Pheochromocytoma 

Updated: Aug 10, 2018
Author: Michael A Blake, MBBCh, MRCPI, FRCR; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

A pheochromocytoma (see the image below) is a rare, catecholamine-secreting tumor that may precipitate life-threatening hypertension. The tumor is malignant in 10% of cases but may be cured completely by surgical removal. Although pheochromocytoma has classically been associated with 3 syndromes—von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN 2), and neurofibromatosis type 1 (NF1)—there are now 10 genes that have been identified as sites of mutations leading to pheochromocytoma.

Axial, T2-weighted magnetic resonance imaging (MRI Axial, T2-weighted magnetic resonance imaging (MRI) scan showing large left suprarenal mass of high signal intensity on a T2-weighted image. The mass is a pheochromocytoma.

Signs and symptoms

Classically, pheochromocytoma manifests as spells with the following 4 characteristics:

  • Headaches
  • Palpitations
  • Diaphoresis
  • Severe hypertension

Typical patterns of the spells are as follows:

  • Frequency may vary from monthly to several times per day
  • Duration may vary from seconds to hours
  • Over time, spells tend to occur more frequently and become more severe as the tumor grows

The following may also occur during spells:

  • Tremor
  • Nausea
  • Weakness
  • Anxiety, sense of doom
  • Epigastric pain
  • Flank pain
  • Constipation

Clinical signs associated with pheochromocytomas include the following:

  • Hypertension: Paroxysmal in 50% of cases
  • Postural hypotension: From volume contraction
  • Hypertensive retinopathy
  • Weight loss
  • Pallor
  • Fever
  • Tremor
  • Neurofibromas
  • Tachyarrhythmias
  • Pulmonary edema
  • Cardiomyopathy
  • Ileus
  • Café au lait spots

See Clinical Presentation for more detail.

Diagnosis

Diagnostic tests for pheochromocytoma include the following:

  • Plasma metanephrine testing: 96% sensitivity, 85% specificity [1]
  • 24-hour urinary collection for catecholamines and metanephrines: 87.5% sensitivity, 99.7% specificity [2]

Test selection criteria include the following:

  • Use plasma metanephrine testing in patients at high risk (ie, those with predisposing genetic syndromes or a family or personal history of pheochromocytoma)
  • Use 24-hour urinary collection for catecholamines and metanephrines in patients at lower risk

Imaging studies should be performed only after biochemical studies have confirmed the diagnosis of pheochromocytoma. Studies are as follows:

  • Abdominal CT scanning: Has accuracy of 85-95% for detecting adrenal masses with a spatial resolution of 1 cm or greater
  • MRI: Preferred over CT scanning in children and pregnant or lactating women; has reported sensitivity of up to 100% in detecting adrenal pheochromocytomas
  • Scintigraphy: Reserved for biochemically confirmed cases in which CT scanning or MRI does not show a tumor
  • PET scanning: A promising technique for detection and localization of pheochromocytomas

Additional studies to rule out a familial syndrome in patients with confirmed pheochromocytoma include the following:

  • Serum intact parathyroid hormone level and a simultaneous serum calcium level to rule out primary hyperparathyroidism (which occurs in MEN 2A)
  • Screening for mutations in the ret proto-oncogene (which give rise to MEN 2A and 2B) [3]
  • Genetic testing for mutations causing the MEN 2A and 2B syndromes
  • Consultation with an ophthalmologist to rule out retinal angiomas (VHL disease)

See Workup for more detail.

Management

Surgical resection of the tumor is the treatment of choice and usually cures the hypertension. Careful preoperative treatment with alpha and beta blockers is required to control blood pressure and prevent intraoperative hypertensive crises.[4]

Preoperative medical stabilization is provided as follows:

  • Start alpha blockade with phenoxybenzamine 7-10 days preoperatively
  • Provide volume expansion with isotonic sodium chloride solution
  • Encourage liberal salt intake
  • Initiate a beta blocker only after adequate alpha blockade, to avoid precipitating a hypertensive crisis from unopposed alpha stimulation
  • Administer the last doses of oral alpha and beta blockers on the morning of surgery

See Treatment and Medication for more detail.

Background

A pheochromocytoma is a rare, catecholamine-secreting tumor derived from chromaffin cells. The term pheochromocytoma (in Greek, phios means dusky, chroma means color, and cytoma means tumor) refers to the color the tumor cells acquire when stained with chromium salts.

About 30% of pheochromocytomas occur as part of hereditary syndromes. Although pheochromocytoma has classically been associated with 3 syndromes—von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN 2), and neurofibromatosis type 1 (NF1)—there are now 10 genes that have been identified as sites of mutations leading to pheochromocytoma. These different genes produce tumors with different ages of onset, secretory profiles, locations, and potential for malignancy.[5]

Because of excessive catecholamine secretion, pheochromocytomas may precipitate life-threatening hypertension or cardiac arrhythmias. [6] If the diagnosis of a pheochromocytoma is overlooked, the consequences can be disastrous, even fatal; however, if a pheochromocytoma is found, it is potentially curable. (See Pathophysiology, Prognosis, and Treatment.)[1]

About 85% of pheochromocytomas are located within the adrenal glands, and 98% are within the abdomen. When such tumors arise outside of the adrenal gland, they are termed extra-adrenal pheochromocytomas, or paragangliomas.

Extra-adrenal pheochromocytomas develop in the paraganglion chromaffin tissue of the nervous system. They may occur anywhere from the base of the brain to the urinary bladder. Common locations for extra-adrenal pheochromocytomas include the organ of Zuckerkandl (close to the origin of the inferior mesenteric artery), bladder wall, heart, mediastinum, and carotid and glomus jugulare bodies. (See Workup.)

Malignancy

Approximately 10% of pheochromocytomas and 35% of extra-adrenal pheochromocytomas are malignant. Only the presence of metastases defines malignancy. However, specific histologic features help to differentiate adrenal pheochromocytomas with a potential for biologically aggressive behavior from those that behave in a benign fashion. Among the features that suggest a malignant course are large tumor size and an abnormal DNA ploidy pattern (aneuploidy, tetraploidy).[6]  Common metastatic sites include bone, liver, and lymph nodes.

Diagnosis

Pheochromocytoma is diagnosed by measuring elevated levels of metanephrines (catecholamine metabolites) in blood or urine. CT scanning or MRI is the preferred technique for localizing pheochromocytomas (see the image below). Surgical resection of the tumor is the treatment of choice and usually cures the hypertension (see Workup and Treatment).

Axial, T2-weighted magnetic resonance imaging (MRI Axial, T2-weighted magnetic resonance imaging (MRI) scan showing large left suprarenal mass of high signal intensity on a T2-weighted image. The mass is a pheochromocytoma.

For discussion of pheochromocytoma in children, see the Medscape Reference article Pediatric Pheochromocytoma.[7] For patient education information, see High Blood Pressure.

Pathophysiology

The clinical manifestations of a pheochromocytoma result from excessive catecholamine secretion by the tumor. Secretion may occur either intermittently or continuously. Catecholamines typically secreted are norepinephrine and epinephrine; some tumors produce dopamine.[8]

The biologic effects of catecholamines are well known. Stimulation of alpha-adrenergic receptors results in elevated blood pressure, increased cardiac contractility, glycogenolysis, gluconeogenesis, and intestinal relaxation. Stimulation of beta-adrenergic receptors results in an increase in heart rate and contractility.[4]

Catecholamine secretion in pheochromocytomas is not regulated in the same manner as in healthy adrenal tissue. Unlike the healthy adrenal medulla, pheochromocytomas are not innervated, and catecholamine release is not precipitated by neural stimulation. The trigger for catecholamine release is unclear, but multiple mechanisms have been postulated, including direct pressure, medications, and changes in tumor blood flow.

Relative catecholamine levels also differ in pheochromocytomas. Most pheochromocytomas secrete norepinephrine predominantly, whereas secretions from the normal adrenal medulla are roughly 85% epinephrine.

