DIAGNOSIS of ENDOCRINE DISEASE: SDHx mutations: beyond pheochromocytomas and paragangliomas

in European Journal of Endocrinology

Mutations in one of the five genes encoding the succinate dehydrogenase (SDHx) or mitochondrial complex II cause the corresponding family syndromes characterized by the occurrence of pheochromocytomas (PHEO) and paragangliomas (PGL). Recently, other solid growths, such as gastrointestinal stromal tumors (GISTs), renal cell carcinomas (RCCs) and pituitary adenomas (PAs) have been associated with these syndromes. In the absence of prospective studies assessing their frequency, at present, their occurrence seems too infrequent to suggest systematic screening for SDHx mutation carriers. However, SDHB immunohistochemistry (IHC) on tumor tissues or SDHx genetic testing on blood or tumor samples should be performed in patients affected by GISTs, RCCs or PAs with clinicopathologic phenotypes suggesting an etiologic role of SDHx genes.

Abstract

Mutations in one of the five genes encoding the succinate dehydrogenase (SDHx) or mitochondrial complex II cause the corresponding family syndromes characterized by the occurrence of pheochromocytomas (PHEO) and paragangliomas (PGL). Recently, other solid growths, such as gastrointestinal stromal tumors (GISTs), renal cell carcinomas (RCCs) and pituitary adenomas (PAs) have been associated with these syndromes. In the absence of prospective studies assessing their frequency, at present, their occurrence seems too infrequent to suggest systematic screening for SDHx mutation carriers. However, SDHB immunohistochemistry (IHC) on tumor tissues or SDHx genetic testing on blood or tumor samples should be performed in patients affected by GISTs, RCCs or PAs with clinicopathologic phenotypes suggesting an etiologic role of SDHx genes.

Introduction

Pheochromocytomas (PHEO) and paragangliomas (PGL) are rare neural crest-derived tumors (1, 2). They comprise adrenal and extra-adrenal chromaffin, sympathetic, catecholamine releasing tumors, namely secreting PGL (sPGL) and tumors of the parasympathetic ganglia in the head and neck region, namely head and neck PGL (HNPGL). These tumors are the most common heritable tumors recorded to date (3, 4). Approximately 35% of them are caused by germline mutations and an additional 10–15% show somatic mutations in the same or other susceptibility genes, which include those encoding the succinate dehydrogenase (SDH) or mitochondrial complex II (5).

SDH is functionally involved in both the Krebs cycle, where it transforms succinate into fumarate, and the electron transport chain. The complex consists of four structural subunits: two hydrophilic catalytic subunits, A and B, encoded by the corresponding SDHA and SDHB genes and two hydrophobic subunits, C and D, encoded by SDHC and SDHD genes anchoring the catalytic subunits to the inner mitochondrial membrane (6). Enzymatic activity requires a functional unit, succinate dehydrogenase complex assembly factor 2 (SDHAF2), responsible for flavination of the catalytic subunit A and encoded by the corresponding SDHAF2 gene (7).

Mutations in any of these five genes cause disassembly of the mitochondrial complex, with loss of SDH enzymatic activity (8, 9) as well as of SDHB expression at immunohistochemistry (IHC) while SDHA is lost, together with SDHB, in SDHA-mutated tumors, but its expression is retained in tumors with other SDH mutations.

Consequently, SDHB IHC (10) has been assumed as a rapid and inexpensive preliminary test on tumor tissue to investigate on tumor’s SDH insufficiency.

Mutations in any of these five genes cause impairment of SDH enzymatic activity and loss of SDHB expression, whereas loss of SDHA expression is only detected in SDHA mutations (8, 9). SDH immunohistochemistry (IHC) has therefore become a rapid and inexpensive tool for testing SDH insufficiency in tumor tissue (10).

Mutations in any of the five SDH genes are responsible for the occurrence of PHEO/PGL.

