Pediatrics

Pheochromocytoma/paraganglioma

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Pheochromocytomas/ Paragangliomas? What are the typical findings for this disease?

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that are derived from neural crest cells. A PHEO is defined as tumor originating from the chromaffin cells of the adrenal medulla, while a PGL is an extra-adrenal sympathetic or parasympathetic ganglion tumor. PGLs can be located anywhere from the base of the skull to the pelvis, and most commonly are found in the head and neck or near the inferior mesenteric artery. PHEO/PGL are rare tumors affecting approximately 1 in 2000 individuals; PHEOs make up about 80-85% of these tumors. The mean age at diagnosis is 43 years, but 10-20% of PHEO/PGL may be diagnosed in childhood. Both sexes are affected equally.

Sympathetic PHEOs/PGLs usually secrete catecholamines (e.g., epinephrine, norepinephrine, and/or dopamine), while most parasympathetic PGLs (located in the head and neck region) are biochemically silent. The metabolism of catecholamines involves conversion into inactive metabolites, such as metanephrines, 3-Methoxy-4-hydroxy-mandelic acid (VMA), and conjugated catecholamines. These metabolites can be detected in peripheral circulation for diagnostic purposes.

Most PHEOs are sporadic; in fact, 5-7% of all adrenal incidentalomas are found to be PHEOs on further work up. However, approximately half of all PHEOs/PGLs, including those that are characterized as sporadic because of the absence of any other signs in the patient or family history, are associated with a germline mutation in one of the PHEO/PGL susceptibility genes (discussed below); more than 75% of all pediatric cases of PHEO/PGLs are associated with an underlying germline mutation. These include defects in the genes causing familial syndromes such as multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1), von Hippel-Lindau (VHL) syndrome, Carney-Stratakis, and the inherited PGL syndromes which are due to succinate dehydrogenase (SDHx) defects.

Malignant PHEOs/PGLs are defined as the presence of metastases to sites where they are not present normally, such as liver and bone. Malignancy occurs in 10-17% of all PHEOs/PGLs, and in up to 50% of PGLs associated with a germline succinate dehydrogenase subunit B (SDHB) gene mutation. Tumor size over 5 cm has been associated with increased malignant potential, as has the location of the primary PGL; namely, in the mediastinum or at the organ of Zuckerkandl. Histologic features alone are not enough to distinguish malignant PHEOs/PGLs from benign tumors, and histologic scoring systems such "pheochromocytoma of the adrenal gland scaled score" (PASS) or the Ki-67 proliferation index have been inconsistent in their ability to predict likelihood of malignancy.

Typical findings

  1. The classic triad of symptoms caused by PHEO or hormone-secreting PGL consists of episodic headache, sweating, and tachycardia. Patients may develop paroxysms characterized by a spike in blood pressure, sudden headache, sweating, flushing or facial pallor, palpitations, and feelings of anxiety or impending doom. The episode may also be accompanied by nausea and vomiting.

  2. Blood pressure spikes, sustained hypertension, or a combination of sustained hypertension with spikes to crisis levels have all been associated with PHEO/PGL, although in children, sustained hypertension is most common.

  3. Other symptoms, particularly in children, include dizziness, visual disturbances, weight loss, fasting hyperglycemia, constipation, polyuria, and polydipsia.

PHEO/PGL hereditary syndromes

MEN2: It is caused by mutations in the rearranged during transfection (RET) proto-oncogene. There are three subtypes, MEN2A, MEN2B, and familial medullary thyroid carcinoma (MTC). MEN2A is associated with MTC, primary hyperparathyroidism, and PHEO. MEN2B is associated with MTC, PHEO, as well as mucosal neuromas, joint deformities, a Marfanoid skeletal habitus, and occasionally developmental delay. Familial MTC, as the name implies, is associated with MTC, but not with any of the other clinical manifestations of the MEN2 syndromes. MTC is typically the first presentation of all three MEN2 subtypes, with PHEOs arising typically in the fourth decade of life. About 50% of MEN2A and MEN2B cases develop PHEOs, and about half of these individuals have bilateral disease. Most of these PHEOs produce epinephrine/metanephrine and metastatic disease is infrequent.

NF1: It is caused by mutations in NF1 gene. This syndrome is characterized by cafe-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic gliomas, as well as bony lesions. MTC, CML, malignant gliomas, and PHEOs are also associated with NF1, although PHEOs only occur in less than 1-2% of patients. PHEOs associated with NF1 are typically unilateral, adrenal in location, epinephrine/metanephrine-producing, and usually benign. Patients with NF1 should be screened for PHEO only if they develop symptoms, as there is a low incidence of PHEO with NF1 patients.

