Version May 2024
INTRODUCTION — Pheochromocytomas and paragangliomas are rare tumors in children. Tumors that arise from the adrenal medulla are termed pheochromocytomas and usually secrete catecholamines. Tumors with extra-adrenal origins are called paragangliomas and either secrete catecholamines or are nonfunctional.
This topic review will discuss the clinical presentation, diagnosis, and management of pheochromocytomas and catecholamine-secreting paragangliomas in children. Given the limited experience with pheochromocytomas in children and the similarity in clinical presentation, diagnosis, and treatment among children and adults, the following discussion includes some data derived from the adult literature. Detailed reviews of these tumors in adults are presented separately. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)
DEFINITIONS
●Pheochromocytoma – Pheochromocytomas are catecholamine-secreting tumors that arise from the chromaffin cells of the adrenal medulla.
●Paraganglioma – Paragangliomas arise from the paraganglia of the autonomic nervous system outside of the adrenal medulla. Those that involve the sympathetic nervous system usually secrete catecholamines and typically are located in the lower mediastinum, abdomen, and pelvis. Those that involve the parasympathetic nervous system are usually nonfunctional and often located in the skull base, neck, and upper mediastinum. This topic review will focus only on catecholamine-secreting tumors and not nonfunctional paragangliomas. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)
Because pheochromocytomas and catecholamine-secreting paragangliomas have similar clinical presentations and are treated with similar approaches, many clinicians use the term "pheochromocytoma" to refer to both types of tumors. However, the distinction between pheochromocytoma and paraganglioma is an important one because of the implications for associated neoplasms, risk for malignancy, and implications for genetic testing.
EPIDEMIOLOGY — Incidence rates of pheochromocytoma and paraganglioma are estimated at 0.3 cases per million per year, with approximately 20 percent of cases diagnosed during childhood [1]. Among hypertensive children, the incidence of surgically confirmed pheochromocytoma or catecholamine-secreting paraganglioma ranges from 0.8 to 1.7 percent [2-4]. Approximately 80 percent of catecholamine-secreting tumors are pheochromocytomas and 20 percent are paragangliomas, in both adults and children [5]. Because these tumors are uncommon, most pediatric case series are small [6-8]. The largest series included 748 patients with pheochromocytoma or paraganglioma, among which 95 (13 percent) presented during childhood [9]. Compared with adults, pheochromocytoma or paraganglioma in children are more likely to be familial, multicentric (image 1), or malignant (image 2), as discussed below.
PATHOPHYSIOLOGY AND GENETICS — Pathogenic variants in susceptibility genes can be identified in most familial cases of pheochromocytoma or paraganglioma, and also in many apparently sporadic cases [10]. In one series, nearly 56 percent of pheochromocytoma cases that were initially thought to be sporadic in childhood were due to germline pathogenic variants in susceptibility genes; when limited to children under age 10, the percentage with identifiable pathogenic variants was as high as 70 to 85 percent [10,11]. Due to our increasing understanding of the genetic component underlying the pathophysiology of pheochromocytoma and paraganglioma in children, it is now imperative that all children who present with these disorders, regardless of the family history, undergo germline genetic testing [12]. Susceptibility genes are categorized by their biochemical phenotype, with cluster 1 indicating a noradrenergic phenotype (norepinephrine and normetanephrine); cluster 2 indicating an adrenergic phenotype (epinephrine and metanephrine); and cluster 3 indicating Wnt signaling pathway (table 1).
The molecular genetics of these disorders are discussed in detail separately. (See "Pheochromocytoma in genetic disorders".)
Sporadic tumors — Approximately two-thirds of pheochromocytomas and paragangliomas in children have no family history of disease [8,13,14]. However, even in patients with apparently sporadic pheochromocytoma or paraganglioma, up to 56 percent will have unsuspected germline pathogenic variants of the RET, VHL, SDHD, SDHB, SDHC, SDHAF2, or SDHA, as well as TMEM127 or MAX genes [11,15] (see 'Familial disease' below). Genetic testing of these patients may identify individuals and families at risk for other associated tumors.
Familial disease — In a large case series, pheochromocytomas or paragangliomas were hereditary in 80.4 percent of children, compared with 52.6 percent of adults [9]. Children showed a higher prevalence than adults of extra-adrenal (66.3 versus 35.1 percent), multifocal (32.6 versus 13.5 percent), metastatic (49.5 versus 29.1 percent), and recurrent (29.5 versus 14.2 percent) disease (see 'Tumor characteristics' below). In addition, children were more likely than adults to have pathogenic variants in cluster 1 genes (76.1 versus 39.3 percent), especially VHL and SDHB, which largely explains their increased prevalence of multifocal, malignant, and recurrent disease [9,16].
Familial pheochromocytoma
●Syndromic – Several familial syndromes are associated with pheochromocytoma, all of which have autosomal dominant inheritance:
•Von Hippel-Lindau syndrome (VHL) – Associated with pathogenic variants in the VHL tumor suppressor gene. Between 10 and 20 percent of patients with VHL have pheochromocytoma or paraganglioma [17]. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)
•Multiple endocrine neoplasia type 2A or 2B (MEN2) – Associated with pathogenic variants in the RET proto-oncogene. Approximately 50 percent of cases of MEN2 include pheochromocytoma [18,19]. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)
•Neurofibromatosis type 1 (NF1) – Due to pathogenic variants in the NF1 gene. Approximately 3 percent of patients with a disease-associated NF1 pathogenic variant develop catecholamine-secreting tumors, which may be adrenal pheochromocytomas or abdominal paragangliomas [20,21]. In one case series, the median age at diagnosis was 41 years (range, 14 to 67), and metastatic or recurrent disease occurred in 7.3 percent [21]. The rate of pheochromocytoma or paraganglioma is substantially higher in those who also have gastrointestinal stromal tumors (GISTs). (See "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Surveillance for complications' and "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'Primary familial GIST syndrome'.)
