A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Renal Cell Carcinoma in 32 Patients

Abstract

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and recently described entity associated with hereditary leiomyomatosis and RCC syndrome. FH-deficient RCC may show variable clinical and pathologic findings, but commonly presents with locally advanced and metastatic disease and carries a poor prognosis. We identified 32 patients with FH-deficient RCC, confirmed by FH immunohistochemistry (IHC) and/or FH mutation analysis, and performed a retrospective review of the clinical and pathologic features. Median age at presentation was 43 years (range, 18 to 69 y), and the M:F ratio was 2.2:1. Median tumor size was 6.5 cm (range, 2.5 to 28 cm), and 71% presented at stage ≥pT3a. After a median follow-up of 16 months (range, 1 to 118 mo) in 26 patients, 19% showed no evidence of disease, 31% were alive with disease, and 50% were dead of disease. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). Viral inclusion-like macronucleoli with perinucleolar clearing were present in almost all cases (96%). All cases were evaluated using FH IHC, and 3 cases (9%) showed retained FH expression. Nineteen cases had germline or tumor mutation analysis confirming a FH mutation, with 79% (11/14) of cases showing mutations within coding regions and 21% (3/14) showing mutations within intronic splice-sites. By IHC, 97% (32/33) of cases were negative for CK7, 93% (27/29) were negative for p63, and 52% (15/29) were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Our overall findings show that FH-deficient RCC is considerably heterogenous in morphology and frequently behaves aggressively. Suspicion for this entity should be raised even in the absence of predominantly papillary architecture and characteristic nucleolar features. We have included cases with uncommonly seen features, including 4 cases with predominantly cribriform/sieve-like architecture as well as one case with pure low-grade oncocytic morphology (9 y of clinical follow-up without evidence of disease). Although FH IHC is a useful tool for identifying cases of FH-deficient RCC, not all cases of FH-deficient RCC show loss of FH staining, and FH mutation analysis should be considered for patients with suspicious clinical or pathologic features, even in cases with retained FH IHC expression.

Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets

“…The histologic growth patterns of FH-deficient tumors are heterogeneous: the large majority of these cases exhibited multiple histologic growth patterns, with papillary being the most frequent histotype (52%), followed by solid (21%), cribiform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%) [ 68 ]. Forde et al showed that the histopathologic features of 18 cases of FH-deficient RCCs were variable, with 7/18 CCRCC, 9/18 PRCC (6/18 type 2 PRCC), 1 collecting duct cancer, 1 with oncocytic cystic morphology [ 69 ].…”

Molecular Genetics of Renal Cell Tumors: A Practical Diagnostic Approach

“…Histologically, they show marked intratumoral heterogeneity with papillary, tubulocystic, solid or cribriform patterns, and usually the presence of large nuclei with deep red nucleoli ( Figure 3A,B). However, no single or a combination of histologic features are diagnostic of FH-deficient RCCs/HLRCCs [101,108,[122][123][124][125][126][127][128].…”

“…Immunohistochemically, FH-deficient RCCs show loss of staining for fumarate hydratase (FH) (sensitivity 80 to 90%) [101,108,[123][124][125][126][127][128][129]. Positive immunohistochemical staining for 2SC (2-Succinocysteine) is supportive feature, however antibody for 2SC is not currently commercially available [123,125,129]. The CNV pattern is heterogeneous, no constant combination of changes has been disclosed so far and it is not possible to use it in differential diagnostic process [124].…”

Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach

“…In fact, the presence of multiple architectural patterns concurring in the same tumor seems to be a diagnostic feature of HLRCC syndrome‐associated RCC/FHdRCC 7,10 . Hence it is not surprising, that prior to the recognition of this tumor entity, these cases have been classified into a variety of tumor entities including papillary renal cell carcinoma (PRCC) type 2, high grade RCCs, unclassified, tubulocystic carcinoma and collecting duct carcinoma 5,7 . Upon recognition of the diverse morphological features of HLRCC syndrome‐associated RCC/FHdRCC, loss of FH expression can be confirmed by immunohistochemistry for fumarate hydratase.…”

“…Upon recognition of the diverse morphological features of HLRCC syndrome‐associated RCC/FHdRCC, loss of FH expression can be confirmed by immunohistochemistry for fumarate hydratase. However, partially retained expression of fumarate hydratase has been reported in several genetically confirmed HLRCC syndrome‐associated RCC/FHdRCC cases 4,5,7,10 …”