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Clinical presentation and diagnosis of pheochromocytoma

Clinical presentation and diagnosis of pheochromocytoma
Literature review current through: Sep 2023.
This topic last updated: Oct 03, 2022.

INTRODUCTION — Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic ganglia are referred to as "pheochromocytomas" and "catecholamine-secreting paragangliomas" ("extra-adrenal pheochromocytomas"), respectively. Because the tumors have similar clinical presentations and are treated with similar approaches, many clinicians use the term "pheochromocytoma" to refer to both adrenal pheochromocytomas and catecholamine-secreting paragangliomas. However, the distinction between pheochromocytoma and paraganglioma is an important one because of implications for associated neoplasms, risk for malignancy, and genetic testing.

The clinical presentation and approach to diagnosis of pheochromocytoma are reviewed here. The genetics and treatment of pheochromocytoma and the clinical manifestations, diagnosis, and treatment of paragangliomas are discussed separately. (See "Pheochromocytoma in genetic disorders" and "Treatment of pheochromocytoma in adults" and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)

EPIDEMIOLOGY — Catecholamine-secreting tumors are rare neoplasms, probably occurring in less than 0.2 percent of patients with hypertension [1,2]. It is estimated that the annual incidence of pheochromocytoma is approximately 0.8 per 100,000 person-years [3]. However, this is likely to be an underestimate as 50 percent of pheochromocytomas were diagnosed at autopsy in one series [4]. Although pheochromocytomas may occur at any age, they are most common in the fourth to fifth decade and are equally common in males and females [5]. Tumor characteristics are described below. (See 'Tumor characteristics' below.)

Most catecholamine-secreting tumors are sporadic. However, approximately 40 percent of patients have the disease as part of a familial disorder; in these patients, the catecholamine-secreting tumors are more likely to be bilateral adrenal pheochromocytomas or paragangliomas.

Hereditary catecholamine-secreting tumors typically present at a younger age than sporadic neoplasms [6]. Sporadic pheochromocytoma is usually diagnosed on the basis of symptoms or an incidental discovery on computed imaging, whereas syndromic pheochromocytoma is frequently diagnosed earlier in the course of disease because of biochemical surveillance or genetic testing. (See "Pheochromocytoma in genetic disorders".)

There are several familial disorders associated with adrenal pheochromocytoma, all of which have autosomal dominant inheritance: von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2), and less commonly, neurofibromatosis type 1 (NF1). The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50 percent in MEN2, and 2 to 3 percent with NF1. (See "Pheochromocytoma in genetic disorders".)

CLINICAL PRESENTATION — Pheochromocytoma is usually suggested by the history in a symptomatic patient, discovery of a lipid-poor incidental adrenal mass, or the family history in a patient with familial disease. In one report of 107 patients, the average age at diagnosis was 47 years, and the average tumor size was 4.9 cm [5].

Symptoms and signs — Symptoms are present in approximately 50 percent of patients with pheochromocytoma, and when present, they are typically paroxysmal.

Classic triad — The classic triad of symptoms in patients with a pheochromocytoma consists of episodic headache, sweating, and tachycardia [1,7]. Approximately one-half have paroxysmal hypertension; most of the rest have either primary hypertension (formerly called "essential" hypertension) or normal blood pressure. Most patients with pheochromocytoma do not have the three classic symptoms [8,9], and patients with primary hypertension may have paroxysmal symptoms [10].

Sustained or paroxysmal hypertension is the most common sign of pheochromocytoma, but approximately 5 to 15 percent of patients present with normal blood pressure. The frequency of normotension is higher in patients with adrenal incidentaloma or in those undergoing periodic screening for familial pheochromocytoma [7,11,12].

Headache, which may be mild or severe and variable in duration, occurs in up to 90 percent of symptomatic patients [12].

Generalized sweating occurs in up to 60 to 70 percent of symptomatic patients. Other symptoms include forceful palpitations, tremor, pallor, dyspnea, generalized weakness, and panic attack-type symptoms (particularly in pheochromocytomas that produce epinephrine) [13].

On rare occasions, patients present with a condition termed pheochromocytoma crisis, or pheochromocytoma multisystem crisis. These individuals may have either hypertension or hypotension, hyperthermia (temperature >40°C), mental status changes, and other organ dysfunction [14].

Less common symptoms and signs

Orthostatic hypotension and others – Other signs and symptoms that may occur include orthostatic hypotension (which may reflect a low plasma volume), visual blurring, papilledema, weight loss, polyuria, polydipsia, constipation, increased erythrocyte sedimentation rate, insulin resistance, hyperglycemia, leukocytosis, psychiatric disorders, and, rarely, secondary erythrocytosis due to overproduction of erythropoietin [7,15]. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Secondary polycythemia'.)

Cardiomyopathy – Rarely, pheochromocytoma is associated with cardiomyopathy attributed to catecholamine excess that is similar to stress-induced (takotsubo) cardiomyopathy [16]. Patients may present with pulmonary edema and may deteriorate with initiation of beta-adrenergic blockade [17]. Global or focal wall motion abnormalities may improve with surgical or medical treatment of the pheochromocytoma. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)

Paroxysmal elevations in blood pressure – Patients with symptoms related to paroxysmal elevations in blood pressure (hypertension, tachycardia, or arrhythmia) during diagnostic procedures (eg, colonoscopy), induction of anesthesia, surgery, with certain foods or beverages containing tyramine, or with certain drugs (such as beta-adrenergic blockers, tricyclic antidepressants, corticosteroids, metoclopramide or monoamine oxidase inhibitors [MAOIs]) should undergo formal evaluation for pheochromocytoma.

