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Introduction:Treatment of benign renal masses may often be unnecessary and can lead to significant morbidity, mortality, and health care costs. However, individual burdens such as decisiona...

BackgroundGermline variants in fumarate hydratase (FH) are associated with autosomal dominant (AD) hereditary leiomyomatosis and renal cell cancer (HLRCC) and autosomal recessive (AR) fumarase deficiency (FMRD). The prevalence and cancer penetrance across different FH variants remain unclear.MethodsA database containing 120,061 records from individuals undergoing cancer germline testing was obtained. FH variants were classified into 3 categories: AD HLRCC variants, AR FMRD variants, and variants of unknown significance (VUSs). Individuals with variants from these categories were compared with those with negative genetic testing.ResultsFH variants were detected in 1.3% of individuals (AD HLRCC, 0.3%; AR FMRD, 0.4%; VUS, 0.6%). The rate of AD HLRCC variants discovered among reportedly asymptomatic individuals without a clear indication for HLRCC testing was 1 in 2668 (0.04%). In comparison with those with negative genetic testing, the renal cell carcinoma (RCC) prevalence was elevated with AD HLRCC variants (17.0% vs 4.5%; P&nbsp

Introduction:We assessed current utilization and sequencing of renal mass biopsy (RMB) and thermal ablation for renal cell carcinoma (RCC) patients in the United States.Methods:The 2004–201...

With the expansion in cross-sectional imaging over the past few decades, there has been an increase in the number of incidentally detected renal masses and an increase in the incidence of renal cell carcinomas (RCCs). The complete characterization of an indeterminate renal mass on CT or MR images is challenging, and the authors provide a critical review of the best imaging methods and essential, important, and optional reporting elements used to describe the indeterminate renal mass. While surgical staging remains the standard of care for RCC, the role of renal mass CT or MRI in staging RCC is reviewed, specifically with reference to areas that may be overlooked at imaging such as detection of invasion through the renal capsule or perirenal (Gerota) fascia. Treatment options for localized RCC are expanding, and a multidisciplinary group of experts presents an overview of the role of advanced medical imaging in surgery, percutaneous ablation, transarterial embolization, active surveillance, and stereotactic body radiation therapy. Finally, the arsenal of treatments for advanced renal cancer continues to grow to improve response to therapy while limiting treatment side effects. Imaging findings are important in deciding the best treatment options and to monitor response to therapy. However, evaluating response has increased in complexity. The unique imaging findings associated with antiangiogenic targeted therapy and immunotherapy are discussed. An invited commentary by Remer is available online. Online supplemental material is available for this article. ©RSNA, 2021.

Renal oncocytoma (RO) accounts for 5% of renal cancers and generally behaves as a benign tumor with favorable long-term prognosis. It is difficult to confidently distinguish between benign RO and other renal malignancies, particularly chromophobe renal cell carcinoma (chRCC). Therefore, RO is often managed aggressively with surgery. We sought to identify molecular biomarkers to distinguish RO from chRCC and other malignant renal cancer mimics. In a 44-patient discovery cohort, we identified a significant differential abundance of nine genes in RO relative to chRCC. These genes were used to train a classifier to distinguish RO from chRCC in an independent 57-patient cohort. The trained classifier was then validated in five independent cohorts comprising 89 total patients. This nine-gene classifier trained on the basis of differential gene expression showed 93% sensitivity and 98% specificity for distinguishing RO from chRCC across the pooled validation cohorts, with a c-statistic of 0.978. This tool may be a useful adjunct to other diagnostic modalities to decrease the diagnostic and management uncertainty associated with small renal masses and to enable clinicians to recommend more confidently less aggressive management for some tumors. PATIENT SUMMARY: Renal oncocytoma is generally a benign form of kidney cancer that does not necessarily require surgical removal. However, it is difficult to distinguish renal oncocytoma from other more aggressive forms of kidney cancer, so it is treated most commonly with surgery. We built a classification tool based on the RNA levels of nine genes that may help avoid these surgeries by reliably distinguishing renal oncocytoma from other forms of kidney cancer.

We reviewed the literature surrounding the role of opioids and their receptors in urological malignancy. Recent studies have suggested clinically significant effects of agonism or antagonism of opioid receptors on cancer related outcomes and tumorigenesis. The focus of these efforts has centered on nonurological malignancies. However, a compelling body of evidence is growing in the fields of prostate, bladder and kidney cancer.A systematic review of English language articles published through 2020 was conducted with key phrases related to kidney, bladder or prostate cancer, and opioids or narcotics. A total of 837 unique records were identified, of which 49 were selected for full text review and 33 were included in the qualitative analysis. Eight records were identified via citation review and 1 study was recently presented at a national meeting.Retrospective reviews suggest poorer disease specific and recurrence-free survival with increased perioperative opioid administration in patients undergoing prostate or bladder cancer surgery. However, the data are controversial. Kappa opioid receptors are implicated in both proliferation and inhibition of prostate cancer cell growth across in vitro studies, with a proposed interaction with the androgen cascade. Similarly opioid growth factor receptor is highly expressed in prostate cancer cells and repressed by androgens. Prostate cancer tissue stains more intensely for the mu opioid receptor, and patients with higher expression have poorer oncologic outcomes. Opioid agonism in vitro induces urothelial cell carcinoma proliferation, migration and invasion, with possible additional influence from interactions with the bradykinin b2 receptor. Agonism of the mu, kappa and delta opioid receptors induces renal cell carcinoma tumorigenesis, possibly via upregulation of survivin. Meanwhile, opioid growth factor receptor agonism has the opposite effect in renal cell carcinoma.Evidence surrounding the role of opioids and their receptors in urological malignancy is provocative and should serve as an impetus for further investigation.

