Skip to main content

Advertisement

SpringerLink
Log in

Old, New, and Emerging Immunohistochemical Markers in Pheochromocytoma and Paraganglioma

  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

The evolution of genetic research over the past two decades has greatly improved the understanding of pheochromocytomas and paragangliomas. It is now accepted that more than one third of pheochromocytoma and paragangliomas arise in the context of syndromic disease, usually hereditary. The genetic profile of these tumors also has important prognostic implications which may help guide treatment. Accompanying the changing molecular landscape is the development of new immunohistochemical markers. Initially used in assisting with diagnosis, immunohistochemical markers have now become an important adjunct to screening programs for inherited conditions and subsequently as prognostic markers. The accessibility and efficiency of immunohistochemistry bring pathologists to the forefront in triaging patients based on tumor genotype-phenotype. In this review, we provide an update on the role of immunohistochemistry in the diagnosis of pheochromocytomas and paragangliomas, as an adjunct to assessment for hereditary disease and finally as a potential tool to assist risk stratification.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Turchini J, Cheung VKY, Tischler AS, De Krijger RR, Gill AJ: Pathology and genetics of phaeochromocytoma and paraganglioma. Histopathology 2018, 72:97–105.

    Article  PubMed  Google Scholar 

  2. Kloeppel G L, Osamura R, Rosai J: Tumours of the Adrenal medulla and extra-adrenal paraganglia. Pathology and Genetics of Endocrine Organs. Lyon: IARC Press, 2017. pp. 179–195 Chapter 5:.

    Google Scholar 

  3. Gill AJ, Benn DE, Chou A, Clarkson A, Muljono A, Meyer-Rochow GY, Richardson AL, Sidhu SB, Robinson BG, Clifton-Bligh RJ: Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol 2010, 41:805–814.

    Article  PubMed  CAS  Google Scholar 

  4. Gill AJ: Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology 2018, 72:106–116.

    Article  PubMed  Google Scholar 

  5. Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP, van Dooren MF, de Herder WW, Tissier F, Plouin PF, van Nederveen FH, Dinjens WN, Gimenez-Roqueplo AP, de Krijger RR: SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab 2011, 96:E1472–E1476.

    Article  PubMed  CAS  Google Scholar 

  6. Tischler AS: Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med 2008, 132:1272–1284.

    PubMed  Google Scholar 

  7. Weissferdt A, Phan A, Suster S, Moran CA: Adrenocortical carcinoma: a comprehensive immunohistochemical study of 40 cases. Appl Immunohistochem Mol Morphol 2014, 22:24–30.

    Article  PubMed  CAS  Google Scholar 

  8. Duregon E, Volante M, Bollito E, Goia M, Buttigliero C, Zaggia B, Berruti A, Scagliotti GV, Papotti M: Pitfalls in the diagnosis of adrenocortical tumors: a lesson from 300 consultation cases. Hum Pathol 2015, 46:1799–1807.

    Article  PubMed  Google Scholar 

  9. Lloyd RV, Blaivas M, Wilson BS: Distribution of chromogranin and S100 protein in normal and abnormal adrenal medullary tissues. Arch Pathol Lab Med 1985, 109:633–635.

    PubMed  CAS  Google Scholar 

  10. Sangoi AR, Fujiwara M, West RB, Montgomery KD, Bonventre JV, Higgins JP, Rouse RV, Gokden N, McKenney JK: Immunohistochemical distinction of primary adrenal cortical lesions from metastatic clear cell renal cell carcinoma: a study of 248 cases. Am J Surg Pathol 2011, 35:678–686.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Enriquez ML, Lal P, Ziober A, Wang L, Tomaszewski JE, Bing Z: The use of immunohistochemical expression of SF-1 and EMA in distinguishing adrenocortical tumors from renal neoplasms. Appl Immunohistochem Mol Morphol 2012, 20:141–145.

    Article  PubMed  CAS  Google Scholar 

  12. Tacha D, Zhou D, Cheng L: Expression of PAX8 in normal and neoplastic tissues: a comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol 2011, 19:293–299.

    Article  PubMed  CAS  Google Scholar 

  13. Alexa A, Baderca F, Lighezan R, Zahoi DE, Izvernariu D: The diagnostic value of EMA expression in the renal parenchyma tumors. Rom J Morphol Embryol 2011, 52:1019–1025.

    PubMed  Google Scholar 

  14. Tischler AS, deKrijger RR: 15 YEARS OF PARAGANGLIOMA: Pathology of pheochromocytoma and paraganglioma. Endocr Relat Cancer 2015, 22:T123–T133.

