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Paragangliomas, previously sometimes called glomus tumors, are uncommon neuroendocrine tumors arising from paraganglia and principally encountered in adults. They are divided into those arising from sympathetic paraganglia (primarily in the chest and abdomen, including pheochromocytoma) and parasympathetic paraganglia (primarily in the head and neck).
The term "glomus" was historically used to describe certain types of neuroendocrine tumors arising from paraganglia. The term is, however, imprecise and can be confused with the glomus bodies and tumors that arise from them, referred to as glomangioma.
It is important to note that paragangliomas and pheochromocytomas are closely related to each other, pathologically, developmentally and functionally. The term pheochromocytoma/paraganglioma is thus often used to group them together 18.
Sporadic paragangliomas are typically diagnosed between the ages of 30 to 50 and predominantly affect women with a female-to-male ratio of 3 to 1. In contrast, hereditary-type paragangliomas are usually diagnosed at a younger age, with an equal male-to-female ratio 17.
Hereditary paragangliomas are related to a variety of mutations and can be part of a number of clinical syndromes 18.
VHL mutations (von Hippel-Lindau syndrome)
RET mutations (multiple endocrine neoplasia 2A)
NF1 mutations (neurofibromatosis type 1)
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.
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.
Paraganglia are clusters of neuroendocrine cells dispersed throughout the body and closely related to the autonomic nervous system, with either parasympathetic or sympathetic functions. The largest cluster of cells is found within the adrenal medulla, with smaller collections in the paravertebral space, and head and neck region.
All paragangliomas consist of 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. Histologically there are no reliable markers of malignant potential.
The incidence of various tumors in the pheochromocytoma/paraganglioma group is far from even with sympathetic paragangliomas accounting for the majority of all paragangliomas and pheochromocytomas being by far the most common in that subgroup 18.
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: most common (40-60%) 18
Sympathetic paragangliomas generally arise in paraganglia below the level of the neck. They tend to secrete catecholamines and can be intra- or extra-adrenal.
intra-adrenal: arise within the adrenal medulla
pheochromocytoma: most common
extra-adrenal: arise outside the adrenal gland along the length of the sympathetic chain 2
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
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 (genes: SDHB, SDHD, SDHA or SDHAF2) 2.
Both anatomical and functional imaging of paragangliomas is required for diagnosis and staging. Anatomical imaging 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
permeative type bone erosion when adjacent to bone such as within the jugular foramen
hypointense to liver and adrenal
salt and pepper appearance due to small hemorrhages producing intrinsic T1 hyperintensity (salt) and hypointenese signal from vascular flow voids (pepper)
'light bulb' appearance described in adrenal pheochromocytoma
T1 C+ (Gd): heterogenous, usually vivid, prolonged enhancement
Targets for functional imaging:
tumor-specific catecholamine production: 123I-MIBG, 18F-FDA and 18F-DOPA
somatostatin receptor (overexpressed in paragangliomas): 68Ga-DOTATATE
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 pheochromocytomas 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.
Malignancy is defined as evidence of metastases. Most common sites for malignancy include lymph nodes, liver, lung, and bone 5.
Risk of malignancy:
sympathetic paraganglioma: 20%
parasympathetic paraganglioma: 2-20%
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 severe hypertension.
