Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline inactivation of the folliculin gene (FLCN). Approximately 25

A 70-year-old man with a 9.1 cm infiltrative right renal mass involving the inferior vena cava (IVC), with retroperitoneal lymphadenopathy and pulmonary nodules, received 27 months of lenvatinib and 6 months of pembrolizumab after biopsy confirmed metastatic clear cell renal cell carcinoma (ccRCC). Restaging imaging demonstrated a reduction of the renal mass to 3.6 cm, resolution of IVC thrombus, lymphadenopathy, and pulmonary metastases. He underwent right robotic cytoreductive radical nephrectomy. Final pathology was ypT0Nx. To our knowledge, this is the first reported case of complete pathologic and radiographic response of metastatic ccRCC predominantly on lenvatinib, with brief duration of pembrolizumab.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is defined by mutations in SDH subunits (A, B, C, or D) and is associated with hereditary paraganglioma-pheochromocytoma syndrome and gastrointestinal stromal tumors (GISTs) in some patients. This multi-institutional study analyzed 5 SDHA-deficient RCCs using morphology, immunohistochemistry (IHC), and next-generation sequencing (NGS). Patients had a median age of 40 years with male predominance (4:1). Initially, tumors were diagnosed as SDHA-deficient RCC (1), collecting duct carcinoma (1), or high-grade RCC, NOS (3). NGS subsequently identified 4 tumors as SDHA-deficient RCC. Common histologic features included papillary (100%) and nested (100%) architecture, solid growth (80%), eosinophilic/flocculent cytoplasm (100%), cytoplasmic vacuoles with inclusions (80%), and nuclear grooves (20%). Four of 5 tumors were high-grade (ISUP/WHO grade 3) with desmoplastic stroma and occasional inflammation. All tumors showed loss of SDHB expression (5/5), while SDHA expression was lost in 4/5, demonstrating that SDHA IHC may be preserved despite SDHA mutation. NGS identified SDHA mutations in four tumors. During follow-up, 2 of 4 patients developed metastases within 14 to 34 months, whereas the remaining 2 had no spread after 11 to 19 months. SDHA-deficient RCC displays a spectrum from classic SDHB-deficient RCC morphology to heterogeneous high-grade tumors. It should be considered in high-grade RCCs, particularly RCC NOS with papillary or collecting duct carcinoma-like morphology and vacuolated tumor cells. NGS is recommended, especially when SDHB loss is detected, as SDHA IHC may be retained. Unlike most SDHB-deficient RCCs, SDHA-deficient RCC appears more aggressive, with increased metastatic risk and poorer prognosis.

INTRODUCTION AND OBJECTIVE:To assess outcomes and complications of partial gland cryoablation (sCRYO) and high-intensity focused ultrasound (sHIFU) for localized radio-recurrent prostate cancer (CaP). METHODS:Fifty-one consecutive patients who underwent focal therapy with curative intent for localized radio-recurrent CaP (sCRYO or sHIFU) between 2011 and 2023 were included (IRB# HS-17-00749). Patients were monitored by prostate biopsy (PBx) 6 to 12 months and every 2 year thereafter. The primary endpoint was treatment failure (TF) defined as any radical treatment, systemic therapy, metastases, or CaP-specific mortality. Secondary endpoints were survival-free from (1) biochemical failure (BF, PSA nadir + 2 ng/ml); (2) clinically significant prostate cancer (CSCaP) on follow-up PBx, and (3) radical treatment. Functional outcomes were assessed by the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF-5). The 90-day Clavien-Dindo complications are recorded. Statistically significant if P < 0.05. RESULTS:A total of 51 patients with radio-recurrent CaP were included. Of these, 41 and 10 underwent sCRYO and sHIFU, respectively. Median baseline characteristics were as follows: age 71 years, PSA 4.48 ng/dl, prostate volume 26 cc. PSA density (PSAD) 0.15 ng/ml2. The short-term free survival rates for TF, CSCaP, Biochemical failure, and radical treatment were 95%, 84%, 76%, and 98%, respectively. The median differences from pre to post-treatment IPSS and IIEF-5 were 0 and 1, respectively. A total of 48 (95%) patients remained continent at follow-up. The 90-day complication rate was 4%. CONCLUSION:Partial gland cryotherapy and HIFU for radio-recurrent localized nonmetastatic CaP provide acceptable 2-year oncologic and functional outcomes, with low perioperative complications.

