Succinate dehydrogenase (SDH) is a mitochondrial enzyme complex composed of 4 protein subunits (SDHA, SDHB, SDHC, and SDHD). Germ line mutations of the genes encoding these SDH subunits result in hereditary syndromes harboring pheochromocytomas/paragangliomas, gastrointestinal stromal tumors, renal cell carcinomas, and pituitary adenomas. SDH-deficient renal cell carcinomas are rare, with a mean age of 38 to 40 years. Histologically, these tumors show a characteristic appearance that includes a solid, nested, or tubular architecture with variable cysts. Cells are typically cuboidal, have indistinct cell borders and eosinophilic cytoplasm, and show flocculent intracytoplasmic inclusions. Loss of immunohistochemical staining for SDHB is the hallmark of these tumors. Although most SDH-deficient renal cell carcinomas are clinically indolent, some tumors may behave aggressively, particularly those with a high nuclear grade, tumor necrosis, or sarcomatoid differentiation. Accurate classification of these tumors is important for clinical follow-up, screening, and genetic evaluation of the patients and other family members for this hereditary tumor syndrome.

Succinate dehydrogenase (SDH) is the key enzyme that converts succinate to fumarate in the tricarboxylic acid cycle, and it is composed of 4 subunits: SDHA, SDHB, SDHC, and SDHD. SDHA and SDHB are catalytic domains, whereas SDHC and SDHD are ubiquinone-binding and membrane-anchorage domains.1  Germ line mutations in the gene encoding SDH predispose patients to neoplastic transformation when there is a loss of the remaining wild-type allele in the somatic cells (ie, loss of heterozygosity), causing a complete loss of enzyme function, which results in the intracytoplasmic accumulation of succinate. This leads to the metabolic reprograming of the “tumor microenvironment” despite normal oxygen levels, providing an advantageous environment for tumor survival, and results in a series of tumor syndromes named hereditary paraganglioma-pheochromocytoma syndromes.2 

SDHD and SDHC mutations are typically associated with multifocal head and neck paragangliomas and less frequently with adrenal pheochromocytomas and extra-adrenal paragangliomas, which are usually benign, with rare cases of metastasis. SDHB mutations mainly result in predisposition to extra-adrenal paragangliomas with high malignant potential, and, to a lesser extent, adrenal pheochromocytomas and head and neck paragangliomas. In addition to malignant paragangliomas, SDHB mutations are also associated with malignant tumors of the extraparaganglial system, including renal cell carcinoma (RCC) and thyroid carcinoma. In addition to multiple paragangliomas, SDHA mutations have also been shown to be associated with neurodegenerative diseases, such as an early-onset encephalopathy known as Leigh syndrome, and a late-onset optic atrophy, ataxia, and myopathy. Mutations of all of the above subunits have been shown to be associated with gastrointestinal stromal tumors (GISTs) with wild-type c-Kit or platelet-derived growth factor receptor α.3 

SDH-deficient RCC was first recognized in 2004 and has been accepted by the 2016 World Health Organization classification of renal tumors as a unique subtype of RCC.4,5  Because of their strong syndromic association and distinct natural history, it is important to appropriately recognize and classify these tumors. Recent large studies of this tumor have shown a wide spectrum of morphology and genetic alterations.610  In this article, we present a short review of SDH-deficient RCCs, with an emphasis on their clinicopathologic characteristics.

EPIDEMIOLOGY AND CLINICAL FEATURES

SDH-deficient RCCs are rare and are estimated to account for 0.05% to 0.2% of all RCCs.9  The age at diagnosis ranges from 14 to 76 years, with a mean age of 38 to 40 years and a slight male predominance.8,9  The great majority of patients with SDH-deficient RCCs have germ line mutations in SDHB, SDHC, SDHA, or SDHD. These mutations result in hereditary syndromes harboring pheochromocytomas/paragangliomas, GISTs, RCCs, and pituitary adenomas.11  SDH-deficient GISTs and paragangliomas can also occur in the syndromic, nonhereditary Carney triad of paraganglioma, pulmonary chondroma, and SDH-deficient GIST, which is caused by SDHC promoter-specific CpG island hypermethylation; however, to date, this epimutation has not been reported in SDH-deficient RCCs.12  The lifetime risk of renal tumors in patients with the SDHB gene mutation has been estimated as 14%.13  Because of this lifelong risk, genetic testing in the appropriate clinical context should be considered for patients with this constellation of tumors.