    Article  PubMed  CAS  Google Scholar 

  15. Lapinski JE, Chen L, Zhou M: Distinguishing clear cell renal cell carcinoma, retroperitoneal paraganglioma, and adrenal cortical lesions on limited biopsy material: utility of immunohistochemical markers. Appl Immunohistochem Mol Morphol 2010, 18:414–421.

    Article  PubMed  CAS  Google Scholar 

  16. Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F, Jouanno E, Jeunemaitre X, Benit P, Tzagoloff A, Rustin P, Bertherat J, Favier J, Gimenez-Roqueplo AP: SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010, 19:3011–3020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Trpkov K, Hes O, Agaimy A, Bonert M, Martinek P, Magi-Galluzzi C, Kristiansen G, Luders C, Nesi G, Comperat E, Sibony M, Berney DM, Mehra R, Brimo F, Hartmann A, Husain A, Frizzell N, Hills K, Maclean F, Srinivasan B, Gill AJ: Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome. Am J Surg Pathol 2016, 40:865–875.

    Article  PubMed  Google Scholar 

  18. Chen YB, Brannon AR, Toubaji A, Dudas ME, Won HH, Al-Ahmadie HA, Fine SW, Gopalan A, Frizzell N, Voss MH, Russo P, Berger MF, Tickoo SK, Reuter VE: Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol 2014, 38:627–637.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Clark GR, Sciacovelli M, Gaude E, Walsh DM, Kirby G, Simpson MA, Trembath RC, Berg JN, Woodward ER, Kinning E, Morrison PJ, Frezza C, Maher ER: Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab 2014, 99:E2046–E2050.

    Article  PubMed  CAS  Google Scholar 

  20. Castro-Vega LJ, Buffet A, De Cubas AA, Cascon A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Curras-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Leton R, Gomez-Grana A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP: Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 2014, 23:2440–2446.

    Article  PubMed  CAS  Google Scholar 

  21. Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gomez-Grana A, de Cubas AA, Inglada-Perez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernandez-Lavado R, Diaz JA, Gomez-Morales M, Gonzalez-Neira A, Roncador G, Rodriguez-Antona C, Benitez J, Mannelli M, Opocher G, Robledo M, Cascon A: Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011, 43:663–7, 667.

    Article  PubMed  CAS  Google Scholar 

  22. Korpershoek E, Koffy D, Eussen BH, Oudijk L, Papathomas TG, van Nederveen FH, Belt EJ, Franssen GJ, Restuccia DF, Krol NM, van der Luijt RB, Feelders RA, Oldenburg RA, van Ijcken WF, de Klein A, de Herder WW, de Krijger RR, Dinjens WN: Complex MAX Rearrangement in a Family With Malignant Pheochromocytoma, Renal Oncocytoma, and Erythrocytosis. J Clin Endocrinol Metab 2016, 101:453–460.

    Article  PubMed  CAS  Google Scholar 

  23. Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Perez L, de Cubas AA, Amar L, Barontini M, de Quiros SB, Bertherat J, Bignon YJ, Blok MJ, Bobisse S, Borrego S, Castellano M, Chanson P, Chiara MD, Corssmit EP, Giacche M, de Krijger RR, Ercolino T, Girerd X, Gomez-Garcia EB, Gomez-Grana A, Guilhem I, Hes FJ, Honrado E, Korpershoek E, Lenders JW, Leton R, Mensenkamp AR, Merlo A, Mori L, Murat A, Pierre P, Plouin PF, Prodanov T, Quesada-Charneco M, Qin N, Rapizzi E, Raymond V, Reisch N, Roncador G, Ruiz-Ferrer M, Schillo F, Stegmann AP, Suarez C, Taschin E, Timmers HJ, Tops CM, Urioste M, Beuschlein F, Pacak K, Mannelli M, Dahia PL, Opocher G, Eisenhofer G, Gimenez-Roqueplo AP, Robledo M: MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 2012, 18:2828–2837.

    Article  PubMed  CAS  Google Scholar 

  24. Toledo RA, Qin Y, Cheng ZM, Gao Q, Iwata S, Silva GM, Prasad ML, Ocal IT, Rao S, Aronin N, Barontini M, Bruder J, Reddick RL, Chen Y, Aguiar RC, Dahia PL: Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas. Clin Cancer Res 2016, 22:2301–2310.

    Article  PubMed  CAS  Google Scholar 

  25. Thompson LD: Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 2002, 26:551–566.

    Article  PubMed  Google Scholar 

  26. Wu D, Tischler AS, Lloyd RV, DeLellis RA, de Krijger R, van Nederveen F, Nose V: Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score. Am J Surg Pathol 2009, 33:599–608.

    Article  PubMed  Google Scholar 

  27. August C, August K, Schroeder S, Bahn H, Hinze R, Baba HA, Kersting C, Buerger H: CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas. Mod Pathol 2004, 17:1119–1128.