Clear cell adenocarcinoma of the urinary tract (CCA-UT) is a rare, potentially aggressive tumor with very limited information regarding its clinicopathologic characteristics and molecular alterations. This study aimed to elucidate the clinicopathologic features and molecular landscape of one of the largest cohorts (35 cases) of this tumor, to identify genomic alterations and potential therapeutic targets. Seventy-nine percent of the patients were women, with a median age of 61 years. The urethra was the most common site (18; 51%), and all cases were ≥pT2 (pT2:15; pT3:11; pT4:8). Twenty-nine percent of the patients died of their disease on follow-up. On whole-exome sequencing, pathogenic/oncogenic alterations were identified in 91% (32/35) cases. These alterations, most frequently involved chromatin modifiers (66% cases), including ATRX , KMT2C , ARID1A , and ARID1B . Other frequently mutated genes included ATM , NF1 , and ERBB2 . Ninety-seven percent (34/35) of cases were microsatellite stable, and tumor mutational burden (TMB) was >10 mut/Mb in 9% (3/35) of cases. Five cases were homologous recombinant-deficient on ScarHRD analysis, and 3 cases showed BRCA mutations. Recurrent copy number loss events in Chr 1(p36.33-p35.3) were the most common copy number alterations (80%; n=28 cases). RNA-sequencing data analysis revealed numerous differentially expressed genes and enrichment of the epithelial-to-mesenchymal transition gene signature in individual samples. However, there was no statistical significance in the progression-free survival between cases with epithelial and mesenchymal phenotypes. CCA-UT are aggressive tumors with a heterogeneous molecular profile, underscoring the role of molecular analysis in identifying potential therapeutic options for the treatment of this pernicious tumor.

Renal tumor classification has moved quickly since the 2022 edition of WHO Classification of Tumours, because now routine molecular testing and pathway-based immunohistochemistry allow us to separate lesions that have a similar morphology but are biologically and clinically distinct. Herein, we highlight entities that have come into clearer diagnostic focus and are increasingly ready for routine practice and incorporation into future classification systems, including low-grade-oncocytic-tumor (LOT), eosinophilic-vacuolated-tumor (EVT), renal cell carcinoma with fibromyomatous-stroma (RCC FMS) (now best approached as at least two molecular subsets, ELOC-mutated and TSC/MTOR-altered, with a residual “not-otherwise-specified” category when molecular confirmation is unavailable), FLCN-mutated oncocytic renal neoplasms, the low-grade-like phenotype of FH-deficient RCC, and biphasic hyalinizing psammomatous RCC (BHPRCC). We also include select WHO-2022 recognized tumor types that have undergone important recent scholarship. A central theme is that “low grade eosinophilic” morphology is not a single bucket but instead reflects distinct driver pathways with different implications for prognosis, syndromic association, and therapy selection. Our goal is not to promote new nomenclature for its own sake, but to provide a practical framework that busy pathologists can use to link morphology with the most informative ancillary tests and to recognize when an apparently indolent tumor has broader clinical significance.

Clear cell renal cell carcinoma (ccRCC) prognosis is guided by a tumor’s pathological features. While radiomics shows promise for non-invasive tumor characterization, it remains unclear whether incorporating the peritumoral region and leveraging multiphase CT imaging improves model performance beyond standard tumor-region analysis. This study aimed to determine whether radiomic features derived from the peritumoral area in standard four-phase CT protocol improve the prediction of ccRCC stage, grade, and aggressiveness compared to intratumoral features alone. A retrospective cohort of 250 patients with ccRCC was analyzed. Using tumor and 5-mm peritumoral regions on four-phase CT, 1874 radiomic features were extracted per region per phase. Elastic Net and Random Forest models were trained with tenfold cross-validation to predict binarized stage, grade, and aggressiveness outcomes using three feature sets: tumor region, peritumoral region, and a combined region including both the tumor and peritumoral regions. Models using only tumor-region features consistently outperformed those using the peritumoral and combined regions. The best tumor-region model achieved area under the receiver operating characteristic curve (AUC) values of 0.875 for stage, 0.697 for grade, and 0.915 for aggressiveness. Multiphase analysis provided no benefit over a single-phase approach, with the nephrographic phase alone yielding equivalent or superior performance to multiphase models across all outcomes. A simplified radiomic approach using features from the tumor region in the nephrographic phase alone provides optimal performance for predicting key ccRCC characteristics. The added complexity of peritumoral and multiphase analysis did not enhance predictive accuracy, potentially streamlining future ccRCC radiomic research.

