Functional implications of fumarate-induced cysteine succination.

Mutations in metabolic enzymes are associated with hereditary and sporadic forms of cancer. For example, loss-of-function mutations affecting fumarate hydratase (FH), the tricarboxylic acid (TCA) cycle enzyme, result in the accumulation of millimolar levels of fumarate that cause an aggressive form of kidney cancer. A distinct feature of fumarate is its ability to spontaneously react with thiol groups of cysteines in a chemical reaction termed succination. Although succination of a few proteins has been causally implicated in the molecular features of FH-deficient cancers, the stoichiometry, wider functional consequences, and contribution of succination to disease development remain largely unexplored. We discuss the functional implications of fumarate-induced succination in FH-deficient cells, the available methodologies, and the current challenges in studying this post-translational modification.

Malignant glomus tumor arising in association with a fumarate hydratase-deficient leiomyoma: An unusual collision tumor.

Collision tumors, defined as "two independent neoplasms that occur in close proximity to one another but maintain distinct boundaries," are quite rare. We report an exceptional collision tumor composed of a genetically confirmed malignant glomus tumor and a fumarate hydratase (FH)-deficient leiomyoma, presenting as a subcutaneous thigh mass in a 38-year-old male who was known to have hereditary leiomyomatosis and renal cell carcinoma syndrome. Microscopic examination identified a biphasic subcutaneous mass comprising sheets and nodules of glomus cells, with nuclear atypia and mitotic activity, and fascicles of mitotically inactive smooth muscle with variably pleomorphic nuclei and intracytoplasmic eosinophilic inclusions, features of FH-deficient leiomyoma. Immunohistochemistry demonstrated loss of FH and robust 2-succinocysteine expression in the smooth muscle, with a normal (FH-retained) expression pattern in the glomus tumor. Next-generation sequencing, performed on the glomus tumor component, identified CARMN::NOTCH2 fusion, characteristic of malignant glomus tumors. Awareness of the distinctive morphologic, immunohistochemical, and molecular genetic features of glomus tumors and FH-deficient leiomyomas is important for correct clinical management of patients with exceptional collision tumors of this type.

A case of reed syndrome with an unusually extensive cutaneous burden treated with fully ablative Erbium:YAG laser resurfacing therapy.

Reed Syndrome, or hereditary leiomyomatosis and renal cell carcinoma syndrome, is a rare, autosomal dominant genetic condition that predisposes individuals to a triad of cutaneous leiomyomas, uterine leiomyomas and renal cell carcinoma. Cutaneous leiomyomas are often the first manifestation of the syndrome, occurring in 76% of patients and average 26 in number. We present a case of a 47 year old female with Reed Syndrome with an unusually extensive cutaneous burden, with a total of 361 cutaneous lesions, far above the average reported number of 26. Due to the extent of her cutaneous burden, painful nature of the lesions and failure to respond to standard therapies, she was referred for fully ablative Erbium:Yag laser resurfacing therapy. The use of fully ablative Erbium:YAG laser resurfacing therapy for treatment of cutaneous leiomyomas has not been reported in the literature to date. One year following laser therapy, the treatment area not only began to repigment, but there was also no evidence of cutaneous leiomyomas recurrence or associated pain. Given the effectiveness of this unique therapy, fully ablative Erbium:YAG laser resurfacing should be kept in mind as a treatment option for both cosmetic and symptomatic cutaneous leiomyomas.

Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling.

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.

Clinicopathological characterisation of renal cell carcinoma in young adults: a contemporary update and review of literature.

AIMS: Renal cell carcinomas are relatively rare in children and young adults. While well characterised in adults, the morphological and molecular characterisation of these tumours in young patients is relatively lacking. The objective of this study was to explore the spectrum of renal cell carcinoma (RCC) subtypes in children and young adults and to determine their clinico-pathological, immunohistochemical and molecular characteristics by evaluating a large retrospective cohort of renal cell carcinoma patients age 30 years or younger. METHODS AND RESULTS: Sixty-eight cases with confirmed diagnosis of renal cell carcinoma at age 30 years or younger were identified at our institution. Clear cell carcinoma accounted for the most common subtype seen in this age group. Translocation renal cell carcinoma and rare familial syndrome subtypes such as succinate dehydrogenase deficient renal cell carcinoma and tuberous sclerosis complex-associated renal cell carcinoma were found relatively more frequently in this cohort. Despite applying the 2016 WHO classification criteria, a high proportion of the tumours in our series remained unclassified. CONCLUSIONS: Our results suggest that renal cell carcinoma in children and young adults is a relatively rare disease that shares many histological similarities to renal cell carcinoma occurring in adults and yet demonstrate some unique clinical-pathological differences. Microphthalmia-associated transcription (MiT) family translocation RCC and rare familial syndrome subtypes are relatively more frequent in the paediatric and adolescent age groups than in adults. Clear cell RCC still accounted for the most common subtype seen in this age group. MiT family translocation RCC patients presented with advanced stage disease and had poor clinical outcomes. The large and heterogeneous subgroup of unclassified renal cell carcinoma contains phenotypically distinct tumours with further potential for future subcategories in the renal cell carcinoma classification.

