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CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(06): 502-508
DOI: 10.1055/s-0043-1775804
Original Article

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

Aswathy A. Menon 
1   Department of Pathology, Neuberg Anand Reference Laboratory, Bengaluru, Karnataka, India
,
Swapnil Rane 
2   Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Uma Sakhadeo
2   Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Gagan Prakash 
3   Department of Urology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Amit Joshi
4   Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Mahendra Pal
3   Department of Urology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Amandeep Arora
3   Department of Urology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Nilesh Sable
5   Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Aparna Katdare
5   Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Palak Popat
5   Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Priyamvada Maitre
6   Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Archi Agarwal
7   Department of Nuclear Medicine, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Vedang Murthy
6   Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Sangeetha B. Desai 
2   Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
,
Santosh Menon 
2   Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
› Author Affiliations Funding None declared.
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Abstract

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.

Keywords

fumarate hydratase-deficient renal cell carcinoma - fumarate hydratase - RCC - FH IHC - HLRCC

Patient Consent

Waiver of consent was obtained since this was a retrospective study with less than minimal risk and participants are de-identified or cannot be contacted.

Ethics clearance letter stating the same has been provided during manuscript submission and also the ethics project approval number is provided within the manuscript.


Department(s) and institution(s) where the work was carried out: Department of Pathology, Tata Memorial Hospital, Mumbai.