Pheochromocytomas and paragangliomas are also associated with Carney-Stratakis dyad, and Carney syndrome or triad (GIST; pulmonary chondromas, paraganglioma, adrenocortical adenoma, and esophageal leiomyoma). The clinical features of these disorders are discussed in detail elsewhere. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'GIST syndromes in pediatric and AYA patients'.)
●Nonsyndromic – Familial pheochromocytoma has also been associated with nonsyndromic disease, due to pathogenic variants in MAX, TMEM127, and occasionally SDHD or SDHB.
Familial paraganglioma — Paragangliomas often arise as a familial disorder with autosomal dominant inheritance. The tumors are located most often in the skull base and neck, but also in the thorax, abdomen, pelvis, and urinary bladder. Most cases are caused by pathogenic variants in the succinate dehydrogenase (SDH) subunit genes (SDHA, SDHAF2, SDHB, SDHC, and SDHD, collectively known as SDHx) and have high rates of multicentric, recurrent, and malignant disease. (See "Pheochromocytoma in genetic disorders".)
TUMOR CHARACTERISTICS
Tumor location
●Pheochromocytomas are located in the adrenal medulla, by definition.
●Catecholamine-secreting paragangliomas are often located in the superior and inferior para-aortic areas (75 percent of extra-adrenal tumors); the bladder (10 percent); the thorax (10 percent); and the skull base, neck, and pelvis (5 percent) [22]. These locations coincide with chromaffin tissues (eg, along the para-aortic sympathetic chain, within the organs of Zuckerkandl at the origin of the inferior mesenteric artery, the wall of the urinary bladder, and the sympathetic chain in the neck or mediastinum) [14,23].
Compared with adults, children with catecholamine-secreting tumors have a higher incidence of familial disease, bilateral adrenal tumors, extra-adrenal tumors (paragangliomas), and multiple tumors [2,6,9,24]. Extra-adrenal tumors have been described in 30 to 66 percent of children (contrasted with 10 to 15 percent of adults) [8,9,22,25,26], and multiple tumors have been described in up to 40 percent (compared with 5 to 13 percent in adults) [9,27]. Multicentric disease is more common in patients with familial disorders such as multiple endocrine neoplasia (MEN2), von Hippel Lindau syndrome (VHL), or those with pathogenic variants in succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) and subunit genes (SDHB, SDHC, SDHD, SDHAF2, and SDHA) (image 1) [28,29].
Malignant disease — Children and adolescents with pheochromocytoma or paraganglioma are at risk for malignant disease, and this risk may be higher than in adults. Two observational studies with long-term follow-up reported that almost 50 percent of children had malignant/metastatic disease [8,9], compared with approximately 30 percent in adults [9]. The increased rate of malignancy among children was largely explained by their higher rate of cluster 1 pathogenic variants, especially SDHB and VHL [9]. Among the pediatric patients, one-quarter of the patients with malignant disease had metastases at presentation (synchronous), and the remainder developed metastases during follow-up. In a series of 30 children with these tumors, statistically significant risk factors for malignancy included paraganglioma, apparent sporadic disease, and tumor size greater than 6 cm [8]. Malignancy is less common (<5 percent) in individuals with pheochromocytomas or paragangliomas associated with MEN2 or neurofibromatosis type 1 (NF1) syndromes; the risk for patients with VHL syndrome or VHL pathogenic variants is probably intermediate (approximately 10 percent) [9,15]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Malignant potential'.)
Malignant pheochromocytomas and paragangliomas are histologically and biochemically the same as benign tumors. The only clue to the presence of a malignant pheochromocytoma is regional invasion or distant metastases, which may occur as long as 50 years after resection [30-32]. Thus, lifelong follow-up is important for any patient with a catecholamine-secreting tumor and particularly for children.
CLINICAL PRESENTATION
Signs and symptoms — The signs and symptoms of pheochromocytomas and paragangliomas are caused by hypersecretion of norepinephrine, epinephrine, and dopamine from the tumor, although some of the sympathetic overactivity may be mediated through the central nervous system [33]. The classic triad of symptoms in these disorders consists of episodic headache, sweating, and tachycardia, usually accompanied by hypertension. However, less than 50 percent of adult patients have one or more of these three classic symptoms [34,35].
Presenting symptoms in children are similar to adults, but the frequency is not well defined, because case series are small. The most common symptoms in children are [8,36,37]:
●Hypertension – 60 to 90 percent [8,36-38]. Hypertension is typically sustained but may be paroxysmal [2,8,25]. Malignant hypertension can occur with its associated complications (eg, increased intracranial pressure and encephalopathy) [2,13,39].
●Episodic sweating, tachycardia, or palpitations – 50 to 60 percent [37].
●Headache – 50 to 80 percent [7,8,36]. The headache may be mild or severe and either episodic or unrelenting.
●Abdominal pain or distension or back pain – 30 percent in one series [8]; these symptoms are due to mass effect of the tumor.
