Sporadic Renal Cell Carcinoma Research Articles

Belzutifan: a novel therapeutic for the management of von Hippel-Lindau disease and beyond.

The identification of the VHL gene and its role in regulating the hypoxia-inducible factor signaling pathway has helped to revolutionize the treatment of renal cell carcinoma (RCC). Belzutifan is a novel small-molecule inhibitor of hypoxia-inducible factor 2α which has demonstrated efficacy in treating von Hippel-Lindau (VHL) disease, earning regulatory approvals for this indication. There is also early evidence for efficacy in sporadic RCC. Belzutifan has a favorable safety profile. Several clinical trials are currently ongoing, which should help in identifying this promising drug's role in RCC and beyond. This review summarizes the history, pharmacology and clinical evidence for belzutifan use to date, and also explores unanswered questions as they relate to this novel therapeutic agent.

Abstract 3226: PRMT1 is a critical dependency in clear cell renal cell carcinoma with roles in post- transcriptional regulation and DNA damage response

Abstract The majority of sporadic renal cell carcinoma (RCC) cases present as the clear cell subtype (ccRCC) and are associated with the biallelic inactivation of the von Hippel-Lindau (VHL) gene, leading to constitutive activation of the cellular hypoxia response and deleterious alterations to gene expression, metabolism, and growth. Despite the near ubiquity of VHL loss, evidence suggests that it alone is insufficient to drive tumor establishment. Additional loss of function (LOF) mutations in epigenetic regulatory proteins including PBRM1, SETD2 and BAP1 have been identified as tumor drivers. The frequency and penetrance of these mutations in epigenetic regulators implicates a vulnerability in ccRCC that may be exploited to develop new therapies. To explore this vulnerability, the Ailles lab completed a screen of the Structural Genomics Consortium’s (SGC) epiprobe library - a panel of inhibitors targeting an array of epigenetic regulators in patient derived ccRCC models. Among the several promising targets identified, a particularly favorable inhibition profile was noted for MS023, an inhibitor of the type I protein arginine methyltransferase family (PRMT1/3/4/6 and 8). PRMTs transfer methyl groups to nuclear histones and cytoplasmic targets, influencing gene expression, mRNA processing and viability. This growth inhibition was corroborated using an additional type I PRMT compound, GSK3368715. CRISPR-mediated deletion of type I PRMT targets indicated that PRMT1 is the main enzyme responsible for growth inhibition in our ccRCC models. Furthermore, genetic depletion of PRMT1 via shRNA phenocopied pharmacological inhibition and proliferative growth was restored in the presence of MS023 by overexpressing PRMT1. Finally, MS023 treatment of mice bearing ccRCC cell line and patient derived xenografts led to significant inhibition of tumor growth in vivo. Transcriptomic profiling of chemical treatment and PRMT1 genetic depletion demonstrated that PRMT1 inhibition triggers a significant down regulation of genes related to cell cycle progression and DNA damage. ccRCC cells treated with MS023 accumulated significant levels of DNA damage before undergoing cell death, with several DDR-related proteins being down-regulated. Proximity ligation and proteomic analysis (Bio-ID) revealed that PRMT1’s interactors skew heavily towards RNA metabolism regulators and widespread alterations in mRNA processing were noted with MS023 treatment. Evidence continues to mount that PRMT1 is implicated in the biology of cancer, but to our knowledge, no thorough investigations have been performed in the context of ccRCC. Our data suggests that inhibition of PRMT1 inhibits processing of mRNA transcripts, compromises DDR mechanisms, leading to an accumulation of double stranded breaks, cytostasis and cell death. Thus PRMT1 represents a viable therapeutic target in ccRCC. Citation Format: Joseph Walton, Karen Arevalo, Angel SN Ng, Jalna Meens, Christina Karamboulas, Panagiotis Prinos, Brian Raught, Eric Chen, Cheryl Arrowsmith, Laurie Ailles. PRMT1 is a critical dependency in clear cell renal cell carcinoma with roles in post- transcriptional regulation and DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3226.

Effect of lipiodol marking before CT-guided cryoablation on the outcome of sporadic renal cell carcinoma.