In 2000, Baysal et al. (5) demonstrated that SDHD mutations result in an inherited familial syndrome, known as familial paragangliomatosis type 1 (PGL1) characterized by the presence of both sPGL and HNPGL (11). Subsequently, other SDHx genes also proved to be PHEO/PGL susceptibility genes (12, 13, 14, 15), and their germline mutations are associated with the corresponding familial syndromes, namely PGL2 to PGL5 (Table 1). The clinical picture of these five PGL syndromes differs in some aspects, but they are all characterized by the presence of PHEO/PGL (16, 17, 18, 19, 20).

Table 1

Clinical characteristics of the SDHx-related syndromes.

GeneLesionsMultiple lesionsPenetranceMalignancyPaternaltransmissionAssociated neoplasms
SDHDHNPGLYesHighVery rareYesGIST
 PGL1Thoracic PGLPA
Abdominal PGLRCC
PHEOPTC (?)
SDHBAbdominal PGLYes (rare)LowFrequentNoGIST
 PGL4HNPGLRCC
PHEOsPA
PTC (?)
SDHCHNPGLRareUnknownUnknownNoGIST
 PGL3Abdominal PGLRCC
PA
SDHAF2HNPGLRareUnknownUnknownYesPA
 PGL2
SDHAAbdominal PGLRareUnknownUnknownNoGIST
 PGL5

HNPGL, head and neck paragangliomas; PA, Pituitary adenoma; PHEO, pheochromocytomas; PGL, paragangliomas; PTC, Papillary Thyroid Carcinoma; RCC, Renal cell carcinoma.

In recent years, germline mutations in SDHx genes have been rarely associated with other solid tumors beyond PHEO/PGL, such as gastrointestinal stromal tumors (GISTs) (21), renal cell carcinomas (RCC) (22) and pituitary adenomas (PAs) (23). To our knowledge, no systematic prospective study has been conducted in SDHx mutation carriers to define the true prevalence of solid tumors other than PHEO/PGL. These additional solid tumors have been sometimes found incidentally in SDHx mutation carriers and most of the papers evaluating the role of SDH in the pathogenesis of these tumors report retrospective studies performed by SDHB IHC on paraffin-embedded tumor tissue. Tumors have been labeled as ‘SDH deficient’ in case of negative SDHB immunostaining but not all the tumors or the patients have then undergone genetic analysis looking for the correspondent SDHx somatic or germline mutations.

This paper reviews these tumors and their characteristics.

Gastrointestinal stromal tumors (GISTs)

GISTs are the most common mesenchymal tumors of the gastrointestinal tract (24), occurring as sporadic or familial with an incidence of 6.8–20 per million (25, 26, 27).

In 85–90% of cases, GISTs result from activating mutations of KIT or PDGFRA genes (28, 29). The other 10–15% non-KIT/PDGFRA-mutated GISTs, incorrectly labeled as ‘wild type’, mainly affect children. Mutations in NF1 (30, 31) or BRAF (32) genes account for 50% of these cases, while the remaining 50% prove negative for SDHB on IHC, and are referred to as SDH-deficient GISTs. They can be sporadic or part of two syndromes, i.e. Carney-Stratakis (33) syndrome and Carney triad (34). In Carney-Stratakis syndrome, dominantly inherited and due to germline SDHx mutations, GISTs are associated with PGL (35, 36), whereas they are associated with PGL and pulmonary chondromas in Carney triad.

Etiology of Carney triad is uncertain (37). Comparative genomic hybridization has shown alterations in the 1q, 1p and less frequently in the 14 q and 22 q chromosomal loci (38). Although SDHB is located on chromosome 1p36.1-p35 and SDHC on 1q21-q23.3, germline mutations of SDHx genes have rarely been found. Nonetheless, the GISTs from Carney triad display loss of immunoreactivity for SDHB (39). This finding can be explained by SDHx somatic losses or by epigenetic silencing of SDHC promoter (40).

SDH-deficient GISTs account for 5–7.5% of all GISTs. Nearly all are located in the stomach, usually multiple, and frequently multinodular, they may metastasize to lymph nodes, but generally present a protracted and indolent course (35, 37, 41).