Other symptoms and signs that occur less frequently include panic attacks or other psychiatric disorders, orthostatic hypotension (which may reflect a low plasma volume), pallor, constipation, blurred vision, papilledema, weight loss, polyuria, polydipsia, hematuria, and dilated cardiomyopathy [2,7,33,40]. Importantly, attention deficit hyperactivity disorder (ADHD) is more common in children with pheochromocytoma and paraganglioma than in the general population. In pediatric patients with hypertension and ADHD symptomatology, an evaluation to rule out pheochromocytoma or paraganglioma is warranted prior to treatment with stimulant medications, which may exacerbate hypertensive crises [41].
The clinical presentation is often different when pheochromocytoma is associated with the multiple endocrine neoplasia type 2 (MEN2). Approximately one-half of patients are asymptomatic, and only one-third have hypertension [42]. Similarly, when pheochromocytoma is associated with von Hippel-Lindau (VHL) disease, approximately 35 percent of patients are asymptomatic and have normal blood pressure and normal catecholamine tests [43]. It is unclear whether the high proportion of asymptomatic patients is due to ascertainment bias due to routine screening for pheochromocytomas in families with MEN2 or VHL, versus a real difference in the clinical expression of the disease in these familial syndromes. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)
Laboratory tests — Patients with pheochromocytoma or paraganglioma typically have normal results of routine laboratory tests, including complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, and urine analysis. These tests are often performed as part of an evaluation for unexplained hypertension. The erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) may be elevated, reflecting the elevated levels of catecholamines. Approximately 40 percent of adult patients have hyperglycemia because catecholamines are counterregulatory hormones to insulin. Hyperglycemia is less common in children with pheochromocytoma or paraganglioma [5].
Renal or abdominal ultrasound have very low sensitivity for detecting pheochromocytomas, although large tumors are occasionally discovered during a routine evaluation for secondary hypertension.
Cardiac tests — Abnormalities of cardiac tests are common in symptomatic adult patients with pheochromocytoma or paraganglioma:
●Electrocardiogram (ECG) – In a small series of adults with pheochromocytoma, three-quarters of whom were symptomatic at presentation, ECG findings were normal (53 percent); left ventricular (LV) hypertrophy (33 percent); sinus tachycardia (8.3 percent), ischemic pattern (3 percent); or supraventricular tachycardia (3 percent) [44].
●Echocardiogram – Echocardiography is indicated in symptomatic patients. However, the echocardiogram is usually normal in asymptomatic patients, including those with asymptomatic hypertension [45]. In the study described above, echocardiographic findings were normal (62.1 percent); concentric LV hypertrophy with normal LV systolic function (27.6 percent); and LV systolic dysfunction (10.3 percent). Three symptomatic patients had catecholamine cardiomyopathy with transient LV dysfunction [44].
APPROACH TO EVALUATION — The sequence of diagnostic testing depends on whether the patient is being evaluated for a catecholamine-secreting tumor because of clinical symptoms or because of a personal or family history of a syndrome or gene pathogenic variant that is associated with these tumors:
Patients with symptoms — For a child presenting with symptoms of sympathetic overactivity, the first step is a focused history and physical examination to determine the level of suspicion for a catecholamine-secreting tumor and exclude other causes of the symptoms, such as hyperthyroidism.
History — Sympathetic activity is increased in several conditions other than pheochromocytoma. The two main causes in children are:
●Sympathomimetic drugs – Drugs that can induce symptoms simulating pheochromocytoma include high-dose phenylpropanolamine (a popular over-the-counter decongestant and appetite-suppressant), cocaine, amphetamines, phencyclidine, epinephrine, phenylephrine, and terbutaline, and the combination of a monoamine oxidase (MAO) inhibitor and ingestion of tyramine-containing foods [33,46-49]. Mercury intoxication also can mimic pheochromocytoma, producing both hypertension and elevated urine and plasma catecholamines [50]. If the clinical history suggests the possibility of exposure to any of these drugs, specific testing is warranted.
●Panic disorder – Panic disorder and ADHD can replicate many of the symptoms of pheochromocytoma because of increased sympathetic activity.
Panic disorder occurs in children, primarily adolescents [51,52]. It is more common among those with a history of other anxiety disorders (see "Anxiety disorders in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, and course"). The potential importance of this disorder in the differential diagnosis of pheochromocytoma was illustrated in a study in which 300 adults were referred for possible pheochromocytoma [53]. Only one had the disease, but 40 percent met the criteria for panic disorder, compared with 5 percent of control patients with hypertension.
Indications for biochemical testing — Biochemical testing for a catecholamine-secreting tumor is indicated for children with any of the following characteristics [54]:
●Hypertension (table 2) with features suggestive of secondary hypertension, after exclusion of other causes, especially renovascular disease. (See "Evaluation of hypertension in children and adolescents".)
●Hypertension in association with other symptoms of sympathetic overactivity, such as episodic headache, sweating, and tachycardia or palpitations (see 'Signs and symptoms' above), if the symptoms are not explained by sympathomimetic drugs or panic disorder. (See 'History' above.)
●Papilledema, focal neurologic deficits, or unrelenting headache, if other causes of intracranial hypertension have been excluded. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".)
●Incidentally discovered adrenal mass.
For these patients, the most appropriate initial diagnostic assay for pheochromocytoma or paraganglioma is measurement of fractionated metanephrines and catecholamines in a 24-hour urine collection, or plasma fractionated metanephrines if an accurate urine collection is not feasible [55]. When interpreting the results of biochemical testing, it is important to take into account the patient's age [56] (see 'Biochemical testing' below). If one of these tumors is identified, the patient should also be evaluated for an underlying genetic pathogenic variant since these are common and their presence affects clinical management. (See 'Genetic testing' below.)
