Untethered Microgrippers for Biopsy in the Upper Urinary Tract.

Untethered microrobots offer the possibility to perform medical interventions in anatomically complex and small regions in the body. Presently, it is necessary to access the upper urinary tract to diagnose and treat Upper Tract Urothelial Carcinoma (UTUC). Diagnostic and treatment challenges include ensuring adequate tissue sampling, accurately grading the disease, achieving completeness in endoscopic treatment, and consistently delivering medications to targeted sites. This work introduces microgrippers (µ-grippers) that are autonomously triggered by physiological temperature for biopsy in the upper urinary tract. The experiments demonstrated that µ-grippers can be deployed using standard ureteral catheters and maneuvered using an external magnetic field. The µ-grippers successfully biopsied tissue samples from ex vivo pig ureters, indicating that the thin-film bilayer springs' autonomous, physiologically triggered actuation exerts enough force to retrieve urinary tract tissue. The quality of these biopsy samples is sufficient for histopathological examination, including hematoxylin and eosin (H&E) and GATA3 immunohistochemical staining. Beyond biopsy applications, the µ-grippers' small size, wafer-scale fabrication, and multifunctionality suggest their potential for statistical sampling in the urinary tract. Experimental data and clinical reports underscore this potential through statistical simulations that compare the efficacy of µ-grippers with conventional tools, such as ureteroscopic forceps and baskets.

Novel PAX3::MAML3 fusion identified in alveolar rhabdomyosarcoma, using DNA methylation profiling to expand the genetic spectrum of "fusion-positive" cases.

Alveolar rhabdomyosarcoma (ARMS) with FOXO1 gene rearrangements is an aggressive pediatric rhabdomyosarcoma subtype that is prognostically distinct from embryonal rhabdomyosarcoma and fusion-negative ARMS. Herein, we report two cases of ARMS with PAX3::MAML3 fusions. The tumors arose in an infant and an adolescent as stage IV metastatic disease (by Children's Oncology Group staging system). Histologically, both cases were small round blue cell tumors arranged in vague nests and solid sheets that were diffusely positive for desmin and myogenin. By methylation profiling and unsupervised clustering analysis, the tumors clustered with ARMS with classic FOXO1 rearrangements and ARMS with variant PAX3::NCOA1/INO80D fusions, but not with biphenotypic sinonasal sarcoma (BSNS) with PAX3::MAML3/NCOA2/FOXO1/YAP1 fusions, nor with other small round blue cell tumors, including embryonal rhabdomyosarcoma. The differentially methylated genes between ARMS and BSNS were highly enriched in genes involved in myogenesis, and 21% of these genes overlap with target genes of the PAX3::FOXO1 fusion transcription factor. On follow-up after initiation of vincristine/actinomycin/cyclophosphamide chemotherapy, the tumors showed partial and complete clinical response, consistent with typical upfront chemotherapy responsiveness of ARMS with the classic FOXO1 rearrangement. We conclude that PAX3::MAML3 is a novel variant fusion of ARMS, which displays a methylation signature distinct from BSNS despite sharing similar PAX3 fusions. These findings highlight the utility of methylation profiling in classifying ARMS with non-canonical fusions.

Molecular imaging for non-invasive risk stratification of renal masses.

Anatomic imaging with contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) has long been the mainstay of renal mass characterization. However, those modalities are often unable to adequately characterize indeterminate, solid, enhancing renal masses - with some exceptions, such as the development of the clear-cell likelihood score on multi-parametric MRI. As such, molecular imaging approaches have gained traction as an alternative to anatomic imaging. Mitochondrial imaging with 99mTc-sestamibi single-photon emission computed tomography/CT is a cost-effective means of non-invasively identifying oncocytomas and other indolent renal masses. On the other end of the spectrum, carbonic anhydrase IX agents, most notably the monoclonal antibody girentuximab - which can be labeled with positron emission tomography radionuclides such as zirconium-89 - are effective at identifying renal masses that are likely to be aggressive clear cell renal cell carcinomas. Renal mass biopsy, which has a relatively high non-diagnostic rate and does not definitively characterize many oncocytic neoplasms, nonetheless may play an important role in any algorithm targeted to renal mass risk stratification. The combination of molecular imaging and biopsy in selected patients with other advanced imaging methods, such as artificial intelligence/machine learning and the abstraction of radiomics features, offers the optimal way forward for maximization of the information to be gained from risk stratification of indeterminate renal masses. With the proper application of those methods, inappropriately aggressive therapy for benign and indolent renal masses may be curtailed.

