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Purpose: Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a newly defined, rare subtype of renal cancer, associated with pathogenic variations in the Succinate Dehydrogenase Subunit B (SDHB) gene. Our aim is to investigate the imaging findings of SDHB-associated renal tumors, utilizing cross-sectional and FDG-PET imaging in patients with pathogenic variations in SDHB gene, to facilitate accurate tumor characterization., Methods: Twenty SDH-deficient tumors from 16 patients with pathogenic variations in SDHB gene were retrospectively evaluated using cross-sectional and FDG-PET imaging. Clinical findings such as demographics, family history, extra-renal findings and metastases were recorded. Tumor imaging characteristics on CT/MRI included were laterality, size, homogeneity, morphology, margins, internal content, T1/T2 signal intensity, enhancement features, and restricted diffusion., Results: Sixteen patients (median age 31 years, IQR 19-41, 8 males) were identified with 68.8 % of patients having a known family history of SDHB variation. 81.3 % of lesions were solitary and majority were solid (86.7 % on CT, 87.5 % on MRI) with well-defined margins in >62.5 % of lesions, without evidence of internal fat, calcifications, or vascular invasion. 100 % of lesions demonstrated restricted diffusion and avid enhancement, with degree >75 % for most lesions on CT and MRI. On FDG-PET, all renal masses showed increased radiotracer uptake. 43.8 % of patients demonstrated extra-renal manifestations and 43.8 % had distant metastasis., Conclusion: SDHB-associated RCC is predominantly noted in young patients with no gender predilection. On imaging, SDH-deficient RCC are frequently unilateral, solitary, and solid with well-defined margins demonstrating avid enhancement with variability in enhancement pattern and showing restricted diffusion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: The aim of this study was to assess the interreader reliability and per-RCC sensitivity of high-resolution photon-counting computed tomography (PCCT) in the detection and characterization of renal masses in comparison to MRI., Materials and Methods: This prospective study included 24 adult patients (mean age, 52 ± 14 years; 14 females) who underwent PCCT (using an investigational whole-body CT scanner) and abdominal MRI within a 3-month time interval and underwent surgical resection (partial or radical nephrectomy) with histopathology (n = 70 lesions). Of the 24 patients, 17 had a germline mutation and the remainder were sporadic cases. Two radiologists (R1 and R2) assessed the PCCT and corresponding MRI studies with a 3-week washout period between reviews. Readers recorded the number of lesions in each patient and graded each targeted lesion's characteristic features, dimensions, and location. Data were analyzed using a 2-sample t test, Fisher exact test, and weighted kappa., Results: In patients with von Hippel-Lindau mutation, R1 identified a similar number of lesions suspicious for neoplasm on both modalities (51 vs 50, P = 0.94), whereas R2 identified more suspicious lesions on PCCT scans as compared with MRI studies (80 vs 56, P = 0.12). R1 and R2 characterized more lesions as predominantly solid in MRIs (R1: 58/70 in MRI vs 52/70 in PCCT, P < 0.001; R2: 60/70 in MRI vs 55/70 in PCCT, P < 0.001). R1 and R2 performed similarly in detecting neoplastic lesions on PCCT and MRI studies (R1: 94% vs 90%, P = 0.5; R2: 73% vs 79%, P = 0.13)., Conclusions: The interreader reliability and per-RCC sensitivity of PCCT scans acquired on an investigational whole-body PCCT were comparable to MRI scans in detecting and characterizing renal masses., Clinical Relevance Statement: PCCT scans have comparable performance to MRI studies while allowing for improved characterization of the internal composition of lesions due to material decomposition analysis. Future generations of this imaging modality may reveal additional advantages of PCCT over MRI., Competing Interests: Conflicts of interest and sources of funding: This research was supported, in part, by the Intramural Research Program of the National Institutes of Health Clinical Center. The National Institutes of Health and Siemens Medical Solutions have a Cooperative Research and Development Agreement providing financial and material support including the photon-counting computed tomography system. One of the study co-authors (Pooyan Sahbaee) is an employee of Siemens Healthineers. The rest of the authors have nothing to declare. Authors unaffiliated with Siemens had full control over the data and information presented in this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pathology grading is an essential step for the treatment and evaluation of the prognosis in patients with clear cell renal cell carcinoma (ccRCC)., Purpose: To investigate the utility of texture analysis in evaluating Fuhrman grades of renal tumors in patients with Von Hippel-Lindau (VHL)-associated ccRCC, aiming to improve non-invasive diagnosis and personalized treatment., Study Type: Retrospective analysis of a prospectively maintained cohort., Population: One hundred and thirty-six patients, 84 (61%) males and 52 (39%) females with pathology-proven ccRCC with a mean age of 52.8 ± 12.7 from 2010 to 2023., Field Strength and Sequences: 1.5 and 3 T MRIs. Segmentations were performed on the T1-weighted 3-minute delayed sequence and then registered on pre-contrast, T1-weighted arterial and venous sequences., Assessment: A total of 404 lesions, 345 low-grade tumors, and 59 high-grade tumors were segmented using ITK-SNAP on a T1-weighted 3-minute delayed sequence of MRI. Radiomics features were extracted from pre-contrast, T1-weighted arterial, venous, and delayed post-contrast sequences. Preprocessing techniques were employed to address class imbalances. Features were then rescaled to normalize the numeric values. We developed a stacked model combining random forest and XGBoost to assess tumor grades using radiomics signatures., Statistical Tests: The model's performance was evaluated using positive predictive value (PPV), sensitivity, F1 score, area under the curve of receiver operating characteristic curve, and Matthews correlation coefficient. Using Monte Carlo technique, the average performance of 100 benchmarks of 85% train and 15% test was reported., Results: The best model displayed an accuracy of 0.79. For low-grade tumor detection, a sensitivity of 0.79, a PPV of 0.95, and an F1 score of 0.86 were obtained. For high-grade tumor detection, a sensitivity of 0.78, PPV of 0.39, and F1 score of 0.52 were reported., Data Conclusion: Radiomics analysis shows promise in classifying pathology grades non-invasively for patients with VHL-associated ccRCC, potentially leading to better diagnosis and personalized treatment., Level of Evidence: 1 TECHNICAL EFFICACY: Stage 2., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: Reoperative partial nephrectomy (RePN) offers several advantages for the treatment of recurrent, multifocal renal masses. RePN has been previously demonstrated to be technically feasible and delay the need for renal replacement therapy. However, there is still inherent complexity and known risks to reoperative nephrectomy. We studied the largest population of RePNs to characterize renal functional outcomes and the likelihood of intra- and postoperative complications., Materials and Methods: Query of an institutional surgical registry was conducted. Demographic data, serum creatinine for estimated glomerular filtration rate (eGFR), and protein dipstick results were assessed within 1 week prior to surgery, and postoperative function assessments were studied within a year of surgery. RePN was defined as serial surgical resection of the ipsilateral renal unit., Results: A total of 1131 partial nephrectomies performed on 663 patients at a single center were retrospectively evaluated. In reoperative cases, median number of operations per renal unit was 2 (range: 2-6). There was a stepwise decline in eGFR with an average decline of 6.1 with each RePN. With each subsequent nephrectomy, surgical duration, estimated blood loss, and incidence of preoperative anemia increased. Postoperative eGFR showed a significant positive association with preoperative eGFR, while negative associations were found with age, number of previous ipsilateral partial nephrectomies, number of tumors, and largest tumor size. High-grade complications were associated with the number of ipsilateral partial nephrectomies, tumor count, and tumor size. Robotic or laparoscopic procedures exhibited a likelihood of grade 3 or greater complications compared to open surgery., Conclusions: RePN contributes to renal dysfunction and an increased risk of surgical complications. Intraoperative blood loss and surgical duration increase with subsequent nephrectomy. Such risks are dependent on the number of prior operative interventions on the kidney, suggesting a stepwise progression of surgical morbidity.

