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Kidney: Succinate dehydrogenase-deficient renal cell carcinoma

Written2019-01Paola Dal Cin
Department of Pathology, Brigham and Women's Hospital, Boston, MA. pdalcin@partners.org

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Identity

ICD-Topo C649
Atlas_Id 6984
Phylum Urinary system: Kidney::Succinate dehydrogenase-deficient renal cell carcinoma
WHO/OMS Classification Urinary system
Other namesKidney: SDH-deficient renal cell carcinoma

Clinics and Pathology

Epidemiology Succinate dehydrogenase-deficient renal cell carcinoma represents between 0.05 and 0.2% of all renal cell carcinoma (RCCs) and is found in young adults. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1).
Clinics Bilateral tumors were observed in 26% of patients. Patients with germ line mutations in succinate dehydrogenase deficient (SDH) subunit genes (SDHA ,B,C and D) are highly sensitive to certain types of neoplasms such as paragangliomas, pheochromocytomas, gastrointestinal stromal tumorsand renal cell carcinomas (Gill AJ .2012).
Pathology
  • Tumors have a tan to light brown well circumscribed cut surface. SDH-deficient RCC cells are comprised of a monomorphic population of eosinophilic, typically low grade tumor cells that have a bubbly appearance due to the presence of cytoplasmic vacuoles (abnormal mitochondria secondary to the SDH mutation); the latter may be lost in higher-grade transformed tumors.
  • Immunohistochemistry All cases with the typical morphology demonstrated negative staining for SDHB. The presence of negative staining for SDHB almost always signifies germline mutation of one of the components of the mitochondrial complex 2 (SDHA, SDHB, SDHC, SDHD, SDHAF2)
  • Prognosis Sarcomatoid changes and necrosis are rare but are associated with poorer outcomes.

    Genetics

    Note Two hit process The two hit process (germ line mutations and loss of the wild-type allele) is involved in the development of SDHB-deficient renal cell carcinoma (Schmidt and Linehan 2016).The risk of renal tumors seems highest for SDHB mutation. The germ line mutations reported were extensively found in exons coding the mitochondrial targeting sequence or 2FE-2S ferredoxin-type iron-sulfur binding domain.
    Next-generation sequencing dataAdditionally, a targeted next-generation sequencing panel did not reveal alterations in other key genes involved in RCC pathogenesis, such as VHL, PIK3CA, AKT, MTOR, MET, or TP53 (Williamson et al. 2015).

    Genes involved and Proteins

     Succinate dehydrogenase (SDH) genes; SDHA, SDHB, SDHC, SDHD, SDHAF2.
    Protein Succinate dehydrogenase (SDH) is a key respiratory enzyme complex that converts succinate to fumarate in the citric acid cycle (CAC) and also functions in the mitochondrial electron transport chain. It comprises 4 subunits, SDHA, SDHB, SDHC, and SDHD, which are each transcribed by ?????? In young adults. ?????? separate nuclear genes.

    Bibliography

    Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia.
    Gill AJ.
    Pathology. 2012;44:285-292.
    PMID 2254421
     
    Genetic predisposition to kidney cancer.
    Schmidt LS, Linehan WM.
    Semin Oncol. 2016 Oct;43(5):566-. Review.
    PMID 27899189
     
    Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma.
    Williamson SR, Eble JN, Amin MB, Gupta NS, Smith SC, et al .
    Mod Pathol. 2015; 28(1):80-94.
    PMID 25034258
     

    Citation

    This paper should be referenced as such :
    Dal Cin P
    Kidney: Succinate dehydrogenase-deficient renal cell carcinom
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version : http://AtlasGeneticsOncology.org/Tumors/SDHdeficientRenalCellCarcID6984.html


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