In a study using cardiac magnetic resonance imaging, Ferreira et al found that patients with pheochromocytoma who underwent curative surgery nonetheless continued to demonstrate systolic and diastolic strain, focal fibrosis, and T1 abnormalities, with the last possibly indicating the presence of diffuse fibrosis. According to the investigators, the study’s results suggest more than just hypertensive heart disease at work and that catecholamine toxicity in pheochromocytoma may be responsible for long-lasting myocardial changes.[9]

In hereditary forms of pheochromocytoma, the secretory profiles vary according to the underlying syndrome. Eisenhofer et al found that pheochromocytomas associated with VHL typically produce norepinephrine only, while those associated with MEN 2 and NF1 typically produce both epinephrine and norepinephrine. Tumors in patients with germline mutations of succinate dehydrogenase subunit genes (SDHB and SDHD), which cause familial paraganglioma, principally produce dopamine.[10]

Precipitants of hypertensive crisis

Precipitants of a hypertensive crisis include the following:

  • Anesthesia induction
  • Opiates
  • Dopamine antagonists: Eg, metoclopramide [11]
  • Cold medications
  • Beta blockers [11]
  • Drugs that inhibit catecholamine reuptake: Eg, tricyclic antidepressants and cocaine
  • Childbirth

Etiology

Although the majority of pheochromocytomas are sporadic, approximately 30% result from inherited mutations. To date, 10 genes associated with pheochromocytoma and paraganglioma have been identified.[5]  Familial syndromes associated with pheochromocytomas include MEN 2A and 2B, neurofibromatosis (von Recklinghausen disease), and VHL disease, as well as others.

MEN 2

The MEN 2A and 2B syndromes have been traced to germline mutations in the ret proto-oncogene on chromosome 10, which encodes a tyrosine kinase receptor involved in the regulation of cell growth and differentiation. Pheochromocytomas occur bilaterally in the MEN syndromes in as many as 70% of cases.

MEN 2A

MEN 2A (Sipple syndrome) is characterized by the following:

  • Medullary thyroid carcinoma
  • Parathyroid adenoma
  • Pheochromocytomas
  • Hirschsprung disease.

Over 95% of cases of MEN 2A are associated with mutations in the ret proto-oncogene affecting 1 of 5 codons, located in exon 10 (codons 609, 611, 618, 620) and exon 11 (codon 634).

Clinical diagnosis of MEN 2A requires the occurrence of 2 or more endocrine tumors in one individual or in close relatives. The risk for medullary thyroid carcinoma is 95%, the risk for pheochromocytoma is 50%, and the risk for parathyroid disease is between 20% and 30%.[12]

MEN 2B

MEN 2B is characterized by the following:

  • Medullary thyroid carcinoma
  • Pheochromocytoma
  • Mucosal neurofibromatosis
  • Intestinal ganglioneuromatosis
  • Hirschsprung disease
  • Marfanoid body habitus

Patients with MEN 2B may also have ganglioneuromatosis of the gastrointestinal (GI) tract, which can cause functional GI problems. A germline missense mutation in the tyrosine kinase domain of the ret proto-oncogene (exon 16, codon 918) has been reported to be present in 95% of patients with MEN 2B.

Clinical diagnosis of MEN 2B is based on the presence of mucosal neuromas of the oral mucosa, enlarged lips with characteristic facial appearance, and marfanoid habitus. Medullary thyroid carcinoma is virtually assured with MEN 2B, and the risk of pheochromocytoma is 50%. Parathyroid disease is uncommon with MEN 2B.[12]  Persons diagnosed with MEN 2B should have a prophylactic thyroidectomy in infancy because of the early and aggressive nature of associated medullary thyroid carcinoma.

Other mutational etiologies

Novel mutations that cause hereditary pheochromocytoma have been identified in the MYC-associated factor X (MAX) gene. Loss of MAX function is correlated with metastatic potential.[13]  Burnichon et al concluded that germline mutations in MAX are responsible for approximately 1% of pheochromocytomas and paragangliomas in patients without evidence of other known mutations.[14]

A number of other genes, such as the GDNF gene, are associated with development of adrenal or extra-adrenal pheochromocytomas. The GDNF gene is also associated with central hypoventilation syndrome and susceptibility to Hirschsprung disease.

The TMEM127 gene also is associated with susceptibility to pheochromocytoma. Several families have been described with unique mutations to this gene that have resulted in the development of pheochromocytoma between young adulthood and middle age. All of these are inherited in an autosomal dominant fashion with incomplete penetrance.

VHL disease

VHL disease is associated with the following:

  • Pheochromocytoma
  • Cerebellar hemangioblastoma
  • Renal cell carcinoma
  • Renal and pancreatic cysts
  • Epididymal cystadenomas

One study found that this syndrome was present in nearly 19% of patients with pheochromocytomas.[15]

VHL disease is caused by mutations in the VHL gene.[16]  This gene encodes a protein that plays a role in cilia formation, regulation of cellular senescence, and the oxygen-sensing pathway.

Neurofibromatosis and other diseases

Neurofibromatosis, or von Recklinghausen disease, is characterized by congenital anomalies (often benign tumors) of the skin, nervous system, bones, and endocrine glands. Only 1% of patients with neurofibromatosis have been found to have pheochromocytomas, but as many as 5% of patients with pheochromocytomas have been found to have neurofibromatosis.

Other neuroectodermal disorders associated with pheochromocytomas include tuberous sclerosis (Bourneville disease, epiloia) and Sturge-Weber syndrome.

Pheochromocytomas may produce calcitonin, opioid peptides, somatostatin, corticotropin, and vasoactive intestinal peptide. Corticotropin hypersecretion has caused Cushing syndrome, and vasoactive intestinal peptide overproduction causes watery diarrhea.

Succinate dehydrogenase complex

The succinate dehydrogenase complex subunit D protein is encoded by the SDHD gene, mutations in which cause pheochromocytomas, paragangliomas, and other tumors. In most tumors, inheritance of the mutation is autosomal dominant with biallelic expression of the SDHD gene. However, paternal imprinting appears to be the inheritance pattern in paragangliomas and, in particular, carotid body tumors resulting from the SDHD gene.

The succinate dehydrogenase complex subunit B protein is encoded by the SDHB gene. Mutations in this gene are known to cause carotid body tumors and paragangliomas and are inherited in an autosomal dominant fashion. Paragangliomas caused by SDHB mutations have a higher rate of malignant transformation that those that are not.

The succinate dehydrogenase subunit C protein is encoded by the SDHC gene, and mutations are known to cause paraganglioma. One family with a mutation in this gene showed maternal inheritance of the condition,[17] but subsequent investigation has suggested an autosomal dominant inheritance pattern without evidence of imprinting.

Other succinate dehydrogenase subunit genes with mutations linked to paraganglioma include SDHA[18] and the newly characterized succinate dehydrogenase complex assembly factor 2 (SDHAF2) gene.[19]  Kunst et al found phenotypic expression of the SDHAF2 mutation only with paternal inheritance, which suggests imprinting of the gene.[19]

Hemihyperplasia

Although its genetics remain incompletely understood, hemihyperplasia (also called hemihypertrophy) is known to increase tumor risk. The condition may be an isolated finding or a part of a larger syndrome such as Beckwith-Wiedemann syndrome, Proteus syndrome, or neurofibromatosis. The tumors most commonly associated with hemihyperplasia are Wilms tumor and hepatoblastoma, but at least one patient has been described with isolated hemihyperplasia and an adrenal pheochromocytoma on the hyperplastic side.[20]

Hemihyperplasia can be caused by paternal uniparental disomy for the 11p15 chromosomal region, as can be seen in isolated hemihyperplasia and Beckwith-Wiedemann syndrome. Methylation of the LIT1 and H19 genes is important to the pathogenesis of hemihyperplasia and underscores the importance of epigenetics in normal growth and in the development of neoplasia.

