Pheochromocytoma: Clinical Presentation and Management

Pheochromocytomas and paragangliomas (also called extra-adrenal pheochromocytomas) are neuroendocrine tumors.

Pheochromocytomas originate in the chromaffin cells of the adrenal medulla, and paragangliomas originate in the negative chromaffin cells of the neural crest . They can occur in the abdomen, thorax, head or neck. Together, they are known as pheochromocytoma and paraganglioma (FPGL). These tumors derive from sympathetic tissue located in the adrenal glands or external to them (extra-adrenal). These are the sympathetic FPGLs.

Tumors can also originate in parasympathetic tissue in the chest or head and neck, called parasympathetic FPGL. 80% of sympathetic FPGL originate in the adrenal glands and the other 20% in the pre- and paravertebral sympathetic ganglia of the thorax, abdomen, and pelvis. FPGL have an annual incidence of around 2 per million in the general population.

They are diagnosed in almost 10% of patients who present a tumor found incidentally in the adrenal gland. Approximately 10% of pheochromocytomas are malignant, as are 25% of paragangliomas.

While most FPGL are sporadic, there are more than 10 different associated genes, meaning that up to 40% of patients are related, and some of these are associated with syndromes, such as multiple endocrine neoplasia syndrome type 2A and 2B, von Hippel-Lindau disease and neurofibromatosis type 1.

The clinical presentation can be with the classic triad of headache, palpitations and sweating.

Hypertension is present in approximately 90% of cases, although in 45% it is paroxysmal. Patients may experience anxiety, nausea, weight loss, fatigue, visual disturbances, paresthesias, cardiomyopathy, and orthostatic hypotension.

Symptoms may be precipitated by pain, endoscopies, intubation, and anesthetic induction, which may raise diagnostic suspicion. About 10-15% of patients are asymptomatic, possibly due to receptor downregulation.

Half of pheochromocytomas are diagnosed incidentally on abdominal images taken for unrelated reasons. FPGL can present as hypertensive crises, with or without a history of sustained arterial hypertension. Severe cases may present as a medical emergency characterized by multiple organ failure, encephalopathy, hypertension, or hypotension. In addition to urgent intensive medical therapy, emergency tumor removal may be indicated.

The function of the adrenal medulla is the production of catecholamines . The initial step in catecholamine synthesis is the conversion of tyrosine to L-2,4-dihydroxyphenylalanine (DOPA), which is decarboxylated to dopamine. Dopamine is then hydroxylated to norepinephrine, which is subsequently converted to adrenaline, in the cytoplasm of chromaffin cells.

Catecholamines are removed from plasma by reuptake by neuronal cells, or by enzymatic breakdown, and then excreted by the kidney. Epinephrine is converted to metanephrine and norepinephrine to normetanephrine, by the action of the enzyme catecholmethyltransferase (COMT).

Metanephrine and normetanephrine are converted to vanillylmandelic acid by the action of the enzyme monoamine oxidase. Monoamine oxidase can also directly metabolize epinephrine or norepinephrine to dihydroxymandelic acid which is then converted to vanillylmandelic acid by COMT.

Pheochromocytoma and paraganglioma tumors secrete excess catecholamines and, therefore, the sympathetic nervous system is stimulated, causing symptoms such as hypertension and palpitations.

Within the sympathetic nerves, presynaptic vesicles are overloaded with catecholamines due to increased production, resulting in an increase in neuronal impulse frequency. Upon stimulation, neurons release excess norepinephrine due to selective desensitization of presynaptic α2 adrenergic receptors, resulting in an exaggerated response.

This dual mechanism explains how severe hypertension can arise from relatively small increases in circulating norepinephrine as well as the paroxysmal nature of hypertension, which is triggered by stressful stimuli such as pain, intubation, or surgery.

Increased circulating catecholamines cause persistent vasoconstriction, leading to increased afterload and myocardial work, which may result in hypertrophic cardiomyopathy or dilated cardiomyopathy.

However, there is evidence that these changes are reversible after tumor resection. Chronic vasoconstriction in patients with FPGL also leads to decreased vascular volume and significant fluid loss is not uncommon.