Introduction: Delayed bleeding is a potentially serious complication after partial nephrectomy (PN), with reported rates of 1%-2%. Patients with multiple renal tumors, including those with hereditary forms of kidney cancer, are often managed with resection of multiple tumors in a single kidney which may increase the risk of delayed bleeding, though outcomes have not previously been reported specifically in this population. The objective of this study was to evaluate the incidence and timing of delayed bleeding as well as the impact of intervention on renal functional outcomes in a cohort primarily made up of patients at risk for bilateral, multifocal renal tumors., Methods: A retrospective review of a prospectively maintained database of patients with known or suspected predisposition to bilateral, multifocal renal tumors who underwent PN from 2003 to 2023 was conducted. Patients who presented with delayed bleeding were identified. Patients with delayed bleeding were compared to those without. Comparative statistics and univariate logistic regression were used to determine potential risk factors for delayed bleeding., Results: A total of 1256 PN were performed during the study period. Angiographic evidence of pseudoaneurysm, AV fistula and/or extravasation occurred in 24 cases (1.9%). Of these, 21 were symptomatic presenting with gross hematuria in 13 (54.2%), decreasing hemoglobin in 4(16.7%), flank pain in 2(8.3%), and mental status change in 2 (8.3%), while 3 patients were asymptomatic. Median number of resected tumors was 5 (IQR 2-8). All patients underwent angiogram with super-selective embolization. Median time to bleed event was 13.5 days (IQR 7-22). Factors associated with delayed bleeding included open approach (OR 2.2, IQR(1.06-5.46), P = 0.04 and left-sided surgery (OR 4.93, IQR(1.67-14.5), P = 0.004. Selective embolization had little impact on ultimate renal functional outcomes, with a median change of 11% from the baseline eGFR after partial nephrectomy and embolization. One patient required total nephrectomy for refractory bleeding after embolization., Conclusions: Delayed bleeding after PN in a cohort of patients with multifocal tumors is an infrequent event, with similar rates to single tumor series. Patients should be counseled regarding timing and symptoms of delayed bleeding and multidisciplinary management with interventional radiology is critical for timely diagnosis and treatment., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Comprehensive molecular characterization and effective therapy in a rare case of metastatic renal oncocytoma.

Aim: To predict renal tumour growth patterns in von Hippel-Lindau syndrome by utilising radiomic features to assist in developing personalised surveillance plans leading to better patient outcomes., Materials and Methods: The study evaluated 78 renal tumours in 55 patients with histopathologically-confirmed clear cell renal cell carcinomas (ccRCCs), which were segmented and radiomics were extracted. Volumetric doubling time (VDT) classified the tumours into fast-growing (VDT <365 days) or slow-growing (VDT ≥365 days). Volumetric and diametric growth analyses were compared between the groups. Multiple logistic regression and random forest classifiers were used to select the best features and models based on their correlation and predictability of VDT., Results: Fifty-five patients (mean age 42.2 ± 12.2 years, 27 men) with a mean time difference of 3.8 ± 2 years between the baseline and preoperative scans were studied. Twenty-five tumours were fast-growing (low VDT, i.e., <365 days), and 53 tumours were slow-growing (high VDT, i.e., ≥365 days). The median volumetric and diametric growth rates were 1.71 cm 3 /year and 0.31 cm/year. The best feature using univariate analysis was wavelet-HLL&#95;glcm&#95;ldmn (area under the receiver operating characteristic [ROC] curve [AUC] of 0.80, p<0.0001), and with the random forest classifier, it was log-sigma-0-5-mm-3D&#95;glszm&#95;ZonePercentage (AUC: 79). The AUC of the ROC curves using multiple logistic regression was 0.74, and with the random forest classifier was 0.73., Conclusion: Radiomic features correlated with VDT and were able to predict the growth pattern of renal tumours in patients with VHL syndrome., (Published by Elsevier Ltd.)