Clinically, most SDH-deficient RCCs present as small, organ-confined tumors that are discovered incidentally by imaging. Rarely, tumors may present with metastatic disease. Multifocal or bilateral tumors are found in as many as 30% of patients at long-term follow-up.9 

GROSS PATHOLOGY

The reported size of the tumor ranges from 0.7 to 20 cm, with a mean reported size of 5.1 cm. Grossly, tumors are usually well circumscribed, with tan-brown to red cut surface. Hemorrhage or partial cystic change may be observed.8,9 

HISTOPATHOLOGY

In SDHB-deficient RCCs, various patterns overlapping with other known histologic subtypes, including oncocytoma, chromophobe RCC, clear cell RCC, papillary RCC, and even sarcomatoid RCC, have been described.49,1416  Tumors are usually well circumscribed but not encapsulated (Figure, A), with a lobulated or pushing border, often entrapping benign tubules at the periphery (Figure, B). Tumor cells are typically cuboidal and have a solid, nested, or tubular growth pattern (Figure, C) and variable cyst formation (Figure, A). The most distinctive histologic feature is the presence of intracytoplasmic vacuoles or flocculent inclusions, which, when prominent, impart a bubbly appearance to the neoplastic cells (Figure, D). The nuclei are homogeneous and have smooth nuclear contours, evenly distributed chromatin, and inconspicuous nucleoli.69,16  Increased nuclear atypia, denser cytoplasm, sparse (or even loss of) distinctive cytoplasmic inclusions—sometimes with sarcomatoid and/or rhabdoid features—and tumor necrosis are indicative of high-grade transformation and a more aggressive clinical course.9  Very often, the tumors show prominent intratumoral mast cells, which can be highlighted by a CD117 stain.8,9 

A, Tumors are well circumscribed but not encapsulated. B, The tumor often has a lobulated or pushing border, entrapping benign tubules. C, The tumor cells are cuboidal, with a solid, nested, or tubular pattern of growth. D, The most distinctive histologic feature is the presence of intracytoplasmic vacuoles or flocculent inclusions, which when prominent impart a bubbly appearance to the tumor cells. The nuclei are homogeneous, have smooth nuclear contours, evenly distributed chromatin, and a neuroendocrine appearance, with inconspicuous nucleoli. E, Loss of immunohistochemistry staining of succinate dehydrogenase B (SDHB) in SDH-deficient renal cell carcinoma (RCC). F, In SDH-deficient RCCs, tumor cells are negative for vimentin (hematoxylin-eosin, original magnifications ×20 [A through C] and ×40 [D]; original magnification ×20 [E and F]).

A, Tumors are well circumscribed but not encapsulated. B, The tumor often has a lobulated or pushing border, entrapping benign tubules. C, The tumor cells are cuboidal, with a solid, nested, or tubular pattern of growth. D, The most distinctive histologic feature is the presence of intracytoplasmic vacuoles or flocculent inclusions, which when prominent impart a bubbly appearance to the tumor cells. The nuclei are homogeneous, have smooth nuclear contours, evenly distributed chromatin, and a neuroendocrine appearance, with inconspicuous nucleoli. E, Loss of immunohistochemistry staining of succinate dehydrogenase B (SDHB) in SDH-deficient renal cell carcinoma (RCC). F, In SDH-deficient RCCs, tumor cells are negative for vimentin (hematoxylin-eosin, original magnifications ×20 [A through C] and ×40 [D]; original magnification ×20 [E and F]).

A very limited number of RCCs have been described in association with SDHC and SDHD mutations, most of which have histology similar to clear cell RCC.7,17,18  In 1 SDHC-deficient case, papillary RCC has also been described.17 

SDHA-deficient RCC demonstrates diverse architectural patterns, including papillary, tubulopapillary, cribriform, solid, and collecting duct carcinoma–like structures embedded in desmoplastic or sclerotic stroma. The tumor cells show high-grade nuclei and abundant eosinophilic cytoplasm. Similar to those described in SDHB-deficient RCC, the distinctive histologic feature is the presence of pale eosinophilic cytoplasmic inclusions, which are identified in all components of the tumor.19,20 

ANCILLARY STUDIES

When any component of the mitochondrial complex 2 undergoes biallelic inactivation, the entire complex becomes unstable, resulting in degradation of the SDHB subunit.11  Therefore, loss of immunohistochemical staining for SDHB is the hallmark of SDH-deficient RCCs (Figure, E). In SDHB-, SDHC-, and SDHD-deficient RCCs, tumor cells are negative for SDHB but positive for SDHA.6,8,9,16,21  In contrast, tumor cells in SDHA-deficient RCCs show negativity for both SDHA and SDHB.19  Why SDHA protein remains stable in the presence of SDHB, SDHC, or SDHD mutations is currently unknown.