PURPOSE: Patients with cancer commonly report distress and fear of cancer recurrence (FCR) impacting quality of life and clinical outcomes. This study aims to test the association between emotional well-being and clinical characteristics of survivors with localized renal cell carcinoma (RCC). MATERIALS AND METHODS: Survivors with localized RCC were invited to participate in this study through social media by the Kidney Cancer Research Alliance. Participants self-reported clinical characteristics, distress (Distress Thermometer), and FCR (Fear of Cancer Recurrence-7). Ordinal regression was used to test the association between emotional well-being and patient characteristics. RESULTS: A total of 412 survivors were included in this analysis. Participants were mostly female (79.4%) and well educated (58.3%), with a median age of 54 years (range, 30-80 years) and median time since diagnosis of 17.5 months. More than one half were diagnosed with stage I disease (56.1%). Most patients (62.3%) had a clear understanding of their diagnosis. A high prevalence of moderate to severe distress (67.0%) and FCR (54.9%) was reported across all survivors of RCC. Higher FCR was associated with female gender, younger age, and lack of understanding of their diagnosis ( P = .001), whereas more recent diagnosis was associated with higher distress levels ( P = .01). CONCLUSION: Our findings suggest that FCR is a common problem that is persistent after therapy and that certain individuals, including female and younger patients, may be at particular risk of experiencing clinically relevant FCR.

Improvements in chemistry, molecular biology, genetics, and bioinformatics have allowed broad use of transcriptomic profiling. Understanding the population of ribonucleic acid (RNA) transcripts can provide important clinical information relevant to kidney cancer care. This includes a better understanding of kidney cancer subtype and distinct clusters within these categories. RNA-sequencing (RNA-seq) is typically done on a region within the tumor, which represents thousands to millions of heterogeneous cells and various components of the microenvironment. Computational tools can deconvolute these populations to provide insight into the microenvironment. Specific signatures of hypoxia, proliferation, angiogenesis and immune infiltration can predict response and survival. Prognostic signatures can risk stratify tumors to aid in identification of patients who might derive benefit from adjuvant therapy. As the cost of sequencing continues to decline and improved bioinformatic tools are developed, the barriers to clinical use of transcriptomic data continue to crumble. Here we review the current literature around the use of transcriptomics in kidney cancer diagnosis and management.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

BACKGROUND: Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (FH). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the FH carrier frequency and kidney cancer penetrance. METHODS: Data sets containing sequencing data for the FH gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the FH gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss-of-function alterations, and 3) highly impactful missense alterations. The cumulative incidence of FH alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence. RESULTS: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10(–3) (1 in 393) and 1.20 × 10(–3) (1 in 835), respectively. There were differences in the allele frequencies of FH alterations between world populations. Based on various estimates of the percentage of kidney cancers with FH alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7% to 5.8%. CONCLUSIONS: FH alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.

Conflicting data have been published on the prognostic significance of histologic parameters in papillary renal cell carcinoma (PRCC). We conducted a comprehensive evaluation of clinical and histologic parameters in PRCC in nephrectomies and their impact on prognosis, with an emphasis on World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grade, tumor architecture (solid, micropapillary, and hobnail), and PRCC type. A total of 185 PRCC cases were evaluated, 117 (63.2%) type 1, 45 (24.3%) type 2, and 11 (5.9%) mixed type 1 and type 2. Using WHO/ISUP grading criteria, PRCCs were graded as follows: 6 (3.2%) grade 1; 116 (62.7%) grade 2; 61 (33.0%) grade 3; and 2 (1.1%) grade 4. The solid architecture was present in 3 cases (1.6%) and comprised 10%, 10%, and 30% of the tumor area. Micropapillary architecture was present in 10 cases (5.4%), ranging from 5% to 30% of the tumor (mean=11%; median=10%). Hobnail architecture was seen in 9 cases (4.9%), with mean percentage of 23% (median=15%; range: 5% to 50%) involvement of tumor area. Parameters associated with worse disease-free survival (DFS) and overall survival (OS) in the univariate analysis included WHO/ISUP grade, pathologic stage, tumor size, and solid, micropapillary, or hobnail architecture (P