Introduction: Accurate diagnosis and treatment of kidney tumors greatly benefit from automated solutions for detection and classification on MRI. In this study, we explore the application of a deep learning algorithm, YOLOv7, for detecting kidney tumors on contrast-enhanced MRI., Material and Methods: We assessed the performance of YOLOv7 tumor detection on excretory phase MRIs in a large institutional cohort of patients with RCC. Tumors were segmented on MRI using ITK-SNAP and converted to bounding boxes. The cohort was randomly divided into ten benchmarks for training and testing the YOLOv7 algorithm. The model was evaluated using both 2-dimensional and a novel in-house developed 2.5-dimensional approach. Performance measures included F1, Positive Predictive Value (PPV), Sensitivity, F1 curve, PPV-Sensitivity curve, Intersection over Union (IoU), and mean average PPV (mAP)., Results: A total of 326 patients with 1034 tumors with 7 different pathologies were analyzed across ten benchmarks. The average 2D evaluation results were as follows: Positive Predictive Value (PPV) of 0.69 ± 0.05, sensitivity of 0.39 ± 0.02, and F1 score of 0.43 ± 0.03. For the 2.5D evaluation, the average results included a PPV of 0.72 ± 0.06, sensitivity of 0.61 ± 0.06, and F1 score of 0.66 ± 0.04. The best model performance demonstrated a 2.5D PPV of 0.75, sensitivity of 0.69, and F1 score of 0.72., Conclusion: Using computer vision for tumor identification is a cutting-edge and rapidly expanding subject. In this work, we showed that YOLOv7 can be utilized in the detection of kidney cancers., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Classification of clear cell renal cell carcinoma (ccRCC) growth rates in patients with Von Hippel-Lindau (VHL) syndrome has several ramifications for tumor monitoring and surgical planning. Using two separate machine-learning algorithms, we sought to produce models to predict ccRCC growth rate classes based on qualitative MRI-derived characteristics., Material and Methods: We used a prospectively maintained database of patients with VHL who underwent surgical resection for ccRCC between January 2015 and June 2022. We employed a threshold growth rate of 0.5 cm per year to categorize ccRCC tumors into two distinct groups-'slow-growing' and 'fast-growing'. Utilizing a questionnaire of qualitative imaging features, two radiologists assessed each lesion on different MRI sequences. Two machine-learning models, a stacked ensemble technique and a decision tree algorithm, were used to predict the tumor growth rate classes. Positive predictive value (PPV), sensitivity, and F1-score were used to evaluate the performance of the models., Results: This study comprises 55 patients with VHL with 128 ccRCC tumors. Patients' median age was 48 years, and 28 patients were males. Each patient had an average of two tumors, with a median size of 2.1 cm and a median growth rate of 0.35 cm/year. The overall performance of the stacked and DT model had 0.77 ± 0.05 and 0.71 ± 0.06 accuracies, respectively. The best stacked model achieved a PPV of 0.92, a sensitivity of 0.91, and an F1-score of 0.90., Conclusion: This study provides valuable insight into the potential of machine-learning analysis for the determination of renal tumor growth rate in patients with VHL. This finding could be utilized as an assistive tool for the individualized screening and follow-up of this population., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction and Objective: Von Hippel-Lindau (VHL) is a hereditary cancer syndrome characterized by bilateral, multifocal renal masses. The cumulative impact of extirpative surgery can depreciate renal function and render patients anephric. In the larger end-stage renal disease population, renal transplant offers both excellent quality of life and functional renal replacement. This case control study aims to examine and compare oncologic and functional outcomes of patients who have undergone renal transplant as renal replacement therapy (RRT) to those who remain anephric., Methods: Patient charts were retrospectively reviewed of patients with germline testing confirmed VHL between 1980 and 2022 for transplant, all prior surgical history (within and outside the NCI), renal function and graft outcomes. Overall survival (OS) was determined from years after radical nephrectomy, and graft time was defined as years of graft function from initial transplant until failure or patient death. Graft survival was determined as time between transplant(s) to last follow up. Kaplan-Meier analysis was conducted to compare graft times of anephric VHL patients to those with transplanted kidneys., Results: A total of 23 VHLD patients were identified as either anephric or candidates for transplant. Out of this cohort, 11 total VHLD received 12 total kidney grafts. Median wait time from nephrectomy to transplant was 22.6 months (IQR: 1.02-40.25 months). Median age at transplant was 32 years (IQR: 23-54 years). OS at 5 and 10 years of anephric patients who did not receive a transplant was 33% and 16.7%, respectively. OS rates of the transplant cohort at 10, 15, and 20 years were 91%, 78%, and 58% years, respectively. Median graft time was 161 months (IQR: 56-214 months). Graft survival at 10, 15, and 20 years was 69.8%, 69.8%, and 26.2%, respectively., Conclusions: We demonstrate that transplant recipients have decreased mortality with no difference in cancer recurrence compared to those who do not receive renal transplant for RRT. This data can aid in informing providers of the optimal window for early RRT planning in VHL, while also improving patient counseling., Competing Interests: Declaration of Competing Interest All authors have no financial conflicts of interest to disclose related to the outcomes or dissemination of this research., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant condition characterized by the development of cutaneous and uterine leiomyomas and risk for development of an aggressive form of papillary renal cell cancer. HLRCC is caused by germline inactivating pathogenic variants in the fumarate hydratase (FH) gene, which encodes the enzyme that catalyzes the interconversion of fumarate and L-malate. We utilized enzyme and protein mobility assays to evaluate the FH enzyme in a cohort of patients who showed clinical manifestations of HLRCC but were negative for known pathogenic FH gene variants. FH enzyme activity and protein levels were decreased by 50% or greater in three family members, despite normal FH mRNA expression levels as measured by quantitative PCR. Direct Nanopore RNA sequencing demonstrated 57 base pairs of retained intron sequence between exons 9 and 10 of polyadenylated FH mRNA in these patients, resulting in a truncated FH protein. Genomic sequencing revealed a heterozygous intronic alteration of the FH gene (chr1: 241498239 T/C) resulting in formation of a splice acceptor site near a polypyrimidine tract, and a uterine fibroid obtained from a patient showed loss of heterozygosity at this site. The same intronic FH variant was identified in an unrelated patient who also showed a clinical phenotype of HLRCC. These data demonstrate that careful clinical assessment as well as biochemical characterization of FH enzyme activity, protein expression, direct RNA sequencing, and genomic DNA sequencing of patient-derived cells can identify pathogenic variants outside of the protein coding regions of the FH gene., (Published by Oxford University Press 2023.)

Objective: To characterize the clinical manifestations and genetic basis of a familial cancer syndrome in patients with lipomas and Birt-Hogg-Dubé-like clinical manifestations including fibrofolliculomas and trichodiscomas and kidney cancer., Methods: Genomic analysis of blood and renal tumor DNA was performed. Inheritance pattern, phenotypic manifestations, and clinical and surgical management were documented. Cutaneous, subcutaneous, and renal tumor pathologic features were characterized., Results: Affected individuals were found to be at risk for a highly penetrant and lethal form of bilateral, multifocal papillary renal cell carcinoma. Whole genome sequencing identified a germline pathogenic variant in PRDM10 (c.2029 T>C, p.Cys677Arg), which cosegregated with disease. PRDM10 loss of heterozygosity was identified in kidney tumors. PRDM10 was predicted to abrogate expression of FLCN, a transcriptional target of PRDM10, which was confirmed by tumor expression of GPNMB, a TFE3/TFEB target and downstream biomarker of FLCN loss. In addition, a sporadic papillary RCC from the TCGA cohort was identified with a somatic PRDM10 mutation., Conclusion: We identified a germline PRDM10 pathogenic variant in association with a highly penetrant, aggressive form of familial papillary RCC, lipomas, and fibrofolliculomas/trichodiscomas. PRDM10 loss of heterozygosity and elevated GPNMB expression in renal tumors indicate that PRDM10 alteration leads to reduced FLCN expression, driving TFE3-induced tumor formation. These findings suggest that individuals with Birt-Hogg-Dubé-like manifestations and subcutaneous lipomas, but without a germline pathogenic FLCN variant, should be screened for germline PRDM10 variants. Importantly, kidney tumors identified in patients with a pathogenic PRDM10 variant should be managed with surgical resection instead of active surveillance., Competing Interests: Declaration of Competing Interest The authors have nothing to declare., (Published by Elsevier Inc.)

The two primary nephron-sparing interventions for treating renal masses such as renal cell carcinoma are surgical partial nephrectomy (PN) and image-guided percutaneous thermal ablation. Nephron-sparing surgery, such as PN, has been the standard of care for treating many localized renal masses. Although uncommon, complications resulting from PN can range from asymptomatic and mild to symptomatic and life-threatening. These complications include vascular injuries such as hematoma, pseudoaneurysm, arteriovenous fistula, and/or renal ischemia; injury to the collecting system causing urinary leak; infection; and tumor recurrence. The incidence of complications after any nephron-sparing surgery depends on many factors, such as the proximity of the tumor to blood vessels or the collecting system, the skill or experience of the surgeon, and patient-specific factors. More recently, image-guided percutaneous renal ablation has emerged as a safe and effective treatment option for small renal tumors, with comparable oncologic outcomes to those of PN and a low incidence of major complications. Radiologists must be familiar with the imaging findings encountered after these surgical and image-guided procedures, especially those indicative of complications. The authors review cross-sectional imaging characteristics of complications after PN and image-guided thermal ablation of kidney tumors and highlight the respective management strategies, ranging from clinical observation to interventions such as angioembolization or repeat surgery. Work of the U.S. Government published under an exclusive license with the RSNA. Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article. Quiz questions for this article are available in the Online Learning Center. See the invited commentary by Chung and Raman in this issue.

Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient-derived tumor samples revealed increased activation of TFEB/TFE3-mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line-derived xenografts (CDXs). Our findings demonstrate in disease-relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: The RENAL nephrometry score (RNS) is widely used to describe renal mass complexity and inform patient counseling for partial nephrectomy (PN). However, in cases with multiple tumors, it is unknown which features drive perioperative outcomes., Objective: To employ a novel scoring equation (multiplex score [MS]) derived from RNS to assess outcomes of multiplex PN at our institution., Design, Setting, and Participants: A total of 62 consecutive multiplex PN (median (range) # tumors = 4(2-11), 65% robotic) were performed by a single surgeon. The MS was defined a priori as a weighted score derived from RNS (# low risk ([LR] lesions) + 2*(# intermediate risk [IR]) + 4*(# high risk [HR]) based on published complication rates., Outcome Measurements and Statistical Analysis: MS was dichotomized into favorable/unfavorable based on median score. Patient outcomes were maintained prospectively. MS was compared with other potential RNS derived scoring systems., Results and Limitation: A total of 249 tumors were scored. Median (range) MS was 6(range 2-20, IQR 3-8). Complications occurred in 10 patients (16.1%). Only 1 complication occurred in the favorable MS(<6) group, and MS was associated with perioperative complication (P = 0.02) and blood loss (P < .001). When compared to other potential scoring systems, MS had the best area under the curve (AUC) to predict operative complications (0.75)., Conclusions: The novel MS was associated with complications and blood loss. This tool may facilitate standardized reporting of complexity for multiplex series, with special relevance for hereditary cancer syndromes., Patient Summary: For patients who have one kidney tumor, there are established scoring systems to help patients and surgeons decide on the surgical plan. However currently, for patients with more than one renal tumor, there is no such scoring system. Here, we present the "Multiplex Score" to aid shared-decision-making in cases with more than one renal tumor., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Inc.)

Background: Radiomics is a type of quantitative analysis that provides a more objective approach to detecting tumor subtypes using medical imaging. The goal of this paper is to conduct a comprehensive assessment of the literature on computed tomography (CT) radiomics for distinguishing renal cell carcinomas (RCCs) from oncocytoma., Methods: From February 15th 2012 to 2022, we conducted a broad search of the current literature using the PubMed/MEDLINE, Google scholar, Cochrane Library, Embase, and Web of Science. A meta-analysis of radiomics studies concentrating on discriminating between oncocytoma and RCCs was performed, and the risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies method. The pooled sensitivity, specificity, and diagnostic odds ratio were evaluated via a random-effects model, which was applied for the meta-analysis. This study is registered with PROSPERO (CRD42022311575)., Results: After screening the search results, we identified 6 studies that utilized radiomics to distinguish oncocytoma from other renal tumors; there were a total of 1064 lesions in 1049 patients (288 oncocytoma lesions vs 776 RCCs lesions). The meta-analysis found substantial heterogeneity among the included studies, with pooled sensitivity and specificity of 0.818 [0.619-0.926] and 0.808 [0.537-0.938], for detecting different subtypes of RCCs (clear cell RCC, chromophobe RCC, and papillary RCC) from oncocytoma. Also, a pooled sensitivity and specificity of 0.83 [0.498-0.960] and 0.92 [0.825-0.965], respectively, was found in detecting oncocytoma from chromophobe RCC specifically., Conclusions: According to this study, CT radiomics has a high degree of accuracy in distinguishing RCCs from RO, including chromophobe RCCs from RO. Radiomics algorithms have the potential to improve diagnosis in scenarios that have traditionally been ambiguous. However, in order for this modality to be implemented in the clinical setting, standardization of image acquisition and segmentation protocols as well as inter-institutional sharing of software is warranted., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Published by Elsevier Inc.)

Purpose: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is associated with an aggressive form of renal cell carcinoma with high risk of metastasis, even in small primary tumors with unequivocal imaging findings. In this study, we compare the performance of ultra-high b-value diffusion-weighted imaging (DWI) sequence (b = 2000 s/mm 2 ) to standard DWI (b = 800 s/mm 2 ) sequence in identifying malignant lesions in patients with HLRCC., Methods: Twenty-eight patients (n = 18 HLRCC patients with 22 lesions, n = 10 controls) were independently evaluated by three abdominal radiologists with different levels of experience using four combinations of MRI sequences in two separate sessions (session 1: DWI with b-800, session 2: DWI with b-2000). T1 precontrast, T2-weighted (T2WI), and apparent diffusion coefficient (ADC) sequences were similar in both sessions. Each identified lesion was subjectively assessed using a six-point cancer likelihood score based on individual sequences and overall impression., Results: The ability to distinguish benign versus malignant renal lesions improved with the use of b-2000 for more experienced radiologists (Reader 1 AUC: Session 1-0.649 and Session 2-0.938, p = 0.017; Reader 2 AUC: Session 1-0.781 and Session 2-0.921, p = 0.157); whereas no improvement was observed for the less experienced reader (AUC: Session 1-0.541 and Session 2-0.607, p = 0.699)., Conclusion: The inclusion of ultra-high b-value DWI sequence improved the ability of classification of renal lesions in patients with HLRCC for experienced radiologists. Consideration should be given toward incorporation of DWI with b-2000 s/mm 2 into existing renal MRI protocols., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Renal cell carcinoma is a heterogenous cancer composed of an increasing number of unique subtypes each with their own cellular and tumor behavior. The study of hereditary renal cell carcinoma, which composes just 5% of all types of tumor cases, has allowed for the elucidation of subtype-specific tumorigenesis mechanisms that can also be applied to their sporadic counterparts. This review will focus on the major forms of hereditary renal cell carcinoma and the genetic alterations contributing to their tumorigenesis, including von Hippel Lindau syndrome, Hereditary Papillary Renal Cell Carcinoma, Succinate Dehydrogenase-Deficient Renal Cell Carcinoma, Hereditary Leiomyomatosis and Renal Cell Carcinoma, BRCA Associated Protein 1 Tumor Predisposition Syndrome, Tuberous Sclerosis, Birt-Hogg-Dubé Syndrome and Translocation RCC. The mechanisms for tumorigenesis described in this review are beginning to be exploited via the utilization of novel targets to treat renal cell carcinoma in a subtype-specific fashion.

A subset of renal tumors (5-8%) are associated with syndromes such as von Hippel-Lindau (VHL) syndrome, Birt-Hogg-Dubé syndrome (BHD), tuberous sclerosis complex (TSC), hereditary papillary renal carcinoma (HPRC), hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), and BRCA1 associated protein (BAP1) tumor predisposition syndrome, succinate dehydrogenase RCC (SDHB/C/D). These syndromes have their specific defined genetic alterations and associated extrarenal manifestations. Due to varying histopathology and aggressiveness of the tumors amongst these syndromes, the management strategies can range from active surveillance to upfront surgical resection. This review delineates specific characteristics of the most common familial renal cancer syndromes and discusses current management strategies.

