Intra-Abdominal Epithelioid Neoplasm With EWSR1::CREB Fusions Involving the Kidney: A Clinicopathologic and Molecular Characterization With an Emphasis on Differential Diagnosis.

Soft tissue neoplasms, harboring fusions between EWSR1 and FUS with genes encoding CREB transcription factors family (ATF1, CREB1, and CREM), are an emerging heterogeneous group of mesenchymal tumors that differ significantly in morphology, immunophenotypes, and behavior. Recently, EWSR1/FUS::CREB fusions have been recognized to define a group of aggressive neoplasms of epithelioid morphology with multiple growth patterns and a striking predilection for mesothelial-lined cavities. These neoplasms presenting as a primary neoplasm of intra-abdominal visceral organs are rare, which could elicit a wide range of differential diagnoses because of their diverse morphologies and immunohistochemical profiles. We report 3 cases of intra-abdominal epithelioid neoplasms with EWSR1::CREB fusions involving the kidney. This study included 2 female patients and 1 male patient, with age at presentation ranging from 17 to 61 years (mean: 32 years). All the patients underwent radical nephrectomy without adjunctive therapies. Grossly, the tumors were large, and all were solitary masses with sizes ranging from 5.6 to 30.0 cm (mean: 14.5 cm). Histologically, the neoplasms showed infiltrating and indistinct borders and were composed predominantly of monomorphic round-to-epithelioid cells with variable amounts of pale-to-clear cytoplasm, arranged in cords, nests, and sheets and embedded in a sclerotic hyalinized stroma with variable lymphoid cuffing either intermixed or at the periphery. Notably, a hemangiopericytomatous growth pattern was commonly seen. Nuclear atypia was mild, and mitotic activity was scarce. Immunohistochemically, all 3 cases were at least focally positive for epithelial membrane antigen and keratin AE1/AE3, with 2 tumors showing focal MUC4 expression and 1 case displaying diffuse CD34 and focal CAIX positivity. Targeted RNA sequencing identified EWSR1::CREM fusion in 2 cases and EWSR1::ATF1 fusion in 1 case. Subsequent fluorescence in situ hybridization analysis confirmed the RNA sequencing results. On follow-up, 1 patient developed multiple spinal bone metastases 5 months after the surgery while the other 2 patients were free of disease 9 and 120 months after diagnosis, respectively. Our findings demonstrate that intra-abdominal epithelioid neoplasms with EWSR1::CREB fusions may rarely occur primarily in the kidney and should be included in the differential diagnosis of primary renal epithelioid mesenchymal neoplasms.

ALK-Rearranged Renal Cell Carcinoma: A Multi-Institutional Study of 9 Cases With Expanding the Morphologic and Molecular Genetic Spectrum.

ALK-rearranged renal cell carcinoma (ALK-RCC) is rare, molecularly defined RCC subtype in the recently published fifth edition of World Health Organization classification of tumors. In this study, we described 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were 6 male and 3 female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for 8 patients and on biopsy specimen for 1. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6 of 9 patients (6-36 months); 5 had no tumor recurrence or metastasis and 1 developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib-targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n = 1), and pale foamy cytoplasm (n = 1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included psammomatous microcalcifications (n = 5), rhabdoid cells (n = 4), prominent intracytoplasmic vacuoles (n = 4), prominent chronic inflammatory infiltrate (n = 3), signet ring cell morphology (n = 2), and pleomorphic cells (n = 2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4 of 8 tested cases showed reactivity for TFE3 protein. By fluorescence in situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n = 2), STRN (n = 1), TPM3 (n = 1), KIF5B (n = 1), HOOK1 (n = 1), SLIT1 (n = 1), and TPM1(3'UTR) (n = 1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.

Protocol for CHAMPION study: a prospective study of maximal-cytoreductive therapies for patients with de novo metastatic hormone-sensitive prostate cancer who achieve oligopersistent metastases during systemic treatment with apalutamide plus androgen deprivation therapy.