There are more than a dozen recognized hereditary forms of kidney cancer. While classic syndromic forms are readily recognizable, more recently described conditions are subtler because of lower penetrance. Adequate counseling and implementation of risk assessment before or after management are important aspects of clinical care. Germline testing to assess hereditary risk has rapidly evolved thanks to multigene panel testing, which can be performed quickly and at relatively low cost. This review discusses what is known about germline risk assessment, namely which individuals should be tested and when and how, and covers many of the uncertainties around this process. Patient summary More than a dozen genes have been linked to predisposition to kidney cancer. We review genetic testing in terms of who should be tested and when and how the testing should be carried out. Results from genetic tests can help in tailoring screening and surgical management and in selecting the most suitable chemotherapy.

CONTEXT: Small renal masses (SRMs; tumors

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.

Germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes lead to hereditary leiomyomatosis and RCC (HLRCC) and hereditary paraganglioma and pheochromocytoma, respectively. The renal cell carcinomas that arise in these conditions are characterized by dysregulated Krebs cycles, accumulation of oncometabolites, downstream changes in gene expression, and epigenetic modifications that carry unique therapeutic implications. In this review, we evaluate the current literature on these tumors, including the epidemiology, clinical course, screening guidelines, and management of localized and metastatic disease.

PURPOSE: We aimed to determine whether insurance expansions implemented through the Affordable Care Act (ACA) were associated with changes in coverage status, disease stage, and treatment of younger adults with testicular germ cell tumors (GCT). MATERIALS AND METHODS: We identified men aged 18–64 diagnosed with testicular GCTs between 2010 and 2015 in the National Cancer Data Base. We defined time periods as: pre-ACA (2010–2013) and post-ACA (2014–2015) and used difference-in-differences (DID) modeling to examine associations between state Medicaid expansion status and changes in insurance, stage at diagnosis, and treatment. RESULTS: Following the ACA, the proportion of patients with any health insurance increased 3.7% (95% CI 3–4.5) in Medicaid expansion states and 3.0% (95% CI 1.5–4.5) in non-expansion states, mainly by gaining Medicaid and private insurance, respectively. The largest increases occurred in low-income patients, where Medicaid expansion was associated with an adjusted increase of 14.5 percentage points (95% CI 7.2–21.8) in Medicaid coverage following the ACA. We did not observe reductions in late-stage diagnoses during the observation period. Changes in the proportion of patients receiving chemotherapy or radiation for advanced-stage cancers were ongoing prior to the ACA and differed between expansion and non-expansion states, limiting assessment of ACA-related effects on individual treatments. CONCLUSIONS: Post-ACA, the proportion of newly diagnosed testicular cancer patients with health insurance increased, with the largest effects seen among lowest income individuals. Our findings that changes in practice preceded the ACA and differed by expansion status highlight the need for caution in assessing the legislation’s impact.

Trials SWOG 8949 and EORTC 30947 had the same eligibility criteria and established the role of cytoreductive nephrectomy for metastatic renal cell carcinoma. The more recently published CARMENA trial calls into question the need for cytoreductive nephrectomy. A systematic comparison of CARMENA and SWOG 8949 suggests that cytoreductive nephrectomy may be beneficial for patients receiving immunotherapy but not targeted therapy. The approval of immune checkpoint inhibitors for previously untreated metastatic renal cell carcinoma underlines the need for another randomized phase 3 trial of cytoreductive nephrectomy for patients receiving powerful modern immunotherapies.

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.

Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT are still under investigation. In this study, we identified a previously unrecognized role of HSP90 in cooperating with signal transducer and activator of transcription 3 (STAT3) to regulate TWIST1 transcription in cancer cells. The HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin suppressed TWIST1 mRNA expression and promoter activity in epithelial ovarian cancer, renal clear cell cancer, and nasopharyngeal cancer cell lines. The interactions between HSP90 and transcription factors were visualized in cancer cell lines and tumor tissues using proximity ligation assays. Our findings reveal that HSP90 promotes the binding of STAT3 to the TWIST1 promoter, leading to the transcription of TWIST1. The inhibition of HSP90 downregulates STAT3 activity and TWIST1 transcription, thereby suppressing EMT and potentially inhibiting tumor progression, metastasis, and chemoresistance in different types of cancers. SIGNIFICANCE STATEMENT: Our study provides new evidence that HSP90 promotes EMT through enhancing TWIST1 transcription, which can be suppressed by HSP90 inhibitors. The HSP90 inhibitor inhibits EMT, thus potentially slowing down tumor growth, invasion, dissemination, metastasis, and drug resistance. These findings will hopefully pave the way for new therapeutic opportunities to target EMT and metastasis using HSP90 inhibitors.