The abnormalities in carbohydrate metabolism that occur (insulin resistance, impaired fasting glucose, apparent type 2 diabetes mellitus) are directly related to the increase in catecholamine production [18]. These changes resolve after removal of the catecholamine-secreting neoplasm [19].

The symptoms of pheochromocytomas are caused by tumoral hypersecretion of one or combinations of the following catecholamines: norepinephrine, epinephrine, and dopamine; increased central sympathetic activity may also contribute [7]. There are two rare presentations of pheochromocytoma: patients with tumors that secrete only epinephrine can present with episodic hypotension [20,21], and rapid cyclic fluctuations (eg, every 7 to 15 minutes) of hypertension and hypotension can occur via an uncertain mechanism [22,23]. Fluid repletion and treatment with an alpha-adrenergic antagonist may be beneficial in the latter patients.

Asymptomatic patients — With the more widespread use of computed imaging and genetic testing, an increasing number of pheochromocytoma patients are diagnosed in the presymptomatic stage; eg, during the evaluation of an adrenal incidentaloma or on germline pathogenic variant-based case detection. In approximately 60 percent of patients, the tumor is discovered incidentally during computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen for unrelated symptoms [8,9,24-26]. (See "Evaluation and management of the adrenal incidentaloma".)

In a study of 296 consecutive patients with pheochromocytoma treated from 2005 to 2016, 61 percent (180 of 296) were discovered as an incidental finding on cross-section imaging (see 'Imaging' below), 27 percent (80 of 296) due to pheochromocytoma-related symptoms, and 12 percent (36 of 296) on mutation-based testing [26]. The germline pathogenic variant-based pheochromocytomas were smaller and required less alpha-adrenergic blockade preoperatively (median cumulative phenoxybenzamine dose 270 versus 375 versus 450 mg for germline pathogenic variant-based, incidental-finding, and symptomatic groups, respectively). In many patients, pheochromocytoma is found only at autopsy [4,27].

Patients with familial pheochromocytoma — When pheochromocytoma is associated with the multiple endocrine neoplasia type 2 (MEN2), symptoms are present in only approximately one-half of patients, and only one-third have hypertension [28]. It is not known whether this difference is due to screening for pheochromocytoma in patients with MEN2 or a real difference in the clinical expression of the disease. A similar finding has been observed with pheochromocytoma associated with von Hippel-Lindau (VHL) disease as 35 percent of patients have no symptoms, a normal blood pressure, and normal laboratory values for fractionated catecholamines and metanephrines [29]. (See "Pheochromocytoma in genetic disorders".)

Tumor characteristics

Location — Approximately 95 percent of catecholamine-secreting tumors are in the abdomen, 85 to 90 percent of which are intraadrenal (pheochromocytoma), and 5 to 10 percent are multiple [7,30]. Approximately 10 to 15 percent of catecholamine-secreting tumors are extra-adrenal and are referred to as catecholamine-secreting paragangliomas. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)

Malignant potential — Approximately 10 percent of all catecholamine-secreting tumors are metastatic (frequency ranges from 8.3 to 13 percent) [7,31-33]. Malignant pheochromocytomas are histologically and biochemically the same as benign ones. The only reliable clue to the presence of a malignant pheochromocytoma is local invasion into surrounding tissues and organs (eg, kidney, liver) or distant metastases, which may occur as long as 53 years after resection [32-34]. Thus, even when pheochromocytomas or paragangliomas are considered "benign" on pathologic examination, long-term follow-up is indicated in all patients to confirm that impression. Patients with the succinate dehydrogenase (SDH) subunit B mutations are more likely to develop metastatic disease [11,35,36].

A variety of immunohistochemical and other prognostic markers have been evaluated for association with malignancy in adrenal pheochromocytomas [37,38], with mixed results to date. According to the 2017 World Health Organization (WHO), all pheochromocytomas have some metastatic potential [38]. This is also true for paragangliomas. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Histology and malignant potential'.)

APPROACH TO INITIAL EVALUATION — The diagnosis of pheochromocytoma is made based upon biochemical confirmation of catecholamine hypersecretion, followed by identifying the tumor with imaging studies. However, biochemical tests can be normal in an asymptomatic patient with a lipid-poor adrenal incidentaloma as these may be discovered in their "prebiochemical" phase. In these cases, the imaging phenotype guides management (see 'Imaging' below). Of note, even among patients suspected to have a pheochromocytoma, the diagnosis is rarely confirmed. In one series, as an example, the diagnosis was established in only 1 of 300 patients evaluated for pheochromocytoma [39].

Indications for testing — Pheochromocytoma should be suspected in patients who have one or more of the following:

The classic triad of headache, sweating, and tachycardia, whether or not they have hypertension.

Hyperadrenergic spells (eg, self-limited episodes of nonexertional palpitations, diaphoresis, headache, tremor, or pallor). However, most patients with spells do not have pheochromocytoma.

Onset of hypertension at a young age (eg, <20 years), resistant hypertension, or hypertension with new-onset or atypical diabetes mellitus (eg, new onset of apparent type 2 diabetes in a slender person).

A familial syndrome that predisposes to catecholamine-secreting tumors (eg, multiple endocrine neoplasia type 2 [MEN2], neurofibromatosis type 1 [NF1], or von Hippel-Lindau [VHL]).

A family history of pheochromocytoma.

Lipid-poor (unenhanced CT attenuation >10 HU) adrenal incidentaloma with or without hypertension.

Pressor response during anesthesia, surgery, or angiography.

Idiopathic dilated cardiomyopathy.

A history of gastric stromal tumor or pulmonary chondromas (Carney triad).