BACKGROUND: The proposed trial is to examine the feasibility of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided cytoreduction plus apalutamide and androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) at oligometastatic state. METHODS: CHAMPION (NCT05717582) is an open-label, single-arm, phase II trial, planning to enroll newly diagnosed mHSPC cases with oligometastases (≤ 10 distant metastatic sites in conventional imaging). Patients will receive 6 cycles of apalutamide plus ADT. Patients with oligometastatic disease at PSMA PET/CT after 3 treatment cycles will receive cytoreductive radical prostatectomy. PSMA PET/CT-guided metastasis-directed external radiation therapy will be determined by the investigators. Apalutamide plus ADT will be continued for 2 weeks postoperatively. The primary endpoint is the proportion of patients with undetectable prostate-specific antigen (PSA), no disease progression, and no symptom deterioration after 6 cycles of apalutamide plus ADT. Secondary endpoints include the percentage of patients with PSA ≤ 0.2 ng/mL and oligometastases by the end of 3 treatment cycles, PSA response rate, and safety. Fleming's two-stage group sequential design will be adopted in the study, where the null hypothesis is that the rate of patients with an undetectable PSA is ≤ 40% after 6 cycles of treatment, while the alternate hypothesis is an undetectable PSA of > 60%; with one-sided α = 0.05, power = 0.80, and an assumed dropout rate of 10%, the required number of patients for an effective analysis is 47. Enrolment in the study commenced in May 2023. DISCUSSION: The multi-modal therapy based on treatment response may improve the prognosis of newly diagnosed mHSPC patients with oligometastases. TRIAL REGISTRATION: The study is registered with Clinical Trials.Gov (NCT05717582). Registered on 8th February 2023.

Prevalence of mismatch repair genes mutations and clinical activity of PD-1 therapy in Chinese prostate cancer patients.

Prostate cancer (PCa) patients with mismatch repair (MMR) genes mutations are potentially responsive to immune checkpoint blockade (ICB). However, aberrations in MMR genes were rare in PCa and there is evidence that MMR genes mutations are highly ethnic specific. Thus, the prevalence and clinical characteristics of this subgroup in Chinese PCa patients are largely unknown. Furthermore, why some of these patients do not respond to ICB also remains unclear. Here, we analyzed the sequencing data from 3338 Chinese PCa patients to profile the mutation spectrum of the MMR genes. We found that in metastatic disease, the pathogenic mutation frequency of MMR genes in Chinese PCa patients was higher than that in the Caucasus population (4.8 vs 2.2%, P = 0.006) and the mutation carriers responded poorer to androgen deprive therapy (ADT) and abiraterone than non-carriers. Besides, we reported a multi-institutional cases series of 11 PCa patients with mismatch repair deficiency (dMMR) or microsatellite instability high (MSI-H) who received programmed cell death receptor-1 (PD-1) inhibitors, and performed multiplex immunohistochemistry (mIF) to explore the relationship between tumor immune microenvironment (TIME) and response to ICB. The results showed that the responders had higher density of intratumoral CD8+ T cells than non-responders. Our data suggested MMR genes mutations may be more common in Chinese PCa patients, and it is associated with poorer response to hormonal therapies. We propose that the density of intratumoral CD8+ T cells could be a promising predictor to help further subdivide the population of PCa patients who can benefit from immunotherapy.

Heterogeneity of [68Ga]Ga-PSMA-11 PET/CT in metastatic castration-resistant prostate cancer: genomic characteristics and association with abiraterone response.

PURPOSE: The aim of this study was to evaluate the impact of the spatial heterogeneity of prostate-specific membrane antigen (PSMA) uptake on circulating tumor DNA (ctDNA) characteristics and the response rate to new hormonal agent (NHA) treatment. METHODS: This retrospective study included 153 patients with metastatic castration-resistant prostate cancer (mCRPC) who underwent gallium-68 [68 Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) and ctDNA sequencing with a less than 2-week interval. SUVhetero was defined as the variance of SUVmean for each PSMA-positive lesion. SUVmax-mean was obtained by subtracting the SUVmax by the SUVmean. Patients receiving abiraterone treatment after [68 Ga]Ga-PSMA-11 PET/CT and ctDNA sequencing and with complete follow-up record were included into prostate-specific antigen (PSA) response rate analysis. PSA response was defined as a reduction of greater than 50% from baseline. RESULTS: The ctDNA detection rate was 65% (100/153). Higher SUVhetero value contributed to higher ctDNA% (Spearman's rho = 0.278, p < 0.002). A total of 60 patients were included in PSA response rate analysis. The median follow-up was 19.3 (IQR 16.2-23.2) months. Compare to patients with higher SUVhetero value, patients with NA SUVhetero had a higher PSA response rate (52% vs. 90%, p = 0.036). A higher SUVmax-mean value was strongly correlated with higher SUVhetero (Spearman's rho = 0.833, p < 0.0001). Patients with higher SUVmax-mean value also had a higher PSA response rate compared to patients with lower SUVmax-mean value (83.3% vs. 53.3%, p = 0.024). An external cohort confirmed baseline SUVmax-mean value was associated with enzalutamide treatment response rate. Patients with alterations in AR, DNA damage repair pathway, TP53, AR-associated pathway, cell cycle pathway, or WNT pathway had higher SUVmax-mean value compared to those without (p < 0.05). CONCLUSION: Spatial heterogeneity of the PSMA uptake was associated with ctDNA characteristics and response rate to NHA treatment.

