Pheochromocytoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

Pheochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands and extra-adrenal chromaffin tissue, which fail to involute after birth, they secrete excessive amounts of catecholamines, usually epinephrine and norepinephrine. Extra-adrenal paragangliomas (often described as extra-adrenal pheochromocytomas) are closely related, though less common. Pheochromocytoma originates from the chromaffin cells of the sympathetic nervous system ganglia and is named based upon the primary anatomical site of origin. The incidence of pheochromocytoma ranges from a low of 0.2 per 100,000 persons to a high of 0.8 per 100,000 persons. The average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases with men and women are equally affected. MRI and CT scan are used for the diagnosis of pheochromocytoma. Surgery is the mainstay of the treatment.

In 1886, Fränkel made the first description of a patient with pheochromocytoma. In 1912, Ludwig Pick formulated the term pheochromocytoma.1912. In 1926, the first surgical removal of pheochromocytoma in the Military Medical Academy in Yugoslavia was performed by Professor Isidor Papo.

Pheochromocytoma arises from chromaffin cells of the adrenal medulla.On gross pathology, pheochromocytoma has a multinodular and a multicentric pattern of growth. On microscopic histopathological analysis, nesting (Zellballen) pattern composed of well-defined clusters of tumor cells separated by fibrovascular stroma is a characteristic finding. It may be benign or malignant, familial origin(multiple endocrine neoplasia type 2) or sporadic one. Both of them have genetic origin depends on a large number of genes: VHL, SDH, NF1, RET.

Pheochromocytoma may be classified based on nature of the tumor into benign and malignant. It can also be classified based on spread into local, regional, and metastatic.Another classification based on origin divides pheochromocytoma into familial, non-familial and sporadic forms.

Pheochromocytoma develops in called chromaffin cells, found in adrenal medulla which secretes adrenaline, noradrenaline, and dopamine. The genetic base of pheochromocytoma depends on 2 clusters: cluster 1 tumors are noradrenergic. Cluster 2 tumors are adrenergic. Familial pheochromocytoma may be caused by a mutation of either SDHD, VHL, SDHB, RET, NF1 genes.

Pheochromocytoma must be differentiated from other causes of paroxysmal hypertension including severe paroxysmal hypertension (Pseudopheochromocytoma), panic disorder, Factitious hypertension, carcinoid syndrome, Migraine headache, Hyperthyroidism, Renovascular hypertension, Hypoglycemia, Labile hypertension (White coat hypertension), Stroke and compression of the lateral medulla, Seizures, Baroreflex failure, and drugs.

The incidence of pheochromocytoma ranges from a low of 0.2 per 100,000 persons to a high of 0.8 per 100,000 persons. The average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases with men and women equally affected.

Pheochromocytoma is more common in third decade of life, people with family history of multiple endocrine neoplasias, Von Hippel-Lindau disease, neurofibromatosis type 1, hereditary paraganglioma syndromes.

Familial pheochromocytoma is associated with multiple endocrine neoplasias, VHL and neurofibromatosis1 and should be screened by plasma fractionated metanephrines levels. The next step is to obtain 24-hour urinaryfractionated metanephrine levels. Imaging should be considered if the initial tests are positive. Genetic testing also should be performed in high-risk patients

Pheochromocytoma is an adrenaline-secreting tumor, usually develop in the fifth decade of life. Symptoms start with tachycardia, hypertension, headache, and sweating. A massive release of catecholamines can cause hyperglycemia, malignant hypertension, and metastasis. The prognosis of pheochromocytoma is generally good but metastatic pheochromocytoma has a 5-year survival rate of approximately 50%.

Symptoms of pheochromocytoma include palpitations, anxiety, and headaches.

Common physical exam findings of pheochromocytoma include tachycardia, hypertension, and orthostatic hypotension.

Laboratory findings consistent with the diagnosis of pheochromocytoma include elevated catecholamines and metanephrine levels.

On EKG, pheochromocytoma is characterized by the presence of sinus tachycardia and supraventricular tachycardia.

There are no x-ray findings associated with pheochromocytoma.

Head, neck, chest, and abdominal CT scans may be helpful in the diagnosis of pheochromocytoma.

Head, neck, chest, and abdominal MRI may be helpful in the diagnosis of pheochromocytoma.

¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy coupled with CT scan imaging can be used for diagnosis of pheochromocytoma.