VHL: It is caused by mutations in the VHL gene. It is associated with a number of tumors, including hemangioblastomas of the brain and spine, retinal angiomas, clear cell renal carcinomas (CCRCC), PHEOs, tumors of the endolymphatic sac of the middle ear, renal cysts, pancreatic cysts, liver cysts, and hemangiomas of the adrenal gland, liver, and lungs. There are two subtypes types of VHL with respect to its association with PHEOs: type 1 do not develop PHEOs, whereas type 2 do. Type 2 is further subdivided into type 2A (without CCRCC), type 2B (with any of the tumors listed above), and type 2C (PHEO/PGL only). Overall, the risk of PHEO development is less than 30% among patients with VHL, and the tumors tend to be adrenal, bilateral, and less frequently malignant as compared with sporadic PHEOs. VHL-associated PHEOs have a low expression of PNMT, the enzyme which converts norepinephrine to epinephrine, and as a result, produce only norepinephrine/normetanephrine in 98% of cases.

Familial isolated PGL syndromes: These are caused by a mutation in one of the subunits of the SDH enzyme (SDHA, SDHB, SDHC, SDHD) or its cofactor (SDHAF2). SDHB is the most common germline mutation among familial PHEO/PGLs (found in over 10% of cases) and is strongly associated with aggressive extra-adrenal sympathetic PGL tumors, metastatic disease, and younger presentation. In fact, all individuals with metastatic PHEOs/PGLs should consider undergoing screening for SDHB germline mutations. However, penetrance is low among SDHB mutation carriers, with only 45% of individuals having disease by age 40.

SDHD mutations commonly are associated with multiple bilateral PGLs in the head and neck (HNPGL), but can also have tumors in other locations such as the mediastinum, abdomen, or adrenal. HNPGLs are usually biochemically silent, but up to 20% may secrete dopamine or its metabolite methoxytyramine. Metastases are rare. Of note, SDHD is maternally imprinted (inactivated), so the disease is exclusively passed down from an affected father.

SDHA, SDHC, and SDHAF2 mutations are much rarer. SDHC and SDHAF2 also associated with multiple HNPGLs with low malignant potential, and SDHAF2 is maternally imprinted, like SDHD. SDHA mutations were first associated (in the homozygote state) with Leigh syndrome, a neurodegenerative disorder; they have also been found now (in the heterozygote state) as a rare cause of PHEO/PGL.

It is important to remember that individuals with SDHx mutations are also at higher risk for other tumors, such as renal cell carcinoma, gastrointestinal stromal tumors (GIST), breast cancer, papillary thyroid carcinomas, and pituitary tumors. Among patients with SDH defects two distinct syndromes diagnostically have been described:

  1. Carney-Stratakis syndrome: It is characterized by PGLs and GISTs. The syndrome appears to be inherited in an autosomal dominant pattern and is caused by SDHx mutations. The GISTs are multifocal and patients may occasionally have other endocrine tumors as well. The PGLs are mostly abdominal, and both functional and non-functional lesions have been described.

  2. Pituitary adenoma (PA), PHEO and PGL association (3PAs): As the name implies the disease describes the co-presence of PA with PHEOs or PGLs. All types of PAs have been linked to SDHx defects from non-functioning to prolactin, growth hormone and corticotropin-producing.

Carney Triad: It is characterized by pulmonary chondromas, GISTs and functioning PGL. The PGLs are frequently multiple, catecholamine-producing, and may cause locally compressive symptoms as well. The tumors can be distributed in the head, neck, thorax, and abdomen, and have a similar rate of metastasis as sporadic PHEOs/PGLs. The disease almost always affects females (very few males have been described with the disorder) and typically presents before the age of 30. The underlying genetic basis has not yet been identified, but the disease has been linked to abnormal methylation of the SDHC gene promoter; less than 10% of the patients with Carney Triad carry mutations in the SDHx genes but the genetic defect in the rest remains unknown.

