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Pheochromocytoma
Other names	Phaeochromocytoma, adrenal medullary tumor, Chromaffin Cell Tumors, Paraganglioma
Normal remnant adrenal gland (left) with a pheochromocytoma (right) involving the adrenal medulla
Pronunciation	/ˌfiːoʊˌkroʊmoʊsʌɪˈtoʊmə/[1] (fee-oh-kroh-moh-sahy-toh-muh)
Specialty	Endocrinology, oncology
Symptoms	Hypertension, tachycardia, sweating, headache, pallor
Complications	Hypertensive crisis
Causes	80% Genetic[2]
Diagnostic method	Elevated plasma free metanephrines, plasma catecholamines, urinary catecholamines, MRI, PET Scan
Treatment	Surgery, chemotherapy, radiation, and pharmacologic agents
Medication	Alpha blocker Doxazosin Prazosin Terazosin
Frequency	0.8 per 100,000 person-years [3]

Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL .^[2][4][5] These neuroendocrine tumors can be sympathetic, where they release catecholamines into the bloodstream which cause the most common symptoms, including hypertension (high blood pressure), tachycardia (fast heart rate), sweating, and headaches.^[6][7] Some PGLs may secrete little to no catecholamines, or only secrete paroxysmally (episodically), and other than secretions, PGLs can still become clinically relevant through other secretions or mass effect (most common with head and neck PGL).^[8] PGLs of the head and neck are typically parasympathetic and their sympathetic counterparts are predominantly located in the abdomen and pelvis, particularly concentrated at the organ of Zuckerkandl at the bifurcation of the aorta.^[9]

Etymology

1920s: from phaeochrome (another term for chromaffin), from Greek phaios 'dusky' + khrōma 'color', + -cyte.

Signs and symptoms

The symptoms of a sympathetic pheochromocytoma are related to sympathetic nervous system hyperactivity.^[10] The classic triad includes headaches (likely related to elevated blood pressure, or hypertension), tachycardia/elevated heart rate, and diaphoresis (excessive sweating, particularly at night, also known as hyperhidrosis).^[7] However, patients are unlikely to experience continuous symptoms. Due to the paroxysmal nature of catecholamine synthesis and release, patients may experience "attacks" or "spells" where they are suddenly overwhelmed with signs and symptoms of their tumor.^[11] Attacks can occur spontaneously (without warning) or may be triggered by a variety of pharmaceutical agents (including histamine, metoclopramide, glucagon^[12] and adrenocorticotropic hormone), foods that contain tyramine (cheese and wine), intraoperative tumor manipulation, intubation, or during anesthetic induction.^[13]

Other clinical manifestations that have been reported include (in no particular order):^[6][13]

• Pallor
• Heat intolerance
• Weight loss
• Chest and/or abdominal discomfort
• Palpitations
• Nausea/vomiting
• Constipation
• Orthostatic hypotension – becoming light-headed or dizzy after swiftly changing positions
• Psychiatric manifestations
  • Anxiety, panic attacks, nervousness, tremors
• Hyperglycemia (high blood sugar)

Complications

While the symptoms of a pheochromocytoma are quite common, the disease has been referred to as "the great mimic".^[14] It is estimated that approximately 0.1% of patients with hypertension have a pheochromocytoma, and it is often misdiagnosed as essential hypertension.^[7] As symptoms are often paroxysmal (episodic/sporadic), patients may not immediately seek treatment as the problem "disappears on its own." Furthermore, when pictured in the ideal clinical scenario (an older woman in her mid-50s), the spontaneous attacks of flushing, sweating, and a racing heart may be mistaken for pre-menopausal related hot flashes. Unmanaged pheochromocytoma is dangerous and can lead to serious, potentially fatal, complications, including stroke and hypertension-induced organ damage.^[15][16] The cardiovascular system is the most commonly involved.^[17][18][19]

In pregnancy, pheochromocytoma is associated with significant maternal and fetal mortality, mainly due to hypertensive crisis in the mother and intrauterine growth restriction in the fetus.^[20][21]

Misdiagnosis of pheochromocytoma can be deadly, as beta-blockers, often perscribed for hypertension, can lead to unopposed alpha in the context of pheochromocytoma.^[22] Most mortality associated with diagnosed pheochromocytoma came from surgery and hypertensive crisis, but mortality has greatly improved.^[23]

Cardiovascular system

1. Hypertensive crisis: Pheochromocytoma-related hypertensive emergencies are one of the most feared clinical manifestations. Attacks are random and may occur secondary to a trigger (see Signs and Symptoms above) or spontaneously after a catecholamine surge.^[18] The prevailing symptom is elevated systolic blood pressure (> 200 mmHg) that is unresponsive to traditional treatment regimens and threatens end-organ damage.^[17] Patients require immediate, life-saving treatment to prevent further damage to other organs and/or death.
2. Myocardial Ischemia/Infarction: A heart attack is often caused by a significant build-up of plaque (atherosclerosis) in the coronary vessels. Patients with pheochromocytoma present with myocardial infarctions despite an overall lack of plaque build-up, indicating a different mechanism for the myocardial infarction. Current research hypothesizes that the tumor secretes massive amounts of catecholamines, which directly interact with myocardial (heart) tissue and exert negative effects including oxygen deprivation, leading to accelerated scarring and cell death.^[17]
3. Toxic Myocarditis: Even in patients without myocardial damage, excessive catecholamines can result in abnormal ST changes on an ECG. Norepinephrine (a catecholamine) is hypothesized to result in damaged cardiac tissue by inhibiting coronary blood flow and depriving cells of oxygen, thus resulting in ischemic tissue.^[19] Fortunately, following tumor excision and the subsequent quelling of catecholamines, the damage has been proven reversible.
4. Cardiomyopathy: Pheochromocytomas have been implicated in various types of cardiomyopathy, including (myocarditis, see above), dilated cardiomyopathy, and stress-induced or Takotsubo cardiomyopathy.^[24] As with the other cardiovascular-related complications, excess catecholamines are responsible for the increased myocardial burden and significant physiologic stress.^{[25][non-primary source needed]} Current literature indicates that most of the catecholamine-induced damage is reversible, thereby strengthening the argument for early and accurate diagnosis in order to allow for cardiac remodeling and prevent further destruction.^[24][25]
5. Arrhythmias: Sinus tachycardia is the most common abnormal heart rhythm associated with a pheochromocytoma and is experienced by patients as the feeling of a "fluttering heart" or palpitations.^[17] Many other tachyarrhythmias (fast heart rate) have also been reported.

Nervous system

1. Cerebrovascular Accident (Stroke): Multiple reports have detailed transient ischemic attacks or strokes in patients with a pheochromocytoma.^{[26][non-primary source needed][27][28][29][30][31][32][non-primary source needed]} In a study of 130 patients with pheochromocytoma, 7 patients were diagnosed with a transient ischemic attack (the neurologic deficit completely resolved) and 3 patients experienced a stroke with persistent symptoms.^[33]
2. Headache: Headaches are one of the core clinical manifestations of a pheochromocytoma and can result in debilitating pain.^[7] The majority of studied patients report their pain began and ended abruptly without warning and described the pain as a severe, bilateral throbbing (although the scale of severity was not published). While 71% of the studied patients reported headaches, just over 20% of the affected patients endorsed associated nausea, vomiting, photophobia, or phonophobia, which are typically associated with migraines.^{[34][non-primary source needed]}

Urinary system

1. Acute Renal Failure: Several reports have detailed rhabdomyolysis (rapid skeletal muscle breakdown) leading to acute kidney injury and the need for transient dialysis in the undiagnosed pheochromocytoma patient as their primary presenting symptom.^{[35][36][37][38][non-primary source needed]} Kidney failure is brought about by catecholamine-induced muscle injury. Norepinephrine causes vessels to narrow, thereby limiting blood flow and inducing ischemia.^[35]

Multiple organ dysfunction syndrome (MODS)^[39]: Caused by an elevated inflammatory response, multiple organ dysfunction is a severe, life-threatening emergency with increasing mortality based on the number of systems involved.^[40] Pheochromocytoma-related MODS is associated with multiple organ failure, hyperthermia > 40 degrees Celsius, neurologic manifestations, and cardiovascular instability resulting in either hypo or hypertension.^[41] In contrast to a hypertensive crisis, pheochromocytoma-associated MODS may not respond to traditional alpha-receptor agents and may require emergent surgical excision if clinical stability is not achieved.^[42]

Genetics

Current estimates predict that upwards of 40% of all pheochromocytomas are related to an inherited germline susceptibility mutation.^[43] Of the remaining 60% of tumors, more than 30% are associated with a somatic mutation.^[44] Given the high association with genetic inheritance, the United States Endocrine Society recommends that all patients diagnosed with a pheochromocytoma undergo an evaluation with a genetic counselor to consider genetic testing.^[45] In the UK eligibility for NHS funded genetic testing is determined by criteria set by NHS England Genomics service.^[46] The criteria in 2023 included all patients with paraganglioma and all patients with unilateral pheochromocytoma aged under 60.^[47] The most recent data indicates that there are 25 pheochromocytoma susceptibility genes; however, just 12 are recognized as part of a well-known syndrome.^[9] Determining the genetic status of a pheochromocytoma patient is crucial – each gene is inherited in a different pattern, associated with specific disease characteristics, and may respond more favorably to certain treatment options. Furthermore, early identification can guide physicians on screening recommendations for first degree relatives of patients with pheochromocytoma.^[48] There is no current consensus for how and when asymptomatic carriers (individual who has a genetic variant associated with pheochromocytoma, but no current evidence of disease) should be evaluated. Conversations should occur at an individual level with the patient and their provider to develop a personalized screening plan that alternates between a biochemical (blood work) evaluation and whole-body imaging to monitor disease progression.^{[49][non-primary source needed]}

Pediatric considerations

Additional practices may help maintain the emotional and psychological well-being of the minor. Screening includes a multidisciplinary team (endocrinologist, oncologist, psychologist, geneticist, parent, and child) where the primary focus is supporting the child.^[50]

• A positive result from testing during family-observed days of celebration may mask the happiness associated with these events in the future.
• Testing one pediatric sibling at a time allows the family to narrow their focus when results are returned and support each sibling individually.
• A negative result may be upsetting to a child if their sibling was positive; an opportunity to ask questions and process results may be helpful.

Hereditary syndromes

The following table(s) detail the clinical characteristics of the well-known hereditary pheochromocytoma gene variants^{[51][52][53][48][44][43][54]}

MEN2 (Multiple Endocrine Neoplasia-2); VHL (von-Hippel Lindau); NF1 (Neurofibromatosis-1); NET (Neuroendocrine Tumor); CNS (Central Nervous System)

SDHx (Succinate Dehydrogenase Subunit x)

Other gene variants

There have been several published case reports of other, rare pheochromocytoma-associated susceptibility genes:

1. Pacak–Zhuang Syndrome^{[55][56][57][58][59]}
   • Hypoxia-inducible factor 2 alpha (HIF2A)
   • Polycythemia
   • Duodenal somatostatinoma
   • Retinal and choroidal vascular changes
   • Paraganglioma/Pheochromocytoma
2. Pheochromocytoma and Giant Cell Tumor of Bone^[60]
   • H3 histone, family 3A (H3F3A), post-zygotic G34W
   • Pheochromocytoma/Paraganglioma
3. Carney Triad^[61]
   • Gastrointestinal stromal tumor
   • Pulmonary chondroma
   • Paraganglioma
4. Carney-Stratakis Syndrome^[62]
   • Gastrointestinal stromal tumor
   • Paraganglioma

Several additional gene variants have been described, but the provided information is inconsistent and a consensus has not been reached in the community if these mutations are truly pheochromocytoma susceptibility genes.^{[citation needed]}

Diagnosis

Differential

The typical primary symptom is hypertension, which may be either episodic or continual. A diagnosis of pheochromocytoma should be suspected when the patient simultaneously presents with hypertension and the classic triad of heart palpitations, headaches, and profuse sweating.^[7]

If a patient has the characteristic signs and symptoms of a pheochromocytoma and the decision is made to pursue additional biochemical (blood work) evaluation, the differential diagnosis is important as it is more likely to be something other than a pheochromocytoma given the relative frequency of 0.8 per 100,000 person-years.^[3]

All patients with phaeochromocytomas are currently considered to have a lifelong risk of metastases and therefore conceptually they are all considered 'malignant'. The risk of metastasis ranges from ~5 to 15%. There is no single histological finding or biomarker to reliably predict metastatic disease, and multiparameter scoring systems have been proposed ^[63]

Notes