Clonidine suppression test may be used in the diagnosis of pheochromocytoma.

Treatment with alpha-blockers (example: phenoxybenzamine) followed by beta-blockers (example: atenolol) is required before surgery. Other drugs can be used such as calcium channel blockers and metyrosine. Adjunctive chemotherapy and radiation are used in metastatic disease. Hypertensive crisis can be managed by using sodium nitroprusside, phentolamine, and nicardipine.

Surgery is the mainstay of treatment for pheochromocytoma. Adrenalectomy; Laparoscopic transabdominal and retroperitoneal approaches have been used successfully for nonmetastatic abdominal pheochromocytomas. The patient should receive glucocorticoid stress coverage in bilateral adrenalectomy.

Biochemical screening for family members of MEN2 patients is mandatory. Genetic testing should be performed in first-degree relatives of a patient with proven germline RET mutation.

Preoperative treatment of pheochromocytoma is the best way to reduce complications and postoperative follow up is the best way to reduce recurrence.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2] Ifrah Fatima, M.B.B.S[3]

Adrenal pheochromocytoma and its typical clinical presentation was first described by Frankel in 1886. The term pheochromocytoma was coined by Ludwig Pick in 1912. In 1926, Cesar Roux in Switzerland, Charles H. Mayo in the United States, and Isidor Papo in Yugoslavia were the first surgeons to successfully remove pheochromocytomas. An autopsy revealed President Eisenhower had a 1.5-cm pheochromocytoma in the left adrenal gland.

• Adrenal pheochromocytoma and its typical clinical presentation was first described by Charles Sugrue in 1800.
• Its histological findings were first reported by Felix Fraenkel and Max Schottelius in 1886.
• Manasse in 1893 reported four cases of adrenocortical tumors and one case of an adrenal medulla tumor.
• Extra-adrenal pheochromocytoma was first described by Alezais and Peyron in 1908.
• The term pheochromocytoma was coined by Ludwig Pick in 1912.
• In 1922, the association between paroxysmal hypertension and pheochromocytoma was described by L’Abbe et al.
• In the early 1900s, there were case reports describing genetic implications in the pathogenesis of pheochromocytomas and its association with syndromes like NF1, VHL, and multiple endocrine neoplasia type 2 (MEN2) emerged.
• Later between 1940 and 1960, literature reviews and case series defined the genetic associations. ^[1]

• In 1926, Cesar Roux in Switzerland, Charles H. Mayo in the United States, and Isidor Papo in Yugoslavia were the first surgeons to successfully surgically remove pheochromocytomas. ^{[2] [3]}

The following are a few famous cases of pheochromocytoma:

• President Eisenhower– After his death, an autopsy revealed a 1.5-cm pheochromocytoma in the left adrenal gland. On analysis of his blood pressure through his life, fluctuating systolic and diastolic blood pressure spikes were documented. ^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

Pheochromocytomas and paragangliomas (collectively referred to as PPGLs) are rare tumors that originate from chromaffin cells in the adrenal medulla (pheochromocytoma) or in the extra-adrenal neural ganglia (paraganglioma). These tumors can be either biochemically active (producing a catecholamine like epinephrine, nor-epinephrine and dopamine) or biochemically silent. PPGLs can be either sporadic or genetic, with association to several familial syndromes. PPGLs can also be classified according to their spread into local, regional, or metastatic. The defining characteristic of malignancy in PPGLs is the presence of metastasis.

Pheochromocytoma and paragangliomas may be classified into several subtypes based on:

• Type of cells
• Nature of tumor
• Location
• Biochemical secretory patterns
• Genetics
• Mutations and pathogenetic pathways

Pheochromocytomas and paragangliomas may be classified according to the cells they are derived from: ^[1]

• Sympathetic– adrenal medulla or sympathetic trunk
• Parasympathetic– carotid body, glomus tympanicum, glomus jugulare, glomus vagale.

• Benign
• Metastatic/ Malignant

Malignant and benign tumors share the same biochemical and histological characters. The only difference is the ability of the malignant tumor to metastasize to distant tissues and have high rates of recurrence.

