Renal Cell Carcinoma Syndrome Research Articles

Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases.

Leiomyoma is the most prevalent benign tumor of the female reproductive system. Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5-2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.

Familial syndromes associated with testicular and paratesticular neoplasms: a comprehensive review.

A syndromic association between a subset of testicular/paratesticular neoplasms is well established. Such examples include Carney complex and large cell calcifying Sertoli cell tumor, Peutz-Jeghers syndrome and intratubular large cell hyalinizing Sertoli cell neoplasia, and VHL syndrome and clear cell papillary cystadenoma of the epididymis.However, recent studies proposed potential novel links between some testicular and paratesticular neoplasms with certain tumor syndromes. While more studies are still needed to solidify these associations, recent research suggests that a subset of Leydig cell tumors may arise in patients with hereditary leiomyomatosis and renal cell carcinoma syndrome or that some seminomas may occur in Lynch syndrome patients. Additionally, an association between testicular sex cord stromal tumors and paratesticular sarcomas with Familial adenomatous polyposis syndrome and DICER1 syndrome, respectively, has been proposed as well. This review provides a comprehensive overview of the intricate relationship between familial syndromes and associated testicular and paratesticular tumors, shedding light on their clinicopathological and molecular characteristics.

Hereditary Renal Cancer Syndromes.

Familial kidney tumors represent a rare variety of hereditary cancer syndromes, although systematic gene sequencing studies revealed that as many as 5% of renal cell carcinomas (RCCs) are associated with germline pathogenic variants (PVs). Most instances of RCC predisposition are attributed to the loss-of-function mutations in tumor suppressor genes, which drive the malignant progression via somatic inactivation of the remaining allele. These syndromes almost always have extrarenal manifestations, for example, von Hippel-Lindau (VHL) disease, fumarate hydratase tumor predisposition syndrome (FHTPS), Birt-Hogg-Dubé (BHD) syndrome, tuberous sclerosis (TS), etc. In contrast to the above conditions, hereditary papillary renal cell carcinoma syndrome (HPRCC) is caused by activating mutations in the MET oncogene and affects only the kidneys. Recent years have been characterized by remarkable progress in the development of targeted therapies for hereditary RCCs. The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs. mTOR downregulation provides significant benefits to patients with tuberous sclerosis. MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

The use of Clinicopathological, immunohistochemistry and molecular detection in the diagnosis of fumarate hydratase-deficient uterine leiomyomas

BackgroundFumarate hydratase-deficient uterine leiomyomas (FH-dUL) are rare, accounting for only 0.4–1.6% of uterine leiomyomas. FH germline mutation gene is associated with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). MethodsIn this study, we aim to investigate Clinicopathological features and FH mutation in FH-dUL. We performed a retrospective analysis of 300 cases of uterine leiomyoma, diagnosed from January 2017 to December 2021, within the archives of the Department of Pathology at Peking University People's Hospital. In our review of the immunohistochemical(IHC) staining was performed on 300 uSMTs to detect FH deficiency. ResultsWe identified 21cases (21/300,7%) of FH-dUL. Nineteen cases (6.33%) displayed negative FH. Twenty-one cases (7%) displayed 2SC diffuse plasma and nuclear staining. The most common FH-d morphological features included staghorn vasculature ( 100%,21/21), alveolar-pattern oedema (71.43%, 15/21), scattered bizarre nuclei (23.81%, 5/21), eosinophilic cytoplasmic (rhabdoid) inclusions (47.62%, 10/21), significant eosinophilic nucleolus with peri-nucleolus hollowing (23.81%, 5/21), ovoid nuclei sometimes arranged in chains (9.52%, 2/21). DNA sequencing for the 21 cases was performed using Next Generation Sequencing (NGS). 6 cases were detected significant variations for the FH gene, 11 cases were detected FH gene mutation forvariants of uncertain significance (VUS), and 2 cases were detected a TP53 gene mutation. No related mutations were detected in the other two cases. ConclusionsFH-dUL is rare. The combination of predictive Clinicopathological evaluation,FH and 2SC IHC test, and molecular test were helpful for the screening of FH-dUL from uSMTs,or even the screening of HLRCC.

The Role of Morphology in Predicting Fumarate Hydratase-deficient Uterine Leiomyomas in Young Women.