Other familial/genetic causes of PHEO/PGL: Recently many rare (<2% of cases) germline mutations associated with PHEO/PGL have been discovered. Mutations in MAX and TMEM127 are both associated with norepinephrine and/or epinephrine producing adrenal PHEOs, and bilateral disease is common in both. Patients are typically diagnosed in their 30s and 40s, respectively. TMEM127-caused PHEOs are typically benign, whereas MAX mutations have an increased susceptibility for metastatic disease. Hypoxia-inducible factor 2-alpha (HIF2A, also known as EPAS1) mutations are associated with multiple PGLs, polycythemia, and somatostatinomas. Other genes found in rare familial cases of PHEO/PGL include KIF1Bβ, PHD2 (also known as EGLN1), fumarate hydratase (FH), malate dehydrogenase (MDH2), and BAP1.

Age of initial screening for PHEO/PGL in asymptomatic children with known genetic mutation:

  • MEN2:

    • MEN2B due to RET mutation M918T: 11 years old

    • MEN2A due to RET mutations in C634: 11 years old

    • All others: 16 years old

  • VHL: 5 years old

  • NF1: screening only needs to be done if signs/symptoms of PHEO develop

  • SDHB, SDHC, and paternally inherited SDHD: 5-7 years old

  • Paternally inherited SDHAF2: 20 years old

What other disease/condition shares some of these symptoms?

  1. Paroxysmal vasodilating headaches

  2. Autonomic dysfunction

  3. Panic attacks

  4. Hypoglycemia

  5. Use of sympathomimetic agents (e.g., cocaine)

  6. Acute drug withdrawal (e.g., clonidine, alcohol)

  7. Paroxysmal atrial tachycardia

  8. Cardiomyopathy

  9. Takotsubo syndrome

  10. Postural tachycardia syndrome (POTS)

  11. Acute malignant hyperthermic crisis

  12. Hyperthyroidism

  13. Carcinoid

What caused this disease to develop at this time?

  • PHEOs/PGLs can occur sporadically or as part of a hereditary syndrome.

    • Hereditary syndromes associated with PHEO/PHLs include MEN2, (either MEN2A or MEN2B), NF1, VHL, familial PHEO/PGL, Carney triad, and Carney-Stratakis syndrome.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • The initial diagnostic test of choice is either plasma free metanephrines or a 24-hour urinary fractionated metanephrines (metanephrine and normetanephrine). The plasma metanephrines are typically elevated more than threefold above the upper limit of normal for the reference range. Urinary normetanephrines are typically elevated >1500 µg/day, and metanephrines >600 μg/day. Plasma and/or 24-hour urine catecholamines can be collected simultaneously with metanephrines, but do not have as high diagnostic accuracy.

    • The conditions under which the samples are obtained are important and may affect the reliability of the results. Patients should be supine 15-20 minutes prior to sampling, blood should be drawn through a previously inserted IV line, and nicotine and alcohol should be avoided for at least 12 hours prior to the test. Drawing plasma metanephrines while seated, rather than supine, may falsely elevate the results.

    • Numerous medications can falsely elevate metanephrines, including acetaminophen, labetalol, phenoxybenzamine, tricyclic antidepressants (TCAs), decongestants, and buspirone.

    • Urine collections should also be measured for creatinine to ensure proper collection.

  • False-positive results occur in 20% of cases; borderline or mildly elevated results typically warrant repeat or further testing (see below).

  • Chromogranin A is a marker of neuroendocrine cells, and can be used to monitor PHEO activity pre- and post-operatively. However, it is non-specific, and is released from other tissues. Proton pump inhibitors (PPIs) interfere with testing for Chromogranin A and should be stopped at least 2 weeks prior to testing.

  • Clonidine suppression test can be used in cases where the diagnosis is uncertain. The alpha receptor blocker clonidine specifically blocks norepinephrine released from neurons, but does not block its release from the adrenal medulla or from PHEO tumors. In healthy individuals, plasma metanephrine levels demonstrate a >40% decrease at 3 hours after clonidine administration. This test may cause significant hypotension, and patients should be monitored during this test. Additionally, it can result in false positives, as some normal stressed individuals may fail to suppress.

  • Rarely PHEOs can be biochemically silent, or only secrete methoxytyramine, a dopamine metabolite, for which commercial biochemical testing is not yet widely available.

  • Urine vanillylmandelic acid (VMA) is inferior to metanephrine testing, and is not commonly employed in the work of up PHEO/PGL.

  • Glucagon stimulation testing is no longer recommended in the work up of PHEO/PGL given its inferior diagnostic sensitivity and risk for side effects.

Would imaging studies be helpful? If so, which ones?

  • Once the biochemical diagnosis has been established, imaging studies should be pursued to localize the tumor.

