Skip to main content
SpringerLink
Log in

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas

Head and Neck Pathology Aims and scope Submit manuscript

Cite this article

Abstract

Updated editions of The World Health Organization Classification of Tumours Pathology & Genetics for both Head and Neck Tumours and Tumours of Endocrine Organs took place in 2016 based on consensus conferences. These editions present unification of concepts in paragangliomas and highlight expanding knowledge of their etiology. There is a major emphasis in the new bluebooks on familial/syndromic paragangliomas, representing ~40% of all head and neck paragangliomas. Ancillary use of immunohistochemical evaluation, specifically of SDHB, allows the pathologist to screen for a large subset of these potentially hereditary cases. In addition, similarly to other neuroendocrine tumors, paragangliomas are now considered to represent a continuum of risk, and are assessed in terms of risk stratification. Tumors with SDHB mutations pose the highest risk for metastasis. There is currently no validated or endorsed histologic grading system. Paragangliomas remain tumors of undetermined biologic potential and should not be termed benign.

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

References

  1. Pacak K, Wimalawansa SJ. Pheochromocytoma and paraganglioma. Endocr Pract. 2015;21:406–12.

    Article  PubMed  Google Scholar 

  2. Boedeker CC, Hensen EF, Neumann HP, Maier W, van Nederveen FH, Suarez C, Kunst HP, Rodrigo JP, Takes RP, Pellitteri PK, Rinaldo A, Ferlito A. Genetics of hereditary head and neck paragangliomas. Head Neck. 2014;36:907–16.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Castro-Vega LJ, Letouze E, Burnichon N, Buffet A, Disderot PH, Khalifa E, Loriot C, Elarouci N, Morin A, Menara M, Lepoutre-Lussey C, Badoual C, Sibony M, Dousset B, Libe R, Zinzindohoue F, Plouin PF, Bertherat J, Amar L, de Reynies A, Favier J, Gimenez-Roqueplo AP. Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6:6044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fishbein L. Pheochromocytoma and paraganglioma: genetics, diagnosis, and treatment. Hematol Oncol Clin North Am. 2016;30:135–50.

    Article  PubMed  Google Scholar 

  6. 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;18:2828–37.

    Article  CAS  PubMed  Google Scholar 

  7. Neumann HP, Sullivan M, Winter A, et al. Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab. 2011;96:E1279–E1282.

    Article  CAS  PubMed  Google Scholar 

  8. 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 Oct;99(10):E2046–E50.

    Article  CAS  PubMed  Google Scholar 

  9. Fliedner S Hypoxia-inducible factor 2α mutation-related paragangliomas classify as discrete pseudohypoxic subcluster. Neoplasia. 2016;18:567–576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Shankavaram U, Fliedner SM, Elkahloun AG, et al. Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas. Neoplasia. 2013;15:435–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH 3rd, Myers EN, Ferrell RE, Rubinstein WS. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002 Mar;39(3):178–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mayers JR, Vander Heiden MG. Famine versus feast: understanding the metabolism of tumors in vivo. Trends Biochem Sci. 2015;40:130–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baysal BE, Maher ER: 15 years of paraganglioma: genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations. Endocr Relat Cancer. 2015;22:T71–82.

    Article  Google Scholar 

  15. Haller F, Moskalev EA, Faucz FR, Barthelmess S, Wiemann S, Bieg M, Assie G, Bertherat J, Schaefer IM, Otto C, Rattenberry E, Maher ER, Strobel P, Werner M, Carney JA, Hartmann A, Stratakis CA, Agaimy A. Aberrant DNA hypermethylation of SDHC. a novel mechanism of tumor development in carney triad. Endocr Relat Cancer. 2014;21:567–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Miettinen M, Wang ZF, Sarlomo-Rikala M, Osuch C, Rutkowski P, Lasota J. 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;35:1712–21.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Williamson SR, Eble JN, Amin MB, et al. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod Pathol 2015;28:80–94.

    Article  CAS  PubMed  Google Scholar 

  19. Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011;35:1578–85.

    Article  PubMed  Google Scholar 

  20. Dwight T, Mann K, Benn DE, et al. Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. J Clin Endocrinol Metab. 2013;98:E1103–E1108.

    Article  CAS  PubMed  Google Scholar 

  21. van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Rivière J, Dannenberg H, Petri BJ, Komminoth P, Pacak K, Hop WC, Pollard PJ, Mannelli M, Bayley JP, Perren A, Niemann S, Verhofstad AA, de Bruïne AP, Maher ER, Tissier F, Méatchi T, Badoual C, Bertherat J, Amar L, Alataki D, Van Marck E, Ferrau F, François 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(8):764–71.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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(6):805–14. doi:10.1016/j.humpath.2009.12.005.

