Pheochromocytoma (Clinical)

Overview

Definition^[1]

Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma is a catecholamine-secreting tumor Tumor Inflammation derived from chromaffin cells Chromaffin cells Cells that store epinephrine secretory vesicles. During times of stress, the nervous system signals the vesicles to secrete their hormonal content. Their name derives from their ability to stain a brownish color with chromic salts. Characteristically, they are located in the adrenal medulla and paraganglia of the sympathetic nervous system. Adrenal Hormones.

Anatomy^[4]

• 98% intra-abdominal
• 90% located in adrenal glands
• Familial cases tend to be bilateral.
• Extra-adrenal pheochromocytoma Extra-Adrenal Pheochromocytoma Pheochromocytoma is referred to as paraganglioma Paraganglioma A neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion, such as the carotid body, or medulla of the adrenal gland (usually called a chromaffinoma or pheochromocytoma). It is more common in women than in men. Hearing Loss:
  • Develops in paraganglion chromaffin tissue of sympathetic ganglia
  • Anywhere from base of brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification to urinary bladder Urinary Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters (ureter), and is held there until urination. Urinary Tract: Anatomy
  • Most common:
    • Organ of Zuckerkandl Organ of Zuckerkandl Pheochromocytoma (at origin of inferior mesenteric artery Inferior mesenteric artery The artery supplying nearly all the left half of the transverse colon, the whole of the descending colon, the sigmoid colon, and the greater part of the rectum. It is smaller than the superior mesenteric artery and arises from the aorta above its bifurcation into the common iliac arteries. Small Intestine: Anatomy)
    • Bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess wall
    • Heart
    • Mediastinum Mediastinum The mediastinum is the thoracic area between the 2 pleural cavities. The mediastinum contains vital structures of the circulatory, respiratory, digestive, and nervous systems including the heart and esophagus, and major thoracic vessels. Mediastinum and Great Vessels: Anatomy
    • Carotid and glomus jugulare bodies

Epidemiology^[1,4,6]

• Most common tumor Tumor Inflammation of adrenal medulla Adrenal Medulla The inner portion of the adrenal gland. Derived from ectoderm, adrenal medulla consists mainly of chromaffin cells that produces and stores a number of neurotransmitters, mainly adrenaline (epinephrine) and norepinephrine. The activity of the adrenal medulla is regulated by the sympathetic nervous system. Adrenal Glands: Anatomy in adults
• Approximately 1,000 cases diagnosed annually in the United States
• Estimated 0.8 per 100,000 persons/year in the United States
• No gender Gender Gender Dysphoria difference
• Age of onset typically 30–50 years old for sporadic Sporadic Selective IgA Deficiency cases
• Approximately 40% associated with hereditary disorders and younger age of onset

Etiology^[4,6,8]

• Chromaffin cell neoplasia Chromaffin Cell Neoplasia Pheochromocytoma (derived from the neural crest Neural crest The two longitudinal ridges along the primitive streak appearing near the end of gastrulation during development of nervous system (neurulation). The ridges are formed by folding of neural plate. Between the ridges is a neural groove which deepens as the fold become elevated. When the folds meet at midline, the groove becomes a closed tube, the neural tube. Hirschsprung Disease)
• 60% or more are sporadic Sporadic Selective IgA Deficiency.
• 10+ gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations have been identified in association with pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma.
• Most common genetic syndromes associated with pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma:
  • Von Hippel-Lindau (VHL)
  • Multiple endocrine neoplasia Multiple endocrine neoplasia Multiple endocrine neoplasia syndromes are autosomal dominant inherited conditions characterized by 2 or more hormone-producing tumors involving the endocrine organs. There are different types of MEN, namely MEN1-4. Multiple Endocrine Neoplasia type 2 (MEN2)
  • Neurofibromatosis type 1 Type 1 Spinal Muscular Atrophy (NF-1)

Mnemonic

The “rule of 10s” for pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma characteristics:

• 10% of cases are malignant.
• 10% of tumors are bilateral.
• 10% of tumors have extra-adrenal locations (e.g., bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess wall, organ of Zuckerkandl Organ of Zuckerkandl Pheochromocytoma).
• 10% of tumors show calcifications on imaging.
• 10% of cases are pediatric.