  • The initial test of choice in pediatric patients is magnetic resonance imaging (MRI) with or without contrast, as it avoids radiation exposure. It has a good sensitivity (93-100%) for detection of PHEOs, and while the sensitivity for the detection of extra-adrenal PGLs and metastatic disease is lower, it is still very high (90%).

    • On T1-weighted imaging, PHEO/PGL have a signal intensity similar to liver, kidney, and muscle, which distinguishes them from the more common and benign cortical adenomas, which appear bright on MRI.

    • On T2-weighted images, PHEO/PGL have a hyperintense appearance.

    • PHEO/PGL usually enhance with gadolinium contrast.

  • In adult patients, the initial test of choice is a CT scan of the chest, abdomen, and pelvis, with a sensitivity between 88-100%. Most PHEO/PGL have greater than 10 Hounsfield units on noncontrast CT, and greater than 60% absolute washout (or 50% relative washout) on delayed contrast images.

    • For adult patients with suspected neck lesions, surgical clips, contrast allergies, pregnancy, recent excessive radiation exposure, or other contraindications to CT, MRI with contrast is preferred.

  • Ultrasound has much poorer sensitivity than CT or MRI, but may be useful in evaluating bladder PGLs or hepatic metastases.

  • Functional Imaging: if the tumor is not localized on CT or MRI, metastatic disease is seen or suspected, or the patient has an SDHB mutation, additional functional imaging should be pursued.

    • 123I-metaiodobenzylguanidine (MIBG) is useful to localize and confirm the presence of PHEO/PGL by utilizing the presence of catecholamine transporters as markers for disease. MIBG has high affinity and uptake by norepinephrine transporters, and is selectively accumulated but not metabolized. 131I-MIBG is less sensitive and emits greater γ radiation than 123I-MIBG, and therefore is no longer recommended. However, false-positivity of MIBG is a significant problem, as up to 50% of normal adrenal glands can demonstrate uptake. Also, MIBG is less sensitive for the detection of malignant, bilateral, or extra-adrenal PHEO/PGL, or those related to MEN2, VHL, or SDHx (sensitivity may be less than 50%).

      • The thyroid will uptake the isotopes, and saturated solution of potassium iodide must be used before and 4 days after to prevent uptake.

      • Medications that can cause false negatives must be discontinued at least two weeks prior to scanning. These medications include agents that deplete catecholamine stores (i.e., amphetamines, labetalol, reserpine), agents that inhibit catecholamine transporters (i.e., cocaine, TCAs, phenothiazines), and calcium channel blockers.

    • PET imaging is superior to MIBG in regards to PGLs or metastatic disease, and is more commonly being used over MIBG in the evaluation of PHEO/PGL.

      • 18F-dihydroxyphenylalanine (FDOPA) has been shown to have excellent sensitivity (>90%) and specificity in metastatic disease, but is not commonly available. Pretreatment with carbidopa inhibits FDOPA metabolism, resulting in improved sensitivity.

      • 18F-fluorodeoxyglucose (FDG) PET is most frequently used and has excellent sensitivity by taking advantage of the increased glucose uptake of PHEO/PGL tumors. However, FDG-PET has lower specificity than FDOPA, as inflammation, infection, benign adrenal adenomas, and other tumors/cancers may also demonstrate positive uptake. Also, in states of hyperglycemia, the elevated circulating glucose may compete with the FDG tracer for uptake, thereby resulting in a false-negative scan.

      • 18F-fluorodopamine (FDA), like FDOPA utilizes substrates of neuroendocrine tumors to detect and localize PHEO/PGL, and has excellent sensitivity in detecting primary thoracic or abdominal tumors. However, FDA is not commonly available and has lower sensitivity in metastatic or familial PHEO/PGL.

      • Recent studies have suggested that PET/MRI may be equivalent to PET/CT in imaging PHEO/PGL, thereby avoiding radiation exposure to the patient.

    • 68Ga-labelled DOTA peptides (DOTATATE, DOTATOC, and DOTANOC) have demonstrated great promise in imaging metastatic PHEO/PGL. In particular, 68Ga-DOTATATE has been shown to be superior to other functional imaging modalities in SDHB metastatic disease and HNPGL, and has exceptional sensitivity and specificity in abdominal and thoracic PGLs as well. It is available in Europe and Australia, but availability in the US is currently limited to a few tertiary centers.

    • Octreoscan: 111I-pentetreotide scintigraphy utilizes somatostatin receptors on PHEO/PGL tumors, and is helpful with solitary adrenal tumors. However, given that the expression of these receptors are variable in PHEO/PGL, false-negative results are common among small tumors/metastases and HNPGL.