Association of Pathological Features and Multiparametric MRI-Based Radiomics With TP53-Mutated Prostate Cancer.

BACKGROUND: TP53 mutations are associated with prostate cancer (PCa) prognosis and therapy. PURPOSE: To develop TP53 mutation classification models for PCa using MRI radiomics and clinicopathological features. STUDY TYPE: Retrospective. POPULATION: 388 patients with PCa from two centers (Center 1: 281 patients; Center 2: 107 patients). Cases from Center 1 were randomly divided into training and internal validation sets (7:3). Cases from Center 2 were used for external validation. FIELD STRENGTH/SEQUENCE: 3.0T/T2-weighted imaging, dynamic contrast-enhanced imaging, diffusion-weighted imaging. ASSESSMENT: Each patient's index tumor lesion was manually delineated on the above MRI images. Five clinicopathological and 428 radiomics features were obtained from each lesion. Radiomics features were selected by least absolute shrinkage and selection operator and binary logistic regression (LR) analysis, while clinicopathological features were selected using Mann-Whitney U test. Radiomics models were constructed using LR, support vector machine (SVM), and random forest (RF) classifiers. Clinicopathological-radiomics combined models were constructed using the selected radiomics and clinicopathological features with the aforementioned classifiers. STATISTICAL TESTS: Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis and area under the curve (AUC). P value <0.05 indicates statistically significant. RESULTS: In the internal validation set, the radiomics model had an AUC of 0.74 with the RF classifier, which was significantly higher than LR (AUC = 0.61), but similar to SVM (AUC = 0.69; P = 0.422). For the combined model, the AUC of RF model was 0.84, which was significantly higher than LR (0.64), but similar to SVM (0.80; P = 0.548). Both the combined RF and combined SVM models showed significantly higher AUCs than the radiomics models. In the external validation set, the combined RF and combined SVM models showed AUCs of 0.83 and 0.82. DATA CONCLUSION: Pathological-radiomics combined models with RF, SVM show the association of TP53 mutations and pathological-radiomics features of PCa. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Identification of prognostic and therapeutic biomarkers in type 2 papillary renal cell carcinoma.

BACKGROUND: Papillary renal cell carcinoma (PRCC) can be divided into type 1 (PRCC1) and type 2 (PRCC2) and PRCC2 share a more invasive phenotype and worse prognosis. This study aims to identify potential prognostic and therapeutic biomarkers in PRCC2. METHODS: A cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes (DEGs) were screened and potential biomarkers were explored by using Kaplan-Meier method and cox regression analysis. Functional enrichment analysis was utilized to evaluate the potential biological functions. Tumor infiltrating immune cells were estimated by CIBERSORT algorithm. Ninety-two PRCC2 samples from Fudan University Shanghai Cancer Center were obtained, and immunostaining was performed to validate prognostic and therapeutic significance of the potential biomarker. RESULTS: PRCC2 has worse overall survival and shares distinct molecular characteristics from PRCC1. There was significant higher expression level of Targeting protein for Xklp2 (TPX2) in PRCC2 compared with normal tissues. Higher expression level of TPX2 was significantly associated with worse overall survival in PRCC2 and kinesin family genes expression were found significantly elevated in high risk PRCC2. Abundance of tumor infiltrating M1 macrophage was significantly higher in PRCC2 and it was also associated with worse overall survival. In the FUSCC cohort, higher TPX2 expression was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%). CONCLUSIONS: TPX2 was a prognostic and therapeutic biomarker in PRCC2. Higher abundance of tumor infiltrating M1 macrophage was significantly associated with worse overall survival in PRCC2. mTOR inhibitors may have good efficacy in patients with high-risk PRCC2.