Epidemiology

Pheochromocytomas are rare, reportedly occurring in 0.05–0.2% of hypertensive individuals. This accounts for only a portion of cases, however, as patients may be completely asymptomatic. A retrospective study from the Mayo Clinic revealed that in 50% of cases of pheochromocytoma, the diagnosis was made at autopsy.[21]  Approximately 10% of pheochromocytomas are discovered incidentally.[22]

A Dutch study, by Berends et al, found an increase in the age-standardized incidence rate (ASR) of pheochromocytomas and sympathetic paragangliomas in the Netherlands between 1995 and 2015. The investigators reported that the ASR between 1995 and 1999 was 0.29 per 100,000 person-years, compared with 0.46 per 100,000 person-years between 2011 and 2015. The ASRs for sympathetic paragangliomas rose between these same two periods from 0.08 to 0.11 per 100,000 person-years. There was also a trend during this 20-year period towards patients being older and tumor size smaller at diagnosis. The investigators suggested that clinical practice changes, along with greater use of imaging and biochemical studies, were at least partially responsible for the incidence increases.[23]

Race- and age-related demographics

Pheochromocytomas occur in people of all races, although they are diagnosed less frequently in blacks. Pheochromocytomas may occur in persons of any age, but the peak incidence is from the third to the fifth decades of life. Approximately 10% occur in children. Fifty percent of pheochromocytomas in children are solitary intra-adrenal lesions, 25% are present bilaterally, and 25% are extra-adrenal.

Prognosis

The 5-year survival rate for people with nonmalignant pheochromocytomas is greater than 95%. In patients with malignant pheochromocytomas, the 5-year survival rate is less than 50%.[24] Although pheochromocytomas are rare, making the diagnosis is critical because the malignancy rate is 10%, pheochromocytomas may be associated with a familial syndrome, they may precipitate life-threatening hypertension, and the patient may be cured completely with their removal.

A retrospective study by Dhir et al suggested that among patients with pheochromocytoma or paraganglioma, the likelihood of malignancy is greater in persons who are younger, have a larger-sized tumor, or specifically have paraganglioma, as well as in those patients with germline SDHB mutations. Among the patients studied, those with malignancy had a median age of 42 years, versus 50 years for patients without malignancy; the median size of malignant versus nonmalignant tumors was 6.5 cm versus 4 cm, respectively.[25]

Many cardiac manifestations are associated with pheochromocytomas.[26] Hypertension is the most common complication. Cardiac arrhythmias, such as atrial and ventricular fibrillation, may occur because of excessive plasma catecholamine levels. Other complications include the following:

  • Myocarditis
  • Signs and symptoms of myocardial infarction [27]
  • Dilated cardiomyopathy
  • Pulmonary edema: Either of cardiac or noncardiac origin

A pheochromocytoma-induced hypertensive crisis may precipitate hypertensive encephalopathy, which is characterized by altered mental status, focal neurologic signs and symptoms, or seizures. Other neurologic complications include stroke from cerebral infarction or an embolic event secondary to a mural thrombus from dilated cardiomyopathy. Intracerebral hemorrhage also may occur, because of uncontrolled hypertension.

Pheochromocytoma during pregnancy is extremely rare (0.002% of all pregnancies),[28]  but undiagnosed pheochromocytoma that occurs during pregnancy carries a grave prognosis, with maternal and fetal mortality rates of 48% and 55%, respectively. However, maternal mortality is virtually eliminated and the fetal mortality rate is reduced to 15% if the diagnosis is made antenatally.

 

Presentation

History

Symptoms and signs of pheochromocytoma include the following:

  • Headache
  • Diaphoresis
  • Palpitations
  • Tremor
  • Nausea
  • Weakness
  • Pallor
  • Anxiety, sense of doom
  • Epigastric pain
  • Flank pain
  • Constipation
  • Weight loss

The classic history of a patient with a pheochromocytoma includes spells characterized by headaches, palpitations, and diaphoresis in association with severe hypertension. These 4 characteristics together are strongly suggestive of a pheochromocytoma. In the absence of these 3 symptoms and hypertension, the diagnosis may be excluded.

The spells may vary in occurrence from monthly to several times per day, and the duration may vary from seconds to hours. Typically, they worsen with time, occurring more frequently and becoming more severe as the tumor grows.

Pheochromocytomas occur in certain familial syndromes. These include multiple endocrine neoplasia (MEN) types 2A and 2B, neurofibromatosis (von Recklinghausen disease), and von Hippel-Lindau (VHL) disease, as well as others (see Etiology). In general, these hereditary cancer syndromes are inherited in an autosomal dominant manner.

Physical Examination

Clinical signs associated with pheochromocytomas include the following:

  • Hypertension: Paroxysmal in 50% of cases
  • Postural hypotension (from volume contraction)
  • Hypertensive retinopathy
  • Weight loss
  • Pallor
  • Fever
  • Tremor
  • Tachyarrhythmias [29]
  • Pulmonary edema
  • Cardiomyopathy
  • Diabetes mellitus [30]
  • Ileus

Sinus tachycardia (presenting as palpitations) is the most common cardiac rhythm abnormality in patients with pheochromocytoma, but more serious ventricular arrhythmias or conduction disturbances may also occur. Other cardiac manifestations include reversible dilated or hypertrophic cardiomyopathy; Takotsubo cardiomyopathy has gained increasing recognition.[29, 31]

When pheochromocytoma occurs as part of a hereditary syndrome, other manifestations of the syndrome may be noted. In patients with neurofibromatosis, these include neurofibromas and café au lait spots. The latter are patches of cutaneous pigmentation that vary from 1-10 mm and can occur any place on the body; characteristic locations include the axillae and intertriginous areas (groin). The name café au lait refers to the color of the lesions, which varies from light to dark brown.

 

DDx

Diagnostic Considerations

Differentials to consider in the diagnosis of pheochromocytoma include the following:

  • Alcohol withdrawal
  • Labile essential hypertension
  • Hyperventilation
  • Orthostatic hypotension
  • Multiple pharmacologic agents: Monoamine oxidase inhibitors (MAOIs), decongestants, and sympathomimetics
  • Illegal drug use: Eg, phencyclidine (PCP), lysergic acid diethylamide (LSD), and cocaine
  • Migraine headache
  • Autonomic neuropathy (baroreflex failure)
  • Stroke
  • Toxemia of pregnancy
  • Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome
  • Acute intermittent porphyria
  • Cardiogenic pulmonary edema
  • Renovascular hypertension
  • Subarachnoid hemorrhage
  • Lead toxicity

Differential Diagnoses

 

Workup

Approach Considerations

The Endocrine Society, the American Association for Clinical Chemistry, and the European Society of Endocrinology have released clinical practice guidelines for the diagnosis and management of pheochromocytoma and paraganglioma (jointly referred to as PPGL).[32, 33]

  • Biochemical testing via measurement of plasma free metanephrines [34] or urinary fractionated metanephrines should be performed in patients suspected of having PPGL.
  • Patients with a known germ-line mutation that predisposes to PPGL should undergo periodic biochemical testing.
  • Computed tomography (CT), rather than magnetic resonance imaging (MRI), is recommended as the first-line imaging technique.
  • Blood pressure, heart rate, and glucose levels should be monitored immediately after surgery.
  • Patients with PPGLs should participate in shared decision-making for genetic testing.