Imaging of Chromophobe Renal Cell Carcinoma with 99mTc-Sestamibi SPECT/CT: Considerations Regarding Risk Stratification and Histologic Reclassification.

PURPOSE: Indeterminate renal masses are increasingly incidentally found on cross-sectional imaging. 99mTc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) scans can be used to identify oncocytomas and oncocytic renal neoplasms, including a subset of chromophobe renal cell carcinomas (chRCCs), which are viewed as false-positive. PROCEDURE: Patients imaged with renal sestamibi scans between 2014 and 2023 were reviewed. Those patients with solitary tumors that were originally classified as chRCC were included in the analysis. Imaging with SPECT/CT from the liver dome down had been carried out 75 min after the administration of 925 MBq of 99mTc-sestamibi. All available H&E and immunostained slides were re-reviewed and classified according to WHO 2022 criteria. Confirmatory immunohistochemical stains were performed in tumors considered morphologically suspicious for non-chRCC entities. RESULT: A total of 18 patients with solitary tumors were included in the final analysis. 13/18 (72.2%) tumors in this cohort remained classified as chRCC, with 4/18 (22.2%) being eosinophilic-variant chRCC. The reclassified tumors (5/18 [27.8%]) included 2/18 (11.1%) low-grade oncocytic tumor (LOT), 1/18 (5.5%) eosinophilic vacuolated tumor (EVT), and 2/18 (11.1%) unclassified low-grade oncocytic neoplasms. As such, only 2/9 (22.2%) qualitatively "hot" tumors were chRCC other than eosinophilic-variant and only 1/9 (11.1%) "cold" tumors was a histology other than chRCC. CONCLUSION: Based on current histopathologic classification methods, it is likely that the "false-positive" rate of uptake on renal sestamibi scans with chRCC has been over-stated. Further study is warranted to better refine the optimal utility of renal sestamibi scans for non-invasive risk stratification of indeterminate renal masses.

Undifferentiated Round Cell Sarcoma With CRTC1::SS18 Fusion: Expanding Clinicopathologic Features of a Rare Translocation Sarcoma With Prominent Desmoplastic Stroma.

Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, 3 cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report 3 additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range, 12-42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round-to-epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor. Immunohistochemical results were nonspecific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exons 1 to 2 of CRTC1 (the 5' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3' partner gene) on chromosome 18. The clinical course was variable. Although 1 previously reported case demonstrated aggressive behavior with a fatal outcome, 2 others had a relatively indolent course with gradual growth for 6 to 7 years prior to resection. Two cases developed metastatic disease, including 1 case with bilateral lung metastasis and 1 with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aimed to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.

Adrenal cysts less than 10 cm can be safely observed.

BACKGROUND: Adrenal cysts are rare and appropriate management is unclear due to a lack of data on their natural history. Understanding adrenal cyst growth patterns would assist in clinical management. METHODS: This single-institution study included all adult patients diagnosed with simple adrenal cysts between 2004 and 2021. Baseline characteristics and outcomes of those who underwent resection (ADX) or observation (OBS) were compared using the chi-squared test, student's t-test, and Wilcoxon rank-sum test. Growth curves and sensitivity analysis were plotted for all patients who had follow-up imaging. RESULTS: We identified 77 patients with imaging-confirmed adrenal cysts. The majority were female (75.3%) and more than half were white (55.8%). One-third of patients underwent ADX, and the remaining were observed. ADX patients were younger (median age [IQR]: 55.5 y [45.0-68.2 y] vs. 44.2 y [38.7-55.0 y], p = 0.01) and more likely to be Hispanic (12% vs. 0%, p = 0.05). ADX patients presented with larger cysts (5.6 vs. 2.6 cm, p = 0.002). The median time from diagnosis to last follow-up was 1.1 y for ADX and 4.1 y for OBS. Average growth for OBS was 0.3 cm/y, while average growth for ADX was 3.9 cm/y. In ADX patients, cysts >10 cm grew significantly faster than cysts <10 cm (median growth rate 13.2 cm/y vs. 0.3 cm/y, p < 0.05). There was no adrenal malignancy diagnosis, hyperfunctionality, or observation-related complications (e.g., rupture). CONCLUSION: While size >4-6 cm has guided surgical referral for solid adrenal masses, this study demonstrates a size threshold of 10 cm, below which asymptomatic, simple adrenal cysts can safely be observed.

