Skip to main content
SpringerLink
Log in

Pheochromocytomas, Paragangliomas, and Pituitary Adenomas (3PAs) and Succinate Dehydrogenase Defects

  • Living reference work entry
  • First Online:
Polyendocrine Disorders and Endocrine Neoplastic Syndromes

Part of the book series: Endocrinology ((ENDOCR))

  • 210 Accesses

Abstract

Mutations in the succinate dehydrogenase (SDH) complex (SDHx) lead to succinate accumulation, pseudohypoxic pathway upregulation, reactive oxygen species production, and ultimately oncogenesis. Although germline SDHx mutations are most frequently associated with pheochromocytoma and/or paraganglioma (PCC/PGL) formation, the tumorigenic potential of other tissues has become more readily appreciated. Recently the association of PCC/PGL and pituitary adenomas (the 3P association or 3PAs) was described in individuals with germline SDHx defects. Although rare, these adenomas seem to be more aggressive (commonly measuring greater than 1 cm in size), biochemically functional, and have unique features on histology. SDHx mutations are also associated with renal cell carcinoma, gastrointestinal stromal tumors, and papillary thyroid carcinoma, and thus 3PAs may be part of a multiple neoplasia syndrome due to SDH deficiency. In this chapter we review SDHx mutations and their associations with PCC/PGL, pituitary adenoma, and other tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Alrezk R, Hannah-Shmouni F, Stratakis CA. MEN4 and CDKN1B mutations: the latest of the MEN syndromes. Endocr Relat Cancer. 2017;24(10):T195–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andrews KA, Ascher DB, Pires DEV, Barnes DR, Vialard L, Casey RT, et al. Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018;55(6):384–94.

    CAS  Google Scholar 

  • Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol. 2010;11(4):366–72.

    Article  CAS  PubMed  Google Scholar 

  • Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91(3):827–36.

    Article  CAS  PubMed  Google Scholar 

  • Bezawork-Geleta A, Rohlena J, Dong L, Pacak K, Neuzil J. Mitochondrial complex II: at the crossroads. Trends Biochem Sci. 2017;42(4):312–25.

    Article  CAS  PubMed  Google Scholar 

  • Boikos SA, Stratakis CA. Pituitary pathology in patients with Carney Complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities. Pituitary. 2006;9(3):203–9.

    Article  CAS  PubMed  Google Scholar 

  • Boikos SA, Xekouki P, Fumagalli E, Faucz FR, Raygada M, Szarek E, et al. Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet. 2016;24(4):569–73.

    Article  CAS  PubMed  Google Scholar 

  • Bravo EL, Gifford RW Jr, concepts C. Pheochromocytoma: diagnosis, localization and management. N Engl J Med. 1984;311(20):1298–303.

    Article  CAS  PubMed  Google Scholar 

  • Castro-Vega LJ, Lepoutre-Lussey C, Gimenez-Roqueplo AP, Favier J. Rethinking pheochromocytomas and paragangliomas from a genomic perspective. Oncogene. 2016;35(9):1080–9.

    Article  CAS  PubMed  Google Scholar 

  • Curras-Freixes M, Pineiro-Yanez E, Montero-Conde C, Apellaniz-Ruiz M, Calsina B, Mancikova V, et al. PheoSeq: a targeted next-generation sequencing assay for pheochromocytoma and paraganglioma diagnostics. J Mol Diagn. 2017;19(4):575–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer. 2014;14(2):108–19.

    Article  CAS  PubMed  Google Scholar 

  • Daly AF, Castermans E, Oudijk L, Guitelman MA, Beckers P, Potorac I, et al. Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. Endocr Relat Cancer. 2018;25(5):L37–42.

    Article  CAS  PubMed  Google Scholar 

  • Denes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab. 2015;100(3):E531–41.

    Article  CAS  PubMed  Google Scholar 

  • Dwight T, Mann K, Benn DE, Robinson BG, McKelvie P, Gill AJ, et al. Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. J Clin Endocrinol Metab. 2013;98(6):E1103–8.

