Pheochromocytoma

Pheochromocytoma (British English: phaeochromocytoma) 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 (PGL). 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. 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). 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 (likely related to elevated blood pressure, or hypertension), tachycardia/elevated heart rate, and hyperhidrosis (excessive sweating, particularly at night). Attacks can occur spontaneously (without warning) or may be triggered by a variety of pharmaceutical agents (including histamine, metoclopramide, glucagon, and adrenocorticotropic hormone), foods that contain tyramine (cheese and wine), intraoperative tumor manipulation, intubation, or during anesthetic induction. thumb|alt=|250x250px|Adrenal gland; the [[Adrenal medulla|medulla (center, red) is the origin of the pheochromocytoma.]]

thumb|There is an adrenal gland, highlighted in yellow, on top of each of the kidneys.

Other clinical manifestations that have been reported include (in no particular order): It is estimated that approximately 0.1% of patients with hypertension have a pheochromocytoma, and it is often misdiagnosed as essential hypertension. The cardiovascular system is the most commonly involved.

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 (see Signs and Symptoms above) or spontaneously after a catecholamine surge. 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. 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.
Headache: Headaches are one of the core clinical manifestations of a pheochromocytoma and can result in debilitating pain.

Urinary system

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. Kidney failure is brought about by catecholamine-induced muscle injury. Norepinephrine causes vessels to narrow, thereby limiting blood flow and inducing ischemia.: 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. Pheochromocytoma-related MODS is associated with multiple organ failure, hyperthermia > 40 degrees Celsius, neurologic manifestations, and cardiovascular instability resulting in either hypo- or hypertension. 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.

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. 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 individually with the patient and their provider to develop a personalized screening plan, alternating between a biochemical (blood work) 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 (endocrinologist, oncologist, psychologist, geneticist, parent, and child) 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

The following table(s) detail the clinical characteristics of the well-known hereditary pheochromocytoma gene variants

{| class="wikitable"

|+Classic Pheochromocytoma Tumor Syndromes

!Gene

!Inheritance

!Penetrance

!Metastatic Potential

!1o Disease Characteristics

!MEN2

|RET

| rowspan="3" |Autosomal Dominant

|40–50%

|<5%

|Medullary thyroid carcinoma, hyperparathyroidism, marfanoid habitus, pheochromocytoma

!VHL

|VHL

|10–30%

|5%

|Renal cell carcinoma, pancreatic NET, retinal and CNS hemangioblastoma, pheochromocytoma

!NF1

|NF1

|1–5%

|12%

|Neurofibromas, cafe-au-lait macules, lisch nodules, pheochromocytoma

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

{| class="wikitable"

|+Hereditary Paraganglioma Syndromes (SDHx)

!Gene

!Inheritance

!Penetrance

!Metastatic Potential

!1o Disease Characteristics

!PGL1

|SDHD

| rowspan="2" |Autosomal Dominant

Paternal Inheritance

|90%

|<5%

|Head and neck paraganglioma, pheochromocytoma, gastrointestinal stromal tumor

!PGL2

|SDHAF2

|100%

|Low

|Head and neck paraganglioma

!PGL3

|SDHC

| rowspan="3" |Autosomal Dominant

|Inconsistent

|Pheochromocytoma, head and neck paraganglioma, gastrointestinal stromal tumor

!PGL4

|SDHB

|30–50%

|30–70%

|Head and neck paraganglioma, pheochromocytoma, gastrointestinal stromal tumor

!PGL5

|SDHA

|10–15%

|Low

|Pheochromocytoma, head and neck paraganglioma, gastrointestinal stromal tumor

SDHx (Succinate Dehydrogenase Subunit x)

{| class="wikitable" style="margin:1em auto;"

|+Other Pheochromocytoma Gene Mutations

!Inheritance

!Penetrance

!Metastatic Potential

!1o Disease Characteristics

!MAX

| rowspan="2" |Autosomal Dominant

|Inconsistent

|<5%

|Bilateral pheochromocytoma

!TMEM127

|Inconsistent

|Low

|Pheochromocytoma, head and neck paraganglioma

Other gene variants

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

Pacak–Zhuang Syndrome
Hypoxia-inducible factor 2 alpha (HIF2A)
Polycythemia
Duodenal somatostatinoma
Retinal and choroidal vascular changes
Paraganglioma/Pheochromocytoma
Pheochromocytoma and Giant Cell Tumor of Bone
H3 histone, family 3A (H3F3A), post-zygotic G34W
Pheochromocytoma/Paraganglioma
Carney Triad
Gastrointestinal stromal tumor
Pulmonary chondroma
Paraganglioma
Carney-Stratakis Syndrome
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 on whether these mutations are truly pheochromocytoma susceptibility genes.

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.

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.

{| class="wikitable"

|+Differential Diagnosis of Pheochromocytoma by System