Patients with family history — An asymptomatic person at risk for disease on the basis of family history of pheochromocytoma or paraganglioma, multiple endocrine neoplasia type 2 (MEN2), or von Hippel-Lindau (VHL) disease should have genetic testing if an affected family member has a known pathogenic variant [57]. (See 'Genetic testing' below and "Pheochromocytoma in genetic disorders".)
If a disease-causing pathogenic variant is identified, biochemical testing for pheochromocytoma/paraganglioma should be performed. Biochemical testing is not indicated if no pathogenic variant is identified and the patient is asymptomatic. (See 'Biochemical testing' below.)
Patients with known pathogenic variants — An asymptomatic person with a genetic disorder known to be associated with pheochromocytoma or paraganglioma should have periodic screening for the development of these and any other associated tumors. This includes patients with VHL disease (or VHL pathogenic variants); MEN2 (or RET pathogenic variants); or those with pathogenic variants in SDHA, SDHAF2, SDHB, SDHC, and SDHD (collectively known as SDHx), TMEM127, or MAX.
For patients with VHL disease or asymptomatic SDHB germline pathogenic variants, biochemical testing and blood pressure measurements should be performed annually beginning at age five years; for those with asymptomatic SDHA, SDHC, or SDHD germline pathogenic variants, this annual screening should be initiated by age 10 years [58-60]. Patients with neurofibromatosis type 1 (NF1) should undergo biochemical testing every three years [21]. For patients with MEN2, screening for pheochromocytoma should begin by age 11 years for children with high-risk pathogenic variants (ATA-H and ATA-HST categories) and by age 16 years in children with moderate-risk pathogenic variants (ATA-MOD category), as recommended in guidelines from the American Thyroid Association (ATA) [61]. The preferred case-detection method in pediatric patients with one of these pathogenic variants is plasma fractionated metanephrines. (See 'Plasma fractionated metanephrines' below.)
In addition to the biochemical and clinical evaluation outlined above, patients with germline succinate dehydrogenase (SDH)-related pathogenic variants should have periodic imaging because their paragangliomas may be biologically silent.
●For patients with germline SDHC and SDHAF2 pathogenic variants:
•Skull base and neck imaging (ultrasound or magnetic resonance imaging [MRI]) every two to three years, because of the risk for paragangliomas arising in those locations (which are typically dopaminergic).
•Abdominal imaging periodically because of the rare association with abdominal paraganglioma [62].
•Total body imaging every five years, consisting of integrated positron emission tomography (PET)/CT with gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC, or 123I-metaiodobenzylguanidine (MIBG) scintigraphy. (See 'Imaging' below.)
●For patients with germline SDHD and SDHB pathogenic variants:
•Skull base and neck imaging (ultrasound or MRI) every two to three years.
•Abdominal imaging (computed tomography [CT] or MRI) every two to three years.
•Total body imaging every five years, consisting of PET/CT with gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC, or 123I-MIBG scintigraphy. (See 'Imaging' below.)
The age at which this imaging surveillance should start has not been established. Until guided by prospective studies, it is reasonable to begin imaging surveillance for asymptomatic children with SDHB pathogenic variants at age 10 years [60]. For asymptomatic patients with other SDHx pathogenic variants, we suggest beginning imaging surveillance at age 15 years or 10 years before the earliest age at diagnosis in the family, whichever is younger.
DIAGNOSTIC TESTING
Biochemical testing — A provisional diagnosis of pheochromocytoma or paraganglioma in the pediatric age group is best made by measurement of 24-hour fractionated urinary metanephrines and catecholamines. In young children in whom an accurate 24-hour urine collection is not possible, measurement of plasma fractionated metanephrines is a reasonable alternative initial test. Patients with positive results should be further evaluated with imaging to confirm and localize the tumor. (See 'Imaging' below.)
Measurements of plasma or urine catecholamines and metabolites are highly sensitive and specific in patients with symptoms (sensitivity 98 percent, and specificity 98 percent), based primarily on studies in adults with testing performed under optimal protocols [2,40,58,63,64]. Virtually all patients with symptomatic pheochromocytoma have clearly abnormal values for any of these tests. However, normotensive and asymptomatic patients with pheochromocytoma may have normal or mildly abnormal values. Thus, when a test result is equivocal, a different test should be done. A variety of drugs can interfere with these tests and should ideally be stopped prior to testing (table 3) (see "Clinical presentation and diagnosis of pheochromocytoma", section on 'Discontinue interfering medications'). Measurements of fractionated metanephrines and catecholamines should be performed in reference laboratories that employ high-performance liquid chromatography (HPLC) or tandem mass spectrometry technology.
Urinary fractionated metanephrines and catecholamines — For patients who are being evaluated because of symptoms, 24-hour urinary measurement of fractionated metanephrines (normetanephrine and metanephrine) and catecholamines (norepinephrine, epinephrine, and dopamine) is the most useful test because of its combined sensitivity and specificity, provided that an accurate urine collection can be performed [64]. Most patients with pheochromocytoma or paraganglioma have increased urinary excretion of these substances [33,46,64]. In general, large tumors produce more metanephrines because the catecholamines are metabolized within the tumor before they are released, whereas small tumors are more likely to release free catecholamines [33].