Differentiation of Prostate Cancer and Stromal Hyperplasia in the Transition Zone With Monoexponential, Stretched-Exponential Diffusion-Weighted Imaging and Diffusion Kurtosis Imaging in a Reduced Number of b Values: Correlation With Whole-Mount Pathology.

OBJECTIVES: The aims of the study were to explore the feasibility of generating a monoexponential model (MEM), stretched-exponential model (SEM) based diffusion-weighted imaging (DWI), and diffusion kurtosis imaging (DKI) by applying the same set of reduced b values and to compare their effectiveness in distinguishing prostate cancer from stromal hyperplasia (SH) in the transition zone (TZ) area. METHODS: An analysis of 75 patients who underwent preoperative DWI ( b values of 0, 700, 1400, 2000 s/mm 2 ) was performed. All lesions were localized on magnetic resonance images according to whole-mount histopathological correlations. The apparent diffusion coefficient (ADC), water molecular diffusion heterogeneity index (α), distributed diffusion coefficient (DDC), mean diffusivity (MD), and mean kurtosis (MK) values were calculated and compared between the TZ cancer and SH groups. Receiver operating characteristic analysis and areas under the receiver operating characteristic curve (AUCs) were carried out for all parameters. RESULTS: Compared with the SH group, the ADC, DDC, α, and MD values of the TZ cancer group were significantly reduced, while the MK value was significantly increased (all P < 0.05). The AUCs of the ADC, DDC, α, MD, and MK were 0.828, 0.801, 0.813, 0.822, and 0.882, respectively. The AUC of MK was significantly higher than that of the other parameters (all P < 0.05). CONCLUSIONS: When using the reduced b -value set, all parameters from MEM, SEM, based DWI, and DKI can effectively distinguish TZ cancer from SH. Among them, DKI demonstrated potential clinical superiority over the others in TZ cancer diagnosis.

Prevalence of comprehensive DNA damage repair gene germline mutations in Chinese prostate cancer patients.

Germline DNA damage repair (DDR) deficiency has been associated with increased cancer risk, poor prognosis and therapeutic opportunity for prostate cancer (PCa) patients. However, the landscape of germline mutations in PCa covering comprehensive DDR genes has not been reported. We performed whole-exome sequencing in 246 patients who meet the National Cancer Center Network guidelines for genetic testing and analyzed variants in 276 DDR genes, which was from the Cancer Genome Atlas. A total of 79 deleterious germline alterations in 60 DDR genes were identified in 31% (76/246) patients. Mutations were found in nine DDR pathways, including 11.8% men in homologous recombination repair (HR) pathways, 2.4% men in mismatch repair (MMR) pathway and 16.7% (41/246) patients in non-HR/MMR pathways. In HRR and MMR pathways, mutations were mostly identified in BRCA2 (5.3%), HFM1 (0.8%), ZSWIM7 (0.8%), MSH2 (0.8%) and MSH3 (0.8%). When compared with the cancer-free cohort, POLN and POLG conferred high risk to PCa with odds ratio 6.9 and 20.5, respectively. We provided a comprehensive view of germline DDR gene mutations in PCa patients. We also identified two potential PCa predisposition genes: POLN and POLG, which have not been reported in the Western population, confirming the necessity of customizing a multigene panel for Chinese PCa patients.

Identification of a methylation panel aid in risk stratification in node-positive penile squamous cell carcinoma.

