Paragangliomas, sometimes called glomus tumors, are rare neuroendocrine tumors arising from paraganglia.
Paraganglia are clusters of neuroendocrine cells dispersed throughout the body and closely related to the autonomic nervous system, with either parasympathetic or sympathetic function. The largest cluster of cells is found within the adrenal medulla, with smaller collections in the paravertebral space, and head and neck region. Tumor arising in the paraganglia are called paragangliomas. They are classified by both location and secretory function.
Sympathetic paragangliomas present with features of catecholamine-excess, such as headaches, palpitations, diaphoresis and hypertension. Whereas, parasympathetic paragangliomas present more commonly with mass-effect such as cranial nerve palsies, a neck mass or tinnitus.
All paragangliomas consist two types of cells; type I and type II. The main components are lobules or nests of chief cells (type I); these structures are known as Zellballen. They are surrounded by a single layer of sustentacular cells (type II) 4.
Malignancy is defined as evidence of metastases. Histologically there are no reliable markers of malignant potential. Most common sites for malignancy include lymph nodes, liver, lung, and bone 5.
Risk of malignancy:
- pheochromocytoma: 10%
- sympathetic paraganglioma: 20%
- parasympathetic panganglioma: 2-20%
It is important to note biopsy (incision or fine needle aspirate) is contraindicated in suspected paragangliomas until biochemical screening is negative for catecholamine excess, due to the risk of catecholamine crisis and serve hypertension.
Parasympathetic paragangliomas arise within paraganglia of the head and neck (see - paragangliomas of the head and neck) in association with the branches of the glossopharyngeal and vagus nerve 1. They are generally non-secretory.
- carotid body paraganglioma (see carotid body tumor)
- juglotympanic paraganglioma
- vagal paraganglioma
- laryngeal paraganglioma
Sympathetic paragangliomas generally arise in paraganglia below the level of the neck. They tend to secrete catecholamines and can be intra- or extra-adrenal.
extra-adrenal: arise outside the adrenal gland along the length of the sympathetic chain 2
- organ of Zuckerkandl
- bladder base
- thorax (see mediastinal paraganglioma)
- paravertebral (aortosympathetic paraganglia)
- great vessels of the chest (aortopulmonary paraganglia)
- cardiac (extremely rare; may be located along the epicardium, in the atrial cavity, the interatrial septum or the ventricles) 3
- intra-adrenal: arise within the adrenal medulla
Immunohistochemical examination confirms neuroendocrine differentiation of chief cells (type I):
Sustentacular cells (type II):
Paragangliomas are the most strongly hereditary group of tumors. The most common genetic cause of hereditary paragangliomas are mutations in the succinate dehydrogenase (SDH) subunit (SDHB, SDHD, SDHA or SDHAF2) 2.
They are also associated with four clinical syndromes:
- von Hippel-Lindau syndrome
- multiple endocrine neoplasia types 2A and 2B
- neurofibromatosis type 1
- Carney-Stratakis syndrome
von Hippel-Lindau syndrome and neurofibromatosis type 1 are more commonly associated with pheochromocytomas. SDH mutations are common in head and neck paragangliomas, except for SDHB, which is associated with sympathetic paragangliomas. SDHB also confers a higher risk of malignancy 2.
Both anatomical and functional imaging of paragangliomas is required for diagnosis and staging. Anatomical imagining includes CT and MRI. Multiple functional imaging modalities exist: 123I-MIBG scintigraphy, 18F-FDA PET, 18F-DOPA PET, 18F-FDG PET and 68Ga-DOTATATE- PET.
CT and MRI are the initial imaging modalities for tumor localization. They have excellent sensitivity, but lack specificity in unequivocally identifying a mass as a paraganglioma.
- density greater than 10 HU on non-contrast imaging (differentiates from adenoma)
- avidly enhances with contrast with delayed washout (due to rich capillary network)
- can detect lesions 0.5 cm in diameter 6
- hypointense to liver and adrenal
- salt and pepper appearance due to enhancing parenchyma (salt) and signal flow voids of vessels (pepper)
- hyperintense 'light bulb' appearance
- salt and pepper enhancement also seen 7
- T1 C+ (Gd): heterogenous prolonged enhancement
Targets for functional imaging:
- tumor-specific catecholamine production: 123I-MIBG, 18F-FDA and 18F-DOPA PET
- glucose: 18F-FDG
- somatostatin receptor (overexpressed in paragangliomas): [68Ga]-DOTATATE-PET
Each modality has strengths and weaknesses in detecting lesions depending on their location, secretory function and underlying genetic mutation.
- strength: pheochromocytomas and extra-adrenal sympathetic paragangliomas 8
- weakness: head and neck, malignant disease, MEN2 9
- strength: head and neck paragangliomas, SDHD-mutations, non-metastatic disease 8,10
- weakness: SDHB mutations 11
- strength: metastatic disease, non-metastatic pharochromocytomas 12
- weakness: limited clinical availability
- strength: malignancy, SHDB-mutations, von Hippel-Lindau syndrome 8,13
- weakness: may lack specificity
- strength: overall viable imaging modality; proven superiority in sporadic disease, SHDB-mutations, head and neck lesions 14-16
- weakness: detection of liver and lung lesions
Treatment and prognosis
Treatment may include surgical resection or radiotherapy. Paragangliomas may metastasize to other locations.