In summary, GISTs occur rarely in SDHx mutation carriers and therefore systematic screening for these tumors does not seem to be cost-effective. However, in the case of a GIST showing characteristics such as childhood onset, gastric location, multiple lesions, nodular/plexyform histology or a positive personal or family history for PHEO/PGL, SDHB immunostaining of the tumor or SDHx genetic testing on patient or tumor DNA should be performed. Indeed, the diagnosis of a familial form has important consequences on the clinical management of the patient and of his/her family members.

Renal cell carcinomas (RCCs)

SDHx mutated RCCs are rare tumors, estimated to account for 0.05–0.2% of all RCCs (42). The first report on SDHB-mutated patients affected by both PHEO/PGL and RCCs was by Vanharanta et al. in 2004 (22). The renal cancers diagnosed in these SDHB mutation carriers appeared to originate from the epithelial cells of the proximal tubule and were composed of a mixture of clear cells and cells with granular-eosinophilic cytoplasm arranged in a variably solid or nested architecture.

In a more recent paper, Gill et al. evaluated the morphology of 36 SDH-deficient RCCs from 27 patients and concluded that the most distinctive histologic feature was the presence of cytoplasmic vacuoles and inclusion-like spaces containing either pale eosinophilic fluid or flocculent material (42). Nonetheless, in some cases, these inclusions were focal and not easy to identify. Ricketts et al. also reported that in 21 cases of SDH-deficient RCC, most tumors exhibited ‘oncocytic’ features although renal tumor histology was variable (43).

SDH-deficient RCC has been recognized as novel entity in the 2016 WHO classification of renal tumors (44, 45). It may show a morphologic spectrum wider than has been previously described (46) and some cases may be essentially indistinguishable from other non-SDH-related RCCs at histology. Of the SDH-deficient RCCs, the most common are those due to SDHB mutations.

According to Gill (42), SDH-deficient RCCs commonly present at a mean age of 37 years (range 14–76) while in the series of Williamson (47), the mean age is 40 years (range 22–72). Multifocal or bilateral tumors are detected in 30% of patients at long-term follow-up.

In summary, the very low prevalence of SDH-deficient RCCs seems to make their systematic research non-cost-effective in SDHx mutation carriers. SDH IHC or SDHx genetic testing should however be considered in RCCs occurring in patients younger than 40 years, as multiple or recurrent tumors, or in the case of a positive personal or family history of PHEO/PGL, GISTs or RCCs.

Pituitary adenomas (PAs)

The first report of an SDH (in this case C) mutation carrier affected by a single HNPGL and a PA was by Lopez-Jimenez et al. in 2008 (48). The authors found loss of heterozygosity (LOH) in the HNPGL but could not verify SDH deficiency of the PA since the tumor tissue was not available. The first description of PAs related to an SDH (in this case D) mutation was by Xekouki et al. in 2012 (23). They published the case of a 37-year-old male SDHD mutation carrier who presented multiple PGL in the neck, thorax and abdomen and a GH-secreting PA exhibiting LOH and downregulation of SDHD protein at immunoblotting and IHC. In 2013, Dwight et al. reported a case of PA arising in the setting of germline SDHA mutation (49).

In 2014 Gill et al. (50) immunohistochemically assessed 309 PAs detecting only one SDHA-negative PA as the result of a double SDHA somatic mutation. Subsequently, Xekouki et al. (51) performed genetic testing on 168 patients affected by PA, of which 146 were sporadic and 22 were familial.

Among the patients with sporadic PAs, 3 also displayed PHEO/PGL, but none of them was an SDHx mutation carrier. Conversely, in the group of patients with familial PAs, 4 also presented PHEO/PGL, 2 were SDHB and 1 SDHD germline mutation carriers.