• According to the WHO 2017 Classification of Tumors of Endocrine Organs, all parangangliomas have metastatic potential and hence the term “malignant” was replaced with “metastatic”. ^[2]
• Common sites of metastasis include:
  • Lung
  • Bone
  • Head
  • Thorax
  • Liver

• 95% of pheochromocytomas are found in the abdomen
• Intra-adrenal– 85-90%
• Extra-adrenal (paragangliomas)– 10-15% are prevertebral and paravertebral sympathetic ganglia of the chest, abdomen, and pelvis.
  • The tumors in the abdomen most commonly arise from the organ of Zuckerkandl which is a collection of chromaffin tissue around the origin of the inferior mesenteric artery or the bifurcation of aorta. ^{[3] [4]}

Pheochromocytoma and paragangliomas (PPGL) can be classified based on the biochemical secretory pattern: ^[2]

• Noradrenergic phenotype (predominant norepinephrine secreting)- associated with Von Hippel-Lindau syndrome
• Adrenergic phenotype (predominant epinephrine secreting)- associated with MEN2 or neurofibromatosis type 1 (NF1)
• Dopamine secreting- associated with SDHB, SDHD or SDHC mutations and potentially metastatic tumors.

• Familial pheochromocytoma is associated with several hereditary disorders such as:
  • Multiple Endocrine Neoplasia types 2A
  • 2B (MEN2) (caused by mutations of the RET gene)
  • Von Hippel-Lindau (VHL) disease (caused by mutations of the VHL gene)
  • Familial paraganglioma of the neck (cause by mutations of the gene for succinate dehydrogenase subunit D (SDHD))
  • Neurofibromatosis type 1 (NF1)

• Resulting from sporadic germ-line mutations, which have been documented in about 20% of cases.
• The majority of them are positive for KIT expression. A partial explanation was provided by the finding of activating mutations in another gene encoding an RTK, the platelet-derived growth factor receptor alpha (PDGFRA) gene in some KIT-negative GISTs

• Most catecholamine-secreting tumors are sporadic. Mutations have been identified in most of the sporadic cases.

• Sporadic tumors may be due to spontaneous mutation, decreased penetrance or maternal imprinting.^[5]
• 50% of patients had a pathogenic mutation in SDHB, SDHD, or VHL.^[6]

Pheochromocytoma and paragangliomas (PPGL) can be classified into the following clusters- ^{[7] [8] [9]}

• Cluster 1
  • Mutations involving in overexpression of vascular endothelial growth factor (VEGF) as a result of pseudohypoxia
  • Impaired DNA methylation leading to increased vascularization
• Cluster 2
  • Activating mutations of Wnt-signaling pathway including Wnt receptor signaling and Hedgehog signaling.
  • Mutations of CSDE1 (Cold shock domain containing E1) and MAML3 (Mastermind like transcriptional coactivator 3) genes7.
• Cluster 3
  • Abnormal activation of kinase signaling pathways like PI3Kinase/AKT, RAS/RAF/ERK, and mTOR pathways.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

It is understood that pheochromocytoma is mediated by excessive secretion of catecholamines and subsequent stimulation of adrenergic receptors. It arises from the chromaffin cells of the adrenal medulla and sympathetic ganglia. The pathophysiology of pheochromocytoma does not depend on the histological subtype. Malignant and benign pheochromocytomas share the same biochemical and histological features. It may be sporadic or familial. All of these forms have genetic origin depending on a large number of genes, for example, VHL, SDH, NF1, RET genes. It is associated with conditions like MEN 2A syndrome, MEN 2B syndrome, VHL disease, and NF1.

Pheochromocytoma is not associated with normal physiology.

• It is understood that pheochromocytoma is the is mediated by excessive secretion of catecholamines and subsequent stimulation of adrenergic receptors.
• Commonly secreted catecholamines include norepinephrine (predominant) and epinephrine. Some tumors may also secrete dopamine. ^[1]
• Excessive secretion of catecholamines may be either continuous or intermittent.
• Pheochromocytoma is a tumor which arises from the chromaffin cells of the adrenal medulla and sympathetic ganglia.
• The pathophysiology of pheochromocytoma does not depend on the histological subtype. Malignant and benign pheochromocytomas share the same biochemical and histological features. ^[2][3][4]
• The exact mechanism responsible for surge in catecholamine secretion remains unclear but it has been postulated that certain medications (such as opiates, metoclopramide or beta blockers) and changes in tumor blood flow and pressure could be responsible factors.
• Binding to β₁ receptors causes renin release from juxtaglomerular cells and lipolysis in adipose tissue. It Increases cardiac output by:
  • Increase in heart rate in sinoatrial node
  • Increase in atrial cardiac muscle contractility
  • Increases in contractility and automaticity of ventricular cardiac muscle
  • Increases in conduction and automaticity of atrioventricular node