    Article  CAS  PubMed  Google Scholar 

  • Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, et al. The prevalence of pituitary adenomas: a systematic review. Cancer. 2004;101(3):613–9.

    Article  PubMed  Google Scholar 

  • Flynn A, Dwight T, Harris J, Benn D, Zhou L, Hogg A, et al. Pheo-type: a diagnostic gene-expression assay for the classification of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2016;101(3):1034–43.

    Article  CAS  PubMed  Google Scholar 

  • Fritz A, Walch A, Piotrowska K, Rosemann M, Schaffer E, Weber K, et al. Recessive transmission of a multiple endocrine neoplasia syndrome in the rat. Cancer Res. 2002;62(11):3048–51.

    CAS  PubMed  Google Scholar 

  • Gaal J, Stratakis CA, Carney JA, Ball ER, Korpershoek E, Lodish MB, et al. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol. 2011;24(1):147–51.

    Article  CAS  PubMed  Google Scholar 

  • Gaston-Massuet C, Andoniadou CL, Signore M, Jayakody SA, Charolidi N, Kyeyune R, et al. Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc Natl Acad Sci U S A. 2011;108(28):11482–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gill AJ, Chou A, Vilain R, Clarkson A, Lui M, Jin R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol. 2010;34(5):636–44.

    PubMed  Google Scholar 

  • Gill AJ, Hes O, Papathomas T, Sedivcova M, Tan PH, Agaimy A, et al. Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol. 2014;38(12):1588–602.

    Article  PubMed  PubMed Central  Google Scholar 

  • Haller F, Moskalev EA, Faucz FR, Barthelmess S, Wiemann S, Bieg M, et al. Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer. 2014;21(4):567–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heesterman BL, Bayley JP, Tops CM, Hes FJ, van Brussel BT, Corssmit EP, et al. High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations. Eur J Hum Genet. 2013;21(4):469–70.

    Article  CAS  PubMed  Google Scholar 

  • Jochmanova I, Pacak K. Pheochromocytoma: the first metabolic endocrine cancer. Clin Cancer Res. 2016;22(20):5001–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jochmanova I, Pacak K. Genomic landscape of pheochromocytoma and paraganglioma. Trends Cancer. 2018;4(1):6–9.

    Article  CAS  PubMed  Google Scholar 

  • Jochmanova I, Wolf KI, King KS, Nambuba J, Wesley R, Martucci V, et al. SDHB-related pheochromocytoma and paraganglioma penetrance and genotype–phenotype correlations. J Cancer Res Clin Oncol. 2017;143(8):1421–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011;96(9):E1472–6.

    Article  CAS  PubMed  Google Scholar 

  • Lecoq AL, Zizzari P, Hage M, Decourtye L, Adam C, Viengchareun S, et al. Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice. J Endocrinol. 2016;231(1):59–69.

    Article  CAS  PubMed  Google Scholar 

  • Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42.

    Article  CAS  PubMed  Google Scholar 

  • Lloyd RV, Ruebel KH, Zhang S, Jin L. Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation. Am J Pathol. 2002;160(3):1171–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopez-Jimenez E, de Campos JM, Kusak EM, Landa I, Leskela S, Montero-Conde C, et al. SDHC mutation in an elderly patient without familial antecedents. Clin Endocrinol. 2008;69(6):906–10.

    Article  CAS  Google Scholar 

  • McNichol AM. Differential diagnosis of pheochromocytomas and paragangliomas. Endocr Pathol. 2001;12(4):407–15.

    Article  CAS  PubMed  Google Scholar 

  • Ngeow J, Mester J, Rybicki LA, Ni Y, Milas M, Eng C. Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations. J Clin Endocrinol Metab. 2011;96(12):E2063–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ni Y, He X, Chen J, Moline J, Mester J, Orloff MS, et al. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependent destabilization of p53. Hum Mol Genet. 2012;21(2):300–10.