If you are able to confirm that the patient has Pheochromocytomas/Paragangliomas, what treatment should be initiated?

The mainstay of treatment is surgical excision for PHEO/PGLs that are secretory. Non-secreting PGLs may be followed by imaging, depending on the size/location of the tumor, and depending on the patient.

  • Medical treatment is aimed at reducing hypertension and blocking the production of catecholamines, in order to minimize life-threatening hypertensive crises in preparation for surgical excision. Many clinicians prefer to use a combination of an alpha-blocker with a beta-blocker. The alpha-blocker should ALWAYS be started first, before initiation of the beta-blocker, in order to avoid unopposed alpha receptor stimulation and an acute worsening of blood pressure.

    • Phenoxybenzamine: non-selective, long-acting alpha adrenergic blocker. The initial dose is 10 mg once to twice a day, and can be increased by 10 mg increments every 2 to 3 days until adequate blood pressure control has been achieved.

    • Selective alpha-1 adrenergic blocking agents: prazosin, terazosin, and doxazosin may be used instead of phenoxybenzamine. Doxazosin is usually started at 2 mg at bedtime to avoid postural hypotension. Prazosin can be started in doses of 2 to 5 mg BID to TID, while Terazosin is usually started 1-2 mg at bedtime and can be titrated up to 10 mg BID. Selective alpha-1 adrenergic blocking agents are less effective than phenoxybenzamine, but are also significantly less expensive, and therefore are often used in patients with mild catecholamine production/low disease burden.

    • Beta-blockers: Atenolol (12.5-25 mg BID or TID) and metoprolol (25-50 mg TID or QID) can be started at least 3 days after alpha-blockade has been initiated, and is primarily used to control tachycardia rather than hypertension. Beta-blockers that contain both beta- and alpha-adrenergic blocking ability (e.g., labetalol) should NOT be used as a single agent or first-line therapy in PHEO/PGL, as their beta-adrenergic activity is more potent than its alpha-blockade, and therefore could cause a hypertensive crisis.

    • Calcium channel blockers: block noradrenergic-induced calcium influx into vascular smooth muscle, thereby treating hypertension and arrhythmias induced by adrenergic excess. Nicardipine SR (30 mg BID), nifedipine (30-60 mg QD or BID), amlodipine (10 mg QD) or verapamil (180-540 mg QD) can also be used, either as adjunct treatment to alpha blockers, or in patients unable to tolerate alpha blockers secondary to side effects. They may also be used in normotensive patients and for treatment of coronary vasospasm secondary to PHEO.

    • Metyrosine: inhibitor of the enzyme tyrosine hydroxylase, which catalyzes the first step of catecholamine synthesis. Consequently, metyrosine depletes catecholamine production in PHEO/PGLs, and is very effective at decreasing circulating catecholamine levels. Starting doses of 250 mg every 6-8 hours are increased by 250 mg every 2 to 3 days as necessary. It should be used as an adjunct treatment to alpha-blockers only when necessary as it can be very expensive, difficult to obtain, and cause side effects such as depression, severe fatigue, nausea, and somnolence.

  • Therapy for acute hypertensive crises:

    • Phentolamine is a rapid-acting alpha-blocker. It is given as a bolus dose (1-3 mg for children) or by IV infusion.

    • Nifedipine 10 mg, when chewed, can be a rapid treatment for paroxysmal hypertension, for home use.

Surgical Treatment: Laparoscopic surgery is the treatment of choice for PHEOs that are <6 cm in diameter. For hereditary PHEOs, partial adrenalectomies that are cortical-sparing are advocated when possible to avoid life-long glucocorticoid and mineralocorticoid replacement. However, this may result in higher rates of tumor recurrence (up to 24%). For tumors >6 cm, or invasive, open surgery may be required. Arterial embolization may be helpful in reducing vascularity for large head and neck PGLs. In the immediate post-operative period, intravascular fluid replacement is required to avoid cardiovascular shock due to withdrawal from hypercatecholaminemia, so IV fluids are frequently started pre-operatively.

Follow-up treatment: Children are at higher risk of tumor recurrence, and long-term follow-up with biochemical evaluation and imaging studies is recommended, particularly for children with an identified genetic mutation. Plasma or 24-hour urine metanephrines levels should be performed once the patient has recovered from surgery (typically 2-6 weeks post-operatively), to avoid false positives. Thereafter, the patient should be evaluated at least annually for recurrence of disease.