• Pheochromocytoma can be transmitted in a sporadic(60-65%) or familial pattern. ^[5][6]

• Genes involved in the pathogenesis of pheochromocytoma include:
  • RET gene (MEN 2A, MEN 2B syndromes)
  • NF1 gene
  • VHL gene (VHL disease)
  • SDHD, SDHB, and SDHC genes of the mitochondrial complex ^[7]
  • SDHA, SDHAF2, TMEM127 (transmembrane protein 127), MAX (myc-associated factor X), FH (fumarate hydratase), PDH1, PDH2 (pyruvate dehydrogenase), HIF1alpha (hypoxia-inducible factor), MDH2 (malate dehydrogenase), and KIF1Bß (kinesin family member) genes. ^[8]

Pheochromocytoma and paragangliomas (PPGL) susceptibility genes can be classified into the following clusters- ^{[9] [10] [11]}

• Cluster 1
  • Mutations involving in overexpression of vascular endothelial growth factor (VEGF) as a result of pseudohypoxia
  • Impaired DNA methylation leading to increased vascularization
• Cluster 2
  • Activating mutations of Wnt-signaling pathway including Wnt receptor signaling and Hedgehog signaling.
  • Mutations of CSDE1 (Cold shock domain containing E1) and MAML3 (Mastermind like transcriptional coactivator 3) genes7.
• Cluster 3
  • Abnormal activation of kinase signaling pathways like PI3Kinase/AKT, RAS/RAF/ERK, and mTOR pathways.

Conditions associated with pheochromocytoma include:

• Multiple endocrine neoplasia (MEN1)
• Multiple endocrine neoplasia (MEN2B)
• Von-Hippel Lindau disease (VHL)
• Neurofibromatosis 1 (NF1)

On gross pathology, the characteristic findings of pheochromocytoma are:

• Small to large tumors usually associated with hemorrhage and necrosis.^[12]
• Usually lobulated
• Bilateral when familial tumors
• Associated with hyperplasia in the adjacent medulla.
• Chromaffin reaction: fresh tumor cut section turns dark brown if add potassium dichromate at pH 5-6.

• 
  Bilateral pheochromocytoma in MEN2. Gross image. Source: https://upload.wikimedia.org/wikipedia/commons/5/5f/Bilateral_pheo_MEN2.jpg

On microscopic histopathological analysis, the characterisitc findings of pheochromocytoma typically include: ^{[13] [14]}

• A nesting (Zellballen) pattern- this pattern is composed of well-defined clusters of tumor cells (round or polygonal epithelioid cells) containing eosinophilic cytoplasm separated by fibrovascular stroma.
• These cells have a central nucleus with an eosinophilic, granular cytoplasm, and clumped chromatin.
• At the periphery, spindle-shaped sustentacular or supporting cells are seen.

• 
  Micrograph of pheochromocytoma. Source: By Nephron – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524
• 
  Histopathology of adrenal pheochromocytoma. Adrenectomy specimen. Source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535945
• 
  Micrograph of pheochromocytoma. Source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535944

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

The most common cause of pheochromocytoma is sporadic mutations. Less common causes of pheochromocytoma include familial associations and association with syndromes. Familial pheochromocytoma may be caused by a mutation of either SDHD, VHL, SDHB, RET, NF1 genes.

• Pheochromocytoma due to any cause may be life-threatening which may result in death.

• In most cases of pheochromocytoma, the cause is unknown.
• Sporadic form is more common

Less common causes of pheochromocytoma include:

• Familial form
• Associated with syndromes- Neurofibromatosis 1, Von Hippel-Lindau disease, Multiple Endocrine Neoplasia 2A and 2B

Pheochromocytoma of the familial type may be caused by a mutation in the following genes:

• RET gene (MEN 2A, MEN 2B syndromes)
• NF1 gene
• VHL gene (VHL disease)
• SDHD, SDHB, and SDHC genes of the mitochondrial complex ^[1]
• SDHA, SDHAF2, TMEM127 (transmembrane protein 127), MAX (myc-associated factor X), FH (fumarate hydratase), PDH1, PDH2 (pyruvate dehydrogenase), HIF1alpha (hypoxia-inducible factor), MDH2 (malate dehydrogenase), and KIF1Bß (kinesin family member) genes. ^[2]