Current Advances in the Management of Nonurothelial Subtypes of Bladder Cancer.

Urothelial cancer (UC) is the most common histology seen in bladder tumors. The 2022 WHO classification of urinary tract tumors includes a list of less common subtypes (formerly known as variants) for invasive UC which are considered high-grade tumors. This review summarizes the most recent advances in the management of selected nonurothelial subtypes of bladder cancer: squamous cell carcinoma, small cell carcinoma, sarcomatoid urothelial carcinoma, micropapillary carcinoma, plasmacytoid carcinoma, adenocarcinoma, and urachal carcinoma. The role of neoadjuvant and adjuvant chemotherapy has not been well characterized for most of these histologies, and prospective data are extremely limited. Participation in clinical trials is recommended in advanced disease.

Benign Islet Cells Within Peripancreatic Lymph Nodes: A Potential Diagnostic Pitfall.

The presence of epithelial cells within lymph node parenchyma is typically indicative of a metastatic malignancy. However, there are rare instances in which non-neoplastic epithelial or epithelioid cells may be found within lymph nodes, either due to aberrant embryologic migration, mechanical displacement, or physiological trafficking. These can potentially lead to serious potential diagnostic pitfalls, as when such situations are encountered by surgical pathologists, there is substantial risk of overdiagnosing these as metastatic malignancy. Herein, we describe 2 cases of benign pancreatic islet cells within peripancreatic lymph nodes, and underscore the potential for misdiagnosis of this phenomenon as foci of metastatic well-differentiated neuroendocrine tumor. The benign nature of these intranodal islet cells was supported by: (1) the absence of a well-differentiated neuroendocrine tumor in the entirely submitted concomitant pancreatic resection specimen and (2) the presence of an admixture of insulin and glucagon expressing cells by immunohistochemistry in a distribution characteristic of non-neoplastic pancreatic islets. Both cases were incidental microscopic findings in pancreatic resections for intraductal papillary mucinous neoplasms that were previously biopsied and showed associated microscopic areas of fibrosis and chronic pancreatitis and thus this phenomenon may be related to mechanical displacement from prior injury and/or biopsy.

Cinematic rendering of primary adrenal lymphoma.

Primary adrenal lymphoma (PAL) is a particularly rare subset of malignant adrenal neoplasms, accounting for ∼1% of all non-Hodgkin's lymphomas. Reported outcomes of PAL, though limited, are dismal, with a 12-month survival rate of ∼20%. PAL is treated with polychemotherapy and early tissue diagnosis to allow initiation of chemotherapy is associated with improved outcomes. Early and accurate radiological diagnosis of PAL is therefore essential in improving outcomes through informing decisions to biopsy and thereby facilitating timely initiation of chemotherapy. To date, however, imaging features of PAL have not been conclusively defined, and a range of divergent imaging appearances have been reported. Cinematic rendering (CR) is a 3D post-processing technique that simulates the propagation and interaction of photons as they pass through the imaged volume. This results in the generation of more photorealistic images that may allow for more comprehensive visualization, description and interpretation of anatomical structures. This manuscript presents the first characterization of the various CR appearances of PAL in the reported literature and provides commentary on the clinical opportunities afforded by CR in the workup of these heterogenous tumors.

Cushing Syndrome Due to a Corticotropin-Releasing Hormone- and Adrenocorticotropic Hormone-Secreting Silent Pheochromocytoma.

