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 ‘HLRCC associated RCC’), encompassing both sporadic (absence of features suggesting syndromic disease) and hereditary (germline) cases

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.

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.

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

The diagnosis is confirmed by combining loss of FH (80% sensitive) (Fig.1B) and overexpression of S-(2-succino)-cysteine (2SC) (Fig.1C)^7-9 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.

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

• 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

• 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.