SDH-deficient RCCs are generally immunoreactive for PAX8 and Ksp-cadherin but negative for CD117, RCC-Ma, p63, carbonic anhydrase 9 (CAIX), vimentin (Figure, F), and neuroendocrine markers.6,8,9,16  Immunoreactivity for epithelial markers is usually negative or focal.9 

By electron microscopy, the distinctive cytoplasmic inclusions in the tumor cells of SDH-deficient RCCs correspond to highly abnormal mitochondria with an excess of mitochondrial matrix and a few degenerate or compressed cristae.21 

Molecular studies have shown that the defining abnormality in SDH-deficient RCCs is double-hit inactivation of the SDH-related genes, in which germ line mutations of SDHB are the most common (75%), followed by SDHC and SDHD.48,11,13,16,21  In the 2 cases of SDHA-deficient RCC with molecular analysis available, the genetic alterations were thought, but not confirmed, to be somatic in nature.19,20  Therefore, the role of SDHA genomic alterations in sporadic cases of RCC needs to be further explored with a larger cohort of cases. To date, no cases harboring mutations of more than 1 of the SDH subunit genes have been reported, since this entity was recently described. Further molecular studies on larger cohorts of cases in the future may be able to shed light on this phenomenon.

DIFFERENTIAL DIAGNOSIS

The main differential diagnosis of SDH-deficient RCC is other oncocytic neoplasms. Renal oncocytoma and SDH-deficient RCCs are both composed of cells with eosinophilic cytoplasm and round, centrally located uniform nuclei; the cells are arranged in variable admixtures of solid or nested, tubular, and cystic architectural patterns. Entrapped nonneoplastic tubules are a common finding in both lesions. However, oncocytomas demonstrate discrete, large, rounded nests of tumor cells dispersed in hyalinized or edematous stroma and sometimes exhibit zones of degenerative nuclear atypia, with enlarged nuclei and smudged nuclear chromatin. The characteristic cytoplasmic vacuoles or flocculent inclusions of eosinophilic material in SDH-deficient RCCs are also a helpful diagnostic feature and are typically absent in oncocytoma. Renal oncocytoma is often positive for CD117 and may show scattered or focal staining for cytokeratin 7 (CK7), whereas most SDH-deficient RCCs are typically negative for CD117 and CK7.8 

The eosinophilic variant of chromophobe RCCs is also a differential diagnostic consideration. This variant of chromophobe RCCs consists of pale and eosinophilic cells with distinct cell borders, perinuclear haloes, irregular nuclear membranes, and occasional binucleated cells.22  Tumor cells generally demonstrate diffuse positivity for CK7 and CD117, which in combination with the absence of intracytoplasmic inclusions, helps in the distinction of this entity from SDH-deficient RCC.23 

Hybrid oncocytic/chromophobe tumors show morphology that overlaps with both chromophobe RCC and renal oncocytoma. These tumors may occur sporadically or in association with Birt-Hogg-Dubé syndrome, which is associated with cutaneous (fibrofolliculoma, trichodiscoma, or acrochordon) and pulmonary (cysts and pneumothorax) lesions. The germ line mutation of the folliculin (FLCN) gene is critical for the definite diagnosis of Birt-Hogg-Dubé syndrome.24  Although the histology may overlap with SDH-deficient RCC, intact staining with SDHB by immunohistochemistry will help resolve the diagnostic dilemma.

Rarely, clear cell RCCs, especially those with a prominent eosinophilic component, may enter the differential diagnosis. Clear cell RCC typically demonstrated a solid and/or acinar growth pattern. Tumor cells may show eosinophilic or clear cytoplasm, and the characteristic “chicken wire” vascular pattern of delicate vessels surrounding nests of tumor cells is usually at least focally identifiable. Clear cell RCC is strongly positive for vimentin and shows diffuse membranous staining with CAIX.23  When the cytoplasm is extensively eosinophilic, SDH-deficient RCCs may enter the differential diagnosis. In clear cell RCC with extensively clear cytoplasm, the immunohistochemical stain for SDHB may be weak and difficult to interpret because of abundant glycogenation of the cytoplasm. This represents a pitfall, and caution must be exercised before interpreting the stain as negative, by paying careful attention to exclude membranous staining for the SDH stain.25 

Focal or negative staining for CKs in SDH-deficient RCCs may also raise the possibility of a differential diagnosis of a microphthalmia family translocation RCC (commonly referred to as translocation RCC). The absence of staining with the transcription factor E3 (TFE3) antibody and negative staining for cathepsin K are helpful in making this distinction, although fluorescence in situ hybridization using a break-apart probe targeting the TFE3 gene is the most specific test to definitively distinguish between the 2 tumor types.8  Interestingly, a recent report demonstrated the presence of both TFE3 translocation and SDHB mutation in the same tumor.26  Given the fact that they are not mutually exclusive, immunohistochemical stains for both TFE3/cathepsin K and SDHB, as well as fluorescence in situ hybridization for the TFE3 translocation, may be considered in suspected cases.