Hereditary leiomyomatosis and renal cell carcinoma is caused by germline mutations in the fumarate hydratase (FH) gene and is associated with an increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma. Pathologic evaluation of uterine leiomyoma can provide an opportunity for early recognition of the syndrome. We reviewed all archived slides of the cases to identify the characteristic morphologic features described for FH-deficient leiomyomas. We performed immunohistochemistry on whole sections of patients with uterine leiomyoma to evaluate for both FH and 2-succinocysteine (2SC) expression. Of the 106 cases, 19 showed the characteristic eosinophilic nucleoli with perinuclear halos, and 24 revealed a characteristic eosinophilic cytoplasmic inclusion consisting of pink globules present within the cytoplasm. Both of these morphologic findings were present together in 15 cases, and hemangiopericytomatous vessels were detected in 23 cases. The loss of FH protein expression was detected in 14 out of 106 cases (13%), and 13 out of 106 cases (12%) were positive for 2SC. We detected 10 cases with both 2SC-positive and FH expression loss. The presence of eosinophilic nucleoli with perinuclear halos and eosinophilic cytoplasmic inclusion was associated with both loss of FH protein expression and 2SC positivity ( P < 0.001). These findings underscore the importance of hematoxylin and eosin-based predictive morphology in FH-deficient uterine leiomyomas. Therefore, morphologic assessment of uterine leiomyomas for features of FH deficiency can serve as a screening tool for hereditary leiomyomatosis and renal cell carcinoma syndrome, allowing patients to be divided according to their hereditary risk assessment.

Genomic profiles of renal cell carcinoma in a small Chinese cohort.

Our aim was to describe the molecular characteristics of Renal Cell Carcinoma (RCC) and develop a small panel of RCC-associated genes from a large panel of cancer-related genes. Clinical data of 55 patients with RCC diagnosed in four hospitals from September 2021 to August 2022 were collected. Among the 55 patients, 38 were diagnosed with clear cell RCC (ccRCC), and the other 17 were diagnosed with non-clear cell RCC (nccRCC), including 10 cases of papillary renal cell carcinoma, 2 cases of hereditary leiomyomatosis and RCC syndrome (HLRCC), 1 eosinophilic papillary RCC, 1 tubular cystic carcinoma, 1 TFE3 gene fusion RCC, and 2 RCC with sarcomatoid differentiation. For each patient, 1123 cancer-related genes and 79 RCC-associated genes were analyzed. The most frequent mutations in a large panel of 1123 cancer-related genes in the overall population of RCC patients were VHL (51%), PBRM1 (35%), BAP1 (16%), KMT2D (15%), PTPRD (15%), and SETD2 (15%). For ccRCC patients, mutations in VHL, PBRM1, BAP1, and SERD2 can reach 74%, 50%, 24%, and 18%, respectively, while for nccRCC patients, the most frequent mutation was FH (29%), MLH3 (24%), ARID1A (18%), KMT2D (18%), and CREBBP (18%). The germline mutation rate in all 55 patients reached 12.7% (five with FH, one with ATM, and one with RAD50). The small panel containing only 79 RCC-associated genes demonstrated that mutations of VHL, PBRM1, BAP1, and SETD2 in ccRCC patients were 74%, 50%, 24%, and 18% respectively, while for the nccRCC cohort, the most frequent mutations were FH (29%), ARID1A (18%), ATM (12%), MSH6 (12%), BRAF (12%), and KRAS (12%). For ccRCC patients, the spectrum of mutations by large and small panels was almost the same, while for nccRCC patients, the mutation spectrum showed some differences. Even though the most frequent mutations (FH and ARID1A) in nccRCC were both demonstrated by large panels and small panels, other less frequent mutations such as MLH3, KMT2D, and CREBBP were not shown by the small panel. Our study revealed that nccRCC is more heterogeneous than ccRCC. For nccRCC patients, the small panel shows a more clear profile of genetic characteristics by replacing MLH3, KMT2D, and CREBBP with ATM, MSH6, BRAF, and KRAS, which may help predict prognosis and make clinical decisions.

