Fumarate Hydratase-deficient Renal Cell Carcinoma Research Articles

Comparison of 68Ga-FAPI-04 and 18F-FDG PET/CT in Fumarate Hydratase-Deficient Renal Cell Carcinoma: A Prospective and Single-Center Study.

Fumarate hydratase-deficient renal cell cancer (FHRCC) is a rare and aggressive form of renal cell carcinoma. The diagnostic value of 68Ga-FAPI PET/CT for FHRCC remains unexplored. Therefore, we compared the potential value of 68Ga-FAPI-04 and 18F-FDG PET/CT in FHRCC. Patients with FHRCC underwent 68Ga-FAPI-04 and 18F-FDG PET/CT from May 2022 to December 2023. The SUVmax and tumor-to-liver ratio (TLR) of both tracers were compared using the Wilcoxon signed rank test. Eleven patients with 83 lesions were enrolled. The rate of 18F-FDG PET/CT in detecting lesions was higher than that of 68Ga-FAPI-04 PET/CT: primary tumors: 75.0% (6/8) versus 50.0% (4/8); lymph nodes: 94.9% (37/39) versus 89.7% (35/39); and bone lesions: 100.0% (21/21) versus 90.5% (19/21). The median SUVmax of primary and metastatic lesions on 18F-FDG PET/CT was comparable to 68Ga-FAPI-04 PET/CT in semiquantitative analysis (primary lesions: 13.86 vs 16.35, P = 1.000; lymph nodes: 10.04 vs 9.33, P = 0.517; bone lesions: 13.49 vs 9.84, P = 0.107; visceral lesions: 8.54 vs 4.20, P = 0.056). However, the median TLRs of primary and metastatic lesions on 68Ga-FAPI-04 PET/CT were higher than that of 18F-FDG PET/CT (primary lesions: 30.44 vs 5.41, P = 0.010; lymph nodes: 17.71 vs 3.95, P = 0.000; bone lesions: 15.94 vs 5.21, P = 0.000; visceral lesions: 9.26 vs 3.44, P = 0.003). 18F-FDG PET/CT detected more primary and metastatic FHRCC lesions than 68Ga-FAPI-04 PET/CT. However, the higher TLR in FHRCC on 68Ga-FAPI-04 PET/CT may indicate therapeutic potential in targeting fibroblast activation protein in FHRCC.

Multi-omics analyses and molecular subtypes to provide potential therapeutic implications in fumarate hydratase-deficient renal cell carcinoma.

Multi-omics analyses and molecular subtypes to provide potential therapeutic implications in fumarate hydratase-deficient renal cell carcinoma.

Fumarate hydratase-deficient renal cell carcinoma: an oncology care institutional experience.

Renal cell carcinoma (RCC) accounts for 2% of all cancer cases worldwide, and majority are sporadic. The latest World Health Organization (WHO) classification of renal cell tumors (fifth edition, 2022) has molecularly defined renal tumor entities, which includes fumarate hydratase (FH)-deficient RCC. FH-deficient RCC is an aggressive carcinoma caused by pathogenic alterations in FH gene, seen in 15% of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) syndrome. These tumors occur more frequently at a younger age and present at an advanced stage, carrying a dismal prognosis. We report a series of 10 cases of FH-deficient RCC. The mean age was 49.8 years, and all cases presented in advanced stages (III and IV). Morphologically, the cases had varied architectural patterns with characteristic eosinophilic macronucleoli and perinucleolar halo. On immunohistochemistry (IHC), all showed diffuse nucleo-cytoplasmic expression of S-(2-succino)-cysteine (2-SC), with loss of FH in seven cases. FH-deficient RCCs are aggressive neoplasms and can be diagnosed using specific IHC markers (FH and 2-SC). These patients should undergo germline testing for FH gene mutation, genetic counseling, and surveillance of family members.