Malignant PHEO/PGL: Treatment is generally not curative, but is aimed at disease stabilization. The first consideration should be resection of the primary mass, if possible. Total adrenalectomy or complete resection of PGL tumors is recommended. Radiofrequency ablation can be used for bone or liver metastasis, in addition to cryoablation or arterial embolization for liver lesions, and external beam radiation for bone metastases.

131I-MIBG treatment can be used for MIBG-positive tumors. Chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) can be effective for rapidly progressive disease. However, this therapy needs to be continued indefinitely, as tumors relapse after cessation of chemotherapy. Tyrosine kinase inhibitors, such as sunitinib, sorafenib, and everolimus have been studied in malignant PHEOs/PGLs, but with limited success.

Recently, investigators have started studying the use of radiolabeled DOTA peptides in the treatment of metastatic PHEO/PGL. Specifically, 177Lu, 90Y, or 111In attached to DOTATATE, DOTATOC, or DOTANOC have had encouraging results in both pediatric and adult populations, although the sample sizes thus far have been very small.

What are the adverse effects associated with each treatment option?

Medical Treatment

  • Alpha blockers: can cause orthostatic hypotension along with reflex tachycardia, dizziness, syncope, and fatigue. Liberal salt intake along with volume expansion can help.

  • Beta blockers: can cause bronchospasm in those with asthma, depression, nausea, diarrhea, bradycardia, orthostasis, and fatigue.

  • Calcium channel blockers: can cause headache, dizziness, nausea, constipation, and muscle cramps.

  • Metyrosine: can cause sedation, depression, fatigue, anxiety, galactorrhea, as well as extra-pyramidal side effects. It can also cause nausea, diarrhea, crystalluria, and urolithiasis.

Treatment for metastatic disease

  • 131I-MIBG treatment: side effects include nausea and sialadenitis. Bone marrow suppression and thrombocytopenia, along with elevated liver enzymes and renal toxicity have been associated with treatment. However, avoidance of doses exceeding 500 mCi, along with use of GCSF-stimulated leukapheresis in order to cryopreserve white blood cells can be useful in cases of prolonged marrow suppression. Additional long-term adverse effects include infertility, along with an increased lifetime risk of second malignancies. Sperm/oocyte cryopreservation is recommended prior to treatment.

  • CVD chemotherapy: myelosuppression, gastrointestinal toxicity, peripheral neuropathy, and/or hair loss, although usually side effects are transient.

What are the possible outcomes of Pheochromocytomas/Paragangliomas?

Surgical removal of the tumor is the primary therapy for PHEO/PGL, and in sporadic cases, recurrent/metastatic disease occurs in only about 15% of cases. However, recurrence may occur many years after the primary tumor, and thus long-term monitoring is recommended. In metastatic disease confined to the abdomen, complete resection can result in biochemical response in up to 40% of individuals at 8 years. For widely metastatic disease, however, surgery is used for palliative, rather than curative purposes and biochemical response is short-lived.

Partial bilateral adrenalectomy may be employed in young children or those with a familial form of PHEO/PGL to avoid adrenal insufficiency, and avoid the need for lifelong glucocorticoid and mineralocorticoid replacement.

What causes this disease and how frequent is it?

The overall prevalence of PHEO is between 1:4500 and 1:1700, and of those, approximately 10-20% are diagnosed during childhood. Average age of diagnosis for children is 11, and the disease is slightly more common in boys. When the disease is diagnosed in children, it is frequently familial, bilateral or multi-focal, and extra-adrenal.

There are several known hereditary syndromes associated with PHEO/PGL, and they each have associated genetic mutations:

MEN2: autosomal dominant syndrome caused by germline activating mutation in the RET proto-oncogene. MEN2 syndromes include MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). Patients with MEN2 develop PHEOs, but very rarely develop PGLs. The estimated prevalence of MEN2 is approximately 2.5 per 100,000 people.

VHL: autosomal dominant syndrome caused by a germline mutation in the VHL protein, which is responsible for degrading proteins, such as the hypoxia inducible factor 1 (HIF1), a transcription factor. The incidence of VHL is approximately 1:36,000, and can manifest itself in childhood, adolescence, or adulthood.

NF1: autosomal dominant syndrome caused by an inactivating mutation/deletion to a tumor suppressor gene, NF1. The product of the NF1 gene is neurofibromin, which regulates Ras, a signaling protein responsible for cell growth. The incidence of the disease is between 1:2600 and 1:3000 people.