EDITORIAL COMMENT

Paragangliomas and pheochromocytomas (PGL/PCC) are rare tumors that are derived from neural crest chromaffin cells either from neuroendocrine tissues distributed along the spine or from within the adrenal gland respectively. Approximately 40% of cases are associated with pathogenic germline variants in genes associated to cancer susceptibility syndromes, such as MAX, NF1, RET, SDHA, and SDHAF2, including several gene that associated with inherited kidney cancer, such as VHL, SDHB, SDHC, SDHD, and TMEM127. 1 Shuch B Ricketts CJ Metwalli AR Pacak K Linehan WM. The genetic basis of pheochromocytoma and paraganglioma: implications for management. Urology. 2014; 83: 1225-1232 Google Scholar ,2 Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer. 2014; 14: 108-119 Google Scholar A recent addition to this list is germline alteration of the FH gene, known to cause hereditary leiomyomatosis and renal cell cancer (HLRCC). 3 Richter S Gieldon L Pang Y et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019; 21: 705-717 Google Scholar , 4 Clark GR Sciacovelli M Gaude E et al. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab. 2014; 99: E2046-E2050 Google Scholar , 5 Muller M Ferlicot S Guillaud-Bataille M et al. Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. Clin Genet. 2017; 92: 606-615 Google Scholar

Germline mutations in hereditary renal cell carcinoma (RCC) genes among 32,240 patients with all cancer types.

4559 Background: Germline pathogenic variants (PVs) in VHL, FH, BAP1 and others cause hereditary syndromes with increased risk of renal cell carcinoma (RCC). Defining the clinical spectrum of these syndromes has been limited by ascertainment bias and their relative rarity. Using a large population of cancer patients who underwent germline and somatic tumor testing, we analyzed the landscape of germline PVs in RCC genes in individuals with all cancer types. Methods: We identified patients with germline PVs in RCC genes ( VHL, FH, SDHB, MET, FLCN, BAP1) in the MSK-IMPACT cohort, an institutional protocol of patients who had somatic and germline sequencing. The MITF E318K variant was analyzed separately given its uncertain role in RCC risk. Objectives were to determine whether patients met clinical criteria for their respective hereditary syndromes, analyze biallelic inactivation in all tumor types, and explore underrecognized cancer associations. Fisher test was used to compare frequency of variants to population. Results: Of 32,240 patients who consented to germline results, 55% were female; most common cancer types were breast (n=3600), pancreas (n=3554), prostate (n=3427), with 1166 (3.6%) with RCC. 110 (0.34%) had a germline variant in a RCC syndrome gene ( BAP1=26, SDHB=24, FH=24, FLCN=19, VHL=16, MET=1). Of 110 germline positive, 56% met clinical criteria for their hereditary syndrome, and 40% had RCC. For VHL, FH, SDHB and MET, a high proportion of patients met criteria for their hereditary syndromes, but this was much less for FLCN (Birt-Hogg-Dubé) and BAP1. Biallelic inactivation in the tumor, supporting causality, was very high except in FLCN. Possible novel cancer associations were liver cancer in BAP1 (n=5;19%) and colon cancer in FLCN (n=4;17%). Additionally, 114 patients had the MITF E318K variant; which was not enriched in RCC cases (only 1 RCC) compared to other cancers or population control (odds ratio 0.45; p-value = 0.16, 95% confidence interval: 0.1 -1.2). Conclusions: Germline analysis in a large pan-cancer cohort identifies a high prevalence of patients with hereditary RCC syndromes, variability in clinical phenotype and suggestion of novel cancer associations. The low number of MITF E318K variant carriers in RCC cases calls into question its role in RCC risk and warrants further study. [Table: see text]

Frequency of pathogenic germline variants in cancer susceptibility genes in 841 renal cell carcinoma cases.