    Article  CAS  PubMed  Google Scholar 

  • Ni Y, Seballos S, Ganapathi S, Gurin D, Fletcher B, Ngeow J, et al. Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer. Endocr Relat Cancer. 2015;22(2):121–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Toole SM, Denes J, Robledo M, Stratakis CA, Korbonits M. 15 YEARS OF PARAGANGLIOMA: the association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer. 2015;22(4):T105–22.

    Article  PubMed  Google Scholar 

  • Otsuka F, Miyoshi T, Murakami K, Inagaki K, Takeda M, Ujike K, et al. An extra-adrenal abdominal pheochromocytoma causing ectopic ACTH syndrome. Am J Hypertens. 2005;18(10):1364–8.

    Article  PubMed  Google Scholar 

  • Papathomas TG, Gaal J, Corssmit EP, Oudijk L, Korpershoek E, Heimdal K, et al. Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis. Eur J Endocrinol. 2014;170(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  • Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, 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(1):79–88.

    Article  CAS  PubMed  Google Scholar 

  • Roszko KL, Blouch E, Blake M, Powers JF, Tischler AS, Hodin R, et al. Case report of a prolactinoma in a patient with a novel MAX mutation and bilateral pheochromocytomas. J Endocr Soc. 2017;1(11):1401–7.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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(6):1531–5.

    PubMed  Google Scholar 

  • Srirangalingam U, Walker L, Khoo B, MacDonald F, Gardner D, Wilkin TJ, et al. Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. Clin Endocrinol. 2008;69(4):587–96.

    Article  CAS  Google Scholar 

  • Teramoto A, Hirakawa K, Sanno N, Osamura Y. Incidental pituitary lesions in 1,000 unselected autopsy specimens. Radiology. 1994;193(1):161–4.

    Article  CAS  PubMed  Google Scholar 

  • Tufton N, Roncaroli F, Hadjidemetriou I, Dang MN, Denes J, Guasti L, et al. Pituitary carcinoma in a patient with an SDHB mutation. Endocr Pathol. 2017;28(4):320–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vicha A, Taieb D, Pacak K. Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer. 2014;21(3):R261–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xekouki P, Stratakis CA. Succinate dehydrogenase (SDHx) mutations in pituitary tumors: could this be a new role for mitochondrial complex II and/or Krebs cycle defects? Endocr Relat Cancer. 2012;19(6):C33–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xekouki P, Pacak K, Almeida M, Wassif CA, Rustin P, Nesterova 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(3):E357–66.

    Article  CAS  PubMed  Google Scholar 

  • Xekouki P, Szarek E, Bullova P, Giubellino A, Quezado M, Mastroyannis SA, et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab. 2015;100(5):E710–9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xekouki P, Brennand A, Whitelaw B, Pacak K, Stratakis CA. The 3PAs: an update on the association of pheochromocytomas, paragangliomas, and pituitary tumors. Horm Metab Res. 2018; https://doi.org/10.1055/a-0661-0341. [Epub ahead of print].

Download references

Acknowledgments

This work is funded through the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Author information

Authors and Affiliations

  1. Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA

    Andrew P. Demidowich & Constantine A. Stratakis

Authors
  1. Andrew P. Demidowich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Constantine A. Stratakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Constantine A. Stratakis .

Editor information

Editors and Affiliations

  1. Neuroendocrine Unit, University of Naples Federico II Neuroendocrine Unit, Naples, Italy

    Annamaria Colao

  2. Dept. Experimental Medicine, University of L'Aquila Dept. Experimental Medicine, L'Aquila, Italy

    Marie-Lise Jaffrain-Rea

  3. Department of Endocrinology, Centre Hospitalier Universitaire de Lièg Department of Endocrinology, Liège, Belgium

    Albert Beckers

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Demidowich, A.P., Stratakis, C.A. (2019). Pheochromocytomas, Paragangliomas, and Pituitary Adenomas (3PAs) and Succinate Dehydrogenase Defects. In: Colao, A., Jaffrain-Rea, ML., Beckers, A. (eds) Polyendocrine Disorders and Endocrine Neoplastic Syndromes. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-73082-0_13-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-73082-0_13-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-73082-0

  • Online ISBN: 978-3-319-73082-0

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation