Paraganglioma

Paragangliomas, sometimes called glomus tumours, are rare neuroendocrine tumours arising from paraganglia. 

Terminology

Paraganglia are clusters of neuroendocrine cells dispersed throughout the body and closely related to the autonomic nervous system, with either parasympathetic or sympathetic functionfunctions. The largest cluster of cells is found within the adrenal medulla, with smaller collections in the paravertebral space, and head and neck region. Tumours arising in the paraganglia are called paragangliomas. They are classified by both location and secretory function. 

Epidemiology

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-type paragangliomas are usually diagnosed at a younger age, with an equal male-to-female ratio ¹⁷.

Associations

Hereditary paragangliomas are most commonly associated with succinate dehydrogenase (SDH) mutations. 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 / Carney triad

Von Hippel-Lindau syndrome and neurofibromatosis type 1 are more commonly associated with phaeochromocytomas. 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. 

Clinical presentation

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. 

Pathology

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.

Location

Parasympathetic paragangliomas

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

• jugulotympanic paraganglioma 

• jugular paraganglioma

• tympanic paraganglioma

• vagal paraganglioma

• laryngeal paraganglioma 

Sympathetic paragangliomas

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

  • abdomen

    • 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

  • phaeochromocytoma

Immunophenotype

Immunohistochemical examination confirms neuroendocrine differentiation of chief cells (type I): 

• neurone-specific enolase (NSE) 

• chromogranin-A

• synaptophysin

Sustentacular cells (type II):

• S100

• GFAP

Genetics

Paragangliomas are the most strongly hereditary group of tumours. The most common genetic cause of hereditary paragangliomas are mutations in the succinate dehydrogenase (SDH) subunit (genes: SDHB, SDHD, SDHA or SDHAF2) ². 

Radiographic features 

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 tumour localisation. They have excellent sensitivity but lack specificity in unequivocally identifying a mass as a paraganglioma.

CT

• 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

MRI 

• T1

  • hypointense to liver and adrenal

  • salt and pepper appearance due to small haemorrhages producing intrinsic T1 hyperintensity (salt) and hypointenese signal from vascular flow voids (pepper)

• T2

  • hyperintense

  • 'light bulb' appearance described in adrenal phaeochromocytoma

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

Nuclear medicine

Targets for functional imaging:

• tumour-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: phaeochromocytomas 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 phaeochromocytomas 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 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:

• phaeochromocytoma: 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

Differential diagnosis differs depending on the location and histology of the paraganglioma but can include ¹⁷:

• melanoma

• mesenchymal tumours

• adrenal cortical tumours