Discontinue interfering medications — Although it is preferred that patients not receive any medication during the diagnostic evaluation, treatment with all antihypertensive medications may be continued. Tricyclic antidepressants interfere most frequently with the interpretation of plasma fractionated metanephrines and 24-hour urinary catecholamines and metabolites. To effectively screen for catecholamine-secreting tumors, treatment with tricyclic antidepressants (including the muscle relaxant cyclobenzaprine) and other psychoactive agents (but not selective serotonin reuptake inhibitors [SSRIs]) listed in the table (table 1) should be tapered and discontinued at least two weeks before any hormonal assessments.

There are certainly clinical situations for which it is contraindicated to discontinue certain medications (eg, antipsychotics), and if biochemical testing is positive, then computed imaging (eg, CT scan of the abdomen and pelvis) would be needed to exclude a catecholamine-secreting tumor. Furthermore, catecholamine secretion may be appropriately increased in situations of physical stress or illness (eg, any significant illness requiring hospitalization, stroke, myocardial infarction, congestive heart failure, obstructive sleep apnea) [40]. Therefore, the clinical circumstances under which catecholamines and metanephrines are measured must be assessed in each case.

Levodopa is the most common and only pharmacotherapeutic agent that causes markedly abnormal levels of dopamine.

Initial biochemical tests — The diagnosis of pheochromocytoma is typically made by measurements of urinary and plasma fractionated metanephrines and catecholamines (algorithm 1). However, there are major regional, institutional, and international differences in the approach to the biochemical diagnosis of pheochromocytoma [2,41-43].

We suggest initial biochemical testing based upon the index of suspicion that the patient has a pheochromocytoma. If there is a low index of suspicion, we suggest 24-hour urinary fractionated catecholamines and metanephrines; if there is a high index of suspicion, we suggest plasma fractionated metanephrines. Our approach differs from the 2014 Endocrine Society clinical practice guideline, which suggests initial biochemical testing using 24-hour urinary fractionated metanephrines or plasma fractionated metanephrines (drawn supine with an indwelling cannula for 30 minutes) [44]. However, many clinicians do not measure plasma fractionated metanephrines under these ideal conditions, and the test is associated with a high false-positive rate [44,45].

The majority of the metabolism of catecholamines is intratumoral, with formation of metanephrine and normetanephrine [46]. Most laboratories now measure fractionated catecholamines (dopamine, norepinephrine, and epinephrine) and fractionated metanephrines (metanephrine and normetanephrine) by high-performance liquid chromatography (HPLC) with electrochemical detection or tandem mass spectroscopy (MS/MS) [47]. These techniques have overcome the problems with fluorometric analysis (eg, false-positive results caused by alpha-methyldopa, labetalol, or sotalol, and false-negative results caused by imaging contrast agents).

The protocols for the collection and storage of the 24-hour urine collection are determined by the laboratory where the assay will be performed. For example, some laboratories standardized their assays on urine that was kept refrigerated during the collection, while some laboratories (eg, Mayo Medical Laboratories) standardized their assays for urine kept at room temperature.

For any of the biochemical tests, sensitivity will be lower and specificity will be higher for hereditary compared with sporadic pheochromocytoma because tumors detected in patients with a familial disposition tend to be small tumors that release catecholamines in amounts that are often too low to be detected. In contrast, sporadic pheochromocytomas tend to be larger and present with typical signs and symptoms of catecholamine excess. Our suggested approach to testing based upon the patient's clinical presentation is discussed here.

Measurement of plasma fractionated metanephrines is useful to rule out pheochromocytoma, but a positive test (ie, plasma normetanephrine above the upper limit of the reference range) only slightly increases suspicion of disease when screening for sporadic pheochromocytoma.

Low risk for pheochromocytoma — 24-hour urinary fractionated catecholamines and metanephrines should be the first test in patients with a somewhat lower index of suspicion for pheochromocytoma. This includes patients with:

Resistant hypertension

Hyperadrenergic spells (eg, self-limited episodes of nonexertional palpitations, diaphoresis, headache, tremor, or pallor)

24-hour urine fractionated metanephrines and catecholamines — At Mayo Clinic, the most reliable case-detection method for identifying catecholamine-secreting tumors is measuring fractionated metanephrines and catecholamines in a 24-hour urine collection (sensitivity = 98 percent, specificity = 98 percent) [41,48,49].

The 24-hour urine collection for fractionated metanephrines and catecholamines should include measurement of urinary creatinine to verify an adequate collection. The diagnostic cutoffs for most 24-hour urinary fractionated metanephrine assays are based on normal ranges derived from a normotensive volunteer reference group, and this can result in a high rate of false-positive results. As an example, in normotensive laboratory volunteers, the 95th percentiles are 428 mcg for normetanephrine and 200 mcg for metanephrine; whereas the 95th percentiles in individuals being tested for pheochromocytoma (but who do not have the neoplasm) as part of routine clinical practice are 71 and 51 percent higher than those of normal volunteers, respectively [49].

High risk for pheochromocytoma — The index of suspicion for a catecholamine-secreting tumor should be high for the following scenarios:

A family history of pheochromocytoma.

A genetic syndrome that predisposes to pheochromocytoma (eg, MEN2).

A past history of resected pheochromocytoma.

An incidentally discovered adrenal mass that has imaging characteristics consistent with pheochromocytoma (eg, unenhanced CT attenuation [measured in Hounsfield units (HU)] >10 HU and marked enhancement with intravenous [IV] contrast medium on CT or high signal intensity on T2-weighted MRI, and or cystic and hemorrhagic changes seen on CT or MRI) [50].

Measuring plasma fractionated metanephrines is a first-line test when there is a high index of suspicion for pheochromocytoma. Plasma fractionated metanephrines are also a good first-line test for children because obtaining a complete 24-hour urine collection is difficult. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)

Plasma fractionated metanephrines — Some groups have advocated that plasma fractionated metanephrines should be a first-line test for pheochromocytoma [42,51]; the predictive value of a negative test is extremely high, and normal plasma fractionated metanephrines exclude pheochromocytoma except in patients with early preclinical disease and those with strictly dopamine-secreting neoplasms [41]. A plasma test is also attractive because of simplicity.

