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We evaluated long-term outcomes of small cell carcinoma of the bladder (SCCB), a rare, aggressive disease. Among 199 patients with SCCB treated from 1990 to 2015, those with nonmetastatic disease had excellent longterm survival following neoadjuvant chemotherapy with 5-year disease-free survival rate of 50%. Patients with metastases had poor survival, with median overall survival of 10.3 months. Pathologic downstaging following neoadjuvant chemotherapy was associated with superior survival and ERCC2 mutations conferred increased likelihood of pathologic response. Introduction: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). Patients and Methods: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. Results: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (< pT2pN0) and pathologic complete response (pT0pN0) rates of 48% and 38%, respectively, with median follow-up of 7.2 years, and median DFS and OS of 5.6 and 14.5 years, respectively. NAC responders (< ypT2N0) had superior median DFS (14.5 vs. 0.6 years, hazard ratio [HR] 0.24, P < .001) and OS (14.5 vs. 2.5 years, HR 0.31, P = .002). DFS rates for responders and nonresponders were 76% and 27% at 5 years, and 71% and 23% at 10 years, respectively. Local and central nervous system recurrences were infrequent. Median progression-free survival (PFS) and OS for M1 disease were 6.9 and 10.3 months, respectively. Genomic profiling was performed on 47 NAC patients. Loss of ERCC2 function was significantly enriched among those with pathologic complete response to NAC (mutations present in 50% of pathologic complete responders vs. 15% nonresponders, P = .045). Conclusion: M0 SCCB is chemosensitive and patients have excellent long-term survival following response to NAC. Patients with M1 disease have poor survival despite systemic therapy. Loss-of-function mutations of ERCC2 were associated with pathologic complete response to NAC. [ABSTRACT FROM AUTHOR]

Summary We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance— KIT , KRAS , and NRAS —exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas. [ABSTRACT FROM AUTHOR]

Summary: Advances in whole slide digital imaging in the past decade necessitate validation of these tools in each organ system in advance of clinical adoption. We assessed reproducibility in reporting prostate needle biopsy parameters among urologic pathologists using routine and digital microscopy in a consultation/second opinion-like setting. Four urologic pathologists evaluated a single core level from 50 diagnostically challenging needle biopsy specimens by routine microscopy and whole slide digital imaging. Interobserver and intraobserver agreement were calculated for primary and secondary Gleason grades, Gleason score, tumor quantitation (percentage and size in millimeters), and perineural invasion. Interobserver agreement for routine microscopy was excellent for primary Gleason grade (κ = 0.72) and good for all other parameters (κ ranging from 0.36 to 0.55). Whole slide digital imaging assessment yielded similar agreement for all parameters. Intraobserver agreement for primary Gleason grade and Gleason score was very good to excellent for all pathologists (all κ ≥ 0.65 and ≥0.73, respectively). Size of tumor in millimeters consistently displayed higher levels of agreement than percentage of tumor across media and pathologists. Digital assessment of routinely reported cancer parameters on prostatic needle biopsy for a given scanned core level is comparable to that of routine microscopy. These findings imply that histologic interpretation using dynamic whole slide images may accurately simulate routine microscopic evaluation in the consultation setting. Implementation of whole slide digital imaging in these scenarios may significantly reduce the workload of large referral centers in the near future and impact the manner in which pathologists seek second opinion consultation on challenging cases. [ABSTRACT FROM AUTHOR]

To review the presentation and long-term oncologic outcomes of patients with regressed ("burnt out") primary testicular germ cell tumors (GCT). Certain testicular GCT can present with complete regression of the primary tumor. It is not well established if this is associated with more aggressive disease or worse oncologic outcomes. We queried our prospectively maintained testicular cancer clinical database at a tertiary cancer center and identified patients without prior chemotherapy who had regressed primary GCT at radical orchiectomy from 1990 to 2023. All specimens were reviewed by a genitourinary pathologist at diagnosis. Long-term clinical outcomes were reported by Kaplan-Meier method. Fifty-six patients met inclusion criteria; at diagnosis, 17 had no evidence of extra-testicular disease and 39 had advanced (clinical stage [CS] II+) GCT. All CSx (no viable disease or germ cell neoplasia in situ at orchiectomy, and no evidence of advanced disease) and CS0 patients were managed with surveillance and had 5-year recurrence-free survival (RFS) of 88% (95% CI: 39%, 98%). All patients with CS II+ disease underwent primary treatment with surgery (n = 5) or first-line chemotherapy (n = 34). Two- and 5-year RFS for patients with CSII+ disease was 94% (95% CI: 78%, 98%) and 90% (95% CI: 72%, 97%), respectively. Patients with regressed primary testicular GCT often present with advanced disease, possibly due to lack of early clinical signs from the primary tumor. Our analysis shows excellent long-term oncologic outcomes similar to those reported in the literature for patients with viable primary testicular GCT. [ABSTRACT FROM AUTHOR]