Diagnostic studies are warranted in patients who present with symptoms of the classic triad and in those who have a familial disorder associated with pheochromocytoma.

The initial studies are biochemical tests, with an increase in catecholamines, followed by radiological identification of the tumor location.

In 30% of cases, a single measurement of catecholamines in urine or serum is not enough to make the diagnosis of FPGL due to its intermittent release and rapid metabolization to metanephrine in the tumor, by the action of COMT.

Metanephrine, unlike catecholamines, is constantly released into the circulation. Therefore, it is recommended to measure urinary or plasma metanephrine and normetanephrine, and not the parent catecholamines.

There is greater sensitivity of blood tests if samples are obtained in the supine position, after the patient has rested in a quiet room for 20-30 minutes before obtaining the sample, after 8 hours of fasting and avoidance of caffeine, tobacco, alcohol and strenuous physical activity in the previous 24 hours.

Medications that affect catecholamine metabolism, such as tricyclic antidepressants or monoamine oxidase inhibitors, may cause a false positive result .

Serum metanephrine levels are measured by electrochemical detection methods or liquid chromatography with mass spectrometry; that may be affected by taking paracetamol in the previous 24 hours. Metanephrine levels that exceed 3 to 4 times the upper limit of normal are diagnostic of FPGL. The severity of the increase also indicates the urgency of the condition.

If diagnostic doubt remains (e.g., patients with features highly suggestive of FPGL but with an increase in metanephrine levels less than 3-4 times the upper limit), a clonidine suppression test may be useful. Clonidine, being a centrally acting α2 agonist, reduces neutron release of catecholamines, but does not affect catecholamine release from FPGL.

Plasma catecholamines are measured before and 3 hours after administration of 0.3 mg clonidine orally. The inability to decrease catecholamine levels by more than 50% of predose levels is strongly suggestive of FPGL.

When clinical and biochemical evidence is available, or the result of screening in those with a genetic predisposition to FPGL, the location of the tumor should be identified by radiological imaging.

Among the recommended images are computed tomography (CT) and magnetic resonance imaging (MRI) as they have a sensitivity of 95%. Contrast-enhanced CT is preferred as a first-line study due to better spatial resolution of images of the chest, abdomen, and pelvis.

T2-weighted MRI is recommended for the detection of metastatic FPGL, skull base and neck tumors, those with allergy to contrast substance, pregnant women, and children. Although very sensitive, CT and MRI lack the specificity necessary to accurately establish that the tumor found is an FPGL. In these cases, functional imaging with I131-metaiodobenzylguanidine] (MIGB) may be useful.

Functional imaging has a high sensitivity for detecting adrenal pheochromocytomas, but its sensitivity is low for detecting extra-adrenal PGLs and metastases. It allows evaluating the presence of multiple tumors or metastases.

When a lesion is confirmed by CT or MRI, tumor size, family history, syndromic presentation, and likelihood of metastatic disease determine the need for functional imaging.

Adrenal tumors <5 cm, secreting adrenaline or metanephrine, are likely to correspond to metastases and do not require functional imaging. Tumors >5 cm that secrete norepinephrine or normetanephrine, or those associated with familial syndrome, require functional imaging due to the increased likelihood of metastasis.

Medications such as opioids, labetalol or tricyclic antidepressants, can prevent the uptake of I123-MIBG at the tumor site leading to a negative result. false Due to the low sensitivity for extra-adrenal PGLs, 18F-FDG-PET scanning is recommended as it is the preferred functional imaging for patients with metastatic disease.

The definitive treatment for FPGL is partial surgical excision rather than total excision.

For small adrenal tumors, such as solitary pheochromocytomas <8 cm in diameter, laparoscopic surgery is preferable, as it has fewer thromboembolic complications and better postoperative analgesia requirements, as well as faster recovery compared to open surgery. This may be necessary for extra or invasive adrenal tumors, and to prevent rupture of large tumors. Surgery can be curative for limited metastatic tumors, or symptomatic in those with extensive metastatic disease and complications due to tumor size.