ONECUT2 is a lineage plasticity driver and therapeutic target in aggressive prostate cancer (PCa). This study investigated whether ONECUT2 gene-body DNA methylation regulates its expression and assessed its potential as a biomarker in clinical specimens. We analyzed associations between ONECUT2 gene-body methylation, expression, and patient survival across multiple datasets. The effect of DNA methylation on ONECUT2 expression was tested in prostate cancer cell lines using a DNA methyltransferase inhibitor (DNMTi). Validation was further performed in needle biopsy samples by targeted bisulfite sequencing for DNA methylation and RT-PCR for gene expression. ONECUT2 expression strongly correlated with gene-body DNA methylation and patient survival in multiple datasets. DNMTi treatment confirmed this relationship in prostate cancer cells. In 208 biopsies from prostate cancer patients, hypermethylation of gene-body of ONECUT2 was linked to higher ONECUT2 expression and effectively distinguished tumor from adjacent normal tissue (p < 0.001 and AUC = 0.86). It also predicted aggressive features, including higher Gleason score (p = 0.01 and AUC = 0.68), advanced T stage (p = 0.04 and AUC = 0.65), seminal vesicle invasion (p = 0.0024 and AUC = 0.76), and lymph node involvement (p = 0.0005 and AUC = 0.80). Assessing ONECUT2 gene-body methylation in biopsies may serve as a surrogate for ONECUT2 expression and provide predictive insights into disease progression before surgery. Furthermore, suppressing ONECUT2 through DNMTi treatment represents a potential therapeutic strategy for aggressive PCa.

Clear cell adenocarcinoma of the urinary tract (CCA-UT) is a rare, potentially aggressive tumor with very limited information regarding its clinicopathologic characteristics and molecular alterations. This study aimed to elucidate the clinicopathologic features and molecular landscape of one of the largest cohorts (35 cases) of this tumor, to identify genomic alterations and potential therapeutic targets. Seventy-nine percent of the patients were women, with a median age of 61 years. The urethra was the most common site (18; 51%), and all cases were ≥pT2 (pT2:15; pT3:11; pT4:8). Twenty-nine percent of the patients died of their disease on follow-up. On whole-exome sequencing, pathogenic/oncogenic alterations were identified in 91% (32/35) cases. These alterations, most frequently involved chromatin modifiers (66% cases), including ATRX , KMT2C , ARID1A , and ARID1B . Other frequently mutated genes included ATM , NF1 , and ERBB2 . Ninety-seven percent (34/35) of cases were microsatellite stable, and tumor mutational burden (TMB) was >10 mut/Mb in 9% (3/35) of cases. Five cases were homologous recombinant-deficient on ScarHRD analysis, and 3 cases showed BRCA mutations. Recurrent copy number loss events in Chr 1(p36.33-p35.3) were the most common copy number alterations (80%; n=28 cases). RNA-sequencing data analysis revealed numerous differentially expressed genes and enrichment of the epithelial-to-mesenchymal transition gene signature in individual samples. However, there was no statistical significance in the progression-free survival between cases with epithelial and mesenchymal phenotypes. CCA-UT are aggressive tumors with a heterogeneous molecular profile, underscoring the role of molecular analysis in identifying potential therapeutic options for the treatment of this pernicious tumor.

