Advances in Anatomic Pathology:
Succinate Dehydrogenase-deficient Tumors: Diagnostic Advances and Clinical Implications
Barletta, Justine A. MD; Hornick, Jason L. MD, PhD
Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
The authors have no funding or conflicts of interest to disclose.
Reprints: Jason L. Hornick, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: firstname.lastname@example.org).
Just over 10 years ago, germline mutations in SDHD, a gene that encodes 1 of the 4 proteins of the succinate dehydrogenase (SDH) complex, were reported in a subset of patients with hereditary paraganglioma-pheochromocytoma syndrome. Since that time, rapid discoveries have been made in this area. It is now recognized that all of the SDH genes are involved in the tumorigenesis of not only paragangliomas/pheochromocytomas, but also other tumor types, most notably gastrointestinal stromal tumors. This review will outline the genetics of SDH-deficient tumors, discuss possible mechanisms of tumorigenesis, and describe how these tumors can be identified by immunohistochemistry.
Succinate dehydrogenase (SDH) is an enzyme complex localized to the inner mitochondrial membrane that plays an integral role in cellular metabolism. It is a member of both the Krebs cycle and the electron transport chain (in which it is known as complex II), catalyzing the oxidation of succinate to fumarate and coupling this reaction to the reduction of ubiquinone.1 SDH is a heterotetrameric complex composed of 4 protein subunits (SDHA, SDHB, SDHC, and SDHD). SDHA and B form the catalytic core, whereas SDHC and D anchor the complex to the inner mitochondrial membrane.2 All of the SDH subunits are encoded by nuclear genes, with the gene products subsequently transported to mitochondria. The SDH genes act as tumor suppressor genes: tumors demonstrate loss of heterozygosity (LOH) in combination with germline-inactivating mutations.3–7 This results not only in a lack of SDH enzyme activity, but also in destabilization of the SDH protein complex (hence “SDH-deficient”). Destabilization of the complex, as a result of a mutation in any of the 4 SDH genes, can be identified by immunohistochemical analysis for SDHB. Although SDHB is ubiquitously expressed (including in normal tissues of patients harboring a germline mutation in an SDH subunit gene), SDH-deficient tumors lack SDHB expression by immunohistochemistry.8 Paragangliomas and pheochromocytomas are the tumors that harbor germline SDH mutations at the highest frequency; however, other tumor types have also been shown to be SDH deficient, including a distinctive subset of gastrointestinal stromal tumors (GISTs) and rare renal cell carcinomas.
SUCCINATE DEHYDROGENASE-DEFICIENT PARAGANGLIOMAS AND PHEOCHROMOCYTOMAS
Pheochromocytomas and paragangliomas are tumors of neural crest origin that arise from cells of the adrenal medulla or paraganglia, respectively. Paragangliomas can be subdivided according to their location. Head and neck paragangliomas (such as carotid body paragangliomas) arise from parasympathetic paraganglia and are almost always nonfunctioning.9 In contrast, paragangliomas located below the neck (predominantly within the abdomen and much less frequently the thorax and pelvis) arise from sympathetic paraganglia and thus are often symptomatic secondary to catecholamine production. Both pheochromocytomas and paragangliomas can be sporadic or can arise as part of a hereditary tumor syndrome, such as multiple endocrine neoplasia type 2 (due to RET germline mutation), von Hippel-Lindau (VHL) disease (due to VHL germline mutation), neurofibromatosis type 1 (due to NF1 germline mutation), and hereditary paraganglioma-pheochromocytoma syndrome (HPGL/PCC).10,11 In 2000, germline mutations in SDHD were discovered in a subset of patients with HPGL/PCC syndrome.3,6 Since that time, mutations in SDHB,6 SDHC,5 SDHA,4 and the related SDHAF2 have also been discovered in patients with HPGL/PCC syndrome. Pheochromocytomas and paragangliomas arising in the setting of SDH deficiency are indistinguishable histologically from tumors with intact SDH expression; however, these tumors show loss of staining for SDHB (Fig. 1).8 The vast majority of SDH-deficient paragangliomas harbor germline SDH mutations, with only rare cases of somatic SDH mutations reported in these tumors.12,13
One of the most remarkable aspects of the discovery of SDH mutations in pheochromocytomas and paragangliomas is the high frequency of germline mutations in these tumors, especially paragangliomas, in which the rate of SDH mutations has been reported to be as high as 54% (this rate is higher than that reported in other studies,14,15 likely in part due to the fact that this analysis detected not only point mutations but also large deletions).16 In discussing the frequency of SDH germline mutations, it is helpful to consider pheochromocytomas, head and neck paragangliomas, and thoracoabdominal paragangliomas separately, as the overall SDH mutation rate and the distribution of specific SDH mutations differ considerably among these groups.
