Histopathologic and Molecular Characterization of IDH-Mutant Prostatic Adenocarcinoma.

Gain-of-function isocitrate dehydrogenase (IDH) mutations are pathogenically significant in many tumor types and are actionable in cholangiocarcinoma, low-grade glioma, and acute myeloid leukemia. Rare IDH mutations have been described in prostatic adenocarcinoma (PCa). Recent publications have suggested that psammomatous calcifications in PCa are associated with IDH1 mutations. In this retrospective study, we queried our institutional clinical sequencing database (cohort 1), and previously published PCa data sets in cBioPortal (cohort 2). Samples were stratified based on oncogenic hotspot IDH mutations at IDH1 R132 and IDH2 R140/R172, and other nonhotspot IDH mutations. Seventeen (0.4%) cases were identified from 4033 PCa cases in cohort 1 harboring mutually exclusive oncogenic hotspot IDH1 (N = 15, 1 of which was subclonal) or IDH2 (N = 2) mutations, and 20 (0.5%) cases had nonhotspot IDH1/2 mutations. A histologic review of 13 cases with IDH1 hotspot mutations and available material showed grade group 3 or higher disease. Immunohistochemistry was performed on cases with IDH1 hotspot mutations when possible and showed AR, PSA, PSMA, and NKX3.1 positive in all the 4 cases stained. In cohort 2, 9 cases (0.3%) harboring IDH1 hotspot mutations were identified from 2749 patients, and 9 cases carried nonhotspot IDH1/2 mutations. The combined cohorts of 23 PCa cases with clonal IDH1 hotspot mutations had no ETS fusions, SPOP hotspot mutations, and somatic or germline alterations in BRCA1/2, ATM, RB1, or AR; 19 cases with successful microsatellite instability testing were all microsatellite stable. Conversely, among 29 cases with nonhotspot IDH mutations, there were 4 with TMPRSS2::ERG fusions, 6 with SPOP hotspot mutations, and 10 with AR amplifications/hotspot mutations; 8 were microsatellite instability high. Notably, two cases with IDH1 hotspot mutations had psammomatous calcifications. Our findings provide evidence that IDH1 hotspot mutations serve as driver alterations in this rare yet distinct molecular subset of PCa. Further studies are warranted to correlate response to androgen deprivation and IDH inhibitors.

Differential NEUROD1, ASCL1, and POU2F3 Expression Defines Molecular Subsets of Bladder Small Cell/Neuroendocrine Carcinoma With Prognostic Implications.

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and prometastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell NEC (LCNEC) assembled in tissue microarrays. Coexpression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence-free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified 5 distinct molecular subtypes in bladder SMC based on the expression of ASCL1, NEUROD1, and POU2F3: ASCL1+/NEUROD1- (n = 33; 34%), ASCL1- /NEUROD1+ (n = 21; 21%), ASCL1+/NEUROD1+ (n = 17; 17%), POU2F3+ (n = 22, 22%), and ASCL1- /NEUROD1- /POU2F3- (n = 5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (P < .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (P < .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1, and POU2F3. POU2F3-expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.

Benign splenic lesions in BAP1-tumor predisposition syndrome: a case series.

BAP1-Tumor Predisposition Syndrome (TPDS) is caused by germline variants in BAP1 and predisposes to solid tumors. After observation of a radiologically malignant-appearing splenic mass with benign pathology in a patient with BAP1-TPDS, we sought to retrospectively characterize splenic lesions in individuals with BAP1-TPDS seen at a comprehensive cancer center. A dedicated radiology review for splenic abnormalities was performed. We identified 37 individuals with BAP1-TPDS, 81% with a history of cancer. Of 33 individuals with abdominal imaging, 10 (30%) had splenic lesions, and none were shown to be malignant on follow-up. Splenectomy in an individual with suspected splenic angiosarcoma showed a benign vascular neoplasm with loss of nuclear staining for BAP1 in a subset of cells. Benign splenic lesions appear to be common and potentially BAP1-driven in individuals with BAP1-TPDS; confirmation of these findings could lead to more conservative management and avoidance of splenectomy.

L1 Cell Adhesion Molecule (L1CAM) Expression and Molecular Alterations Distinguish Low-Grade Oncocytic Tumor From Eosinophilic Chromophobe Renal Cell Carcinoma.

Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the "other oncocytic tumors" category in the 2022 World Health Organization classification system. Although the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data are relatively limited. The morphologic overlap between LOT and other low-grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n = 67) and E-chRCC (n = 69) and revealed notable differences between the 2 entities. Clinically, LOT predominantly affected women, whereas E-chRCC showed a male predilection. Histologically, although almost all LOTs were dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the tuberous sclerosis complex (TSC)-mTOR complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations, and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1 cell adhesion molecule (L1CAM), a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with a benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to "Oncocytic Principal Cell Adenoma of the Kidney" may be a better way to define and describe this entity.

Update on Selected High-grade Renal Cell Carcinomas of the Kidney: FH-deficient, ALK-rearranged, and Medullary Carcinomas.

High-grade renal cell carcinoma (RCC), often diagnosed at advanced stages, significantly contributes to renal cancer-related mortality. This review explores the progress in understanding specific subtypes of high-grade RCC, namely fumarate hydratase (FH)-deficient RCC, anaplastic lymphoma kinase (ALK)-rearranged RCC, and SMARCB1-deficient renal medullary carcinoma, all of which are now recognized as molecularly defined entities in the WHO classification system (2022). While these entities each exhibit a morphologic spectrum that overlaps with other high-grade RCC, ancillary tools developed based on their distinctive molecular alterations can help establish a specific diagnosis, underscoring the importance of integrating molecular findings into diagnostic paradigms. It is important to exclude these specific tumor types in cases with similar morphologic spectrum before rendering a diagnosis of high-grade papillary RCC, collecting duct carcinoma, or RCC, NOS. Several gray areas exist within the spectrum of high-grade uncommon types of RCC, necessitating continued research to enhance diagnostic precision and therapeutic options.

Immunometabolic coevolution defines unique microenvironmental niches in ccRCC.

Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. To study IMH, we profiled tumor/normal regions from clear cell renal cell carcinoma (ccRCC) patients. A common pattern of IMH transcended all patients, characterized by correlated fluctuations in the abundance of metabolites and processes associated with ferroptosis. Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clinical significance of RNA biomarkers in ccRCC, we inferred metabolomic profiles from the RNA sequencing data of ccRCC patients enrolled in 7 clinical trials, and we ultimately identifyied metabolite biomarkers associated with response to anti-angiogenic agents. Local metabolic phenotypes, therefore, emerge in tandem with the immune microenvironment, influence ongoing tumor evolution, and are associated with therapeutic sensitivity.

Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer.

Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR-Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect of the interferon receptor genes cluster as an adaptive mechanism to deleterious chromosomal instability in metastatic progression. This work provides critical knowledge on drivers of renal cell carcinoma progression and defines the primary role of interferon signaling in constraining the propagation of aneuploid clones in cancer evolution.

Neurofibromatosis Type 2-Yes-Associated Protein and Transcriptional Coactivator With PDZ-Binding Motif Dual Immunohistochemistry Is a Reliable Marker for the Detection of Neurofibromatosis Type 2 Alterations in Diffuse Pleural Mesothelioma.

Neurofibromatosis type 2 (NF2) loss occurs in approximately 30% to 50% of diffuse pleural mesothelioma (DPM) with accumulation of yes-associated protein (YAP) 1 and transcriptional coactivator with PDZ-binding motif (TAZ) in tumor nuclei. NF2 and YAP/TAZ represent potential therapeutic targets. We investigated the performance of NF2-YAP/TAZ dual immunohistochemistry (IHC) in identifying DPM that harbors NF2 alterations and in distinguishing DPM from benign mesothelial proliferations. NF2-YAP/TAZ IHC was subsequently performed in a Discovery cohort of DPMs with (n = 10) or without (n = 10) NF2 alterations detected by next-generation sequencing (NGS) and 9 benign cases. The cutoff values for loss of NF2 expression and YAP/TAZ overexpression using IHC were determined in the Discovery cohort. The performance characteristics of NF2-YAP/TAZ IHC were investigated in a Validation cohort (20 DPMs and 10 benign cases). In the Discovery cohort, all DPMs with NF2 alterations using NGS showed NF2 IHC scores of <2, whereas all NF2-wild-type DPMs showed scores of ≥2. NF2-altered DPMs had significantly higher YAP/TAZ H-scores (P < .001) than NF2-wild-type DPM and benign pleura (median H-scores: 237.5 [range, 185-275], 130.0 [range, 40-225], and 10.0 [range, 0-75], respectively). NF2-YAP/TAZ IHC demonstrated 95.2% sensitivity, 100% specificity, 100% positive predictive value, and 95% negative predictive value for detecting NF2 alterations in DPM (n = 40) with NGS as the gold standard and 87.5% sensitivity and 100% specificity for distinguishing DPM (n = 40) from benign mesothelial proliferations (n = 19). NF2-YAP/TAZ IHC has a high sensitivity and specificity for detecting NF2 alterations in DPM and a high specificity for malignancy, highlighting potential utility for guiding NF2-targeted therapies and distinguishing DPM from benign mimics.

Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape.

BACKGROUND: Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. METHODS: Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. RESULTS: Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. CONCLUSIONS: These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment. TRIAL REGISTRATION: The study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015.

FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.

Renal Medullary Carcinomas Harbor a Distinct Methylation Phenotype and Display Aberrant Methylation of Genes Related to Early Nephrogenesis.

Renal medullary carcinomas (RMC) are rare aggressive tumors of the kidneys, characterized by a loss of SMARCB1. Characteristically, these tumors arise in patients with sickle cell trait or other hemoglobinopathies. Recent characterization efforts have unraveled oncogenic pathways that drive tumorigenesis. Among these, gene sets that characterize replicative stress and the innate immune response are upregulated in RMCs. Despite comprehensive genetic and transcriptomic characterizations, commonalities or differences to other SMARCB1 deficient entities so far have not been investigated. We analyzed the methylome of seven primary RMC and compared it to other SMARCB1 deficient entities such as rhabdoid tumors (RT) and epithelioid sarcomas using 850 K methylation arrays. Moreover, we evaluated the differential gene expression of RMC using RNA-sequencing in comparison to other rhabdoid tumors. In accordance with previous gene expression data, we found that RMCs separate from other SMARCB1 deficient entities, pointing to a potentially different cell of origin and a role of additional genetic aberrations that may drive tumorigenesis and thus alter the methylome when compared to rhabdoid tumors. In a focused analysis of genes that are important for nephrogenesis, we particularly detected genes that govern early nephrogenesis such as FOXI1 to be hypomethylated and expressed at high levels in RMC. Overall, our analyses underscore the fact that RMCs represent a separate entity with limited similarities to rhabdoid tumors, warranting specific treatment tailored to the aggressiveness of the disease.

Molecular Characterization of the Tumor Microenvironment in Renal Medullary Carcinoma.

Renal medullary carcinoma (RMC) is a highly aggressive disease associated with sickle hemoglobinopathies and universal loss of the tumor suppressor gene SMARCB1. RMC has a relatively low rate of incidence compared with other renal cell carcinomas (RCCs) that has hitherto made molecular profiling difficult. To probe this rare disease in detail we performed an in-depth characterization of the RMC tumor microenvironment using a combination of genomic, metabolic and single-cell RNA-sequencing experiments on tissue from a representative untreated RMC patient, complemented by retrospective analyses of archival tissue and existing published data. Our study of the tumor identifies a heterogenous population of malignant cell states originating from the thick ascending limb of the Loop of Henle within the renal medulla. Transformed RMC cells displayed the hallmarks of increased resistance to cell death by ferroptosis and proteotoxic stress driven by MYC-induced proliferative signals. Specifically, genomic characterization of RMC tumors provides substantiating evidence for the recently proposed dependence of SMARCB1-difficient cancers on proteostasis modulated by an intact CDKN2A-p53 pathway. We also provide evidence that increased cystine-mTORC-GPX4 signaling plays a role in protecting transformed RMC cells against ferroptosis. We further propose that RMC has an immune landscape comparable to that of untreated RCCs, including heterogenous expression of the immune ligand CD70 within a sub-population of tumor cells. The latter could provide an immune-modulatory role that serves as a viable candidate for therapeutic targeting.

A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma.

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. SIGNIFICANCE: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221.

Clinical and Genomic Characterization of Bladder Carcinomas With Glandular Phenotype.

PURPOSE: To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy. METHODS: We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared. RESULTS: Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53, KRAS, and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens. CONCLUSION: The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.

Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series.