To the best of our knowledge, 74 patients affected by both PHEO/PGL and PA have been reported so far (52, 53). Of the 72 patients collectively analyzed by O’Toole et al. (52), 23 (32%) harbored no mutations but had a personal or family history suggestive of a hereditary endocrine syndrome, 28 (39%) had no mutations and no suggestive personal or family history and 21 (29%) were found to be mutated for a susceptibility gene, such as menin (4 patients), RET (1 patient), SDHB (6 patients), SDHD (5 patients), SDHC (1 patient) and SDHAF2 (1 patient). The patient age at diagnosis ranged from 15 to 84 years with a mean of 44 years. Of the 72 patients, 34 (47.2%) presented a macroadenoma, 11 (15.3%) a microadenoma and in 27 (37.5%), the size of the PA was unavailable.

PA secretion varied but consisted mainly of GH (27patients, 37.5%) and PRL (23 patients 31.9%). Overall, 13 (18.1%) patients had a non-functioning PA, 2 (2.8%) an ACTH-secreting tumor and 1 (1.4%) a mixed GH/PRL-secreting adenoma. In 1 (1.4%) patient, PA was diagnosed as chromophobic, and in 5 (6.9%), the secretion was not determined.

In summary, the occurrence of PAs in SDH germline mutation carriers is rare, and systematic screening does not seem to be recommended. Conversely, SDHx genetic testing or SDHB IHC is advisable in the case of familial PAs, phenotypically aggressive and/or therapy-resistant PAs, early-onset PAs or patients with a positive personal or family history for PHEO/PGL.

Other tumors

In addition to GISTs, RCCs and PAs, other tumors have been reported to be associated with PHEO/PGL in SDHx germline mutation carriers; however, very few cases have been found to be related to SDH deficiency.

In 2004, Neumann et al. (16) reported the occurrence of papillary thyroid carcinoma (PTC) in one out of 53 SDHB mutation carriers and in one out of 47 SDHD mutation carriers, although the tumor SDH dependency was not investigated.

The causal role of SDH in differentiated thyroid cancers (DTC) was evaluated by Ni et al. (54) in 754 cases. Germline SDHx missense variants were found in 48 (6%) patients, but were generally classified as non-pathogenic. However, papillary and follicular thyroid tumors showing consistent loss of SDHC/D gene expression were associated with earlier disease onset and higher pathologic stage. Although these findings identify SDHx as modifier genes in the clinical presentation of DTC, Papathomas et al. argued against a positive link between PTC and SDH-deficient state (55). Indeed, all the 60 cases of PTC under study proved immunoreactive for SDHB. Similarly, the authors did not find any SDHB-negative tumor among 47 neuroblastic tumors, 50 testicular seminomas and 10 adenomatoid adrenal tumors.

An association between SDHx mutations and lymphoid malignancies has been recently reported by Renella et al. (56) in two families. In one family, a young female SDHB mutation carrier was affected with abdominal PGL and nodular lymphocyte-predominant Hodgkin lymphoma staining for SDHB. The pedigree of the other family included a 15-year-old SDHC mutation carrier with metastatic GIST/PHEO and a 24-year-old maternal aunt diagnosed with stage IV-B Hodgkin lymphoma whose specimen was not available for IHC.

Finally, a pancreatic neuroendocrine tumor showing SDHB negativity, SDHA positivity and LOH has been reported in an SDHD mutation carrier who was also affected with oligodendroglioma and multiple HNPGL (53).

Discussion

In addition to PHEO/PGL, SDHx gene mutations are responsible for the occurrence of other solid tumors, mainly GISTs, RCCs and PAs.

The frequency of these non-neural-crest-derived tumors seems to be very rare, although the cases reported in the literature may result underestimated as no systematic studies aimed at diagnosing these tumors have been performed in SDHx mutation carriers. Nevertheless, SDHx mutation carriers are generally (and hopefully) enrolled in a lifelong screening looking for the occurrence of HNPGL as well as of PHEO/PGL and therefore tumors like RCC and PA should be diagnosed during radiological screening procedures, by CT or MRI, carried out on the abdomen or head and neck respectively.