Purpose: Upfront knowledge of tumor growth rates of clear cell renal cell carcinoma in von Hippel-Lindau syndrome (VHL) patients can allow for a more personalized approach to either surveillance imaging frequency or surgical planning. In this study, we implement a machine learning algorithm utilizing radiomic features of renal tumors identified on baseline magnetic resonance imaging (MRI) in VHL patients to predict the volumetric growth rate category of these tumors., Materials and Methods: A total of 73 VHL patients with 173 pathologically confirmed Clear Cell Renal Cell Carcinoma (ccRCCs) underwent MRI at least at two different time points between 2015 and 2021. Each tumor was manually segmented in excretory phase contrast T1 weighed MRI and co-registered on pre-contrast, corticomedullary and nephrographic phases. Radiomic features and volumetric data from each tumor were extracted using the PyRadiomics library in Python (4544 total features). Tumor doubling time (DT) was calculated and patients were divided into two groups: DT <  = 1 year and DT > 1 year. Random forest classifier (RFC) was used to predict the DT category. To measure prediction performance, the cohort was randomly divided into 100 training and test sets (80% and 20%). Model performance was evaluated using area under curve of receiver operating characteristic curve (AUC-ROC), as well as accuracy, F1, precision and recall, reported as percentages with 95% confidence intervals (CIs)., Results: The average age of patients was 47.2 ± 10.3 years. Mean interval between MRIs for each patient was 1.3 years. Tumors included in this study were categorized into 155 Grade 2; 16 Grade 3; and 2 Grade 4. Mean accuracy of RFC model was 79.0% [67.4-90.6] and mean AUC-ROC of 0.795 [0.608-0.988]. The accuracy for predicting DT classes was not different among the MRI sequences (P-value = 0.56)., Conclusion: Here we demonstrate the utility of machine learning in accurately predicting the renal tumor growth rate category of VHL patients based on radiomic features extracted from different T1-weighted pre- and post-contrast MRI sequences., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To evaluate whether bilateral, multifocal clear cell renal cell carcinoma (ccRCC) patients can be differentiated by VHL mutation analysis into cases that represent either multiple independently arising primary tumors, or a single primary tumor which has spread ipsilaterally as well as to the contralateral kidney. The nature of kidney cancer multifocality outside of known hereditary syndromes is as yet poorly understood., Materials and Methods: DNA from multiple tumors per patient were evaluated for somatic VHL gene mutation and hypermethylation. A subset of tumors with shared VHL mutations were analyzed with targeted, next-generation sequencing assays., Results: This cohort contained 5 patients with multiple tumors that demonstrated a shared somatic VHL mutation consistent with metastatic spread including to the contralateral kidney. In several cases this was substantiated by additional shared somatic mutations in ccRCC-associated genes. In contrast, the remaining 14 patients with multiple tumors demonstrated unique, unshared VHL alterations in every analyzed tumor, consistent with independently arising kidney tumors. None of these latter patients showed any evidence of local spread or distant metastasis., Conclusion: The spectrum of VHL alterations within evaluated bilateral, multifocal ccRCC tumors from a single patient can distinguish between multiple independent tumor growth and metastasis. This can be performed using currently available clinical genetic tests and will improve the accuracy of patient diagnosis and prognosis, as well as informing appropriate management., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions., Methods: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions., Results: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC., Conclusions: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment., Lay Summary: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer., (© 2021 American Cancer Society.)

Purpose: Historically, open techniques have been favored over minimally invasive approaches for complex surgeries. We aimed to identify differences in perioperative outcomes, surgical footprints, and complication rates in patients undergoing either open or robotic reoperative partial nephrectomy., Materials and Methods: A retrospective review of patients undergoing reoperative partial nephrectomy was performed. Patients were assigned to cohorts based on current and prior surgical approaches: open after open, open after minimally invasive surgery, robotic after open, and robotic after minimally invasive surgery cohorts. Perioperative outcomes were compared among cohorts. Factors contributing to complications were assessed., Results: A total of 192 patients underwent reoperative partial nephrectomy, including 103 in the open after open, 10 in the open after minimally invasive surgery, 47 in the robotic after open, and 32 in the robotic after minimally invasive surgery cohorts. The overall and major complication (grade ≥3) rates were 65% and 19%, respectively. The number of blood transfusions, overall complications, and major complications were significantly lower in robotic compared to open surgical cohorts. On multivariate analysis, the robotic approach was protective against major complications (OR 0.3, p=0.02) and estimated blood loss was predictive (OR 1.03, p=0.004). Prior surgical approach was not predictive for major complications., Conclusions: Reoperative partial nephrectomy is feasible using both open and robotic approaches. While the robotic approach was independently associated with fewer major complications, prior approach was not, implying that prior surgical approaches are less important to perioperative outcomes and in contributing to the overall surgical footprint.

The diagnosis, evaluation and management of patients with renal cell carcinoma has transformed in the 21st century. Utilizing biological discoveries and technological advances, the field has moved from blunt surgical and largely ineffective medical treatments, to nuanced and fine-tuned approaches based on biology, extent of disease and patient preferences. In this review we will summarize the last 25 years of progress in kidney cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To investigate the diagnostic performance of a deep convolutional neural network for differentiation of clear cell renal cell carcinoma (ccRCC) from renal oncocytoma., Methods: In this retrospective study, 74 patients (49 male, mean age 59.3) with 243 renal masses (203 ccRCC and 40 oncocytoma) that had undergone MR imaging 6 months prior to pathologic confirmation of the lesions were included. Segmentation using seed placement and bounding box selection was used to extract the lesion patches from T2-WI, and T1-WI pre-contrast, post-contrast arterial and venous phases. Then, a deep convolutional neural network (AlexNet) was fine-tuned to distinguish the ccRCC from oncocytoma. Five-fold cross validation was used to evaluate the AI algorithm performance. A subset of 80 lesions (40 ccRCC, 40 oncocytoma) were randomly selected to be classified by two radiologists and their performance was compared to the AI algorithm. Intra-class correlation coefficient was calculated using the Shrout-Fleiss method., Results: Overall accuracy of the AI system was 91% for differentiation of ccRCC from oncocytoma with an area under the curve of 0.9. For the observer study on 80 randomly selected lesions, there was moderate agreement between the two radiologists and AI algorithm. In the comparison sub-dataset, classification accuracies were 81%, 78%, and 70% for AI, radiologist 1, and radiologist 2, respectively., Conclusion: The developed AI system in this study showed high diagnostic performance in differentiation of ccRCC versus oncocytoma on multi-phasic MRIs., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To describe the X-Capsular Incision for Tumor Enucleation (X-CITE) technique to resect endophytic renal tumors while preserving the overlying renal parenchyma., Subjects and Methods: We reviewed 1-year outcomes of 12 consecutive patients with a history of bilateral or multifocal renal tumors who presented to our institution with completely endophytic renal masse(s) between August 2017 and August 2018. Endophytic tumors were resected by making an X-shaped incision in the renal capsule and developing parenchymal flaps overlying the tumor pseudocapsule. Following tumor enucleation, the overlying parenchymal flaps were reapproximated., Results: Median follow up was 19.9 months (range 10.6-14.9). Most patients also had additional exophytic tumors with a median of 5 renal tumors removed per operation with a median largest renal tumor size of 3.2 cm. No intraoperative or postoperative complications occurred. There was no decline in renal function after surgery when comparing median pre- and 12-month postoperative eGFR (94.5 vs 91.5, P= 0.18).). Postoperative nuclear mercaptoacetyltriglycine (MAG-3) renal scans demonstrated equal differential kidney function after surgery. Limitations include short-term follow-up and referral bias at center specializing in multi-focal kidney surgery., Conclusion: The X-Capsular Incision for Tumor Enucleation technique is feasible, safe and effective with minimal collateral damage in the treatment of completely endophytic renal masses. Further investigation should identify which patients may benefit from this procedure and explore intermediate and long-term outcomes., (Published by Elsevier Inc.)

Purpose: To assess differences in FDG-PET/CT uptake among four subtypes of renal tumors: clear cell RCC (ccRCC), papillary type I and II RCC (pRCC), and oncocytoma., Methods: This retrospective study investigated 33 patients with 98 hereditary renal tumors. Lesions greater than 1 cm and patients with a timeframe of less than 18 months between preoperative imaging and surgery were considered. FDG-PET/CT images were independently reviewed by two nuclear medicine physicians, blinded to clinical information. Volumetric lesion SUV mean was measured and used to calculate a target-to-background ratio respective to liver (TBR). The Shrout-Fleiss intra-class correlation coefficient was used to assess reliability between readers. A linear mixed effects model, accounting for within-patient correlations, was used to compare TBR values of primary renal lesions with and without distant metastasis., Results: The time interval between imaging and surgery for all tumors had a median of 77 (Mean: 139; Range: 1-512) days. Intra-class reliability of mean TBR resulted in a mean κ score of 0.93, indicating strong agreement between the readers. The mixed model showed a significant difference in mean TBR among the subtypes (p < 0.0001). Pairwise comparison showed significant differences between pRCC type II and ccRCC (p < 0.0001), pRCC type II and pRCC type I (p = 0.0001), and pRCC type II and oncocytoma (p = 0.0016). Furthermore, a significant difference in FDG uptake was present between primary pRCC type II renal lesions with and without distant metastasis (p = 0.023)., Conclusion: pRCC type II lesions demonstrated significantly higher FDG activity than ccRCC, pRCC type I, or oncocytoma. These findings indicate that FDG may prove useful in studying the metabolic activity of renal neoplasms, identifying lesions of highest clinical concern, and ultimately optimizing active surveillance, and personalizing management plans.