Other therapeutic options include radiation therapy, radiofrequency ablation, external beam radiation, and targeted chemotherapy. Molecular therapies are being investigated for the treatment of FPGL.

> Preoperative management

The best outcomes for patients with FPGL are achieved by better management through the participation of a multidisciplinary team with surgeons, anesthetists and endocrinologists. The main objectives of preoperative preparation are: control of blood pressure, restoration of intravascular volume and heart rate, control of arrhythmias, optimization of myocardial function, correction of glucose abnormalities and electrolytes.

Investigations should include routine blood tests (complete blood count, uremia, determination of electrolytes and estimated glomerular filtration rate). On the other hand, the immediate provision of cross-compatible blood must be guaranteed for transfusion if necessary.

Cardiac evaluation includes a 12-lead ECG and echocardiogram, to evaluate systolic, diastolic, and valve function. Cardiac catheterization may be indicated before tumor removal, particularly in patients with angina and previous ECG changes, myocardial infarction, or congestive heart failure. To adequately optimize the patient for surgery, the Roizen criteria are used:

• Blood pressure <160/80 mmHg.
   
• Orthostatic hypotension; at least 15% drop in blood pressure but with a systolic pressure of no less than 80 mmHg.
   
• No more than 5 ventricular ectopic beats in 1 minute.
   
• No new ST or T changes on ECG during the past week.

Current recommendations point to a target blood pressure <130/85 mmHg in the sitting position and a systolic pressure of no less than 90 mmHg systolic in the standing position; there does not necessarily have to be orthostatic hypotension.

> α-adrenergic receptor blockers

Blood pressure control is achieved with antihypertensive medications, with α-blockers being the initial drugs of choice. α-Blockers are usually started 10-14 days before surgery and have been shown to reduce the incidence and severity of hemodynamic instability, intraoperative blood loss, and arrhythmias.

The most used is phenoxybenzamine , at a dose of 10 mg, 2/day. It is preferred due to its prolonged action and non-competitive antagonism that can reduce the effects of increased catecholamines. It is recommended to discontinue phenoxybenzamine 24-48 hours before surgery, as its prolonged half-life may lead to postoperative hypotension. It also blocks presynaptic α2-adrenergic receptors, which reduces the negative feedback caused by the release of norepinephrine, causing an increase in norepinephrine available at β1-adrenergic receptors causing tachycardia.

Recently, shorter-acting α1 blockers , such as doxazosin, have been used when the severity of the patient’s hypertension is not severe enough to justify the use of a long-acting α-adrenergic blocker. Due to its more selective nature, it does not cause tachycardia and has been shown to reduce the incidence of postoperative hypotension.

> Calcium channel blockers

They are indicated when blood pressure control is not achieved with α- and β-adrenergic blockers, or in patients who cannot tolerate α-blockers due to side effects such as orthostatic hypotension. They are also used as first-line drugs in patients who have normotension or mild hypertension. Evidence suggests that used alone they are as effective in preventing intraoperative instability as α-blockers, although they are not as effective in preventing episodes of intraoperative hypertension.

> Metyrosine

Metyrosine, a competitive inhibitor of tyrosine hydroxylase, inhibits catecholamine synthesis, thereby depleting adrenal catecholamine stores. Compared with normal adrenal tissue, FPGLs have significantly higher tyrosine hydroxylase activity. It is usually given for a short period along with α-blockers to improve blood pressure and volume loss. Its use is reserved for patients who do not tolerate or do not respond to α blockers or calcium channel blockers. Its main side effects are sedation, depression and anxiety.

> ß-adrenergic receptor blockers

These blockers are used to control preoperative arrhythmias or tachycardia induced by excess catecholamines or secondary to the action of α-blockers. β-blockers should only be initiated after α-blockers have been established, as β2-mediated vasodilation is inhibited, which can cause dangerous increases in blood pressure. For this reason, selective β1 antagonists such as atenolol or metoprolol are preferred. Labetalol should be avoided as it may result in paradoxical hypertension due to its greater affinity for β-adrenergic receptors. 