Therefore, at present, a systematic search for neoplasms other than PHEO/PGL in SDHx mutation carriers does not seem advisable although prospective studies aimed at establish their frequency are necessary. Nevertheless, these tumors may at times present clinical or histologic features suggestive of SDHx dependency, thereby recommending SDHB IHC on tumor tissue or SDHx genetic testing on patient’s blood or tumor DNA. However, when testing tumor tissue by IHC, it must be recalled that SDHB IHC should be interpreted with caution, due to possible false positive (i.e. positive or weakly diffuse SDHB staining) sometimes observed in SDHD-mutated tumors (57). As a whole, a negative SDHB immunostaining proves that the tumor depends on a loss of SDH expression. This result should then be confirmed by genetic analysis on blood and/or tumor DNA to detect the type of mutation and whether the mutation is germline or somatic. When available, tumor DNA analysis for SDHx mutations should be performed for first. Other tools aimed at proving tumor SDH impairment are SDHB expression by western blot analysis or the measurement of SDH activity in tumor tissue.

Finally, in spite of the low frequency of tumors other than PHEO/PGL, when screening SDHx mutation carriers clinicians should accurately inquire on signs or symptoms associated to GISTs, RCCs or PAs. Conversely, in patients affected by GISTs, RCCs or Pas, clinicians should collect an accurate personal and family history searching for the occurrence of PHEO/PGL. Indeed, the diagnosis of a genetic syndrome is clinically relevant both for the index case as well as for the family members.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review reported.

Funding

This work was supported by the Paradifference Foundation and by the Fondazione Cassa di Risparmio di Pistoia e Pescia (Prot. 2016.0241/gi) to M M; L C, T E, E R, S M and M M are members of the ENS@T (European Network for the Study of Adrenal Tumors).

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    MatyakhinaLBeiTAMcWhinneySRPasiniBCameronSGunawanBStergiopoulosSGBoikosSMuchowMDutraA Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. Journal of Clinical Endocrinology and Metabolism 2007 92 29382943. (doi:10.1210/jc.2007-0797)

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    • Search Google Scholar
    • Export Citation
  • 39

    GaalJStratakisCACarneyJABallERKorpershoekELodishMBLevyIXekoukiPvan NederveenFHden BakkerMA SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinalstromal tumors. Modern Pathology 2011 24 147151. (doi:10.1038/modpathol.2010.185)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    HallerFMoskalevEAFauczFRBarthelmessSWiemannSBiegMAssieGBertheratJSchaeferIMOttoC Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocrine-Related Cancer 2014 21 567577. (doi:10.1530/ERC-14-0254)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    ZhangLSmyrkTCYoungWFStratakisCACarneyJA. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. American Journal of Surgical Pathology 2010 34 5364. (doi:10.1097/PAS.0b013e3181c20f4f)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    GillAJHesOPapathomasTŠedivcováMTanPHAgaimyAAndresenPAKedzioraAClarksonAToonCW Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. American Journal of Surgical Pathology 2014 38 15881602. (doi:10.1097/PAS.0000000000000292)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    RickettsCJShuchBVockeCDMetwalliARBratslavskyGMiddeltonLYangYWeiMHPautlerSEPetersonJ Succinate Dehydrogenase Kidney Cancer (SDH-RCC): an aggressive example of the Warburg effect in cancer. Journal of Urology 2012 188 20632071. (doi:10.1016/j.juro.2012.08.030)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    GillAAminMBSmithSTrpkovK. Succinate dehydrogenase-deficient renal carcinoma. In WHO Classification of Tumors of the Kidney Bladder and Male Genital Tract. Eds MochHHumphreyPE. Lyon: IARC Press. 2004

    • Search Google Scholar
    • Export Citation
  • 45

    SrigleyJRDelahuntBEbleJNEgevadLEpsteinJIGrignonDHesOMochHMontironiRTickooSK The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. American Journal of Surgical Pathology 2013 37 14691489. (doi:10.1097/PAS.0b013e318299f2d1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46

    KurodaNYoritaKNagasakiMHaradaYOheCJerucJRaspolliniMRMichalMHesOAminMB. Succinate Dehydrogenase Kidney Cancer (SDH-RCC): an aggressive example of the Warburg effect in cancer. Polish Journal of Pathology 2016 67 37. (doi:10.5114/pjp.2016.59227)