Background/Objective: Ectopic cosecretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in silent (ie, non-catecholamine-secreting) pheochromocytoma is a rare cause of Cushing syndrome. Case Report: A 57-year-old woman rapidly developed hypercortisolism, clinically manifesting as fatigue, muscle weakness, weight gain, and worsening hypertension and biochemically characterized by hypokalemia and marked increases in the serum cortisol and plasma ACTH levels. This acute presentation suggested a diagnosis of ectopic ACTH syndrome (EAS). Imaging studies revealed a right adrenal mass that enhanced after administration of the radioisotope gallium-68-DOTATATE. Plasma metanephrines were normal in 2 separate measurements. The possibility of a silent pheochromocytoma was considered. After controlling her hypercortisolism with metyrapone and surgical preparation with alpha blockade, the patient underwent elective right adrenalectomy. Pathology revealed a pheochromocytoma that stained focally for ACTH and CRH. Postoperatively, the cortisol levels normalized, the hypothalamic-pituitary-adrenal axis was not suppressed, and clinical symptoms from hypercortisolism abated. Discussion: Patients who exhibit a rapid progression of ACTH-dependent hypercortisolism should be screened for EAS. The use of functional imaging radioisotopes (eg, gallium DOTA-peptides) improves the detection of ACTH-secreting tumors. Preoperative treatment with steroidogenesis inhibitors helps control clinical and metabolic derangements associated with severe hypercortisolemia, whereas alpha blockade prevents the onset of an adrenergic crisis. Conclusion: We present a rare case of EAS due to a silent pheochromocytoma that cosecreted ACTH and CRH. Pheochromocytoma should be considered in patients with EAS who have an adrenal mass even in the absence of excessive catecholamine secretion.

TFE3 -Rearranged PEComa/PEComa-like Neoplasms : Report of 25 New Cases Expanding the Clinicopathologic Spectrum and Highlighting its Association With Prior Exposure to Chemotherapy.

Since their original description as a distinctive neoplastic entity, ~50 TFE3 -rearranged perivascular epithelioid cell tumors (PEComas) have been reported. We herein report 25 new TFE3 -rearranged PEComas and review the published literature to further investigate their clinicopathologic spectrum. Notably, 5 of the 25 cases were associated with a prior history of chemotherapy treatment for cancer. This is in keeping with prior reports, based mainly on small case series, with overall 11% of TFE3 -rearranged PEComas being diagnosed postchemotherapy. The median age of our cohort was 38 years. Most neoplasms demonstrated characteristic features such as nested architecture, epithelioid cytology, HMB45 positive, and muscle marker negative immunophenotype. SFPQ was the most common TFE3 fusion partner present in half of the cases, followed by ASPSCR1 and NONO genes. Four of 7 cases in our cohort with meaningful follow-up presented with or developed systemic metastasis, while over half of the reported cases either recurred locally, metastasized, or caused patient death. Follow-up for the remaining cases was limited (median 18.5 months), suggesting that the prognosis may be worse. Size, mitotic activity, and necrosis were correlated with aggressive behavior. There is little evidence that treatment with MTOR inhibitors, which are beneficial against TSC -mutated PEComas, is effective against TFE3 -rearranged PEComas: only one of 6 reported cases demonstrated disease stabilization. As co-expression of melanocytic and muscle markers, a hallmark of conventional TSC -mutated PEComa is uncommon in the spectrum of TFE3 -rearranged PEComa, an alternative terminology may be more appropriate, such as " TFE3 -rearranged PEComa-like neoplasms," highlighting their distinctive morphologic features and therapeutic implications.

High-Grade, Nonsarcomatoid Chromophobe Renal Cell Carcinoma: A Series of 22 Cases With Novel Molecular Features on a Subset.

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma and typically exhibits indolent behavior, though a rare subset can exhibit high-grade morphologic features and is associated with a poor prognosis. Although there are limited data on the molecular characteristics of metastatic and sarcomatoid ChRCC, the molecular features of high-grade, nonsarcomatoid ChRCC remain unexplored. Herein, we characterize 22 cases of ChRCC with high-grade, nonsarcomatoid components. High-grade ChRCC frequently demonstrated advanced stage at diagnosis (64% ≥pT3a or N1), with regions of extrarenal extension, nodal metastases, and vascular invasion consisting solely of high-grade ChRCC morphologically. We performed spatially guided panel-based DNA sequencing on 11 cases comparing high-grade and low-grade regions (n = 22 samples). We identified recurring somatic alterations emblematic of ChRCC, including deletions of chromosomes 1, 2, 6, 10, 13, 17, and 21 in 91% (10/11) of cases and recurring mutations in TP53 (81.8%, n = 9/11) and PTEN (36.4%, n = 4/11). Notably, although PTEN and TP53 alterations were found in both high-grade and low-grade regions, private mutations were identified in 3 cases, indicating convergent evolution. Finally, we identified recurring RB1 mutations in 27% (n = 3) of high-grade regions leading to selective protein loss by immunohistochemistry not observed in adjacent low-grade regions. This finding was confirmed in The Cancer Genome Atlas cohort where 2 of 66 cases contained RB1 mutations and demonstrated unequivocal high-grade, nonsarcomatoid morphology. We also detected multiple chromosomal gains confined to the high-grade regions, consistent with imbalanced chromosome duplication. These findings broaden our understanding of the molecular pathogenesis of ChRCC and suggest that subclonal RB1 mutations can drive the evolution to high-grade, nonsarcomatoid ChRCC.

