Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a very rare type of renal cell carcinoma (RCC). It can be part of the hereditary leiomyomatosis and RCC (HLRCC) syndrome (germline mutation) or it can be sporadic (somatic mutation). As opposed to conventional RCC, it affects younger individuals mostly in their forties and carries a poorer prognosis, since it tends to metastasize early even with small tumor size.
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Terminology
Fumarate hydratase-deficient renal cell carcinoma was newly defined in the WHO classification of urogenital tumors (5th edition, 2022) and included in the new category of molecularly defined RCC (previously categorized as HLRCC syndrome-associated RCC).
Epidemiology
Fumarate hydratase-deficient renal cell carcinoma is a very rare tumor, with only a few hundred cases in literature. FH mutation carriers have a 15% lifetime risk to develop RCC. If there is a germline mutation and thus part of the HLRCC syndrome, the lifetime risk of RCC rises to 21%.
Peak incidence is on average 20-25 years earlier than with other renal carcinomas, and even with small tumor size it often is metastatic at presentation.
Pathology
FH-RCC is due to an inactivating mutation of the fumarate hydratase (FH) gene (located on the long arm of chromosome 1). There are cases due to a somatic mutation and others due to a germline mutation of the FH gene, in which the renal cell carcinoma is part of the autosomal-dominant hereditary leiomyomatosis and RCC (HLRCC) syndrome.
Microscopic appearance
On histopathology, it resembles papillary renal cell carcinoma type 2 (and therefore has often been misclassified into this group in the past). In order to establish the correct diagnosis, immunostaining for S-(2-succinyl) cysteine (2SC) and negativity for FH, CK7, and AMACR expression is required, and even gene sequencing may be necessary 3.
Clinical presentation
often detected incidentally or during screening in familial cases or in patients with multiple cutaneous leiomyomas
hematuria
flank pain
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when syndromic
multiple cutaneous leiomyomas
multiple uterine leiomyomas in younger women
Radiographic features
Typically, these are solitary and unilateral tumors (unlike other familial RCC syndromes that are characterized by bilateral multifocal tumors).
Approximately 65% (range 50-80%) have a large (>75%) cystic component, often polycystic with smooth walls, with an eccentric solid component. Peak enhancement is in the nephrogenic phase (similar to papillary RCC type 2) may differentiate from other types of RCC, otherwise, there no specific differentiating features.
Other malignant features include 1:
infiltrative margin
involvement of renal sinus fat in ~80%
involvement of the hilar collecting system in 50%
renal vein tumor thrombus in ~40%
~70% retroperitoneal nodal metastases
CT
cystic or polycystic appearing tumor with smooth septa and eccentric solid component (up to 25% of germline cases may appear purely solid on CT) 2
only a minority of cases have calcifications
no specific features to differentiate from other types of renal cell carcinoma, especially from papillary renal cell carcinoma type 2
often (but not always) malignant features carrying bad prognoses as named above, like infiltration of strategic structures
MRI
often cystic or polycystic tumor with solid components, cystic portion >75% of total volume
T2 inhomogeneity, heterogenous tumor enhancement and diffusion restriction of solid component
Treatment and prognosis
prognosis poorer than other more common RCC subtypes as distant metastases are present in 45-75% at presentation 1,3
often early metastasis, even with small tumors
for patients with proven FH gene mutations lifetime screening for renal cell carcinoma is recommended due to estimated lifetime risk of 15-21%.
therapy is surgical resection, and possibly targeted therapy based on the molecular characteristics
Practical points
Multiple uterine leiomyomas in a woman under age 50, the kidneys should be reviewed carefully (or suggest an examination of the kidneys and of the skin to look for cutaneous leiomyomas) ref.
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