    • Search Google Scholar
    • Export Citation
  • 47

    WilliamsonSREbleJNAminMBGuptaNSSmithSCShollLMMontironiRHirschMSHornickJL. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Modern Pathology 2015 28 8094. (doi:10.1038/modpathol.2014.86)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48

    López-JiménezEde CamposJMKusakEMLandaILeskeläSMontero-CondeCLeandro-GarcíaLJVallejoLAMadrigalBRodríguez-AntonaC SDHC mutation in an elderly patient without familial antecedents. Clinical Endocrinology 2008 69 906910. (doi:10.1111/j.1365-2265.2008.03368.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    DwightTMannKBennDERobinsonBGMcKelviePGillAJWinshipIClifton-BlighRJ. Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. Journal of Clinical Endocrinology and Metabolism 2013 98 E1103E1108. (doi:10.1210/jc.2013-1400)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50

    GillAJToonCWClarksonASiosonLChouAWinshipIRobinsonBGBennDEClifton-BlighRJDwightT. Succinate dehydrogenase deficiency is rare in pituitary adenomas. American Journal of Surgical Pathology 2014 38 560566. (doi:10.1097/PAS.0000000000000149)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51

    XekoukiPSzarekEBullovaPGiubellinoAQuezadoMMastroyannisSAMastorakosPWassifCARaygadaMRentiaN Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice dehydrogenase defects in humans and mice. Journal of Clinical Endocrinology and Metabolism 2015 100 E710E719. (doi:10.1210/jc.2014-4297)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    O’TooleSMDénesJRobledoMStratakisCAKorbonitsM. 15 years of paraganglioma: the association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocrine-Related Cancer 2015 22 T105T122. (doi:10.1530/ERC-15-0241)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53

    NiemeijerNDPapathomasTGKorpershoekEde KrijgerRROudijkLMorreauHBayleyJPHesFJJansenJCDinjensWNM Succinate dehydrogenase (SDH)-deficient pancreatic neuroendocrine tumor expands the SDH-related tumor spectrum. Journal of Clinical Endocrinology and Metabolism 2015 100 E1386E1393. (doi:10.1210/jc.2015-2689)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54

    NiYSeballosSGanapathiSGurinDFletcherBNgeowJNagyRKloosRTRingelMDLaFramboiseT Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer. Endocrine-Related Cancer 2015 22 121130. (doi:10.1530/ERC-14-0537)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    PapathomasTGGaalJCorssmitEPOudijkLKorpershoekEHeimdalKBayleyJPMorreauHvan DoorenMPapaspyrouK Non-pheochromocytoma/paraganglioma tumors in patients with succinate dehydrogenase-related pheochromocytoma-paraganglioma syndromes: a clinicopathologic and molecular analysis. European Journal of Endocrinology 2013 170 112. (doi:10.1530/EJE-13-0623)

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  • 56

    RenellaRCarnevaleJSchneiderKAHornickJLRanaHQJanewayKA. Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies. Familial Cancer 2014 13 507511. (doi:10.1007/s10689-014-9725-4)

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  • 57

    SantiRRapizziECanuLErcolinoTBaroniGFucciRCostaGMannelliMNesiG. Potential pitfalls of SDH immunohistochemical detection in paragangliomas and pheochromocytomas harbouring germline SDHx mutations. Anticancer Research 2017 37 805812. (doi:10.21873/anticanres.11381)

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    LendersJWEisenhoferGMannelliMPacakK. Phaeochromocytoma. Lancet 2005 366 665675. (doi:10.1016/S0140-6736(05)67139-5)

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    WelanderJSoderkvistPGimmO. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-Related Cancer 2011 18 R253R276. (doi:10.1530/ERC-11-0170)

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    GhezziDGoffriniPUzielGHorvathRKlopstockTLochmüllerHD’AdamoPGaspariniPStromTMProkischH SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDHdefective infantile leukoencephalopathy. Nature Genetics 2009 41 654656. (doi:10.1038/ng.378)