The diagnostic cutoffs used for these tests tend to cause some false-positive testing because they are based on a reference group of healthy normotensive volunteers, rather than individuals with hypertension but without tumors, who tend to have somewhat higher values. As an example, in normotensive volunteers, the 95th percentiles are 428 mcg for normetanephrine and 200 mcg for metanephrine, whereas in individuals being tested for pheochromocytoma (but who do not have the neoplasm), the 95th percentiles are 71 percent and 51 percent higher than these values, respectively [65]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on '24-hour urine fractionated metanephrines and catecholamines'.)
A 24-hour urine sample is usually collected for these measurements in stable patients; the urinary creatinine should also be measured in the sample to verify an adequate collection. Shorter collections (eg, an overnight urine collection) may be more convenient [66] but are also more likely to yield false-positive results if they capture acute events associated with sympathetic activity [67].
Plasma fractionated metanephrines — For patients who are being evaluated because of strong risk factors for a catecholamine-secreting tumor, such as those with known pathogenic variants for familial pheochromocytoma, measurement of plasma fractionated metanephrines is the diagnostic test of choice. This test is somewhat more sensitive than 24-hour urinary fractionated metanephrines, but the increased sensitivity comes at the expense of a suboptimal false-positive rate of 15 percent when performed in a clinical setting [68]. The test is also appropriate for individuals who are unable to perform an accurate 24-hour urine collection, such as young children. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Plasma fractionated metanephrines'.)
To minimize false-positive results, blood should be sampled from an intravenous catheter with the patient calm and relaxed; patients should be fasting and avoid caffeine and strenuous physical activity for at least 8 to 12 hours before testing [15].
Other — Measurement of fractionated catecholamines in plasma is not useful in the diagnostic evaluation of the child or adolescent for possible pheochromocytoma, because of high false-positive rates. The tests discussed above (plasma fractionated metanephrines, and 24-hour urinary fractionated metanephrines and catecholamines) are superior.
Selective venous sampling is not recommended, because of high rates of false-positive results (due to the marked asymmetry in adrenal catecholamine concentrations in individuals without pheochromocytoma) [69,70].
Imaging — Abnormal urine or serum test results should be followed by radiologic evaluation to locate the tumor [33,46]. As noted above, 40 to 70 percent of catecholamine-secreting tumors in children are in the adrenals (pheochromocytomas), and 30 to 60 percent are extra-adrenal (paragangliomas), which are often located in the superior and inferior para-aortic areas [8,22,25,26]. (See 'Tumor location' above.)
Computed tomography or magnetic resonance imaging — Patients with positive results of biochemical testing should be further evaluated with CT or MRI of the abdomen and pelvis [25,40]. Either test detects almost all sporadic tumors because most symptomatic neoplasms are 3 cm or larger in diameter. In a selected group of adults with a 40 percent incidence of pheochromocytoma, the respective positive and negative predictive values of CT were 69 and 98 percent [33]. The false-positive tests were largely caused by adrenal "incidentalomas" (an incidental finding on imaging unrelated to the clinical problem) that are not a major issue in children.
The choice between CT and MRI depends upon the cost and certain other factors [40]. With CT, there is some exposure to radiation and contrast dye is used [71]. MRI employs gadolinium and has inferior spatial resolution compared with CT, but avoids exposure to radiation and contrast dye. In T2-weighted images, pheochromocytomas appear hyperintense and other benign adrenal tumors hypointense, as compared with the liver (image 1) [58]. Abdominal ultrasound does not have the imaging sensitivity needed to localize pheochromocytoma or paraganglioma.
Radionuclide scintigraphy and positron emission tomography — Additional imaging may be appropriate for certain patients. Available techniques include scintigraphy with 123I-metaiodobenzylguanidine (MIBG) and integrated positron emission tomography (PET)/CT or MRI using somatostatin receptor-based diagnostic radionuclides such as gallium Ga-68 DOTATATE, gallium Ga-68 DOTATOC, 18F-fluorodeoxyglucose (FDG), or other compounds [72]. Considerations about the choice of imaging techniques are discussed in a separate topic review. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Additional imaging'.)
Candidates for these tests fall into one of two categories:
●Positive biochemical tests, negative CT or MRI of the abdomen and pelvis – In this case, total body imaging with 123I-MIBG or PET/CT or MRI is indicated to evaluate for paragangliomas not detected by abdominal CT or MRI [33].
●Positive biochemical tests, positive CT or MRI – In these patients one of these imaging techniques may be performed to evaluate for possible additional tumors, but expert opinion varies as to whether this is helpful. Multiple tumors are found in up to 40 percent of children, particularly those with extra-adrenal tumors [22,27]. Some clinicians have suggested that MIBG scintigraphy or PET-based imaging should be performed in all children with catecholamine-secreting tumors, even if a tumor was identified on the CT scan [25]. However, MIBG scintigraphy has identified apparent extra-adrenal "tumors" that were not confirmed at surgery [73]. In addition, most clinicians with experience with these patients find that it does not add to the clinical management of patients with solitary adrenal pheochromocytoma identified by CT or MRI [74-76].
We suggest total body imaging with 123I-MIBG or integrated PET/CT or MRI for the following groups of patients:
●Patients with biochemical documented disease but negative CT or MRI of the abdomen and pelvis.
●Patients with paragangliomas because these patients have a relatively high risk of metastatic disease as well as additional paragangliomas.