This retrospective study evaluates the impact of preoperative lipiodol marking on the outcomes of computed tomography (CT)-guided cryoablation for histologically diagnosed sporadic renal cell carcinoma (RCC). This study analyzed the data of 173 patients who underwent CT-guided cryoablation for histologically proven sporadic RCC at a single institution between April 2014 and December 2020. The local control rate (LCR), recurrence-free survival rate (RFSR), overall survival rate (OSR), changes in renal function, and complications in patients with (n = 85) and without (n = 88) preoperative lipiodol marking were compared. The 5-year LCR and 5-year RFSR were significantly higher in patients with lipiodol marking (97.51% and 93.84%, respectively) than in those without (72.38% and 68.10%, respectively) (P value <0.01, log-rank test). There were no significant differences between the two groups regarding the 5-year OSR (97.50% vs. 86.82%) or the deterioration in chronic kidney disease stage (12.70% vs. 16.43%). Grade ≥3 complications occurred in patients with lipiodol marking (n = 2, retroperitoneal hematoma and cerebral infarction in 1 patient each) and without (n = 5; urinary fistula in 2, colonic perforation in 2, urinary infection in 1). Lipiodol marking before CT-guided cryoablation for sporadic RCC is a feasible approach to improving local control and RFS while mitigating the decline in renal function. Additionally, it may help reduce complications.

A study on sporadic renal cell carcinoma in young adults, our institutional experience

Background: Renal cell carcinoma (RCC) accounts for around 2–3% of all adult malignant neoplasms. Most RCC instances are sporadic, with about 4–6% being familial. Sporadic RCC is uncommon in young patients under 45, accounting for 3–7% of all instances. We report our experience with sporadic RCCs in young adults between the age of 20 and 45 years. Aims and Objectives: The aim is to study clinical presentation, evaluation, management, and prognosis of sporadic RCC in young adults. Materials and Methods: A retrospective review of 22 patients diagnosed with sporadic RCC between ages 20 and 45 years during a period of 7 years from 2016 to 2022 was performed at Government Stanley Medical College. Demographic details such as age, gender, clinical condition, blood investigations, radiological imaging, and histopathological evaluation were conducted. Patients were assessed for long-term outcomes by comparing metastasis and lymph node involvement with survival outcomes. Results: The mean age at diagnosis was 37 years. Most patients belong to lower socioeconomic status (54.5%), Tumors were detected incidentally in 9 patients (41%) and were symptomatic in 13 (59%). Around 87% of patients were not having any associated comorbidities. The average duration of presenting complaints in symptomatic patients was 41 days. About 59% of patients were smokers or chewing tobacco before diagnosis. Renal biopsy was performed in 27% of patients before definitive surgery. The difference in prognosis was found to be insignificant between patients who were asymptomatic at the time of diagnosis compared to patients who were symptomatic. The tumor stage and grade had a significant impact on survival. The mean postoperative follow-up was 38 months. Conclusion: The result of our study shows that sporadic RCC does not behave aggressively in young adults. The most important determinants in prognosis are tumor stage and histological grade. The type of surgical procedure does not affect the overall outcome.

Novel Approaches with HIF-2α Targeted Therapies in Metastatic Renal Cell Carcinoma

Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.

Metabolic alterations in hereditary and sporadic renal cell carcinoma.

Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC. Molecular analyses of hereditary and sporadic forms of RCC have revealed that this complex and deadly disease is characterized by metabolic pathway alterations in cancer cells that lead to deregulated oxygen and nutrient sensing, as well as impaired tricarboxylic acid cycle activity. These metabolic changes facilitate tumour growth and survival. Specifically, studies of the metabolic features of RCC have led to the discovery of oncometabolites - fumarate and succinate - that can promote tumorigenesis, moonlighting functions of enzymes, and substrate auxotrophy owing to the disruption of pathways that enable the production of arginine and cholesterol. These metabolic alterations within RCC can be exploited to identify new therapeutic targets and interventions, in combination with novel approaches that minimize the systemic toxicity of metabolic inhibitors and reduce the risk of drug resistance owing to metabolic plasticity.

Renal cell carcinoma outcomes in end-stage renal disease: A 40-year study from two Japanese institutions.

The objective of the study was to analyze the outcomes of patients with renal cell carcinoma (RCC) arising in end-stage renal disease (ESRD) over a 40-year span. We retrospectively evaluated data of patients with ESRD-RCC diagnosed between 1979 and 2020 at two institutions. We assessed changes in stage, surgical approaches, and cancer-specific survival (CSS) following nephrectomy according to era between ESRD-RCC and sporadic RCC. Furthermore, perioperative outcomes in patients with ESRD-RCC were compared between laparoscopic and open surgery. Patients with ESRD-RCC (n = 549) were diagnosed at an earlier stage (p = 0.0276), and the ratio of laparoscopic nephrectomy was increased (p < 0.0001) according to eras. Since 2000 (i.e., after implementation of laparoscopic nephrectomy), patients with ESRD-RCC (n = 305) had significantly shorter CSS (p = 0.0063) after nephrectomy than sporadic RCC (n = 2732). After adjustment by multivariate analysis and propensity score matching, ESRD status was independently associated with shorter CSS (p = 0.0055 and p = 0.0473, respectively). Improved CSS in sporadic RCC (p < 0.0001), but not ESRD-RCC (p = 0.904), according to era contributed to this difference. Laparoscopic nephrectomy showed favorable outcomes, including shorter surgery time, lower estimated bleeding volumes, transfusion rates, and readmission rates, and shorter postoperative hospitalization than open nephrectomy (p < 0.05). Advances in diagnostic and treatment modalities potentially enable early diagnosis and minimally invasive surgery for patients with ESRD-RCC. As ESRD-RCC may not present indolently, careful post-operative monitoring is needed.

Diagnostic miRNA Signatures in Paired Tumor, Plasma, and Urine Specimens From Renal Cell Carcinoma Patients.

The incidence of patients diagnosed with renal cell carcinoma (RCC) is increasing. There are no approved biofluid biomarkers for routine diagnosis of RCC patients. This retrospective study aims to identify cell-free microRNA (cfmiR) signatures in urine samples that can be utilized as biomarkers for early diagnosis of sporadic RCC patients. Tissue, plasma, and urine samples (n = 221) from 56 sporadic RCC patients and respective normal healthy donors were profiled for 2083 microRNAs (miRs) using the next-generation sequencing-based HTG EdgeSeq miR Whole Transcriptome Assay. DESeq2 (FC |1.2|, false discovery rate <0.05) was performed to identify differentially expressed miRs. Data from RCC tissue samples of The Cancer Genome Atlas database were used for miR validation. We found a 10-miR signature that distinguished RCC tissues from remote normal kidney tissue or benign kidney lesion samples. Additionally, we identified subtype-specific miRs (miR-122-5p, miR-210-3p, and miR-21-3p) and miRs specific for all RCC subtypes (miR-106b-3p, miR-629-5p, and miR-885-5p). We observed that miR-155-5p was associated with tumor size. Using The Cancer Genome Atlas data sets, we validated the miRs found in RCC tissue samples. In plasma or urine analysis, we found cfmiRs that were consistently and significantly upregulated in RCC tissue samples. A 15-cfmiR signature was proposed in urine samples of RCC patients, of which miR-1275 was consistently upregulated in tissue, plasma, and urine samples. This integrative study found diagnostic miRs/cfmiRs for RCC patients, which were validated using The Cancer Genome Atlas data sets. Distinctive cfmiR signatures found in urine may have clinical utility for the diagnosis of RCC.

MiT/TFE Family Renal Cell Carcinoma.

The microphthalmia-associated transcription factor/transcription factor E (MiT/TFE) family of transcription factors are evolutionarily conserved, basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors, consisting of MITF, TFEB, TFE3, and TFEC. MiT/TFE proteins, with the exception of TFEC, are involved in the development of renal cell carcinoma (RCC). Most of the MiT/TFE transcription factor alterations seen in sporadic RCC cases of MiT family translocation renal cell carcinoma (tRCC) are chimeric proteins generated by chromosomal rearrangements. These chimeric MiT/TFE proteins retain the bHLH-Zip structures and act as oncogenic transcription factors. The germline variant of MITF p.E318K has been reported as a risk factor for RCC. E 318 is present at the SUMOylation consensus site of MITF. The p.E318K variant abrogates SUMOylation on K 316, which results in alteration of MITF transcriptional activity. Only a few cases of MITF p.E318K RCC have been reported, and their clinical features have not yet been fully described. It would be important for clinicians to recognize MITF p.E318K RCC and consider MITF germline testing for undiagnosed familial RCC cases. This review outlines the involvement of the MiT/TFE transcription factors in RCC, both in sporadic and hereditary cases. Further elucidation of the molecular function of the MiT/TFE family is necessary for better diagnosis and treatment of these rare diseases.