    Article  PubMed  CAS  Google Scholar 

  28. Kumaki N, Kajiwara H, Kameyama K, DeLellis RA, Asa SL, Osamura RY, Takami H: Prediction of malignant behavior of pheochromocytomas and paragangliomas using immunohistochemical techniques. Endocr Pathol 2002, 13:149–156.

    Article  PubMed  Google Scholar 

  29. Clarke MR, Weyant RJ, Watson CG, Carty SE: Prognostic markers in pheochromocytoma. Hum Pathol 1998, 29:522–526.

    Article  PubMed  CAS  Google Scholar 

  30. Kimura N, Watanabe T, Noshiro T, Shizawa S, Miura Y: Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol 2005, 16:23–32.

    Article  PubMed  Google Scholar 

  31. Ricketts CJ, Forman JR, Rattenberry E, Bradshaw N, Lalloo F, Izatt L, Cole TR, Armstrong R, Kumar VK, Morrison PJ, Atkinson AB, Douglas F, Ball SG, Cook J, Srirangalingam U, Killick P, Kirby G, Aylwin S, Woodward ER, Evans DG, Hodgson SV, Murday V, Chew SL, Connell JM, Blundell TL, Macdonald F, Maher ER: Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat 2010, 31:41–51.

    Article  PubMed  CAS  Google Scholar 

  32. Assadipour Y, Sadowski SM, Alimchandani M, Quezado M, Steinberg SM, Nilubol N, Patel D, Prodanov T, Pacak K, Kebebew E: SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery 2017, 161:230–239.

    Article  PubMed  Google Scholar 

  33. Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K: 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.

    Article  PubMed  CAS  Google Scholar 

  34. Ghayee HK, Havekes B, Corssmit EP, Eisenhofer G, Hammes SR, Ahmad Z, Tessnow A, Lazurova I, Adams KT, Fojo AT, Pacak K, Auchus RJ: Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior. Endocr Relat Cancer 2009, 16:291–299.

    Article  PubMed  CAS  Google Scholar 

  35. Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A, Nigawara T, Ito S, Kimura I, Naruse M, Phaeochromocytoma Study Group in J: Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer 2014, 21:405–414.

    Article  PubMed  CAS  Google Scholar 

  36. Koh JM, Ahn SH, Kim H, Kim BJ, Sung TY, Kim YH, Hong SJ, Song DE, Lee SH: Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma. PLoS One 2017, 12:e0187398.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Salmenkivi K, Haglund C, Ristimaki A, Arola J, Heikkila P: Increased expression of cyclooxygenase-2 in malignant pheochromocytomas. J Clin Endocrinol Metab 2001, 86:5615–5619.

    Article  PubMed  CAS  Google Scholar 

  38. van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Riviere J, Dannenberg H, Petri BJ, Komminoth P, Pacak K, Hop WC, Pollard PJ, Mannelli M, Bayley JP, Perren A, Niemann S, Verhofstad AA, de Bruine AP, Maher ER, Tissier F, Meatchi T, Badoual C, Bertherat J, Amar L, Alataki D, Van Marck E, Ferrau F, Francois J, de Herder WW, Peeters MP, van Linge A, Lenders JW, Gimenez-Roqueplo AP, de Krijger RR, Dinjens WN: 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Joseph NM, Solomon DA, Frizzell N, Rabban JT, Zaloudek C, Garg K: Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients. Am J Surg Pathol 2015, 39:1529–1539.

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Anthony J. Gill and Angela Chou contributed equally to this work.

Authors and Affiliations

  1. Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW, 2065, Australia

    Veronica K. Y. Cheung, Anthony J. Gill & Angela Chou

  2. NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, 2065, Australia

    Veronica K. Y. Cheung & Anthony J. Gill

  3. University of Sydney, Sydney, NSW, 2006, Australia

    Anthony J. Gill & Angela Chou

  4. Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia

    Anthony J. Gill

  5. Department of Anatomical Pathology, SydPATH St Vincent’s Hospital, Sydney, 2010, Australia

    Angela Chou

  6. Department of Anatomical Pathology, SydPATH, St Vincent’s Hospital, Darlinghurst, NSW, 2010, Australia

    Angela Chou

Authors
  1. Veronica K. Y. Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony J. Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Anthony J. Gill or Angela Chou.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheung, V.K.Y., Gill, A.J. & Chou, A. Old, New, and Emerging Immunohistochemical Markers in Pheochromocytoma and Paraganglioma. Endocr Pathol 29, 169–175 (2018). https://doi.org/10.1007/s12022-018-9534-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12022-018-9534-7

Keywords

Search

Navigation