothelial carcinoma. Many of the glands had cribriform features lined by non-mucin producing cuboidal to columnar cells. Urothelial carcinoma with villoglandular differentiation are high-grade tumors typically seen in elderly males, characterized by superficial filliform processes lined by glands intimately admixed with high-grade urothelial carcinoma (in situ or invasive) and other aggressive variants of urothelial carcinoma. These relatively rare tumors should be recognized as a variant of urothelial carcinoma.

Lymphoid neoplasms of the urinary tract and male genital organs are relatively rare, comprising less than 5% of all primary extranodal lymphomas; only a handful of small case series and isolated case reports have been published describing their predominant sites and subtypes. We identified 40 patients with lymphoid neoplasms of the urinary tract and male genital organs. Hematoxylin and eosin slides and immunohistochemical stains were reviewed, and follow-up data were also obtained. Twenty-six of 40 cases (65%) were primary genitourinary lymphomas. Mean age at diagnosis was 56 years (range 4-86 years). Among renal, bladder, and ureter lymphomas, a male predominance was noted (1.6:1). The subtypes of the lymphoid neoplasms observed were diffuse large B-cell lymphoma (17 cases, 43%); Burkitt lymphoma, extranodal marginal zone lymphoma, SLL/CLL, and follicular lymphoma (4 cases, or 10% each); B-cell ALL (2 cases, 5%); B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, mantle cell lymphoma, plasmacytoma, polymorphic post-transplant lymphoproliferative disorder, and peripheral T-cell lymphoma NOS (1 case, or 2.5% each). In most cases, the genitourinary tract was the site of initial presentation. Genitourinary tract lymphomas most commonly occurred in the kidney. B-cell non-Hodgkin's lymphomas predominated, with diffuse large B-cell lymphoma being the most common subtype in the entire group. Extranodal marginal zone lymphoma was seen only in the kidney, rather than the bladder, where it is typically thought to be more common. Although this study confirms the predominance of diffuse large B-cell lymphoma in extranodal sites, the findings also highlight the variety of lymphomas that may occur in the genitourinary tract. This diversity of subtypes affirms the importance of fully characterizing lymphomas by immunohistochemistry and other modalities, which are indispensable for accurate diagnosis.

BackgroundA large percentage of patients with recurrent ovarian cancer develop resistance to the taxane class of chemotherapeutics. While mechanisms of resistance are being discovered, novel treatment options and a better understanding of disease resistance are sorely needed. The mitotic kinase Aurora-A directly regulates cellular processes targeted by the taxanes and is overexpressed in several malignancies, including ovarian cancer. Recent data has shown that overexpression of Aurora-A can confer resistance to the taxane paclitaxel.MethodsWe used expression profiling of ovarian tumor samples to determine the most significantly overexpressed genes. In this study we sought to determine if chemical inhibition of the Aurora kinase family using VE-465 could synergize with paclitaxel to induce apoptosis in paclitaxel-resistant and sensitive ovarian cancer cells.ResultsAurora-A kinase and TPX2, an activator of Aurora-A, are two of the most significantly overexpressed genes in ovarian carcinomas. We show that inhibition of the Aurora kinases prevents phosphorylation of a mitotic marker and demonstrate a dose-dependent increase of apoptosis in treated ovarian cancer cells. We demonstrate at low doses that are specific to Aurora-A, VE-465 synergizes with paclitaxel to induce 4.5-fold greater apoptosis than paclitaxel alone in 1A9 cells. Higher doses are needed to induce apoptosis in paclitaxel-resistant PTX10 cells.ConclusionOur results show that VE-465 is a potent killer of taxane resistant ovarian cancer cells and can synergize with paclitaxel at low doses. These data suggest patients whose tumors exhibit high Aurora-A expression may benefit from a combination therapy of taxanes and Aurora-A inhibition.