Long-term response of metastatic hereditary leiomyomatosis and renal cell carcinoma syndrome associated renal cell carcinoma to bevacizumab plus erlotinib after temsirolimus and axitinib treatment failures.

BACKGROUND: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare hereditary kidney cancer syndrome in which affected individuals are at risk of skin and uterine leiomyomatosis and kidney cancer. HLRCC-associated kidney cancer is a lethal disease with a highly aggressive behavior, and there is no standard treatment option for metastatic disease. CASE PRESENTATION: Here, we report a 29-year-old patient with a locally advanced HLRCC-assiciated RCC. He was administrated temsirolimus initially, then underwent surgical removal of kidney, retroperitoneal lymph nodes, inferior vena cava and tumor thrombi. Unfortunately, multiple liver metastases were confirmed 1 month after surgery, so axitinib was given but failed immediately. We tried bevacizumab plus erlotinib, which achieved long-term good response lasting more than 18 months. He is alive with disease and maintains bevacizumab plus erlotinib treatment. CONCLUSION: The promising results obtained in this patient suggest that combined bevacizumab plus erlotinib may offer a valid treatment option for advanced HLRCC-associated kidney cancer, even after failures of mTOR inhibitor and/or VEGFR TKI based therapies.

Utility of prospective pathologic evaluation to inform clinical genetic testing for hereditary leiomyomatosis and renal cell carcinoma.

BACKGROUND: Patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) resulting from fumarate hydratase (FH) mutations may present with skin, uterine, and renal tumors, with each having unique pathologic features. This study investigated the association between prospectively identified suspicious pathology (SP) and FH mutations when patients were referred for genetic testing. METHODS: This was an institutional review board-approved cohort study of patients receiving FH testing from 2008 to 2013. SP was defined as a report of HLRCC histologic features identified during a prospective pathologic assessment. The association between SP and FH mutations was analyzed. RESULTS: FH testing was performed in 29 patients with a median age of 37 years; 15 (52%) were female, and 18 (62%) were white. Pathologists reported SP from kidney tumors (11 of 18), leiomyomas (9 of 15: uterus [n = 8] and bladder [n = 1]), and metastatic tumors (3 of 6) in 23 of 39 associated specimens (59%) from 21 of the 29 patients (72%). Patients with SP were younger (35 vs 51 years; P = .010), and those with kidney tumors more often had stage pT3 or higher renal cell carcinoma than those without SP (100% vs 33%; P = .006). FH mutations were present in 8 patients with SP (38%) and in 1 patient without SP (13%; P = .37); 7 of these patients had kidney cancer (n for SP = 7), all with N1 disease. Analyzing SP by tissue type identified only SP from renal tumors as being significantly associated with positive testing for an FH mutation (P = .013). CONCLUSIONS: SP from kidney tumors was statistically associated with FH mutations. An expert pathologic assessment of renal tumors will facilitate the clinical identification of HLRCC cases, and this will result in genetic testing and targeted cancer screening for patients and at-risk family members. Cancer 2017;123:2452-58. © 2017 American Cancer Society.

The clinicopathologic and molecular features, and treatment outcome of fumarate hydratase-deficient renal cell carcinoma: a retrospective comparison with type 2 papillary renal cell carcinoma.

BACKGROUND: To compare clinicopathologic, molecular features, and treatment outcome between fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) and type 2 papillary renal cell carcinoma (T2 pRCC). METHODS: Data of T2 pRCC patients and FH-dRCC patients with additional next-generation sequencing information were retrospectively analyzed. The cancer-specific survival (CSS) and disease-free survival (DFS) were primary endpoint. RESULTS: A combination of FH and 2-succino-cysteine (2-SC) increased the rate of negative predictive value of FH-dRCC. Compared with T2 pRCC cases, FH-dRCC cases displayed a greater prevalence in young patients, a higher frequency of radical nephrectomy. Seven FH-dRCC and two T2 pRCC cases received systemic therapy. The VEGF treatment was prescribed most frequently, with an objective response rate (ORR) of 22.2% and a disease control rate (DCR) of 30%. A combined therapy with VEGF and checkpoint inhibitor reported an ORR of 40% and a DCR of 100%. FH-dRCC cases showed a shortened CSS (P = 0.042) and DFS (P < 0.001). The genomic sequencing revealed 9 novel mutations. CONCLUSIONS: Coupled with genetic detection, immunohistochemical biomarkers (FH and 2-SC) can distinguish the aggressive FH-dRCC from T2 pRCC. Future research is awaited to illuminate the association between the novel mutations and the clinical phenotypes of FH-dRCC in the disease progression.