Pheochromocytoma and paragangliomas (PPGL) susceptibility genes can be classified into the following clusters- ^{[3] [4] [5]}

• Cluster 1
  • Mutations involving in overexpression of vascular endothelial growth factor (VEGF) as a result of pseudohypoxia
  • Impaired DNA methylation leading to increased vascularization
• Cluster 2
  • Activating mutations of Wnt-signaling pathway including Wnt receptor signaling and Hedgehog signaling.
  • Mutations of CSDE1 (Cold shock domain containing E1) and MAML3 (Mastermind like transcriptional coactivator 3) genes7.
• Cluster 3
  • Abnormal activation of kinase signaling pathways like PI3Kinase/AKT, RAS/RAF/ERK, and mTOR pathways.

List of causes of the disease in alphabetical order:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

Pheochromocytoma must be differentiated from other causes of paroxysmal hypertension including severe paroxysmal hypertension (pseudopheochromocytoma), panic disorder, factitious hypertension, carcinoid syndrome, migraine headache, hyperthyroidism, renovascular hypertension, hypoglycemia, labile hypertension (White coat hypertension), stroke, compression of the lateral medulla, seizures, baroreflex failure and drugs.

Pheochromocytoma must be differentiated from other causes of paroxysmal hypertension. The differentials include:

Pheochromocytoma must be differentiated from other adrenal tumors such as adrenocortical adenoma, adrenal metastasis, and Cushing’s syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2]Mohammed Abdelwahed M.D[3]

The incidence of pheochromocytoma ranges 0.2-0.8 per 100,000 persons. The median age at diagnosis is 24.9 years in familial cases and 43.9 years in sporadic cases. Both men and women are affected equally by pheochromocytoma.

• In the USA, the incidence of pheochromocytoma ranges from 0.2-0.8 per 100,000 persons.^{[1] [2]}
• Annually reported cases range from 500 to 1600 in the United States.^[3]
• Autopsy studies have discovered a higher number of cases than the actual prevalence rates. Ten percent of pheochromocytomas cases are discovered by chance. 

• In the USA, the prevelance of pheochromocytoma ranges from 0.2-0.8 per 100,000 persons.^[1]
• The prevalence of pheochromocytoma in patients with hypertension in general outpatient clinics ia about 0.1%. ^[4]
• The prevalence of pheochromocytoma is approximately 1.7% in children with hypertension.
• About 5% of patients with incidentally discovered adrenal masses on imaging actually have pheochromocytoma.
• The prevalence of pheochromocytoma in individuals carrying a germline mutation in pheochromocytoma susceptibility genes may be around 50%.

• The incidence of pheochromocytoma ranges from 0.2-0.8 per 100,000 persons with a perioperative case-fatality rate/mortality rate of about 2.4%.^{[1] [5]}
• Metastatic PPGLs were associated with a 2.40-fold higher risk of mortality than non-metastatic PPGLs (95% confidence interval, 1.38 to 4.17; P=0.002). ^[6]

• Patients of all age groups may develop pheochromocytoma. Approximately 10% occur in children.
• The median age at diagnosis is 40 years.
• The average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases.^[1]
• Hereditary tumors present at a younger age than sporadic.

• There is no racial predilection to pheochromocytoma. ^[7]

• Pheochromocytoma affects men and women are equally. ^[1]

• Pheochromocytoma is a rare disease that tends to affect all populations equally.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2] Ifrah Fatima, M.B.B.S[3]

The most potent risk factor for pheochromocytoma is a family history of multiple endocrine neoplasias, Von Hippel-Lindau disease, neurofibromatosis type 1, hereditary paraganglioma syndromes.

The most potent risk factor in the development of pheochromocytoma is a family history of multiple endocrine neoplasias, Von Hippel-Lindau disease, neurofibromatosis type 1 or hereditary paraganglioma syndromes.