The plasmacytoid variant of urothelial carcinoma is rare, of which less than 40 cases have been reported in the English language literature. Herein we report the largest series to date of 17 cases of urothelial carcinoma with plasmacytoid features and report the associated clinicopathologic findings. The architectural pattern of the tumor varied from cells arranged in cords and single cells (35%), small nests (17%), solid sheetlike growth (29%), and diffuse discohesive patternless architecture (23%). The plasmacytoid component varied from 15% to 100% of the specimen analyzed; in 12 cases the plasmacytoid component composed greater than 50% of the tumor. The individual tumor cells had striking morphologic overlap with plasma cells with an eccentrically placed nucleus and abundant amphophilic to eosinophilic cytoplasm. The nuclei were of low to intermediate nuclear grade with minimal nuclear pleomorphism. Thirteen of 17 cases (76%) were associated with conventional high-grade invasive urothelial carcinoma and 9 cases showed very focal intracytoplasmic vacuoles mimicking signet ring cells. One case also showed sarcomatoid dedifferentiation. The tumor cells were positive for cytokeratin 7 (94%) and cytokeratin 20 (31%); CD138 was positive in 94% of cases. All cases were invasive -- 7 into at least the lamina propria, 7 into at least the muscularis propria, and 3 into perivesical fat. Follow-up information was available in 16 cases (range: 2 wk to 43 mo; mean 10 mo; median 5.5 mo). Eleven patients died of disease and 5 patients were alive with disease. Plasmacytoid variant of urothelial carcinoma is an aggressive subtype associated with poor prognosis. In limited samples, it may be misdiagnosed as chronic cystitis or plasmacytoma, a pitfall further compounded by CD138 expression. Distinction from metastatic carcinoma from other primary sites such as stomach and breast is critical due to differing therapeutic implications.

OBJECTIVES To assess the interpretation of modern criteria for evaluating surgical margins (SMs), by examining the incidence of positive SMs (PSMs) and subsequent biochemical recurrence in a single-surgeon series of radical prostatectomy (RP) at two institutions, as the criteria for determining PSMs after RP are subject to individual interpretation, and this might explain some of the variability in biochemical recurrence rates with different rates of PSMs. PATIENTS AND METHODS We reviewed 301 consecutive perineal RPs by one surgeon (T.K.) at Emory University Hospital (EUH) and the Medical University of South Carolina (MUSC), with each pathology department using modern criteria to evaluate the SMs. The SM status and biochemical recurrence (BCR) were analysed, the latter defined as a prostate-specific antigen level of ≥0.2 ng/mL. RESULTS There were 158 perineal RPs at EUH followed by 143 at MUSC. PSMs were reported in 39 patients (24.7%) at EUH, whereas six (4.2%) were positive at MUSC. The overall BCR rates were similar between the groups, but BCR within margin-positive cases was 100% at MUSC vs 25.6% at EUH (P

Mitochondrial DNA (mtDNA) mutations, inherited and somatically acquired, are common in clinical prostate cancer. We have developed model systems designed to study specific mtDNA mutations in controlled experiments. Because prostate cancer frequently metastasizes to bone we tested the hypothesis that mtDNA mutations enhance prostate cancer growth and survival in the bone microenvironment.The pathogenic nucleotide position (np) 8993 mDNA mutation was introduced into PC3 prostate cancer cells by cybrid formation. Wild-type and mutant cybrids were grown as nude mouse subcutaneous xenografts with or without bone stromal cell co-inoculation. Cybrids were also grown in the intratibial space. Tumor growth was assayed by direct tumor measurement and luciferase chemiluminescence. Gene expression was assayed using cDNA microarrays confirmed by real time PCR, western blot analysis and immunohistochemistry.Cybrids with the 8,993 mtDNA mutation grew faster than wild-type cybrids. Further growth acceleration was demonstrated in the bone microenvironment. A 37 gene molecular signature characterized the growth advantage conferred by the mtDNA mutation and bone microenvironment. Two genes of known importance in clinical prostate cancer, FGF1 and FAK, were found to be substantially upregulated only when both mtDNA mutation and bone stromal cell were present.The ATP6 np 8,993 mtDNA mutation confers a growth advantage to human prostate cancer that is most fully manifest in the bone microenvironment. The identification of specific molecular alterations associated with mtDNA mutation and growth in bone may allow new understanding of prostate cancer bone metastasis.