e16551 Background: Hereditary Renal cell carcinoma (RCC) syndrome accounts for approximately 5-10% of all kidney cancers. However, the genetic architecture of susceptibility to RCC is not well defined. In this study, we investigated the prevalence and spectrum of pathogenic/likely pathogenic germline variants of cancer susceptibility genes in unselected RCC patients in the real-world Chinese population. Methods: We retrospectively profiled the germline mutations of 841 unselected RCC patients using a next-generation sequencing panel consisting of 808 cancer-related genes. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Genomic alterations include single nucleotide variations (SNV), short insertions/deletions (INDEL) and copy number variations (CNV). Results: Within 841 unselected RCC patients included in this study, 132 germline pathogenic/likely pathogenic (P/LP) variants were identified in 125 patients (14.9%), of which 114 (13.6%) were mutations of SNV/INDEL and 11 (1.3%) were CNV. Overall, 46 patients (5.5%) carried mutations of hereditary RCC syndrome-associated genes such as VHL (13, 1.5%), FH (13, 1.5%) and FLCN (8, 1.0%). Interestingly, variants in other cancer-predisposition genes not traditionally associated with RCC occurred in 9.4% of the unselected series, including 55 (6.5%) patients carried mutations in DNA damage (DDR)-related genes (e.g., MUTYH, CHEK2 and BRCA1/2) and the other 24 (2.9%) had germline mutations of non-DDR-related genes (e.g., SPINK1 and APC). The median age of patients with mutations of RCC syndrome-associated genes was 38 (range 19-77), while the median age of patients with mutations of other cancer-predisposition genes was 52(range 22-82). Furthermore, in patients older than 46 years, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes were 1.9% and 6.7%, respectively. Notably, among 125 patients with identified germline mutations, nearly half (56, 44.8%) did not meet the recommended criteria for genetic testing. Conclusions: Our findings confirm a high prevalence of pathogenic germline variants in genes associated with both hereditary RCC and other cancer predispositions in the unselected Chinese RCC population. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing and expand the range of genes in RCC population with advanced age.

PD07-10 OUTCOMES OF PARTIAL NEPHRECTOMY FOR NON-METASTATIC cT2 RENAL TUMORS: RESULTS FROM A CANADIAN MULTI-INSTITUTIONAL COLLABORATIVE

You have accessJournal of UrologyCME1 Apr 2023PD07-10 OUTCOMES OF PARTIAL NEPHRECTOMY FOR NON-METASTATIC cT2 RENAL TUMORS: RESULTS FROM A CANADIAN MULTI-INSTITUTIONAL COLLABORATIVE Rahul Bansal, Raees Cassim, Ryan Sun, Ranjeeta Mallick, Antonio Finelli, Simon Tanguay, Darrel Drachenberg, Frederic Pouliot, Luke Lavallee, Alan So, Ricardo Rendon, Lori Wood, Anil Kapoor, Aly-Khan Lalani, Naveen Basappa, Lucas Dean, Bimal Bhindi, Georg Bjarnason, and Rodney Breau Rahul BansalRahul Bansal More articles by this author , Raees CassimRaees Cassim More articles by this author , Ryan SunRyan Sun More articles by this author , Ranjeeta MallickRanjeeta Mallick More articles by this author , Antonio FinelliAntonio Finelli More articles by this author , Simon TanguaySimon Tanguay More articles by this author , Darrel DrachenbergDarrel Drachenberg More articles by this author , Frederic PouliotFrederic Pouliot More articles by this author , Luke LavalleeLuke Lavallee More articles by this author , Alan SoAlan So More articles by this author , Ricardo RendonRicardo Rendon More articles by this author , Lori WoodLori Wood More articles by this author , Anil KapoorAnil Kapoor More articles by this author , Aly-Khan LalaniAly-Khan Lalani More articles by this author , Naveen BasappaNaveen Basappa More articles by this author , Lucas DeanLucas Dean More articles by this author , Bimal BhindiBimal Bhindi More articles by this author , Georg BjarnasonGeorg Bjarnason More articles by this author , and Rodney BreauRodney Breau More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003231.