AIM: Clinicopathologic characterisation of a contemporary series of neuroendocrine (NE) differentiation in the setting of prostatic carcinoma (PCa) was examined. METHODS AND RESULTS: We reviewed institutional databases for in-house cases with a history of PCa and histopathologic evidence of NE differentiation during the disease course. In all, 79 cases were identified: 32 primary and 47 metastases. Metastatic lesions were in liver (n = 15), lymph node (n = 9), bone (n = 6), lung (n = 3), brain (n = 1), and other sites (n = 13). In all, 63 of 76 (82%) cases with NE differentiation and available history were posttherapy: six postradiation therapy (RT), 24 post- androgen-deprivation therapy (ADT), and 33 post-RT + ADT. Morphologic assessment (n = 79): (i) 23 pure small-cell/high-grade NE carcinoma (HGNEC): 20/23 metastatic; (ii) 10 combined high-grade PCa and small-cell/HGNEC: 9/10 primary; (iii) 15 PCa with diffuse NE immunohistochemistry (IHC) marker positivity/differentiation, associated with nested to sheet-like growth of cells with abundant cytoplasm and prominent nucleoli, yet diffuse positivity for at least one prostatic and one NE IHC marker: all metastatic; (iv) 11 PCa with patchy NE differentiation, displaying more than single-cell positivity for NE IHC: five primary / six metastatic; (v) nine PCa with focal NE marker positive cells: four primary / five metastatic; (vi) 11 PCa with 'Paneth cell-like' change: all primary. CONCLUSIONS: In this contemporary series, the majority of NE differentiation in the setting of PCa was seen posttherapy. We highlight the tendencies of small-cell/HGNEC and PCa with diffuse NE differentiation by IHC to occur in metastatic settings, while morphologically combined high-grade PCa + small-cell/HGNEC and 'Paneth cell-like' change occur in primary disease.

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy.

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 (

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates.

PURPOSE: To assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non-clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients had advanced non-clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. RESULTS: A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n = 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n = 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations. CONCLUSION: Cabozantinib plus nivolumab showed promising efficacy in most non-clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non-clear-cell RCC variants warrant further study as predictors of response.

Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas.

BACKGROUND: Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes. OBJECTIVE: To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Somatic alterations were identified using clinical pipelines, with allele-specific copy number alterations (CNAs) identified using FACETS. Mass spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors. RESULTS AND LIMITATIONS: Tumors were analyzed for 42 patients (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCCs harbored a germline alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic germline FH variants. SDHRCCs had a lower mutation burden (p = 0.02) and CNA burden (p = 0.0002) than FHRCCs. All SDHRCCs presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCCs demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCCs and FHRCCs exhibited significant idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines. These characteristic metabolic changes allowed identification of a previously unrecognized SDH-deficient RCC. CONCLUSIONS: Despite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities. PATIENT SUMMARY: Kidney cancers driven by loss of the gene encoding either the succinate dehydrogenase or fumarate hydratase enzyme are rare. We sought to define and compare the genetic and metabolic features of these cancer entities.

Phase II Study of Neoadjuvant Nivolumab in Patients with Locally Advanced Clear Cell Renal Cell Carcinoma Undergoing Nephrectomy.

Immune checkpoint inhibitor therapy improves survival in patients with metastatic renal cell carcinoma (RCC) but has not been studied well preoperatively in patients with localized disease undergoing nephrectomy. We conducted a single-center study to evaluate the safety and feasibility of neoadjuvant nivolumab in patients undergoing nephrectomy for localized RCC. Eligible patients had a >20% risk of recurrence, as estimated by a preoperative nomogram. Patients received nivolumab every 2 wk for four treatments prior to surgery. The primary endpoints were feasibility, defined as completing at least three treatments without significant surgical delay, and safety, defined as the rate of surgical complications. Treatment effects were assessed by radiomics and immunohistochemistry. A total of 18 patients (11 men; median age 60 yr) with clear cell RCC were enrolled. All received at least one dose of nivolumab and proceeded to nephrectomy without delay; 16/18 patients completed all four doses. Two patients discontinued nivolumab for immune-related adverse events, and four had surgical complications as per the Clavien-Dindo classification. Integrated pathology plus radiomic analysis demonstrated an association between post-treatment immune infiltration and low entropy apparent diffusion coefficient on magnetic resonance imaging. Nivolumab prior to nephrectomy was safe and feasible, without significant surgical delays and with an expected rate of immune-related adverse events. PATIENT SUMMARY: We evaluated the outcomes for patients with localized kidney cancer who received immunotherapy prior to surgery to remove their kidney tumor. In a small group of patients who had cancer confined to the kidney, this approach appeared safe and feasible.