Fumarate Hydratase–deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome

Abstract

Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas (RCC) are difficult to diagnose prospectively. We used immunohistochemistry (IHC) to identify fumarate hydratase (FH)-deficient tumors (defined as FH negative, 2-succinocysteine [2SC] positive) in cases diagnosed as "unclassified RCC, high grade or with papillary pattern," or "papillary RCC type 2," from multiple institutions. A total of 124 tumors (from 118 patients) were evaluated by IHC for FH and 2SC. An FH deficiency was found in 24/124 (19%) cases. An indeterminate result (only 1 marker abnormal) was found in 27/124 (22%) cases. In a tissue microarray of 776 RCCs of different types, only 2 (0.5%) tumors, initially considered papillary type 2, were FH deficient. FH mutations were found in 19/21 FH-deficient tumors (with confirmed germline mutations in 9 of 9 tumors in which germline status could be assessed) and in 1/26 FH-indeterminate tumors identified by IHC. No FH mutations were found in 2/21 FH-deficient RCCs, 25/26 FH-indeterminate RCCs, and 10/10 RCCs demonstrating FH expression by IHC. Patients with FH-deficient RCC had a median age of 44 years (range, 21 to 65 y). Average tumor size was 8.2 cm (range, 0.9 to 18 cm). FH-deficient RCCs were characterized by at least focal macronucleoli and demonstrated 2 or more growth patterns in 93% cases. Papillary was the most common (74%) and dominant (59%) pattern, whereas other common patterns included: solid (44%), tubulocystic (41%), cribriform (41%), and cystic (33%). At presentation, 57% were stage ≥pT3, 52% had positive nodes, and 19% had distant metastases. After a mean follow-up of 27 months (range, 1 to 114 mo), 39% of patients were dead of disease, and 26% had disease progression. We conclude that FH and 2SC are useful IHC ancillary tools, which allow recognition of FH-deficient RCC.

Cascade Fumarate Hydratase mutation screening allows early detection of kidney tumour: a case report

“…Cells share a characteristic appearance; a large nucleus and prominent inclusion-like eosinophilic nucleoli surrounded by a clear halo [12]. Immunohistochemistry demonstrates a lack of FH protein expression and increased 2SC levels in the tumor [13–15]; a finding that should prompt genetic screening of affected individuals. Traditionally ‘type 2 papillary RCCs’ were the renal lesion most commonly associated with HLRCC, however a recent genomic analysis has suggested that ‘type 2 papillary RCC’ is not in fact a single tumor type, but instead consists of sub-groups with different molecular backgrounds [16].…”

Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci

“…The second cohort of cases studied is composed of two published, well characterized cohorts of cases with FH-deficient status (n=23) (18) or HLRCC-RCC (n=9) (14). These previously reported cases were reviewed to determine whether any TC-PD morphology were apparent, at least focally.…”

“…Importantly, HLRCC-RCCs are exceptionally aggressive tumors, often presenting at high stage, underscoring the importance of their recognition (12, 14). Thus recent reports propose immunohistochemical adjuncts for screening for HLRCC-RCCs, including staining for FH protein expression, which may be lost in a majority of cases (15-18) and for aberrant succination of nuclear and cytoplasmic proteins (S-(2-succino)-cysteine, 2SC), which is induced upon loss of FH function (14, 17, 19, 20). …”

Morphologic, Molecular, and Taxonomic Evolution of Renal Cell Carcinoma: A Conceptual Perspective With Emphasis on Updates to the 2016 World Health Organization Classification

“…46 Recently, immunohistochemistry for FH and S-(2-succino)cysteine have been shown to be useful for detecting HLRCC-associated RCCs. [51][52][53] In these tumors, loss of heterozygosity at the FH locus results in loss of cytoplasmic FH protein expression in most cases ( Figure 2, D); in addition, loss of the FH protein function leads to accumulation of aberrantly succinated proteins, which can be detected as increased cytoplasmic/nuclear S-(2-succinyl)cysteine expression. 54 Together, these 2 immunostains have a high sensitivity and specificity for detecting HLRCC-associated RCCs.…”

“…54 Together, these 2 immunostains have a high sensitivity and specificity for detecting HLRCC-associated RCCs. 51,52 In general, HLRCC-associated RCC has an aggressive clinical course, with frequent metastasis and subsequent death. 48 As such, the identification of patients with HLRCC-associated RCC is important because these patients (and their families) should undergo genetic evaluation and counseling.…”