Although measurement of plasma fractionated metanephrines has a sensitivity of 96 to 100 percent [41,42], the specificity is poor at 85 to 89 percent [41,42,52]; the specificity falls to 77 percent in patients older than 60 years [41]. It has been estimated that 97 percent of patients with hypertension seen in a tertiary care clinic who have positive plasma fractionated metanephrine measurements will not have a pheochromocytoma [52].

This high rate of false-positive tests results in excessive health care expenditures because of subsequent imaging and potentially inappropriate surgery [52]. Thus, plasma fractionated free metanephrines lack the necessary specificity to be recommended as a first-line test; therefore, this measurement is reserved for cases for which the index of suspicion is high (algorithm 1).

Measurement of urinary or plasma dopamine or plasma methoxytyramine may be very useful in detecting the rare tumor with selective dopamine hypersecretion because plasma metanephrine fractions are not direct metabolites of dopamine and may be normal in the setting of a dopamine-secreting tumor [41,53].

Normal results — If results are normal, no further evaluation is necessary, except for patients being evaluated for spells. Testing should be repeated during a spell: patients are instructed to start the 24-hour urine collection when they have a typical spell by recalling back to when they last urinated before the spell and collect to that time point the next day. If results are still normal on repeat testing, other causes of spells should be investigated.

Positive case-detection test — A positive test for a catecholamine-secreting tumor includes one or more of the following findings:

24-hour urine fractionated metanephrines and catecholamines:

Normetanephrine >900 mcg/24 hours or metanephrine >400 mcg/24 hours (algorithm 1)

Norepinephrine >170 mcg/24 hours

Epinephrine >35 mcg/24 hours

Dopamine >700 mcg/24 hours

Plasma fractionated metanephrines:

The normal ranges for plasma metanephrine and normetanephrine depend upon the method used to obtain the blood sample:

For an indwelling cannula, for 20 minutes following an overnight fast before the blood draw, the diagnostic cutoffs to exclude pheochromocytoma are metanephrine <0.3 nmol/L and/or normetanephrine <0.66 nmol/L [54].

For venipuncture in a seated, ambulant, nonfasting patient, the diagnostic cutoffs to exclude pheochromocytoma are slightly higher: metanephrine <0.5 nmol/L and/or normetanephrine <0.9 nmol/L [34].

For patients with biochemical confirmation of the diagnosis, the next step is radiologic evaluation to locate the tumor. (See 'Imaging' below.)

Indeterminate case-detection test — For patients with indeterminate test results (ie, above the upper limit of the reference interval for the laboratory but below the threshold for positive case detection), additional testing is based upon the clinical index of suspicion that the patient has a pheochromocytoma.

For patients with high index of suspicion (family history, incidentally discovered adrenal mass with imaging characteristics consistent with pheochromocytoma), obtain (or repeat) plasma fractionated metanephrines. If the initial sample was a seated plasma fractionated metanephrines, it is reasonable to obtain a supine sample [45].

For patients with low index of suspicion (eg, resistant hypertension, self-limited episodes of nonexertional palpitations, diaphoresis, headache, tremor, or pallor), obtain (or repeat) 24-hour urinary fractionated catecholamines, metanephrines, and creatinine.

Approaches for specific patient groups

Spells – Patients with spells (defined as a sudden onset of a symptom or symptoms that are recurrent, self-limited, and stereotypic in nature) that relate to paroxysmal elevations in blood pressure should be evaluated for pheochromocytoma [10]. However, the clinician should recognize that most patients with spells do not have a pheochromocytoma [10].

We suggest initial screening with 24-hour urinary fractionated metanephrines in this setting because we do not consider these patients to be at high risk for pheochromocytoma. The 24-hour urinary fractionated metanephrines are similar in sensitivity to plasma fractionated metanephrines but higher in specificity, in our experience (algorithm 1) [41,48]. If initial results are normal, testing should be repeated during a spell. (See 'Normal results' above.)

Other possible causes of "spells" that may be confused with pheochromocytoma include hyperthyroidism, menopausal symptoms, idiopathic flushing disorder (eg, unexplained flushing spells), carbohydrate intolerance, hyperadrenergic spells, labile primary hypertension (formerly called "essential" hypertension), renovascular disease, hypoglycemia, postural orthostatic tachycardia syndrome (POTS), mast cell disease, and carcinoid syndrome (table 2).

Additional evaluation for other causes, in particular endocrine causes such as carcinoid syndrome, should be based upon patient presentation. As an example, a patient who presents with flushing and diarrhea rather than pallor with associated pheochromocytoma-like symptoms should undergo 24-hour urinary excretion of 5-hydroxyindoleacetic acid (HIAA). However, we do not suggest testing this in all patients who are being evaluated for possible pheochromocytoma.

Adrenal incidentalomas – If the noncontrast CT attenuation is less than 10 HU, biochemical testing for pheochromocytoma is not needed [55]. In a series of 158 adrenal pheochromocytomas measuring more than 4 cm in diameter, the median noncontrast radiodensity was 33 HU (range 18 to 60 HU)] [55]. In a multicenter, retrospective study of 533 patients with 548 histologically confirmed pheochromocytomas, unenhanced CT attenuation data were available in 376, of which 374 pheochromocytomas had an unenhanced CT attenuation of >10 HU (99.5 percent). In the two exceptions (0.5 percent), the unenhanced CT attenuation was exactly 10 HU [56].