Molecular prognostic factors for individualized treatment of squamous cell carcinoma (SCC) are poorly defined. Our study developed and validated a novel molecular tools aid in preinguinal and postinguinal lymphadenectomy risk stratification in node-positive penile SCC. Patients with node-positive penile SCC who underwent inguinal or ilioinguinal lymphadenectomy were divided into three cohorts: a discovery set, a development set and a validation set. The local ethics committee approved the study. The primary endpoint was cancer-specific survival (CSS). At the discovery stage, 17 CpG sites were significantly associated with CSS. In the development set, we constructed a 3-CpG-based prognostic score for survival prediction. The hazard ratio (HR) of the panel (dichotomized using the optimal cutoff) was 5.8 in the multivariate analyses (P < .001). The addition of the methylation score significantly improved the pN-stage C-index from 0.70 to 0.79 (incremental C = 0.09, P < .001). In the validation set, the methylation panel showed a HR of 9.9 in the multivariate analyses. The addition of the molecular marker improved the pN-stage C-index from 0.69 to 0.78 (incremental C = 0.09, P < .001). The methylation score remarkably separated survival curves in different pN stages, which indicate that the tool can be applied to tailor the treatment in both preinguinal and postinguinal lymphadenectomy settings. We developed and validated a prognostic methylation panel for node-positive penile SCC. The tool may aid in the risk stratification of the population with heterogeneous outcomes and needs prospective validation. Patients in high-risk group may benefit from more aggressive therapy or clinical trials.

Inherited Mutations in Chinese Men With Prostate Cancer.

BACKGROUND: Although China accounts for 7.8% of worldwide new prostate cancer (PCa) cases and 14.5% of new deaths according to GLOBOCAN 2020, the risk of PCa associated with germline mutations is poorly defined, hampered in part by lack of nationwide evidence. Here, we sequenced 19 PCa predisposition genes in 1,836 Chinese patients with PCa and estimated disease risk associated with inherited mutations. PATIENTS AND METHODS: Patients were recruited from 4 tertiary cancer centers (n=1,160) and a commercial laboratory (n=676). Germline DNA was sequenced using a multigene panel, and pathogenic/likely pathogenic (P/LP) mutation frequencies in patients with PCa were compared with populations from the gnomAD (Genome Aggregation Database) and ChinaMAP (China Metabolic Analytics Project) databases. Clinical characteristics and progression-free survival were assessed by mutation status. RESULTS: Of 1,160 patients from hospitals, 89.7% had Gleason scores ≥8, and 65.6% had metastases. P/LP mutations were identified in 8.49% of Chinese patients with PCa. Association with PCa risk was significant for mutations in ATM (odds ratio [OR], 5.9; 95% CI, 3.1-11.1), BRCA2 (OR, 15.3; 95% CI, 10.0-23.2), MSH2 (OR, 15.8; 95% CI, 4.2-59.6), and PALB2 (OR, 5.9; 95% CI, 2.7-13.2). Compared with those without mutations, patients with mutations in ATM, BRCA2, MSH2, or PALB2 showed a poor outcome with treatment using androgen deprivation therapy and abiraterone (hazard ratio, 2.19 [95% CI, 1.34-3.58] and 2.47 [95% CI, 1.23-4.96], respectively) but similar benefit from docetaxel. CONCLUSIONS: The present multicenter study confirmed that a significant proportion of Chinese patients with PCa had inherited mutations and identified predisposition genes in this underreported ethnicity. These data provide empirical evidence for precision prevention and prognostic estimation in Chinese patients with PCa.

Prognostic Value of Germline DNA Repair Gene Mutations in De Novo Metastatic and Castration-Sensitive Prostate Cancer.

