ParagangliomasD35.-

Paragangliomas (PGLs) are rare, primarily benign, unique, neuroendocrine tumors in the extra-adrenal sympathetic and parasympathetic paraganglionary system. Paragangliomas can occur at any anatomical site with chromaffin-containing autonomous tissue from the base of the skull to the pelvis.

Adrenal paragangliomas are called pheochromocytomas (PCCs).

Extra-adrenal paragangliomas are usually referred to "only" as paragangliomas (DeLellis RA et al. 2004). Extra-adrenal paragangliomas are called

• sympathetic paragangliomas
• or as
• parasympathetic paragangliomas.

Depending on the affected ganglion, a distinction is made between:

• Adrenal paragangliomas (pheochromocytomas)
• Extraadrenal paragangliomas

Depending on the location and origin of the extra-adrenal paragangliomas are distinguished:

• Paraganglioma caroticum (carotid fork tumor): localized in the adventitia of the division of the A. carotis communis; this form accounts for about 60% of all paragangliomas.
• Paraganglioma jugulare: located on the parasympathetic paraganglion in the jugular fossa
• Paraganglioma tympanicum: paraganglion located in the middle ear, in the tympanic nerve. Note: The paragangliomas of the two paraganglia of the middle ear (Glomus tympanicum and Glomus jugulare) are the most frequent tumors of the middle ear.
• Vagal paraganglioma: located at the jugular foramen of the base of the skull
• Paraganglioma aorticum (mediastinal paraganglioma): located in the anterior mediastinum, pulmonary artery or aorta (starting from the corpora paraaortica, the so-called sugar canal organ near the bifurcation of the aorta).
• Peritoneal gangliomas (retroperitoneal paragangliomas): localized at the abdominal aorta
• Internal organs (visceral paragangliomas): located on the internal organs - mainly in the bladder
• Peripheral paragangliomas (glomus tumors, also called Masson tumors): starting from arteriovenous anastomoses (often localized in the skin, e.g. subungual localization, see below) Glomus tumor - dermatology)

Hereditary paragangliomas (multiple glomus tumors): Autosomal dominant inherited with multiple glomus tumors in skin and internal organs

Pheochromocytomas and paragangliomas are rare tumors. Their prevalence is unknown, but has been estimated at 1: 6500 to 1: 2500 in the USA (Ariton M et al. 2000). Paragangliomas are the most common tumours of the middle ear; ♀ > ♂ (2:1).

Sympathetic paragangliomas develop from chromaffin cells of paraganglions along the sympathetic chains and are usually located in the chest, abdomen or pelvis. Sympathetic paragangliomas (PGLs/PCCs) usually produce catecholamines (Karagiannis A et al. 2007). Hypersecretion of catecholamines may be associated with high morbidity and mortality.

Parasympathetic paragangliomas develop from peripheral arteriovenous anastomoses (glomerula), which are distributed mainly along the parasympathetic nerves in the head, neck and upper mediastinum and are therefore usually called head and neck paragangliomas. Not infrequently they are also located in the fingertip area and there subungually (subungual paragangliomas/subungual glomus tumors). Parasympathetic paragangliomas usually do not produce catecholamines.

Up to 40% of PCCs / PGLs are associated with germline mutations in susceptibility genes.

Paragangliomas can also occur with familial frequency (autosomal dominant inheritance).

The tumours can occur at any age, but have the highest incidence between 40 and 50 years of age with a roughly equal gender distribution (Mannelli M et al. 2009).

In a larger Spanish study of 693 unselected pheochromocytoma / paraganglioma patients, 69% of patients were diagnosed with pheochromocytoma, 15% with sympathetic paraganglioma and 22% with parasympathetic paraganglioma (Cascon A et al. 2009).

A smaller proportion proved to be a mixed type.

Most localizations are derived from the names of the paragangliomas. Other localizations are the posterior mediastinum, the pharynx, the lung, the orbit, the nasal cavity, the kidneys, the gall bladder, the urinary bladder)

Sympathetic paragangliomas (PGLs/PCCs) produce catecholamines (Karagiannis A et al. 2007). Hypersecretion of catecholamines may be associated with high morbidity and mortality. Catecholamine-producing catecholamines can manifest as "pheochromocytoma syndrome".

The paragangliomas of the middle ear (Paraganglioma tympanicum and Paraganglioma jugolare) usually do not initially cause any symptoms; later, however, pulse-synchronous tinnitus occurs. Otoscopically, the tumour formations are visible through the eardrum and move pulse-synchronously. If a paraganglioma is located near the lingual nerve, it can cause disturbances in taste or swallowing. Advanced paragangliomas of the middle ear can infiltrate the surrounding bone structures (infiltration of the jugular foramen: cranial nerves IX to XI =foramen-jugular syndrome).

Blood and urine tests to determine the excretion of catecholamine.

Radiological procedures like MRI, CT, angiography.

Functional magnetic resonance imaging (fMRI). Somatostatin scintigraphy: differentiation from other vascular processes.

Positron emission tomography (PET): detection of multilocular growth of the glomus tumour.

Sympathetic paragangliomas correspond in their fine tissue structure to a pheochromocytoma. With 40% they show a significantly higher malignancy rate than pheochromocytomas of the adrenal medulla.

The paragangliomas of the two paraganglia of the middle ear (Glomus tympanicum and Glomus jugulare) form highly vascularized cell clusters surrounded by lattice fibres (so-called "cell cluster pattern")with an angiomatous or angiomatous pattern. Mitoses and necroses are absent. The nest-like arranged cell clusters are surrounded by S100 protein-positive sustentacular cells (SZ), which form a network with barbed wire-like morphology by means of their cell extensions. In adrenal and extraadrenal paragangliomas, the prevalence of SC correlates inversely with the prognosis of the patients.

Immunohistologically paragangliomas are NSE- and chromatogranin-positive. Furthermore, serotonin, gastrin, somatostatin, ACTH, GRP (gastrin related peptides) can be detected irregularly.

Removal of the tumour (possible via different access routes). The treatment of paragangliomas of the middle ear depends not only on the individual characteristics of the patient concerned, but also on the type of tumour. In many cases, surgical removal is possible. In the case of jugular paraganglioma, it is very promising with a success rate of 96 percent; however, permanent damage is possible.

Paragangliomas that have infiltrated the bone are often difficult to remove completely by surgery. 10 to 40% of tumours are malignant; the exact number varies depending on which paraganglion is affected. Without successful treatment they can spread or metastasize and thus affect other organs (Taïeb D et al. 2014).

The majority of pheochromocytomas and paragangliomas are benign. Malignancy, defined as the occurrence of distant metastases and occurs in 5-13% of pheochromocytomas. 15-23% of patients with sympathetic paragangliomas and 2-20% (depending on location) of paragangliomas with parasympathetic paragangliomas have to expect distant metastases (most frequently in bone, liver and lung - Chrisoulidou A et al. 2007). The prognosis for malignant PCC and paraganglioma is poor, with a 5-year mortality rate > 50% (Chrisoulidou A et al. 2007). Furthermore, the prognosis for different paragangliomas is characterized by their different localizations.

Vagal paragangliomas: This form of paraganglioma occurs in the upper cervical region in the immediate vicinity of the vagus nerve. This variant of paraganglioma recurs and metastasizes in 15-20% of cases.

The Paragangioloma aorticum is characterized by invasive growth. It is associated with a mortality rate of about 50%. The new formation mainly affects men between 40 and 50 years of age. The tumor growth extends from the height of the left atrium to the descending aorta.

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