The epithelial-to-mesenchymal transition (EMT) is crucial for the migration and invasion of many epithelial tumors, including prostate cancer. Although it is known that ZEB1 overexpression promotes EMT primarily through down-regulation of E-cadherin in a variety of cancers, the soluble ligands responsible for the activation of ZEB1 have yet to be identified. In the present study, we investigated the role of insulin-like growth factor-I (IGF-I) in the regulation of ZEB1 during EMT associated with prostate tumor cell migration. We found that ZEB1 is expressed in highly aggressive prostate cancer cells and that its expression correlates directly with Gleason grade in human prostate tumors (P < 0.001). IGF-I up-regulates ZEB1 expression in prostate cancer cells exhibiting an epithelial phenotype. In prostate cancer cells displaying a mesenchymal phenotype, ZEB1 inhibition reverses the suppression of E-cadherin protein and down-regulates the expression of the mesenchymal markers N-cadherin and fibronectin. Furthermore, ZEB1 blockade decreases migratory and invasive potential in ARCaPM compared with the control. These results identify ZEB1 as a key transcriptional regulator of EMT in prostate cancer and suggest that the aberrant expression of ZEB1 in prostate cancer cells occurs in part in response to IGF-I stimulation. [Cancer Res 2008;68(7):2479–88]

Claudin-7 and claudin-8 code for tight junction proteins expressed in distal nephron epithelium. In a recent oligonucleotide microarray study, we identified claudin-7 and claudin-8 as candidate markers to distinguish chromophobe renal cell carcinoma from other renal tumors, including oncocytoma. Distinction of these lesions can be difficult by light microscopy but is clinically important because chromophobe renal cell carcinoma has malignant biological potential, whereas renal oncocytoma is benign. Claudin-7 and claudin-8 expression was studied by immunohistochemistry in 11 chromophobe renal cell carcinomas and 17 oncocytomas using formalin-fixed paraffin-embedded tissue sections of tumor with adjacent nonneoplastic kidney. Steam antigen retrieval was performed before immunohistochemistry. Specificity was verified by negative control reactions without primary antibody and appropriate membranous staining patterns in positive control tissues (colon carcinoma and adjacent nonneoplastic kidney). Claudin-7 protein was expressed in a membranous pattern in 10 of 11 chromophobe renal cell carcinomas and 4 of 17 oncocytomas (P < .01). Claudin-8 was expressed in multiple patterns: In oncocytoma, 11 of 17 cases showed cytoplasmic, 4 of 17 membranous, and 2 of 17 negative reactions. In chromophobe renal cell carcinoma, 0 of 11 cases showed cytoplasmic, 3 of 11 membranous, and 8 of 11 negative reactions (P < .01). The immunohistochemical pattern of membranous claudin-7 and negative claudin-8 was seen in 7 of 11 chromophobe renal cell carcinomas and 1 of 17 oncocytomas (63% sensitivity, 84% specificity, 88% positive predictive value for chromophobe renal cell carcinoma). Negative claudin-7 and cytoplasmic claudin-8 were observed in 10 of 17 oncocytomas and 0 of 11 chromophobe renal cell carcinomas (59% sensitivity, 100% specificity and positive predictive value for oncocytoma). The distal nephron proteins claudin-7 and claudin-8 have potential use as immunohistochemical biomarkers in the differential diagnosis of chromophobe renal cell carcinoma and oncocytoma. Expression of claudin-7 and claudin-8 may reflect the relationship of chromophobe renal cell carcinoma and oncocytoma to intercalated cells of the cortical collecting duct. It may be necessary to identify additional biomarkers to include with claudin-7 and claudin-8 in a larger immunohistochemical panel to improve diagnostic sensitivity and specificity.