Succinate Dehydrogenase Germline Mutations in Pheochromocytomas
Pheochromocytoma has long been referred to as the “10% tumor”; however, we now know that the actual percentage of hereditary cases is in fact significantly higher.10,11,17,18 Although this is in part due to unexpected VHL and RET mutations, the discovery of SDH mutations also contributed to the increase. In a study by Amar et al,10 the rate of SDH mutations in 264 pheochromocytomas was found to be 4.5%, with an approximately equal number of SDHB and SDHD mutations (7 cases of SDHB, and 5 cases of SDHD). Fairly similar results were reported by Mannelli et al11 in a large cohort that consisted of 501 consecutive patients diagnosed with pheochromocytomas and/or paragangliomas. The authors found that the rate of SDH mutations in pheochromocytomas was 2.8%, again with nearly equal numbers of patients with SDHB and SDHD mutations (5 cases of SDHB, and 4 cases of SDHD). These studies, along with an additional study specifically searching for SDHC mutations,19 indicate that SDHC mutations do not significantly contribute to the development of pheochromocytomas. Although patients harboring germline SDH mutations are more likely to develop pheochromocytomas at a younger age and have a higher incidence of bilateral disease, clinical history can be misleading. In a study by Neumann et al18 evaluating the frequency of RET, VHL, SDHD, and SDHB germline mutations among 271 consecutive patients who presented with nonsyndromic pheochromocytomas without a family history of disease, the authors found that 80% of cases with SDHB or SDHD mutations were solitary pheochromocytomas with 40% of such tumors arising in patients over 30 years of age. Thus, these studies indicate both that the rate of familial tumors is higher than previously thought and that hereditary predisposition (ie, the presence of a germline mutation) may not be readily apparent on the basis of clinical history.
Succinate Dehydrogenase Germline Mutations in Head and Neck Paragangliomas
Head and neck paragangliomas account for the majority of paragangliomas,9 and a striking number of these tumors harbor SDH germline mutations. In the above mentioned study by Mannelli et al,11 SDH germline mutations were detected in 33 (31%) of 106 patients with head and neck paragangliomas, with a much higher rate of SDHD mutations compared with SDHB and SDHC (26% SDHD, 4% SDHB, and 3% SDHC). Additional studies have confirmed that SDHD mutations are the most frequent SDH mutations in patients with head and neck paragangliomas.19,20 SDHD mutations are not only associated with head and neck paragangliomas but also disease multifocality. Patients harboring germline mutations in SDHD are more likely to have multifocal disease compared with patients with SDHB and SDHC mutations.14–16,19,20 In a study by Neumann et al15 comparing clinical features of patients with SDHD and SDHB mutations, multiple tumors occurred in 9 (28%) of 32 patients with germline SDHB mutations and 25 (74%) of 34 patients with germline SDHD mutations. Although patients with a positive family history have a very high rate of SDHD mutation (as high as 97%16), SDHD mutations also occur in apparently sporadic head and neck paragangliomas, with reported rates ranging from 8% to 36%.20,21 This range is in part secondary to ethnic variation due to founder mutations.21 For SDHD mutations, a parent-of-origin mode of inheritance likely contributes to the high rate of SDHD germline mutations in apparently sporadic tumors. Although HPGL/PCC is a dominantly inherited disorder, only offspring with paternally inherited SDHD mutations develop tumors (offspring with maternally inherited SDHD mutations are silent carriers).3 This parent-of-origin pattern of inheritance, not seen with SDHA, SDHB, or SDHC mutations, suggests imprinting. Although maternal imprinting of the SDH gene would seem to be a reasonable explanation for this inheritance pattern, there is evidence indicating that SDHD is not in fact the imprinted gene.3,22 Instead, there may be a paternally imprinted gene/gene cluster near SDHD that is driving this mode of inheritance.22
Succinate Dehydrogenase Germline Mutations in Thoracoabdominal Paragangliomas
Although thoracoabdominal paragangliomas (ie, sympathetic/functional paragangliomas) are not nearly as common as pheochromocytomas and head and neck paragangliomas,9,11 the higher rate of malignancy in these tumors imparts them with particular clinical significance. We now know that the frequency of specific SDH mutations likely contributes to the higher rate of malignancy in paragangliomas at these sites. In the previously described study by Mannelli et al,11 18 (33%) of 54 patients with sympathetic paragangliomas were found to have germline SDH mutations: 26% had SDHB mutations, 6% had SDHD mutations, and 2% had SDHC mutations. Thus, in contrast to head and neck paragangliomas in which SDHD mutations are more frequent, in thoracoabdominal paragangliomas SDHB mutations predominate. Similar results were reported by Amar et al10 who found that 24 (41%) of 58 sympathetic paragangliomas harbored mutations in SDHB or SDHD. Again, the rate of SDHB mutations was significantly higher than that of SDHD mutations (29% and 12%, respectively). Moreover, just as is the case for pheochromocytomas and head and neck paragangliomas, the presence of a germline mutation may not be readily apparent on the basis of clinical history. Possible explanations for germline SDHB mutations in apparently sporadic tumors include lack of a complete family health history, de novo mutations, and incomplete penetrance.
Identifying SDHB mutations in paragangliomas and pheochromocytomas is important not only to prompt genetic counseling, but also due to the fact that the SDHB mutation status has prognostic implications. SDHB mutations correlate with malignant behavior in both paragangliomas and pheochromocytomas.10,15,23,24 The reported rate of malignancy for tumors with SDHB mutations ranges from 38% to 71%,10,15 which is significantly higher than that for tumors with SDHD mutations (approximately 3%) and SDHC mutations (virtually always benign).10,15,19,24 In a study evaluating the frequency of SDHB mutations in malignant pheochromocytomas and paragangliomas, 43% of malignant tumors were found to have germline SDHB mutations.25 Moreover, even among patients with malignant pheochromocytomas and paragangliomas, the presence of SDHB mutations confers a worse prognosis, with a significant and independent association with mortality (relative risk 2.7).25 The fact that SDHB mutations are prognostically significant is especially important in pheochromocytomas and paragangliomas, given that there are no reliable histologic features that predict malignancy for these tumors.