Differential diagnosis differs depending on the location and histology of the paraganglioma but can include 17:
- 1. Williams M. Paragangliomas of the Head and Neck: An Overview from Diagnosis to Genetics. Head Neck Pathol. 2017;11(3):278-87. doi:10.1007/s12105-017-0803-4 - Pubmed
- 2. Lam A. Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours. Endocr Pathol. 2017;28(3):213-27. doi:10.1007/s12022-017-9484-5 - Pubmed
- 3. Grebenc M, Rosado de Christenson M, Burke A, Green C, Galvin J. Primary Cardiac and Pericardial Neoplasms: Radiologic-Pathologic Correlation. Radiographics. 2000;20(4):1073-103; quiz 1110-1, 1112. doi:10.1148/radiographics.20.4.g00jl081073 - Pubmed
- 4. International Agency for Research on Cancer, Otmar D. Wiestler. WHO Classification of Tumours of the Central Nervous System. (2016) ISBN: 9789283244929 - Google Books
- 5. Fliedner S, Lehnert H, Pacak K. Metastatic Paraganglioma. Semin Oncol. 2010;37(6):627-37. doi:10.1053/j.seminoncol.2010.10.017 - Pubmed
- 6. Baez J, Jagannathan J, Krajewski K et al. Pheochromocytoma and Paraganglioma: Imaging Characteristics. Cancer Imaging. 2012;12(1):153-62. doi:10.1102/1470-7330.2012.0016 - Pubmed
- 7. Blake M, Kalra M, Maher M et al. Pheochromocytoma: An Imaging Chameleon. Radiographics. 2004;24 Suppl 1(suppl_1):S87-99. doi:10.1148/rg.24si045506 - Pubmed
- 8. Timmers H, Taieb D, Pacak K. Current and Future Anatomical and Functional Imaging Approaches to Pheochromocytoma and Paraganglioma. Horm Metab Res. 2012;44(5):367-72. doi:10.1055/s-0031-1299712 - Pubmed
- 9. Bhatia K, Ismail M, Sahdev A et al. 123I-Metaiodobenzylguanidine (MIBG) Scintigraphy for the Detection of Adrenal and Extra-Adrenal Phaeochromocytomas: CT and MRI Correlation. Clin Endocrinol (Oxf). 2008;69(2):181-8. doi:10.1111/j.1365-2265.2008.03256.x - Pubmed
- 10. Hoegerle S, Ghanem N, Altehoefer C et al. 18F-DOPA Positron Emission Tomography for the Detection of Glomus Tumours. Eur J Nucl Med Mol Imaging. 2003;30(5):689-94. doi:10.1007/s00259-003-1115-3 - Pubmed
- 11. Treglia G, Cocciolillo F, de Waure C et al. Diagnostic Performance of 18F-Dihydroxyphenylalanine Positron Emission Tomography in Patients with Paraganglioma: A Meta-Analysis. Eur J Nucl Med Mol Imaging. 2012;39(7):1144-53. doi:10.1007/s00259-012-2087-y - Pubmed
- 12. Timmers H, Chen C, Carrasquillo J et al. Comparison of 18F-Fluoro-L-DOPA, 18F-Fluoro-Deoxyglucose, and 18F-Fluorodopamine PET and 123I-MIBG Scintigraphy in the Localization of Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab. 2009;94(12):4757-67. doi:10.1210/jc.2009-1248 - Pubmed
- 13. Timmers H, Kozupa A, Chen C et al. Superiority of Fluorodeoxyglucose Positron Emission Tomography to Other Functional Imaging Techniques in the Evaluation of Metastatic SDHB-Associated Pheochromocytoma and Paraganglioma. J Clin Oncol. 2007;25(16):2262-9. doi:10.1200/JCO.2006.09.6297 - Pubmed
- 14. Janssen I, Chen C, Millo C et al. PET/CT Comparing (68)Ga-DOTATATE and Other Radiopharmaceuticals and in Comparison with CT/MRI for the Localization of Sporadic Metastatic Pheochromocytoma and Paraganglioma. Eur J Nucl Med Mol Imaging. 2016;43(10):1784-91. doi:10.1007/s00259-016-3357-x - Pubmed
- 15. Janssen I, Blanchet E, Adams K et al. Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma. Clin Cancer Res. 2015;21(17):3888-95. doi:10.1158/1078-0432.CCR-14-2751 - Pubmed
- 16. Janssen I, Chen C, Taieb D et al. 68Ga-DOTATATE PET/CT in the Localization of Head and Neck Paragangliomas Compared with Other Functional Imaging Modalities and CT/MRI. J Nucl Med. 2016;57(2):186-91. doi:10.2967/jnumed.115.161018 - Pubmed
- 17. Berends A, Buitenwerf E, de Krijger R et al. Incidence of Pheochromocytoma and Sympathetic Paraganglioma in the Netherlands: A Nationwide Study and Systematic Review. Eur J Intern Med. 2018;51:68-73. doi:10.1016/j.ejim.2018.01.015 - Pubmed
- 18. Gill AJ, de Krijger R, Erickson LA, Tischler AS, Hicks M, Mete O, Kimura N, Jarzembowski JA, Assi G, Parasympathetic and Sympathetic paragangliomas. In: WHO Classification of Tumours Editorial Board. Endocrine and Neuroendocrine tumours. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 10). https://publications.iarc.fr