Fumarate hydratase–deficient renal cell carcinoma

2021-11-05   Paola Dal Cin , Michelle S. Hirsch 

1. Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2.Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)

Classification

Definition

Fumarate hydratase (FH)-deficient renal cell carcinoma (FH-def RCC) is closely related to the renal cancers found in the rare hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, an autosomal dominant hereditary disease characterized by multiple uterine and cutaneous leiomyomas and renal cell carcinoma predisposition. The term FH-def RCC is the more appropriate terminology (in contrast to u2018HLRCC associated RCCu2019), encompassing both sporadic (absence of features suggesting syndromic disease) and hereditary (germline) cases

Clinics and Pathology

Epidemiology

Rare lesions. The renal carcinomas associated with HLRCC syndrome OMIM:150800 have been reported in about 30% of HLRCC families 1,2. However, patients may initially present only with skin or uterine leiomyomas or less commonly with renal cell carcinoma, and renal tumors may demonstrate a delayed presentation, or the patients may lack the other HLRCC syndromic features. FH-deficient leiomyomas in the absence of a renal mass are more frequently sporadic, whereas FH-def RCCs regardless of the presence of absence of leiomyomas are more frequently associated with a germline mutation.

Clinical features

More frequently in male patients, with a median age of 44 years, typically present as a single unilateral large tumor, and often demonstrate a high-stage disease at presentation. Unlike other familial RCC syndromes, patients may present with single unilateral cutaneous lesion on the arms or thorax, which can be painful.

Histopathology

FH-def RCCs show variable morphology with solid, papillary, tubulocystic, cribriform and cystic architecture and eosinophilic cytology (Fig.1)3,4,5,6. The majority of FH-def RCC demonstrate characteristic nuclear features which include a macronucleoli and perinucleolar halos (Fig.1A,inset).

Immunohistochemistry

The diagnosis is confirmed by combining loss of FH (80% sensitive) (Fig.1B) and overexpression of S-(2-succino)-cysteine (2SC) (Fig.1C)7,8,9 which correlate closely with molecular studies. 2.


Fig 1: Fumarate hydratase (FH)-deficient RCCs frequently demonstrated papillary architecture, eosinophilic cytologic features, and high grade nuclei (A); the latter typically contain prominent nucleoli with perinucleolar halos (inset). The absence (loss) of FH (B) and the presence of 2SC (C) in tumor cells by immunohistochemistry confirms the diagnosis of FH-deficient RCC.

Genetics

Microarray

• Copy number variation pattern in FH-def RCC/HLRCC appears to be highly variable, affecting mainly chromosomes 4, 9, 13, 14, 15, and does not provide a useful diagnostic tool in identifying these cases 11

Mutations

FH gene mutation results in either complete loss or reduction of the FH enzymatic activity, resulting in accumulation of intracellular fumarate, with an increased protein succination and accumulation of 2SC 12,13.

FH gene located at 1q42.3- q43 and codes for an enzyme involved in the tricarboxylic acid cycle (Kerbs cycle), which hydrates fumarate to form malate 14.

Cytogenetics

Prognosis and treatment

FH-def RCC typically presents with advanced disease and is characterized by very aggressive behavior, compared with renal tumors in other hereditary renal cancer syndromes. If FH-def RCC is diagnosed, the possibility of HLRCC should be first considered clinically, and prompt genetic counselling and FH mutational analysis in these patients and their families should be recommended 10

Bibliography

Reference NumberPubmed IDLast YearTitleAuthors
1159370702006Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.Wei MH et al
2281964072017Comprehensive genomic and phenotypic characterization of germline FH deletion in hereditary leiomyomatosis and renal cell carcinoma.Vocke CD et al
3178957612007The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.Merino MJ et al
4269008162016Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome.Trpkov K et al
5276359462016Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci: A Frequent Morphologic Pattern of Fumarate Hydratase-deficient Renal Cell Carcinoma.Smith SC et al
6305653012019New and emerging renal entities: a perspective post-WHO 2016 classification.Trpkov K et al
7294104892018Pattern 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.Muller M et al
8312992662019Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC.Gupta S et al
9320160422019Immunohistochemical screening for the diagnosis of succinate dehydrogenase-deficient renal cell carcinoma and fumarate hydratase-deficient renal cell carcinoma.Trpkov K et al
10250122572014Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment.Menko FH et al
11307850292019Fumarate hydratase deficient renal cell carcinoma: Chromosomal numerical aberration analysis of 12 cases.Pivovarcikova K et al
12146953142004Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors.Lehtonen R et al
13236334572013Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.Linehan WM et al
14155790342004Hereditary leiomyomatosis and renal cell cancer (HLRCC).Kiuru M et al

Citation

Paola Dal Cin ; Michelle S. Hirsch

Fumarate hydratase–deficient renal cell carcinoma

Atlas Genet Cytogenet Oncol Haematol. 2021-11-05

Online version: http://atlasgeneticsoncology.org/solid-tumor/208909/fumarate-hydratase-deficient-renal-cell-carcinoma