SDHA and SDHAF2 Mutations in Pheochromocytomas/Paragangliomas
The discussion thus far has focused on SDHB, SDHC, and SDHD, but what about SDHA? For several years, SDHA mutations were thought not to contribute to HPGL/PCC; however, in 2010 Burnichon et al4 reported a germline SDHA mutation in a patient with an abdominal catecholamine-secreting paraganglioma. A subsequent study evaluating for SDHA mutations in 316 apparently sporadic pheochromocytomas and paragangliomas identified mutations in 3% of tumors.26 Of the 7 tumors with SDHA mutations, 2 were abdominal paragangliomas, 1 was a malignant bladder (sympathetic) paraganglioma, 1 was a thoracic paraganglioma, 2 were head and neck paragangliomas, and 1 was a pheochromocytoma. Interestingly, the SDHA germline mutations detected in the patients with these tumors were also identified in a healthy control group, albeit at a lower frequency (0.3%).26 There is compelling evidence that the mutations identified are deleterious; for example, the p.Arg 31X mutation leads to a truncated protein, and all reported tumors with this SDHA mutation also showed LOH for SDHA. This result suggests a low penetrance of paragangliomas and pheochromocytomas in germline SDHA mutation carriers. Another rare occurrence in patients with head and neck paragangliomas is mutation in the SDHAF2 gene.27 SDHAF2 is involved in flavination of SDHA and is required for stabilization of the SDH complex. Interestingly, SDHAF2, like SDHD, shows a parent-of-origin mode of inheritance, with tumor development occurring only with paternal inheritance of the mutation.27 In a study by Bayley et al, evaluating 443 paragangliomas and pheochromocytomas that lacked SDHB, SDHC, and SDHD mutations, no tumors possessed SDHAF2 germline mutations or deletions.28 On the basis of this study, SDHAF2 mutation appears to be a very rare event in pheochromocytomas and paragangliomas. Thus, the majority of SDH-deficient pheochromocytomas/paragangliomas will have SDHD or SDHB mutations, significantly fewer will harbor SDHC mutations, and only rare cases will possess an SDHA or SDHAF2 mutation.
SUCCINATE DEHYDROGENASE-DEFICIENT GASTROINTESTINAL STROMAL TUMORS
GISTs are the most common clinically significant mesenchymal tumors of the gastrointestinal tract with approximately 5000 new cases each year in the United States.29,30 Although activating mutations in KIT or the PDGFRA gene have a central role in the development of the majority of GISTs,31,32 15% of GISTs in adults and >90% of GISTs in pediatric patients lack these mutations.33–35 Tumors lacking KIT and PDGFRA mutations have been termed “wild-type GISTs.” Wild-type GISTs are most often sporadic; however, they can also occur as part of a tumor syndrome, including Carney-Stratakis syndrome and Carney triad (defined below).
Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumors Associated With Carney-Stratakis Syndrome and Carney Triad
In 2007 the first link between GISTs and SDH germline mutations was made, with the report of a GIST in a patient with an SDHB germline mutation.36 Soon after, SDHB, SDHC, and SDHD mutations were discovered in patients with Carney-Stratakis syndrome.37,38 Carney-Stratakis syndrome is characterized by the development of gastric GISTs and paragangliomas.39 This rare syndrome is inherited in an autosomal dominant manner and affects both men and women. The GISTs that occur in these patients arise exclusively in the stomach, are often multifocal, and frequently spread to lymph nodes.39 These tumors lack KIT and PDGFRA mutations.38 Instead, SDH deficiency appears to be driving tumorigenesis. GISTs from Carney-Stratakis syndrome patients have been shown to be SDH deficient, reflected by loss of immunohistochemical staining for SDHB.40 Moreover, in a series of 11 patients with Carney-Stratakis syndrome, 8 were found to harbor germline mutations in SDH genes (5 SDHB, 2 SDHC, and 1 SDHD).38 SDH-deficient gastric GISTs are also part of Carney triad. Carney triad is characterized by gastric GISTs, paragangliomas, and pulmonary chondromas.41,42 Unlike Carney-Stratakis syndrome, Carney triad affects mostly female patients and is not inherited. GISTs arising in the setting of Carney triad have distinct clinical and pathologic features.43 In a series of 104 patients with Carney triad, most patients were young women (88% women; mean age 22 y), and the majority presented with gastrointestinal bleeding. The GISTs in these patients were exclusively gastric and predominantly arose in the antrum (66%). They had epithelioid morphology (86%), were hypercellular with scant stroma (86%), and were all positive for KIT by immunohistochemistry. In contrast to conventional GISTs, these tumors were frequently multifocal/multinodular, and many (29%) had associated regional lymph node metastases. Distant metastases were also common, including metastases to the liver (occurring in 25% of patients). Despite multiple metastases and recurrences, GISTs in patients with Carney triad have a better prognosis than typical metastatic GISTs.44 In addition, the clinical course of these tumors cannot be predicted by widely used consensus criteria for risk stratification of GISTs.43,45 As these tumors lack KIT and PDGFRA mutations, they demonstrate minimal response to imatinib mesylate.43,46 Although the gastric GISTs of Carney triad lack SDHB expression by immunohistochemistry40,47 and hence are SDH deficient, unlike the GISTs of Carney-Stratakis syndrome, which occur in patients with germline mutations in SDH genes, GISTs of Carney triad do not harbor SDHA, SDHB, SDHC, or SDHD mutations.44,48 Currently, the etiology of SDH deficiency in these tumors is not known; possible mechanisms include allelic losses of SDH complex subunits, epigenetic modifications of the SDH genes, or deficiency of or alterations in other proteins involved in stabilization of the SDH complex.
