Paraganglioma

Last revised by Michael P Hartung on 26 Sep 2023

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.

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. 

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

  • extra-adrenal: arise outside the adrenal gland along the length of the sympathetic chain 2

    • abdomen

    • 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 SDHAF22

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

  • T1

    • 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)

  • T2

  • T1 C+ (Gd): heterogenous, usually vivid, prolonged enhancement

Targets for functional imaging:

  • tumor-specific catecholamine production: 123I-MIBG, 18F-FDA and 18F-DOPA

  • glucose: 18F-FDG

  • 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. 

  • 123I-MIBG scintigraphy

    • strength: pheochromocytomas and extra-adrenal sympathetic paragangliomas 8 

    • weakness: head and neck, malignant disease, MEN2 9 

  • 18F-DOPA PET

    • strength: head and neck paragangliomas, SDHD-mutations, non-metastatic disease 8,10 

    • weakness: SDHB mutations 11 

  • 18F-FDA PET

    • strength: metastatic disease, non-metastatic pheochromocytomas 12 

    • weakness: limited clinical availability

  • 18F-FDG PET

    • strength: malignancy, SHDB-mutations, von Hippel-Lindau syndrome 8,13 

    • weakness: may lack specificity

  • 68Ga-DOTATATE PET

    • 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 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:

  • pheochromocytoma: 10% 

  • 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:

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Cases and figures

  • Figure 1: paragangliomas
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  • Figure 2: histology - carotid body tumor
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  • Case 1: DSA
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  • Case 2: carotid body tumor
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  • Case 3: glomus jugulare
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  • Case 4: adrenal pheochromocytoma
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  • Case 5: spinal - unusual location
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  • Case 6: paraduodenal
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  • Case 7
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  • Case 8: multiple
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  • Case 9
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  • Case 10: glomus jugulotympanicum paraganglioma
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  • Case 11
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  • Case 12
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  • Case 13: Extra adrenal pheochromocytoma
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  • Case 14
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  • Case 15
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