Case report: Uterine leiomyoma with fumarate hydratase deficiency.

Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant disease caused by mutations in the fumarate hydratase gene. The syndrome is characterized by skin leiomyomatosis, uterine leiomyomatosis, and renal cell carcinoma. Herein, we report a case of fumarate hydratase deficient leiomyoma. The patient was a young female presenting with large uterine leiomyoma and multiple kidney angiomyolipomas. The report presents the chosen treatment and the challenges of differential diagnosis.

Fumarate hydratase mutation associated uterine leiomyomas: A case report and literature review.

The patient was found to have multiple uterine myomas at the age of 19, underwent laparoscopic myomectomy at the age of 20, and underwent laparotomic myomectomy again at the age of 23 due to the recurrence of uterine myoma. At the age of 25, the patient reappeared with symptoms and recurrence, and was diagnosed with uterine leiomyomas (ULMs) of FH mutation and high-grade squamous intraepithelial lesion (HSIL/CIN III) with gland involvement, after complete examination. Fumarate hydratase (FH) mutation screening is important when gynecologists encounter patients with early onset and multiple ULMs, it can give early diagnosis and treatment and fertility guidance. The patient had their uterus removed at the age of 26. FH mutation screening is important when gynecologists encounter patients with early onset and multiple ULMs, it can give early diagnosis and treatment and fertility guidance. It is also helpful for early diagnosis of renal cell carcinoma.

A 23-year bibliometric analysis of the development of global research on hereditary renal carcinoma.

Objectives: Medical research continues to be extensively devoted to investigating the pathogenesis and treatment approaches of hereditary renal cancer. By aspect including researchers, institutions, countries, journals, and keywords, we conduct a bibliometric analysis of the literature pertaining to hereditary renal cancer over the last 23 years. Methods: From the Web of Science Core Collection, we conducted a search for publications published between January 1, 2000 and November 28, 2023. Reviews and original articles were included. Results: A cumulative count of 2,194 publications met the specified criteria for inclusion. The studies of the included articles involved a collective of 2,402 institutions representing 80 countries. Notably, the United States exhibited the highest number of published documents, constituting approximately 45.49% of the total. The preeminent institution in this discipline is the National Cancer Institute (NCI), which maintains a publication volume of 8.98%. In addition to being the most prolific author (125 publications), Linehan WM's works received the highest number of citations (11,985). In a comprehensive count, 803 journals have published related articles. In the top 10 most recent occurrences were the terms "hereditary leiomyomatosis" and "fumarate hydratase." Conclusion: This is the first bibliometric analysis of the literature on hereditary renal cancer. This article offers a thorough examination of the present status of investigations concerning hereditary renal cancer during the previous 23 years.

Fumarate Hydratase-Deficient Abdominal Wall Leiomyoma Presenting a Decade Post-Fumarate Hydratase-Deficient Uterine Leiomyoma Excision: An Incidental or Syndromic Association?

Background. The occurrence of fumarate hydratase-deficient leiomyoma of the abdominal wall is exceptionally rare. Case Presentation. A 50-year-old female patient with a past medical history of fumarate hydratase-deficient uterine leiomyoma presented with a left lower quadrant abdominal mass that has been present for the past 2 years. An ultrasound revealed a 3.5 cm oval hypoechoic mass. A subsequent CT scan showed a 3.5 cm hyperdense mass within the left internal oblique musculature. No family history is noted. A biopsy of the mass exhibited bundles of spindle cell neoplasm exhibiting bizarre ovoid nuclei and eosinophilic cytoplasm. No evidence of mitotic figures or tumor necrosis was noted. Immunohistochemical staining showed positive staining for desmin and smooth muscle actin (SMA), but negative staining for MART-1, S100, and CD34. Lesional cells showed expression of 2-succinocysteine and loss of fumarate hydratase expression. A diagnosis of fumarate hydratase-deficient leiomyoma was rendered. Conclusion. This report reinforces the importance of considering genetic testing for fumarate hydratase mutations in the evaluation of extra-uterine leiomyomatous lesions. Comprehensive follow-up and clinical screening in individuals with new lesions and a known history of fumarate hydratase-deficient neoplasms is mandatory. Recent recommendations support the integration of morphology-based evaluation along with immunohistochemical staining and genetic testing as a part of the standard evaluation for all uterine leiomyomas.