Molecular-genetic and cytogenetic characteristics of sporadic kidney cancer: literature review

To compile this literature review, we studied at least 100 publications devoted to the genetic basis of clear cell, papillary, and chromophobic sporadic kidney cancer pathogenesis. Each of them considered the role of somatic gene and chromosomal mutations in the initiation, promotion, and tumor progression of sporadic renal cell carcinoma, emphasized the importance of determining the mutagenic profile of renal cell carcinoma for the future fate of patients.

Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease.

Around 95% of patients with clinical features that meet the diagnostic criteria for von Hippel–Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the E3 ubiquitin ligase complex comprising pVHL, elongin C, elongin B, cullin 2 and ring box 1 (VCB-CR complex), which plays a key role in oxygen sensing and degradation of hypoxia-inducible factors. To date, only variants in VHL have been shown to cause VHL disease. We undertook trio analysis by whole-exome sequencing in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband’s kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma (RCC) dataset was undertaken. A de novo pathogenic variant in ELOC NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent RCC and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of an RCC from the proband showed similar findings to that in somatically ELOC-mutated RCC (expression of hypoxia-responsive proteins, no somatic VHL variants and chromosome 8 loss). These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant.

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases

A distinct renal tumor has recently been described as “high-grade oncocytic renal tumor” and “sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm”. The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name “eosinophilic vacuolated tumor” (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15–72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5–11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.

Hereditary kidney cancer - easily clarified and diagnosed with ToSCaNA

In recent years great improvements in the diagnosis and differentiation of hereditary syndroms with predisposition for kidney cancer have been achieved. It has been assumed that 5-8% of all kidney cancer have a hereditary origin. In reality, this number will probably be much higher as many genetic aspects of kidney cancer are still not entirely known. Hereditary kidney cancer usually shows two characteristic properties: While the median age of diagnosis of sporadic renal cell carcinoma is 64 years, patients with a hereditary tumor predisposition are about 20 years younger at the time of diagnosis. Additionally, their tumors often occur multifocal/bilateral. Therefore, a special management with extended diagnostics is necessary for these young kidney cancer patients. In literature many reports on hereditary syndromes with kidney cancer predisposition exist. Though, these papers usually put their focus on single syndromes rather than on the aspects of kidney cancer. The goal of this article is to present the practicing urologist with a compact overview of the most important hereditary syndromes with kidney cancer predisposition and by this improve the primary diagnostic and treatment of renal cancer patients and their relatives. We conducted a literature search on the five most important hereditary syndromes with kidney cancer association and summarized the results in a chart. Additionally, we formed the acronym ToSCaNA combining the most important extrarenal manifestations of the syndromes. Based on this data, a diagnostic workflow and treatment path was established. All in all, hereditary kidney cancer is a rare entity, which nonetheless could present as a significant number in high-volume centers. For doctors who scarcely get in contact with these types of tumors, the acronym and workflow could pose a valuable asset for their clinical diagnostic portfolio. An early identification and diagnostic work-up of affected patients and their relatives is crucial for appropriate treatment and surveillance and allows the identification/treatment of additionally affected relatives. In patients with young age of onset and multifocal/bilateral occurrence of kidney cancer, hereditary syndromes should always be considered. The initial suspicion of a hereditary genesis of the cancer can be further evaluated by the acronym ToSCaNA and the presented workflow.

Genetic Analysis Reveals the Important Role of the APC Gene in Clear Cell Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. The aim of this study was to elucidate the molecular pathogenesis of sporadic RCC in Taiwan. Fifteen patients with RCC were screened for mutations in the von Hippel-Lindau (VHL) gene by PCR and Sanger sequencing. The methylation status of promoters of 24 tumor suppressor genes by methylation sensitive multiplex ligation-dependent probe amplification analysis was also determined. Inactivation of the VHL gene was observed in 5 cases: three missense somatic mutations, one promoter methylation, and one small deletion. In RCCs, methylation was most frequently observed in APC (100%), CDKN2B (92.9%), CASP8, MLH1_167, and KLLN (85.7.4%), but not in FHIT, MLH1_463, DAPK1, or HIC1 (0%). In addition to VHL inactivation, promoter methylation of APC may be a universal pathognomonic event in the tumorigenesis of RCC and a candidate diagnostic and therapeutic biomarker.