Emergence of the Concept of Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumors
The features of pediatric and “pediatric-type” GISTs are essentially identical to those of Carney triad.49,50 Pediatric GISTs, which account for 1% to 2% of GISTs, occur most often in young girls. The tumors frequently show a multinodular/plexiform growth pattern, are hypercellular, and demonstrate a pure or predominantly epithelioid cytomorphology. Lymphovascular invasion and lymph node metastases are common in pediatric GISTs. And again, as described for patients with Carney triad, these tumors pursue a relatively indolent course despite frequent recurrences and distant metastases, their behavior is not predictable by risk assessment criteria, and they show little sensitivity to imatinib.33 In addition, the majority of pediatric GISTs, despite showing strong KIT immunoreactivity, lack KIT and PDGFRA mutations, and show a transcriptional signature similar to GISTs from Carney triad patients.33 Recently, it was recognized that occasional GISTs in adults, so-called “pediatric-type” GISTs, show virtually identical histopathologic features as seen in pediatric patients51; moreover, these tumors also demonstrate a similar clinical course (biological behavior independent of risk assessment criteria, frequent lymph node metastases, relatively indolent disease course despite frequent metastases) and are imatinib resistant.51,52 Thus, GISTs arising in the setting of Carney-Stratakis syndrome and Carney triad, pediatric GISTs, and adult pediatric-type GISTs are strikingly similar.
We now know that these GISTs are similar due to the fact that they are all SDH deficient (Figs. 2, 3). Hence, the above description of these tumors characterizes SDH-deficient GISTs (which have also been termed “type 2 GISTs”).47,53 The group of SDH-deficient GISTs was described by Gill and colleagues, who demonstrated loss of SDHB expression in Carney triad-associated GISTs, pediatric GISTs, and adult GISTs with similar features.47,53 A study by Doyle et al54 evaluating for loss of SDHB expression in a series of genotyped GISTs confirmed the unique clinical and pathologic features of SDH-deficient GISTs. Interestingly, only a subset of SDH-deficient pediatric and pediatric-type GISTs harbor SDHB, SDHC, or SDHD germline mutations. In a study by Janeway and colleagues evaluating wild-type GISTs for defects in SDH, 4 (12%) of 34 tumors were found to harbor SDH germline mutations (3 SDHB mutations and 1 SDHC mutation). Three of these mutations were in patients less than 21 years of age, and the fourth was identified in a 22-year-old individual. Whereas only 12% of tumors possessed SDH mutations, a significantly higher number were SDH deficient by immunohistochemistry. Thus, as was stated for Carney triad, other mechanisms besides germline mutations in SDHB, SDHC, or SDHD must be driving SDH deficiency in these tumors. Although tumors from Carney triad patients have been evaluated for mutations in SDHA, relatively few SDH-deficient pediatric and pediatric-type GISTs have been screened for SDHA mutations thus far. Recently, loss-of-function SDHA germline mutations were reported in 4 wild-type gastric GISTs.55,56 Thus, in addition to the alternative mechanisms proposed above in the discussion of Carney triad, SDHA germline mutations are another potential explanation for SDH deficiency in SDH-deficient pediatric and pediatric-type GISTs.
How prevalent are SDH-deficient GISTs? In a study by Miettinen et al57 evaluating 756 gastric GISTs for SDH deficiency on the basis of loss of SDHB expression, 66 tumors were found to be SDH deficient (and wild type for KIT and PDGFRA). Miettinen and colleagues estimated that approximately 7.5% of gastric GISTs are SDH deficient. An additional 378 nongastric GISTs showed intact SDHB expression, suggesting that SDH-deficient GISTs occur only in the stomach. The rate of SDH deficiency in gastric GISTs depends significantly on patient age. In Miettinen and colleagues’ study, the age range of patients with SDH-deficient GISTs was 8 to 77 years. Almost all (94%) of the study patients under 21 years of age had SDH-deficient GISTs. GISTs found in young adults (21 to 30 y of age) also had a high rate of SDH deficiency (approximately 50%), whereas only rare GISTs in older adults were SDH deficient (in a different study, the frequency of SDH deficiency in unselected adults with apparently sporadic GISTs was 3%47). Although SDH-deficient GISTs are uncommon in adult patients overall, they account for a significant subset of wild-type GISTs. In the study by Doyle et al,54 22 (42%) of 53 wild-type tumors showed loss of SDHB expression.