We suggest measuring 24-hour urinary fractionated metanephrines and catecholamines routinely in patients with adrenal incidentalomas when the CT attenuation is 10 HU or greater (algorithm 1) [57]. Approximately 3 percent of adrenal incidentalomas prove to be pheochromocytomas [58]. We suggest that plasma fractionated metanephrines also be measured if the lipid-poor adrenal mass is vascular in concert with other features (eg, cystic and hemorrhagic changes) to suggest pheochromocytoma [50,58]. Plasma fractionated metanephrines are very sensitive (97 to 100 percent) but not very specific (85 to 89 percent) for pheochromocytoma.

If the biochemical tests in patients with adrenal masses more than 2 cm in diameter are negative, a functioning adrenal pheochromocytoma is excluded. However, small adrenal pheochromocytomas (<2 cm in diameter) may not be biochemically detectable [26]. Adrenal incidentalomas should be followed with both imaging and repeat biochemical testing. The evaluation of adrenal incidentalomas is reviewed in detail separately. (See "Evaluation and management of the adrenal incidentaloma".)

Paroxysmal hypertension – Patients with hypertension that is paroxysmal or poorly responsive to standard therapy should be evaluated. The pretest probability of a pheochromocytoma in this scenario is low. We would therefore suggest testing with 24-hour urinary fractionated metanephrines (algorithm 1). If the results are normal, no further testing is needed, while if the results are significantly elevated, imaging with CT or MRI is indicated. The biochemical criteria for a positive test depend on the reference laboratory that is used. As an example, if the 24-hour urinary fractionated metanephrines are tested at Mayo Medical Laboratories, the diagnostic cutoffs are >400 mcg for metanephrines, >900 mcg for normetanephrines, and >1000 mcg for total metanephrines (algorithm 1).

Paroxysmal hypertension is a classic sign of pheochromocytoma, but patients with this finding rarely have the disorder. Its presence commonly initiates an aggressive evaluation to uncover a pheochromocytoma; after a pheochromocytoma has been excluded, the condition usually remains undiagnosed, thereby resulting in ineffective therapy. This disorder, named pseudopheochromocytoma or hyperadrenergic spells, may be due to stress or emotional distress that is only uncovered after careful psychological evaluation [59]. (See "Paroxysmal hypertension (pseudopheochromocytoma)".)

Increased sympathetic activity – Sympathetic activity is also increased in several conditions other than pheochromocytoma. As an example, abrupt discontinuation of a short-acting sympathetic antagonist drug (such as clonidine or propranolol) can lead to severe hypertension and coronary ischemia, probably due to upregulation of sympathetic receptors during the period of sympathetic blockade. When this obvious cause and effect relationship is evident, testing for pheochromocytoma is not needed. (See "Withdrawal syndromes with antihypertensive drug therapy".)

Increased sympathetic activity potentially leading to severe hypertension can also occur in patients with several other disorders. These include [60]:

Autonomic dysfunction, as in the Guillain-Barré syndrome or post-spinal cord injury.

A stress response after cardiac bypass surgery or during a panic reaction [61]. Hypertension in the latter patients occurs primarily during treatment with a tricyclic antidepressant drug, which may increase the degree of sympathetic arousal.

Pheochromocytoma is often considered in patients with undiagnosed panic disorder, in whom many of the symptoms are due to increased sympathetic activity (see "Management of panic disorder with or without agoraphobia in adults"). In one study, 40 percent of patients evaluated for pheochromocytoma met the criteria for panic disorder, as compared with 5 percent of control patients with hypertension [61].

The use of sympathomimetic drugs, such as cocaine, amphetamines, phencyclidine, epinephrine, phenylephrine, terbutaline, or the combination of a monoamine oxidase inhibitor (MAOI) and the ingestion of tyramine-containing foods [62-66]. Tyramine, which is produced from the bacterial breakdown of tyrosine, is normally inactivated by monoamine oxidase in the intestinal tract. This inactivation does not occur in the presence of an MAOI, leading to the absorption of tyramine, which increases the release of norepinephrine from nerve endings and epinephrine from the adrenal gland. The ensuing hypertensive reaction is dose dependent and can be exacerbated if the patient is also taking a sympathomimetic drug.

The three major MAOIs available in the United States are the antidepressant drugs tranylcypromine, phenelzine, and isocarboxazid. The following foods contain relatively high concentrations of tyramine and should be avoided by patients being treated with an MAOI: fermented cheeses; imported beer; Chianti and some other wines; champagne; soy sauce; avocados; bananas; overripe or spoiled food; and any fermented, smoked, or aged fish or meat (such as salami, pepperoni, and bologna) [66].

Patients considered to be at high risk for pheochromocytoma include:

Familial pheochromocytoma – We suggest plasma fractionated metanephrines as the best case-detection test in patients considered to be at high risk for pheochromocytoma (high-risk familial syndromes such as MEN2 and VHL syndrome, previously surgically resected pheochromocytomas or paragangliomas). A normal value excludes a symptomatic catecholamine-secreting neoplasm but mildly elevated values of normetanephrine could be falsely positive, in which case we suggest doing 24-hour urinary fractionated metanephrines, catecholamines, and imaging (algorithm 1).

Special situations

Renal failure – Measurements of urinary catecholamines and metabolites may be invalid if the patient has advanced kidney disease [67]. Serum chromogranin A levels have poor diagnostic specificity in these patients [68]. In patients without pheochromocytoma who are receiving hemodialysis, plasma norepinephrine and dopamine concentrations are increased threefold and twofold above the upper limit of normal, respectively [69]. However, standard reference ranges can be used for interpreting plasma epinephrine concentrations [70]. Therefore, when patients with renal failure have plasma norepinephrine concentrations more than threefold above the upper normal limit or epinephrine concentrations greater than the upper normal limit, pheochromocytoma should be suspected.