Renal cell carcinoma (RCC) is not a single disease but is made up of several different histologically defined subtypes that are associated with distinct genetic alterations which require subtype specific management and treatment. Papillary renal cell carcinoma (pRCC) is the second most common subtype after conventional/clear cell RCC (ccRCC), representing ~20% of cases, and is subcategorized into type 1 and type 2 pRCC. It is important for preclinical studies to have cell lines that accurately represent each specific RCC subtype. This study characterizes seven cell lines derived from both primary and metastatic sites of type 1 pRCC, including the first cell line derived from a hereditary papillary renal carcinoma (HPRC)-associated tumor. Complete or partial gain of chromosome 7 was observed in all cell lines and other common gains of chromosomes 16, 17, or 20 were seen in several cell lines. Activating mutations of MET were present in three cell lines that all demonstrated increased MET phosphorylation in response to HGF and abrogation of MET phosphorylation in response to MET inhibitors. CDKN2A loss due to mutation or gene deletion, associated with poor outcomes in type 1 pRCC patients, was observed in all cell line models. Six cell lines formed tumor xenografts in athymic nude mice and thus provide in vivo models of type 1 pRCC. These type 1 pRCC cell lines provide a comprehensive representation of the genetic alterations associated with pRCC that will give insight into the biology of this disease and be ideal preclinical models for therapeutic studies., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Objectives: To characterize the clinical presentation, genomic alterations, pathologic phenotype and clinical management of microphthalmia-associated transcription factor (MITF) familial renal cell carcinoma (RCC), caused by a member of the TFE3, TFEB, and MITF family of transcription factor genes., Methods: The clinical presentation, family history, tumor histopathology, and surgical management were evaluated and reported herein. DNA sequencing was performed on blood DNA, tumor DNA and DNA extracted from adjacent normal kidney tissue. Copy number and gene expression analyses on tumor and normal tissues were performed by Real-Time Polymerase chain reaction. TCGA gene expression data were used for comparative analysis. Protein expression and subcellular localization were evaluated by immunohistochemistry., Results: Germline genomic analysis identified the MITF p.E318K variant in a patient with bilateral, multifocal type 1 papillary RCC and a family history of RCC. All tumors displayed the MITF variant and were characterized by amplification of chromosomes 7 and 17, hallmarks of type 1 papillary RCC. We demonstrated that MITF p.E318K variant results in altered transcriptional activity and that downstream targets of MiT family members, such as GPNMB, are dysregulated in the tumors., Conclusion: Association of the pathogenic MITF variant with bilateral and multifocal type 1 papillary RCC in this family supports its role as a risk allele for the development of RCC and emphasizes the importance of screening for MITF variants irrelevant of the RCC histologic subtype. This study identifies potential biomarkers for the disease, such as GPNMB expression, that may facilitate the development of targeted therapies for patients affected with MITF-associated RCC., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Renal cell carcinoma is a term that represents multiple different disease processes, each driven by different genetic alterations, with distinct histology, and biological potential which necessitates divergent management strategies. This review discusses the genetic alterations seen in several forms of hereditary kidney cancer and how that knowledge can dictate when and how to intervene with a focus on the surgical management of these tumors.

Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Renal medullary carcinoma (RMC) is a rare, aggressive disease that predominantly afflicts individuals of African or Mediterranean descent with sickle cell trait. RMC comprises 1% of all renal cell carcinoma diagnoses with a median overall survival of 13 months. Patients are typically young (median age-22) and male (male:female ratio of 2:1) and tumors are characterized by complete loss of expression of the SMARCB1 tumor suppressor protein. Due to the low incidence of RMC and the disease's aggressiveness, treatment decisions are often based on case reports. Thus, it is critical to develop preclinical models of RMC to better understand the pathogenesis of this disease and to identify effective forms of therapy. Two novel cell line models, UOK353 and UOK360, were derived from primary RMCs that both demonstrated the characteristic SMARCB1 loss. Both cell lines overexpressed EZH2 and other members of the polycomb repressive complex and EZH2 inhibition in RMC tumor spheroids resulted in decreased viability. High throughput drug screening of both cell lines revealed several additional candidate compounds, including bortezomib that had both in vitro and in vivo antitumor activity. The activity of bortezomib was shown to be partially dependent on increased oxidative stress as addition of the N-acetyl cysteine antioxidant reduced the effect on cell proliferation. Combining bortezomib and cisplatin further decreased cell viability both in vitro and in vivo that single agent bortezomib treatment. The UOK353 and UOK360 cell lines represent novel preclinical models for the development of effective forms of therapy for RMC patients., (© 2020 The Authors. Genes, Chromosomes & Cancer published by Wiley Periodicals, Inc.)

Background Identification of markers to aid in understanding the growth kinetics of Von Hippel-Lindau (VHL)-associated clear cell renal cell carcinoma (ccRCC) has the potential to allow individualization of patient care, thereby helping prevent unnecessary screening and optimizing intervention. Purpose To determine whether the degree of restricted diffusion at baseline MRI holds predictive potential for the growth rate of VHL-associated ccRCC. Materials and Methods Patients with VHL disease who underwent surgical resection of tumors between November 2014 and October 2017 were analyzed retrospectively in this HIPAA-compliant study. The change in ccRCC volume between two time points and apparent diffusion coefficient (ADC) at baseline was calculated by using segmentations by two readers at nephrographic-phase CT and diffusion-weighted MRI, respectively. Intraclass correlation coefficient was used to assess agreement between readers. Repeated-measures correlation was used to investigate relationships between ADC (histogram parameters) and tumor size at baseline with growth rate and volume doubling time (VDT). Predictive performance of the ADC parameter with highest correlation and tumor size at baseline was reviewed to differentiate tumors based on their VDT (≤1 year or >1 year). Results Forty-six patients (mean age, 46 years ± 7 [standard deviation]; 25 women) with 100 ccRCCs were evaluated. Interreader agreement resulted in mean κ scores of 0.89, 0.82, and 0.93 for mean ADC, baseline tumor volume, and follow-up tumor volume, respectively. ADC percentiles correlated negatively with tumor growth rate but correlated positively with VDT. Lower ADC values demonstrated stronger correlations. The 25th percentile ADC had the strongest correlation with growth rate (ρ = -0.52, P < .001) and VDT (ρ = 0.60, P < .001) and enabled prediction of VDT (≤1 year or >1 year) with an area under the receiver operating characteristic curve of 0.86 (sensitivity, 67%; specificity, 89%) ( P < .001). Conclusion Apparent diffusion coefficient at baseline was negatively correlated with tumor growth rate. Diffusion-weighted MRI may be useful to identify clear cell renal cell carcinomas with higher growth rates. © RSNA, 2020See also the editorial by Goh and Prezzi in this issue.