• Common risk factors in the development of pheochromocytoma include harboring the following genes:
  • RET gene (MEN 2A, MEN 2B syndromes)
  • NF1 gene
  • VHL gene (VHL disease)
  • SDHD, SDHB, and SDHC genes of the mitochondrial complex ^[1]

• Less common risk factors in the development of pheochromocytoma include harboring the following genes:
  • SDHA
  • SDHAF2
  • TMEM127 (transmembrane protein 127)
  • MAX (myc-associated factor X)
  • FH (fumarate hydratase)
  • PDH1, PDH2 (pyruvate dehydrogenase)
  • HIF1alpha (hypoxia-inducible factor)
  • MDH2 (malate dehydrogenase)
  • KIF1Bß (kinesin family member) genes. ^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Familial pheochromocytoma is associated with multiple endocrine neoplasias, VHL and neurofibromatosis1 and should be screened by plasma fractionated metanephrines levels. The next step is to obtain 24-hour urinary fractionated metanephrine levels. Imaging should be considered if the initial tests are positive. Genetic testing also should be performed in high-risk patients.

• According to the Endocrine Society, biochemical screening for pheochromocytoma in recommended among patients with:
  • VHL syndrome– started at 5 years of age with biochemical surveillance every year for the rest of life.
  • Signs or symptoms suggesting catecholamine excess, especially if the symptoms are paroxysmal.
  • Unexpected blood pressure changes to drugs, surgery, or anesthesia
  • Unexplained blood pressure variability
  • Incidentaloma, even if the patient is normotensive
  • Blood pressure that is difficult to control
  • History of previous treatment for pheochromocytoma or paraganglioma
  • Hereditary risk of pheochromocytoma or paraganglioma in family members
  • Syndromic features relating to a pheochromocytoma-related hereditary syndromes ^[1]
• Plasma fractionated metanephrine level is the best test. If elevated, 24-hour urinary fractionated metanephrines should be done.

Anatomic imaging should be used when norepinephrine levels are elevated more than two times upper normal limits.^[2]

• For high-risk children, screening for pheochromocytoma should begin by 11 years of age.
• For moderate risk patients, screening should be started by 16 years of age.
• If positive, adrenal imaging (CT) or (MRI) should be performed.

• Genetic testing should be performed in:^[1]
  • Patients with a family history of pheochromocytoma
  • Tumors or malignant or extra-adrenal pheochromocytoma
  • Families whose infants or young children have Hirschsprung disease
  • First-degree relatives of a patient with proven germline RET mutation
  • Patients with cutaneous lichen amyloidosis
  • Patients with known RET mutations.
  • Parents whose young children have MEN 2A/2B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

Pheochromocytoma is an adrenaline secreting tumor, that usually develops in the fifth decade of life. Symptoms start with tachycardia, hypertension, headache and sweating. Massive release of catecholamines may cause hyperglycemia, malignant hypertension and metastasis. The prognosis of pheochromocytoma is generally good but metastatic pheochromocytoma has a 5-year survival rate of approximately 50%.

• The symptoms of pheochromocytoma usually develop in the fifth decade of life.
• Common symptoms are with tachycardia, hypertension, headache, and sweating.
• If left untreated, hyperglycemia and hypertensive emergency. It may lead to heart failure andcerebrovascular strokes.
• If malignant, It can metastasize to lymph nodes, bones, lungs, and liver. ^[1]

Common complications of pheochromocytoma include:

• Damage to cardiac myocytes due to either a compromise of the coronary microcirculation or the direct toxic effects of catecholamines on cardiac myocytes.^[2]
• Hyperglycemia due to opposition of insulin effect by high doses of adrenaline secreted by the tumor.
• Malignant hypertension that may cause cerebrovascular accidents such as:
  • Intracranial hemorrhage
  • Acute coronary syndrome
  • Aortic dissection
  • Heart failure
• Metastasis to:
  • Lymph nodes
  • Bones
  • Lungs
  • Liver

• The prognosis of pheochromocytoma is generally good with treatment. The 5-year survival rate in patients with metastatic pheochromocytoma is approximately 50%.^[3]
• Prognosis and survival rate varies with the location of the primary tumor, sites of metastases, Tumor burden, and rate of progression.
• Metastasis to the brain and liver has a worse prognosis than other metastases.

Post-surgical prognosis

• Factors associated with a favourable prognosis include:
  • Small tumor size
  • Short duration of surgery
  • Systolic blood pressure < 160 mmHg
  • Low levels of urinary catecholamines.^[4]
• Approximately 10% recur after being resected.
• Recurrence is more common in patients with familial pheochromocytoma and extra-adrenal tumors.^[5]