Fumarate Hydratase-Deficient Renal Cell Carcinoma with Nucleolar Pattern of GATA3 Immunoexpression: Report of 2 Cases.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare aggressive type of renal cell carcinoma. The significant morphologic overlap with other types of renal neoplasia and the limited availability of FH and 2-succinylcholine immunostains for diagnostic use outside large referral centers have created numerous diagnostic pitfalls. As FH-deficient RCC can be associated with hereditary leiomyomatosis and renal cell cancer syndrome, the importance of an accurate diagnosis goes beyond the prognosis and treatment of an individual patient. We present 2 patients with FH-deficient RCC showing a peculiar pattern of GATA3 immunoexpression restricted to tumor nucleoli. If confirmed in further larger studies, this could provide an additional diagnostic clue for considering the FH-deficient RCC diagnosis, and given the frequent papillary morphology and possible hilar location can lead to the misdiagnosis as high-grade urothelial carcinoma, and is an important diagnostic pitfall to be aware of.

Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

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.

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). 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. 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. 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.

Expression of programmed cell death ligand 1 and clinicopathological and immunological characteristics in fumarate hydratase-deficient renal cell carcinoma

Objective: To investigate the expression of programmed cell death ligand 1 (PD-L1), clinicopathologic features, immunohistochemical expression and molecular characteristics in fumarate hydratase (FH)-deficient renal cell carcinoma and to explore the potential application of immunotherapy in the patients. Methods: There were six patients with FH-deficient renal cell carcinoma treated at the First Affiliated Hospital of Fujian Medical University between January 2020 and October 2022. The clinical data, histological morphology, immunophenotype, PD-L1 expression and next-generation sequencing results were tabulated and analyzed. Results: There were 6 patients, all male, age ranged from 37 to 72 years (mean 45.7 years). Four cases were high-grade (WHO/ISUP grade3-4) with 2 or more histologic patterns, including papillary (most common), glandular, tubular, vesicular, ethmoid, nest-like, cystic and solid structures. Two cases were low-grade which showed nest-like, glandular, or tubular arrangement with eosinophilic flocculent cytoplasm and small intracellular vacuoles. Immunohistochemical analysis revealed strong expression of 2SC in all 6 cases, negative expression of FH in 5 cases, and positive expression of GATA3 in 5 cases. In high-grade cases, the mean values of CD4 and CD8 positive T-lymphocytes in advanced tumor invasion were 180.3/mm2 and 130.5/mm2, respectively. PD-L1 combined positive scores (CPS) were 20, 50, 5 and 30, respectively. The Ki-67 proliferative index were 20%, 20%, 10% and 30%, respectively. In low-grade cases, the mean values of CD4 and CD8 positive T-lymphocytes were 123.0/mm2 and 100.5/mm2, respectively. The PD-L1 CPS score was 1, and the Ki-67 proliferation index was 3%. High-throughput sequencing showed FH gene somatic mutation in 3 cases, FH gene germline mutation in 2 cases, and FH gene mutation was not detected in one case. Conclusion: FH-deficient renal cell carcinoma is more commonly high-grade than low grade. FH and 2SC are immunohistochemical markers used in the diagnosis of FH-deficient renal cell carcinoma, and GATA3 positivity is supportive of the diagnosis. The tumor infiltration of high-grade FH-deficient renal cell carcinoma shows an increase in CD4 and CD8 positive T-lymphocytes, and high expression of PD-L1; thus, anti-PD-L1 immunotherapy can be used as a treatment option.

Redefining Renal Cell Carcinoma: A Molecular Perspective on Classification and Clinical Implications

Renal cell carcinoma (RCC) is the most common primary tumour of the kidney. RCC is a clinically and pathologically heterogenous entity, which has traditionally been classified under two broad categories: clear-cell and non-clear cell. With improved molecular diagnostic methodologies and genetic testing, the classification of RCC has shifted from a morphological basis to a molecular/genetic focus, and has been systematically updated to reflect these advancements. The new 2022 World Health Organization (WHO) classification of RCC is the most recent of these updates, and contains significant changes, as compared to the previous 2016 classification. The most substantial of these changes is the establishment of a new category of molecularly-defined RCC, including TFE3-rearranged RCC, TFEB-altered RCC, ELOC-mutated RCC, fumarate hydratase-deficient RCC, succinate dehydrogenase-deficient RCC, ALK-rearranged RCC, and SMARCB1-deficient renal medullary carcinoma. In this narrative review, the authors briefly summarise the histopathological characteristics, clinical course, current treatment standards, and future treatment directions of each of these molecularly-defined RCC subtypes.