Pathophysiology

Excessive catecholamine secretion Secretion Coagulation Studies by tumor Tumor Inflammation^[1,13]

• Intermittent or continuous
• Most pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma secrete predominantly norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS (normal medulla approximately 85% epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs); may also secret dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS.
• Secretion Secretion Coagulation Studies is not regulated by neural pathways like the normal medulla.
• Triggers for secretion Secretion Coagulation Studies may include:
  • Direct pressure
  • Postural changes
  • Medications: inhibitors of catecholamine reuptake (e.g., tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants)
  • Changes in tumor Tumor Inflammation blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure
  • Emotional or physiological stress
• Transient increase in secretion Secretion Coagulation Studies may precipitate hypertensive crisis Hypertensive Crisis Oxazolidinones.

Effects of catecholamine secretion Secretion Coagulation Studies^[1,13]

• 𝛂-adrenergic stimulation:
  • ↑ Blood pressure
  • ↑ Cardiac contractility
  • ↑ Glycogenolysis Glycogenolysis The release of glucose from glycogen by glycogen phosphorylase (phosphorolysis). The released glucose-1-phosphate is then converted to glucose-6-phosphate by phosphoglucomutase before entering glycolysis. Glycogenolysis is stimulated by glucagon or epinephrine via the activation of phosphorylase kinase. Glycogen Metabolism
  • ↑ Gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
  • ↑ Intestinal relaxation
• 𝜷-adrenergic stimulation:
  • ↑ Heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology
  • ↑ Cardiac contractility

Malignant potential^[1,8]

• No biochemical or histologic difference between benign Benign Fibroadenoma and malignant pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
• Malignancy Malignancy Hemothorax defined by:
  • Local invasion of surrounding tissues
  • Distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis (may occur as late as 50 years after resection)

Clinical Presentation

Symptoms and signs of pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma are typically paroxysmal.^{[1,4,6,8,10,13]}

• Classic triad (most patients rarely present with all 3 symptoms):
  1. Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess: 90% of symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  2. Sweating: 60%–70% of symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  3. Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
• Sustained or paroxysmal hypertension Paroxysmal Hypertension Pheochromocytoma is the most common symptom.
• Hyperadrenergic spells Hyperadrenergic Spells Pheochromocytoma (pallor, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, palpitations Palpitations Ebstein’s Anomaly, tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies)
• Orthostatic hypotension Orthostatic hypotension A significant drop in blood pressure after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm hg decrease in systolic pressure or a 10-mm hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include dizziness, blurred vision, and syncope. Hypotension (from catecholamine-induced volume contraction)
• Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types (catecholamine-induced)
• 5%–15% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may have normal blood pressure and no other symptoms:
  • Pre-biochemical phase (normal catecholamine levels)
  • Tumor Tumor Inflammation incidentally discovered on imaging
• Pheochromocytoma crisis Pheochromocytoma Crisis Pheochromocytoma (rare):
  • Hyper- or hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Hyperthermia (> 40℃)
  • Mental status changes
  • Multiple organ dysfunction

Mnemonic

To recall the most common clinical features of pheochromocytoma or episodic hyperadrenergic spells, remember the “5 Ps“: 

• Pressure (high blood pressure) 
• Pain ( headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess) 
• Perspiration 
• Palpitations 
• Pallor

Diagnosis

Biochemical confirmation of the diagnosis should be followed by radiologic imaging to locate the tumor Tumor Inflammation.

History^[4–6]

• Presence of classic triad
• Hyperadrenergic spells Hyperadrenergic Spells Pheochromocytoma (pallor, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, palpitations Palpitations Ebstein’s Anomaly, tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies)
• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension onset at young age (< 20 years old)
• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension with poor response to medications
• Family history Family History Adult Health Maintenance of pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
• Family history Family History Adult Health Maintenance of VHL, MEN2, or NF-1
• Idiopathic Idiopathic Dermatomyositis dilated cardiomyopathy Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy and a common cause of heart failure (HF). The cause may be idiopathic, familial, or secondary to a variety of underlying conditions. The disease is characterized by the enlargement of 1 or both ventricles and reduced systolic function. Dilated Cardiomyopathy
• Carney triad Carney Triad Pheochromocytoma: gastric stromal tumors + pulmonary chondromas + paraganglioma Paraganglioma A neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion, such as the carotid body, or medulla of the adrenal gland (usually called a chromaffinoma or pheochromocytoma). It is more common in women than in men. Hearing Loss

Physical exam^[6,10]

• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
• Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
• Pallor
• Orthostatic hypotension Orthostatic hypotension A significant drop in blood pressure after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm hg decrease in systolic pressure or a 10-mm hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include dizziness, blurred vision, and syncope. Hypotension

Biochemical testing^[4–6,8,12]