Uterine leiomyoma are commonly diagnosed in women of reproductive age. However, these benign tumors may present with clinical signs and symptoms that are consistent with ovarian carcinoma.A 47-year-old gravida 0 presented with a large pelvic mass, ascites, bilateral pleural effusions, and an elevated CA 125 worrisome for ovarian carcinoma. Exploratory laparotomy revealed a 20,120 g pelvic mass, with 2 L ascites, and pelvic and periaortic lymphadenopathy. Final pathology was consistent with a benign giant leiomyoma. Postoperative course was complicated by reaccumulation of pleural effusion requiring therapeutic thoracentesis and diuretics. Patient had return to full activity with 50 pound weight loss at 8 weeks after surgery.Elevated CA 125 levels and ascites are often associated with ovarian carcinoma, but it is also important to keep benign processes in the differential diagnosis when considering malignancy.

Mucinous adenocarcinoma of the prostate is one of the least common variants of prostate cancer. The prognosis of this variant of prostate cancer remains controversial. We present 47 cases (1991 to 2006) of mucinous carcinomas treated by radical prostatectomy. Mean patient age at diagnosis was 56 years (range: 44 to 69 y). The mean preoperative prostate-specific antigen (PSA) level was 9.0 ng/mL (range: 1.9 to 34.3 ng/mL). Clinical stages were T1c (34 cases), T2a (7 cases), and T2b (6 cases). The mean percentage of tumor composed of the mucinous component was 52% (range: 25% to 90%). The mean Gleason score was 7 with scores of 6 in 6 cases (12.8%), 7 in 37 cases (78.7%), and 8 in 4 cases (8.5%). Margins were positive in 4 cases of mucinous adenocarcinoma of the prostate. Only 2 cases had isolated margin positivity in the nonmucinous acinar component of cancer. In 12 cases (25.5%), mucinous adenocarcinoma had established extraprostatic extension (EEPE). Eight cases (17.0%) had isolated EEPE of nonmucinous cancer. The 1 lymph node metastasis contained nonmucinous cancer. All together, taking into account both the mucinous and nonmucinous tumor, 20/47 cases (42.5%) had EEPE and 6/47 (12.7%) had positive margins. The 1 lymph node metastasis contained nonmucinous cancer. The mean follow-up for those without progression was 5.6 years (median 6 y, range: 1 to 15 y). One patient (2.1%) progressed 3 years after his radical prostatectomy (5 y actuarial progression-free risk 97.2%). Using the Kattan nomogram, the predicted mean 5-year PSA progression-free risk for nonmucinous prostate cancer with the same PSA and postoperative findings as in the current study was 85.4%. This study confirms that mucinous adenocarcinoma of the prostate treated by radical prostatectomy is not more aggressive, and possibly even less aggressive than nonmucinous prostatic adenocarcinoma.

568 Background: Programmed cell death protein 1 (PD-1) immune checkpoint inhibitors have been shown to have activity in advanced renal cell carcinoma (RCC), prompting research into PD-1 as a potential biomarker. In this study, we evaluate tumor PD-1 expression and its prognostic value in patients with localized clear cell RCC. Methods: Patients that underwent nephrectomy for localized clear cell RCC (T1-T3) with >4 years of follow-up were queried from our nephrectomy database. Tissue blocks with tumor and adjacent benign renal parenchyma were selected for analysis. Immunohistochemical staining for PD-1 was performed on tumor specimens using anti-PD-1 clone NAT105 (Abcam). Focusing on immune cells, PD-1 positivity was defined as >1% expression and graded in 10% increments. The relationship between PD-1 positivity, FNG, and TNM stage was evaluated using Pearson’s chi-square test. The impact of PD-1 positivity on overall and recurrence-free survival was evaluated using the Kaplan-Meir method. Results: Fifty-three patients were included in the study. The distribution of PD-1 expression in 10% increments can be seen in Table. No statistically significant correlation was found between PD-1 positivity, TNM stage and FNG (chi-square test; p=0.15, p=0.62, respectively). No statistically significant differences in overall or recurrence-free survival were found between positive and negative PD-1 expression groups (log-rank; p=0.32, p=0.43, respectively). Conclusions: Our data show that primary tumor PD-1 expression varies widely in patients with clear cell RCC and that PD-1 positivity does not correlate with commonly reported histopathological features such as TNM stage and FNG. Further, PD-1 positivity does not have a significant impact on overall and recurrence-free survival. These findings contrast with previous studies of PD-1 expression in RCC, suggesting that further research into the role of PD-1 in tumor progression as well as methods of case/tissue block selection and PD-1 quantification is needed. [Table: see text]