Prognostic significance of pT3a staging subclassifications in renal cell carcinoma: Not all pT3a are equal.

OBJECTIVE: To examine the prognostic significance of perinephric fat, renal sinus fat, and renal vein invasion in patients with pT3a renal cell carcinoma (RCC) by histologic type. METHODS: A population-based retrospective cohort study of patients with pT3aN0M0 RCC was performed using Surveillance, Epidemiology, and End Results (SEER) data for the years 2010 through 2019. Cox proportional hazards models were used to examine the relationship between pT3a subclassification groups and cancer-specific survival (CSS) by histological subtype (clear cell, papillary, chromophobe, and other). RESULTS: The cohort consisted of 10,170 patients with pT3a RCC, including 8,446 (83.0%) with clear cell RCC and 1,724 (17.0%) with nonclear cell RCC (nccRCC). Median follow up was 36 months. Differences in CSS by pT3a subclassification groups were observed in all histological subtypes but were most pronounced in nccRCC, specifically papillary RCC. Compared to perinephric fat (PF) invasion only, renal vein (RV) invasion (HR = 4.9, 95%CI: 2.5-9.3, P < 0.01), renal sinus fat invasion (HR = 3.0, 95%CI: 1.4-6.2), RV and PF invasion (HR = 7.5, 95%CI: 3.5-16.0), and combination of all three characteristics (HR = 4.4, 95%CI: 1.2-15.5) were associated with worse CSS in patients with papillary RCC. CONCLUSION: We examined the prognostic role of pT3a staging subclassifications in RCC by histologic subtype and observed survival differences, particularly in papillary RCC. Our findings highlight the need to refine pT3a staging criteria to help guide individualized, multimodal treatment strategies for locally advanced RCC.

Robotic-assisted cytoreductive partial nephrectomy for metastatic sarcomatoid renal cell carcinoma following dramatic response to combination immunotherapy in a young female.

Novel immune checkpoint inhibitors (ICI) have yielded remarkable response rates in metastatic renal cell carcinoma (RCC), including sarcomatoid RCC (sRCC). Here, we show the feasibility and efficacy of robotic-assisted cytoreductive partial nephrectomy (cPN) following a remarkable response to combination ICI for metastatic sRCC in a young female. A female in her late 40s presented with poor-risk, metastatic sRCC emanating from a 6.5 cm left renal mass including pulmonary involvement, retroperitoneal lymphadenopathy, and a scalp metastasis. She received 4 cycles of combination ipilimumab and nivolumab followed by maintenance nivolumab with a remarkable and durable response. Given the apparent downstaging of her primary tumor, a robotic cPN was pursued for residual ypT1aNoRo sRCC and found to be both feasible and safe with exceptional perioperative outcomes. She has since done well clinically and oncologically. Our unique case of metastatic sRCC in a young female highlights several aspects pertinent to the contemporary management of metastatic RCC including the role for cytoreductive nephrectomy in selected patients, the safety and feasibility of a nephron-sparing and minimally-invasive approach to cytoreduction after downstaging with ICI, and remarkable sensitivity of sRCC-a classically aggressive entity-to ICI.

Vascular Expression of Prostate-specific Membrane Antigen (PSMA) in MiTF Family Translocation Renal Cell Carcinoma and Related Neoplasms.

