Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.

PTEN (phosphatase and tensin homolog on chromosome 10) is one of the most frequently lost tumor suppressor genes in human cancers and it has been described in more than two-thirds of patients with advanced/aggressive prostate cancer. Previous studies suggest that, in prostate cancer, genomic PTEN loss is associated with tumor progression and poor prognosis. Thus, we evaluated whether immunohistochemical PTEN expression in prostate cancer glands was associated with higher risk of recurrence, using a nested case–control study that included 451 men who recurred and 451 men who did not recur with clinically localized prostate cancer treated by radical prostatectomy. Recurrence was defined as biochemical recurrence (serum prostate-specific antigen >0.2 ng/ml) or clinical recurrence (local recurrence, systemic metastases, or prostate cancer-related death). Cases and controls were matched on pathological T stage, Gleason score, race/ethnicity, and age at surgery. Odds ratios of recurrence and 95% confidence intervals were estimated using conditional logistic regression to account for the matching factors and to adjust for year of surgery, preoperative prostate-specific antigen concentrations, and status of surgical margins. Men who recurred had a higher proportion of PTEN negative expression (16 vs 11%, P = 0.05) and PTEN loss (40 vs 31%, P = 0.02) than controls. Men with markedly decreased PTEN staining had a higher risk of recurrence (odds ratio = 1.67; 95% confidence intervals 1.09, 2.57; P = 0.02) when compared with all other men. In summary, in patients with clinically localized prostate cancer treated by prostatectomy, decreased PTEN expression was associated with an increased risk of recurrence, independent of known clinicopathological factors.

Like many carcinomas, urothelial carcinoma (UroCa) is associated with chronic injury. A better understanding of this association could inform improved strategies for preventing and treating this disease. We investigated the expression, regulation, and function of the transcriptional regulator SRY-related high-mobility group box 9 (Sox9) in urothelial development, injury repair, and cancer. In mouse bladders, Sox9 levels were high during periods of prenatal urothelial development and diminished with maturation after birth. In adult urothelial cells, Sox9 was quiescent but was rapidly induced by a variety of injuries, including exposure to the carcinogen cyclophosphamide, culture with hydrogen peroxide, and osmotic stress. Activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was required for Sox9 induction in urothelial injury and resulted from activation of the epidermal growth factor receptor (Egfr) by several Egfr ligands that were dramatically induced by injury. In UroCa cell lines, SOX9 expression was constitutively upregulated and could be suppressed by EGFR or ERK1/2 blockade. Gene knockdown showed a role for SOX9 in cell migration and invasion.

Background Bladder urothelial carcinoma (UrCa) proclaims high rates of mortality and morbidity. Identifying novel molecular prognostic factors and targets of therapy is crucial. mTOR pathway plays a pivotal role in establishing cell shape, migration and proliferation. Design TMA were constructed from 132 cystectomies (1994-2002). IHC was performed for Pten, c-Myc, p27, phosAkt, phosS6, and 4E-BP1. Markers were evaluated for pattern, percent and intensity of staining. Results Mean length of F/U was 62.6 months (1-182). Disease progression, overall survival (OS) and disease specific survival (DSS) rates were 42%, 60% and 68%, respectively. Pten showed loss of expression in 35% of UrCa. All markers showed lower expression in invasive UrCa compared to benign urothelium with the exception of 4E-BP1. Pten, p27, phosAkt, phosS6 and 4E-BP1 expression correlated with pathologic stage (pT; p<0.03). Pten, 4E-BP1, and phosAkt expression correlated with divergent aggressive histology and invasion. PhosS6 expression inversely predicted OS (p=0.01), DSS (p=0.001) and progression (p=0.05). c-Myc expression inversely predicted progression (p=0.01). In a multivariate analysis model that included: TNM stage grouping, divergent aggressive histology, concomitant CIS, phosS6 and c-Myc expression; phosS6 was an independent predictor of DSS (p=0.03; HR: -.19) while c-Myc was an independent predictor of progression (p=0.02; HR:-.38). In a second model substituting organ confined disease and lymph node status for TNM stage grouping, phosS6 and c-Myc remained independent predictors of DSS (p=0.03; HR: -.21) and progression (p=0.03; HR:-.34), respectively. Conclusions We found an overall downregulation of mTOR pathway in UrCa. PhosS6 independently predicted DSS and c-Myc independently predicted progression.