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The role of partial nephrectomy (PN) is not well defined for cT2 renal cell carcinoma (RCC) as compared to radical nephrectomy (RN). The aim of this study was to examine oncological outcomes of PN as compared to RN for non-metastatic cT2 RCC. METHODS: The Canadian Kidney Cancer information system was used to define patients who underwent surgery for non-metastatic cT2 RCC from January 2011 to October 2022. Patients with clear-cell, papillary, and chromophobe RCC were included. Other histology, multiple tumours, and hereditary RCC syndrome patients were excluded. Each PN patient was individually matched to RN up to 1:4 depending on availability of patients based on tumor size (+/-1cm), histology, grade (clear cell and papillary), and necrosis (clear cell). Matched patients were analyzed as clusters. RESULTS: A total of 1523 patients were identified, and 50 PN patients met study criteria who were then matched to 185 RN patients. Both groups had similar age, gender, smoking status, BMI, Charlson comorbidity index score, symptoms at presentation, baseline eGFR, hemoglobin and pathological characteristics. PN patients had smaller tumors (7.6 cm [IQR 23] vs 8.4 [IQR 2.4], p=0.0479), had higher likelihood of undergoing open surgery (72.9% vs 31.8%, p<0.0001) and less likely received adrenalectomy (2% vs 24.3%, p=0.0004). Positive surgical margin rates were similar in both groups (8.2% in PN vs 3.4% in RN, p=0.2296). Median follow up was not significantly different in either group (3.6 yrs [IQR 4.7] in PN vs 3.3 [4.7] yrs in RN, p=0.975). During the follow up period, PN patients had higher risk of local recurrence (HR 3.0, 95%CI 1.08-8.37) and lower risk of metastasis (HR 0.36, 95%CI 0.15-0.88), overall survival (HR 0.36, 95%CI 0.18-1.78) as compared to RN. Cancer specific recurrence was similar between both groups (HR 0.56 ,95%CI 0.18,1.78). PN patients preserved more GFR than RN patients (-14.4 [SD 17.9] vs -23.7[SD 15], p=0.0006). Complications rates were similar between PN and RN (18% vs 8.65%, p=0.0571). CONCLUSIONS: In this multi-institutional Canadian cohort of patients with non-metastatic cT2 RCC undergoing surgery, PN compared to RN was associated with higher local recurrence, lower risk of distant metastasis, and death from any cause with similar complications and better preservation of renal function. Despite individual patient matching, there is likely unadjusted selection bias resulting in superior cancer survival associated with PN. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e166 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rahul Bansal More articles by this author Raees Cassim More articles by this author Ryan Sun More articles by this author Ranjeeta Mallick More articles by this author Antonio Finelli More articles by this author Simon Tanguay More articles by this author Darrel Drachenberg More articles by this author Frederic Pouliot More articles by this author Luke Lavallee More articles by this author Alan So More articles by this author Ricardo Rendon More articles by this author Lori Wood More articles by this author Anil Kapoor More articles by this author Aly-Khan Lalani More articles by this author Naveen Basappa More articles by this author Lucas Dean More articles by this author Bimal Bhindi More articles by this author Georg Bjarnason More articles by this author Rodney Breau More articles by this author Expand All Advertisement PDF downloadLoading ...