In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T > G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare, autosomal dominant tumor predisposition syndrome characterized by variable development of multiple skin and uterus leiomyomas and aggressive forms of renal cell carcinoma (RCC). Mutations in fumarate hydratase (FH), one of the proteins in homologous recombination repair, precede the development of HLRCC with high penetrance. Considering the risk of early metastasis of RCC, FH has been included in mutation screening panels. The identification of a pathogenic FH variant guides the screening for tumors in the carriers. However, variants of uncertain significance (VUS) are frequent findings, limiting the clinical value of the mutation screening. Here, we describe the associated phenotype and an in-depth, multi-step Bioinformatic evaluation of the germline FH c.199T > G (p.Tyr67 > Asp) variant segregated in an HLRCC family. Evidence for FH c.199T > G; (p.Tyr67Asp) pathogenicity includes the variant segregation with the disease in three affected family members, its absence in populational databases, and the deep evolutionary conservation of the Tyr67 residue. At the protein level, this residue substitution causes the loss of molecular bonds and ionic interactions, affecting molecular dynamics and protein stability. Considering ACMG/AMP criteria, we propose the reclassification of the FH c.199T > G; (p.Tyr67Asp) variant to "likely pathogenic". In addition, the in-depth, in silico approach used here allowed us to understand how and why FH c.199T > G; (p.Tyr67Asp) could cause HLRCC. This could help in clinical management decisions concerning the monitoring of unaffected family members having this variant.

Hereditary Renal Cell Carcinoma Syndromes.

Up to 5% of renal cell carcinomas (RCCs) can be associated with a known hereditary RCC syndrome. In addition to the well-characterized RCC syndromes, there are also emerging syndromes associated with increased RCC risk. In the last few years, consensus guidelines have outlined recommendations for who should be referred for genetic evaluation, and what screening should be done for early detection of RCC. Although much progress has been made, work is still needed-guidelines are still mostly based on expert opinion and the role of emerging genetic associations will need to be clarified.

Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma.

BACKGROUND: FH-deficient renal cell carcinoma (RCC) is a rare and exceptionally aggressive RCC subtype. There is currently limited understanding of the molecular alterations, pathogenesis, survival outcomes, and systemic therapy efficacy for this cancer. OBJECTIVE: To perform a retrospective multicenter analysis of molecular profiling and clinical outcomes for patients with FH-deficient RCC, with an emphasis on treatment response to first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI/TKI) versus bevacizumab plus erlotinib (Bev/Erlo) combination therapy in patients with advanced disease. DESIGN, SETTING, AND PARTICIPANTS: The study included 77 cases of FH-deficient RCC from 15 centers across China. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical characteristics, molecular correlates, 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, and treatment outcomes were analyzed. RESULTS AND LIMITATIONS: A total of 77 patients were identified, including 70 cases with a germline FH alteration (hereditary leiomyomatosis RCC syndrome [HLRCC]-associated RCC) and seven patients with somatic FH loss. Recurrent pathogenic alterations were found in NF2 (six/57, 11%), CDH1 (six/57, 11%), PIK3CA (six/57, 11%), and TP53 (five/57, 8.8%). Sixty-seven patients were evaluable for response to first-line systemic therapy with Bev/Erlo (n = 12), TKI monotherapy (n = 29), or ICI/TKI (n = 26). ICI/TKI combination therapy was associated with more favorable overall survival on systemic treatment (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.90) and progression-free survival on first-line therapy (HR 0.22, 95% CI 0.07-0.71) compared to Bev/Erlo combination therapy. The main limitation is the retrospective study design. CONCLUSIONS: We described the genomic characteristics of FH-deficient RCC in an Asian population and observed a favorable response to ICI/TKI combinational therapy among patients with advanced disease. PATIENT SUMMARY: This real-world study provides evidence supporting the antitumour activity of combining molecular targeted therapy plus immunotherapy for kidney cancer deficient in fumarate hydratase. Further studies are needed to investigate the efficacy of this combination strategy in this rare cancer.

Diseases of Hereditary Renal Cell Cancers.

Germline mutations in tumor suppressor genes and oncogenes lead to hereditary renal cell carcinoma (HRCC) diseases, characterized by a high risk of RCC and extrarenal manifestations. Patients of young age, those with a family history of RCC, and/or those with a personal and family history of HRCC-related extrarenal manifestations should be referred for germline testing. Identification of a germline mutation will allow for testing of family members at risk, as well as personalized surveillance programs to detect the early onset of HRCC-related lesions. The latter allows for more targeted and therefore more effective therapy and better preservation of renal parenchyma.