Genistein is a soy isoflavone with anti-tumor properties. Genistein-induced apoptosis involves Bcl-2 down-regulation. However, overexpression of Bcl-2 in breast cancer has been associated with better prognosis and response to hormonal therapy. To examine genistein's effect on breast cancer cells with different Bcl-2 levels, we established control (MCF-7/PV) and Bcl-2 overexpressing MCF-7 (MCF-7/Bcl-2) cell lines and characterized genistein regulated apoptosis and cell cycle progression in these cells. Our results demonstrate that overexpression of Bcl-2 rendered MCF-7 cells more sensitive, rather than resistant, to genistein. We found that genistein induces enhanced cytochrome c release and mitochondrial membrane depolarization in MCF-7/Bcl-2 cells, as compared to control. We also found that genistein increases Bcl-2 levels and Bcl-2/Bax ratio in the mitochondrial fractions of MCF-7/Bcl-2 cells, suggesting that disturbed Bcl-2/Bax distribution may cause cytochrome c release and apoptosis in these cells. Cell cycle analysis indicated that genistein induces G0/G1 arrest in MCF-7/PV cells but increases in G2/M arrest in MCF-7/Bcl-2 cells. This was accompanied by modified responses of several cell cycle regulators, such as p21 and cyclin Bl. Taken together, our results indicate that genistein-Bcl-2 interaction switches Bcl-2 from an anti-apoptotic protein into a proapoptotic protein, which involves disturbed Bcl-2/Bax distribution in mitochondria, increased cytochrome c release and modified cell cycle regulation.

Prostate cancer remains the second leading cause of cancer death in American men, but biomarkers that can predict outcome following treatment are urgently needed to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we have performed global RNA-sequencing on 106 formalin-fixed, paraffin-embedded (FFPE) prostatectomy samples from 100 patients at three independent sites, and identified a new set of biomarkers of biochemical recurrence composed of a 24-gene panel including 22 protein-coding genes and two non-coding genes. We observed excellent correlation between TaqMan and RNAseq values, as well as for RNAseq between replicate libraries. We validated this 24-gene panel on an independent publicly available dataset of 140 patients and this new panel outperformed previously published markers based on cell proliferation gene sets. In addition, we have identified genes that are differentially expressed between African-American and Caucasian prostate cancer patients, and mitochondrial SNPs that are associated with both race and outcome. We observed a number of genes relevant to prostate cancer biology including ETV5, ZEB1, ZEB2, B2M, FYN, and miR-183 that were differentially expressed between African-American and Caucasian patients. These genes may play a role in the disparities observed in African-American patients who have significantly worse outcomes relative to Caucasian patients with prostate cancer. Citation Format: Jianpeng Xu, Qi Long, Adeboye O. Osunkoya, Soma Sannigrahi, Brent A. Johnson, Wei Zhou, Theresa Gillespie, Jong Y. Park, Robert K. Nam, Linda Sugar, Aleksandra Stanimirovic, Arun K. Seth, John A. Petros, Carlos S. Moreno. Global transcriptome sequencing of ethnically diverse formalin-fixed patient samples identifies biomarkers of recurrence in prostate cancer. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C68. doi:10.1158/1538-7755.DISP13-C68