Hereditary renal tumor syndromes.

Kidney tumors may develop in association with hereditary tumor syndromes. The clinical presentation of these disorders is various, and in some cases, the renal tumor is the first manifestation of the syndrome. Thus, pathologists need to be aware of the gross and histological signs that may suggest the possibility of a tumor syndrome. In this paper, we summarize and illustrate the characteristics of kidney tumors, genetic background along with the extrarenal manifestations in the following diseases: Von Hippel-Lindau syndrome, hereditary papillary renal cell carcinoma syndrome, hereditary leiomyomatosis and renal cell carcinoma syndrome, Birt-Hogg-Dubé syndrome, tuberous sclerosis, hereditary paraganglioma and pheochromocytoma syndrome, and inherited BAP1 tumor syndrome. At the end of the manuscript, we discuss the tumor syndromes with increased risk of Wilms tumors. Such patients require a holistic approach and multidisciplinary care. Our work aims to make those involved in the diagnosis and treatment of kidney tumors aware of these rare diseases that require life-long surveillance. Orv Hetil. 2023; 164(10): 363-375.

Outcomes of partial nephrectomy for non-metastatic cT2 renal tumors: Results from a Canadian multi-institutional collaborative.

690 Background: The role of partial nephrectomy (PN) is not well defined for cT2 renal cell carcinoma (RCC) as compared to radical nephrectomy (RN). The aim of this study was to examine oncological outcomes of PN as compared to RN for non-metastatic cT2 RCC. Methods: The Canadian Kidney Cancer information system was used to define patients who underwent surgery for non-metastatic cT2 RCC from January 2011 to October 2022. Patients with clear-cell, papillary, and chromophobe RCC were included. Other histology, multiple tumours, and hereditary RCC syndrome patients were excluded. Each PN patient was individually matched to RN up to 1:4 depending on availability of patients based on tumor size (+/- 1cm), histology, grade (clear cell and papillary), and necrosis (clear cell). Matched patients were analyzed as clusters. Results: A total of 1523 patients were identified, and 50 PN patients met study criteria who were then matched to 185 RN patients. Both groups had similar age, gender, smoking status, BMI, Charlson comorbidity index score, symptoms at presentation, baseline eGFR, hemoglobin and pathological characteristics. PN patients had smaller tumors (7.6 cm [IQR 2] vs 8.4 [IQR 2.4], p=0.05), had higher likelihood of undergoing open surgery (72.9% vs 31.8%, p&lt;0.0001) and less likely received adrenalectomy (2% vs 24.3%, p=0.0004). Positive surgical margin rates were similar in both groups (8.2% in PN vs 3.4% in RN, p=0.2). Median follow up was not significantly different in either group (3.6 yrs [IQR 4.7] in PN vs 3.3 [4.7] yrs in RN, p=0.9). During the follow up period, PN patients had higher risk of local recurrence (HR 3.0, 95%CI 1.08-8.37), lower risk of distant metastasis (HR 0.36, 95%CI 0.15-0.88), better cancer specific survival (HR 0.56, 95%CI 0.18-1.78) and overall survival (HR 0.36, 95%CI 0.11-1.19) and as compared to RN. At 6 months and beyond after surgery, PN patients had less decline in eGFR than RN patients (-16.6 [SD 21.1] vs -24.4[SD 16.2], p=0.0002). Complications rates between PN and RN were (18% vs 9%, p=0.057). Conclusions: In this multi-institutional Canadian cohort of patients with non-metastatic cT2 RCC undergoing surgery, PN compared to RN was associated with slightly higher risk of peri-operative complications, better preservation of renal function, and higher risk of local recurrence. The lower risk of distant metastasis and death was likely from residual confounding unaccounted for in the individual patient match. [Table: see text]

Role of ultra-high b-value DWI in the imaging of hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is associated with an aggressive form of renal cell carcinoma with high risk of metastasis, even in small primary tumors with unequivocal imaging findings. In this study, we compare the performance of ultra-high b-value diffusion-weighted imaging (DWI) sequence (b = 2000s/mm2) to standard DWI (b = 800s/mm2) sequence in identifying malignant lesions in patients with HLRCC. Twenty-eight patients (n = 18 HLRCC patients with 22 lesions, n = 10 controls) were independently evaluated by three abdominal radiologists with different levels of experience using four combinations of MRI sequences in two separate sessions (session 1: DWI with b-800, session 2: DWI with b-2000). T1 precontrast, T2-weighted (T2WI), and apparent diffusion coefficient (ADC) sequences were similar in both sessions. Each identified lesion was subjectively assessed using a six-point cancer likelihood score based on individual sequences and overall impression. The ability to distinguish benign versus malignant renal lesions improved with the use of b-2000 for more experienced radiologists (Reader 1 AUC: Session 1-0.649 and Session 2-0.938, p = 0.017; Reader 2 AUC: Session 1-0.781 and Session 2-0.921, p = 0.157); whereas no improvement was observed for the less experienced reader (AUC: Session 1-0.541 and Session 2-0.607, p = 0.699). The inclusion of ultra-high b-value DWI sequence improved the ability of classification of renal lesions in patients with HLRCC for experienced radiologists. Consideration should be given toward incorporation of DWI with b-2000s/mm2 into existing renal MRI protocols.

33327 A case of reed syndrome with an unusually extensive cutaneous burden

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 (CLMs), uterine leiomyomas and renal cell carcinoma. CLMs are often the first manifestation of the syndrome, occurring in 76% of patients typically in their second to fourth decade of life. CLMs are smooth-surfaced, reddish-brown papules or nodules that range 0.2 to 2.0 cm in diameter and average 25 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 25. 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 laser resurfacing therapy. The use of fully ablative erbium laser resurfacing therapy for treatment of CLMs has not been reported in the literature to date. One year following laser therapy, the treatment area not only healed with normal repigmentation, but there was also no evidence of CLMs recurrence. Given the effectiveness of this unique therapy, fully ablative erbium laser resurfacing should be kept in mind as a treatment option for both cosmetic and symptomatic CLMs.