Publication History

Article published online:
07 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Moch H, Amin MB, Berney DM. et al. The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours. Eur Urol 2022; 82 (05) 458-468
    CrossrefPubMedSearch in Google Scholar
  • 2 Shuch B, Li S, Risch H, Bindra RS, McGillivray PD, Gerstein M. Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer. Cancer 2020; 126 (16) 3657-3666
    CrossrefPubMedSearch in Google Scholar
  • 3 Srinivasan R, Gurram S, Al Harthy M. et al. Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer. J Clin Oncol 2020; 38 (15) 5004-5004
    CrossrefSearch in Google Scholar
  • 4 Gleeson JP, Nikolovski I, Dinatale R. et al. Comprehensive molecular characterization and response to therapy in fumarate hydratase-deficient renal cell carcinoma. Clin Cancer Res 2021; 27 (10) 2910-2919
    CrossrefPubMedSearch in Google Scholar
  • 5 Adamane S, Desai S, Menon S. Hereditary leiomyomatosis and renal cell cancer syndrome associated renal cell carcinoma. Indian J Pathol Microbiol 2017; 60 (01) 108-110
    CrossrefPubMedSearch in Google Scholar
  • 6 Alam NA, Bevan S, Churchman M. et al. Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43. Am J Hum Genet 2001; 68 (05) 1264-1269
    CrossrefPubMedSearch in Google Scholar
  • 7 Menko FH, Maher ER, Schmidt LS. et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer 2014; 13 (04) 637-644
    CrossrefPubMedSearch in Google Scholar
  • 8 Tomlinson IP, Alam NA, Rowan AJ. et al; Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30 (04) 406-410
    CrossrefPubMedSearch in Google Scholar
  • 9 Lobo J, Ohashi R, Amin MB. et al. WHO 2022 landscape of papillary and chromophobe renal cell carcinoma. Histopathology 2022; 81 (04) 426-438
    CrossrefPubMedSearch in Google Scholar
  • 10 Crooks DR, Maio N, Lang M. et al. Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer. Sci Signal 2021; 14 (664) eabc4436
    CrossrefPubMedSearch in Google Scholar
  • 11 Brunner JS, Finley LWS. Metabolic determinants of tumour initiation. Nat Rev Endocrinol 2023; 19 (03) 134-150
    CrossrefPubMedSearch in Google Scholar
  • 12 Chen YB, Brannon AR, Toubaji A. et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol 2014; 38 (05) 627-637
    CrossrefPubMedSearch in Google Scholar
  • 13 Trpkov K, Hes O. New and emerging renal entities: a perspective post-WHO 2016 classification. Histopathology 2019; 74 (01) 31-59
    CrossrefPubMedSearch in Google Scholar
  • 14 Lau HD, Chan E, Fan AC. et al. A clinicopathologic and molecular analysis of fumarate hydratase-deficient renal cell carcinoma in 32 patients. Am J Surg Pathol 2020; 44 (01) 98-110
    CrossrefPubMedSearch in Google Scholar
  • 15 Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol 2007; 31 (10) 1578-1585
    CrossrefPubMedSearch in Google Scholar
  • 16 Billis A, Assis-Mendonça GR, Tavares TF. et al. Fumarate hydratase-deficient renal cell carcinoma: a tumor with diverse morphology including cannibalism, lymphocytic emperipolesis, and defective autophagy. Ann Diagn Pathol 2022; 56: 151844
    CrossrefPubMedSearch in Google Scholar
  • 17 Kuroda N, Tsutsui M, Iguchi M. et al. Fumarate hydratase-deficient renal cell carcinoma: a clinicopathological study of seven cases including hereditary and sporadic forms. Ann Diagn Pathol 2020; 49: 151599
    CrossrefPubMedSearch in Google Scholar
  • 18 Muller M, Guillaud-Bataille M, Salleron J. et al. Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration. Mod Pathol 2018; 31 (06) 974-983
    CrossrefPubMedSearch in Google Scholar
  • 19 Trpkov K, Hes O, Agaimy A. et al. Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol 2016; 40 (07) 865-875
    CrossrefPubMedSearch in Google Scholar
  • 20 Pan X, Zhang M, Yao J. et al. Fumaratehydratase-deficient renal cell carcinoma: a clinicopathological and molecular study of 13 cases. J Clin Pathol 2019; 72 (11) 748-754
    CrossrefPubMedSearch in Google Scholar
  • 21 Pivovarcikova K, Martinek P, Grossmann P. et al. Fumarate hydratase deficient renal cell carcinoma: chromosomal numerical aberration analysis of 12 cases. Ann Diagn Pathol 2019; 39: 63-68
    CrossrefPubMedSearch in Google Scholar
  • 22 Smith SC, Trpkov K, Chen YB. et al. Tubulocystic carcinoma of the kidney with poorly differentiated foci: a frequent morphologic pattern of fumarate hydratase-deficient renal cell carcinoma. Am J Surg Pathol 2016; 40 (11) 1457-1472
    CrossrefPubMedSearch in Google Scholar
  • 23 Ohe C, Smith SC, Sirohi D. et al. Reappraisal of morphologic differences between renal medullary carcinoma, collecting duct carcinoma, and fumarate hydratase-deficient renal cell carcinoma. Am J Surg Pathol 2018; 42 (03) 279-292
    CrossrefPubMedSearch in Google Scholar
  • 24 Li Y, Reuter VE, Matoso A, Netto GJ, Epstein JI, Argani P. Re-evaluation of 33 ‘unclassified’ eosinophilic renal cell carcinomas in young patients. Histopathology 2018; 72 (04) 588-600
    CrossrefPubMedSearch in Google Scholar
  • 25 Gupta S, Swanson AA, Chen YB. et al. Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC. Hum Pathol 2019; 91: 114-122
    CrossrefPubMedSearch in Google Scholar
  • 26 Mannan R, Wang X, Bawa PS. et al. Characterization of protein S-(2-succino)-cysteine (2SC) succination as a biomarker for fumarate hydratase-deficient renal cell carcinoma. Hum Pathol 2023; 134: 102-113
    CrossrefPubMedSearch in Google Scholar
  • 27 Choi Y, Keam B, Kim M. et al. Bevacizumab plus erlotinib combination therapy for advanced hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma: a multicenter retrospective analysis in Korean patients. Cancer Res Treat 2019; 51 (04) 1549-1556
    CrossrefPubMedSearch in Google Scholar
  • 28 Carril-Ajuria L, Colomba E, Cerbone L. et al. Response to systemic therapy in fumarate hydratase-deficient renal cell carcinoma. Eur J Cancer 2021; 151: 106-114
    CrossrefPubMedSearch in Google Scholar