Treatment options for metastatic renal cell carcinoma (RCC) continue to expand. Three recent phase III trials, Checkmate 214, Keynote-426, and Javelin Renal 101, have led to FDA approval of three new regimens for patients with clear cell RCC: nivolumab plus ipilimumab, pembrolizumab plus axitinib, and avelumab plus axitinib, respectively. At the same time, the dearth of treatment options for non-clear cell RCC has changed very little. The role of cytoreductive nephrectomy has also come into question after the publication of the CARMENA and SURTIME trials. This review will examine recent changes in therapeutic options in clear cell RCC and non-clear RCC, and the role of surgery in the treatment of metastatic RCC.

Purpose: Published series of growth rates of renal tumors on active surveillance largely consist of tumors without pathologic or genetic data. Growth kinetics of genetically defined renal tumors are not well known. Here, we evaluate the growth of genetically defined renal tumors and their association with patient clinical and genetic characteristics., Patients and Methods: We evaluated patients with an inherited kidney cancer susceptibility syndrome as a result of a pathologic germline alteration of VHL, MET, FLCN, or BAP1 with at least 1 solid renal mass managed with active surveillance at our institution. Tumor growth rates (GR) were calculated and patients were stratified by genetic alteration and other clinical and genetic factors to analyze differences in growth rates using linear regression and comparative statistics., Results: A total of 292 patients with 435 genetically defined tumors were identified, including 286 VHL -deficient, 91 FLCN -deficient, 52 MET -activated, and 6 BAP1 -deficient tumors. There were significant differences in GRs when stratified by genetic alteration. BAP1 -deficient tumors had the fastest median GR (0.6 cm/y; interquartile range [IQR], 0.57-0.68 cm/y), followed by VHL -deficient tumors (GR, 0.37 cm/y; IQR, 0.25-0.57 cm/y), FLCN -deficient tumors (GR, 0.10 cm/y; IQR, 0.04-0.24 cm/y), and tumors with MET activation (GR, 0.15 cm/y; IQR, 0.053-0.32 cm/y; P < .001). Tumors from the same patient had similar GRs. Younger age was independently associated with higher GR ( P = .005)., Conclusion: In a cohort of genetically defined tumors, tumor growth rates varied in a clinically and statistically different manner according to genetic subtype. Rapid growth of BAP1 -deficient tumors indicates that these patients should be managed with caution. The faster growth of tumors in younger patients may support more frequent imaging, whereas the slower growth of other tumors may support extended surveillance beyond annual imaging in some instances.

Purpose of Review: To describe current paradigms for genetic testing, screening, and treatment of patients with inherited kidney cancer syndromes., Recent Findings: We describe various new aspects of hereditary kidney cancer. Recent data now support that hereditary kidney cancer may account for 5-8% of kidney cancers diagnosed. Methods of testing have evolved including the introduction of multigene next-generation sequencing panels. We continue to learn more about the natural history and management of classic hereditary cancer syndromes. New emerging conditions with lower kidney cancer penetrance have been recognized adding the growing list of syndromes associated with kidney cancer development. The surgical management strategies of enucleation remain however systemic therapy options are being explored both for localized and advanced settings., Summary: Genetic predisposition to kidney cancer is likely more common than once thought. Knowledge of clinical manifestation and genetic testing strategies are needed to properly identify and treat patient and their families.

Objectives: To study the short and intermediate surgical, renal functional, and oncologic outcomes of multiplex partial nephrectomy (mPN) and standard partial nephrectomy (sPN) in the setting of a solitary kidney., Patients and Methods: Review of a prospectively maintained database of patients undergoing solitary kidney partial nephrectomy at our institution was performed. Patients were stratified into 2 cohorts: mPN-where 3 or more renal tumors were resected and sPN-where 1 or 2 tumors were resected. Perioperative, renal functional, and oncological outcomes were compared., Results: Ninety-three patients with a solitary kidney underwent a total of 121 surgical procedures; 43 (35.5%) were sPN and 78 (64.4%) were mPN. The total and major (Clavien Grade III and IV) complication rates between sPN and mPN were similar (57.1% vs. 70.1%, P = 0.2; 31.0% vs. 35.1%, P = 0.3). At 12 months post-op, the percentage of patients with eGFR > 45 was similar in each group (sPN 87.0%, mPN 73.7%; P = 0.2), and long-term hemodialysis rates were 4.7% and 6.4%, respectively. Completion nephrectomy was performed in 2.3% of sPN and 2.6% of mPN. At a median follow-up of 40.1 months, the metastasis rate was 8.6% in the sPN group and 4.1% in the mPN group (P = 0.4)., Conclusions: Partial nephrectomy in the setting of a solitary kidney can effectively preserve renal function. The renal functional and oncologic outcomes were similar in sPN and mPN, with low hemodialysis rates and complication rates within the expected range of these operations. Three or more tumors in a solitary kidney should not be a contraindication for nephron sparing surgery., (Published by Elsevier Inc.)

