Pheochromocytomas (pheos) and paragangliomas (paras) are rare neuroendocrine tumours which arise from chromaffin cells found mainly in the adrenal glands, and the paraganglia of the sympathetic and parasympathic nervous system.
The adrenal glands in humans lie atop the kidneys and receive hormonal and nervous system messages and responds by secreting hormones. The adrenals are made up of two parts – an outer cortex which produces androgens (sex hormones), cortisol and aldosterone (causes kidneys to retain salt); and an inner medulla, which is made up of chromaffin cells which produce and secrete catecholamines- adrenaline and noradrenaline which are humans stress response hormones. The adrenal glands are essential for life, but if they are surgically removed the hormones can be replaced with daily medications.
The sympathetic nervous system has nerve fibres running from the brain via a chain of ganglia (a structure containing a collection of nerve cell bodies) in the thoracic and lumbar regions. It sends our nerves to blood vessels, the heart, lungs, abdominal organs, skin and controls functions by reflex action. They cause the reflex of ‘fight or flight’ in response to a stress (dry mouth, increased heart rate, constriction of blood vessels and increased blood pressure, increased breathing rate, dilated pupils etc).
The parasympathetic nervous system has nerve fibres running from the brain and the lower part of the spinal cord and sends nerves out to blood vessels, glands and the majority of internal organs (heart,lungs, abdominal organs etc). The actions of the parasympathetic system are opposite or antagonize that of the sympathetic system and cause increased secretions, slowing of the heart rate, relaxation of smooth muscles and constriction of pupils etc.
Pheochromocytomas (PH) are rare neuroendocrine tumors with an annual incidence of 1–4 cases per millionpopulation. They arise from the adrenal (adrenal medulla) glands that lie atop the kidneys. 60% of these tumours produce excessive amounts of catecholamines (adrenaline and noradrenaline) which produce symptoms of high blood pressure, sweating, headaches. 40% do not secrete these hormones and are asymptomatic, remaining undiagnosed for many years. Pheochromocytomas affect men and women equally with a peak age at diagnosis between 40-50 years, but 20% of all pheochromocytomas are found in children and adolescents.
Paragangliomas (PG) are rare neuroendocrine tumours that arise from ‘paraganglia’ outside the adrenal glands and can be parasympathetic or sympathetic. Paragangliomas can also be referred as ‘extra-adrenal pheochromocytomas’ which can lead to confusion.
Parasympathetic paragangliomas are mainly located in the head and neck and do not usually secrete adrenaline/noradrenaline but may grow and spread locally.
Sympathetic paragangliomas (SPG) arise in the head, neck (1-5%), thorax (15%), abdomen (80%) or pelvis and usually produce adrenaline/noradrenaline, causing symptoms (high blood pressure, etc) and are more frequently metastatic.
Symptoms and signs
Pheochromocytomas and paragangliomas are often misdiagnosed and go undetected. The average delay from the onset of high blood pressure and other symptoms and the subsequent diagnosis of a pheochromocytoma is 3 years.
Some pheochromocytomas are asymptomatic and do not secrete significant amounts of hormones, however the classic triad of fast heart rate (tachycardia), excessive sweating (diaphoresis) and headache is very sensitive and specific for the diagnosis of a pheochromocytoma.
Other symptoms that can be caused by having a pheochromocytoma or paraganglioma are:
High blood pressure (hypertension)
Symptoms and signs of anxiety or panic attacks (palpitations, dry mouth, tremulousness)
- Chest pain
- Abdominal pain
- Nausea and vomiting
The diagnosis of a pheochromocytoma or paraganglioma relies on clinical history, biochemical tests and radiological and nuclear medicine imaging.
Pheochromocytomas and paragangliomas can secrete catecholamines (adrenaline, noradrenaline), the body rapidly metabolizes these to the by-products of met-adrenaline and met-noradrenaline which are then excreted by the kidneys and passed into urine.
- 24 hour urinary 5 HIAA
- CT (computed tomography) Scanning
CT scans are sensitive in detecting adrenal and extra-adrenal masses when they are greater than 0.5-1cm in size.
- MRI Scanning
MRI is slightly more sensitive than CT
- Functional imaging (nuclear medicine scans)
Nuclear medical imaging methods used for the localization of phaeochromocytomas or paragangliomas can be: a) specific, relying on the tumour cells (chromoffin cells) taking up precursors of catecholamine synthesis or b) non-specific, relying on the tumour’s high glucose metabolism or expression of somatostatin receptors.
Metaiodobenzylguinidine (MIBG) is a catecholamine precursor taken into pheochromocytoma cells which is labeled with radioactive iodine [I123]. This complex is injected into the blood stream, taken up by the tumour and detected by gamma cameras.
Positron Emission Tomography (PET)
Dopamine and its precursor, dihydroxyphenylalanine (DOPA) are substances that are converted into catecholamines (adrenaline and noradrenaline) and can be labeled with fluorine [F18] and are very sensitive in localizing pheochromocytomas and paragangliomas with PET scans.
PET scanning with [F18]- labeled deoxyglucose (FDG) is particularly useful for metastatic pheochromocytomas which are negative in respect to the other functional imaging modalities.