The patient is a 72-year-old man who presented with hematuria. On cystoscopy, a large friable mass was identified involving the left bladder wall. A transurethral resection of the bladder tumor was performed. Histologically, the tumor was composed of superficial finger-like processes lined by epithelium with true glandular lumina with intraluminal mucin, intimately admixed with invasive high grade urothelial carcinoma. Several glands also had cribriform features and some were lined by non-mucin producing cuboidal to columnar cells. Variable amounts of intraluminal necrosis, apoptotic bodies, and eosinophilic secretions were also present. The tumor invaded the muscularis propria (Detrusor muscle). A diagnosis of urothelial carcinoma with villoglandular differentiation with made. Urothelial carcinoma with villoglandular differentiation is a relatively recently described aggressive variant of urothelial carcinoma. Mean patient age at presentation is 70 years (range: 4684 years) with a male predominance (5:1). Other aggressive variants of urothelial carcinoma have also been associated with this tumor including, micropapillary urothelial carcinoma, plasmacytoid urothelial carcinoma, sarcomatoid urothelial carcinoma and small cell carcinoma. Tumors that may mimic urothelial carcinoma with villoglandular differentiation include colorectal adenocarcinoma, prostatic ductal adenocarcinoma, urachal carcinoma, villous adenoma and other entities.

Hyperspectral imaging (HSI) is an emerging modality for various medical applications. Its spectroscopic data might be able to be used to noninvasively detect cancer. Quantitative analysis is often necessary in order to differentiate healthy from diseased tissue. We propose the use of an advanced image processing and classification method in order to analyze hyperspectral image data for prostate cancer detection. The spectral signatures were extracted and evaluated in both cancerous and normal tissue. Least squares support vector machines were developed and evaluated for classifying hyperspectral data in order to enhance the detection of cancer tissue. This method was used to detect prostate cancer in tumor-bearing mice and on pathology slides. Spatially resolved images were created to highlight the differences of the reflectance properties of cancer versus those of normal tissue. Preliminary results with 11 mice showed that the sensitivity and specificity of the hyperspectral image classification method are 92.8% to 2.0% and 96.9% to 1.3%, respectively. Therefore, this imaging method may be able to help physicians to dissect malignant regions with a safe margin and to evaluate the tumor bed after resection. This pilot study may lead to advances in the optical diagnosis of prostate cancer using HSI technology.

Introduction: Approximately 20 to 30% of patients who undergo nephrectomy with curative intent for kidney cancer will recur and die of the disease. No adjuvant therapy has been shown to reduce the risk of relapse. Risk of recurrence is largely based on T stage, Fuhrman nuclear grade and nodal status allowing the frequency of surveillance to be adjusted based on low, intermediate and high risk categories. Though C-reactive protein (CRP) has long been recognized as an adverse prognostic factor for clear cell renal cell carcinoma (ccRCC), it has not been incorporated into the risk stratification protocols of current adjuvant clinical trials. Methods: Patients with clinically localized (T1-T3N0M0) ccRCC were followed for 1 year postoperatively. Metastases were identified radiographically and mortality confirmed with the social security death registry. Univariate and multivariate binary logistic regression analyses examined 1-year relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics. Serum CRP levels were measured prior to nephrectomy and approximately one month after surgery. Patients were assigned retrospectively to the pCRP(+) group if the perioperative (either preoperative or postoperative) serum CRP level was >10 mg/L. All others were assigned to the pCRP(−) group. Results: Of the 109 patients in the study, 17 patients (15.6%) developed metastases and 6 died (5.5%). The pCRP algorithm was employed to ascertain risk of recurrence with 25 patients assigned to the high risk category and 84 patients to the low risk category. Fourteen of 25 patients in the pCRP(+) group recurred at 1 year including all 6 who died. Only 3 of the remaining 84 patients in the pCRP(−) group recurred with no deaths. The sensitivity and specificity of the pCRP algorithm for metastasis were 82% and 88%, respectively, with a positive predictive value (PPV) of 56% and a negative predictive value (NPV) of 96%. The sensitivity and specificity of the pCRP algorithm for mortality were 100% and 82%, respectively, with a PPV of 24% and a NPV of 100%. The p values for metastasis and mortality were both Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5169. doi:10.1158/1538-7445.AM2011-5169