The findings of one study suggested that plasma concentrations of fractionated metanephrines are increased approximately twofold in patients with renal failure and may be useful in the biochemical evaluation of patients with marked chronic kidney disease or renal failure [71]. However, the results from a different study suggested that concentrations of plasma fractionated metanephrines could not distinguish between 10 patients with pheochromocytoma and 11 patients with end-stage kidney disease who required long-term hemodialysis [72].

Factitious pheochromocytoma – As with other similar disorders, factitious pheochromocytoma can be very difficult to confirm [73,74]. The patient usually has a medical background. The patient may "spike" the 24-hour urine container or the catecholamines may be administered systemically [75,76].

ADDITIONAL EVALUATION AFTER BIOCHEMICAL DIAGNOSIS

Imaging — Biochemical confirmation of the diagnosis should be followed by radiological evaluation to locate the tumor [1,7], not the other way around (algorithm 1). Approximately 15 percent of the tumors are extra-adrenal, but 95 percent are within the abdomen and pelvis [20]. Although any site containing paraganglionic tissue may be involved, the most common extra-adrenal locations of catecholamine-secreting paragangliomas are the superior and inferior abdominal paraaortic areas (75 percent of extra-adrenal tumors); the urinary bladder (10 percent); the thorax (10 percent); and the skull base, neck, and pelvis (5 percent) [30].

CT and MRI

Sporadic pheochromocytoma – CT or MRI of the abdomen and pelvis is usually performed first. Either test is a reasonable first test as both detect almost all sporadic symptomatic tumors because most are 3 cm or larger in diameter.

In sporadic pheochromocytoma, both CT and MRI are quite sensitive (98 to 100 percent) but are only approximately 70 percent specific because of the higher prevalence of adrenal "incidentalomas" (see "Evaluation and management of the adrenal incidentaloma"). The choice between CT and MRI depends upon the cost and certain other factors described below.

With CT, there is some exposure to radiation but no risk of exacerbation of hypertension if current radiographic contrast agents are given. CT with low-osmolar contrast is safe for patients with pheochromocytoma even without alpha- or beta-adrenergic blocker pretreatment, as illustrated in a report of 22 such patients [77]. After intravenous (IV) low-osmolar contrast administration for CT scan, there was a significant increase in diastolic blood pressure but no increase in plasma catecholamine levels or episodes of hypertensive crises.

With MRI, there is neither radiation nor dye. This more expensive test can distinguish pheochromocytoma from other adrenal masses; on T2-weighted images, pheochromocytomas appear hyperintense and other adrenal tumors isointense, as compared with the liver (image 1) [20]. However, MRI lacks the superior spatial resolution of CT.

Familial pheochromocytoma – In patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome, computing imaging may miss approximately one-quarter of the tumors [28]. In a selected group of patients with a 40 percent incidence of pheochromocytoma, the respective positive and negative predictive values of CT were 69 and 98 percent [7].

Imaging phenotype of pheochromocytoma/paragangliomas

Increased attenuation on nonenhanced CT (most are >20 Hounsfield units [HU])

Increased mass vascularity

Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent)

High signal intensity on T2-weighted MRI

Cystic and hemorrhagic changes

Variable size and may be bilateral

Additional imaging — If abdominal and pelvic CT or MRI is negative in the presence of clinical and biochemical evidence of pheochromocytoma, one ought to first reconsider the diagnosis. If the diagnosis is still considered likely, a total body nuclear imaging study may be indicated. These include: gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3 octreotate (gallium Ga-68 DOTATATE)-positron emission tomography (Ga-68 DOTATATE PET); fludeoxyglucose-positron emission tomography (FDG-PET); and iobenguane I-123 (diagnostic; also known as metaiodobenzylguanidine [MIBG]) scintigraphy.

Total body nuclear imaging is superfluous in patients with small sporadic solitary adrenal pheochromocytoma identified on CT/MRI [78].However, it is indicated in patients with large (eg, >8 cm) adrenal pheochromocytomas (increased risk of metastatic disease) or paraganglioma (increased risk of multiple tumors and malignancy) (image 2) [30].

68-Ga DOTATATE PET — Gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3 octreotate (gallium Ga-68 DOTATATE)-positron emission tomography (Ga-68 DOTATATE PET) is proving to be more sensitive in some patients than iobenguane I-123, CT/MRI, or FDG-PET for detection of metastatic disease (image 3) [79]. In addition, Ga-68 DOTATATE PET offers higher spatial resolution than conventional 111-In pentetreotide scintigraphy. Ga-68 DOTATATE injection as a radioactive diagnostic agent for PET imaging was approved by the US Food and Drug Administration (FDA) in June 2016. A second radiotracer, gallium Ga-68 DOTATOC (DOTA-0-Phe1-Tyr3-octreotide) was approved in 2019 [80] and appears to have comparable diagnostic accuracy to Ga-68 DOTATATE [81].

FDG-PET — Fludeoxyglucose-positron emission tomography (FDG-PET) is more sensitive than iobenguane I-123 and CT/MRI for detection of metastatic disease (image 4) [82-86]. The utility of integrated FDG-PET/CT imaging as compared with iobenguane I-123 and conventional cross-sectional imaging with CT or MRI was directly addressed in a prospective study of 216 patients with suspected pheochromocytoma/paraganglioma; 60 patients had nonmetastatic disease, 95 had metastatic disease, and 61 did not have pheochromocytoma/paraganglioma [83].

For the primary tumor, the sensitivity of PET/CT for nonmetastatic tumors was similar to that of iobenguane I-123 but less than that of CT/MRI (77, 75, and 96 percent, respectively). Among the patients who had paraganglioma/pheochromocytoma ruled out, specificity was comparable (90, 92, and 90 percent, respectively). When the analysis was limited to 26 paragangliomas of the head and neck, PET/CT was more sensitive than iobenguane I-123 (85 versus 52 percent).