Catecholamines produced by pheochromocytomas are metabolized within chromaffin cells. Norepinephrine is metabolized to normetanephrine and epinephrine is metabolized to metanephrine. Because this process occurs within the tumor, independently of catecholamine release, pheochromocytomas are best diagnosed by measurement of these metabolites rather than by measurement of the parent catecholamines.[35]

Guidelines from the North American NeuroEndocrine Tumor Society (NANETS) recommend biochemical testing for pheochromocytoma in the following cases[35] :

  • Symptomatic patients
  • Patients with an adrenal incidentaloma
  • Patients who have a hereditary risk for developing a pheochromocytoma or paraganglioma (extra-adrenal pheochromocytoma)

The choice of diagnostic test should be based on the clinical suspicion of a pheochromocytoma. Plasma metanephrine testing has the highest sensitivity (96%) for detecting a pheochromocytoma, but it has a lower specificity (85%).[36]  In comparison, a 24-hour urinary collection for catecholamines and metanephrines has a sensitivity of 87.5% and a specificity of 99.7%.[37]

General laboratory features of pheochromocytoma include the following:

  • Hyperglycemia
  • Hypercalcemia
  • Erythrocytosis

Imaging studies should be performed only after biochemical studies have confirmed the diagnosis of pheochromocytoma. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) can be used for detection of the disorder. Scintigraphy may be used when these techniques fail to localize the tumor. Positron emission tomography (PET) scanning has shown promising results as an imaging modality for pheochromocytoma.

Metanephrine and Catecholamine Testing

High-risk patients, including those who have a genetic syndrome that predisposes them to pheochromocytoma (eg, multiple endocrine neoplasia [MEN] types 2A or 2B, von Hippel-Lindau [VHL] disease, neurofibromatosis, a prior history of a pheochromocytoma, a family history of a pheochromocytoma), should be screened with plasma metanephrine testing. In these scenarios, a higher-sensitivity test that lacks specificity is justified.[38]

A fractionated plasma free metanephrine level may be measured in a standard venipuncture sample, drawn about 15-20 minutes after intravenous catheter insertion. Positioning of the patient for the venipuncture is controversial. Although some experts advocate having the patient seated, NANETS guidelines recommend drawing the sample with the patient in a supine position, as tests in seated patients have a higher false-positive rate.[35]

Perform a 24-hour urine collection for creatinine, total catecholamines, vanillylmandelic acid, and metanephrines. Measure creatinine in all collections of urine to ensure adequacy of the collection. The collection container should be dark and acidified and should be kept cold to avoid degradation of the catecholamines. Optimally, collect urine during or immediately after a crisis.

Some authors have reported good experience with evaluating epinephrine and norepinephrine separately (in part to confirm the total catecholamine level and in part to determine whether levels reflect the high norepinephrine-to-epinephrine ratio expected). Separate measurement of metanephrine and normetanephrine, to confirm the total metanephrine level and the normetanephrine-to-metanephrine ratio, has also proved useful.

Although dopamine is a major catecholamine, measurement of dopamine levels in 24-hour urine is not useful, because most urinary dopamine is derived from renal extraction.

Factors affecting test results

Major physical stress may interfere with the assay and cause false elevations of metanephrines and normetanephrines. Ethanol and multiple prescription drugs, including the following, may also cause such results:

  • Tricyclic antidepressants
  • Phenoxybenzamine
  • Levodopa
  • Beta blockers [39]
  • Labetalol
  • Amphetamines
  • Buspirone
  • Methyldopa
  • Chlorpromazine

Other compounds decrease 24-hour urine levels of metanephrines. These include methyltyrosine, which inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, and methylglucamine, which is present in radiocontrast media.

Additional Laboratory Tests

Provocative testing was used in the past to confirm or exclude pheochromocytoma. However, such testing can cause dangerous hypertensive episodes. In addition provocative testing with glucagon has been shown to have less than 50% sensitivity.[40]

Suppression tests using phentolamine and clonidine can also be used for diagnostic purposes. NANETS guidelines recommend clonidine suppression testing when plasma metanephrine values are less than 4-fold above the upper reference limit.[35]

Chromogranin A is an acidic monomeric protein that is stored with and secreted with catecholamines. Plasma levels of chromogranin A reportedly are 83% sensitive and 96% specific for identifying a pheochromocytoma. Chromogranin A levels are sometimes used to detect recurrent pheochromocytomas.

CT Scanning

Abdominal CT scanning has an accuracy of 85-95% for detecting adrenal masses with a spatial resolution of 1 cm or greater but is less accurate for lesions smaller than 1 cm. Differentiating an adenoma from a pheochromocytoma is more difficult using CT scanning. While most pheochromocytomas have CT attenuation of greater than 10 Hounsfield units (HU), they rarely contain sufficient intracellular fat to have an attenuation of less than 10 HU.[41]  In fact, a retrospective study by Buitenwerf et al found that out of 222 pheochromocytomas, only one had an attenuation value at or below 10 HU on unenhanced CT scanning, indicating a sensitivity of 99.6% for the 10 HU threshold.[42]

However, most pheochromocytomas, although hypervascular, have variable enhancement loss that may, in some cases, be similar to that of adrenal metastases but in others may be similar to enhancement loss of adrenal adenomas.[43]  Therefore, in patients in whom pheochromocytomas are strongly suspected, adrenal pheochromocytomas cannot be entirely excluded from the list of differential diagnoses of adrenal neoplasms with an attenuation value of less than 10 HU and a washout of greater than 60% on delayed scanning.

Although it has been thought that the use of intravenous contrast poses a risk of inducing hypertensive crisis in patients with pheochromocytomas, a controlled, prospective study in patients receiving low-osmolar CT-scan contrast[44]  and a retrospective review in patients who received nonionic contrast[45]  concluded that this use of intravenous contrast is safe, even in patients not receiving alpha or beta blockers. A CT scan of a paraganglioma appears below.

Abdominal computed tomography (CT) scan demonstrat Abdominal computed tomography (CT) scan demonstrating left suprarenal mass of soft-tissue attenuation representing a paraganglioma.

MRI and MR Spectroscopy

MRI is preferred for detection of pheochromocytoma in children and in pregnant or lactating women. MRI has a reported sensitivity of up to 100% in detecting adrenal pheochromocytomas, does not require contrast, and does not expose the patient to ionizing radiation. MRI is also superior to CT scanning for detecting extra-adrenal pheochromocytomas.

In approximately 70% of cases, pheochromocytomas appear hyperintense on T2-weighted images (as demonstrated in the image below), because of their high water content.[46]

Axial, T2-weighted magnetic resonance imaging (MRI Axial, T2-weighted magnetic resonance imaging (MRI) scan showing large left suprarenal mass of high signal intensity on a T2-weighted image. The mass is a pheochromocytoma.

Initial studies have suggested that MR spectroscopy can be used to distinguish pheochromocytomas from other adrenal masses.[47, 48]  Specifically, a resonance signature of 6.8 ppm appears to be unique to pheochromocytomas; the signature apparently is attributable to the catecholamines and catecholamine metabolites present in pheochromocytomas.[48]

Scintigraphy

A scan with iodine-123 (123I)–labeled metaiodobenzylguanidine (MIBG) is reserved for cases in which a pheochromocytoma is confirmed biochemically but CT scanning or MRI does not show a tumor. MIBG is a substrate for the norepinephrine transporter and concentrates within adrenal or extra-adrenal pheochromocytomas. MIBG scanning is frequently used in cases of familial pheochromocytoma syndromes, recurrent pheochromocytoma, or malignant pheochromocytoma.

Estimates of the sensitivity and specificity of 123I-MIBG vary widely. Reported sensitivity ranges from 53-94% and specificity ranges from 82-92%.[49, 50, 51]  123I has a short half-life and is expensive.

A somatostatin receptor analog, indium-111 (111In) pentetreotide, is less sensitive than MIBG. However, it may be used to visualize pheochromocytomas that do not concentrate MIBG.

PET Scanning

PET scanning with 18F-fluorodeoxyglucose (18F-FDG), which is selectively concentrated as part of the abnormal metabolism of many neoplasms, has been demonstrated to detect occult pheochromocytomas. Pheochromocytomas usually show increased uptake on PET scanning, as do adrenal metastases. In SDHB-related metastatic paraganglioma, 18F-FDG-PET has a sensitivity approaching 100%.[52]

The most impressive results to date have been with 6-[18F]-fluorodopamine (FDOPA) PET scanning and carbon-11 hydroxyephedrine (11C-HED) PET scanning. Studies suggest that scans performed with these radioisotopes are extremely useful in the detection and localization of pheochromocytomas. Further study results with these agents are eagerly awaited.