Rarely, SDH-deficient RCCs can have very prominent nucleoli, which may raise the possibility of hereditary leiomyomatosis-associated RCCs (HLRCC), because of the predominantly eosinophilic nature of the tumor. Hereditary leiomyomatosis-associated RCC is an autosomal dominant disorder that results from mutations in the fumarate hydratase gene. Many patients with a diagnosis of HLRCC also have cutaneous and/or uterine leiomyomata clinically, although synchronous or metachronous occurrence of RCC and leiomyoma is relatively rare.27  Histologically, HLRCC usually shows a papillary or tubulocystic appearance, and tumors frequently resemble type 2 papillary RCC. Furthermore, the hallmark of HLRCC is the presence of a prominent eosinophilic nucleolus surrounded by perinucleolar clearing, which resembles that of a cytomegalovirus inclusion. By immunohistochemistry, HLRCC shows strong cytoplasmic staining for S-(2-succino)-cysteine and shows intact staining with SDHB.28  For the suspected cases of HLRCC, the recommendation is to refer the patients to a genetic counselor to identify a germ line mutation in the fumarate hydratase gene.

CURRENT TREATMENT

Early surgical intervention is recommended for SDH-deficient RCCs. Partial nephrectomy to preserve the kidney can be an option for patients with a solitary tumor that is at an early stage. In cases with metastatic disease, molecular targeted therapy for vascular endothelial growth factor, mammalian target of rapamycin, and tyrosine kinase may be administered.29,30 

Accurate classification of these tumors is also important for appropriate clinical follow-up, and the pathologist is often the first to recognize this entity and alert the clinician to the possibility of a clinical syndrome. In most series to date, the diagnosis of SDH-deficient RCC was initially raised by the pathologist because of the characteristic morphologic features, and it was subsequently confirmed by lack of SDH protein expression by immunohistochemistry.610  Because this is a relatively recently described entity, it remains possible that the morphologic spectrum of SDH-deficient RCC may expand to include additional histologic features that have been unrecognized thus far. Therefore, it is reasonable that immunohistochemistry for SDHB be performed on renal tumors with compatible histology or those occurring in a clinical setting suggestive of syndromic disease, such as onset at young age, multifocality, bilaterality, and family history of other SDH-related tumors.9,31  In patients with a germ line SDH mutation, a more aggressive screening regimen for paraganglioma and subsequent renal tumors is typically recommended, because paragangliomas in this setting are often aggressive and proven to be fatal. Genetic evaluation of first-degree relatives for the presence of the mutation may be considered because of the implications of this diagnosis. In patients younger than 45 years, the possible diagnosis of SDH-deficient RCC should be considered even in the absence of family history.7  Typically, individuals are recommended to undergo annual biochemical (serum catecholamine production, for pheochromocytoma) and clinical surveillance as well as imaging studies, such as computed tomography or magnetic resonance imaging. Clinicopathologic correlation is critical for the management of these patients.

PROGNOSIS

Most SDH-deficient RCCs are uniformly low grade and have a favorable prognosis. The metastatic rate has been found to be approximately 11% at long-term follow-up.6  However, it is now known that a subset of SDH-deficient RCCs with adverse histologic features, including those with a high nuclear grade, coagulative necrosis, or sarcomatoid dedifferentiation, have the potential to behave aggressively.7,9,19  Metastases to the liver, bone, brain, lung, and lymph nodes have been documented.69,19,31  In a study by Gill et al,9  4 of 27 patients (15%) also had SDH-deficient GISTs, and 4 of 27 patients (15%) developed paragangliomas in addition to their renal tumors. There were 5 patients (19%) in this study who had a first-degree relative with RCC, and 1 patient who had a second-degree relative with RCC. Also, there were 5 first-degree and 2 second-degree relatives with pheochromocytoma/paraganglioma, and 1 first-degree relative with SDH-deficient GIST.9  Although SDHB mutations mainly result in predisposition to extra-adrenal paragangliomas with high malignant potential, the 3 patients in this study who had died had all died of the metastatic RCC.9 

CONCLUSIONS

In renal oncocytic tumors with nuclear and architectural variability, especially in relatively young patients, pathologists should always raise the possibility of SDH-deficient RCC. A careful search for intracytoplasmic inclusions should be performed by the pathologist. Even when inclusions are not present or not prominent, immunohistochemical staining for SDHB should be performed in suspected cases, especially in younger patients.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.