BACKGROUND: Germline DNA damage repair gene mutations (gDDRm) have been found in approximately 12% of patients with metastatic prostate cancer (mPCa). Previous studies of the clinical impact of gDDRm have mainly been in the setting of metastatic castration-resistant prostate cancer (mCRPC). This study aimed to determine the prognostic value of gDDRm in de novo metastatic and castration-sensitive prostate cancer (mCSPC). MATERIALS AND METHODS: We retrospectively collected the records of 139 consecutive men with de novo mCSPC who initially received systemic therapies following guidelines. This included 128 patients who underwent genetic testing at our center and 11 patients referred to our center after being identified as gDDRm carriers. Time to mCRPC was collected. Kaplan-Meier and log-rank analysis were used to analyze the association between gDDRm and clinical outcomes. Survival outcomes were adjusted using multivariable Cox regression models. RESULTS: Of the 139 patients with de novo mCSPC, 28 gDDRm carriers were identified. Median time progressing to mCRPC was significantly shorter in patients carrying gDDRm than in those without mutations (8.3 vs 13.2 months; hazard ratio [HR], 2.37; p < .001). Moreover, median progression time was almost halved in BRCA2 carriers (6.3 vs. 13.2 months; HR, 3.73; p < .001). Subgroup analysis revealed that the presence of gDDRm indicated poor therapy response regardless of disease volume and prostate-specific antigen nadir within the first 7 months. Presence of gDDRm remained independently associated with increased risk of progression to mCRPC in multivariate analysis (adjusted HR, 1.98; p = .006). CONCLUSION: Our study suggested that positive gDDRm status predicted rapid progression to castration resistance in patients with de novo mCSPC. We propose identifying gDDRm status at the time of diagnosis for mCSPC patients, considering it is the first step of tailoring individualized treatment. In addition, DNA repair genes were a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and our results call for more frontline targeted therapy trials in gDDRm carriers to prolong the progression time. IMPLICATIONS FOR PRACTICE: Results of this study suggested that positive germline DNA damage repair gene mutation (gDDRm) status predicted earlier progression to castration resistance in patients with de novo metastatic and castration-sensitive prostate cancer (mCSPC). These findings indicated the importance of intense therapy for some subgroups of mCSPC, especially for mCSPC harboring gDDRm with low-volume disease. Moreover, gDDRm was a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and these findings call for more molecular marker driven trials moving to the mTNPC setting.

Germline mutations of renal cancer predisposition genes and clinical relevance in Chinese patients with sporadic, early-onset disease.

BACKGROUND: An inherited susceptibility to renal cancers is associated with multiple predisposing genes, but most screening tests are limited to patients with a family history. Next-generation sequencing (NGS)-based multigene panels provide an efficient and adaptable tool for investigating pathogenic germline mutations on a larger scale. This study investigated the frequency of pathogenic germline mutations in renal cancer predisposition genes in patients with sporadic, early-onset disease. METHODS: An NGS-based panel of 23 known and potential renal cancer predisposition genes was used to analyze germline mutations in 190 unrelated Chinese patients under the age of 45 years who presented with renal tumors. The detected variants were filtered for pathogenicity, and then their frequencies were calculated and correlated with clinical features. Germline variants of the fumarate hydratase (FH) and BRCA1-associated protein 1 (BAP1) genes were comprehensively analyzed because of their aggressive potential. RESULTS: In total, 18 patients (9.5%) had germline mutations in 10 genes. Twelve of these 18 patients had alterations in renal cancer predisposition genes (6.3%), and 6 patients had mutations in potential predisposition genes such as BRCA1/2. Notably, pathogenic mutation carriers had a significant family history in second-degree relatives in comparison with those without pathogenic mutations (P < .001). Variants of unknown clinical significance in FH and BAP1 demonstrated evidence of additional somatic loss in tumors. CONCLUSIONS: In patients with early-onset disease, a multigene panel identified a high pathogenic germline mutation rate in renal cancer predisposition genes. This study emphasizes the importance of screening patients with early-onset disease for mutations in cancer predisposition genes. Germline screening should be encouraged in early-onset patients to provide personalized medicine and improve patient outcomes.

Differentiation of Gastric Schwannoma From Gastric Gastrointestinal Stromal Tumor With Dual-Phase Contrast-Enhanced Computed Tomography.

OBJECTIVE: To identify the computed tomographic features to differentiate gastric schwannoma from gastric gastrointestinal stromal tumor. METHODS: Computed tomographic images of 103 pathologically confirmed patients with gastric schwannoma (n = 23) or gastric gastrointestinal stromal tumor (n = 80) were retrospectively studied. Sex, morphology, location, border, growth pattern, enhancement pattern, necrosis, calcification, ulceration, and perigastric lymph nodes were analyzed. Age, short diameter, long diameter, and the degree of enhancement were measured. Statistical analyses were performed, and receiver operating characteristic curve, sensitivity, and specificity values were analyzed. RESULTS: Female, age younger than 57.5 years, round or ovoid morphology, extraluminal growth, homogeneous enhancement, lack of necrosis, presence of perigastric lymph nodes, and an enhancement degree of less than 15.4 Hounsfield units in the arterial phase were significant variables for differentiating gastric schwannoma from gastric gastrointestinal stromal tumor (P < 0.05). CONCLUSIONS: Dual-phase contrast-enhanced computed tomography can help to differentiate gastric schwannoma from gastric gastrointestinal stromal tumor.

Smoking increased the risk of prostate cancer with grade group ≥ 4 and intraductal carcinoma in a prospective biopsy cohort.

OBJECTIVE: To investigate the association between smoking and different prostate cancer (PCa) pathological subtypes incidence in Chinese men. PATIENTS AND METHODS: We prospectively included 1795 patients who underwent prostate biopsies in one tertiary center between March 2013 and April 2016. Clinical data and biopsy outcomes were collected. Logistic regression was used to evaluate the association between cigarette smoking and PCa incidence. RESULTS: A total of 737 men, 480 men and 58 men were diagnosed with PCa, high-grade PCa (HGPCa, grade group ≥ 4 as accepted by the 2014 ISUP) and intraductal carcinoma of the prostate (IDC-P), respectively. Current smokers had a significantly higher risk of HGPCa than never smokers (OR = 1.89, 95%CI: 1.44-2.48). No such association was observed for low-grade disease and cigarette smoking (OR = 0.84, 95%CI: 0.61-1.16). In a sub-analysis, men who had smoked longer than 30 years had a higher risk of HGPCa, compared with men who had smoked fewer than 30 years (OR = 1.50, 95%CI: 1.09-2.06). Current smokers were more likely to develop IDC-P than never smokers (OR = 2.29, 95%CI: 1.14-4.59). CONCLUSION: Among men in this Chinese biopsy cohort, current smoking was associated with highly malignant PCa incidence, such as HGPCa and IDC-P. The duration of smoking may be associated with HGPCa.

Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement.

Xp11 translocation renal cell carcinomas are characterized by several different translocations involving the TFE3 gene. Tumors with different specific gene fusions may have different clinicopathological manifestations. Fewer than 10 renal cell carcinoma cases with NONO-TFE3 have been described. Here we examined eight additional cases of this rare tumor using clinicopathological, immunohistochemical, and molecular analyses. The male-to-female ratio of our study cohort was 1:1, and the median age was 30 years. The most distinctive feature of the tumors was that they exhibited glandular/tubular or papillary architecture that was lined with small-to-medium cuboidal to high columnar cells with indistinct cell borders and an abundantly clear or flocculent eosinophilic cytoplasm. The nuclei were oriented toward the luminal surface and were round and uniform in shape, which resulted in the appearance of secretory endometrioid subnuclear vacuolization. The distinct glandular/tubular or papillary architecture was often accompanied by sheets of epithelial cells that presented a biphasic pattern. Immunohistochemically, all eight cases demonstrated moderate (2+) or strong (3+) positive staining for TFE3, CD10, RCC marker, and PAX-8. None of the tumors were immunoreactive for CK7, Cathepsin K, Melan-A, HMB45, Ksp-cadherin, Vimentin, CA9, 34ßE12 or CD117. NONO-TFE3 fusion transcripts were identified in six cases by RT-PCR. All eight cases showed equivocal split signals with a distance of nearly 2 signal diameters and sometimes had false-negative results. Furthermore, we developed a fluorescence in situ hybridization (FISH) assay to serve as an adjunct diagnostic tool for the detection of the NONO-TFE3 fusion gene and used this method to detect the fusion gene in all eight cases. Long-term follow-up (range, 10-102 months) was available for 7 patients. All 7 patients were alive with no evidence of recurrent disease or disease progression after their initial resection. This report adds to the known data regarding NONO-TFE3 renal cell carcinoma.

Prognostic value of pathological features of primary lesion in metastatic renal cell carcinoma treated with sorafenib.

AIM: This study aimed to investigate whether the pathological features of primary lesions show additional prognostic value in patients with metastatic renal cell carcinoma who are treated with sorafenib. PATIENTS & METHODS: A consecutive cohort of 284 patients was included from Fudan University Shanghai Cancer Center between 2007 and 2013. The association between survival and pathological features of primary tumors was assessed using the Cox proportional hazards model. The incremental value of prognostication was evaluated. RESULTS: We found that the pathological features of primary lesions provided added prognostic value over the Memorial Sloan-Kettering Cancer Center model in patients with metastatic renal cell carcinoma who were treated with sorafenib. CONCLUSION: Addition of a pathological score in the clinical setting could better identify patients at risk of poor survival.

[Clear cell papillary renal cell carcinoma: a distinct low-grade renal tumour].

OBJECTIVE: To study the clinicopathologic features of clear cell papillary renal cell carcinoma (CCPRCC). METHODS: The clinical, morphologic and immunohistochemical characteristics of 6 cases of CCPRCC were reviewed, with analysis of follow-up data. RESULTS: There were altogether 3 men and 3 women. The mean age of patients was 56 years. The size of tumors ranged from 1.0 to 4.5 cm in greatest dimension. They had solid or solid-cystic cut surface. Histologically, the tumors were encapsulated and showed several morphologic patterns, with tubules, papillae, acini, interconnecting ribbons and macro/microcysts lined by single layer of cells with clear or small amount of eosinophilic cytoplasm and low-grade nuclei (corresponding to Fuhrman grade 1 or 2). Mitotic figures were rarely seen. Characteristically, there was linear arrangement of the nuclei away from the basement membrane, conferring an appearance similar to that of endometrial glands in early secretory phase. Tubules and cysts contained serosanguineous fluid or colloid-like secretion were identified. No foamy histiocytes, psammomatous calcifications or hemosiderin was present in the papillary areas. Two of the tumors showed focal or extensive angioleiomyoma/leiomyoma-like components. No coagulative necrosis, sarcomatoid dedifferentiation, nor microscopic vascular invasion was observed. Immunohistochemically, all tumors showed strong co-expression of CK7 and CA9 (with characteristic "goblet" staining pattern). The staining for EMA, CK (AE1/AE3), vimentin, CK8, CK18, CK19 and PAX-8 were also positive in all cases. Ki-67 was expressed in less than or about 5% of the tumor cell nuclei. The staining for CD10, P504S, CD117, TFE3 and TFEB was negative. Follow-up data were available in all patients, with mean duration of 14 months (range = 7 to 27 months). All of the patients were disease-free after operation. CONCLUSION: CCPRCC is a special type of low-grade renal neoplasm with characteristic histopathologic and immunohistochemical features. It needs to be distinguished from clear cell renal cell carcinoma or papillary renal cell carcinoma.

Downregulation of DAB2IP results in cell proliferation and invasion and contributes to unfavorable outcomes in bladder cancer.

The DOC-2/DAB2 interactive protein (DAB2IP) is a member of the Ras GTPase-activating protein family. It has been shown to be often downregulated and a poor prognostic factor in several human malignancies. In this study, we analyzed the clinicopathological features and outcomes of DAB2IP expression in 135 patients with urothelial carcinoma of the bladder (UCB) treated by radical cystectomy plus bilateral lymph node dissection, and evaluated the effect of DAB2IP knockdown in vitro using the MTT method, colony formation assay, cell cycle assay, and cell migration and invasive assay. We found low expression of DAB2IP was significantly associated with high pathological stage (P = 0.002), high pathological grade (P = 0.02), tumor size more than 3 cm (P = 0.04), and presence of histological variants (P = 0.01). DAB2IP was an independent prognostic factor of disease recurrence (hazard ratio, 2.67; P = 0.034) and cancer-specific survival (hazard ratio, 2.79; P = 0.038). Knockdown of DAB2IP could promote cell proliferation, migration, and invasion. Downregulation of DAB2IP could activate the ERK and Akt pathways and was correlated with the expression of epithelial-mesenchymal transition markers, such as E-cadherin and vimentin. In conclusion, downregulation of DAB2IP is associated with features of biologically aggressive UCB and results in cell proliferation, migration, and invasion of bladder cancer. DAB2IP may serve as a promising biomarker in patients with UCB treated by radical cystectomy and bilateral lymph node dissection.

Testicular desmoplastic small round cell tumor: a case report and review of literature.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an uncommon and highly aggressive malignancy with undetermined histogenesis and poor prognosis. To date, no case of testicular DSRCT has been reported in the literature. CASE: A 42-year-old Chinese man presented with painless swelling of his left testis and a painless palpable nodule in his left inguinal region. Computed tomography showed a solid mass in the left testis and multiple metastases in the body. Laboratory tests gave no abnormal results. Left radical orchiectomy was performed, and histopathological and molecular pathological examination showed typical features of DSRCT. Six cycles of chemotherapy were administrated after the operation, leading to partial remission. Postoperative 9-month follow-up indicated no progression.