A 7-month-old male infant presented with a 2 month history of a solitary, well circumscribed, 1.2 cm right parietal scalp lesion. An MRI excluded intracranial extension of the lesion. Grossly the excised lesion was tan-grey, soft to rubbery with focal areas of hemorrhage. On histology, the lesion demonstrated elongated strands of haphazardly arranged fibrous tissue and meningothelial elements with clusters of plump, cuboidal epitheloid cells extending along connective tissue planes in the dermis and subcutaneous tissue. The meningothelial elements were intimately admixed with mature adipose tissue and proliferation of small to medium sized vessels. The overlying epidermis was unremarkable. No mitotic figures or areas of necrosis were identified. The meningothelial cells were positive for Vimentin and Epithelial Membrane Antigen. S-100 protein was negative and CD-34 was positive only in the endothelial cells. The gross, histologic and immunohistochemical features are consistent with ectopic meningothelial hamartoma of the scalp. The meningothelial elements characteristic of this entity are believed to arise from displaced, ectopic meningothelial rests in the scalp and are thus regarded as simply representing a proliferation of the hamartomatous process.

We examined contralateral prostate cancer potentially left behind by focal therapy.We investigated 100 completely embedded radical prostatectomy specimens in which needle biopsy predicted limited disease (less than 3 positive cores, 50% or less involvement of any positive core, Gleason score 6 or less) and all positive needle cores were unilateral. Clinical stage was T1c in 85 and T2a in 15 cases with the palpable lesion on the positive biopsy side.There was 1 positive core in 66 cases. On average 13.9% of each positive core was involved with tumor. The mean number of separate tumor nodules per radical prostatectomy was 2.9. In 65 radical prostatectomy specimens there was some tumor contralateral to the positive biopsy side. Total tumor volume in the radical prostatectomy contralateral to the positive biopsy side averaged 0.2 cm(3) (largest 1.3). In 23 cases contralateral tumor volume was greater than biopsy positive side tumor volume. There were 13 cases in which more than 0.5 cm(3) cancer was contralateral to the positive biopsy and 7 with predominantly anterior tumor. Volume contralateral to positive biopsy side could not be predicted by the number of positive cores (1 vs 2) or maximum percent of the core involved. Gleason pattern 4, extraprostatic extension or positive margins were seen contralateral to the positive biopsy side in 13, 1 and 2 cases, respectively.In a highly selected population with limited unilateral biopsy cancer, tumor contralateral to the positive biopsy side at radical prostatectomy is typically small. However, 20% of radical prostatectomy specimens had some contralateral adverse pathology in terms of size, extraprostatic extension, grade or margins.

4504 Introduction and Objective: Prostate cancer (PCa) bone metastasis often present in patients after a long latent period. Dormant cancer cells in contact with bone stromal cells can be reactivated under certain pathophysiologic conditions. We characterized novel molecular pathways leading to PCa bone metastasis in animal models. Methods: Tissue microarrays of normal (4), PIN (13), benign (22), primary (19) PCa and PCa bone metastasis (58) were analyzed by IHC for the expression of β2-microglobulin (β2-M), a novel growth factor and signaling molecule, focal adhesion kinase (FAK), a key cell adhesion molecule, LIV-1, a zinc transporter involved in epithelial to mesenchymal transition, BDNF, a chemokine, and heparanase (HPSE), a heparan sulfate (HS) degrading enzyme. IHC was scored blindly by one pathologist. Data were analyzed by Kruskal-Wallis test for p-value and logistic regression analysis to differentiate Gleason scores. Results: PCa cells with mitochondrial DNA mutations or activated by β2-M provoked consistently higher levels of reactive oxygen species (ROS) production. ROS stimulated HS proteoglycan, perlecan, expression and augmented PCa cell growth in bone microenvironment. Downstream targets of ROS, HS/perlecan and β2-M signaling were identified: FAK, LIV-1, and BDNF. Results showed that β2-M (p

Supplementary Colorized images Using Elevation and Azimuthal directions of Principal Component Histogram

An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes-including FH-performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC-. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH-/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC- cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term "FH-deficient RCC" as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.