Although SDH-deficient GISTs are relatively infrequent, recognizing them is important, as the diagnosis of an SDH-deficient GIST has prognostic, therapeutic, and syndromic implications, as previously indicated. Tumors showing pathologic features (gastric location, multinodular/plexiform growth pattern, and epithelioid or mixed morphology) or biological behavior (lymphovascular invasion, lymph node metastases) suggestive of SDH deficiency, and GISTs from patients with a clinical history suggestive of SDH deficiency (pediatric patients, young adults, or patients with a personal or family history of paraganglioma/pheochromocytoma), should all be evaluated for loss of SDHB expression. In addition, the findings by Doyle et al54 suggest that although SDH-deficient tumors can be recognized histologically, as the frequency of SDH-deficient tumors is substantial among wild-type GISTs, it would be reasonable to test all wild-type gastric GISTs for loss of SDHB expression so that cases that are not recognized histologically are not overlooked.
OTHER SUCCINATE DEHYDROGENASE-DEFICIENT TUMORS
Pheochromocytomas, paragangliomas, and gastric GISTs account for the vast majority of SDH-deficient tumors. However, rare cases of additional tumor types have been reported in patients with germline SDH mutations, including renal cell carcinomas, a renal oncocytoma, papillary thyroid carcinomas, a seminoma, a neuroblastoma, and, most recently, a pituitary adenoma.
Approximately 1% to 4% of renal cell carcinomas are familial.58 Although most familial renal cell carcinomas are caused by germline mutations in VHL, MET, or FLCN (the underlying mutation in Birt-Hogg-Dube syndrome), or by constitutional chromosome 3 translocations,58,59 rare cases of familial renal cell carcinoma may be the result of germline SDH mutations. In 2004, the first renal cell carcinomas associated with SDHB germline mutations were described.60 In this report, 3 patients (all men, 24 to 28 y of age) with renal cell carcinoma and a personal/family history of paragangliomas were found to have SDHB germline mutations in addition to LOH for SDHB in their renal cell carcinomas. Since this first report, additional cases of renal cell carcinoma with underlying SDHB germline mutations have been described in patients with and without a personal or family history of paraganglioma.15,59,61–64 Recently, these renal cell carcinomas have been shown to have loss of staining for SDHB.63,64 In a study evaluating for SDHB, SDHC, and SDHD germline mutations in 68 patients with features of inherited nonsyndromic renal cell carcinoma without VHL and FLCN mutations, an SDHB germline mutation was detected in 3 (4.4%) patients (no SDHC or SDHD mutations were found).59 The patients’ ages at the time of diagnosis of renal cell carcinoma ranged from 24 to 46 years, and 2 patients had bilateral tumors.
Just as SDH-deficient GISTs have diagnostic histologic features, SDH-deficient renal cell carcinomas may also have a distinct morphology. Gill et al63 described the histologic features of 5 SDH-deficient renal cell carcinomas. The tumors had a well-circumscribed or lobulated border, with non-neoplastic renal elements trapped within the tumor at the periphery. The tumor architecture was solid to tubular with areas of cystic change. The tumor cells were cuboidal with eosinophilic to vacuolated cytoplasm and round nuclei with inconspicuous nucleoli. All of the tumors were reported to contain distinctive cytoplasmic inclusions (either pale eosinophilic fluid-like material or bubbly areas of clearing associated with delicate eosinophilic material), and one of the tumors showed sarcomatoid differentiation. On the basis of the findings of this study, it would seem reasonable to evaluate for loss of SDHB expression in cases with suspicious histology, in cases of hereditable renal cell carcinoma (especially in the absence of other associated mutations), or in cases from patients with a personal or family history of pheochromocytoma/paraganglioma or gastric GIST.
A limited amount of information currently exists regarding the remaining tumors reported in patients with germline SDH mutations. In the case of the reported growth hormone–producing pituitary adenoma (with an SDHD germline mutation)65 and the testicular seminoma (also harboring an SDHD mutation),66 LOH studies were conducted, making it likely that SDH deficiency played a role in the development of these tumors. However, neither LOH studies nor SDHB immunohistochemical analysis was performed on the reported renal oncocytoma,67 2 papillary thyroid carcinomas,15 or the neuroblastoma61; it is thus unclear whether these tumors were coincident or truly SDH deficient. Hopefully, future studies will provide more insights into the relationship between these tumors and SDH mutations.