●Patients who carry a disease-causing SDHx pathogenic variant (SDHA, SDHAF2, SDHB, SDHC, or SDHD); we perform a total body screen scan periodically (eg, every five years). (See 'Patients with known pathogenic variants' above.)
DIAGNOSIS — Pheochromocytoma or paraganglioma is suspected because of suggestive signs or symptoms or because of a family history in a patient with familial disease. The diagnosis is confirmed by biochemical testing for 24-hour fractionated urinary metanephrines and catecholamines or plasma fractionated metanephrines, followed by radiographic localization of the tumor with CT or MRI. For selected patients, further imaging with 123I-metaiodobenzylguanidine (MIBG) or integrated positron emission tomography (PET)/CT or MRI, using gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC, may be appropriate. (See 'Biochemical testing' above and 'Imaging' above.)
GENETIC TESTING — Genetic testing should be performed for any pediatric patient diagnosed with pheochromocytoma or paraganglioma; germline pathogenic variants are more common in children with these tumors compared with adults [10,54]. The type of germline pathogenic variant guides clinical management. For example, in those patients with MEN2A RET-proto-oncogene pathogenic variants, testing and treatment for medullary thyroid cancer and primary hyperparathyroidism are indicated.
The approach to genetic testing depends on the patient's characteristics:
●Pheochromocytoma or paraganglioma and known syndrome – Patients with pheochromocytoma or paraganglioma in association with familial disease (von Hippel-Lindau [VHL] disease, multiple endocrine neoplasia type 2 [MEN2], neurofibromatosis type 1 [NF1], or familial paraganglioma) should have targeted pathogenic variant testing for the causal genes. (See 'Familial disease' above.)
●Sporadic pheochromocytoma or paraganglioma – Patients with apparently sporadic disease (ie, no associated syndrome or family history) also should undergo genetic testing. Germline pathogenic variants are present in up to 25 percent of patients with sporadic disease [11]. 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 pathogenic variants as a package. The suggested approach is described in a separate topic review. (See "Pheochromocytoma in genetic disorders", section on 'Suggested approach'.)
●Family history of catecholamine-secreting tumor or related syndrome – Targeted genetic testing is appropriate for some asymptomatic individuals without known pheochromocytoma or paraganglioma, but who are at risk because of a family history of pheochromocytoma or paraganglioma, MEN2, VHL disease, or NF1. The decision to proceed with testing depends on the patient's age and relation to affected family members and should be guided by genetic counseling. (See 'Familial disease' above and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Genetic screening' and "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)
Genetic testing can be complex. Testing one family member has implications for related individuals. Genetic counseling is recommended to help families understand the implications of genetic test results, to coordinate testing of at-risk individuals, and to help families work through the psychosocial issues that may arise before, during, or after the testing process.
The clinician may obtain a list of clinically approved molecular genetic diagnostic laboratories at the Genetic Testing Registry website. Other details related to genetic testing are discussed separately. (See "Pheochromocytoma in genetic disorders", section on 'Genetic screening'.)
TREATMENT — Once a pheochromocytoma is diagnosed, the patient should undergo surgery after appropriate medical preparation. Preoperative resolution of symptoms and normalization of blood pressure are predictors of an uncomplicated outcome [77].
Medical preparation for surgery — In patients with catecholamine-secreting tumors, surgery can provoke hypertensive crises and malignant arrhythmias due to catecholamine release. Patients are also at risk for postoperative hypotension due to chronic vasoconstriction and volume contraction. Medical preparation for surgery is designed to prevent these events [54,78]. Antihypertensive treatment (typically with adrenergic blockade) is recommended for all patients, regardless of whether they have hypertension preoperatively. In a large case series of patients who underwent intrathoracic or intra-abdominal pheochromocytoma or paraganglioma resection, intraoperative hemodynamic variability was greater with higher preoperative levels of adrenergic activity [79]. However, substantial variability was observed even in patients with adrenergic activity levels within the normal range. Patients with large tumors are particularly at risk for a volatile hemodynamic course and more severe postoperative complications [80].
●Alpha-adrenergic blockade method – Although no method of preparation for surgery in children with pheochromocytomas is universally accepted, a common approach is to initiate alpha-adrenergic blockade, followed by beta-adrenergic blockade if needed:
•Alpha-adrenergic blockade – In our practice, we generally use alpha-adrenergic blockade with phenoxybenzamine (Dibenzyline) unless contraindicated because of cardiopulmonary concerns. The starting dose of phenoxybenzamine in children is 0.25 to 1.0 mg/kg per day or 10 mg once daily; the dose is increased every few days until the patient's symptoms and blood pressure are controlled [13]. Due to the high cost of phenoxybenzamine, some clinicians may choose to a selective alpha-1 antagonist (eg, doxazosin, terazosin, or prazosin). Typically, alpha-adrenergic blockade is started 7 to 14 days before surgery. Treatment targets include resolution of paroxysmal symptoms and a systolic blood pressure that is in the lower end of the normal range for age.
•Volume expansion – On the second or third day of alpha-adrenergic blockade, patients are encouraged to start a diet high in sodium content because of the catecholamine-induced volume contraction and the orthostasis associated with alpha-adrenergic blockade. This causes intravascular volume expansion, which may be contraindicated in patients with heart failure or renal insufficiency.