Objective: To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs).Patients and Methods: Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes.Results: Among 568 patients with GCTs, 8.1% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3%), 11 (22.4%), and 13 (6.1%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8% vs 19.2%, P = .02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7%), RRAS2 (11.8%), CBL (6.5%), NRAS (4.3%), MAP2K1 (2.2%), and RAC1 (2.2%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9% of patients developed metastases and 95.7% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95% confidence interval 1.1-78.4, P = .04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95% confidence interval 0.1-4.3, P = .76).Conclusion: Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy. [ABSTRACT FROM AUTHOR]

Objective: To assess which patients respond best following cytoreductive nephrectomy for renal cell carcinoma (RCC) with sarcomatoid dedifferentiation (sRCC) and whether outcomes are improving over time.Methods: We identified 562 patients with metastatic RCC treated between 1989 and 2018 with cytoreductive nephrectomy. We reviewed baseline clinical and pathologic characteristics, including the presence of sRCC, and metastatic sites at time of nephrectomy. The primary study endpoint was overall survival (OS). Univariate and multivariate Cox-regression analyses were used to identify significant predictors of OS.Results: The study cohort had 192 sRCC patients, with a median age of 59 years. Frequently involved metastatic locations were lung (n = 115), retroperitoneal nodes (n = 63), and axial skeleton (n = 43). Lung metastasis were more prevalent in clear cell histology (P = .0017) whereas nodal involvement was associated with nonclear cell subtypes (P = .0064). Median follow-up was 14 months. Estimated 2- and 5-year OS were 34.1% and 14.8%, respectively. On multivariate analysis, metastases to the liver (HR = 1.64; 95% CI 1.02-2.63; P = .04), lung (HR = 1.50; 95% CI 1.05-2.14; P = .03), retroperitoneal nodes (HR = 1.52; 95% CI 1.03-2.25; P = 0.04) and nonclear cell histology (HR = 1.61; 95% CI 1.10-2.35; P = .01) were associated with worse OS in the sRCC cohort.Conclusion: OS after cytoreductive nephrectomy for sRCC and non-sRCC is improving over time. In patients with sRCC, presentations with unifocal metastasis not involving the liver or lung, clear cell histology and node negative disease have better outcomes following cytoreductive nephrectomy and may yield greater benefit from the procedure. [ABSTRACT FROM AUTHOR]

Aim To develop a nomogram from clinical and computed tomography (CT) data for pre-treatment identification of indolent renal cortical tumours. Patients and methods A total of 1201 consecutive patients underwent dedicated contrast-enhanced CT prior to nephrectomy for a renal cortical tumour between January 2000 and July 2011. Two radiologists evaluated all tumours on CT for size, necrosis, calcification, contour, renal vein invasion, collecting system invasion, contact with renal sinus fat, multicystic tumour architecture, nodular enhancement, and the degree of nephrographic phase enhancement. CT and clinical predictors (gender, body mass index [BMI], age) were incorporated into the nomogram. We employed multivariable logistic regression analysis to predict tumour type and internally validated the final model using the data from reader 1. External validation was performed by using all data from reader 2. We applied Wilcoxon rank sum test and Fisher’s exact test to investigate for differences in tumour size, BMI, age, and differences in CT imaging features between patients with aggressive and those with indolent tumours. Results 63.6% (764/1201) of patients had clear-cell or other aggressive non-clear-cell RCC (i.e. papillary RCC type 2, unclassified RCC) and 36.4% (437/1201) had indolent renal cortical tumours (i.e. papillary RCC type 1, chromophobe RCC, angiomyolipoma, or oncocytoma). On CT, indolent tumours were significantly smaller (p < 0.001) than aggressive tumours and significantly associated with well-defined tumour contours (p < 0.001). Aggressive RCC were significantly associated with necrosis, calcification, renal vein invasion, collecting system invasion, contact with renal sinus fat, multicystic tumour architecture, and nodular enhancement (all, p < 0.001). The nomogram’s concordance index (C-index) was 0.823 after internal and 0.829 after external validation. Concluding statement We present a nomogram based on 1201 patients combining CT features with clinical data for the prediction of indolent renal cortical tumours. When externally validated, this nomogram resulted in a C-index of 0.829. [ABSTRACT FROM AUTHOR]

Summary Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort. [ABSTRACT FROM AUTHOR]

