Stains & molecular markers
Fumarate Hydratase (FH), S-(2-succino) cysteine (2SC)

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Minor changes: 8 November 2019

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Cite this page: Wei JJ. Fumarate Hydratase (FH), S-(2-succino) cysteine (2SC). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsFH2SC.html. Accessed May 26th, 2020.
Definition / general
  • Fumarate Hydratase (FH) is an enzyme that catalyzes the reversible hydration / dehydration of fumarate to malate
  • S-(2-succino) cysteine (2SC) is a chemical modification of proteins and increases when biallelic FH is inactivated
  • 2SC is a sensitive marker in detecting defective FH enzyme function
  • FH is available commercially for clinical use but 2SC is not
Essential features
  • Complete loss of immunoreactivity for FH and diffuse immunopositivity for 2SC are reliable biomarkers for detection of tumors with biallelic inactivation of FH
    Clinical features
    • Germline mutations of FH are seen in hereditary leiomyomatosis, skin pillar leiomyoma and renal cell carcinoma syndrome (HLRCC), also known as Reed syndrome
    • Somatic biallelic inactivation and loss of FH can also be seen in leiomyoma with bizarre nuclei and rarely in usual type leiomyoma
    • Biallelic inactivation / mutations of FH are seen in:
    • Most leiomyomas with FH inactivation / loss have characteristic histologic features, defined as smooth muscle tumors with fumarate hydratase aberration, including high cellularity with eosinophilic macronucleoli, perinucleolar halos, eosinophilic cytoplasmic globules, neurilemmoma-like growth pattern and branching staghorn vessels (Int J Gynecol Pathol 2018;37:421, Am J Surg Pathol 2016;40:923, Mod Pathol 2014;27:1020)
    • Using the two IHC stains in combination with FH mutational analysis appears to be an extremely reliable way to confirm FH alterations and diagnosis of hereditary leiomyomatosis and renal cell carcinoma
      Uses by pathologists
      Prognostic factors
      • Germline mutations of FH portend a high risk of renal cell carcinoma as well as frequent skin and uterine leiomyoma at younger age (Am J Surg Pathol 2014;38:627)
      • Most smooth muscle tumors with FH alterations seem to be acquired or somatic FH inactivation / mutations (Am J Surg Pathol 2016;40:599)
        Microscopic (histologic) images
        Contributed by Jian-Jun Wei, M.D.

        Uterine leiomyoma with FH alteration

        Skin leiomyoma with FH alteration

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        2SC positive stain

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        FH negative stain

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        2SC negative stain



        Figures 1-3 from Trpkov et al., Am J Surg Pathol 2016;40(7):865, Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome, with permission.
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        FH deficient RCC, FH and 2SC

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        RCC with indeterminate FH status, FH and 2SC


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        HLRCC, 2SC

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        Other types of RCC, 2SC

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        FH deficient leiomyoma, FH

        Positive stains
        • FH immunopositivity: strong and diffuse staining (dot-like and granular) in cytoplasm and mitochondria (Int J Gynecol Pathol 2018;37:421)
          • FH Positive staining: normal myometrium and tumors without FH alteration
        • 2SC immunopositivity: strong and diffuse staining (block-like) in cytoplasm and nucleus for 2SC (Int J Gynecol Pathol 2018;37:421)
          • 2SC Positive staining: in tumors with biallelic inactivation of FH
        Negative stains
        • FH immunonegativity: a complete absence of immunoreactivity in tumor cells
        • Immunopositivity for FH in vessels (endothelial cells and intima) can be used as internal positive control for stain
          • FH Negative staining: tumors with biallelic inactivation of FH, including FH related renal cell carcinoma, skin leiomyoma and uterine leiomyoma
        • 2SC immunonegativity: a complete absence of immunoreactivity in tumor cells
          • 2SC Negative staining: normal myometrium and tumors without FH alteration
        Board review style question #1
          Biallelic inactivation of fumarate hydratase (FH) is associated with which of the following:

        1. Exclusively present in germline mutation
        2. Hereditary leiomyomatosis and renal cell carcinoma
        3. Intravenous leiomyomatosis
        4. Loss of both FH and 2SC by immunohistochemical stain
        Board review answer #1
        B. Hereditary leiomyomatosis and renal cell carcinoma

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