Hereditary leiomyomatosis and renal cell carcinoma: a case series and literature review.

BACKGROUND: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare genodermatosis characterized by cutaneous leiomyoma (CLM), uterine leiomyoma (ULM) and renal cell carcinoma (RCC). Five HLRCC patients are presented with a compiled database of published HLRCC cases to increase understanding of HLRCC. Furthermore, a surveillance program is suggested. Our review is based on a PubMed search which retrieved case reports and cohort studies published before November 2019. The search yielded 97 original papers with a total of 672 HLRCC patients. RESULTS: CLMs were present in 474 patients (71.5%), developed at the mean age of 28 years. Five patients had cutaneous leiomyosarcomas. ULMs were present in 356 women (83%), while two had uterine leiomyosarcoma. ULMs were diagnosed at a mean age of 32 years, with the youngest diagnosed at age 17 years. The most common surgical treatment for ULMs was hysterectomy, performed at a mean age of 35 years, with the youngest patient being 19 years old. RCCs were present in 189 patients (34.9%), of which half had metastatic disease. The mean age of diagnosis was 36 years with the youngest patient diagnosed with RCC at the age of 11 years. CONCLUSION: We suggest a surveillance program for HLRCC including a dermatological examination once every 2 years, annual magnetic resonance imaging starting at the age of 10 years to monitor for early RCCs, annual gynecological examinations from the age of 15 years and counseling regarding risk of hysterectomy and family planning at the age of 18 years. CLMs are often the earliest manifestation of HLRCC, which is why recognizing these lesions, performing a biopsy, and making a prompt referral to genetic counseling is important in order to diagnose HLRCC early.

Hereditary Leiomyomatosis and Renal Cell Cancer: Recent Insights Into Mechanisms and Systemic Treatment.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant hereditary cancer syndrome characterized by a predisposition to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). It is known to be caused by germline mutations of the fumarate hydratase (FH) gene, which encodes an enzyme component of the citric acid cycle and catalyzes the conversion of fumarate to L-malate. Currently, there is no standardized treatment for HLRCC, which may be due in part to a lack of understanding of the underlying mechanisms. Here, the underlying molecular mechanisms by which the inactivation of FH causes HLRCC are discussed. Additionally, potential therapeutic pharmacological strategies are also summarized to provide new perspectives for the prevention and treatment of HLRCC.

Imaging features of fumarate hydratase-deficient renal cell carcinomas: a retrospective study.

BACKGOUND: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a subtype of RCC that is increasingly recognized pathologically. The aim of this study was to evaluate the imaging features of FH-RCC on computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG PET), and to determine the pre-operative diagnostic potential of imaging. METHODS: This single-site retrospective study included patients with histologically confirmed FH-RCC or with a renal cancer and known germline FH mutation; imaging of the renal mass before treatment with contrast-enhanced CT, contrast-enhanced MRI, or FDG PET/CT between October 2007 and May 2019. Clinical information, pathological data, and imaging features were analyzed and reported descriptively. RESULTS: Sixteen patients with sixteen tumors were included (median age 46 years, interquartile range 38-53 years; 31 % female). Almost all tumors were unifocal (15/16, 94 %). Most tumors had infiltrative margins (14/16, 88 %); few were circumscribed (2/16, 12 %). A large cystic tumor component (> 75 % of tumor volume) was seen in 8/16 (50 %) of tumors. Involvement of renal sinus fat was seen in 13/16 (81 %) of tumors, involvement of the hilar collecting system in 8/16 (50 %), and renal vein tumor thrombus in 6/16 (38 %). All 12 tumors (100 %) imaged with MRI had heterogenous tumor enhancement and heterogenous T2 signal. Of those patients that had diffusion-weighted imaging, 11/11 (100 %) of tumors had diffusion restriction in the solid portions of the tumor. Of the patients who had PET, 3/3 (100 %) tumors showed high metabolic activity with mean maximum standardized uptake value (SUVmax) of 16.4 (range 9.6-21.9). Patients presented with retroperitoneal nodal metastases in 69 % of cases and distant metastases in 75 %. Of those four patients without metastatic disease at presentation, three (75 %) developed metastases within 4 years of diagnosis. CONCLUSIONS: In our study, the majority of tumors (≥ 75 %) were unifocal, had an infiltrative margin, invaded the renal sinus fat, and presented with distant metastases. On MRI, most tumors had heterogenous T2 signal and diffusion restriction in their solid components. The small number of cases that had PET imaging showed high metabolic activity.