FDOPA

FDOPA, an amino acid precursor, is preferentially stored by neuroendocrine tumors, in which it has been shown to accumulate more readily than does FDG or somatostatin analogues. In a study of 30 consecutive patients presenting to a tertiary care center with suspected pheochromocytoma or paraganglioma, Fottner et al estimated the sensitivity and specificity of FDOPA-PET scanning to be 98% and 100%, respectively. Sensitivities were 94% for adrenal and extra-adrenal abdominal lesions and 100% for thoracic/cervical lesions.[50]

In a comparison of FDOPA-PET scanning combined with CT scanning versus FDOPA-PET or CT scanning alone in images from 25 consecutive patients with suspected pheochromocytoma, 19 lesions were detected by all 3 modalities. All 19 were identified positively as pheochromocytoma by PET/CT and PET scanning, whereas CT scanning produced one false-negative finding. PET/CT and CT scanning also definitively localized all lesions, but PET scanning alone definitively localized only 15 lesions. Overall, the authors estimated the sensitivity and specificity of FDOPA-PET/CT scanning to be 100% and 88%, respectively.[53]

HED

HED is a catecholamine substrate analogue that is transported into sympathetic neurons by the norepinephrine transporter and stored in vesicles. Yamamoto et al reported 91% sensitivity and 100% specificity for pheochromocytoma by HED-PET scanning. HED accumulation, as measured by maximum standardized uptake value (SUVmax), was higher in metastases and in the presence of sympathetic symptoms and correlated significantly with biochemical findings (plasma normetanephrine, urinary norepinephrine).[54]

Testing for Genetic Disorders

Once the diagnosis of pheochromocytoma is made, additional studies to rule out a familial syndrome may be indicated. Testing for every possible gene would be inappropriate and expensive; however, the following information can suggest which genetic tests to select[35] :

  • Biochemical profile of catecholamine secretion
  • Age of the patient
  • Site of the primary tumor
  • Family history

Profiles of plasma catecholamine metabolites in patients with hereditary pheochromocytoma that can serve as a guide to genotype testing include the following[10, 35] :

  • Increased metanephrine (epinephrine metabolite): All patients with MEN 2 and neurofibromatosis type 1 (NF1)
  • Increased normetanephrine only (norepinephrine metabolite): Most patients with VHL
  • Increased methoxytyramine (dopamine metabolite): 70% of patients with SDHB and SDHD mutations; increased normetanephrine may also be present

Eisenhofer et al found that the combination of increased normetanephrine and metanephrine differentiated patients with NF1 and MEN 2 from those with VHL, SDHB mutations, and SDHD mutations in 99% of cases.[10]

In MEN 2, VHL, and NF1, pheochromocytomas are almost always in the adrenal gland, whereas SDHB -related tumors are found in extra-adrenal sites. Patients with MEN 2, VHL, and NF1 often have a positive family history, but currently only 10% of patients with SDHB mutations have a positive family history for pheochromocytoma or paraganglioma.[38]

Perform screening for mutations in the ret proto-oncogene in any patient with a familial syndrome or to distinguish a sporadic pheochromocytoma from a familial pheochromocytoma.[16]  Mutation analysis involves amplification of sequences, including exons 10, 11, 13, 14, and 16 of the ret proto-oncogene from the patient's genomic deoxyribonucleic acid (DNA), followed by sequence analysis.

Particular attention is given to specific sequences for the codons known to be hot spots for mutations causing the MEN 2A and 2B syndromes. Over 95% of cases of MEN 2A and 85% of cases of familial medullary thyroid cancer are associated with mutations affecting 1 of 5 codons located in exons 10 (codon 609, 611, 618, and 620) and 11 (codon 634). Over 95% of individuals with MEN 2B have a germline mutation in codon 918 of exon 16.

In patients with MEN 2A, also obtain a serum intact parathyroid hormone level and a simultaneous serum calcium level to rule out primary hyperparathyroidism (which occurs in MEN 2A). Obtain a serum calcitonin level as well. Some investigators advocate a pentagastrin infusion test; however, genetic screening tests for the ret proto-oncogene may eliminate the need for this provocative test.

In patients with VHL disease, obtain a consultation with an ophthalmologist to rule out retinal angiomas, and consider brain MRI to exclude cerebellar hemangioblastomas. Obtain a CT scan of the kidneys and pancreas to rule out cysts.

Venous Sampling and Arteriography

Because of the high sensitivity of MRI and CT scanning, procedures are rarely indicated for localization of pheochromocytomas. Selective venous sampling is seldom performed to localize pheochromocytomas but has occasionally been used to detect extra-adrenal pheochromocytomas that were not found at surgery.

In most cases, this procedure is not helpful in detecting extra-adrenal tumors, because catecholamine levels have marked variability. An exception to this rule, however, occurs if the norepinephrine concentration is greater than the epinephrine concentration in the venous effluent. Because the primary catecholamine produced and stored in the adrenal gland is epinephrine, a ratio of norepinephrine to epinephrine that is greater than 1 suggests a pheochromocytoma.

Arteriography is rarely indicated. It provides little additional information compared with MRI or CT scanning, and the direct use of intra-arterial contrast may induce a hypertensive crisis.

Histologic Findings

Pheochromocytomas vary from 2 g to 3 kg but, on average, weigh 100 g (a healthy adrenal gland weighs 4-6 g). These tumors are well encapsulated, highly vascular, and appear reddish brown on cut section.

Histologically, the tumor cells are arranged in balls and clusters separated by endothelium-lined spaces; this classic pattern characteristic of pheochromocytoma is termed zellballen. The cells vary in size and shape and have finely granular basophilic or eosinophilic cytoplasm. The nuclei are round or oval with prominent nucleoli. Nuclear gigantism and hyperchromasia are common and do not portend prognosis.

 

Treatment

Approach Considerations

The Endocrine Society, the American Association for Clinical Chemistry, and the European Society of Endocrinology have released clinical practice guidelines for the diagnosis and management of pheochromocytoma and paraganglioma (jointly referred to as PPGL)[32, 33] :

  • Preoperative blockade of hormonally functional PPGL to prevent cardiovascular complications is recommended, along with preoperative medical treatment to normalize blood pressure and heart rate and a high-sodium diet with fluid intake to prevent severe hypotension after removal of the tumor.
  • Blood pressure, heart rate, and glucose levels should be monitored immediately after surgery.
  • Minimally invasive (eg, laparoscopic) adrenalectomy should be performed for most adrenal pheochromocytomas, with open resection reserved for very large or invasive pheochromocytomas; open resection is suggested for paragangliomas, but laparoscopic resection is an option for smaller tumors; partial adrenalectomy is also an option for certain patients.

Surgical resection of the tumor is the treatment of choice for pheochromocytoma and usually results in cure of the hypertension. Careful preoperative management is required to control blood pressure, correct fluid volume, and prevent intraoperative hypertensive crises.[55]  A study by Kwon et al indicated that independent risk factors for a hypertensive attack during adrenalectomy for pheochromocytoma include a large tumor size and preoperative elevation of the urinary epinephrine level.[56]

A retrospective study by Butz et al found that among patients with pheochromocytoma/paraganglioma associated with neurofibromatosis type 1 (NF1), multiple endocrine neoplasia type 2A (MEN 2A), or von Hippel-Lindau (VHL) disease, the most volatile intraoperative course hemodynamically, as well as more severe postoperative complications, occurred in patients with NF1. The investigators attributed this to the presence of large tumors secreting great amounts of catecholamine in these patients, along with the high proportion of the NF1 patients who were treated with open resection. Postoperative outcomes between the three groups did not differ significantly for patients who were treated laparoscopically.[57]

Although there is no consensus regarding the preferred drugs for preoperative blood pressure control, alpha blockers, beta blockers, calcium channel blockers, and angiotensin receptor blockers have all been used.[58]  Start alpha blockade with phenoxybenzamine 10-14 days preoperatively to allow for expansion of blood volume. The patient should undergo volume expansion with isotonic sodium chloride solution. Encourage liberal salt intake.