> Volume Resuscitation

Hyperglycemia may occur due to increased glycogenolysis (α1), impaired insulin release (α2), and insulin resistance (ß2).

Intra- and postoperative blood glucose levels should be monitored for at least 24 hours after surgery and the necessary treatment should be provided immediately.

Chronic vasoconstriction often causes patients with FPGL to develop hypovolemia, which can be effectively corrected with the administration of an oral electrolyte solution with high sodium content in the diet, in addition to the α-blocker. This management may improve the impact of orthostatic hypotension preoperatively and reduce the incidence and severity of postoperative hypotension.

Alternatively, patients may also be admitted the day before surgery for intravenous fluid supplementation. Despite recent evidence suggesting that α-blockers and fluid resuscitation do not reliably improve intraoperative hemodynamic stability, both practices are still recommended.

> Supervision

There is no clear evidence of the superiority of one anesthetic technique over another. However, it should be considered to avoid excessive release of catecholamines, through maneuvers or anesthetic drugs. Hemodynamic responses to tumor manipulation and episodes of hypotension after tumor devascularization should be minimized.

Due to the high risk of intraoperative hemodynamic instability , placement of an intra-arterial catheter prior to induction of general anesthesia, followed by provision of venous access along with monitoring following local guidelines for anesthetic monitoring, is strongly recommended. 

Urinary catheterization may be useful to evaluate renal perfusion and guide fluid therapy. Non-invasive monitoring of cardiac output may be a useful adjunct to the management of fluid therapy, both in the intraoperative and postoperative periods, although there is no evidence to support its use.

Intraoperative temperature and normothermia must be monitored to keep it preserved, following anesthesiological criteria (body and fluid warmers).

Intravenous access must be large caliber. Fluid infusers should be inserted and warmed quickly and be immediately available in case of massive bleeding.

> Drugs

Propofol, thiopentone or etomidate can be used for anesthetic induction. Ketamine should be avoided due to its sympathomimetic effect. Benzodiazepines may be useful as premedication to decrease anxiety-related catecholamine release. Pancuronium and atracurium are generally avoided as they are associated with the release of catecholamines and histamine.

Suxamethonium can cause hypertension and arrhythmias, due to the elevation of intra-abdominal pressure and compression of the gland during fasciculation, as well as direct stimulation of the autonomic ganglia. Cisatracurium, rocuronium, and vecuronium are considered the safest muscle relaxants.

Halothane should be avoided due to its arrhythmogenic potential.

Desflurane is also generally avoided because of its potential sympathetic stimulant action. There is no contraindication to the use of nitrous oxide. Sevoflurane and isoflurane are the safest most commonly used volatile agents.

> Analgesia

With respect to opioids, drugs that may be associated with histamine release, such as morphine, should be administered slowly or avoided. Pethidine should be avoided due to its sympathomimetic effect. Fentanyl can be safely used as boluses or as an infusion. Central neuraxial blocks can be safely instituted and may be useful in conjunction with general anesthesia, although they will not attenuate the effect of catecholamine surges resulting from tumor manipulation.

> Antiemetics

Metoclopramide and droperidol should be avoided as they may precipitate a hypertensive crisis through blocking effects on presynaptic dopamine receptors.

> Management of hypertension and hemodynamic storms

Intraoperative hemodynamic instability has been shown to be an independent factor of postoperative morbidity. The anesthetic team must be vigilant, maintaining adequate depth of anesthesia and muscle relaxation during the use of vasoactive substances to minimize blood pressure oscillations.

Intraoperative hemodynamic instability is more likely with higher preoperative norepinephrine levels, large tumors, and mean arterial pressure >100 mmHg before induction. Surgical manipulation of the tumor and insufflation of the pneumoperitoneum are almost always associated with uncontrolled release of catecholamines into the circulation, resulting in hypertensive crises, regardless of preoperative optimization of blood pressure.

The surgical team must manipulate the tumor very carefully while minimizing intra-abdominal pressures when possible. To achieve the best result, clear and open communication between both teams is essential.