• Catecholamines Catecholamines A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. Adrenal Hormones are metabolized to metanephrines in chromaffin cells Chromaffin cells Cells that store epinephrine secretory vesicles. During times of stress, the nervous system signals the vesicles to secrete their hormonal content. Their name derives from their ability to stain a brownish color with chromic salts. Characteristically, they are located in the adrenal medulla and paraganglia of the sympathetic nervous system. Adrenal Hormones, which can be measured in the urine and plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products
• Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products free fractionated metanephrines:
  • High sensitivity (96%–100%)
  • Poor specificity (85%–89%, in general; < 80% for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship > 60 years old)
  • Use as 1st test if suspicion is high ( family history Family History Adult Health Maintenance or genetic syndromes).
  • Usually preferred test in children for whom 24-hour urine collection may be difficult
  • Draw sample when the patient is in the supine position.
• 24-hour urine for fractionated metanephrine Metanephrine Product of epinephrine o-methylation. It is a commonly occurring, pharmacologically and physiologically inactive metabolite of epinephrine. Pheochromocytoma, vanillylmandelic acid Vanillylmandelic Acid Neuroblastoma, and catecholamines Catecholamines A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. Adrenal Hormones:
  • Similar/lower sensitivity (77%–90%)
  • Better specificity than plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products metanephrines (82%–98%)
  • Preferred 1st test in low-suspicion cases
• Increases of ≥ 2–3 times the upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal are expected for symptomatic pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma.^[4]
• For patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with spells, testing should ideally be performed at the time of the spell.
• Medications affecting test results:
  • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants
  • Psychoactive medications
  • Phenoxybenzamine Phenoxybenzamine An alpha-adrenergic antagonist with long duration of action. It has been used to treat hypertension and as a peripheral vasodilator. Antiadrenergic Drugs
  • Beta-blockers Beta-blockers Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs

Imaging^[4–6,8,9]

Once biochemical evidence of pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma is obtained, imaging is performed to localize the tumor Tumor Inflammation.

• Contrast-enhanced CT:
  • Usually 1st-line option
  • Excellent spatial resolution for thorax, abdomen, and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 “hip” bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy
• MRI:
  • Alternative test
  • Preferred in children, pregnant women, and those with recent excessive radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma exposure
• Iodine Iodine A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126. 90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. Thyroid Hormones metaiodobenzylguanidine ( MIBG MIBG Pheochromocytoma) scintigraphy Scintigraphy Sjögren’s Syndrome:
  • Radioactive iodine Radioactive iodine Unstable isotopes of iodine that decay or disintegrate emitting radiation. I atoms with atomic weights 117-139, except I 127, are radioactive iodine isotopes. Antithyroid Drugs taken by adrenergic tissues similar to norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS
  • Can detect multiple tumors or tumors not visualized on CT or MRI
  • Consider if:
    • CT or MRI do not localize tumor Tumor Inflammation
    • At risk for multifocal Multifocal Retinoblastoma disease 
• ¹⁸F-fluorodeoxyglucose PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging/CT:
  • Preferred over MIBG MIBG Pheochromocytoma scintigraphy Scintigraphy Sjögren’s Syndrome for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with metastatic disease
  • Note: PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging imaging is contraindicated in pregnant women.
• Contraindicated: image-guided biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma → may precipitate catecholamine release and severe hypertensive crisis Hypertensive Crisis Oxazolidinones

Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies^[4–7,15]

• Strongly consider referring the patient to a genetic counselor for a risk evaluation for a hereditary syndrome.
• Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies is often recommended in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with:
  • Personal or family history Family History Adult Health Maintenance of clinical features suggestive of hereditary pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma– paraganglioma Paraganglioma A neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion, such as the carotid body, or medulla of the adrenal gland (usually called a chromaffinoma or pheochromocytoma). It is more common in women than in men. Hearing Loss syndrome
  • Bilateral or multifocal Multifocal Retinoblastoma tumors 
  • Sympathetic or malignant extra-adrenal paragangliomas 
  • Age < 40 years
• If a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is identified, predictive genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies should be offered to asymptomatic at-risk family members.

Management

Management may vary depending on practice location. The following information is based on US, UK, and European literature and guidelines for adult patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship. A multidisciplinary team, including endocrinology, oncology, and surgery, can help guide therapeutic decisions.