    Article  CAS  PubMed  Google Scholar 

  23. Papathomas TG, Oudijk L, Persu A, Gill AJ, van Nederveen F, Tischler AS, Tissier F, Volante M, Matias-Guiu X, Smid M, Favier J, Rapizzi E, Libe R, Currás-Freixes M, Aydin S, Huynh T, Lichtenauer U, van Berkel A, Canu L, Domingues R, Clifton-Bligh RJ, Bialas M, Vikkula M, Baretton G, Papotti M, Nesi G, Badoual C, Pacak K, Eisenhofer G, Timmers HJ, Beuschlein F, Bertherat J, Mannelli M, Robledo M, Gimenez-Roqueplo AP, Dinjens WN, Korpershoek E, de Krijger RR. SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). Mod Pathol. 2015;28(6):807–21.

    Article  CAS  PubMed  Google Scholar 

  24. 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(9):E1472–6.

    Article  CAS  PubMed  Google Scholar 

  25. Benn DE, Robinson BG, Clifton-Bligh RJ. 15 Years of paraganglioma: clinical manifestations of paraganglioma syndromes types 1–5. Endocr Relat Cancer. 2015;22:T91–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee JH, Barich F, Karnell LH, Robinson RA, Zhen WK, Gantz BJ, Hoffman HT; American College of Surgeons Commission on Cancer; American Cancer Society. National cancer data base report on malignant paragangliomas of the head and neck. Cancer. 2002;94(3):730–7.

    Article  PubMed  Google Scholar 

  27. Sethi RV, Sethi RK, Herr MW, Deschler DG. Malignant head and neck paragangliomas: treatment efficacy and prognostic indicators. Am J Otolaryngol. 2013;34(5):431–8. doi:10.1016/j.amjoto.2013.03.010.

    Article  PubMed  Google Scholar 

  28. Ellis RJ, Patel D, Prodanov T, Nilubol N, Pacak K, Kebebew E. The presence of SDHB mutations should modify surgical indications for carotid body paragangliomas. Ann Surg. 2014;260(1):158–62.

    Article  PubMed  Google Scholar 

  29. Dénes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, Xekouki P, Moran L, Kumar A, Wassif C, Fersht N, Baldeweg SE, Morris D, Lightman S, Agha A, Rees A, Grieve J, Powell M, Boguszewski CL, Dutta P, Thakker RV, Srirangalingam U, Thompson CJ, Druce M, Higham C, Davis J, Eeles R, Stevenson M, O’Sullivan B, Taniere P, Skordilis K, Gabrovska P, Barlier A, Webb SM, Aulinas A, Drake WM, Bevan JS, Preda C, Dalantaeva N, Ribeiro-Oliveira A Jr, Garcia IT, Yordanova G, Iotova V, Evanson J, Grossman AB, Trouillas J, Ellard S, Stratakis CA, Maher ER, Roncaroli F, Korbonits M. 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–E41. doi:10.1210/jc.2014-3399.

    Article  PubMed  Google Scholar 

  30. Jamilloux Y, Favier J, Pertuit M, Delage-Corre M, Lopez S, Teissier MP, Mathonnet M, Galinat S, Barlier A, Archambeaud F. A MEN1 syndrome with a paraganglioma. Eur J Hum Genet. 2014;22(2):283–5.

    Article  CAS  PubMed  Google Scholar 

  31. Lee JH, Barich F, Karnell LH, Robinson RA, Zhen WK, Gantz BJ, Hoffman HT. National cancer data base report on malignant paragangliomas of the head and neck. Cancer. 2002;94:730–7.

    Article  PubMed  Google Scholar 

  32. Rodríguez-Cuevas S, López-Garza J, Labastida-Almendaro S. Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level. Head Neck. 1998;20:374–8.

    Article  PubMed  Google Scholar 

  33. Amato B, Bianco T, Compagna R, Siano M, Esposito G, Buffone G, et al. Surgical resection of carotid body paragangliomas: 10 years of experience. Am J Surg. 2014;207:293–8.

    Article  PubMed  Google Scholar 

  34. Langerman A, Athavale SM, Rangarajan SV, Sinard RJ, Netterville JL. Natural history of cervical paragangliomas: outcomes of observation of 43 patients. Arch Otolaryngol Head Neck Surg. 2012;138:341–5.

    Article  PubMed  Google Scholar 

  35. O’Neill S, O’Donnell M, Harkin D, Loughrey M, Lee B, Blair P. A 22-year Northern Irish experience of carotid body tumours. Ulster Med J. 2011;80:133–40.

    PubMed  PubMed Central  Google Scholar 

  36. Qin RF, Shi LF, Liu YP, Lei DL, Hu KJ, Feng XH, et al. Diagnosis and surgical treatment of carotid body tumors: 25 years’ experience in China. Int J Oral Maxillofac Surg. 2009;38:713–8.

    Article  PubMed  Google Scholar 

  37. Sajid MS, Hamilton G, Baker DM, Joint Vascular Research Group. A multicenter review of carotid body tumour management. Eur J Vasc Endovasc Surg. 2007;34:127–30.