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    SimiLSestiniRFerruzziPGaglianòMSGensiniFMascalchiMGuerriniLPratesiCPinzaniPNesiG Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X. Journal of Medicine Genetics 2005 42 e52. (doi:10.1136/jmg.2004.030353)

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    AstutiDLatifFDallolADahiaPLDouglasFGeorgeESköldbergFHusebyeESEngCMaherER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics 2001 69 4954. (doi:10.1086/321282)

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    HaoHXKhalimonchukOSchradersMDephoureNBayleyJPKunstHDevileePCremersCWSchiffmanJDBentzBG SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 2009 325 11391142. (doi:10.1126/science.1175689)

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    NeumannHPPawluCPeczkowskaMBauschBMcWhinneySRMuresanMBuchtaMFrankeGKlischJBleyTA Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 2004 292 943951. (doi:10.1001/jama.292.8.943)

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    BurnichonNRohmerVAmarLHermanPLeboulleuxSDarrouzetVNiccoliPGaillardDChabrierGChabolleF The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. Journal of Clinical Endocrinology and Metabolism 2009 94 28172827. (doi:10.1210/jc.2008-2504)

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    RickettsCJFormanJRRattenberryEBradshawNLallooFIzattLColeTRArmstrongRKumarVKMorrisonPJ Tumor risks and genotype–phenotype–proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Human Mutation 2010 31 4151. (doi:10.1002/humu.21136)

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    BennDEGimenez-RoqueploAPReillyJRBertheratJBurgessJBythKCroxsonMDahiaPLElstonMGimmO Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Journal of Clinical Endocrinology and Metabolism 2006 91 827836. (doi:10.1210/jc.2005-1862)

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    McWhinneySRPasiniBStratakisCA. Familial gastrointestinal stromal tumors and germ-line mutations. New England Journal of Medicine 2007 357 10541056. (doi:10.1056/NEJMbib71191)

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    VanharantaSBuchtaMMcWhinneySRVirtaSKPeczkowskaMMorrisonCDLehtonenRJanuszewiczAJarvinenHJuholaM Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable. Paraganglioma. American Journal of Human Genetics 2004 74 153159. (doi:10.1086/381054)

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    XekoukiPPacakKAlmeidaMWassifCARustinPNesterovaMde la Luz SierraMMatroJBallEAzevedoM Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH? Journal of Clinical Endocrinology and Metabolism 2012 97 E357E366. (doi:10.1210/jc.2011-1179)

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    CarneyJAStratakisCA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. American Journal of Human Genetics 2002 108 132139.

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    JanewayKAKimSYLodishMNoséVRustinPGaalJDahiaPLMLieglBBallERRaygadaM Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. PNAS 2011 108 314318. (doi:10.1073/pnas.1009199108)

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    PasiniBMcWhinneySRBeiTMatyakhinaLStergiopoulosSMuchowMBoikosSAFerrandoBPacakKAssieG 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. European Journal of Human Genetics 2008 16 7988. (doi:10.1038/sj.ejhg.5201904)

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    BoikosSAStratakisCA. The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations. Endocrine 2014 47 401408. (doi:10.1007/s12020-014-0346-3)

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  • 38

    MatyakhinaLBeiTAMcWhinneySRPasiniBCameronSGunawanBStergiopoulosSGBoikosSMuchowMDutraA Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. Journal of Clinical Endocrinology and Metabolism 2007 92 29382943. (doi:10.1210/jc.2007-0797)

    • Crossref
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  • 39

    GaalJStratakisCACarneyJABallERKorpershoekELodishMBLevyIXekoukiPvan NederveenFHden BakkerMA SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinalstromal tumors. Modern Pathology 2011 24 147151. (doi:10.1038/modpathol.2010.185)

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    • Search Google Scholar
    • Export Citation
  • 40