Factors influencing the detection rate of fumarate peak in 1H MR spectroscopy of fumarate hydratase-deficient renal cell carcinoma at 3 T MRI

To identify factors that may be associated with fumarate detection rate in 1H-magnetic resonance spectroscopy (MRS) in fumarate hydratase-deficient renal cell carcinoma (FH-RCC). Between February 2018 and March 2022, 16 FH-RCC patients with 30 lesions underwent 1H-MRS. Detection results were classified as having a detected fumarate peak (n=12), undetected peak (n=10), or technical failure (n=8). Factors including tumour size, tumour location, treatment history, and metastasis status were collected and analysed. A Bayesian logistic regression model was applied to evaluate the association between these factors and the detection result. Bayesian analysis demonstrated significant associations between fumarate detection results and the following factors: long-axis diameter (odds ratio [OR] of 1.64; 95% confidence interval [CI] of 1.07-2.53), short-axis diameter (OR of 1.90; 95% CI of 1.19-3.06), voxel size (OR of 2.85; 95% CI of 1.70-4.75), treatment history (OR of 0.35; 95% CI of 0.21-0.58), non-metastatic state (OR of 2.45; 95% CI of 1.48-4.06), and lymph node metastasis (OR of 0.35; 95% CI of 0.21-0.58). Technical failure results were associated with factors such as treatment history (OR of 2.59; 95% CI of 1.37-4.66), non-metastatic state (OR of 0.36; 95% CI of 0.19-0.66), and lymph node metastasis (OR of 2.61; 95% CI of 1.39-4.74). Tumour size, treatment history, and metastasis character were associated with the detection of abnormal fumarate accumulation. This finding will serve as a reference for interpreting 1H-MRS results and for selecting suitable scenarios to evaluate FH-RCC.

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase-deficient renal cell carcinoma.

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent plasma biomarkers for early diagnosis. These 2 molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

Genomic and transcriptomic features between primary and paired metastatic fumarate hydratase–deficient renal cell carcinoma

BackgroundFumarate hydratase–deficient renal cell carcinoma (FH-RCC) is a rare highly aggressive subtype of kidney cancer for which the distinct genomic, transcriptomic, and evolutionary relationships between metastatic and primary lesions are still unclear.MethodsIn this study, whole-exome, RNA-seq, and DNA methylation sequencing were performed on primary-metastatic paired specimens from 19 FH-RCC cases, including 23 primary and 35 matched metastatic lesions. Phylogenetic and clonal evolutionary analyses were used to investigate the evolutionary characteristics of FH-RCC. Transcriptomic analyses, immunohistochemistry, and multiple immunofluorescence experiments were performed to identify the tumor microenvironmental features of metastatic lesions.ResultsPaired primary and metastatic lesions generally showed similar characteristics of tumor mutation burden, tumor neoantigen burden, microsatellite instability score, CNV burden, and genome instability index. Notably, we identified an FH-mutated founding MRCA (the most recent common ancestor) clone that dominated the early evolutionary trajectories in FH-RCC. Although both primary and metastatic lesions manifested high immunogenicity, metastatic lesions exhibited higher enrichment of T effector cells and immune-related chemokines, together with upregulation of PD-L1, TIGIT, and BTLA. In addition, we found that concurrent NF2 mutation may be associated with bone metastasis and upregulation of cell cycle signature in metastatic lesions. Furthermore, although in FH-RCC metastatic lesions in general shared similar CpG island methylator phenotype with primary lesions, we found metastatic lesions displaying hypomethylated chemokine and immune checkpoints related genomic loci.ConclusionsOverall, our study demonstrated the genomic, epigenomic, and transcriptomic features of metastatic lesions in FH-RCC and revealed their early evolutionary trajectory. These results provided multi-omics evidence portraying the progression of FH-RCC.