MECHANISMS OF TUMORIGENESIS
Although the mechanisms of tumorigenesis in SDH-deficient tumors have not been entirely elucidated, there is considerable evidence indicating that these tumors arise, at least in part, because of activation of the hypoxia response pathway. The induction of a hypoxic response under normoxic conditions (pseudohypoxia) in SDH-deficient tumors has been shown to be mediated by the transcription factor hypoxia-inducible factor (HIF). HIF is a heterodimer composed of HIFα and HIFβ.68 In normoxic conditions, HIFα undergoes proteasomal degradation after ubiquitination by a ubiquitin ligase complex targeted to HIFα by the VHL protein.69 Binding of VHL to HIF requires hydroxylation of proline residues in HIFα, which is mediated by the oxygen-dependent activity of a prolyl hydroxylase-domain (PHD) protein,70 an enzyme that also converts α-ketoglutarate to succinate.71 As the activity of PHD is oxygen dependent, hypoxia leads to decreased activity of PHD, which, in turn, results in reduced hydroxylation of HIFα, lack of VHL-mediated ubiquitination of HIFα, and ultimately stabilization (and hence accumulation) of HIFα.72 When HIFα accumulates, it migrates to the nucleus where it dimerizes with HIFβ to form an active transcription factor that induces expression of genes involved in glycolysis and angiogenesis (including vascular endothelial growth factor).73,74
In SDH-deficient tumors, the accumulation of succinate underlies the stabilization of HIFα in normoxic conditions.71 As previously stated, SDH converts succinate to fumarate; thus, SDH deficiency results in an accumulation of succinate. This succinate migrates to the cytoplasm where it inhibits PHD (by product inhibition), which, in turn, triggers downstream signals similar to those seen with hypoxia. There is considerable evidence in support of the pseudohypoxia model. A number of studies have shown that SDH-deficient paragangliomas have activation of the hypoxia response pathway.4,75–77 These tumors have been shown to have increased levels of succinate compared with non–SDH-deficient paragangliomas.76 In addition, SDH-deficient tumors have been shown to have high levels of HIFα and vascular endothelial growth factor expression.4,24,76 As both SDH and VHL deficiencies trigger activation of the hypoxia response pathway, it might be expected that tumors with these alterations demonstrate molecular similarities. In fact, it has been shown that pheochromocytomas arising in the setting of VHL deficiency and SDH deficiency have a common hypoxic transcriptional signature.4,78,79 Other factors may also contribute to the development of SDH-deficient tumors. For example, SDH mutations may result in redox stress as a result of increased production of reactive oxygen species. Future studies may indicate that additional mechanisms also play a role in the development of SDH-deficient tumors.
IMMUNOHISTOCHEMICAL ANALYSIS OF SUCCINATE DEHYDROGENASE-DEFICIENT TUMORS
When SDH germline mutations were initially described in pheochromocytomas and paragangliomas, there was considerable debate regarding how molecular testing for SDH mutations should be implemented. Although it was recognized that detection of these mutations was important to aid in assessing the risk of malignant behavior, to help predict the likelihood of developing additional tumors, and to guide genetic counseling, testing all patients with these tumors was clearly going to be labor intensive and financially demanding. In 2009, van Nederveen et al8 reported that immunohistochemistry for SDHB could be used to identify cases with underlying SDH germline mutations. In this study, immunohistochemistry for SDHB was performed on 220 pheochromocytomas and paragangliomas. All 102 tumors with germline SDH mutations (36 SDHB, 5 SDHC, and 61 SDHD mutations), regardless of the type of mutation (missense, nonsense, splice site, or frameshift), were negative for SDHB by immunohistochemical staining. Thus, immunohistochemical staining for SDHB showed 100% sensitivity in detecting tumors harboring SDH germline mutations. All tumors with germline mutations in RET and VHL (24 and 29 cases, respectively) and all 12 cases with clinical manifestations of NF1 showed intact SDHB expression. Of the remaining 53 tumors without germline SDH, RET, or VHL mutations, 6 tumors showed loss of SDHB expression. There are several possible explanations for the absence of SDH mutations in these cases. These tumors could have SDHB, SDHC, or SDHD germline mutations that escaped detection by the mutation analysis (such as deleterious mutations in untranslated, intronic, or promoter regions of the genes), they could have epigenetic modifications of the SDH genes, SDHA, or SDHAF2 mutations, or deficiency of or alterations in other proteins involved in stabilization of the SDH complex.
For the rare paragangliomas and pheochromocytomas with germline SDHA mutations, immunohistochemical staining for SDHA can be used specifically to detect the SDHA mutation. Tumors with SDHB, SDHC, or SDHD germline mutations will show loss of staining for SDHB but intact staining for SDHA (why the SDHA protein is not degraded in the presence of SDHB, SDHC, or SDHD mutations is not known currently). In contrast, tumors with SDHA germline mutations will show loss of immunohistochemical staining for both SDHB and SDHA. Two recent studies have demonstrated that paragangliomas and pheochromocytomas with loss of SDHA expression possess germline SDHA mutations.4,26 Moreover, no tumors with loss of SDHA expression harbored SDHB, SDHC, or SDHD germline mutations,4 and no SDHA germline mutations were identified in tumors with intact SDHA expression.26 Therefore, loss of staining for both SDHB and SDHA indicates the presence of an SDHA mutation.
For GISTs, intact staining for SDHB in KIT-mutant and PDGFRA-mutant tumors, along with the correlation between loss of SDHB staining and distinct clinical and histologic features in these tumors, illustrates the utility of immunohistochemistry for SDHB in this group. For example, in the study by Doyle et al,54 all 179 tumors with KIT mutations (154 in exon 11, 17 in exon 9, 4 in exon 13, and 4 in exon 17) and all 32 tumors with PDGFRA mutations (25 in exon 11, 4 in exon 12, and 3 in exon 14) showed intact immunohistochemical staining for SDHB. Furthermore, all cases with histologic features indicative of SDH deficiency showed loss of SDHB expression.
Although immunohistochemical staining for SDHB is highly effective for identifying SDH-deficient tumors, a few words of caution regarding the interpretation of this stain are warranted. Due to the fact that the SDH complex is located in mitochondria, intact staining is cytoplasmic and granular. Loss of staining in tumors should always be interpreted in the context of internal positive controls. In paragangliomas and pheochromocytomas, endothelial cells and sustentacular cells (which are not neoplastic) will retain SDHB expression (Fig. 2). For GISTs, endothelial cells or adjacent normal tissue can serve as an internal positive control (Fig. 3). Staining for SDHB can be somewhat patchy in distribution. For a tumor to be considered SDH deficient, the entire tumor must lack SDHB staining. For cases with large areas of loss of staining with only focal SDHB positivity in the tumor, we would suggest reporting the stain as equivocal. In these equivocal cases, mutation analysis could be performed to assess for SDH germline mutations. Tumors that show a weak cytoplasmic blush for SDHB should also be interpreted with caution. In our experience, some tumors with SDH germline mutations can show a cytoplasmic blush, especially in the context of prior tumor embolization. In a case that shows such a staining pattern for SDHB, we would advise reporting the stain as equivocal so that SDH mutation analysis can be performed and a potential germline mutation is not missed.
Once a tumor is found to be SDH deficient, mutation analysis needs to be performed to evaluate for the presence of a germline SDH mutation. For pheochromocytomas and paragangliomas, the vast majority will harbor a germline SDH mutation, whereas for GISTs, a germline mutation may or may not be detected. If a tumor is SDHB deficient, but shows no SDHB, SDHC, or SDHD germline mutation, we would suggest evaluating for the presence of SDHA expression by immunohistochemistry. If such a tumor shows a lack of SDHA staining, mutation analysis should then be performed to confirm the presence of an SDHA germline mutation.
The rapid discoveries in the field of SDH-deficient tumors have altered the evaluation of patients with pheochromocytomas/paragangliomas and wild-type gastric GISTs. Recognition of SDH deficiency in these tumors has informed prognostication, treatment planning, and genetic counseling for these patients. However, although we have learned a great deal about these tumors, there is still much to be discovered. For example, why do some patients with SDH germline mutations develop pheochromocytomas/paragangliomas, whereas others develop gastric GISTs, with or without pheochromocytomas/paragangliomas? Why do SDHB and SDHD germline mutations (which both result in destabilization of the SDH complex) show phenotypic differences in terms of rates of multifocality and malignancy in pheochromocytomas/paragangliomas? And finally, are there ways to target the pathways of tumorigenesis in SDH-deficient tumors? There certainly remains much to look forward to learning about this fascinating, newly recognized family of tumors.
1. Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005;5:857–866
2. Sun F, Huo X, Zhai Y, et al. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 2005;121:1043–1057
3. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–851
4. Burnichon N, Briere JJ, Libe R, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010;19:3011–3020
5. Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000;26:268–270
6. Astuti D, Douglas F, Lennard TW, et al. Germline SDHD mutation in familial phaeochromocytoma. Lancet. 2001;357:1181–1182
7. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69:49–54
8. van Nederveen FH, Gaal J, Favier J, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009;10:764–771
9. Erickson D, Kudva YC, Ebersold MJ, et al. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab. 2001;86:5210–5216
10. Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005;23:8812–8818
11. Mannelli M, Castellano M, Schiavi F, et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009;94:1541–1547
12. Gimm O, Armanios M, Dziema H, et al. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res. 2000;60:6822–6825
13. van Nederveen FH, Korpershoek E, Lenders JW, et al. Somatic SDHB mutation in an extraadrenal pheochromocytoma. N Engl J Med. 2007;357:306–308
14. Benn DE, Gimenez-Roqueplo AP, Reilly JR, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91:827–836
15. Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292:943–951
16. Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009;94:2817–2827
17. Dluhy RG. Pheochromocytoma—death of an axiom. N Engl J Med. 2002;346:1486–1488
18. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–1466
19. Schiavi F, Boedeker CC, Bausch B, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA. 2005;294:2057–2063
20. Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002;39:178–183
21. Taschner PE, Jansen JC, Baysal BE, et al. Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. Genes Chromosomes Cancer. 2001;31:274–281
22. Hensen EF, Jordanova ES, van Minderhout IJ, et al. Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene. 2004;23:4076–4083
23. Brouwers FM, Eisenhofer G, Tao JJ, et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006;91:4505–4509
24. Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003;63:5615–5621
25. Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007;92:3822–3828
26. Korpershoek E, Favier J, Gaal J, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011;96:E1472–E1476
27. Hao HX, Khalimonchuk O, Schraders M, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325:1139–1142
28. Bayley JB, Kunst HP, Cascon A, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol. 2010;11:366–372
29. Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch. 2010;456:111–127
30. Parfitt JR, Streutker CJ, Riddell RH, et al. Gastrointestinal stromal tumors: a contemporary review. Pathol Res Pract. 2006;202:837–847
31. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–710
32. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–580
33. Agaram NP, Laquaglia MP, Ustun B, et al. Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res. 2008;14:3204–3215