Differential diagnosis differs depending on the location and histology of the paraganglioma but can include 17:
- 1. Williams MD. Paragangliomas of the Head and Neck: An Overview from Diagnosis to Genetics. (2017) Head and neck pathology. 11 (3): 278-287. doi:10.1007/s12105-017-0803-4 - Pubmed
- 2. Lam AK. Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours. (2017) Endocrine pathology. 28 (3): 213-227. doi:10.1007/s12022-017-9484-5 - Pubmed
- 3. Grebenc ML, Rosado de Christenson ML, Burke AP, Green CE, Galvin JR. Primary cardiac and pericardial neoplasms: radiologic-pathologic correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 20 (4): 1073-103; quiz 1110-1, 1112. doi:10.1148/radiographics.20.4.g00jl081073 - Pubmed
- 4. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK "WHO Classification of Tumours of the Central Nervous System. 4th Edition Revised" ISBN: 9789283244929
- 5. Fliedner SM, Lehnert H, Pacak K. Metastatic paraganglioma. (2010) Seminars in oncology. 37 (6): 627-37. doi:10.1053/j.seminoncol.2010.10.017 - Pubmed
- 6. Baez JC, Jagannathan JP, Krajewski K, O'Regan K, Zukotynski K, Kulke M, Ramaiya NH. Pheochromocytoma and paraganglioma: imaging characteristics. (2012) Cancer imaging : the official publication of the International Cancer Imaging Society. 12: 153-62. doi:10.1102/1470-7330.2012.0016 - Pubmed
- 7. Blake MA, Kalra MK, Maher MM, Sahani DV, Sweeney AT, Mueller PR, Hahn PF, Boland GW. Pheochromocytoma: an imaging chameleon. (2004) Radiographics : a review publication of the Radiological Society of North America, Inc. 24 Suppl 1: S87-99. doi:10.1148/rg.24si045506 - Pubmed
- 8. Timmers HJ, Taieb D, Pacak K. Current and future anatomical and functional imaging approaches to pheochromocytoma and paraganglioma. (2012) Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 44 (5): 367-72. doi:10.1055/s-0031-1299712 - Pubmed
- 9. Bhatia KS, Ismail MM, Sahdev A, Rockall AG, Hogarth K, Canizales A, Avril N, Monson JP, Grossman AB, Reznek RH. 123I-metaiodobenzylguanidine (MIBG) scintigraphy for the detection of adrenal and extra-adrenal phaeochromocytomas: CT and MRI correlation. (2008) Clinical endocrinology. 69 (2): 181-8. doi:10.1111/j.1365-2265.2008.03256.x - Pubmed
- 10. Hoegerle S, Ghanem N, Altehoefer C, Schipper J, Brink I, Moser E, Neumann HP. 18F-DOPA positron emission tomography for the detection of glomus tumours. (2003) European journal of nuclear medicine and molecular imaging. 30 (5): 689-94. doi:10.1007/s00259-003-1115-3 - Pubmed
- 11. Treglia G, Cocciolillo F, de Waure C, Di Nardo F, Gualano MR, Castaldi P, Rufini V, Giordano A. Diagnostic performance of 18F-dihydroxyphenylalanine positron emission tomography in patients with paraganglioma: a meta-analysis. (2012) European journal of nuclear medicine and molecular imaging. 39 (7): 1144-53. doi:10.1007/s00259-012-2087-y - Pubmed
- 12. Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Havekes B, Eisenhofer G, Martiniova L, Adams KT, Pacak K. Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. (2009) The Journal of clinical endocrinology and metabolism. 94 (12): 4757-67. doi:10.1210/jc.2009-1248 - Pubmed
- 13. Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, Adams KT, Solis D, Lenders JW, Pacak K. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. (2007) Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 25 (16): 2262-9. doi:10.1200/JCO.2006.09.6297 - Pubmed
- 14. Janssen I, Chen CC, Millo CM, Ling A, Taieb D, Lin FI, Adams KT, Wolf KI, Herscovitch P, Fojo AT, Buchmann I, Kebebew E, Pacak K. PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. (2016) European journal of nuclear medicine and molecular imaging. 43 (10): 1784-91. doi:10.1007/s00259-016-3357-x - Pubmed
- 15. Janssen I, Blanchet EM, Adams K, Chen CC, Millo CM, Herscovitch P, Taieb D, Kebebew E, Lehnert H, Fojo AT, Pacak K. Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma. (2015) Clinical cancer research : an official journal of the American Association for Cancer Research. 21 (17): 3888-95. doi:10.1158/1078-0432.CCR-14-2751 - Pubmed
- 16. Janssen I, Chen CC, Taieb D, Patronas NJ, Millo CM, Adams KT, Nambuba J, Herscovitch P, Sadowski SM, Fojo AT, Buchmann I, Kebebew E, Pacak K. 68Ga-DOTATATE PET/CT in the Localization of Head and Neck Paragangliomas Compared with Other Functional Imaging Modalities and CT/MRI. (2016) Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 57 (2): 186-91. doi:10.2967/jnumed.115.161018 - Pubmed