A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Pheochromocytoma and Paraganglioma.

Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase ( FH ) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)-tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk.

MR Spectroscopy for Detecting Fumarate Hydratase Deficiency in Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome.

Background Noninvasive in vivo detection of fumarate accumulation may help identify fumarate hydratase deficiency in renal cancer related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Purpose To investigate the feasibility of MR spectroscopy (MRS) in detecting elevated fumarate levels in HLRCC-associated renal cancers. Materials and Methods This study included an experimental xenograft mouse model and prospective clinical cohort. First, MRS was performed on patient-derived tumor xenograft models and control models to detect fumarate. Then, consecutive participants with clinical suspicion of HLRCC-associated renal tumors were enrolled. For the detection of fumarate, MRS results were classified as detected, borderline, undetected, or technical failure. The sensitivity, specificity, and accuracy of MRS for diagnosing HLRCC-associated renal cancer were assessed. The signal-to-noise ratio (SNR) of the fumarate peak was calculated and evaluated with receiver operating characteristic curve analysis. Results Fumarate peaks were detected at 6.54 parts per million in all three patient-derived xenograft models. A total of 38 participants (21 men; mean age, 47 years [range, 18-71 years]) with 46 lesions were analyzed. All primary HLRCC-associated renal cancers showed a fumarate peak; among the seven metastatic HLRCC-associated lesions, a fumarate peak was detected in three lesions and borderline in two. When only detected peaks were regarded as positive findings, the sensitivity, specificity, and accuracy of MRS at the lesion level were 69% (nine of 13 lesions), 100% (33 of 33 lesions), and 91% (42 of 46 lesions), respectively. When borderline peaks were also included as a positive finding, the sensitivity, specificity, and accuracy reached 85% (11 of 13 lesions), 88% (29 of 33 lesions), and 87% (40 of 46 lesions), respectively. The SNR of fumarate showed an area under the receiver operating characteristic curve of 0.87 for classifying HLRCC-associated tumors. Conclusion MR spectroscopy of fumarate was sensitive and specific for hereditary leiomyomatosis and renal cell carcinoma-associated tumors. © RSNA, 2022 Online supplemental material is available for this article.

Major heritable renal cell carcinoma syndromes: novel treatment options and future perspectives.

To provide an overview of diagnosis, genetic abnormalities, clinical signs and treatment options for the major heritable renal cell carcinoma (RCC) syndromes. RCC in major hereditary syndromes are disorders which are typically autosomal dominant. They predispose patients to early onset of RCC and may exhibit other extrarenal manifestations. Early recognition of these diseases allows correct screening at appropriate ages as well as early detection of RCC. Moreover, expedient identification may optimize the management of extra renal manifestations as well as allow for genetic testing and screening of at-risk relatives. The risk of RCC in these major heritable syndromes is higher than sporadic disease. They occur at earlier age groups and can be multifocal or bilateral. Tumours are observed until at least 3 cm before any intervention, while nephron sparing surgery is widely considered as the treatment of choice except for hereditary leiomyomatosis with renal cell cancer, of which radical nephrectomy is treatment of choice. Intervention should be timeous as there is a highly reported incidence of early metastasis. Molecular therapies have been used in the setting of patients with metastasis, some of which show favourable outcomes.

Abstract 3112: Metabolic hallmarks of rare renal cell carcinoma patient-derived xenograft models