Iobenguane I-123 — Iobenguane I-123 (diagnostic) is a compound resembling norepinephrine that is taken up by adrenergic tissue. This scan can detect tumors not detected by CT or MRI or multiple tumors when CT or MRI is positive [7].

Surgery is never indicated based on iobenguane I-123 findings alone; MIBG findings should always be corroborated by findings on computed imaging. Normal adrenal glands take up iobenguane I-123, and the uptake may be asymmetric.

Procedures to avoid

Selective adrenal venous sampling (AVS) may result in inappropriate adrenalectomy. When AVS for catecholamines was performed in 18 patients without pheochromocytoma, epinephrine and norepinephrine concentrations were significantly higher in the right versus the left adrenal vein (up to 83-fold difference for epinephrine) [87]. These data highlight why AVS should not be used in the investigation of adrenal pheochromocytoma.

Image-guided needle biopsy – Image-guided needle biopsy of suspected pheochromocytoma or paraganglioma should be avoided due to a high rate of biopsy-related complications. This was illustrated in a report of 20 patients who were diagnosed at the time of needle biopsy, of whom 14 (70 percent) developed a biopsy-related complication [88]. Complications included: increased difficulty of the definitive operation in 7 of 17 (41 percent) operative cases, with one patient requiring conversion to an open procedure; severe hypertension (15 percent); hematoma (30 percent); incorrect or inadequate biopsy (25 percent); severe pain (25 percent); and delay in surgical treatment (15 percent) [88].

Genetic testing — Genetic testing should be considered in all patients with pheochromocytoma or paraganglioma. Although most catecholamine-secreting tumors are sporadic, approximately 40 percent have the disease as part of a familial disorder. In these patients, the catecholamine-secreting tumors are more likely to be bilateral adrenal pheochromocytomas or paragangliomas [6]. Genetic testing is usually performed postoperatively after a pathologic diagnosis has been confirmed.

The familial disorders associated with pheochromocytoma (all of which have autosomal dominant inheritance) include von Hippel-Lindau (VHL), MEN2, and neurofibromatosis type 1 (NF1). The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50 percent in MEN2, and 3 percent with NF1. These disorders are reviewed separately. (See "Pheochromocytoma in genetic disorders".)

Germline pathogenic variants contributing to pheochromocytoma and paraganglioma have two general transcription signatures: cluster 1, genes encoding proteins that function in the cellular response to hypoxia; and cluster 2, genes encoding proteins that activate kinase signaling (table 3). Cluster 1 tumors are mostly extra-adrenal paragangliomas (except in VHL, where most tumors are localized to the adrenal), and nearly all have a noradrenergic biochemical phenotype [89]. In contrast, cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic biochemical phenotype. Since 1990, 16 different pheochromocytoma/paraganglioma susceptibility genes have been reported: NF1, RET, VHL, SDHD, SDHC, SDHB, EGLN1 (PHD2), EGLN2 (PDH1), KIF1B, SDHAF2, IDH1, TMEM127, SDHA, MAX, HIF2A, and FH (table 3) [83].

Most cases of familial paraganglioma are caused by pathogenic variants in the succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) subunit genes (SDHB, SDHC, SDHD, SDHAF2, SDHA). (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)

The clinician may obtain a list of clinically approved molecular genetic diagnostic laboratories at Genetic Testing Registry. The field of genetic testing is rapidly evolving, and at many clinical laboratories, sequential genetic testing is no longer done, as it is less expensive to utilize next-generation sequencing technology for all clinically available mutations as a package. However, in those patients with neck and skull base paragangliomas, a case can be made for obtaining an SDHx panel (to test for an SDHB, SDHC, SDHAF2, SDHA, or SDHD mutation).

The approach to genetic testing is reviewed in more detail separately. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Approach to genetic testing'.)

PHEOCHROMOCYTOMA IN PREGNANCY

Paradoxical supine hypertension — Pheochromocytoma is a rare cause of hypertension during pregnancy, with clinical features similar to those in the general population [90,91]. However, the supine position during pregnancy may allow the gravid uterus to compress the tumor, causing paradoxical supine hypertension with normal blood pressure in the sitting or erect position. Furthermore, if hypertension and proteinuria occur, pheochromocytoma may be difficult to distinguish from preeclampsia.

Placental cells contain monoamine oxidase (MAO) and catechol o-methyl transferase (COMT), which serve as a protective barrier for the fetus against excessive catecholamine exposure. Thus, fetal loss associated with maternal pheochromocytoma is not a direct consequence of maternal catecholamines acting on the fetus. However, the uteroplacental circulation is responsive to alpha-adrenergic stimulation.

High concentrations of catecholamines induce marked vasoconstriction of the maternal uterine arterial circulation, resulting in uteroplacental insufficiency, which may lead to spontaneous abortion, fetal growth restriction, fetal hypoxia, and intrauterine fetal death. In addition, paroxysmal hypertension may lead to placental abruption, and rebound hypotensive episodes may lead to severe intrauterine hypoxia and adverse fetal outcomes [91].

As in nonpregnant women, the diagnosis is usually based upon the results of 24-hour urinary fractionated metanephrines and catecholamines and plasma fractionated metanephrines. MRI without gadolinium is the imaging test of choice in the pregnant woman. Stimulation tests and iobenguane I-123 (also known as metaiodobenzylguanidine [MIBG]) scintigraphy are not considered safe for pregnant women.

