Pheochromocytoma
Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is a pharmacologically volatile, potentially lethal catecholamine-containing tumor of chromaffin tissue. It is part of the paraganglioma. These neuroendocrine tumors can be sympathetic, where they release catecholamines into the bloodstream which cause the most common symptoms, including hypertension, tachycardia, sweating, and headaches. Some PGLs may secrete little to no catecholamines, or only secrete paroxysmally, and other than secretions, PGLs can still become clinically relevant through other secretions or mass effect. 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.
Signs and symptoms
The symptoms of a sympathetic pheochromocytoma are related to sympathetic nervous system hyperactivity. The classic triad includes headaches, tachycardia/elevated heart rate, and hyperhidrosis. 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. Attacks can occur spontaneously or may be triggered by a variety of pharmaceutical agents, foods that contain tyramine, intraoperative tumor manipulation, intubation, or during anesthetic induction.Other clinical manifestations that have been reported include :
- Pallor
- Heat intolerance
- Weight loss
- Chest or abdominal discomfort
- Palpitations
- Nausea/vomiting
- Constipation
- Orthostatic hypotension — becoming lightheaded or dizzy after swiftly changing positions
- Psychiatric manifestations
- * Anxiety, panic attacks, nervousness, tremors
- Hyperglycemia
Complications
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.
Misdiagnosis of pheochromocytoma can be deadly, as beta blockers, often prescribed for hypertension, can lead to unopposed alpha-adrenergic receptor stimulation in the context of pheochromocytoma. Most mortality associated with diagnosed pheochromocytoma came from surgery and hypertensive crisis, but mortality has greatly improved.
Cardiovascular system
- Hypertensive crisis: Pheochromocytoma-related hypertensive emergencies are one of the most feared clinical manifestations. Attacks are random and may occur secondary to a trigger or spontaneously after a catecholamine surge. The prevailing symptom is elevated systolic blood pressure that is unresponsive to traditional treatment regimens and threatens end-organ damage. Patients require immediate, life-saving treatment to prevent further damage to other organs and/or death.
- Myocardial ischemia/Infarction: A heart attack is often caused by a significant build-up of plaque 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 tissue and exert negative effects, including oxygen deprivation, leading to accelerated scarring and cell death.
- Toxic myocarditis: Even in patients without myocardial damage, excessive catecholamines can result in abnormal ST changes on an ECG. Norepinephrine is hypothesized to result in damaged cardiac tissue by inhibiting coronary blood flow and depriving cells of oxygen, thus resulting in ischemic tissue. Fortunately, following tumor excision and the subsequent quelling of catecholamines, the damage has been proven reversible.
- Cardiomyopathy: Pheochromocytomas have been implicated in various types of cardiomyopathy, including myocarditis, dilated cardiomyopathy, and stress-induced or Takotsubo cardiomyopathy. As with the other cardiovascular-related complications, excess catecholamines are responsible for the increased myocardial burden and significant physiologic stress. Current literature indicates that most of the catecholamine-induced damage is reversible, thereby strengthening the argument for early and accurate diagnosis to allow for cardiac remodeling and prevent further destruction.
- 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. Many other tachyarrhythmias have also been reported.
Nervous system
- Cerebrovascular accident : Multiple reports have detailed transient ischemic attacks or strokes in patients with a pheochromocytoma. In a study of 130 patients with pheochromocytoma, 7 patients were diagnosed with a transient ischemic attack, and 3 patients experienced a stroke with persistent symptoms.
- Headache: Headaches are one of the core clinical manifestations of a pheochromocytoma and can result in debilitating pain. The majority of studied patients reported their pain began and ended abruptly without warning and described the pain as a severe, bilateral throbbing. 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.
Urinary system
- Acute renal failure: Several reports have detailed rhabdomyolysis leading to acute kidney injury and the need for transient dialysis in the undiagnosed pheochromocytoma patient as their primary presenting symptom. Kidney failure is brought about by catecholamine-induced muscle injury. Norepinephrine causes vessels to narrow, thereby limiting blood flow and inducing ischemia.
Genetics
Current estimates predict that upwards of 40% of all pheochromocytomas are related to an inherited germline susceptibility mutation. Of the remaining 60% of tumors, more than 30% are associated with a somatic mutation. 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. In the UK, eligibility for NHS-funded genetic testing is determined by criteria set by the NHS England Genomics service. The criteria in 2024 included all patients with paraganglioma and all patients with unilateral pheochromocytoma aged under 60. The most recent data indicates that there are 25 pheochromocytoma susceptibility genes; however, just 12 are recognized as part of a well-known syndrome. 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. There is no current consensus for how and when asymptomatic carriers should be evaluated. Conversations should occur individually with the patient and their provider to develop a personalized screening plan, alternating between a biochemical evaluation and whole-body imaging to monitor disease progression.Pediatric considerations
Additional practices may help maintain the emotional and psychological well-being of the minor. Screening includes a multidisciplinary team where the primary focus is supporting the child.- 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 upset a child if their sibling was positive; an opportunity to ask questions and process results may be helpful.
Hereditary syndromes
| Gene | Inheritance | Penetrance | Metastatic Potential | 1o Disease Characteristics | |
| MEN2 | RET | Autosomal Dominant | 40–50% | <5% | Medullary thyroid carcinoma, hyperparathyroidism, marfanoid habitus, pheochromocytoma |
| VHL | VHL | Autosomal Dominant | 10–30% | 5% | Renal cell carcinoma, pancreatic NET, retinal and CNS hemangioblastoma, pheochromocytoma |
| NF1 | NF1 | Autosomal Dominant | 1–5% | 12% | Neurofibromas, cafe-au-lait macules, lisch nodules, pheochromocytoma |
MEN2 ; VHL ; NF1 ; NET ; CNS
| Gene | Inheritance | Penetrance | Metastatic Potential | 1o Disease Characteristics | |
| PGL1 | SDHD | Autosomal Dominant Paternal Inheritance | 90% | <5% | Head and neck paraganglioma, pheochromocytoma, gastrointestinal stromal tumor |
| PGL2 | SDHAF2 | Autosomal Dominant Paternal Inheritance | 100% | Low | Head and neck paraganglioma |
| PGL3 | SDHC | Autosomal Dominant | Inconsistent | Inconsistent | Pheochromocytoma, head and neck paraganglioma, gastrointestinal stromal tumor |
| PGL4 | SDHB | Autosomal Dominant | 30–50% | 30–70% | Head and neck paraganglioma, pheochromocytoma, gastrointestinal stromal tumor |
| PGL5 | SDHA | Autosomal Dominant | 10–15% | Low | Pheochromocytoma, head and neck paraganglioma, gastrointestinal stromal tumor |
SDHx
| Inheritance | Penetrance | Metastatic Potential | 1o Disease Characteristics | |
| MAX | Autosomal Dominant | Inconsistent | <5% | Bilateral pheochromocytoma |
| TMEM127 | Autosomal Dominant | Inconsistent | Low | Pheochromocytoma, head and neck paraganglioma |