The objective of our study was to evaluate the cost-effectiveness of active surveillance (AS) versus nephron-sparing surgery (NSS) in patients with a Bosniak IIF or III renal cyst.Markov models were developed to estimate life expectancy and lifetime costs for 60-year-old patients with a Bosniak IIF or III renal cyst (the reference cases) managed by AS versus NSS. The models incorporated the malignancy rates, reclassification rates during follow-up, treatment effectiveness, complications and costs, and short- and long-term outcomes. An incremental cost-effectiveness analysis was performed to identify management preference under an assumed $75,000 per quality-adjusted life-year (QALY) societal willingness-to-pay threshold, using data from studies in the literature and the 2015 Medicare Physician Fee Schedule. The effects of key parameters were addressed in a multiway sensitivity analysis.The prevalence of malignancy for Bosniak IIF and III renal cysts was 26% (25/96) and 52% (542/1046). Under base case assumptions for Bosniak IIF cysts, the incremental cost-effectiveness ratio of NSS relative to AS was $731,309 per QALY for women, exceeding the assumed societal willingness-to-pay threshold, and AS outperformed NSS for both life expectancy and cost for men. For Bosniak III cysts, AS yielded greater life expectancy (24.8 and 19.4 more days) and lower lifetime costs (cost difference of $12,128 and $11,901) than NSS for men and women, indicating dominance of AS over NSS. Superiority of AS held true in sensitivity analyses for men 46 years old or older and women 57 years old or older even when all parameters were set to favor NSS.AS is more cost-effective than NSS for patients with a Bosniak IIF or III renal cyst.

To evaluate trends in the utilization of active surveillance (AS) in a nationally representative cancer database. AS has been increasingly recognized as an effective strategy for patients with small renal masses but little is known about national usage patterns.We identified patients with clinical T1a renal masses within the National Cancer Database in 2010 through 2014. Patients were classified according to initial management strategy received including AS, surgery, ablation, or other treatment. We characterized time trends in the use of AS vs definitive therapy and examined clinical and socio-demographic determinants of AS among patients with small renal masses using multivariable logistic regression models.We identified 59,189 patients who satisfied the inclusion criteria. Of the total cohort, 1733 (2.9%) individuals received initial management with AS, while 57,456 (97.1%) received definitive treatment. Surveillance rates remained below 5% in all years. On multivariate analysis, patient age (OR: 1.08, 95% CI 1.08-1.09), smaller tumor size of2 cm vs ≥2 cm (OR: 2.43, 95% CI: 2.20-2.7, P.0001), management at an academic center vs community center (OR: 2.05, 95% CI: 1.83-2.29), and African American vs Caucasian race (OR: 1.56, 95% CI:1.35-1.80) were independently associated with use of AS as initial management.In a representative national cohort of patients with small renal masses, we observed clinical and facility-level differences in the utilization of active surveillance in patients with T1a renal masses. Further investigation is warranted to better understand the forces underlying initial management decisions for patients with small renal masses.

Background Patients treated for renal cell carcinoma (RCC) may be diagnosed with a metachronous, contralateral tumor. We evaluated the risks of contralateral tumor development using the Surveillance, Epidemiology, and End Results database. Methods Among RCC patients, we identified those with a metachronous, contralateral RCC diagnosed ≥1 year after primary diagnosis. We performed a competing risks analysis to evaluate associations between clinicopathologic factors and metachronous, bilateral RCC. Cumulative incidence and standardized incidence ratios (SIRs) were calculated. Results There were 80,403 cases of RCC identified, with a median follow-up of 8.3 years; of these, 1063 (1.3%) developed metachronous, contralateral RCC (median of 6 years after diagnosis). The cumulative incidence at 10, 20, and 30 years of follow-up was 1.5%, 3.1%, and 4.7%, respectively. An increased risk was observed among men (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.20-1.55), blacks (HR, 2.00; 95% CI, 1.71-2.33), and those with papillary histology (HR, 1.72; 95% CI, 1.41-2.10). Risk of metachronous disease decreased with increasing age at primary diagnosis (HR per 1-year increase, 0.97; 95% CI, 0.96-0.97). The SIRs were highest among those diagnosed at a younger age and remained elevated even after extended follow-up (>10 years). Conclusions Our findings suggest that the cumulative incidence of metachronous, contralateral RCC may be higher than previously reported. Younger age, black race, papillary histology, and male sex increase the risk of metachronous, contralateral RCC development. The high SIRs seen in all demographic groups may support a rationale for lifelong surveillance, especially in high-risk subgroups with early disease onset.

