Fumarate hydratase deficient renal cell carcinoma: a retrospective study performed at NHLS Universitas Academic laboratories, 2001 to 2017

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Du Preez, Michelle
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University of the Free State
Background: Fumarate hydratase deficient renal cell carcinoma (FH deficient RCC) has, in recent years, been described as part of a morphologic spectrum of renal tumours associated with hereditary leiomyomatosis and renal cell carcinoma (HLCRCC) syndrome and is currently recognized as a distinct entity in the 2013 International Society of Urological Pathology (ISUP) Vancouver classification of renal tumours and is included in the 2016 World Health Organization (WHO) classification. FH deficient RCC is an aggressive neoplasm which often presents at a high pathologic stage, with local and distant metastases at the time of diagnosis. FH deficient RCC has a wide variety of morphological patterns, however, the presence of pattern multiplicity, sarcomatoid/rhabdoid morphology and the presence of characteristic nuclear features, i.e. nuclei with prominent viral inclusion-like macronucleoli and perinuclear halos should prompt genetic testing of the tumour. Characteristic immunohistochemical staining patterns, i.e. loss of cytoplasmic expression of fumarate hydratase (FH) and aberrant nuclear expression of S-(2-succino)-cyteine (2SC) have a 100% positive predictive value for identifying FH deficient RCC, however, only FH is available for commercial use. Retention of cytoplasmic staining for FH does not exclude FH deficient RCC since the gene may still be functional in missense variants of the FH gene. To our knowledge, there is presently no published research regarding FH deficient RCC and its association with HLRCC syndrome in Africa. The impact of this disorder in South African patients, is therefore unknown. Aim: The aim of this study was to determine the number and profile of patients with FH deficient RCC seen by the Department of Anatomical Pathology, University of the Free State over a 17-year period, from 1 January 2001 to 31 December 2017. Methods: A retrospective, cross-sectional study was performed. All cases of primary renal cell carcinoma and RCC subtypes diagnosed between 1 January 2001 and 31 December 2017 were included. An immunohistochemical stain for FH was performed on all the cases. All the cases with the typical phenotype for FH deficient RCC were submitted for molecular analysis and genotyping. Results: 172 patients were included in the study. Ninety (52.33%) were male and 82 (47.67%) were female. The mean age at presentation was 54.2 years and most patients presented in the 5th to 6th decades of life. All cases showed retained cytoplasmic staining with FH. One (0.58%) case of FH deficient RCC with the characteristic phenotype and a missense mutation in Exon 7 of the FH gene was identified. The patient was a 53-year-old black female and no information regarding the presence of uterine leiomyomas or family history of RCC was available. Conclusion: All cases of RCC displaying the typical phenotype of FH deficient RCC (whether immunolabeling for FH is retained or lost) should be submitted for molecular testing in order to identify patients with HLRCC syndrome or confirm the diagnosis of sporadic FH deficient RCC to minimize morbidity and mortality in such patients and their families.
Dissertation (M.Med. (Anatomical Pathology))--University of the Free State, 2021, Fumarate hydratase, Urological Pathology (ISUP), World Health Organization (WHO), leiomyomatosis and renal cell carcinoma