34. Corless CL. Assessing the prognosis of gastrointestinal stromal tumors: a growing role for molecular testing. Am J Clin Pathol. 2004;122:11–13
35. Janeway KA, Liegl B, Harlow A, et al. Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res. 2007;67:9084–9088
36. Bolland M, Benn D, Croxson M, et al. Gastrointestinal stromal tumour in succinate dehydrogenase subunit B mutation-associated familial phaeochromocytoma/paraganglioma. ANZ J Surg. 2006;76:763–764
37. McWhinney SR, Pasini B, Stratakis CA. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med. 2007;357:1054–1056
38. Pasini B, McWhinney SR, Bei T, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008;16:79–88
39. Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002;108:132–139
40. Gaal J, Stratakis CA, Carney JA, et al. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol. 2011;24:147–151
41. Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc. 1999;74:543–552
42. Carney JA, Sheps SG, Go VL, et al. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med. 1977;296:1517–1518
43. Zhang L, Smyrk TC, Young WF Jr, et al. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol. 2010;34:53–64
44. Matyakhina L, Bei TA, McWhinney SR, et al. Genetics of Carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. J Clin Endocrinol Metab. 2007;92:2938–2943
45. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459–465
46. Diment J, Tamborini E, Casali P, et al. Carney triad: case report and molecular analysis of gastric tumor. Hum Pathol. 2005;36:112–116
47. Gill AJ, Chou A, Vilain R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol. 2010;34:636–644
48. Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med. 2009;266:43–52
49. Miettinen M, Lasota J, Sobin LH. Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol. 2005;29:1373–1381
50. Prakash S, Sarran L, Socci N, et al. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol. 2005;27:179–187
51. Rege TA, Wagner AJ, Corless CL, et al. “Pediatric-type” gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior. Am J Surg Pathol. 2011;35:495–504
52. Agaimy A, Wunsch PH. Lymph node metastasis in gastrointestinal stromal tumours (GIST) occurs preferentially in young patients < or =40 years: an overview based on our case material and the literature. Langenbecks Arch Surg. 2009;394:375–381
53. Gill AJ, Chou A, Vilain RE, et al. “Pediatric-type” gastrointestinal stromal tumors are SDHB negative (type 2) GISTs. Am J Surg Pathol. 2011;35:1245–1247; author reply 1247–1248
54. Doyle LA, Nelson D, Heinrich MC, et al. Loss of SDHB expression is limited to a distinctive subset of gastric wild-type gastrointestinal stromal tumors: a comprehensive genotype-phenotype correlation study. Histopathology. 2012 (In press)
55. Pantaleo MA, Astolfi A, Indio V, et al. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J Natl Cancer Inst. 2011;103:983–987
56. Pantaleo MA, Nannini M, Astolfi A, et al. A distinct pediatric-type gastrointestinal stromal tumor in adults: potential role of succinate dehydrogenase subunit A mutations. Am J Surg Pathol. 2011;35:1750–1752
57. Miettinen M, Wang ZF, Sarlomo-Rikala M, et al. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011;35:1712–1721
58. Pavlovich CP, Schmidt LS. Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer. 2004;4:381–393
59. Ricketts C, Woodward ER, Killick P, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst. 2008;100:1260–1262
60. Vanharanta S, Buchta M, McWhinney SR, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet. 2004;74:153–159
61. Schimke RN, Collins DL, Stolle CA. Paraganglioma, neuroblastoma, and a SDHB mutation: resolution of a 30-year-old mystery. Am J Med Genet A. 2010;152A:1531–1535
62. Srirangalingam U, Walker L, Khoo B, et al. Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. Clin Endocrinol (Oxf). 2008;69:587–596
63. Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011;35:1578–1585
64. Gill AJ, Pachter NS, Clarkson A, et al. Renal tumors and hereditary pheochromocytoma-paraganglioma syndrome type 4. N Engl J Med. 2011;364:885–886
65. Xekouki P, Pacak K, Almeida M, et al. Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH? J Clin Endocrinol Metab. 2012;97:E357–E366
66. Galera-Ruiz H, Gonzalez-Campora R, Rey-Barrera M, et al. W43X SDHD mutation in sporadic head and neck paraganglioma. Anal Quant Cytol Histol. 2008;30:119–123
67. Henderson A, Douglas F, Perros P, et al. SDHB-associated renal oncocytoma suggests a broadening of the renal phenotype in hereditary paragangliomatosis. Fam Cancer. 2009;8:257–260
68. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002;64:993–998
69. Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004;22:4991–5004
70. Safran M, Kaelin WG Jr. HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest. 2003;111:779–783
71. Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7:77–85
72. Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: O2
sensing and cancer. Nat Rev Cancer. 2008;8:865–873
73. Covello KL, Simon MC. HIFs, hypoxia, and vascular development. Curr Top Dev Biol. 2004;62:37–54
74. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9:677–684
75. Baysal BE. On the association of succinate dehydrogenase mutations with hereditary paraganglioma. Trends Endocrinol Metab. 2003;14:453–459
76. Pollard PJ, Briere JJ, Alam NA, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14:2231–2239
77. Pollard PJ, Wortham NCTomlinson IP. The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase. Ann Med. 2003;35:632–639
78. Dahia PL, Ross KN, Wright ME, et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005;1:72–80
79. Lopez-Jimenez E, Gomez-Lopez G, Leandro-Garcia LJ, et al. Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol Endocrinol. 2010;24:2382–2391
This article has been cited 2 time(s).
Modern PathologyLoss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumorsModern Pathology
European Journal of Vascular and Endovascular SurgeryParaganglioma of the Carotid Body: Treatment Strategy and SDH-gene MutationsEuropean Journal of Vascular and Endovascular Surgery
succinate dehydrogenase; paraganglioma; pheochromocytoma; gastrointestinal stromal tumor; Carney-Stratakis syndrome
© 2012 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.