    HallerFMoskalevEAFauczFRBarthelmessSWiemannSBiegMAssieGBertheratJSchaeferIMOttoC Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocrine-Related Cancer 2014 21 567577. (doi:10.1530/ERC-14-0254)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    ZhangLSmyrkTCYoungWFStratakisCACarneyJA. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. American Journal of Surgical Pathology 2010 34 5364. (doi:10.1097/PAS.0b013e3181c20f4f)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    GillAJHesOPapathomasTŠedivcováMTanPHAgaimyAAndresenPAKedzioraAClarksonAToonCW Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. American Journal of Surgical Pathology 2014 38 15881602. (doi:10.1097/PAS.0000000000000292)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    RickettsCJShuchBVockeCDMetwalliARBratslavskyGMiddeltonLYangYWeiMHPautlerSEPetersonJ Succinate Dehydrogenase Kidney Cancer (SDH-RCC): an aggressive example of the Warburg effect in cancer. Journal of Urology 2012 188 20632071. (doi:10.1016/j.juro.2012.08.030)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    GillAAminMBSmithSTrpkovK. Succinate dehydrogenase-deficient renal carcinoma. In WHO Classification of Tumors of the Kidney Bladder and Male Genital Tract. Eds MochHHumphreyPE. Lyon: IARC Press. 2004

    • Search Google Scholar
    • Export Citation
  • 45

    SrigleyJRDelahuntBEbleJNEgevadLEpsteinJIGrignonDHesOMochHMontironiRTickooSK The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. American Journal of Surgical Pathology 2013 37 14691489. (doi:10.1097/PAS.0b013e318299f2d1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46

    KurodaNYoritaKNagasakiMHaradaYOheCJerucJRaspolliniMRMichalMHesOAminMB. Succinate Dehydrogenase Kidney Cancer (SDH-RCC): an aggressive example of the Warburg effect in cancer. Polish Journal of Pathology 2016 67 37. (doi:10.5114/pjp.2016.59227)

    • Search Google Scholar
    • Export Citation
  • 47

    WilliamsonSREbleJNAminMBGuptaNSSmithSCShollLMMontironiRHirschMSHornickJL. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Modern Pathology 2015 28 8094. (doi:10.1038/modpathol.2014.86)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48

    López-JiménezEde CamposJMKusakEMLandaILeskeläSMontero-CondeCLeandro-GarcíaLJVallejoLAMadrigalBRodríguez-AntonaC SDHC mutation in an elderly patient without familial antecedents. Clinical Endocrinology 2008 69 906910. (doi:10.1111/j.1365-2265.2008.03368.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    DwightTMannKBennDERobinsonBGMcKelviePGillAJWinshipIClifton-BlighRJ. Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. Journal of Clinical Endocrinology and Metabolism 2013 98 E1103E1108. (doi:10.1210/jc.2013-1400)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50

    GillAJToonCWClarksonASiosonLChouAWinshipIRobinsonBGBennDEClifton-BlighRJDwightT. Succinate dehydrogenase deficiency is rare in pituitary adenomas. American Journal of Surgical Pathology 2014 38 560566. (doi:10.1097/PAS.0000000000000149)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51

    XekoukiPSzarekEBullovaPGiubellinoAQuezadoMMastroyannisSAMastorakosPWassifCARaygadaMRentiaN Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice dehydrogenase defects in humans and mice. Journal of Clinical Endocrinology and Metabolism 2015 100 E710E719. (doi:10.1210/jc.2014-4297)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    O’TooleSMDénesJRobledoMStratakisCAKorbonitsM. 15 years of paraganglioma: the association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocrine-Related Cancer 2015 22 T105T122. (doi:10.1530/ERC-15-0241)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53

    NiemeijerNDPapathomasTGKorpershoekEde KrijgerRROudijkLMorreauHBayleyJPHesFJJansenJCDinjensWNM Succinate dehydrogenase (SDH)-deficient pancreatic neuroendocrine tumor expands the SDH-related tumor spectrum. Journal of Clinical Endocrinology and Metabolism 2015 100 E1386E1393. (doi:10.1210/jc.2015-2689)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54

    NiYSeballosSGanapathiSGurinDFletcherBNgeowJNagyRKloosRTRingelMDLaFramboiseT Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer. Endocrine-Related Cancer 2015 22 121130. (doi:10.1530/ERC-14-0537)

    • Crossref
    • PubMed
    • Search Google Scholar
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