The early diagnosis of pheochromocytoma in the pregnant woman is key to preventing morbidity and mortality. Before 1969, the fetal mortality rate due to maternal pheochromocytoma was high (55 percent), with a slight difference between cases diagnosed antepartum and those diagnosed postpartum (50 versus 57 percent, respectively) [92]. During the period of 1969 to 1979, the overall fetal mortality was 47 percent (42 percent antepartum diagnosis versus 56 percent postpartum diagnosis) [93]. Studies completed during the time period of 1980 to 1987, reported that the fetal mortality rate decreased to 25 percent, and this was markedly influenced by early diagnoses (12 versus 39 percent) [94]. During the time period of 1987 to 2000, the overall fetal mortality rate decreased to 15 percent and the importance of early diagnosis was confirmed (12 percent antepartum diagnosis versus 25 percent postpartum diagnosis) [95].

In a multicenter retrospective study of patients with pheochromocytoma and pregnancy, 232 patients were identified who had a total of 249 pregnancies (1980 to 2019) while harboring a catecholamine-secreting tumor [91]. The diagnosis of pheochromocytoma was made before (15 percent), during pregnancy (54 percent), or after delivery (31 percent). For patients diagnosed antepartum, alpha-adrenergic blockade prevented adverse outcomes (odds ratio [OR] 3.6, 95% CI 1.1-13.2), while antepartum surgery was not associated with better outcomes (no surgery versus surgery OR 0.9, 95% CI 0.3-3.9). Unrecognized and untreated pheochromocytoma was associated with a 27-fold higher risk of either maternal or fetal complications. Fetal death occurred in 15 (7 percent) pregnancies and severe maternal complications or death in 13 (6 percent) pregnancies [91].

Medical therapy should be initiated with alpha-adrenergic blockade (either alpha-1 selective with doxazosin or nonselective with phenoxybenzamine), followed, if necessary, by beta-adrenergic blockade [96,97]. The timing of surgical intervention, which may be performed laparoscopically for adrenal neoplasms, is more controversial. Some authors recommend surgery if the fetus is previable (less than 24 weeks of gestation) and medical management when the pregnancy is further along [98-101]. The rationale for surgery is that phenoxybenzamine crosses the placenta, and reports of perinatal depression and transient hypotension have been described [99]. However, phenoxybenzamine has generally been safe for the fetus [96].

In patients managed medically during pregnancy, cesarean section can be followed by tumor resection a few weeks later after uterine involution [102]. Spontaneous labor and delivery should be avoided. Cesarean section is the preferred mode of delivery since it appears to carry less risk of maternal death than vaginal delivery [96]. The management of catecholamine-secreting paragangliomas in pregnancy may require modification of these guidelines depending on tumor location [103].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adrenal incidentaloma" and "Society guideline links: Pheochromocytoma and paraganglioma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Pheochromocytoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

Epidemiology – Most catecholamine-secreting tumors are sporadic. However, approximately 40 percent of patients have the disease as part of a familial disorder; in these patients, the catecholamine-secreting tumors are more likely to be bilateral adrenal pheochromocytomas or multiple paragangliomas. (See 'Epidemiology' above.)

Clinical presentation – Symptoms are present in approximately 50 percent of patients with pheochromocytoma, and when present, they are typically paroxysmal. (See 'Symptoms and signs' above.)

Diagnostic testing – The diagnosis of pheochromocytoma is made based upon biochemical confirmation of catecholamine hypersecretion, followed by identifying the tumor with imaging studies. Many patients are tested for possible sporadic pheochromocytoma, but few will ultimately be diagnosed with the disorder (approximately 1 in 300). (See 'Indications for testing' above.)

Biochemical evaluation – We suggest initial biochemical testing based upon the index of suspicion that the patient has a pheochromocytoma. If there is a low index of suspicion, we suggest 24-hour urinary fractionated catecholamines and metanephrines; if there is a high index of suspicion, we suggest plasma fractionated metanephrines (algorithm 1). Medications that can interfere with results are reviewed above (table 1). (See 'Discontinue interfering medications' above and 'Initial biochemical tests' above.)

For patients with biochemical confirmation of the diagnosis, the next step is radiologic evaluation to locate the tumor. (See 'Positive case-detection test' above.)

Imaging – Biochemical confirmation of the diagnosis should be followed by radiologic evaluation to locate the tumor [60,62], not the other way around (algorithm 1). In sporadic pheochromocytoma, CT or MRI of the abdomen and pelvis is usually performed first. Either test detects almost all sporadic tumors because most are 3 cm or larger in diameter. (See 'CT and MRI' above.)

If CT or MRI is negative in the presence of clinical and biochemical evidence of pheochromocytoma, one ought first to reconsider the diagnosis. If it is still considered likely, then total body nuclear imaging with Gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3 octreotate (gallium Ga-68 DOTATATE)-positron emission tomography (68-Ga DOTATATE PET), fludeoxyglucose-positron emission tomography (FDG-PET), or iobenguane I-123 (also known as metaiodobenzylguanidine [MIBG]) scintigraphy may be done; these scans can detect tumors not detected by CT or MRI. (See '68-Ga DOTATATE PET' above and 'FDG-PET' above and 'Iobenguane I-123' above.)

Genetic testing – Genetic testing should be considered in all patients with pheochromocytoma or paraganglioma. (See 'Genetic testing' above.) (table 3)

Pheochromocytoma in pregnancy – Pheochromocytoma is a rare cause of hypertension during pregnancy, with clinical features similar to those in the general population. The approach to diagnosis is the same as for nonpregnant women. Maternal and fetal mortality rates are high, particularly in those who are not diagnosed until delivery. Alpha-adrenergic blockade is associated with fewer adverse outcomes. (See 'Pheochromocytoma in pregnancy' above.)

ACKNOWLEDGMENTS — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier versions of this topic review.

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Topic 130 Version 46.0

References

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