Fumarate hydratase-deficient renal cell carcinoma: a case report and review of the literature

BackgroundFumarate hydratase-deficient renal cell carcinoma is a rare pathological subtype that was defined by the World Health Organization (WHO 5th edition) in 2022. At present, only a few hundreds of cases have been reported worldwide, mainly in Europe and the United States. A case of a Chinese patient is reported here, along with a literature review.Case reportA 60-year-old Asian male who complained of hematuria for 20 days was admitted to the hospital. Contrast enhanced Computer Tomography showed that the volume of the right kidney was increased, with a patchy low-density shadow with infiltrative growth inside that had a significantly lower signal intensity than the renal cortex; thus, the possibility of collecting duct carcinoma or lymphoma, was considered. Enlarged perirenal and retroperitoneal lymph nodes were also seen, along with bilateral renal cysts. Eight years prior, ultrasonography had shown a complex renal cyst in the right kidney, and no treatment was administered at that time. Laparoscopic radical nephrectomy of the right kidney was performed this time, and the postoperative specimens were submitted for pathological examination. Because immunohistochemistry showed the loss of fumarate hydratase protein expression and the possibility of fumarate hydratase-deficient renal cell carcinoma was considered, corresponding molecular pathological tests were performed, and the results showed an FHp.R233H (arginine > histidine) germline mutation (inactivation mutation). The postoperative pathological diagnosis was fumarate hydratase-deficient renal cell carcinoma in the right kidney, T3aN1M0. The patient was treated with sunitinib, and bone and liver metastases developed half a year later. The treatment was then changed to axitinib and toripalimab. At present, the patient is in stable condition, and there has been no progression of the metastases.ConclusionFumarate hydratase-deficient renal cell carcinoma is a very rare renal tumor that is defined on a molecular basis. It is highly malignant and metastasizes early. Therefore, fully understanding the disease, enabling detection and diagnosis and administering treatment are particularly important.

Diffuse Carbonic Anhydrase 9 and GATA3 Expression in Fumarate Hydratase Deficient Renal Cell Carcinoma - A Case Report and Immunoprofile Review.

Fumarate hydratase deficient renal cell carcinoma (FHRCC) can exhibit a heterogenous immunoprofile. In the present case, a solitary 10.5 cm mixed cystic and solid left kidney tumor showed various growth patterns, involving renal sinus adipose tissue and the renal pelvis. Tumor cells showed prominent nucleoli and perinucleolar halos. Aberrant diffuse (>90%), strong, and membranous carbonic anhydrase 9 and variable GATA3 expression were present. Diagnostic loss of fumarate hydratase expression and 2-succinyl cysteine overexpression (cytoplasmic and nuclear) were identified. Carbonic anhydrase 9 and GATA3 expression in FHRCC is rarely reported in the literature, and may cause misdiagnosis of clear cell RCC and/or urothelial carcinoma.

Expression of GPNMB in renal eosinophilic tumors and its value in differential diagnosis

Objective: To investigate the expression of glycoprotein non metastatic melanoma protein B (GPNMB) in renal eosinophilic tumors and to compare the value of GPNMB with CK20, CK7 and CD117 in the differential diagnosis of renal eosinophilic tumors. Methods: Traditional renal tumor eosinophil subtypes, including 22 cases of renal clear cell carcinoma eosinophil subtype (e-ccRCC), 19 cases of renal papillary cell carcinoma eosinophil subtype (e-papRCC), 17 cases of renal chromophobe cell carcinoma eosinophil subtype (e-chRCC), 12 cases of renal oncocytoma (RO) and emerging renal tumor types with eosinophil characteristics [3 cases of eosinophilic solid cystic renal cell carcinoma (ESC RCC), 3 cases of renal low-grade eosinophil tumor (LOT), 4 cases of fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) and 5 cases of renal epithelioid angiomyolipoma (E-AML)], were collected at the Affiliated Drum Tower Hospital of Nanjing University Medical School from January 2017 to March 2022. The expression of GPNMB, CK20, CK7 and CD117 was detected by immunohistochemistry and statistically analyzed. Results: GPNMB was expressed in all emerging renal tumor types with eosinophil characteristics (ESC RCC, LOT, FH-dRCC) and E-AML, while the expression rates in traditional renal eosinophil subtypes e-papRCC, e-chRCC, e-ccRCC and RO were very low or zero (1/19, 1/17, 0/22 and 0/12, respectively); the expression rate of CK7 in LOT (3/3), e-chRCC (15/17), e-ccRCC (4/22), e-papRCC (2/19), ESC RCC (0/3), RO (4/12), E-AML(1/5), and FH-dRCC (2/4) variedly; the expression of CK20 was different in ESC RCC (3/3), LOT(3/3), e-chRCC(1/17), RO(9/12), e-papRCC(4/19), FH-dRCC(1/4), e-ccRCC(0/22) and E-AML(0/5), and so did that of CD117 in e-ccRCC(2/22), e-papRCC(1/19), e-chRCC(16/17), RO(10/12), ESC RCC(0/3), LOT(1/3), E-AML(2/5) and FH-dRCC(1/4). GPNMB had 100% sensitivity and 97.1% specificity in distinguishing E-AML and emerging renal tumor types (such as ESC RCC, LOT, FH-dRCC) from traditional renal tumor types (such as e-ccRCC, e-papRCC, e-chRCC, RO),respectively. Compared with CK7, CK20 and CD117 antibodies, GPNMB was more effective in the differential diagnosis (P<0.05). Conclusion: As a new renal tumor marker, GPNMB can effectively distinguish E-AML and emerging renal tumor types with eosinophil characteristics such as ESC RCC, LOT, FH-dRCC from traditional renal tumor eosinophil subtypes such as e-ccRCC, e-papRCC, e-chRCC and RO, which is helpful for the differential diagnosis of renal eosinophilic tumors.