Multiple studies have demonstrated prostate-specific membrane antigen (PSMA) expression in the neo-vasculature of non-prostate tumors including clear cell renal cell carcinoma (ccRCC). However, PSMA expression in rare renal tumors including MiTF family translocation renal cell carcinoma has not been previously characterized. We examined PSMA expression by immunohistochemistry in a series of MiTF family translocation renal cell carcinomas as well as in several genetically related tumors including alveolar soft part sarcoma and PEComas with TFE3 rearrangements. PSMA expression was also studied in several cases of ccRCC and papillary RCC. Overall, PSMA immunohistochemistry was performed in 61 samples from 58 patients. Vascular PSMA expression was seen with the highest frequency in ccRCC [88% (14/16)] (38% focal, 50% diffuse). Translocation RCC (tRCC) demonstrated the second highest frequency of PSMA expression [71% (22/28)] (57% focal, 14% diffuse), followed by alveolar soft part sarcoma [50% (4/8)] (38% focal, 12% diffuse). No PSMA expression was seen in PEComas with TFE3 rearrangement (0/3) or papillary RCC (0/6). PSMA expression was only present in tumor-associated neo-vasculature. A patient with oligometastatic tRCC underwent 68 Ga-PSMA-11 PET imaging which detected multiple putative metastatic lesions not detected on conventional computed tomography imaging performed 2 weeks prior, supporting the potential utility of PSMA imaging in tRCC. These findings have potential implications for the utility of PSMA guided diagnostic and therapeutic agents in both common and uncommon renal cell carcinoma subtypes as well as genetically related mesenchymal neoplasms.

"Oncocytoid Renal Cell Carcinomas After Neuroblastoma" Represent TSC -mutated Eosinophilic Solid and Cystic Renal Cell Carcinomas : Association With Prior Childhood Malignancy and Multifocality With Therapeutic Implications.

The concept of oncocytoid renal cell carcinoma in patients who have survived neuroblastoma as a distinct biologic entity has been controversial since its original description in 1999. This is in part because similar oncocytoid renal cell carcinomas have been described in association with other pediatric cancers, and also because other renal cell carcinoma subtypes (such as MiT family translocation renal cell carcinoma) have been described in children who have survived neuroblastoma. We identified an index case of a child who survived medulloblastoma and developed multifocal bilateral oncocytoid renal cell carcinomas with morphology and immunophenotype compatible with eosinophilic solid and cystic renal cell carcinoma (ESC RCC) and demonstrated that both neoplasms harbored distinctive mutations in the TSC1/TSC2 genes. Remarkably, the child's remaining bilateral multifocal renal neoplasms completely responded to MTOR inhibitor therapy without need for further surgery. To confirm our hypothesis that oncocytoid renal cell carcinomas after childhood cancer represent ESC RCC, we obtained formalin-fixed paraffin-embedded tissue blocks from 2 previously published cases of oncocytoid renal cell carcinoma after neuroblastoma, confirmed that the morphology and immunophenotype was consistent with ESC RCC, and demonstrated that both cases harbored somatic TSC gene mutations. Both expressed markers previously associated with neoplasms harboring TSC gene mutations, glycoprotein nonmetastatic B, and cathepsin K. Of note, one of these patients had 2 ESC RCC which harbored distinctive TSC2 mutations, while the background kidney of the other patient had multiple small cysts lined by similar oncocytoid cells which showed loss of TSC2 protein. We then reviewed 3 of 4 cases from the original 1999 report of oncocytoid renal cell carcinomas after neuroblastoma, found that all 3 demonstrated morphology (including basophilic cytoplasmic stippling) that is characteristic of ESC RCC, showed that all 3 overexpressed glycoprotein nonmetastatic B, and showed that both cases with adequate material demonstrated loss of TSC2 protein and expressed cytokeratin 20 and cathepsin K by immunohistochemistry. In summary, "oncocytoid renal cell carcinomas after neuroblastoma" represent ESC RCC which are often multifocal in patients who have survived childhood cancer, likely representing an incompletely characterized tumor predisposition syndrome. MTOR-targeted therapy represents an effective therapeutic option for such patients to preserve functional nephrons.

Ossifying Fibromyxoid Tumor of the Genitourinary Tract: Report of 4 Molecularly Confirmed Cases of a Diagnostic Pitfall.