Context The epidemiological signature of renal cell carcinoma (RCC) during the past decades is explained by overdetection and overtreatment of indolent cancers; furthermore, a non-negligible proportion of patients undergoing surgery for suspected RCC harbour benign renal tumours. As the gold standard for RCC diagnosis remains histopathological analysis of surgical or biopsy specimens, implementation of noninvasive diagnostic strategies to discriminate between benign and malignant renal masses is an urgent unmet need. Objective To systematically review novel liquid biomarkers and imaging modalities for RCC diagnosis. Evidence acquisition A systematic review of the recent English-language literature was conducted according to the European Association of Urology guidelines and the PRISMA statement recommendations (PROSPERO ID: CRD42020190773) using the MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov databases. Risk-of-bias assessment was performed according to the QUADAS 2 tool. Evidence synthesis Overall, 15 studies (six on biomarkers and nine on imaging) and eight clinical trials were included. None of the biomarkers or imaging modalities has been validated or shown to have a distinct clinical value for RCC. Specific combinations of urinary cell-free and exosomal miRNAs, urinary miR-15a, and specific panels of urinary metabolites assessed by metabolomics appear promising. In addition, machine/deep learning algorithms and radiomics applied to cross-sectional images may have potential to improve RCC diagnosis. Most studies are limited by the retrospective design, size, and lack of external validation. Conclusions Liquid biomarkers or imaging modalities are not ready for integration in the clinic and further well-designed studies must validate preliminary findings and explore utility in clinical decision-making. Patient summary We provide a comprehensive overview of the currently available biomarkers (measured in blood or urine) and novel imaging tests (other than conventional imaging) to discriminate kidney cancer from benign renal masses in a noninvasive fashion. None of the biomarkers or imaging modalities studied was validated or added clinical value; therefore, none of them can be implemented in the clinic. However, these approaches appear to be promising for improving the diagnosis of kidney cancer in the future.

INTRODUCTION AND OBJECTIVE:Surgical resection remains the standard of care for localized Renal Cell Carcinoma (RCC). Approximately 75 percent of RCC patients will be diagnosed with localized diseas...

Background Although obesity is an established risk factor for renal cell carcinoma (RCC), it is unclear whether this relationship varies across histologic subtypes. Methods We conducted a nested case-control study within the Kaiser Permanente Northern California (KPNC) health care network, and meta-analysis combining our results with those of previously published studies. Our KPNC study included 685 RCC cases [421 clear cell; 65 papillary; 24 chromophobe; 35 other; 141 not otherwise specified (NOS)] and 4266 controls. Subtype-specific odds ratios (ORs) and 95% confidence intervals (CIs) for categories of body mass index (BMI) and were computed from the case-control data using polytomous logistic regression. Findings from this and other relevant studies were combined by meta-analysis using a random effects model. Results In the KPNC study, obesity (BMI ≥ 30 kg/m2) was associated with clear cell RCC (OR 1.5, 95% CI 1.1–2.1) and chromophobe RCC (OR 2.5, 95%CI 0.8–8.1), but not with papillary RCC (OR 1.0, 95% CI 0.5–1.9). In meta-analysis including three additional studies, a similar pattern of summary relative risks (SRR) for obesity was observed across subtypes (clear cell: SRR 1.8, 95% CI 1.5–2.2; chromophobe: SRR 2.2, 95% CI 1.3–3.7; papillary, SRR 1.2, 95% CI 0.8–1.6). Conclusions These findings support the hypothesis that histologic subtypes of RCC possess distinct etiologic pathways, with obesity important for the development of clear cell and, possibly, chromophobe RCC, but not papillary RCC.

Purpose: Tumor heterogeneity may represent a barrier to preoperative genomic characterization by needle biopsy in clear cell renal cell carcinoma (ccRCC). The extent of heterogeneity in small renal tumors remains unknown. Therefore, we set out to evaluate heterogeneity in resected large and small renal tumors. Experimental Design: We conducted a study from 2013 to 2016 that evaluated 47 consecutive ccRCC tumors resected during radical or partial nephrectomy. Cases were designated as small (7 cm) tumors. Each tumor had three regions sampled. Copy-number variation (CNV) was assessed and gene expression analysis was performed to characterize the clear-cell A and B (ccA/ccB) profile and the cell-cycle progression (CCP) score. Genomic heterogeneity between three regions was evaluated using CNV subclonal events, regional expression profiles, and correlation between gene expression. Results: Twenty-three small and 24 large tumors were analyzed. Total CNVs and subclonal CNVs events were less frequent in small tumors (P < 0.001). Significant gene expression heterogeneity was observed for both CCP scores and ccA/ccB classifications. Larger tumors had more variance in CCP scores (P = 0.026). The distribution of ccA/ccB differed between small and large tumors with mixed ccA/ccB tumors occurring more frequently in the larger tumors (P = 0.024). Analysis of five mixed tumors (with both ccA/ccB regions) demonstrated the more aggressive ccB phenotype had greater CNV events (P = 0.014). Conclusions: Small renal tumors have much less genomic complexity and fewer subclonal events. Pretreatment genomic characterization with single-needle biopsy in small tumors may be useful to assess biologic potential and may influence therapy. Clin Cancer Res; 24(17); 4137–44. ©2018 AACR.