Ephedrine has indirect α- and β-adrenergic actions and may cause exaggerated release of catecholamines from the tumor and should be avoided before it is resected. Intraoperative use of magnesium sulfate and a higher preoperative dose of β-blockers appear to be protective factors against intraoperative hemodynamic instability.

Magnesium sulfate has been shown to prevent hemodynamic instability, inhibit the release of adrenal catecholamines, reduce the sensitivity of α-adrenergic receptors to catecholamines, have antiarrhythmic effects, and cause arteriolar vasodilation, reducing afterload. A loading dose of 40-60 mg/kg is administered before intubation, followed by a maintenance infusion of 2 g/hour. A 20 mg/kg bolus can be used to maintain blood pressure within 30 mmHg of baseline.

Remifentanil may be useful in reducing hemodynamic oscillations, as occurs during induction and intubation. However, it is not effective in controlling oscillations secondary to manipulation of large tumors, in which case fentanyl may be more beneficial.

Dexmedetomidine is an α2 agonist, which acts selectively on presynaptic α2-adrenergic receptors, reducing the release of norepinephrine . It also reduces average arterial pressure and heart rate, due to its analgesic properties.

Dexmedetomidine has been used for the treatment of hemodynamic oscillations that occur in FPGL, where it is usually administered as a loading dose of 1 ug/kg followed by a maintenance dose by infusion of 0.2-0. 7 mg/kg/hour.

Several direct-acting vasodilators , used to treat intraoperative hypertension, such as phentolamine (a short-acting α-blocker), sodium nitroprusside, and glyceryl trinitrate, have been tested safely .

The intravenous calcium channel blocker nicardipine has also been used ; but it cannot be titled as quickly as the other agents. Likewise, the ultrashort-acting intravenous calcium channel blocker clevidipine can be used to control hypertensive crises in FPGL. It is metabolized by plasma esterases and rapidly cleared, resulting in minimal accumulation without pharmacokinetic alterations, even when infused for several hours.

Short-acting β-blockers (such as esmolol), magnesium, and intravenous lidocaine have been used successfully to control tachyarrhythmias in FPGL.

Periods of hypotension are quite common and may be due to the action of anesthetic and therapeutic drugs used for hypertensive episodes. After tumor ligation, the release of catecholamines into the systemic circulation ceases. This sudden catecholamine deficiency and downregulation of catecholamine receptors after chronic catecholamine elevation can lead to hypotension.

The severity of hypotension is strongly related to the amount of catecholamines newly secreted by the resected tumor. These episodes can be treated with fluid boluses, discontinuation of vasodilators, and administration of vasopressors.

Vasopressin is particularly useful for the treatment of hypotension after tumor resection. It acts on vasopressin 2 receptors, increasing water reabsorption within the renal tubules, and on vasopressin 1 receptors in vascular smooth muscle, causing vasoconstriction.

Vasopressin is believed to be safer than catecholamine infusion as it prevents vasoconstriction within the pulmonary, coronary, and cerebral vessels. On the other hand, it does not depend on adrenergic receptors, so it is particularly useful after a resection of the FPGL. Methylene blue has also been used for the management of catecholamine-resistant shock.

The postoperative period should take place in a high dependency unit, for at least 24 hours, to monitor complications such as hypotension or hypertension, arrhythmias, hemorrhage and hypoglycemia.

Postoperative hypertension can be the result of pain, preexisting hypertension, or even incomplete tumor resection or accidental ligation of the renal artery. About 25% of patients remain hypertensive after surgery.

Addison’s crisis is a known complication, especially in patients who underwent partial or complete bilateral adrenalectomy. The combination of hypotension and hypoglycemia warrants urgent investigations, such as measurement of plasma and urinary cortisol and plasma ACTH levels, in addition to instituting replacement steroid treatment, if necessary.

Patients with FPGL require follow-up after hospital discharge, with biochemical testing to confirm that the resection was complete and successful. It is usually done within 6 weeks of surgery. The reported recurrence rate is around 17%, so it is recommended that patients with FPGL remain under lifelong follow-up.