Objective: To evaluate, in detail, the histopathologic features of metastatic testicular germ cell tumors to retroperitoneal lymph nodes treated with primary retroperitoneal lymph node dissection (RPLND) and correlate the findings with patients' outcomes. Materials and Methods: We studied 183 patients with documented pathologic stage II disease with or without elevated serum tumor markers, selected from 453 patients who underwent primary RPLND at our institution from 1989 to 2002. Tumor type(s), size and extent of disease, and amount of tumor necrosis were assessed and correlated with outcome. Results: Embryonal carcinoma was the most common tumor type, present as the only component in 99 cases (54%) and the predominant tumor type (>50%) in 142 (78%). The number of positive lymph nodes ranged from 1 to 40 from a total of 2-80 lymph nodes examined (median, 28). Extranodal extension (ENE) was identified in 120 cases (66%). Among 73 patients followed up expectantly and with normal serum tumor markers, 19 experienced relapse, the probability of which was higher in patients with more positive nodes, larger metastases, and presence of ENE. However, none of these differences was statistically significant (all P >.2). The predominance of embryonal carcinoma and the presence of tumor necrosis were not significantly associated with outcome. Conclusion: In this cohort, most patients treated with primary RPLND and with positive lymph nodes also had ENE. We did not identify any variables to be significantly associated with relapse after RPLND in patients managed expectantly. Additional studies with more patients are needed to validate our findings. [Copyright &y& Elsevier]

Abstract: Background: Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown. Objective: To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC. Design, setting, and participants: Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded. Outcome measurements and statistical analysis: The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]). Results and limitations: PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p =0.01 and p =0.001, respectively). Small tumors (<4cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p =0.001). BAP1 mutations tend to occur in Fuhrman grade III–IV tumors (p =0.052) and are associated with worse CSS (p =0.01). Clinical outcome data are limited by the number of events. Conclusions: Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted. [Copyright &y& Elsevier]

Abstract: Objectives: To evaluate 5-alpha-reductase (5αR) expression in benign and malignant urothelium and to assess the relationship between 5αR expression and tumor stage, tumor grade, and clinical outcome in patients with urothelial carcinoma/transitional cell carcinoma. Methods: We performed immunohistochemistry for 5αR on 53 urothelial specimens from 36 patients with transitional cell carcinoma treated at our institution between June 2002 and July 2003. For each tumor and the adjacent nontumor urothelium, a semiquantitative staining score was calculated. We used t tests and analysis of variance to compare the staining score across groups. Kaplan-Meier and logistic regression analyses were performed to assess the relationship between 5αR expression and clinical outcome. Results: 5αR was expressed throughout the non-neoplastic urothelium. Nontumor urothelium had greater mean staining scores than did tumor specimens (160.1 versus 105.5, P <0.01). Low staining scores were associated with high grade (P <0.05), Stage pT3, pT4, and pTis (P <0.05), and disease progression (P <0.05). A staining score less than the median was a risk factor for progression (odds ratio 6.2, P <0.01) on univariate regression analysis. Patients with a staining score less than the median had a greater likelihood of disease progression (log-rank P <0.05) and cause-specific mortality (log-rank P <0.05). Conclusions: We demonstrated 5αR expression in human urothelium and found that expression is decreased in transitional cell carcinoma in relation to tumor grade and stage. Decreased 5αR expression was associated with disease progression and cause-specific mortality. [Copyright &y& Elsevier]

Objectives: To evaluate the expression of the androgen receptor (AR) in transitional cell carcinoma (TCC) of the bladder, and to assess whether its expression correlated with pathologic tumor stage. TCC of the bladder is three times more common in males than in females. The origin of this sex difference in incidence is unknown.Methods: We evaluated tumor specimens from 49 consecutive patients treated for TCC of the bladder at our institution between July 2002 and June 2003. Immunohistochemistry was performed using a monoclonal mouse anti-AR antibody on paraffin-embedded tissue sections of tumors obtained from transurethral resection, radical cystectomy, or resection of metastases. Specimens were assessed for AR expression, and, in tumors that demonstrated AR staining, the percentage of nuclei that stained positive was recorded.Results: Of the 49 tumors, 26 (53.1%) expressed the AR. The percentage of tumors that expressed the AR decreased with increasing pathologic stage, from 88.9% of pTa lesions to 0% of pT3 tumors. Overall, 75% of superficial tumors (pTa + pT1 + carcinoma in situ) expressed the AR compared with 21.4% of invasive tumors (pT2 + pT3; P = 0.002). In addition, among AR-expressing tumors, the mean percentage of nuclei that stained positive for the AR was significantly greater in pTa tumors (62.5%) than in pT1 (31%) or pT2 (20%) tumors (P = 0.005).Conclusions: We found a decrease in AR protein expression in tumors with increased pathologic stage. Our data suggest that the loss of AR expression is associated with invasive bladder cancer. [Copyright &y& Elsevier]

We report a case of renal cell carcinoma (RCC) with extensive oncocytoid features developing in a 12-year-old African-American boy after chemotherapy for cardiac leiomyosarcoma at 3 months of age. The tumor showed histopathologic features similar to those previously reported in RCC after chemotherapy for neuroblastoma and now considered a specific entity in the World Health Organization classification of renal tumors as “RCC associated with neuroblastoma.” Our report expands the spectrum of tumors (beyond neuroblastoma) in which RCCs with such an appearance can arise in the pediatric age group after chemotherapy. [Copyright &y& Elsevier]