Once a pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma is diagnosed, all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should undergo resection (if possible), following appropriate medical preparation.^[3,5]

Surgery^{[4–6,10,14]}

• Only definitive treatment
• Laparoscopic adrenalectomy Adrenalectomy Excision of one or both adrenal glands. Cushing Syndrome is the standard of care Standard of care The minimum acceptable patient care, based on statutes, court decisions, policies, or professional guidelines. Malpractice for adrenal pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma.
• Bilateral partial adrenalectomy Adrenalectomy Excision of one or both adrenal glands. Cushing Syndrome or cortical-sparing adrenalectomy Adrenalectomy Excision of one or both adrenal glands. Cushing Syndrome should be performed for bilateral lesions.
• Total bilateral adrenalectomy Adrenalectomy Excision of one or both adrenal glands. Cushing Syndrome often considered in MEN2 because of high recurrence risk
• Laparoscopic resection also feasible for some abdominal paragangliomas
• Open resections reserved for large, difficult-to-access, or locally invasive tumors

Preoperative preparation

Goals:^[5,10]

• Control hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension and tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children to prevent hypertensive crisis Hypertensive Crisis Oxazolidinones.
  • Blood pressure goals:
    • Seated blood pressure < 130/80 mm Hg 
    • Standing systolic pressure > 90 mm Hg
  • Heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology goals:
    • Seated: 60–70 beats/min
    • Standing: 70–90 beats/min
• Volume expansion with IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids

Medical therapy:^[4–6,10]

• α-Adrenergic blockade:
  • To control hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension and prevent volume contraction
  • Started at least 7–14 days preoperatively and titrated to hit blood pressure target
  • Preferred drug: phenoxybenzamine Phenoxybenzamine An alpha-adrenergic antagonist with long duration of action. It has been used to treat hypertension and as a peripheral vasodilator. Antiadrenergic Drugs, but other α-adrenergic receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers can be used
• High-sodium and fluid diet:
  • Started on 2nd–3rd day of α-blockade
  • Aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS in volume expansion
  • Reduces risk of orthostatic hypotension Orthostatic hypotension A significant drop in blood pressure after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm hg decrease in systolic pressure or a 10-mm hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include dizziness, blurred vision, and syncope. Hypotension due to medications
• 𝛃-Adrenergic blockade:
  • To control tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
  • Usually started 3–4 days after initiating α-adrenergic blockade and after volume expansion has been accomplished
  • Should be started cautiously at a low dose for concerns of catecholamine-induced cardiomyopathy Catecholamine-Induced Cardiomyopathy Pheochromocytoma
• Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers:
  • May also be added for additional blood pressure control
  • Use as monotherapy (in place of α-adrenergic blockade) is rarely indicated.
• Metyrosine Metyrosine Pheochromocytoma:
  • Inhibitor of catecholamine synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Can add for a short period before surgery if α-blockade is not effective enough to control blood pressure.

Metastatic pheochromocytoma Metastatic Pheochromocytoma Pheochromocytoma^{[4,6,9,10,12]}

• No curative treatment
• Resection of primary and metastatic disease should be attempted whenever possible.
• Other therapies:
  • External beam radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • Ablative therapies:
    • Radiofrequency
    • Cryoablation Cryoablation Fibroadenoma
    • Percutaneous ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism injection
  • Chemoembolization (for liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis)
  • Metaiodobenzylguanidine ( MIBG MIBG Pheochromocytoma)
    • Similar in structure to norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS, thus taken up by sympathetic nerve cells, including those of the pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
  • Chemotherapy Chemotherapy Osteosarcoma:
    • Somatostatin Somatostatin A 14-amino acid peptide named for its ability to inhibit pituitary growth hormone release, also called somatotropin release-inhibiting factor. It is expressed in the central and peripheral nervous systems, the gut, and other organs. SRIF can also inhibit the release of thyroid-stimulating hormone; prolactin; insulin; and glucagon besides acting as a neurotransmitter and neuromodulator. In a number of species including humans, there is an additional form of somatostatin, srif-28 with a 14-amino acid extension at the n-terminal. Gastrointestinal Secretions analogs
    • Cytotoxic Cytotoxic Parvovirus B19 therapy ( cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants, dacarbazine Dacarbazine An antineoplastic agent. It has significant activity against melanomas. Alkylating Agents and Platinum, vincristine Vincristine An antitumor alkaloid isolated from vinca rosea. Microtubule and Topoisomerase Inhibitors, doxorubicin)
    • Tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors inhibitors (sunitinib)
  • Palliative therapy

Postoperative period Postoperative period The period following a surgical operation. Postoperative Care^[5,6,14]

• Potential complications to be aware of:
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension or hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Rebound hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease (if bilateral tumors removed)
• Monitor closely for 24–48 hours:
  • Blood pressure
  • Heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
• Adjust medications as needed.
• If adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease is a potential complication → cosyntropin-stimulation test

Follow-up^{[4,5,8,10,12,15]}

Owing to the risk of recurrence, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be educated on the importance of long-term follow-up.