PURPOSE:To assess factors associated with patients' self-assessed pain scores during prostate biopsy (PBx) performed exclusively under local anesthesia (LA). MATERIALS AND METHODS:Consecutive patients who underwent MRI followed by a transperineal (TP) or transrectal (TR) PBx under LA were prospectively assessed. Race and ethnicity were self-reported according to NIH standards. Socioeconomic status was assessed using the Distressed Community Index (DCI). Pain was evaluated with a visual analog scale (0-10) after the procedure. Univariable and multivariable linear regression analyses were performed to correlate clinical parameters related to pain. RESULTS:A total of 419 patients underwent TP (77%) or TR (23%) PBx. Overall, 14% of patients were Asian, 5% Black, 17% Latino, 12% Others, and 53% White. Of the cohort, 20% of Black and 27% of Latino patients were most distressed (DCI 80-100) compared with 4% of Asian, 9% of Other, and 5% of White patients (p<0.001). The median (IQR) self-assessed pain levels were higher for Black 5 (2-5) and Latino 4 (3-5) compared to Asian 3 (2-4), Other 3 (2-5), and White 3 (2-4) patients (p=0.01). On multivariable analysis, younger patients, Black or Latino patients, and the number of lesions on MRI were independent predictors for pain levels. CONCLUSIONS:PBx under LA alone are generally well tolerated; however, there is a subset of patients who experience more pain, including Black and Latino, younger patients, and those with more MRI suspicious lesions. Discussion of these pain risk factors is important for patients when choosing to have a biopsy performed under LA versus sedation.

OBJECTIVES:To develop a novel transparent and lightweight machine learning model, the Green Learning (GL), for automated prostate segmentation (PS) and clinically significant prostate cancer (csPCa) detection on magnetic resonance imaging (MRI). PATIENTS AND METHODS:Men who underwent 3-T MRI and prostate biopsy (PBx) were identified. MRI was acquired and interpreted according to the Prostate Imaging-Reporting and Data System (PI-RADS), version 2 or 2.1. The GL was created to automate PS and csPCa detection on biparametric MRI. The performance was compared to the standard-of-care radiologists using PI-RADS, and a conventional deep learning (DL) U-Net model as benchmarking. The PS performance was evaluated by the Dice similarity coefficient (DSC). The area under the curve (AUC) for patient-level csPCa detection was assessed. Model size and computational workload, measured by floating point operations (FLOPs), were reported. RESULTS:A total of 602 MRIs were randomly divided for training (N = 483) and testing (N = 119). Overall, 224 patients had csPCa on PBx. The median DSC for PS was higher for GL than U-Net (0.91 vs 0.88, P < 0.001). The AUC for csPCa detection of GL was similar to PI-RADS (0.75 vs 0.76, P = 0.8) and U-Net (vs 0.74, P = 0.3). A combination of GL and PI-RADS showed a higher AUC of 0.81 than PI-RADS alone (P = 0.02). Compared with U-Net, the GL had smaller magnitude parameters (1.21× 106 vs 177× 106) and less computational workload (9.8× 109 vs 1027× 109 FLOPs). CONCLUSION:A novel GL model fully automatically detects csPCa on prostate biparametric MRI with comparable performance to PI-RADS and DL. Combined with PI-RADS, GL significantly improves csPCa detection.

Urinary bladder lymphomas are rare and may mimic urothelial carcinoma by morphology or unexpected expression of putative "urothelial" markers such as p63/ GATA3, the latter of which has not been thoroughly explored. Herein, we evaluate the clinicopathologic features of bladder lymphomas and assess the incidence of p63/GATA3 expression. A multi-institutional review identified 28 bladder lymphomas. Slides were re-reviewed for lymphoma subtype, growth pattern, urothelial colonization, and concurrent urothelial carcinoma. Clinical features recorded including age, presentation, procedure type, and cystoscopic impression. Immunohistochemistry for p63 and GATA3 was performed and semi-quantitatively scored for staining intensity and extent. The cohort included 28 tumors (mean age 71 years; male-to-female ratio = 4:3), most of which were primary bladder lymphomas (68%). Diffuse large B-cell lymphoma was the most common subtype (53% overall). A diffuse growth pattern predominated (93%), and 32% demonstrated colonization of the overlying urothelium. Concurrent urothelial carcinoma was present in 11% of tumors. By immunohistochemistry, 57% of lymphomas showed p63 positivity and 50% showed GATA3 positivity, with dual expression in 43%. p63/GATA3 expression occurred across multiple lymphoma subtypes. Staining intensity/extent was generally low to moderate but potentially misleading in specimens with sheet-like growth or urothelial colonization. Lymphomas involving the bladder frequently show morphologic and immunophenotypic overlap with urothelial carcinoma including diffuse architecture, urothelial colonization, and p63/GATA3 expression. These shared features constitute a significant diagnostic pitfall with potential therapeutic consequences. Awareness of this overlap and use of a broad immunohistochemical panel (eg, CD45, pankeratin) are essential for accurate diagnosis in unusual bladder tumors.