Familial paragangliomas: autosomal dominant syndrome caused by mutations in genes that code for a mitochondrial complex element, succinate dehydrogenase complex II (SDHx), which has four subunits and a cofactor. PGL1 is caused by an inactivating mutation of the SDHD gene. PGL2 is caused by an inactivating mutation to the SDHAF2 gene. PGL3 is caused by the inactivating mutation to the SDHC gene. PGL4 is caused by mutation of the SDHB gene, and PGL5 is caused by a mutation in SDHA. Mutations in SDHx are also associated with the development of other tumors. SDHB and SDHD mutations account for about 10% and 9% of cases of PHEO/PGL, respectively, whereas the other three SDHx mutations are much rarer. Mutations in other genes associated with PHEO/PGL (e.g., MAX, TMEM127, HIF2A, KIF1Bβ, PHD2, FH, MDH2, and BAP1 are also exceedingly rare.

Carney Triad: The defect for most patients remains unknown to date; the disease has been linked to abnormal SDHC methylation, and less than 10% of the patients carry mutations in the SDHx genes. The disease is much more common in women, and patients present early, typically before the age of 30.

Carney-Stratakis syndrome: It appears to be inherited in an autosomal dominant pattern with incomplete penetrance. Germline SDHx mutations have been discovered in patients with this syndrome.

Pituitary adenoma (PA), PHEO and PGL association (3PAs): It is caused by SDHx defects and is associated with non-functioning, as well as prolactin-, growth hormone- and corticotropin-producing PAs. Patients may present at any age.

How do these pathogens/genes/exposures cause the disease?

Microarray analyses of hereditary PHEO/PGL have purported two separate expression "clusters". VHL, SDHx, HIF2A, FH, MDH2, and PHD2 have been hypothesized to be associated with a "pseudo-hypoxic" response, resulting in stabilization/increased activity of Hypoxic Inducible Factors (HIFs). These transcription factors in turn cause increased VEGF activity, and dysregulated angiogenesis, energy metabolism, and apoptosis. On the other hand, RET, NF1, TMEM127, MAX, and KIF1Bβ are involved in kinase signaling pathways (e.g., Ras/MAPK, PI3K/Akt, mTOR). Mutations in these genes cause aberrant protein expression and impaired apoptosis. Other disease-causing pathways have also been proposed.

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

Recurrence of disease is a common occurrence in children with PHEOs/PGLs, and has been reported to occur in up to a third of patients. For this reason, annual screening is recommended in all patients, even in those that appear cured.

Are additional laboratory studies available; even some that are not widely available?

The measurement of methoxytyramine in the plasma can be useful for tumors that hypersecrete dopamine. As such, it is a good method to differentiate patients with tumors from SDHB and SDHD mutations from those resulting from MEN2, NF1, and VHL. This test is not widely commercially available currently.

Histological testing of tumors for SDHB, particularly for malignant or extra-adrenal PHEO/PGL, has been proposed. If staining is negative for SDHB, then a mutation in SDHB is highly likely, whereas weak SDHB staining likely represents a mutation in one of the other SDHx genes (particularly SDHD). Also, because mutations in SDHA may be hard to identify on genetic screening, given highly homologous redundant pseudo-genes, a lack of staining of SDHA on immunohistochemistry may be helpful in making the diagnosis.

How can Pheochromocytomas/Paragangliomas be prevented?

Unfortunately, there is no way to prevent PHEO/PGL; however, genetic testing for associated hereditary syndromes can assist in early diagnosis. Children with known hereditary syndromes associated with PHEO/PGL should be screened for the presence of PHEO/PGL in order to diagnose the disease early and prevent the development of other associated tumors.

In case of a clinical finding that points toward a particular hereditary syndrome, such as MEN2, NF1, or VHL, testing should be directed towards identification of known genetic mutations associated with their respective syndrome. Any child at risk for MEN2 (i.e., known family history) should be screened annually for biochemical evidence of the tumor, or if they develop signs or symptoms of PHEO, as screening for the RET gene mutation at an early age can prevent medullary thyroid carcinoma if prophylactic thyroidectomy is performed, and biochemical monitoring for PHEO can allow for early diagnosis and therapy.

In non-obviously syndromic cases, pediatric patients diagnosed with PGLs should be tested for the SDHB mutation first and SDHD second (with the order reversed in HNPGL). In PHEOs limited to the adrenals, primarily adrenergic-secreting tumors should be screened for RET mutations, whereas noradrenergic tumors should be screened for VHL, followed by SDHD and SDHB. Dopaminergic adrenal PHEOs should be screened for SDHD followed by SDHB. Guidelines with a full algorithm of genetic testing have been previously published by the Endocrine Society.