PD24-09 PHASE II, MULTI-CENTER STUDY OF SINTILIMAB IN COMBINATION WITH AXITINIB IN PATIENTS WITH ADVANCED FUMARATE HYDRATASE-DEFICIENT RENAL CELL CARCINOMA

PD24-09 PHASE II, MULTI-CENTER STUDY OF SINTILIMAB IN COMBINATION WITH AXITINIB IN PATIENTS WITH ADVANCED FUMARATE HYDRATASE-DEFICIENT RENAL CELL CARCINOMA

Characterization of Protein (2SC) Succination as a Biomarker for Fumarate Hydratase-deficient Renal Cell Carcinoma.

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is an aggressive, rare genetic disease affecting the kidney and other organ systems. We constructed a specialized multi-institutional cohort of 20 primary FH-deficient RCC cases with aims of characterizing a new commercially available antibody, S-(2-succino)-cysteine (2SC). Herein, we present our findings on the biomarker characterization and performance of 2SC expression by immunohistochemistry (IHC) in FH-deficient RCC, and other common and rare RCC subtypes. Morphological assessment revealed characteristic cytomorphologic features and a majority (55%) of FH-deficient RCC had mixed architectural growth patterns. We observed predominantly diffuse and strong cytoplasmic staining with limited nuclear positivity for 2SC staining on IHC. Receiver operating characteristic curves (ROC) for 2SC identified the threshold IHC score (cut-off) as 90; with the sensitivity and specificity being 100% and 91% respectively. The findings of the present study along with the prior evidence in literature encourages utilization of 2SC as a positive marker along with the loss of fumarate hydratase (FH) expression by anti-FH IHC staining as a negative marker, in clinical and/or pathologic scenarios when considering FH-deficient RCC in the differential diagnosis. FH-/2SC+ may serve as a comprehensive IHC panel in identifying such cases and excluding morphologically similar entities.

Update on Selected Oncocytic Renal Cell Tumors

Renal cell tumors with eosinophilic/oncocytic cells include oncocytic papillary renal neoplasm with reverse polarity, oncocytoma, chromophobe renal cell carcinoma, hybrid oncocytic/chromophobe renal tumor, succinate dehydrogenase-deficient renal cell carcinoma, translocation-associated renal cell carcinoma, etc. Recently, several novel and evolving oncocytic renal tumors have been identified, such as eosinophilic solid and cystic renal cell carcinoma, eosinophilic vacuolated tumor, and low-grade oncocytic tumor. In addition, fumarate hydratase-deficient renal cell carcinoma occasionally presents with a low-grade oncocytic morphology. Although these entities demonstrate some overlapping morphological features with oncocytoma and chromophobe renal cell carcinoma, they do have some unique morphological, immunohistochemical, and molecular profiles. In this review, we present an update on selected oncocytic renal cell tumors (eosinophilic vacuolated tumor, low-grade oncocytic tumor, eosinophilic solid and cystic renal cell carcinoma, low-grade fumarate hydratase-deficient renal cell carcinoma, and hybrid oncocytic/chromophobe renal tumor) and discuss their morphologies, immunohistochemical profiles, molecular genetic profiles, and biological behaviors.