Initiate a beta blocker only after adequate alpha blockade (usually, 2 days). If beta blockade is started prematurely, unopposed alpha stimulation could precipitate a hypertensive crisis. Administer the last doses of oral alpha and beta blockers on the morning of surgery.

No distinction is found in hypertensive episodes during surgery for pheochromocytoma associated with MEN 2 and non-MEN–associated pheochromocytoma. Therefore, pretreatment using alpha and beta-adrenergic blockers remains a standard of care in both groups of patients.[59]

Test plasma free metanephrines 2 weeks postoperatively. If results are within the reference range, resection is deemed complete; in such cases, patient survival approaches age-matched controls. In addition, ensure resolution of the hypertension and any associated complications.

For surgical follow-up, obtain plasma metanephrine levels yearly for 10 years. Ensure that blood pressure is under control. In patients with an underlying genetic mutation, lifelong follow-up is mandatory.

Laparoscopic Adrenalectomy

Surgical mortality rates are less than 2-3% when the operation is performed by a surgeon and an anesthesiologist who are experienced.

Use an arterial line, cardiac monitor, and Swan-Ganz catheter. Administer stress-dose steroids if bilateral resection is planned.

An anterior midline abdominal approach was used in the past; in current practice, however, laparoscopic adrenalectomy is the preferred procedure for lesions smaller than 8 cm. If the pheochromocytoma is intra-adrenal, the standard approach is to remove the entire adrenal gland. In the case of a malignant pheochromocytoma, resect as much of the tumor as possible.[3, 60, 61]

A study by Scholten et al found that unilateral subtotal adrenalectomy is a feasible strategy in patients with MEN2 who have pheochromocytoma. It has comparable recurrence rates and less complications of steroid replacement compared with unilateral total adrenalectomy.[62]

In a study by Paraby et al, severe hypertension (systolic blood pressure >200 mm Hg) was associated with 5 of 35 pheochromocytoma resections (14.3%), compared with 2 of 106 nonpheochromocytoma adrenal tumor resections (1.9%).[3]  However, no patient in either group had transient or persistent systolic blood pressure of greater than 220 mm Hg. There were no significant differences in recovery room hemodynamic parameters, frequency of persistent hypotension, or occurrence of heart rates greater than 120/min between the 2 groups.

Pheochromocytoma in Pregnancy

If pheochromocytoma is found during pregnancy, initiate alpha-adrenergic blockade (with phenoxybenzamine) as soon as the diagnosis is confirmed. Remove the tumor by laparoscopic adrenalectomy as soon as possible during the first 2 trimesters, after proper preparation. Pregnancy need not be terminated. Spontaneous abortion is very likely, however.

During the third trimester, the patient should be managed medically until fetal lung maturity is confirmed. Cesarean delivery is preferred, as mortality may be higher with vaginal delivery. The tumor may be removed during the same session as the cesarean section, or it can be removed postpartum.[28]

A study by Donatini et al suggested that in pregnant women with bilateral pheochromocytomas, unilateral adrenalectomy for the larger tumor during pregnancy may be a useful strategy to avoid adrenal insufficiency, with contralateral adrenalectomy performed a few months after delivery.[63]

 

Guidelines

Guidelines Summary

In 2014, the Endocrine Society (ES), the American Association for Clinical Chemistry (AACC), and the European Society of Endocrinology (ESE) released joint clinical practice guidelines for the management of pheochromocytoma and paraganglioma (referred to together as PPGL). The guidelines include recommendations (based on strong evidence) and suggestions (based on weaker evidence).[64]

In patients suspected of having PPGL, biochemical testing via measurement of plasma free metanephrines or urinary fractionated metanephrines is recommended. The use of liquid chromatography with mass spectrometry or electrochemical detection methods is suggested over other laboratory methods. Patients with a known germline mutation that predisposes to PPGL should undergo periodic biochemical testing.[64]

The 2010 guidelines from the North American Neuroendocrine Tumor Society (NANETS) recommend biochemical testing for pheochromocytoma that includes measurements of fractionated metanephrines in plasma, urine, or both, as available, in the following cases[35] :

  • Symptomatic patients
  • Patients with an adrenal incidentaloma
  • Patients who have a hereditary risk for developing a pheochromocytoma or paraganglioma (extra-adrenal pheochromocytoma)

For imaging studies, the joint ES/AACC/ESE guidelines recommend CT scanning as first line, rather than MRI. However, MRI is an option in certain patients, such as those with metastatic PPGL, those allergic to CT contrast media, and those for whom radiation exposure should be limited, such as pregnant women.[64]

The National Comprehensive Cancer Network guidelines recommend the following tests for the evaluation of suspected PPGL[65] :

  • Plasma free or 24-hour urine fractionated metanephrines
  • Contrast-enhanced chest/abdominal/pelvic multiphasic CT scanning or MRI
  • Genetic counseling

If metastatic disease is suspected, the guidelines recommend the following additional tests[65] :

  • MIBG scan
  • Somatostatin receptor scintigraphy
  • Fluorodeoxyglucose PET (FDG-PET)/CT scan
  • If bone symptoms, bone scan

For genetic testing, ES/AACC/ESE recommendations are as follows[64] :

  • Patients with PPGLs should be engaged in shared decision-making for genetic testing
  • Patients with paraganglioma should undergo testing of succinate dehydrogenase mutations
  • Patients with metastatic disease should undergo testing for SDHB mutations
  • Genetic testing should include pretest and posttest genetic counseling

 For preoperative management, ES/AACC/ESE recommendations include the following[64] :

  • Blockade of hormonally functional PPGL to prevent cardiovascular complications
  • Medical treatment to normalize blood pressure and heart rate
  • A high-sodium diet with supplemental fluid intake to prevent severe hypotension after removal of the tumor

The ES/AACC/ESE guidelines recommend minimally invasive (eg, laparoscopic) adrenalectomy for most adrenal pheochromocytomas, with open resection reserved for very large or invasive pheochromocytomas. Open resection is suggested for paragangliomas, although laparoscopic resection is an option for smaller tumors. Partial adrenalectomy is also a possibility for certain types of patients.[64]

In the immediate postoperative period, the ES/AACC/ESE guidelines recommend monitoring of blood pressure, heart rate, and glucose levels. Postoperative measurement of plasma or urine metanephrine levels and lifelong annual biochemical testing are suggested.[64]

The 2010 NANETS recommendations for treatment of advanced disease include the following[35] :

  • Surgical debulking to release tumor pressure on surrounding tissues or to decrease tumor mass
  • In select patients, radiofrequency ablation or cryoablation are options
  • Chemotherapy is preferred in patients with negative MIBG scintigraphy and in those with rapidly progressing tumors
  • External-beam irradiation of bone metastases or radiofrequency and cryoablation in selected cases only
 

Medication

Medication Summary

Medical therapy is used for preoperative preparation prior to surgical resection,[66] for acute hypertensive crises, and as primary therapy for patients with metastatic pheochromocytomas. Preoperative preparation requires combined alpha and beta blockade to control blood pressure and to prevent an intraoperative hypertensive crisis. Alpha-adrenergic blockade, in particular, is required to control blood pressure and prevent a hypertensive crisis. High circulating catecholamine levels stimulate alpha receptors on blood vessels and cause vasoconstriction.

Beta blockers are used if significant tachycardia occurs after alpha blockade. Beta blockers are not administered until adequate alpha blockade has been established, however, because unopposed alpha-adrenergic receptor stimulation can precipitate a hypertensive crisis. Noncardioselective beta blockers, such as propranolol (Inderal) or nadolol (Corgard), are the usual choice; however, cardioselective agents, such as atenolol (Tenormin) and metoprolol (Lopressor), also may be used.