    Article  CAS  PubMed  Google Scholar 

  38. Carlson ML, Sweeney AD, Pelosi S, Wanna GB, Glasscock ME 3rd, Haynes DS. Glomus tympanicum: a review of 115 cases over 4 decades. Otolaryngol Head Neck Surg. 2015;152:136–42.

    Article  PubMed  Google Scholar 

  39. Manolidis S, Shohet JA, Jackson CG, Glasscock ME 3rd. Malignant glomus tumors. Laryngoscope. 1999;109:30–4.

    Article  CAS  PubMed  Google Scholar 

  40. Capatina C, Ntali G, Karavitaki N, Grossman AB. The management of head-andneck paragangliomas. Endocr Relat Cancer. 2013;20:R291–305.

    Article  PubMed  Google Scholar 

  41. Taïeb D, Kaliski A, Boedeker CC, Martucci V, Fojo T, Adler JR Jr, et al. Current approaches and recent developments in the management of head and neck paragangliomas. Endocr Rev. 2014;35:795–819.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kunst HP, Rutten MH, de Mönnink JP, Hoefsloot LH, Timmers HJ, Marres HA, et al. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011;17:247–54.

    Article  CAS  PubMed  Google Scholar 

  43. Capatina C, Ntali G, Karavitaki N, Grossman AB. The management of head-and-neck paragangliomas. Endocr Relat Cancer. 2013;20(5):R291–305. doi:10.1530/ERC-13-0223.

    Article  PubMed  Google Scholar 

  44. Heinrich MC, Harris AE, Bell WR. Metastatic intravagal paraganglioma. Case report and review of the literature. Am J Med. 1985;78(6 Pt 1):1017–24.

    Article  CAS  PubMed  Google Scholar 

  45. Ferlito A, Milroy CM, Wenig BM, Barnes L, Silver CE. Laryngeal paraganglioma versus atypical carcinoid tumor. Ann Otol Rhinol Laryngol. 1995;104(1):78–83.

    Article  CAS  PubMed  Google Scholar 

  46. Barnes L. Paraganglioma of the larynx. A critical review of the literature. ORL J Otorhinolaryngol Relat Spec. 1991;53:220–34.

    Article  CAS  PubMed  Google Scholar 

  47. de Azevedo-Gamas A, Gloor F. A very unusual case of tumor of the larynx. Unexpected anatomopathologic diagnosis. Ann Otolaryngol Chir Cervicofac. 1968;85:329–35.

    PubMed  Google Scholar 

  48. Ferlito A, Barnes L, Wenig BM. Identification, classification, treatment, and prognosis of laryngeal paraganglioma. Review of the literature and eight new cases. Ann Otol Rhinol Laryngol. 1994;103:525–36.

    Article  CAS  PubMed  Google Scholar 

  49. Rüfenacht H, Mihatsch MJ, Jundt K, Gächter A, Tanner K, Heitz PU. Gastric epitheloid leiomyomas, pulmonary chondroma, non-functioning metastasizing extra-adrenal paraganglioma and myxoma: a variant of Carney’s triad. Report of a patient. Klin Wochenschr. 1985;63:282–4.

    Article  PubMed  Google Scholar 

  50. Gimenez-Roqueplo AP, Caumont-Prim A, Houzard C, Hignette C, Hernigou A, Halimi P, et al., EVA Investigators. Imaging work-up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers:a multicenter prospective study from the PGL. J Clin Endocrinol Metab. 2013;98:E162–73.

    Article  CAS  PubMed  Google Scholar 

  51. Pasini B, Stratakis CA. SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med. 2009;266:19–42.

    Article  CAS  PubMed  Google Scholar 

  52. Offergeld C, Brase C, Yaremchuk S, Mader I, Rischke HC, Glasker S, Schmid KW, Wiech T, Preuss SF, Suarez C, Kopec T, Patocs A, Wohllk N, Malekpour M, Boedeker CC, Neumann HP. Head and neck paragangliomas: clinical and molecular genetic classification. Clinics. 2012;67(Suppl 1):19–28.

    Article  PubMed  PubMed Central  Google Scholar 

  53. HP, Maier W, van Nederveen FH, Suárez C, et al. Genetics of hereditary head and neck paragangliomas. Head Neck. 2014;36:907–16.

    Article  Google Scholar 

  54. Burnichon N, Brière JJ, Libé R, Vescovo L, Rivière J, Tissier F, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010;19:3011–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Head and Neck Section, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 085, Houston, TX, 77030, USA

    Michelle D. Williams

  2. Department of Pathology and Laboratory Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA

    Arthur S. Tischler

Authors
  1. Michelle D. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arthur S. Tischler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michelle D. Williams.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Special Issue: World Health Organization Classification Update

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Williams, M.D., Tischler, A.S. Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas. Head and Neck Pathol 11, 88–95 (2017). https://doi.org/10.1007/s12105-017-0786-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12105-017-0786-1

Keywords

search

Navigation