Succinate Dehydrogenase-Deficient Renal Cell Carcinoma
Definition
- Renal carcinoma with vacuolated, eosinophilic to clear cells and is defined by the loss of immunohistochemical expression of succinate dehydrogenase (SDH) B—a marker of dysfunction of mitochondrial complex II.
- Most patients have germline mutations in an SDH gene
Alternate/Historical Names
SDHB-negative renal cell carcinoma
SDH-deficient renal oncocytoma
Diagnostic Criteria
- Requirement: Loss of immunohistochemical staining for SDHB
- Loss of staining with SDHB signifies a mutation in either SDHA, SDHB, SDHC, or SDHD
- Tumors associated with SDHA mutation also show loss of staining for SDHA
- Be cautious with cells with clear cytoplasm as they may show only faint (but not negative) staining
- Eosinophilic cells with flocculent cytoplasm
- Cytoplasmic vacuoles or flocculent inclusions
- Eosinophilic or pale, wispy material that may appear bubbly
- Cytoplasmic inclusions may be focal
- Neuroendocrine-like nuclei
- Smooth nuclear contours, evenly dispersed chromatin, and inconspicuous nucleoli
- Usually nested, solid, or tubular architectural patterns
- Well-circumscribed with lobulated or pushing border
- May entrap surrounding tubules
- Often has scattered cysts
- Sometimes contain eosinophilic material
- Often intratumoral mast cells
- May have areas of dedifferentiation
Supplemental studies
- Requirement: Loss of immunohistochemical staining for SDHB
- Consider doing SDHB immunohistochemistry in cases with compatible morphology or clinical characteristics
- PAX8 positive
- Cytokeratin expression in only ~30% of tumors
- CD117 and CK7 staining is very rare (<3%)
- CD117 may highlight intratumoral mast cells
- Synaptophysin/chromograinin negative
- Carbonic Anhydrase IX (CAIX) negative
- S100A1 and AMACR variable (positive or negative)
- CD10 variable, often focal or negative
Grading/Staging
Use WHO/ISUP grading system for clear cell and papillary renal cell carcinomas
- Although this grading system has not been validated as an indicator of prognosis for other types of renal cell neoplasia (due primarily to small numbers of reported cases), the system can be used to describe the morphologic features of these tumors
- Grade should be assigned on the bases is these criteria within the single high-power field showing the greatest degree of nuclear pleomorphism.
Grade 1 |
Nucleoli are absent or inconspicuous and basophilic at 400x magnification |
Grade 2 |
Nucleoli are conspicuous and eosinophilic at 400x and visible but not prominent at 100x |
Grade 3 |
Nucleoli are conspicuous and eosinophilic at 100x |
Grade 4 |
Extreme nuclear pleomorphism, multinucleate giant cells, and/or rhabdoid and/or sarcomatoid differentiation |
Clinical
- Very rare (0.05 to 0.2% of all renal carcinomas)
- Classically presents in young adults (mean age 38)
- Slight male predominance
- Strong hereditary link
- Great majority of patients have germline mutations in SDHB, SDHC, SDHA, or SDHD
- These germline mutations are associated with an autosomal dominant tumor syndrome characterized by SDH-deficient renal cell carcinoma, paraganglioma/pheochromocytoma, or gastrointestinal stromal tumors
- All patients with SDH-deficient tumors should be offered genetic testing
- Patients need long-term surveillance for other SDH-deficient neoplasms
- May be multifocal/bilateral
- Relatively good prognosis (metastatic rate of ~10%)
- Outcome less favorable with dedifferentiation and necrosis
Differential diagnosis
- Chromophobe Renal Cell Carcinoma
- Oncocytoma
- Acquired cystic disease-associated renal cell carcinoma
SDHB Negative |
SDHB Positive |
CK7 and CD117 negative |
Commonly CK7 and CD117 Positive |
Neuroendocrine-like nuclei |
Rasinoid or Koilocytic nuclei |
Cytoplasmic inclusions present |
Cytoplasmic inclusions absent |
Plant-like, prominent cell borders absent |
Plant-like, prominent cell borders present |
Perinuclear clearing absent |
Prominent perinuclear clearing |
Entrapped non-neoplastic tubules common |
Entrapped non-neoplastic tubules rare |
SDHB Negative |
SDHB Positive |
CK7 and CD117 negative |
CD117 Positive, CK7 typically negative |
Varied architecture, rarely has hypocellular stroma |
Nests floating in hypocellular stroma |
Intracytoplasmic inclusions present |
Intracytoplasmic inclusions absent |
Flocculent eosinophilic cytoplasm |
Granular eosinophilic cytoplasm |
May show dedifferentiation |
May show degenerative atypia (enlarged nuclei with smudged chromatin) |
- Both have eosinophilic cytoplasm with bland, central, uniform round nuclei in variable admixtures of solid or nested, tubular, and cystic architectural patterns
- Both of these tumors may or may not possess a pseudocapsule
- Entrapped non-neoplastic tubules are a common finding in both tumors
SDHB Negative |
SDHB Positive |
Typically young patients with a germline mutation |
Occurs in patients with end-stage renal disease and acquired cystic disease (often on dialysis) |
Neuroendocrine-like nuclei |
Large, irregular nuclei with prominent nucleoli |
Although often has intracytoplasmic inclusions and vacuoles, lumina are absent |
Intra and Intercytoplasmic lumina bestowing a cribriform appearance |
No intratumoral crystals |
Intratumoral calcium oxalate crystals |
- Both often CK7 negative
- Both may be multifocal/bilateral
Lists
Renal epithelial neoplasms
- Classical types
- Newer variants and types
- Renal medullary carcinoma
- Mucinous tubular and spindle cell carcinoma
- Tubulocystic carcinoma
- Hereditary leiomyomatosis associated renal cell carcinoma
- MiT family translocation carcinoma
- Neuroblastoma associated renal cell carcinoma
- Renal cell carcinoma associated with end stage renal disease
- Succinate dehydrogenase-deficient renal cell carcinoma
- Thyroid-like follicular carcinoma of the kidney
- Clear cell papillary renal cell carcinoma
- Oncocytic papillary renal cell carcinoma
- Neuroendocrine tumors
- Carcinoid
- Neuroendocrine carcinoma
Bibliography
- Moch H, Humphrey PA, Ulbright TM, Reuter VE eds. World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. 4th Ed. IARC Press: Lyon 2016.
- Udager AM, Mehra R. Morphologic, Molecular, and Taxonomic Evolution of Renal Cell Carcinoma: A Conceptual Perspective With Emphasis on Updates to the 2016 World Health Organization Classification. Arch Pathol Lab Med. 2016 Oct;140(10):1026-37.
- Williamson SR, Eble JN, Amin MB, Gupta NS, Smith SC, Sholl LM, Montironi R, Hirsch MS, Hornick JL.Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod Pathol. 2015 Jan;28(1):80-94.
- Gill AJ et al. Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol. 2014 Dec;38(12):1588-602.
Kurt Schaberg MD
John P Higgins MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342
Original posting 11/22/16