•Beta-adrenergic blockade – After adequate alpha-adrenergic blockade has been achieved, which typically occurs two to three days preoperatively, beta-adrenergic blockade is initiated if needed to control tachycardia. The beta-adrenergic blocker should never be started first because blockade of vasodilatory peripheral beta-adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in blood pressure [54]. The clinician should exercise caution if the patient is asthmatic or has heart failure. Chronic catecholamine excess can produce a cardiomyopathy that may become evident with the initiation of beta-adrenergic blockade, resulting in acute pulmonary edema. Therefore, when the beta-adrenergic blocker is administered, it should be used cautiously and at a low dose. The dose is then increased as necessary to control the tachycardia.
In most cases, the patient is ready for surgery in 10 to 14 days after starting the alpha-adrenergic blockade.
●Other methods – Although perioperative alpha blockade is widely recommended, a second regimen that has been utilized in adults at the Cleveland Clinic and in France involves the administration of a calcium channel blocker for blood pressure control [81,82]. In a review of 113 adult patients who underwent removal of pheochromocytomas, fewer perioperative complications were observed in those not given alpha-adrenergic antagonists [81]. (See "Treatment of pheochromocytoma in adults".)
A third approach is to administer metyrosine (alpha-methyl-para-tyrosine), which inhibits catecholamine synthesis by blocking the enzyme tyrosine hydroxylase [83,84]. Metyrosine should be used with caution and only when other agents have been ineffective or if significant tumor manipulation is anticipated. Although some centers have used this agent routinely, most clinicians reserve metyrosine primarily for patients who cannot be treated with the combined alpha- and beta-adrenergic blockade protocol because of intolerance or cardiopulmonary concerns. The starting dose of metyrosine in children is 125 mg once or twice daily (250-mg capsules can be reduced to a 125 mg dose by a pharmacist). We then titrate the dose up over at least 8 days to a maximum of 2.5 g daily [37,84], based on clinical symptoms or a target decline in fractionated metanephrines and catecholamines (unpublished personal experience). Side effects of metyrosine can include orthostatic hypotension, diarrhea, sedation, extra-pyramidal symptoms and crystalluria. The use of metyrosine is also limited by its high cost. (See "Treatment of pheochromocytoma in adults".)
Surgery — Surgical removal of pheochromocytomas or paragangliomas in children usually results in the restoration of normal blood pressure [4,14,25], unless a remaining tumor is present. The late return of hypertension frequently signals recurrent disease [27,40]. With removal of all tumor tissue, catecholamine secretion and the blood pressure should fall to normal levels within one week.
Laparoscopic surgery may be performed in patients with unilateral or bilateral adrenal pheochromocytoma [85-88]. Paragangliomas usually require an open surgical approach.
When bilateral adrenal pheochromocytomas are present, as sometimes occurs in patients with von Hippel-Lindau (VHL) disease or multiple endocrine neoplasia type 2 (MEN2) (image 1), bilateral total laparoscopic adrenalectomy should be considered in patients with MEN2; whereas bilateral cortical sparing adrenalectomy can be considered in non-MEN2 patients [89]. The intent of cortical-sparing adrenalectomy is to leave enough cortex intact to avoid permanent adrenal insufficiency [89-95]. However, it is important for clinicians and the child's family to understand that in the setting of MEN2, the medullary involvement is diffuse and that it is impossible to preserve cortex without also preserving adrenal medulla. In the setting of MEN2 treated with cortical-sparing surgery, diseased medulla is purposely being left behind and over time it may grow large enough to necessitate a second operation. Thus, the risk of cortical-sparing adrenalectomy in patients with MEN2 is recurrent pheochromocytoma, which occurred in 3 of 14 patients (21 percent) in one series [91].
Outcomes of cortical-sparing versus total adrenalectomy were illustrated in a report of 625 patients with bilateral pheochromocytoma undergoing 849 adrenalectomies, in which 324 (52 percent) were planned as cortical-sparing and were successful in 248 of 324 patients (76.5 percent) [89]. Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5 percent of patients treated with attempted cortical-sparing adrenalectomy. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13 percent) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median of eight years. Familial pheochromocytoma patients with unilateral disease should be treated with unilateral adrenalectomy, even though they are at risk for metachronous disease in the contralateral gland [96]. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Pheochromocytoma'.)
Malignant disease — Surgical removal of the tumor is the primary therapy for malignant pheochromocytoma and can be curative [97-99]. Patients with metastatic disease should be treated by surgical debulking and chronic medical therapy with alpha-adrenergic and, if needed, beta-adrenergic blockade to control symptoms [97].
The clinical course of patients with malignant pheochromocytoma and paraganglioma is highly variable. In a series of 272 patients (primarily adults) with metastatic pheochromocytoma or paraganglioma, metastases were present at initial diagnosis in 35 percent (synchronous disease), and the remainder developed during the follow-up period at a median of 5.5 years (range 0.3 to 53.4 years) [32]. Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Rapid disease progression was associated with male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of the primary tumor. In children with malignant pheochromocytoma/paraganglioma, the 5-year survival rate is estimated at 78 percent, and the 10-year survival rate is estimated at 31 percent, with mean survival of 157±32 months [8].
Because of the variable clinical course of patients with metastatic disease, an individualized approach is warranted [99]. After the initial surgical resection, observation to determine the pace of the disease is frequently the first management step. Systemic chemotherapy may be useful in some patients with excessive tumor burden and rapidly progressive disease [14,97,100]. A more experimental and noncurative approach for distant metastases has been the administration of high-dose 131I-metaiodobenzylguanidine (MIBG) [101,102]. Radiofrequency ablation of hepatic metastases and cryoablation of bone metastases may be effective in selected patients [103,104].