• Lifelong monitoring with biochemical screening Screening Preoperative Care is advised:
  • Obtain baseline testing postoperatively
  • European guidelines recommend repeat test 2–6 weeks after surgery^[10]
  • Follow annually
• Follow-up CT, MRI, or functional imaging:
  • May be ordered every 2–3 years, depending on tumor Tumor Inflammation characteristics and metastatic potential
  • If results of postsurgical biochemical testing are elevated → repeat imaging 3–6 months after surgery would be indicated^[10]

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas^[4]

• Tumors can recur, even if benign Benign Fibroadenoma.
• Recurrence is higher for familial forms.
• For malignant/metastatic disease, prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas depends on:
  • Tumor Tumor Inflammation burden
  • Location of metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
  • Rate of progression

Differential Diagnosis

• Malignant hypertension Malignant Hypertension Hypertensive Retinopathy: severely elevated blood pressure that can lead to end organ-damage. Malignant hypertension Malignant Hypertension Hypertensive Retinopathy mostly affects patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a long-standing history of hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension associated with renal disease or medication noncompliance Noncompliance Clinician–Patient Relationship. Malignant hypertension Malignant Hypertension Hypertensive Retinopathy needs to be recognized and treated emergently.
• Hyperthyroidism Hyperthyroidism Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. Thyrotoxicosis and Hyperthyroidism: a condition caused by excessive secretion Secretion Coagulation Studies of thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormone by the thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy gland. Presentation can include anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, sweating, palpitations Palpitations Ebstein’s Anomaly, and heat Heat Inflammation intolerance. The diagnosis is established by measurement of plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products levels of thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy and thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones.
• Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorder: psychiatric disorder often associated with physical manifestations. Presentation can include palpitations Palpitations Ebstein’s Anomaly, sweating, tremors, and shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. The diagnosis is established by ruling out other medical conditions.
• Carcinoid syndrome Carcinoid syndrome A symptom complex associated with carcinoid tumor and characterized by attacks of severe flushing of the skin, diarrheal watery stools, bronchoconstriction, sudden drops in blood pressure, edema, and ascites. The carcinoid tumors are usually located in the gastrointestinal tract and metastasize to the liver. Symptoms are caused by tumor secretion of serotonin, prostaglandins, and other biologically active substances. Cardiac manifestations constitute carcinoid heart disease. Carcinoid Tumors and Syndrome: constellation of symptoms associated with a hormone-producing carcinoid tumor Tumor Inflammation. Presentation commonly includes flushing, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, and asthma-like symptoms. Carcinoid syndrome Carcinoid syndrome A symptom complex associated with carcinoid tumor and characterized by attacks of severe flushing of the skin, diarrheal watery stools, bronchoconstriction, sudden drops in blood pressure, edema, and ascites. The carcinoid tumors are usually located in the gastrointestinal tract and metastasize to the liver. Symptoms are caused by tumor secretion of serotonin, prostaglandins, and other biologically active substances. Cardiac manifestations constitute carcinoid heart disease. Carcinoid Tumors and Syndrome is usually caused by the secretion Secretion Coagulation Studies of serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS. The diagnosis is established by urinary 5-hydroxyindoleacetic (5-HIAA) levels.
• Insulinoma Insulinoma A benign tumor of the pancreatic beta cells. Insulinoma secretes excess insulin resulting in hypoglycemia. Pancreatic Neuroendocrine Tumors (PanNETs): an insulin-secreting tumor Tumor Inflammation. Presentation commonly includes symptoms of hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia such as weakness, confusion, and palpitations Palpitations Ebstein’s Anomaly. The diagnosis is suspected based on low blood glucose Low blood glucose Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dl (≤ 3. 9 mmol/l) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia levels associated with symptoms.
• Paroxysmal supraventricular tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children: episodic condition with abrupt onset of tachyarrhythmia Tachyarrhythmia A tachyarrhythmia is a rapid heart rhythm, regular or irregular, with a rate > 100 beats/min. Tachyarrhythmia may or may not be accompanied by symptoms of hemodynamic change. Tachyarrhythmias. Paroxysmal supraventricular tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children is caused by cardiac conduction abnormalities. Presentation can include palpitations Palpitations Ebstein’s Anomaly and associated anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder. The diagnosis is established by electrophysiological studies. 
• Munchausen’s syndrome: psychiatric disorder in which patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship deliberately falsify symptoms of illness. Symptoms can be induced by medication ingestion. The diagnosis may be challenging and requires detailed medical and psychosocial history.