Carcinome à cellules rénales FH (fumarate hydratase)-déficient : à propos d’un cas

Fumarate hydratase deficient renal cell carcinoma (FH-RCC) is a rare malignant neoplasia caused by constitutive or somatic mutations in the FH gene whose diagnosis is primordial, requiring genetic counselling. Because of histological heterogeneity, such tumors have been in the past misclassified as "type 2papillary carcinoma", "tubulo-cystic renal cell carcinoma" or "high grade papillary carcinoma". We report here a case of FH deficient renal cell carcinoma (FH-RCC) in a 69years old patient. Through this observation, we precise the epidemiological and histological aspects and diagnosis criteria of this rare tumor.

Phase II multi-center study of sintilimab in combination with axitinib in patients with advanced fumarate hydratase-deficient renal cell carcinoma.

685 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and highly aggressive cancer mainly caused by germline or somatic aberrant of FH gene. Unfortunately, there are no standard treatment. Here we report the preliminary results of a phase II study investigating the efficacy and safety of sintilimab in combination with axitinib in patients with FH-RCC. Methods: Patients were treated at mutli-center in hospitals of the republic of China. Eligibility criteria included age ≥ 18 years and newly diagnosed as FH-RCC by FH immunohistochemistry and next-generation sequencing or multiplex ligation-dependent probe amplification. Patients received sintilimab (intravenous injection, every 3 week) in combination with axitinib (5mg, orally taken per day) as first-line treatment until disease progression or intolerant to treatment. The primary end point was objective response rate (ORR; RECIST v1.1). This study is registered with ClinicalTrials.gov, NCT04387500. Results: Between July 2021 and October 2022, 21 patients were enrolled. At this preliminary analysis (data cutoff, October, 2022), median follow-up was 9 months (0.9-15.2 months). Nineteen patients were available for efficacy assessment. Confirmed complete response rate was 15.8% (3/19), ORR was 63.1% (12/19). Disease-controlled rate (DCR) was 89.4% (17/19). The median of progression-free survival (PFS) was not reached, with a high 12-month PFS rate of 72.3%. All grade and ≥ 3 treatment-emergent adverse events occurred in 95% (20/21) and 23.8% (5/21), respectively. Conclusions: Sintilimab in combination with Axitinib had a manageable safety profile and achieved a promising tumor response rate in patients with advanced FH-RCC. The trial is an ongoing study, with a total of planned 41 patients from 8 sites. The study start date was June 2, 2021. Clinical trial information: NCT04387500 .

The role of immunotherapy in non-clear cell renal cell carcinoma.

The category of non-clear cell renal cell carcinoma (nccRCC) includes several clinically, histologically, and molecularly diverse entities. Traditionally, they comprise type 1 and type 2 papillary, chromophobe, unclassified, and other histologies (medullary, collecting duct carcinoma, and translocation-associated). Molecular knowledge has allowed the identification of some other specific subtypes, such as fumarate hydratase-deficient renal cell carcinoma (RCC) or succinate dehydrogenase-associated RCC. In addition, it has recognized some alterations with a possible predictive role, e.g., MET proto-oncogene receptor tyrosine kinase (MET) alterations in papillary tumors. Standard therapies for the management of advanced clear cell RCC (ccRCC), i.e., vascular endothelial growth factor receptor (VEGFR) pathway inhibitors and mammalian target of rapamycin inhibitors, have shown poorer results in nccRCC patients. Therefore, there is a need to improve the efficacy of the treatment for advanced nccRCC. Immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting programmed death 1/programmed death ligand 1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), has demonstrated a significant survival benefit in several malignant neoplasias, including ccRCC, with a proportion of patients achieving long survival. The combinations of ICI or ICI + VEGFR tyrosine kinase inhibitors (TKIs) are the standard of care in advanced ccRCC. Unfortunately, major pivotal trials did not include specific nccRCC populations. In recent years, several studies have retrospectively or prospectively evaluated ICIs alone or in combination with another ICI or with TKIs in nccRCC patients. In this article, we review data from available trials in order to elucidate clinical and molecular profiles that could benefit from immunotherapy approaches.