Pheochromocytomas and paragangliomas, similar to other neuroendocrine tumours have somatostatin receptors on their cells. PET scanning utilizing octreotide labeled to indium [I111] or gallium [Ga68] is sensitive in detecting metastatic disease in 90% of cases.
Genetics of pheochromocytomas and paragangliomas
Over the last ten years, the understanding and knowledge of the genetic causes of pheochromocytomas and paragangliomas has increased significantly. Current research suggests that more than 30% of patients with these tumours have a hereditary (genetic) predisposition and more than 50% of patients with metastatic disease have genetic causes.
It is essential that patients with pheochromocytomas and paragangliomas seek genetic testing and counseling.
SDH (succinate dehydrogenase) mutations
The gene encoding for the subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) is the most important contributor to hereditary malignant/metastatic pheochromocytoma (occurs in 10%) and paraganglioma (occurs in >50%).
Mutations in the genes for other SDH subunits – D and HAF2 also appear to be related to paragangliomas.
These mutations are autosomal dominant and can be inherited in 50% of offspring of affected patients. The risk of carrying these gene mutations and the development of pheochromocytomas or paragangliomas is variable and dependent on the ‘penetrance’ of the mutation.
Von-Hippel Lindau (VHL)
Von-Hippel Lindau is disease characterized by the development of haemangioblastomas in the central nervous system (cerebellum and spinal cord), kidney and blood vessels of the eye (retina) adrenal pheochromocytomas, renal cell carcinoma and pancreatic neuroendocrine cancers.
Carney Triad is considered to be a specific type of multiple endocrine neoplasia (MEN). The three classically associated tumours are gastric epithelioid leiomyosarcoma (including gastrointestinal stromal tumour – GIST), pulmonary chondroma and extra-adrenal paraganglioma.
Carney-Stratakis Diad – describes the diad of hereditary GIST and paraganglioma, this is caused by germline mutations in mitochondrial tumour suppressor gene pathway involving succinate dehydrogenase subunits SDHD, SDHC and SDHB.
Treatment of pheochromocytomas and paragangliomas
Surgical resection of primary pheochromocytomas and paragangliomas can be curative, however for most patients with metastatic disease it not curative but can be used to ‘debulk’ the tumour and help decrease the excessive catecholamine (adrenaline and noradrenaline) secretion.
Prior to surgery, patients with pheochromocytomas and paragangliomas must be adequately prepared with alpha- and beta- adrenergic blockade and restoration of fluids and electrolytes and be closely monitored intra and post operatively.
More than 60% of metastatic pheochromocytomas and paragangliomas show avid uptake of [I131] MIBG. In larger doses, [I131] MIBG can be used therapeutically to treat the disease. The radio-isotope is taken up into the tumour and decays, emitting β particles and γ rays which result in disruption to the cellular function and death of the tumour cells. Approximately 30% of tumours ‘shrink’ in response to this treatment and 40% remain stable.
Another class of radionuclides that use the DOTA peptide linked to Yttrium99 and lutetium177 (lutate) have been used in a few centres for the treatment of metastatic pheochromocytoma or paragangliomas which display somatostatin (SSTR) receptors. More study is needed in this area, but recent results show some promise.
Due to the rarity of pheochromocytomas and paragangliomas, extensive studies into the different chemotherapeutic agents is lacking. The best studied and used regimens are cyclophosphamide-based and dacarbazine-based with vincristine or doxorubicin.
Other chemotherapeutic agents used in small populations of patients are temozolamide; cisplatin and 5-fluoruracil; etoposide, carboplatin and streptozocin.
In most patients, these regimens are well tolerated with bone marrow suppression, nausea and vomiting being most problematic side effects.
Targeted molecular therapies
The improved understanding of the relationship between inactivated SDHB gene and the hypoxia-inducible vascular endotheliam growth factor (VEGF) and platelet derived-growth factor (PDGF) which promotes tumour blood vessel growth has lead to more interest in targeted molecular therapies.
In this setting, the use of sunitib (Sutent®), a tyrosine kinase inhibitor which targets VEGF and PDGF and has anti-tumour activity has been shown to have some benefit in patients who have the SDHB mutation. Sunitinib (Sutent®) is listed on the Pharmaceutical Benefits Scheme (PBS) in Australia for use in treatment of renal cell cancers, pancreatic neuroendocrine cancers and gastrointestinal stromal tumours (GIST).
Another intracellular pathway that is targeted in neuroendocrine tumours, including pheochromocytomas and paragangliomas is the mTOR pathway. A recent phase 2 clinical study into the use of everolimus (Afinitor®) for neuroendocrine tumours, pheochromocytomas and paragangliomas showed some modest benefits.
Further studies into combinations of targeted molecular therapies may be warranted.
External beam radiotherapy has been used to treat inoperable tumours or to help palliate symptoms. It is unclear if pheochromocytomas or paragangliomas are sensitive to radiotherapy and more study is needed.
Management of bone metastases
About 70% of metastatic pheochromocytomas and paragangliomas have bone involvement. Many patients suffer bone pain, pathological fractures and occasionally raised calcium levels in their blood.
In some patients the use of bisphosphonates is recommended.