Fumarate hydratase-deficient renal cell carcinoma: A clinicopathological study of seven cases including hereditary and sporadic forms

Tsutsui, Miho; Iguchi, Mitsuko; Nobuoka, Emi; Uehara, Takeshi; Sonobe, Yuta; Morinaga, Yukiko; Shibuya, Shinsuke; Oda, Wakako; Yanai, Hiroyuki; Kawada, Chiaki; Karashima, Takashi; Yamasaki, Ichiro; Inoue, Keiji; Nagashima, Yoji

doi:10.1016/j.anndiagpath.2020.151599

Cited by 12 publications

(6 citation statements)

References 18 publications

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“…In literature, the most predominant pattern encountered was papillary followed by tubulopapillary, intracystic papillae, tubulocystic, cribriform/sieve like, sarcomatoid, and low-grade oncocytic. 12 14 15 16 17 18 19 20 21 An infiltrating collecting duct carcinoma-like morphology and tubulocystic carcinoma with poorly differentiated foci have also been described. 5 12 22 23 In our study, the most predominant pattern was also papillary followed by tubulocystic and cribriform with minor patterns including solid and nested and three cases with a collecting duct carcinoma-like morphology.…”

Section: Discussionmentioning

confidence: 99%

Fumarate Hydratase-Deficient Renal Cell Carcinoma—A Clinicopathological Study of a Series of 11 Cases

Menon,

Rane,

Sakhadeo

et al. 2024

Indian J Med Paediatr Oncol

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Introduction Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare, molecularly defined renal tumor with aggressive behavior. The diagnosis of these tumors is challenging because of varied morphology and limited access to molecular testing and immunohistochemistry (IHC) for FH and 2-succinocysteine. We aim to elucidate the histomorphology, clinical presentation, and follow-up of this tumor in this first series of cases of FH-deficient RCCs from India. Objectives This article aims to understand and elucidate the clinical presentation, pathologic findings, treatment options, and outcomes of FH-deficient RCC. Materials and Methods Diagnosed cases of FH-deficient RCC between January 2021 and January 2023 including clinical details were retrieved from the electronic medical record database. Histopathological and immunohistochemical slides were reviewed. Results Out of 11 cases of FH-deficient RCC, 36% had been referred with a diagnosis of type 2 papillary RCC. One patient presented with metastatic disease. All had mixed histologic patterns with the predominant pattern being papillary and showed FH loss on IHC. The classically described inclusion like nucleoli was present only focally in most cases. A subset of tumors had low-grade solid-nested morphology and these patients presented at an earlier stage (T2a). Two patients on multikinase inhibitors are alive with disease at 14 months' follow-up. Conclusion FH-deficient RCCs can have varied histologic patterns within the same tumor and show loss of FH expression by IHC. A subset has low grade morphology and tends to have a more indolent course. It is important to have a high index of suspicion for this diagnosis due to its varied histological appearance and aggressive behavior.

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Section: Discussionmentioning

confidence: 99%

Fumarate Hydratase-Deficient Renal Cell Carcinoma—A Clinicopathological Study of a Series of 11 Cases

Menon,

Rane,

Sakhadeo

et al. 2024

Indian J Med Paediatr Oncol

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“…At present, observations suggest that the clinical behavior of FH-dRCC and HLRCC-associated RCC is similar. [ 2 , 11 , 14 ]. All of FH-dRCC cases in our cohort had no known family history of HLRCC and due to the lack of definitive genetic or clinical information at their initial presentations, we use the term “FH-dRCC” to include both HLRCC-associated RCC and disseminated cases of FH-dRCC.…”

Section: Discussionmentioning

confidence: 99%

“…As a rare subtype of renal cell carcinoma (RCC), fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) is characteristic of pathologic germline/ somatic mutations in the FH gene [1][2][3] while lesions with germline mutations are associated with hereditary leiomyomatosis and RCC (HLRCC) syndrome. The latter, an autosomal dominant disorder, usually predisposes individuals to cutaneous leiomyomas (CL), multiple uterine leiomyomas (MUL), and RCC [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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

Bai,

Li,

Wen

et al. 2024

Aging

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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.

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“…Several previously reported Japanese families with HLRCC exhibited different pathogenic variants, including missense variants and a splice site variant that had not been reported in Caucasian families [ 18 , 19 , 20 , 21 , 22 , 23 ]. To the best of our knowledge, ours is the first report of a whole-gene FH deletion in Japan.…”

Section: Discussionmentioning

confidence: 99%

Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling

Ueki

Sugano

Misu

et al. 2021

IJMS

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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.

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Fumarate hydratase-deficient renal cell carcinoma: A clinicopathological study of seven cases including hereditary and sporadic forms

Cited by 12 publications

References 18 publications

Fumarate Hydratase-Deficient Renal Cell Carcinoma—A Clinicopathological Study of a Series of 11 Cases

Fumarate Hydratase-Deficient Renal Cell Carcinoma—A Clinicopathological Study of a Series of 11 Cases

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

Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling

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