Ossifying fibromyxoid tumors (OFMTs) are rare mesenchymal neoplasms which typically present in the superficial subcutaneous tissues and have not been reported to arise in visceral organs. We now report 4 molecularly confirmed cases of OFMT involving the genitourinary tract. All patients were males, ranging in age from 20 to 66 years (mean: 43 y). One case each arose in the kidney, ureter, perirenal soft tissue, and penis. All neoplasms demonstrated bland epithelioid to spindled cells set in a variably fibrous to fibromyxoid stroma, and only 1 had a peripheral shell of lamellar bone. All cases appeared well-circumscribed on gross/radiologic examination, though the primary renal neoplasm permeated between native renal tubules. By immunohistochemistry, S100 protein was negative in all 4 cases, while desmin was positive in 2 cases. In 2 cases, the Illumina TruSight RNA Fusion Panel demonstrated a PHF1::TFE3 and EP400::PHF1 fusion, respectively. In the remaining 2 cases, PHF1 gene rearrangement was confirmed by fluorescence in situ hybridization analysis. Due to unusual clinical presentation, lack of S100 positivity, and only occasional bone formation, the correct diagnosis was challenging in the absence of molecular testing. In summary, OFMT may rarely present primarily in the genitourinary tract. Given their nonspecific morphology and immunophenotype, molecular analysis is crucial to establish the correct diagnosis.

Identifying Men Who Can Remain on Active Surveillance Despite Biopsy Reclassification to Grade Group 2 Prostate Cancer.

PURPOSE: Men on active surveillance with Grade Group 1 prostate cancer who reclassify to Grade Group 2 on surveillance biopsy often leave active surveillance. We aimed to identify subgroups of men who can safely remain on active surveillance despite preoperative reclassification to Grade Group 2. MATERIALS AND METHODS: We studied 249 active surveillance patients with surveillance biopsies classified as Grade Group 1 or Grade Group 2 who underwent radical prostatectomy. Perineural invasion, cancer volume, linear length and maximum percentage of Gleason pattern 4, and prostate-specific antigen density were evaluated. Radical prostatectomy adverse pathology was defined by any of: pN1; ≥pT3; ≥Grade Group 2 with ≥20% Gleason pattern 4; intraductal carcinoma; large cribriform glands. RESULTS: A multivariable logistic regression model incorporating prostate-specific antigen density and perineural invasion stratified radical prostatectomy adverse pathology risk among Grade Group 1 and Grade Group 2 active surveillance patients. 57% (39/68) of Grade Group 1 men reclassified to Grade Group 2 while on active surveillance had favorable radical prostatectomy pathology. Those without biopsy perineural invasion and with low prostate-specific antigen density were more likely to have favorable radical prostatectomy pathology. CONCLUSIONS: Most Grade Group 1 men who enter active surveillance and subsequently reclassify to Grade Group 2 have favorable findings at radical prostatectomy and can remain on active surveillance. Among patients reclassified to Grade Group 2, those with low prostate-specific antigen density and without perineural invasion had the lowest risk of radical prostatectomy adverse pathology, comparable to (or below) that of Grade Group 1 patients who were not reclassified to Grade Group 2 preoperatively. Prostate-specific antigen density and perineural invasion stratify risk in active surveillance patients reclassified to Grade Group 2 and, if concordant with other clinicopathological and radiographic findings, can enable more patients to remain on active surveillance. Reclassification to Grade Group 2 alone should not disqualify men from remaining on active surveillance.

Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma.

With a rapidly developing immunotherapeutic landscape for patients with metastatic clear cell renal cell carcinoma, biomarkers of efficacy are highly desirable to guide treatment strategy. Hematoxylin and eosin (H&E)-stained slides are inexpensive and widely available in pathology laboratories, including in resource-poor settings. Here, H&E scoring of tumor-infiltrating immune cells (TILplus) in pre-treatment tumor specimens using light microscopy is associated with improved overall survival (OS) in three independent cohorts of patients receiving immune checkpoint blockade. Necrosis score alone does not associate with OS; however, necrosis modifies the predictive effect of TILplus, a finding that has broad translational relevance for tissue-based biomarker development. PBRM1 mutational status is combined with H&E scores to further refine outcome predictions (OS, p = 0.007, and objective response, p = 0.04). These findings bring H&E assessment to the fore for biomarker development in future prospective, randomized trials, and emerging multi-omics classifiers.