Immunohistochemical Characterization of Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) in Cutaneous Leiomyomas for Detection of Familial Cancer Syndromes

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by germline mutations in the FH gene, and is associated with increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma (HLRCC-associated RCC). Absent immunohistochemical expression of fumarate hydratase (FH) has previously been used to diagnose HLRCC-associated RCC, but immunohistochemical staining of leiomyomas is not standard practice. We performed immunohistochemistry (IHC) on whole sections from consecutive cutaneous leiomyomas from our archives to evaluate for both FH and succinate dehydrogenase B expression, in addition to clinicopathologic data collection and review of all hematoxylin and eosin-stained slides for blinded morphologic evaluation of features reported to be seen in HLRCC-associated uterine leiomyomas. Ninety-six cutaneous leiomyomas from 87 patients were identified; 12 of these specimens were from 7 patients with documented HLRCC. FH expression by IHC was absent in 9 specimens and retained in 85 specimens; 2 cases were equivocal with minimal FH expression. Seven of the 9 absent expression specimens were from patients with HLRCC, as were both of the equivocal specimens. The overall sensitivity and specificity of absent FH expression in leiomyomas for detection of patients with HLRCC were 70.0% and 97.6%, respectively. Inclusion of cases classified as equivocal increased sensitivity to 75.0%. Succinate dehydrogenase B expression was retained in 95 specimens and equivocal in 1 specimen. None of the evaluated morphologic features showed any association with leiomyomas in HLRCC. Loss of FH immunohistochemical expression in cutaneous leiomyomas is a sensitive and specific marker for detection of HLRCC, thus suggesting a role for prospective FH IHC in patients with these tumors to screen for HLRCC.

Fumarate hydratase expression is retained in atypical intradermal smooth muscle neoplasms and cutaneous leiomyosarcomas

“…Consistent with prior reports, FH expression was absent in a subset (10%) of pilar leiomyomas, and no morphological features correlated with FH deficiency in our series. While the absence of FH expression by immunohistochemistry is highly specific for FH deficiency, the sensitivity of this assay was estimated to be approximately 70% in a prior study of cutaneous leiomyomas in patients with HLRCC . Illustrating this difficulty, the only case in this study associated previously with HLRCC showed retained FH expression; analogous to succinate dehydrogenase deficiency in gastrointestinal stromal tumour, it is possible that a subset of cases may have functional FH deficiency despite maintained protein expression.…”

“…Interestingly, such morphological features are not seen consistently in sporadic or HLRCC-associated FH-deficient pilar leiomyoma. 2 Cutaneous leiomyosarcomas are characterized by increased cellularity, cytological atypia and infiltrative growth. Prior studies have shown that cutaneous leiomyosarcomas confined to the dermis demonstrate Correspondence 1023 essentially no metastatic potential, and tumours with these features are therefore referred to as atypical intradermal smooth muscle neoplasms (AISMN).…”

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC): A Contemporary Review and Practical Discussion of the Differential Diagnosis for HLRCC-Associated Renal Cell Carcinoma

“…A small subset of patients with HLRCC-associated RCC may demonstrate equivocal results or retain FH expression within the tumor; a correlated finding reported in the literature is that tumors from patients with FH missense mutations may show equivocal or retained FH expression because of alteration in protein-antibody interactions. 25,43 Immunohistochemical evaluation of FH and 2SC on cutaneous or uterine leiomyoma specimens may be helpful in identifying patients who should undergo further clinical workup or germline mutation testing for HLRCC. 23,25,[43][44][45] Another group has suggested molecular screening of uterine leiomyoma tissue.…”

Clues to recognition of fumarate hydratase‐deficient renal cell carcinoma: Findings from cytologic and limited biopsy samples

“…Most relevant to prospective diagnostic practice, recent reports have established the utility of immunohistochemistry for FH and antibodies detecting aberrant succination (anti‐S‐[2‐succino]‐cysteine [2SC]) for the recognition of this tumors. On the basis of experience with FH and 2SC in the workup of kidney tumors, noting many cases with immunohistochemical and morphologic findings suggestive of HLRCC syndrome but nearly always without available data on stigmata, family history, or genetic testing at the time of sign out, we recently proposed the term FH‐deficient RCC as a provisional diagnostic term to phenotypically label cases.…”

“…6 Now an accepted entity in the World Health Organization classification, 7 increasing scholarship has confirmed the broad morphologic range 8,9 and relatively frequent tubulocystic pattern, 10 which appears to be a useful morphologic marker for differentiation from other high-grade, infiltrative renal tumors. 11 Most relevant to prospective diagnostic practice, recent reports have established the utility of immunohistochemistry for FH 8,12 and antibodies detecting aberrant succination (anti-S-[2-succino]-cysteine [2SC]) 9 for the recognition of this tumors. On the basis of experience with FH and 2SC in the workup of kidney tumors, noting many cases with immunohistochemical and morphologic findings suggestive of HLRCC syndrome but nearly always without available data on stigmata, family history, or genetic testing at the time of sign out, we recently proposed the term FH-deficient RCC as a provisional diagnostic term 10 to phenotypically label cases.…”