Abstract Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare but highly aggressive malignancies that are often refractory to the therapies used for the more common RCCs. FH-deficient RCC most often occurs in individuals with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) and is characterized by loss of FH activity, a key metabolic enzyme. Bevacizumab plus erlotinib (B+E) is a preferred first-line therapy for FH-deficient RCC. RMC is characterized by loss of SMARCB1, which is involved in ATP-dependent chromatin remodeling. Platinum-based chemotherapy consisting of either cisplatin or carboplatin plus paclitaxel is the preferred first-line therapy for RMC. We developed patient-derived xenograft (PDX) models of tumors exposed to the commonly used first-line therapies to allow functional characterization of the metabolic hallmarks of treatment-experienced RMC and FH-deficient RCC. Methods: Resected tumor tissue was immediately implanted into NSG male and female mice. After tumor engraftment, animals were euthanized, and the tumor tissue implanted into another set of NSG mice. PDX tissues were confirmed to be genetically identical to the original patient tissue by short tandem repeat analysis. Histology was confirmed to be identical between original patient tumor and PDX by a trained clinical pathologist. Four tumors from each PDX model and four normal human kidney tissue samples were analyzed using reverse phase protein array (RPPA). Expression of proteins shown to be highly expressed by RPPA were further validated by Western blots. Results: We successfully generated one PDX model for RMC and one for FH-deficient RCC, respectively. The RMC model was generated from a 28-year old male with sickle cell trait, who had previously received cisplatin plus paclitaxel followed carboplatin plus paclitaxel. His lesion was characterized as ypT3apN1pMx and histology was consistent with RMC. The FH-deficient RCC model was generated from a 24-year-old female with HLRCC, who had been previously treated with B+E. Her lesion was characterized as pT3apN1pM1 and histology consistent with FH-deficient RCC. Germline testing revealed a R233H pathogenic mutation in the FH gene. RPPA revealed higher expression of hexokinase II (10x HLRCC, 16x RMC), lactate dehydrogenase A (27x HLRCC, 17x RMC), and glutaminase (4x HLRCC) in PDX tissue compared to normal kidney tissue. Western blots confirmed higher expression of glutaminase 1 in both HLRCC and RMC compared to normal kidney. Furthermore, we observed substantially higher hypoxia inducible factor 2α (HIF2α) protein expression in PDX tissue from FH-deficient RCC compared to RMC PDX tumors and normal kidney. Conclusions: Our study revealed distinct metabolic features in PDX models of FH-deficient RCC following treatment with B+E, and of platinum-experienced RMC, these differences may confer targetable vulnerabilities. Citation Format: Manuel Ozambela, Alberto Pieretti, Graciela M. Nogueras Gonzalez, Tapati Maity, Lei Wang, Carolyn De La Cerda, Breanna Alonzo, Luis Segarra, Angelita Alaniz, Priya Rao, Nizar Tannir, Jose A. Karam, Christopher G. Wood, Pavlos Msaouel, Niki M. Zacharias. Metabolic hallmarks of rare renal cell carcinoma patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3112.

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

BackgroundFH-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. ObjectiveTo 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 participantsThe study included 77 cases of FH-deficient RCC from 15 centers across China. Outcome measurements and statistical analysisClinical characteristics, molecular correlates, 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, and treatment outcomes were analyzed. Results and limitationsA 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. ConclusionsWe 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 summaryThis 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.

Clinicopathological and molecular characteristics of fumarate hydratase–deficient uterine smooth muscle tumors: a single-center study of 52 cases

The fumarate hydratase (FH) gene germline mutations cause hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), predisposing carriers to uterine and cutaneous leiomyomas and renal cell carcinoma. In this study, we aim to investigate morphology and the correlation between FH mutation in FH-deficient (FH-d) uterine smooth muscle tumors (uSMTs). We conducted immunohistochemical staining in 161 cases of uSMTs to detect FH deficiency. We identified 52 cases (52/161, 32%)of FH-d, including 34 leiomyomas with bizarre nuclei, 10 uSMTs of uncertain malignant potential (STUMPs), 4 cellular leiomyomas, 3 usual type leiomyomas, and 1 leiomyosarcoma. Patients with FH-d were aged 24-67 years (median, 40 years). The most common FH-d morphological features included staghorn-shaped blood vessels (87%), bizarre nuclei (81%), alveolar pattern edema (65%), macronucleoli surrounded by a halo (65%), cytoplasmic eosinophilic globules (56%), and chain-like distribution of smooth muscle cells (52%). A targeted next-generation sequence was performed in 11 of 52 FH-d tumors. Five cases (5/11, 45%) were found with FH germline mutations, including 4 leiomyomas with bizarre nuclei and 1 STUMP. The median age of patients with germline FH mutation was 30 years. The germline mutations included 3 pathogenic, 1 likely pathogenic, and 1 rare uncertain clinical significance variants. Our results revealed that FH-d uSMTs usually exhibit the distinct morphology features and high frequency of FH germline mutations. The combination of predictive morphology evaluation, FH immunotype, and molecular testing is helpful for the screening of HLRCC in uSMTs.