Labetalol (Trandate, Normodyne) is a noncardioselective beta-adrenergic blocker and selective alpha-adrenergic blocker that has been shown to be effective in controlling hypertension associated with pheochromocytoma. However, it has also been associated with paradoxic episodes of hypertension thought to be secondary to incomplete alpha blockade. Thus, its use in the preoperative treatment of patients with pheochromocytoma is controversial.

During surgery, intravenous phentolamine, a rapid-acting alpha-adrenergic antagonist, is used to control blood pressure. Rapid-acting intravenous beta blockers, such as esmolol, are also used to normalize blood pressure.

Selective alpha1 blocking agents, such as prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura), have more favorable adverse effect profiles and are used when long-term therapy is required (metastatic pheochromocytoma). These medications are not used to prepare patients for surgery, because of their incomplete alpha blockade.

Iobenguane I 131 was approved by the US Food and Drug Administration (FDA) in July 2018 for iobenguane scan–positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma in patients aged 12 years or older in whom systemic anticancer therapy is needed. The drug’s efficacy was demonstrated in a single-arm, open-label, phase-2 clinical trial performed under a special protocol assessment with the FDA. Seventeen (25%) of the study’s 68 evaluable patients were able to reduce all antihypertensive medication by 50% or more for at least 6 months; 15 patients (22%) obtained an overall tumor response.[67]

Alpha Blockers, Antihypertensives

Phenoxybenzamine hydrochloride (Dibenzyline)

This is a long-acting adrenergic alpha-receptor blocker that can produce and maintain a chemical sympathectomy. Phenoxybenzamine lowers supine and upright blood pressure. It does not affect the parasympathetic nervous system. Reflex tachycardia is a concern and may require the addition of a beta blocker.

Phentolamine mesylate (OraVerse)

Phentolamine mesylate is a nonselective alpha-adrenergic blocking agent that produces transient and incomplete alpha-adrenergic blockade. This agent is often used immediately before or during adrenalectomy to prevent or control paroxysmal hypertension resulting from anesthesia, stress, or operative manipulation of the tumor. It is an alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension that results from catecholamine effects on alpha receptors.

Prazosin (Minipress, Prazin, Prazo)

Prazosin is a quinazoline compound that is a selective alpha1 adrenergic antagonist. Prazosin causes peripheral vasodilation by selective, competitive inhibition of vascular postsynaptic alpha1-adrenergic receptors, thus reducing peripheral vascular resistance and blood pressure.

Terazosin (Hytrin)

Terazosin is a quinazoline compound that is a a selective alpha1 adrenergic antagonist. Terazosin causes peripheral vasodilation by selective, competitive inhibition of vascular postsynaptic alpha1-adrenergic receptors, thus reducing peripheral vascular resistance and blood pressure.

BPH, Alpha Blocker

Doxazosin mesylate (Cardura, Cardura XL)

Doxazosin mesylate is a quinazoline compound that is a selective alpha1-adrenergic antagonist. It inhibits postsynaptic alpha-adrenergic receptors, resulting in the vasodilation of veins and arterioles and a decrease in total peripheral resistance and blood pressure.

Vasodilators

Nitroprusside sodium (Nipride, Nitropress, Sodium Nitroprusside)

Nitroprusside is a direct vasodilator that relaxes arterial vessels and venous smooth muscle. It has a short half-life and its effect disappears within 5 minutes of stopping infusion. The drug may be used to control paroxysmal hypertension intraoperatively. Nitroprusside produces vasodilation and increases the inotropic activity of the heart. At higher dosages, it may exacerbate myocardial ischemia by increasing the heart rate.

Beta Blockers, Nonselective

Propranolol (Inderal LA, InnoPran XL)

Propranolol is a nonselective beta-adrenergic receptor blocker. The drug has membrane-stabilizing activity and decreases the automaticity of contractions.

After primary treatment with an alpha receptor blocker, propranolol may be used as adjunctive therapy if control of tachycardia becomes necessary before or during surgery. It may be used to treat excessive beta receptor stimulation in patients with inoperable metastatic pheochromocytoma. Propranolol is not suitable for the emergency treatment of hypertension; do not administer it intravenously in hypertensive emergencies.

Beta Blockers, Beta1 Selective

Atenolol (Tenormin)

Atenolol selectively blocks beta1 (cardioselective) receptors, with little or no effect on beta2 types. After primary treatment with an alpha receptor blocker, atenolol may be used as adjunctive therapy if control of tachycardia becomes necessary before or during surgery.

Metoprolol (Lopressor)

Metoprolol selectively blocks beta1 (cardioselective) receptors, with little or no effect on beta2 types at low doses. However, at higher plasma concentrations, metoprolol also inhibits beta2 receptors. After primary treatment with an alpha receptor blocker, metoprolol may be used as adjunctive therapy if control of tachycardia becomes necessary before or during surgery.

Esmolol (Brevibloc)

Esmolol is a short-acting beta1 selective beta blocker administered via continuous intravenous infusion. In low doses, esmolol selectively blocks sympathetic stimulation mediated by beta1-adrenergic receptors in the heart and vascular smooth muscle. Esmolol's extremely short duration of action makes the drug useful for acute control of hypertension or certain supraventricular arrhythmias.

Antihypertensives, Other

Metyrosine (Demser)

Metyrosine inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. In patients with pheochromocytoma, administration of metyrosine reduces catecholamine biosynthesis by 35-80%, as measured by urinary catecholamine levels.

Metyrosine is indicated in patients with pheochomocytoma who are awaiting surgery, for long-term management of patients with malignant pheochromocytoma, or in cases of pheochromocytoma in which surgery is contraindicated. It can be useful in patients whose condition is refractory to phenoxybenzamine therapy, or it can be administered as an adjunct to that therapy.

Radiopharmaceuticals

Class Summary

Iobenguane I 131 is the first drug approved by the FDA for pheochromocytomas or paragangliomas that cannot be removed by surgery.

Iobenguane I 131 (Azedra)

Iobenguane is similar in structure to the neurotransmitter norepinephrine (NE) and is subject to the same uptake and accumulation pathways as NE. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and accumulates in adrenergically innervated tissues (eg, heart, lungs, adrenal medulla, salivary glands, liver, spleen), as well as in tumors of neural crest origin. Following intravenous (IV) administration and cell uptake, radiation resulting from radioactive decay of I 131 causes cell death and tumor necrosis.

Iobenguane I 131 is indicated in adults and children aged 12 years or older when systemic anticancer therapy is needed for iobenguane scan–positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma.

 

Questions & Answers

Overview

What is a pheochromocytoma?

What are the characteristics of pheochromocytomas spells?

What are the typical progression of pheochromocytomas spells?

What are symptoms associated with pheochromocytomas spells?

What are the clinical signs of pheochromocytomas?

Which tests are used to diagnose pheochromocytomas?

What is the basis for diagnostic test selection for pheochromocytomas?

What is the role of imaging in the diagnosis of pheochromocytomas?

Which studies are used to rule out a familial syndrome in confirmed pheochromocytoma?

What is the treatment of choice for pheochromocytomas?

What is preoperative medical stabilization for pheochromocytoma?

What is a pheochromocytoma?

What is the role of genetics in the etiology of pheochromocytomas?

What are life-threatening manifestations of pheochromocytomas?

Where are pheochromocytomas located most commonly?

What is the likelihood of malignancy for pheochromocytomas?

How are pheochromocytomas diagnosed?

What are the clinical manifestations of pheochromocytomas?

What is the role of catecholamine in the pathogenesis of pheochromocytomas?

What myocardial changes have been revealed on cardiac MRI following surgical removal of pheochromocytoma?

What are the clinical manifestations of hereditary forms of pheochromocytomas?

What are the precipitants of hypertensive crisis in pheochromocytomas?