Smooth muscle tumors of the scrotum are very uncommon, and those with degenerative-appearing atypia, variably designated as "atypical," "symplastic," or "bizarre" leiomyomas, are extremely rare with only 11 cases in the literature. Given their rarity, the diagnostic criteria and prognosis of symplastic leiomyomas are not well established. We describe 9 cases of scrotal symplastic leiomyomas and compare their histopathologic characteristics to 10 usual leiomyomas and 5 leiomyosarcomas of the scrotum. The preoperative diagnosis was scrotal tumor or cyst in all cases. The mean age was 46 years (range, 32 to 60 y) for usual, 59 (range, 48 to 79) for symplastic leiomyomas, and 57 (range, 49 to 65) for leiomyosarcoma. Submitting diagnoses for symplastic leiomyomas were: atypical spindle cell lesion (n=3); probably leiomyosarcoma (n=1); leiomyosarcoma (n=1); and none given (n=4). Symplastic leiomyomas were diagnosed when there was moderate-severe cytologic atypia, yet was degenerative-appearing with multinucleation or smudged chromatin in the setting of low nuclear/cytoplasmic ratio, low cellularity, and no mitotic activity. The mean size was 1.0 cm for usual leiomyomas, 1.0 cm for symplastic leiomyomas, and 2.0 cm for leiomyosarcomas. Leiomyosarcomas had high nuclear/cytoplasmic ratio, high cellularity, nuclear pleomorphism, and hyperchromasia. Five of 10 usual and 3/9 symplastic leiomyomas showed at least 1 ill-defined border simulating infiltrative growth. Three leiomyosarcomas were grade 1, and 2/5 were grade 2. Resection margins were positive in 5/10 usual and 3/9 symplastic leiomyomas and in 1/5 leiomyosarcoma. Ki67 labeling in usual leiomyomas was on average 2.4% (range, 1% to 5%) and in symplastic leiomyomas was 1.8% (range, 1% to 5%). Mitoses were absent in all cases of usual and symplastic leiomyomas. Mitotic figures averaged 4.7 (range, 1 to 7) and 13.5 (range, 7 to 20) per 10 HPF for the grade 1 and 2 leiomyosarcomas, respectively. None of the symplastic leiomyomas recurred after a median follow-up of 27 months. The 2 patients with grade 2 leiomyosarcoma had no evidence of metastases at 6 and 7 months follow-up, respectively. Scrotal symplastic leiomyomas may have an ill-defined infiltrative border, which along with their atypia mimic malignancy. Ki67 is low in symplastic leiomyomas, which along with their favorable follow-up and experience in other organs justifies a benign diagnosis. High cellularity and high mitotic activity are the most reliable features for the diagnosis of scrotal leiomyosarcoma.

Accurate recognition of Gleason pattern (GP) 4 prostate carcinoma (PCa) on needle biopsy is critical for patient management and prognostication. "Poorly formed glands" are the most common GP4 subpattern. We studied the diagnostic reproducibility and the quantitative threshold of grading GP4 "poorly formed glands" and the criteria to distinguish them from tangentially sectioned GP3 glands. Seventeen urologic pathologists were first queried for the definition of "poorly formed glands" using cases representing a spectrum of PCa glandular differentiation. Cancer glands with no or rare lumens, elongated compressed glands, and elongated nests were considered "poorly formed glands" by consensus. Participants then graded a second set of 23 PCa cases that potentially contained "poorly formed glands" with a fair interobserver agreement (κ = 0.34). The consensus diagnoses, defined as agreement by > 70% participants, were then correlated with the quantitative (≤ 5, 6 to 10, >10) and topographic features of poorly formed glands (clustered, immediately adjacent to, and intermixed with other well-formed PCa glands) in each case. Poorly formed glands immediately adjacent to other well-formed glands regardless of their number and small foci of ≤ 5 poorly formed glands regardless of their location were not graded as GP4. In contrast, large foci of >10 poorly formed glands that were not immediately adjacent to well-formed glands were graded as GP4. Grading "poorly formed glands" is challenging. Some morphologic features are, however, reproducible for and against a GP4 diagnosis. This study represents an important step in standardization of grading of "poorly formed glands" based on quantitative and topographic morphologic features.