PURPOSE: Renal cell carcinoma (RCC) incidence is higher among black than white Americans. The reasons for this disparity remain unclear. METHODS: We calculated race- and sex-specific population attributable risk percentages (PAR%) and their 95% confidence intervals (CI) for hypertension and chronic kidney disease (CKD) among black and white subjects ≥50 years of age from the US Kidney Cancer Study (USKC; 965 cases, 953 controls), a case-control study in Chicago and Detroit, and a nested case-control study in the Kaiser Permanente Northern California health care network (KPNC; 2,162 cases, 21,484 controls). We also estimated PAR% for other modifiable RCC risk factors (cigarette smoking, obesity) in USKC. RESULTS: In USKC, the PAR% for hypertension was 50% (95%CI 24-77%) and 44% (95%CI 25-64%) among black women and men, respectively; and 29% (95%CI 13-44%) and 27% (95%CI 14-39%) for white women and men, respectively. In KPNC, the hypertension PAR% was 40% (95%CI 18-62%) and 23% (95%CI 2-44%) among black women and men, and 27% (95%CI 20-35%) and 19% (95%CI 14-24%) among white women and men, respectively. The PAR% for CKD in both studies ranged from 7-10% for black women and men but was negligible (

A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM). Currently, there are no uniform guidelines on the definition of hereditary prostate cancer and genetic testing. With the advent of next-generation sequencing, which is capable of testing multiple genes simultaneously, and the approval of olaparib for BRCA1/BRCA2 or ATM-mutated, metastatic, castrate-resistant prostate cancer, it is being recognized that the results of genetic testing have an impact on therapeutic strategies. In this review, the authors examine the role of genetic counseling and testing, the challenges of insurance coverage for testing, the available germline and somatic testing panels, and the complexity of each testing method and its implications. Cancer 2018. © 2018 American Cancer Society.

Currently, drug development efforts and clinical trials to test them are often prioritized by targeting genes with high frequencies of somatic variants among tumors. However, differences in oncogenic mutation rate-not necessarily the effect the variant has on tumor growth-contribute enormously to somatic variant frequency. We argue that decoupling the contributions of mutation and cancer lineage selection to the frequency of somatic variants among tumors is critical to understanding-and predicting-the therapeutic potential of different interventions. To provide an indicator of that strength of selection and therapeutic potential, the frequency at which we observe a given variant across patients must be modulated by our expectation given the mutation rate and target size to provide an indicator of that strength of selection and therapeutic potential. Additionally, antagonistic and synergistic epistasis among mutations also impacts the potential therapeutic benefit of targeted drug development. Quantitative approaches should be fostered that use the known genetic architectures of cancer types, decouple mutation rate, and provide rigorous guidance regarding investment in targeted drug development. By integrating evolutionary principles and detailed mechanistic knowledge into those approaches, we can maximize our ability to identify those targeted therapies most likely to yield substantial clinical benefit.

Background: Leukocyte telomere length (LTL) is a potential biomarker of cancer prognosis; however, evidence for renal cell carcinoma (RCC) is inconsistent. Methods: We investigated LTL and RCC-specific survival among 684 cases from the US kidney cancer study (USKC) and 241 cases from the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO). Leukocyte telomere length was measured by quantitative polymerase chain reaction, and hazard ratios (HRs) and 95% confidence intervals (CIs) computed using multivariable Cox models. Results: Short LTL was associated with poorer disease-specific survival in both USKC (lowest vs highest quartile: HR: 2.3, 95% CI: 1.2–4.4; P for trend=0.02) and PLCO (HR: 2.4, 95% CI: 1.0–5.4; P=0.04). Among USKC cases, the association was strongest for stage-I RCC (HR: 5.5, 95% CI: 1.6–19.0; P=0.006). Conclusions: Our findings suggest that shorter LTL is an independent marker of poor RCC prognosis, particularly for stage-I disease.

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.

Introduction The modern treatment paradigms for early stage kidney cancer include ablative therapies. Unlike surgical ablation, percutaneous ablation uses a radiographic platform, potentially altering the role of the urologist. We compared surgical and percutaneous ablation regarding treatment processes and outcomes. Methods Using SEER (Surveillance, Epidemiology and End Results)-Medicare data, we identified subjects undergoing surgical or percutaneous ablation between 2006 and 2009 for stage I kidney cancer. We evaluated outcomes relating to 30-day complications, unplanned hospital admissions, long-term survival and mortality. Adjusting for patient characteristics, we compared processes and outcomes according to ablation approach using generalized estimating equations and Cox proportional hazard models, respectively. Results We identified 376 subjects (45.8%) treated with surgical ablation and 444 (54.1%) treated with percutaneous ablation. Use of percutaneous ablation increased substantially during the study period. Compared to surgical ablation, percutaneous ablation was applied more often in the outpatient setting (71.2% vs 2.4%, p Conclusions Percutaneous ablation has become the most common ablative modality for early stage kidney cancer. Although percutaneous ablation carries a more favorable safety profile, posttreatment morbidity occurs with some frequency, highlighting the need for continued urologist engagement.