How is multiple endocrine neoplasia type 2A (MEN 2A) characterized?

What is the genetic etiology of pheochromocytomas?

What is the role of multiple endocrine neoplasia type 2 (MEN 2) in the etiology of pheochromocytomas?

Which mutations are associated with multiple endocrine neoplasia type 2A (MEN 2A) in pheochromocytomas?

How is multiple endocrine neoplasia type 2A (MEN 2A) diagnosed and what is the risk of developing pheochromocytomas?

How is multiple endocrine neoplasia type 2B (MEN 2B) characterized?

Which mutations are associated with multiple endocrine neoplasia type 2B (MEN 2B)?

How is multiple endocrine neoplasia type 2B (MEN 2B) diagnosed and what is the risk for pheochromocytomas?

What are novel mutations that cause hereditary pheochromocytoma?

Which medical conditions are associated with von Hippel-Lindau (VHL) disease?

What is the prevalence of von Hippel-Lindau (VHL) disease in patients with pheochromocytoma?

What is the cause of von Hippel-Lindau (VHL) disease?

What are characteristics of neurofibromatosis (von Recklinghausen disease) and what is the prevalence in patients with pheochromocytomas?

Which neuroectodermal disorders are associated with pheochromocytomas?

Which hormones may be produced by pheochromocytomas?

What is the role of the SDHD gene in the etiology of pheochromocytomas?

Which conditions are caused by mutations in the SDHD gene?

What is the inheritance pattern for succinate dehydrogenase complex?

Which succinate dehydrogenase subunit genes are associated with pheochromocytomas?

What is the role of hemihyperplasia in the etiology of pheochromocytomas?

What is the prevalence of pheochromocytomas?

What are the racial predilections of pheochromocytoma?

How does the prevalence of pheochromocytoma vary by age?

What are the survival rates pheochromocytoma?

Which factors increase the likelihood of malignancy for pheochromocytomas?

What are the possible complications of pheochromocytomas?

What are neurologic complications of pheochromocytoma?

What is the prognosis of pheochromocytoma in pregnant patients?

Presentation

What are the symptoms and signs of pheochromocytoma?

What history findings suggest pheochromocytoma?

How do pheochromocytoma spells vary in frequency and duration?

Which familial syndromes are characterized by pheochromocytomas?

What are the clinical signs of pheochromocytomas?

What is the most common cardiac rhythm abnormality in pheochromocytoma?

What physical findings are characteristic of pheochromocytoma in patients with neurofibromatosis?

DDX

What conditions should be included in the differential diagnoses of pheochromocytoma?

What are the differential diagnoses for Pheochromocytoma?

Workup

What are Endocrine Society, the American Association for Clinical Chemistry, and the European Society of Endocrinology joint diagnostic guidelines for pheochromocytoma?

How are catecholamines measured in the workup of pheochromocytomas?

What are the North American NeuroEndocrine Tumor Society (NANETS) guidelines for biochemical testing in the evaluation of pheochromocytomas?

What is the basis for selecting diagnostic tests for pheochromocytoma?

What are the general lab features of pheochromocytoma?

When are imaging studies indicated for the diagnosis of pheochromocytoma?

Which patients should be screened for pheochromocytoma and what test should be used?

How are plasma metanephrine and catecholamine testing used to diagnose pheochromocytoma?

What is the efficacy of plasma metanephrine and catecholamine testing to screen for pheochromocytomas?

Which factors may affect the accuracy of screening tests for pheochromocytomas?

Which compounds decrease 24-hour urine levels of metanephrines in screening tests for pheochromocytomas?

How is provocative testing used for the diagnosis of pheochromocytomas?

How are suppression tests used for the diagnosis of pheochromocytomas?

How are chromogranin A levels used for the diagnosis of pheochromocytoma?

What is the role of CT scanning in the diagnosis of pheochromocytoma?

What is the role of MRI for the detection of pheochromocytoma?

What is the role of scintigraphy in the diagnosis of pheochromocytoma?

What is the efficacy of scintigraphy for the diagnosis of pheochromocytoma?

What is the role of PET scanning for the diagnosis of pheochromocytoma?

What is the role of FDOPA-PET scanning in the diagnosis of pheochromocytoma?

What is the efficacy of FDOPA-PET scanning for the diagnosis of pheochromocytomas?

What is the role of HED-PET scanning in the diagnosis of pheochromocytoma?

How are genetic tests selected in the evaluation of pheochromocytoma?

Which profiles of plasma catecholamine metabolites guide genetic testing for pheochromocytoma?

How are normetanephrine and metanephrine measures used to differentiate hereditary etiologies of pheochromocytoma?

What does the locations of pheochromocytomas vary among hereditary etiologies?

When is screening for mutations in the ret proto-oncogene indicated in the diagnosis of pheochromocytoma?

What should be the focus of genetic testing for MEN 2A and 2B in the diagnosis of pheochromocytoma?

What is the role of selective venous sampling in the diagnosis of pheochromocytoma?

What is the role of arteriography in the diagnosis of pheochromocytoma?

Which histologic findings are characteristic of pheochromocytomas?

Treatment

What are the Endocrine Society, the American Association for Clinical Chemistry, and the European Society of Endocrinology joint treatment guidelines for pheochromocytoma?

What is the treatment of choice for pheochromocytomas?

Which medications are used in the treatment of pheochromocytomas?

What is the role of beta blockers in the treatment of pheochromocytomas?

Why are plasma free metanephrines monitored following surgical resection of pheochromocytomas?

What is included in the follow-up of surgery for pheochromocytoma?

What are the surgical mortality rates for pheochromocytomas?

What is needed for a laparoscopic adrenalectomy in patients with pheochromocytoma?

What is the role of the anterior midline abdominal approach in the surgical treatment of pheochromocytoma?

When is unilateral subtotal adrenalectomy indicated in the surgical treatment of pheochromocytoma?

How does hypertension affect the surgical treatment of pheochromocytoma?

What are the treatments options for pheochromocytomas during pregnancy?

Guidelines

Which organizations have released treatment guidelines for pheochromocytoma?

Which biochemical tests are recommended for the diagnosis of pheochromocytoma?

What are the North American Neuroendocrine Tumor Society (NANETS) guidelines for biochemical testing for pheochromocytoma?

What are the ES/AACC/ESE guidelines recommendations for the use of imaging to diagnose pheochromocytoma?

What are the NCCN guidelines for evaluation of pheochromocytoma?

What are the NCCN guidelines for evaluation of suspected metastatic pheochromocytoma?

What are the ES/AACC/ESE recommendations for genetic testing in patients with pheochromocytomas?

What are the ES/AACC/ESE recommendations for preoperative care in patients with pheochromocytomas?

When is minimally invasive adrenalectomy indicated for the surgical treatment of pheochromocytoma?

What are the ES/AACC/ESE recommendations for immediate postoperative care following surgery for pheochromocytoma?

What are the NANETS recommendations for the treatment of advanced pheochromocytoma?

Medications

What is the role of medical therapy in the treatment of pheochromocytoma?

What is the role of beta blockers in the treatment of pheochromocytoma?

What is the role of selective alpha1 blocking agents in the treatment of pheochromocytomas?

What is the role of Iobenguane I 131 in the treatment of pheochromocytomas?

Which medications in the drug class Antihypertensives, Other are used in the treatment of Pheochromocytoma?

Which medications in the drug class Beta Blockers, Beta1 Selective are used in the treatment of Pheochromocytoma?

Which medications in the drug class Beta Blockers, Nonselective are used in the treatment of Pheochromocytoma?

Which medications in the drug class Vasodilators are used in the treatment of Pheochromocytoma?

Which medications in the drug class BPH, Alpha Blocker are used in the treatment of Pheochromocytoma?

Which medications in the drug class Alpha Blockers, Antihypertensives are used in the treatment of Pheochromocytoma?

Which medications in the drug class Radiopharmaceuticals are used in the treatment of Pheochromocytoma?