Recurrent disease — Recurrent disease is a common problem in children with pheochromocytomas, particularly in those with familial disease [27,40]. In one report of 14 children, four (28 percent) recurred within six years [40]. The symptoms were those of pheochromocytoma but not necessarily the same as at initial presentation. Surgical removal of the recurrent tumor led to at least temporary cure of the disease because some children had multiple recurrences. In adults, the disease recurs after surgery in approximately 15 percent of cases and is often malignant. (See "Treatment of pheochromocytoma in adults", section on 'Prognosis'.)
Monitoring — Because of the risks for metastatic or recurrent disease, long-term monitoring is indicated in all patients, even those who are apparently cured. All patients should be evaluated annually, using biochemical testing (plasma or 24-hour urine fractionated metanephrines). Those at increased risk for recurrent disease (eg, those with familial, large, extra-adrenal, or bilateral disease) should be reevaluated annually [105]. Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group [106,107].
Surveillance with MRI is indicated in the following clinician scenarios:
●Patients who had a nonfunctioning paraganglioma or pheochromocytoma resected because they lack a tumor marker that can be measured in the blood or urine.
●Patients at high risk for developing nonfunctioning (typically in the skull base, neck, and upper mediastinum) paragangliomas (eg, SDHx or VHL pathogenic variant carriers). However, routine surveillance imaging for pheochromocytoma or paraganglioma is not indicated in patients with MEN2 or neurofibromatosis type 1 (NF1). To avoid the discovery and management of pheochromocytoma in pregnancy, abdominal MRI can be considered in women with MEN2, VHL, or NF1 as part of pre-pregnancy planning.
●Patients with any SDHx pathogenic variant should have periodic MRI of the abdomen, pelvis, skull base, and neck (eg, every two to three years). (See 'Patients with known pathogenic variants' above.)
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: Pheochromocytoma and paraganglioma" and "Society guideline links: Adrenal incidentaloma".)
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
●Definitions and epidemiology – Pheochromocytomas and paragangliomas are rare tumors in children, accounting for approximately 1.7 percent of cases of hypertension. Those originating from the adrenal medulla are defined as pheochromocytomas, and non-adrenal tumors are paragangliomas. (See 'Epidemiology' above and 'Definitions' above.)
●Clinical presentation – Presenting symptoms of these tumors in children are paroxysmal or sustained hypertension (60 to 90 percent), episodic sweating, tachycardia or palpitations (50 to 60 percent), headache (50 to 80 percent), and effects related to the abdominal mass; the "classic triad" of episodic headache, sweating, and tachycardia is an unusual presentation, particularly in children. (See 'Clinical presentation' above.)
●Pathophysiology and genetics – Compared with adults, these tumors in children are more likely to be familial, multicentric, or malignant. (See 'Tumor characteristics' above.)
•Approximately 80 percent of these tumors in children are familial, associated with multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau (VHL) disease, neurofibromatosis type 1 (NF1), or familial paraganglioma. (See 'Familial disease' above.)
•Among apparently sporadic (nonfamilial) tumors, up to 56 percent will have unsuspected germline pathogenic variants of the genes involved in the above familial syndromes. Thus, genetic testing is appropriate for any child presenting with pheochromocytoma or paraganglioma. (See 'Sporadic tumors' above and 'Genetic testing' above.)
●Clinical presentation and diagnosis – Pheochromocytoma or paraganglioma is suspected because of suggestive signs or symptoms or because of a family history in a patient with familial disease. The diagnosis is confirmed by biochemical testing for 24-hour fractionated urinary metanephrines and catecholamines (or plasma fractionated metanephrines), followed by radiographic localization of the tumor with CT or MRI. (See 'Diagnosis' above and 'Biochemical testing' above and 'Imaging' above.)
●Surveillance for at-risk patients – For asymptomatic patients with known germline pathogenic variants for familial pheochromocytoma or paraganglioma, annual biochemical screening for the development of pheochromocytoma should begin in early childhood. The optimal screening test for this scenario is plasma fractionated metanephrines. (See 'Patients with known pathogenic variants' above and 'Plasma fractionated metanephrines' above.)
●Treatment
•Care team – Optimal care of children with pheochromocytoma or paraganglioma includes a multidisciplinary team approach at an experienced center. Typical members of the multidisciplinary team include pediatricians and internists with expertise with very rare neoplasms, endocrine surgeons, radiologists, geneticists, and anesthesiologists. (See 'Treatment' above.)
•Surgery – Surgical resection is the primary treatment. Surgical removal of pheochromocytomas or paragangliomas in children usually results in the restoration of normal blood pressure unless a remaining tumor is present.
•Medical preparation for surgery – For all patients undergoing surgical resection, we recommend a preoperative medical regimen to reduce the risk of perioperative complications from catecholamine release (Grade 1B). Performing surgery without this medical preparation may provoke hypertensive crises or malignant arrhythmias, which can be fatal. We suggest using the combination of alpha-adrenergic blockade followed by beta-adrenergic blockade, if necessary, rather than another regimen (Grade 2C). Alternate choices for preoperative preparation include calcium channel blockers and metyrosine. (See 'Medical preparation for surgery' above.)
●Risk of malignancy – Up to one-half of these tumors in children are malignant; metastatic disease may be present at the initial diagnosis or become apparent many years later. Lifelong surveillance for recurrence and metastases is needed. (See 'Malignant disease' above.)
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