Tumor size has been used for decision making in the management of patients with renal masses. Active surveillance in selected patients is now increasingly common in tumors ≤4 cm in size. Clear cell renal cell carcinoma (CCRCC) is the most common type of renal malignancy. Adverse histopathologic characteristics that correlate with worse prognosis have been described in CCRCCs. The aim of our study was to determine the frequency and extent of adverse histopathologic characteristics in CCRCCs ≤4 cm and their association with patient outcome. A search of a single institution for nephrectomies performed for CCRCC identified 631 consecutive cases. Cases were reviewed for the following morphologic features: high nuclear grade, necrosis, lymphovascular invasion, and rhabdoid or sarcomatoid histology. Relationships between the variables were examined by Kruskal-Wallis test, Wilcoxon test, χ test, and logistic regression. We found adverse tumor histopathologic characteristics were significantly related to size: In CCRCCs4 versus ≤4 cm, there were more high nuclear grade (45% vs. 15%, P0.01), necrosis (46% vs. 21%, P0.01), and lymphovascular invasion (17% vs. 3%, P0.01). Although adverse histologic features are less commonly seen in CCRCCs ≤4 cm, their presence was associated with lower disease-free survival (P0.01). Adverse histopathologic characteristics in CCRCCs ≤4 cm correlated with worse prognosis and identification of these features through needle core biopsy examination may guide clinical management, especially in patients for whom active surveillance is considered.

Background Brain metastases (BM) are frequently observed in advanced renal-cell carcinoma (RCC). Historically these individuals have been excluded from clinical trials, but recently, with better local control, many can receive aggressive therapy after treatment. We evaluate our single-institution experience over various treatment eras. Patients and Methods Patients undergoing evaluation for RCC BM from 2001 to 2018 were identified from our institutional database. Clinical notes, demographics, comorbidities, histology, central nervous system (CNS) treatments, systemic therapy, and outcomes were reviewed. Overall survival (OS) and CNS recurrence-free survival (RFS) were evaluated by the Kaplan-Meier method. Cumulative incidence was evaluated using a competing risk model. Results We identified 158 patients with RCC BM, of whom 94.4% had clear-cell RCC, and 90.6% had extracranial metastases at diagnosis. Of these patients, 94 (60%) developed RCC BM over time, while 46 (29.1%) had RCC BM at initial presentation. Clinical symptoms were noted in 81.9% of patients. The median OS after diagnosis of RCC BM was 8.4 months, with a 3-year OS of 28.2%. The median CNS RFS was 8.5 months overall; however, those with one and more than one lesion had median CNS RFS of 12.4 and 6 months, respectively (P Conclusion The majority of RCC patients with BM are symptomatic and had prior metastatic disease that progressed to the brain. Those with a solitary RCC BM are less likely to develop CNS recurrence after local therapy and are ideal candidates for enrollment onto clinical trials.

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.

An incomplete understanding of the biology of the human kidney, including the relative abundances of and interactions between intrinsic and immune cells, has long constrained the development of therapies for kidney disease. The small amount of tissue obtained by renal biopsy has previously limited the ability to use patient samples for discovery purposes. Imaging mass cytometry (IMC) is an ideal technology for quantitative interrogation of scarce samples, permitting concurrent analysis of more than 40 markers on a single tissue section. Using a validated panel of metal-conjugated antibodies designed to confer unique signatures on the structural and infiltrating cells comprising the human kidney, we performed simultaneous multiplexed imaging with IMC in 23 channels on 16 histopathologically normal human samples. We devised a machine-learning pipeline (Kidney-MAPPS) to perform single-cell segmentation, phenotyping, and quantification, thus creating a spatially preserved quantitative atlas of the normal human kidney. These data define selected baseline renal cell types, respective numbers, organization, and variability. We demonstrate the utility of IMC coupled to Kidney-MAPPS to qualitatively and quantitatively distinguish individual cell types and reveal expected as well as potentially novel abnormalities in diseased versus normal tissue. Our studies define a critical baseline data set for future quantitative analysis of human kidney disease.

Context Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few years. Objective To review and summarise the recent preclinical and clinical literature in hereditary renal cancer. Evidence acquisition A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management. Evidence synthesis Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy. Conclusions There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection. Patient summary This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.

INTRODUCTION AND OBJECTIVES:Young adults are historically the least likely to have health insurance in the United States. We aimed to investigate whether implementation of key provisions of the Aff...

We present the case of a young woman with Von Hippel Lindau (VHL) disease who underwent a combined pheochromocytoma resection along with pancreaticoduodenectomy. Her preoperative management, including effective alpha-blockade, was conducted remotely via telemedicine video visits, patient-entered vital sign data, and secure messaging between provider and patient. Similar remote management was undertaken before a subsequent pheochromocytoma resection while the patient was pregnant, and both surgeries had positive outcomes. This represents the first time that telemedicine and mobile health monitoring have been successfully used for preoperative alpha-blockade in a high-acuity patient before a complex multivisceral surgery.