Objective: To describe a family in which 3 members presented with mixed epithelial tumor of the kidney (MEST) and were found to possess a germline mutation in CDC73, a gene which is associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT)., Materials and Methods: Blood and tumor DNA from three family members who presented with a primary diagnosis of MEST was subjected to targeted gene sequencing to identify potential genetic components., Results: A germline start codon mutation (p.M1I) in CDC73 was identified in all 3 family members who presented with MEST and 2 tumors from 1 patient demonstrated somatic copy-neutral loss of heterozygosity. Patients presented with no evidence of hyperparathyroidism or jaw tumors, but both female patients had hysterectomies at an early age due to excessive bleeding and numerous fibroids, which is common in HPT-JT. A germline p.M1I mutation has been previously reported in a family with clinical features of HPT-JT., Conclusion: Patients with MEST may be at risk for HPT-JT and CDC73 germline mutation testing of MEST patients should be considered., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To assess the use of a handheld optical coherence tomography (OCT) probe for the evaluation of intraoperative surgical margins during partial nephrectomy (PN)., Methods: In an initial feasibility study, a radical nephrectomy specimen with a 9-cm tumor was cut into 19 sections, exposing 0 mm (n = 8), 1 mm (n = 6), and 2 mm (n = 5) gross margins. OCT was used to determine the margin width in each specimen. Second, a prospective ex vivo assessment of 15 PN tumor specimens was performed with OCT to determine margin status and to measure the attenuation coefficient of tumor and renal parenchyma., Results: Median OCT margin width measurements for sectioned samples were 0 mm, 0.9 mm (range 0.7-2.9 mm), and 2.7 (range 1.65-2.8 mm) for grossly 0 mm (positive), 1 mm, and 2 mm margins, respectively. The difference between measurements from all margin groups was statistically significant (P <.04). The sensitivity and specificity for identifying positive margins were both 100%. In the PN specimens, OCT correctly found that all specimens had negative margins (within <.0001)., Conclusion: We have demonstrated the feasibility of using a handheld OCT probe to assess margins ex vivo during PN. OCT may reduce the need for intraoperative frozen section and aid in minimizing parenchymal excision., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene ( P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies ( P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1 -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: The accumulation of somatic genetic alterations drives carcinogenesis. Little is known, however, about how the level of genetic alteration across an entire cancer genome affects tumor grade, stage or survival., Objective: To investigate the influence of somatic mutation count (MC) and copy number variation (CNV) on pathologic and oncologic outcomes in patients with genitourinary malignancies in The Cancer Genome Atlas (TCGA)., Design, Setting, and Participants: TCGA data sets for adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), chromophobe renal cell carcinoma (RCC; KICH), clear cell RCC (KIRC), papillary RCC (KIRP), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), and testis germ cell tumor (TGCT) were accessed via cBioportal., Outcome Measurements and Statistical Analysis: Median MC and CNV were compared among and within each tumor type. Patients were stratified by grade and stage, and differences in MC and CNV were compared. Correlation of MC and CNV with overall survival (OS) and recurrence-free survival (RFS) was analyzed when these data were available., Results and Limitations: Among the tumor types analyzed, BLCA had the highest MC at 167, followed by ACC (89), KIRP (71), TGCT (55), KIRC (45), PRAD (34), PCPG (14), and KICH (12). The tumor type with the highest fraction of the genome with CNV was KICH (0.94), followed by ACC (0.58), TGCT (0.41), BLCA (0.29), KIRP (0.15), PCPG (0.13), KIRC (0.12), and PRAD (0.06). MC was associated with higher T stage in ACC, N stage in KIRC, M stage in ACC, grade in BLCA, and primary Gleason score in PRAD, and was associated with OS and RFS in KICH. CNV was associated with higher N stage in PRAD, grade in KIRC, and Gleason grade in PRAD. In addition, higher CNV was independently associated with inferior RFS for KIRC, as well as inferior OS and RFS for KIRP., Conclusions: MC and CNV vary greatly among tumor types., Patient Summary: Cancers with higher levels of genomic alterations are associated with worse pathologic features and survival. The degree of genomic alterations could serve as a useful marker of disease aggressiveness., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To determine the impact of transesophageal echocardiography on the surgical management of patients undergoing nephrectomy and inferior vena cava tumor thrombectomy for renal cell carcinoma., Materials and Methods: We retrospectively analyzed intraoperative records of 67 patients with renal cell carcinoma and level II-IV invasion of the inferior vena cava who underwent nephrectomy with tumor thrombectomy between 2007 and 2015. Based on preoperative imaging, patients were categorized according to vena cava thrombus level. Diagnostic utility and impact on surgical management were extracted from the operative note, anesthesia record, and intraoperative echocardiography report., Results: Twelve of 34 patients (35%) with level II thrombus, 14 of 18 (78%) with level III thrombus, and 15 of 15 (100%) with level IV thrombus had intraoperative transesophageal echocardiography. With increasing level of tumor thrombus, the diagnostic yield and surgical impact increased. Echocardiography provided new diagnostic information in 7 of 12 (58%) patients with level II thrombus and altered surgical management in 16%. Among level III thrombus patients, echocardiography provided new diagnostic information in 12 of 14 (86%) and altered surgical management in 21%. Echocardiography provided new diagnostic information and impacted surgical management in all 15 (100%) patients with a level IV thrombus., Conclusion: The diagnostic yield of intraoperative transesophageal echocardiography increases in patients with greater vena caval tumor thrombus extension. This information has a significant influence on surgical decision-making., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Despite advances in systemic therapy for metastatic renal cell carcinoma, durable responses remain rare and surgical management remains a mainstay of treatment for many patients with metastatic disease. Management of the primary tumor in metastatic patients can occur as 1) palliative nephrectomy for symptomatic patients in whom cure is not achievable, 2) cytoreductive nephrectomy before systemic therapy, or 3) consolidative nephrectomy after systemic therapy. Palliative nephrectomy is rarely performed in centers where angioembolization is available. The evidence for cytoreductive nephrectomy is based on randomized trials in the cytokine era and retrospective studies in the more recent targeted therapy era. Consolidative nephrectomy is utilized after systemic therapy for intermediate- and poor-risk patients or in patients with potentially unresectable disease based on retrospective evidence. Resection of metastatic lesions, or metastasectomy, is utilized in select patients, with efficacy predicated on the organs involved and the extent of resection that is achievable, based on retrospective data. Herein, the evidence for surgical management of both the primary tumor and metastatic lesions in patients with metastatic renal cell carcinoma is reviewed.

Purpose: This study investigates whether the addition of preoperative Tc-MIBI SPECT/CT can increase the degree of diagnostic confidence in the differentiation of benign from malignant enhancing renal masses., Patients and Methods: Patients were recruited as part of an institutional review board-approved prospective clinical trial. Forty-eight patients with clinical stage T1 solid renal masses who underwent a Tc-MIBI SPECT/CT before partial or radical nephrectomy were evaluated. Conventional CT and MRI, which were approximately performed within 8 weeks before Tc-MIBI, were retrospectively retrieved. Based on a 5-point scale (1 = definitely benign, 5 = definitely malignant), 2 blinded readers recorded their degree of confidence for each lesion using conventional imaging before and after reviewing the Tc-MIBI uptake ratios. Surgical pathology was considered as the reference standard., Results: Additional review of Tc-MIBI SPECT/CT uptake ratios increased diagnostic confidence in the differentiation of solid renal masses in 14/48 lesions (29.2%). In 9 lesions, the addition of Tc-MIBI changed the initial confidence levels of malignancy toward benign diagnosis. Postsurgical pathology confirmed the diagnosis of benign histology (oncocytoma/hybrid oncocytic-chromophobe tumors) in 7 and chromophobe renal cell carcinoma (behave as indolent) in 2 of these lesions. Tc-MIBI increased the confidence level toward malignancy in 5 cases; all were confirmed as RCC on surgical pathology. The area under the receiver operative characteristic curve was 0.60 for conventional imaging alone and 0.85 after reviewing Tc-MIBI (P for difference = 0.03)., Conclusions: Preoperative Tc-MIBI SPECT/CT enhances the performance of conventional imaging, improving the characterization of benign histologies and lowering the possibility of misclassification.

Objective: To compare outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) in patients 65 years and older., Materials and Methods: Our institutional renal mass registry was queried for patients 65 and older with solitary cT1-T2 renal mass resected by PN or RN. Clinicopathologic features and perioperative outcomes were compared between groups. Renal function outcomes measured by change in estimated glomerular filtration rate (eGFR) and freedom from eGFR< 45 mL/min/1.73 m 2 were analyzed. Multivariate Cox proportional hazard models for overall survival and cancer-specific survival were analyzed., Results: Overall, 787 patients met inclusion criteria. Of these, 437 (55.5%) underwent PN and 350 (44.5%) underwent RN. Median follow-up was 36 months. Patients in the PN cohort were younger (median age 70.3 years vs 71.9 years, P < .001), had lower American Society of Anesthesiologists scores (2.6 vs 2.8, P = .001), smaller tumors (tumor diameter 2.8 cm vs 5.0 cm, P < .001), and lower proportion of renal cell carcinoma (76.7% vs 87.4%, P < .001). Perioperative outcomes were similar between PN and RN groups as were complications (37.8% vs 38.9%). Estimated change in eGFR was less in PN vs RN (6.4 vs 19.7, P < .001) at last follow-up. Overall survival and cancer-specific survival were equivalent between modalities., Conclusion: Because the renal functional benefit of PN is realized over many years and the procedure has a higher historical complication rate than RN, some suspected elderly patients might benefit more from RN over PN. However, these data suggest that elderly patients are not harmed and may potentially benefit from PN. Age alone should not be a contraindication to nephron-sparing surgery., Competing Interests: Financial Disclosure: The authors declare that they have no relevant financial interests., (Copyright © 2016 Elsevier Inc. All rights reserved.)