Single-Cell RNA-seq Identification of the Cellular Molecular Characteristics of Sporadic Bilateral Clear Cell Renal Cell Carcinoma.

Bilateral renal cell carcinoma (RCC) is a rare disease that can be classified as either familial or sporadic. Studying the cellular molecular characteristics of sporadic bilateral RCC is important to provide guidance for clinical treatment. Cellular molecular characteristics can be expressed at the RNA level, especially at the single-cell degree. Single-cell RNA sequencing (scRNA-seq) was performed on bilateral clear cell RCC (ccRCC). A total of 3,575 and 3,568 high-quality single-cell transcriptome data were captured from the left and right tumour tissues, respectively. Gene characteristics were identified by comparing left and right tumours at the scRNA level. The complex cellular environment of bilateral ccRCC was presented by using scRNA-seq. Single-cell transcriptomic analysis revealed high similarity in gene expression among most of the cell types of bilateral RCCs but significant differences in gene expression among different site tumour cells. Additionally, the potential biological function of different tumour cell types was determined by gene ontology (GO) analysis. The transcriptome characteristics of tumour tissues in different locations at the single-cell transcriptome level were revealed through the scRNA-seq of bilateral sporadic ccRCC. This work provides new insights into the diagnosis and treatment of bilateral RCC.

Risk Prediction for Renal Cell Carcinoma: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Prospective Cohort Study.

Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives. Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure. The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679-0.721]). Our model had slightly improved discrimination (0.714 [0.694-0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025. Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population. Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.

A new cancer on the block: Tuberous sclerosis-associated renal cell carcinoma

Purpose: The purpose of this article is to present the first reported case of a renal tumour classified as tuberous sclerosis complex-associated renal cell carcinoma in the UK and discuss its clinical implications. Case report: A female, aged 65 years, with tuberous sclerosis complex was found on surveillance imaging to have interval growth of multiple right renal tumours up to 19 mm. Right partial nephrectomy was performed. Histology showed multiple tiny angiomyolipomas and a 20 mm tumour classified as tuberous sclerosis complex-associated renal cell carcinoma. These tumour cells showed abundant clear cytoplasm with a branched elongated arrangement encircled in dense smooth muscle stroma. Literature review: Renal cell carcinoma in patients with tuberous sclerosis complex is rare, occurring in approximately 4% of cases. Tuberous sclerosis complex-associated renal cell carcinoma is a relatively new histological entity, having previously been described as clear cell or chromophobe-like, with only one published case series from the USA. These tumours have three histological entities which are distinct from all other renal cell carcinoma classifications. Based on case series, tuberous sclerosis complex-associated renal cell carcinoma tends to occur more often in females, present at a younger age, have multiple tumours, and tend to show an indolent course, although metastases have been reported. Learning points: Patients with tuberous sclerosis complex can develop renal cell carcinoma, though the risk is thought to be no higher than for sporadic renal cell carcinoma. Given the limited literature, more evidence is required to help predict the future behaviour of these tumours. Level of evidence: 5

Bilateral renal cell carcinoma operated as right radical nephrectomy and left partial nephrectomy with histopathologically confirmed R0 resection

Bilateral renal tumors remain relatively uncommon, accounting for 1-5% of patients with renal cell carcinoma. Most sporadic renal cell carcinomas are unilateral and unifocal. Bilateral involvement can be synchronous or asynchronous and is found in 2-4% of sporadic renal cell carcinomas. We report a case of 70 years old male who was incidentally found to have bilateral renal masses. Right sided radical nephrectomy and left partial nephrectomy was performed. Histopathological examination of the specimen revealed clear cell carcinoma and confirmed R0 resection. The patient was discharged on 7th postoperative day.

Birt-Hogg-Dubé syndrome-associated renal cell carcinoma: Histopathological features and diagnostic conundrum.