Renal cell carcinomas associated with syndromes of a heritable nature account for about 4% of all renal cell carcinomas. They are characterized by an earlier age of onset, and are often multicentric and bilateral. Some of these patients may fit into well-characterized kidney cancer syndromes, while many more may have a genetic component that is not fully recognized or understood. The presence of extrarenal clinical features may suggest a specific renal tumor susceptibility syndrome. Moreover, each syndrome is associated with specific renal pathology findings. Recognition of individuals and families with a high risk of renal neoplasia is important so that surveillance for renal tumors may be initiated. This manuscript reviews the clinical, pathological, and molecular features of hereditary renal cell carcinoma syndromes with emphasis on the morphologic features of these tumors and the molecular mechanisms of hereditary renal tumorigenesis.

e17066 Background: Minimally invasive partial nephrectomy (PN) and percutaneous cryoablation (Cryo) are treatment strategies for renal cell carcinoma (RCC). The purpose of this study is to assess the cost-effectiveness of PN and Cryo for stage Ia RCC. Methods: A decision-analysis model was constructed over 5 years from a health care sector’s perspective using TreeAge Pro Suite 2019 (TreeAge Software LLC, Cambridge, MA). The two evaluated strategies were PN and Cryo. The model incorporated the clinical course of stage Ia RCC after either treatment, including costs and quality of life associated with major complications, imaging surveillance (based on 2014 National Comprehensive Cancer Network guidelines), local and metastatic recurrences, and cancer-specific mortality. All clinical parameters were derived from the literature. A willingness-to-pay threshold of $100,000/quality adjusted life year (QALY) was used. 1 QALY is equivalent to 1 year of life in perfect health. Outcomes were measured by incremental effectiveness ratio. Base case calculations, Monte Carlo Simulations with 10,000 iterations using bootstrapping for parameters from their distributions, and multiple sensitivity analyses were performed. Results: Five-year local recurrence-free, metastasis-free, and cancer-specific survival from recent literature were 97.7% versus 95.9% ( p = 0.18), 98.0% versus 100% ( p = 0.14), 99.3% versus 100% % ( p = 0.7) for PN and Cryo. PN and Cryo yielded similar health benefits of 3.63 QALY and 3.64 QALY. Overall costs were $26,343 and $19,346 for PN and Cryo. A total of 89.28% of the 10,000 simulations showed higher cost-effectiveness of Cryo than PN. One-way sensitivity analyses varying long-term outcomes after Cryo while keeping outcomes after PN constant, revealed that Cryo is more cost-effective than PN when its local recurrence risk is < 3.94% per year (18.2% over 5 years), metastasis risk is < 1.51% per year (7.33% over 5 years), or cancer-specific mortality risk is < 0.96% per year (4.7% over 5 years). PN is more cost-effective if Cryo local recurrence risk is 3.5% higher than PN per year, when the metastasis risk is 1.1% higher than PN per year, or when its cancer-specific mortality is more than 0.9% higher than PN per year. Cryo is more cost-effective than PN if its cost is not more than $1,000 higher than PN. Conclusions: Our study showed that Cryo is more cost-effective than PN for stage Ia RCC patients with comparable effectiveness at a lower cost, based on multiple probabilistic and deterministic sensitivity analyses.

5066 Background: We queried whether the landscape of genomic alterations (GA) would differ in patients with metastatic RCC under 40 years of age (under40) and patients 40 years of age or older (over40). Methods: FFPE tissues from 2,128 clinically advanced RCC and 25 RSC underwent hybrid-capture based CGP to evaluate all classes of GA. Samples were classified at time of sequencing as the following RCC subtypes: clear cell (ccRCC), papillary (papRCC), chromophobe (chrRCC), medullary (medRCC), collecting duct (cdRC), sarcomatoid (sarcRCC) and NOS (nosRCC). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: The male preponderance increased in the over40 patients. The GA/tumor increased in the over40 cohorts except for medRCC. Similarly, TMB was consistently higher in over40 groups. MSI high status was virtually absent. PD-L1 expression, available only in small subsets, was generally absent although 44% high positive staining in sarcRCC was noteworthy. Differences in GA in under40 vs over40 RCC were seen and included increased PBRM1 and SETD2 GA in over40 vs under40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in over40 vs under40 papRCC; increased TP53 and decreased VHL, BAP1, SETD2 and PTEN in over40 vs under40 chrRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in over40 vs under 40 sarcRCC; and increased TP53, VHL and TERT in over40 vs under40 nosRCC. Changes in GA in under40 vs over40 medRCC, cdRCC and RSC were noted but insufficient cases prevented further evaluation. Conclusions: When separately evaluated by under/over 40 years of age, CGP of clinically advanced RCC demonstrates differences in genomic landscapes with over40 cases featuring increasing male preponderance, higher GA/tumor, higher TMB and increases in a variety of GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of metastatic RCC. [Table: see text]