Table of Contents
Most of the norepinephrine secretion into the blood is from sympathetic neuronal innervation of blood vessels. The secretion of epinephrine and norepinephrine is responsible for many physiological actions that help the body adapt to stress.
Catecholamines increase blood glucose levels through the activation of lipolysis and gluconeogenesis. They increase blood pressure, heart rate, and cardiac contractility. Catecholamine-secreting tumors can be sporadic or familial and are associated with other disorders such as multiple endocrine neoplasia syndrome II (MEN II), Von Hippel Lindau syndrome, and neurofibromatosis type I (NF I).
About 10% of catecholamine-secreting tumors arise from extra-adrenal sites, while 90% are from the adrenal medulla. Likewise, 10% are benign while 90% are malignant with local and distant spread to other organs.
The average diameter of sporadic tumors is about 6 cm. Malignant tumors are usually large in size with capsular invasion and/or distant metastasis. The coexistence of parathyroid tumors and medullary thyroid carcinoma is part of the MEN II syndrome. Paragangliomas can arise on both sides of the aorta, carotid artery, and along nerve pathways.
Clinical Picture of Pheochromocytoma
Patients with familial pheochromocytoma exhibit varying presentations according to other comorbidities. Fewer than 50% of patients complain of hypertension or tachycardia, which are most common. The levels of circulating catecholamines appear in the normal range. Catecholamines are usually released after abdominal compression, anesthesia, postural changes, or emotional stress.
Episodic release of catecholamines into the circulation leads to paroxysmal presentations of headache, palpitation, sweating, postural hypotension, cold skin, angina, nausea, vomiting, dyspnea, and vision abnormalities. Some patients present with secondary or resistant hypertension, impaired glucose tolerance, tremors, cardiomyopathy, and panic attacks.
Diagnosis of Pheochromocytoma
The diagnosis of hormone-secreting tumors depends on both the measurement of hormone levels and imaging studies. Determination of 24-hour urinary metanephrine and catecholamine levels is the primary test of choice. Metanephrines are breakdown products of catecholamines that are excreted in the urine.
Epinephrine and norepinephrine are metabolized into free and sulfate-conjugated metanephrines. Normally, metanephrine levels in the blood are extremely low.
Elevated levels of catecholamines and metanephrines are highly suggestive of pheochromocytoma and the biochemical tests used have a diagnostic sensitivity close to 100%. The next step is the measurement of plasma-fractionated metanephrines and plasma catecholamines.
The presence of an adrenal mass alone is not conclusive for the diagnosis of pheochromocytoma. The diagnosis should be confirmed in conjunction with elevated catecholamine levels. Incidentalomas are non-functioning tumors that are discovered accidentally during imaging studies or clinical examinations. They usually do not cause symptoms.
Hormonal testing should be indicated in the following cases:
- Typical clinical presentation of tachycardia, sweating, and headache
- Patients with familial MEN II syndrome, NF II, and Von Hippel Lindau syndrome
- Patients < 20 years of age with early-onset hypertension or those with resistant hypertension
- Patients with idiopathic cardiomyopathy or those having an adrenal mass (detected during radiography)
- Young, slim individuals with atypical type II diabetes mellitus
CT and MRI are sensitive and specific imaging techniques to study adrenal tumors, especially sporadic pheochromocytomas, which are > 3 cm in diameter.
Iodine metaiodobenzylguanidine scintigraphy (MIBG) measures the radioactive iodine uptake by adrenergic tissues and is therefore a useful technique to detect large adrenal masses or to study small tumors arising in the paraganglia. Genetic testing should be performed in patients with familial pheochromocytoma or associated familial syndromes.
Venous sampling is not reliable since catecholamine levels will be higher than normal and yield false-positive results. A guided biopsy should be avoided due to the high risk of complications.
Staging of Pheochromocytoma
- Localized: The tumor is localized to one or both adrenal glands, and to one side only in case of paraganglioma
- Regional: The tumor has spread to the regional lymph nodes and/or regional tissues
- Metastatic: The tumor has spread to distant organs including the liver, lung, brain, and bones
Management of Patients with Pheochromocytoma
Genetic counseling is the first step to evaluate other risk factors or familial syndromes associated with the disease. Indications for genetic testing include a positive family history of familial pheochromocytoma syndrome, diagnosis made before the age of 40 years, bilateral disease, or malignant tumor. Genetic testing is recommended for the family members of patients with a confirmed diagnosis and positive genetic mutations.
Symptomatic treatment is indicated for patients with a confirmed diagnosis of pheochromocytoma who experience hypertension and symptoms such as headaches and palpitations.
Medications that control the heart rate and blood pressure include beta- and alpha-blockers, respectively. A combination of alpha-blockers such as phenoxybenzamine or doxazosin and beta-blockers including propranolol is the best treatment regimen to control blood pressure and heart rate before surgery. These drugs should be used for three weeks prior to surgery. Alpha blockade should precede beta blockade to prevent stimulation of the alpha receptors, which could otherwise result in severe hypertension.
Nitroprusside infusion is used in a hypertensive crisis during surgery. Hypotension following bilateral adrenalectomy is managed using norepinephrine infusion and hydrocortisone injection. Hydrocortisone is used after bilateral adrenalectomy to avoid adrenal insufficiency.
Surgical adrenalectomy is the definitive treatment of choice. The adrenal gland is removed with the local lymph nodes, followed by the measurement of catecholamines, in order to determine hormone levels. Lifelong hormonal replacement is indicated in the case of bilateral adrenalectomy.
Surgical treatment according to the stage
Unilateral total adrenalectomy is performed on localized tumors. Regional tumors are removed along with the other organs that the tumor has spread, which can include the kidneys, lymph nodes, a part of the liver, and blood vessels. Metastatic tumors are treated using palliative surgery to improve the quality of life in patients.
Other treatment options include tumor ablation, arterial embolization, radiation therapy, and chemotherapy. Targeted therapy using the tyrosine kinase inhibitor, sunitinib, is used for recurrent and metastatic pheochromocytomas. Familial pheochromocytoma is treated by partial removal of tumors from both glands to avoid total bilateral adrenalectomy and prevent lifelong hormonal replacement.
Follow-up includes the measurement of blood- and urine-catecholamine levels. A CT scan, MRI, and MIBG are necessary to exclude recurrent tumors and determine treatment plans.