Birt‐Hogg‐Dubé (BHD) syndrome is associated with the development of hereditary renal cell carcinoma (RCC) and is caused by a germline mutation in the folliculin gene. Most cases of BHD syndrome‐associated RCC (BHD‐RCC) are less aggressive than sporadic clear cell RCC and multifocal. Therefore, it is critical to distinguish BHD‐RCC from its sporadic counterparts to identify and monitor affected families and to preserve renal function for as long as possible. The World Health Organization/International Society of Urological Pathology consensus classification defined distinct entities for certain hereditary RCC; however, BHD‐RCC was not included in this classification. Although the clinical features and molecular mechanisms of BHD‐RCC have been investigated intensively over the last two decades, pathologists and urologists occasionally face difficulties in the diagnosis of BHD‐RCC that require genetic testing. Affected patients usually have miscellaneous benign disorders that often precede renal carcinogenesis. In the present review, we summarize the current understanding of the histopathological features of BHD‐RCC based on our epidemiological studies of Japanese families and a literature review. Pathological diagnostic clues and differential diagnosis of BHD‐RCC from other hereditary RCC are also briefly discussed.

"Renal Cell Carcinoma With Leiomyomatous Stroma" Harbor Somatic Mutations of TSC1, TSC2, MTOR, and/or ELOC (TCEB1): Clinicopathologic and Molecular Characterization of 18 Sporadic Tumors Supports a Distinct Entity.

Renal cell carcinoma with (angio) leiomyomatous stroma (RCCLMS) is included as a provisional entity in the 2016 World Health Organization (WHO) classification of renal epithelial neoplasia; however, debate remains whether it represents a distinct entity or a heterogenous group of renal cell carcinomas (RCCs) with overlapping morphology. Also, its relationship to similar tumors occurring in the setting of tuberous sclerosis complex (TSC) is not fully addressed. We analyzed the clinicopathologic, immunohistochemical, and molecular characteristics of 23 sporadic RCCs associated with smooth muscle stroma and classified them into 2 groups, independent of molecular results: (1) RCCLMS (n=18) and (2) clear cell renal cell carcinoma (CCRCC) (n=5). The classification of a case as "RCCLMS" was based on morphologic comparison with 5 "index" RCCs from 3 patients with TSC showing similar features and the presence of diffuse CK7 expression. To investigate mutational and copy number alterations, a 170-gene solid tumor panel was utilized to sequence 14 RCCLMSs and control of 5 CCRCCs. Also, 4 RCCLMSs, suspicious for chromosome 8 monosomy, were further evaluated by a broader 479 gene sequencing panel that included ELOC (also referred to as TCEB1). Clinical information and follow-up data were obtained from electronic medical records. The mean age of patients with RCCLMS was 52 years (range, 33 to 69) with male:female ratio of 1:2. Macroscopically, all tumors were solitary and predominantly (82%) tan/red, circumscribed, and solid. The average tumor size was 2.3 cm (range, 1.1 to 4.5). Microscopically, the distinctive feature included tumor nodules of elongated and frequently branching tubules lined by cells with voluminous clear to mildly eosinophilic cytoplasm (100%), separated by focal to prominent smooth muscle stroma. Additional frequently identified features included: biphasic pattern of collapsed acini surrounding tubules with voluminous cytoplasm (50%), focal papillary architecture (39%), peritumoral lymphoid aggregates (39%), and hemosiderin-laden macrophages (33%). All 11 (100%) RCCLMSs with available staging information were pT1; 78% were WHO/International Society of Urologic Pathology (ISUP) grade 2 and 22% grade 3. Immunophenotypically, RCCLMSs were characterized by diffuse CK7, CAM5.2 and CD10 reactivity (100%). All patients with available follow-up (n=10) were alive and without disease progression after a mean and median follow-up of 25.2 (range: 1 to 58) and 25 months, respectively. The molecular results showed recurrent mutations in all RCCLMS: TSC1 (4), TSC2 (4), MTOR (6), and/or ELOC (2). Five control CCRCCs demonstrated primary alterations in VHL gene, while all 14 RCCLMS cases tested had intact VHL gene. Of 2 RCCLMSs with confirmed monosomy 8, 1 showed a hotspot ELOC mutation without TSC/MTOR mutations, and 1 showed a previously undescribed 3-bp in-frame ELOC deletion, along with a truncating TSC1 mutation. In conclusion, RCCLMS, as defined herein, harbors recurrent mutations of TSC1/TSC2, MTOR, and/or ELOC, consistent with hyperactive MTOR complex. Our findings argue that these tumors represent the sporadic counterpart to morphologically identical tumors occurring in TSC patients. Finally, the data support that RCCLMS is a novel subtype of RCC with unique morphologic, immunohistochemical, and molecular characteristics that is distinct from CCRCC and clear cell-papillary RCC.