title: Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma.
abstract: Patients with germline mutation of succinate dehydrogenase (SDH) subunit genes are prone to develop paraganglioma, gastrointestinal stromal tumor, and rarely renal cell carcinoma (RCC). However, SDH-deficient RCC is not yet widely recognized. We identified such tumors by distinctive morphology and confirmed absence of immunohistochemical staining for SDHB. Immunohistochemical features were evaluated using a panel of antibodies to renal tumor antigens. Targeted next-generation sequencing was performed on DNA extracted from paraffin-embedded tissue. Eleven tumors were identified from 10 patients, 22-72 years of age (median 40). Two patients had paragangliomas, 1 bilateral SDH-deficient RCC, and 1 contralateral oncocytoma. Grossly, tumors were tan or red-brown, 2-20 cm in diameter (median 4.25 cm). Fuhrman grade was 2 (n=10) or 3 (n=1). Stage was pT1a-pT2b. One patient developed widespread metastases 16 years after nephrectomy and died of disease 6 years later. All tumors were composed of uniform eosinophilic cells containing vacuoles or flocculent cytoplasmic inclusions. Architecture was primarily solid; entrapped renal tubules and intratumoral mast cells were common. By immunohistochemistry, tumor cells were negative for SDHB (11/11) and rarely SDHA (1/11). Labeling was uniformly positive for PAX8 and kidney-specific cadherin and absent for KIT, RCC, and carbonic anhydrase IX. Staining for broad-spectrum epithelial markers was often negative or focal (positive staining for AE1/AE3 in 4/10, CAM5.2 3/7, CK7 1/11, EMA 10/10). By sequencing, SDHB mutation and loss of the second allele were present in 5/6 tumors; the SDHA-deficient tumor showed no SDHB abnormality. SDH-deficient RCC is a unique neoplasm that is capable of progression, often harboring SDHB mutation. A monomorphic oncocytic renal tumor with solid architecture, cytoplasmic inclusions of flocculent material, and intratumoral mast cells should prompt evaluation of SDH status, as it may have implications for screening the patient and relatives. Negative immunohistochemistry for KIT and heterogeneous labeling for epithelial antigens are other supportive features.
authors.affiliation: Department of Pathology and Laboratory Medicine, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Sean R
authors.identifier: 0000000238981460
authors.initials: SR
authors.lastname: Williamson
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Eble
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Mahul B
authors.initials: MB
authors.lastname: Amin
authors.affiliation: Department of Pathology and Laboratory Medicine, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Nilesh S
authors.initials: NS
authors.lastname: Gupta
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Smith
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Institute of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Montironi
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Hirsch
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D013385:Succinate Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D055815:Young Adult
chemical_list: D013385:Succinate Dehydrogenase