In patients with known mutations but without evidence of disease, annual testing with plasma fractionated metanephrines, as well as blood pressure monitoring, should be performed, as discussed above. In addition, periodic imaging is recommended for patients with known SDHx mutations.

What is the evidence?

Ein, SH, Shandling, B, Wesson, D, Filler, R. "Recurrent pheochromocytomas in children". J Pediatric Surgery.. vol. 25. 1990. pp. 1063.

(Retrospective review of the diagnosis and treatment of 13 children with 20 pheochromocytomas treated between 1958-1987.)

Lenders, JW, Pacak, K, Walther, MM, Linehan, WM. "Biochemical diagnosis of pheochromocytoma: which test is best". JAMA. vol. 287. 2002. pp. 1427-1434.

(Multicenter cohort study evaluating the sensitivity and specificity of plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid in 214 patients with and 644 patients without pheochromocytoma.)

Pacak, K, Eisenhofer, G, Ahlman, H, Bornstein, SR. "International symposium on Pheochromocytoma: recommendations for clinical practice from the first International Symposium". National Clinical Practice Endocrinology and Metabolism. vol. 3. 2007. pp. 92-102.

(International Symposium on the diagnosis, localization, genetic testing, and treatment of pheochromocytoma.)

Stratakis, CA, Carney, JA. "The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications". J Intern Med. vol. 266. 2009 Jul. pp. 43-52.

(An investigation into the genetic basis of Carney Triad and Carney-Stratakis syndrome, demonstrating a possible link to mutations in SDHx.)

King, KS, Chen, CC, Alexopoulos, DK, Whatley, MA. "Functional imaging of SDHx-related head and neck paragangliomas: comparison of 18F-fluorodihydroxyphenylalanine, 18F-fluorodopamine, 18F-fluoro-2-deoxy-D-glucose PET, 123I-metaiodobenzylguanidine scintigraphy, and 111In-pentetreotide scintigraphy". J Clin Endocrinol Metab. vol. 96. 2011 Sep. pp. 2779-85.

(Prospective analysis of 10 patients with 26 head and neck paragangliomas who were evaluated with 5 functional imaging techniques for localization of head and neck paragangliomas.)

Ellis, RJ, Patel, D, Prodanov, T, Sadowski, S. "Response after surgical resection of metastatic pheochromocytoma and paraganglioma: can postoperative biochemical remission be predicted". J Am Coll Surg. vol. 217. 2013 Sep. pp. 489-96.

(Retrospective analysis of surgical outcomes of metastatic PHEO/PGL in a single referral center.)

Lenders, JW, Duh, QY, Eisenhofer, G, Gimenez-Roqueplo, AP. "Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline". J Clin Endocrinol Metab. vol. 99. 2014 Jun. pp. 1915-42.

(Guidelines for the diagnosis and management of PHEO/PGL.)

Haller, F, Moskalev, EA, Faucz, FR, Barthelmeß, S. "Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad". Endocr Relat Cancer. vol. 21. 2014 Aug. pp. 567-77.

(Describes that aberrant DNA methylation - an epigenetic phenomenon - at the SDHC gene locus may be responsible for the tumor formation seen in Carney Triad)

Wells, SA, Asa, SL, Dralle, H, Elisei, R. "Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma". Thyroid. vol. 25. 2015 Jun. pp. 567-610.

(Guidelines for MTC and MEN2 syndromes, including the screening and treatment of MEN2-associated PHEOs.)

Boikos, SA, Xekouki, P, Fumagalli, E, Faucz, FR. "Carney triad can be (rarely) associated with germline succinate dehydrogenase defects". Eur J Hum Genet. vol. 24. 2016 Apr. pp. 569-73.

(About 10% of individuals with Carney Triad have a germline mutation in SDHx and therefore should be offered genetic screening for these loci.)

Ongoing controversies regarding etiology, diagnosis, treatment

  • The exact biochemical pathways of PHEO/PGL tumor formation are still being elucidated.

  • More underlying predisposing genetic mutations likely will be discovered.

  • The choice of optimal functional imaging, particularly depending on the underlying genetic mutation or disease characteristics (single tumor vs. metastatic disease, HNPGL vs. intra-abdominal, etc.), is still being elucidated, particularly with the new DOTA peptides.

  • Radiolabeled DOTA chemotherapy needs further investigation to determine its place in the physician's armamentarium for metastatic PHEO/PGL.

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