Pheochromocytoma: Symptoms, Types, Causes and Treatment

Pheochromocytoma is a rare but potentially life-threatening tumor that arises from the adrenal glands’ chromaffin cells, causing excessive production of catecholamines (adrenaline and noradrenaline). While these tumors are uncommon, recognizing and understanding them is crucial, as their symptoms can mimic other conditions and, if left untreated, may lead to severe complications. In this article, we explore the essential aspects of pheochromocytoma: its symptoms, types, causes, and modern approaches to treatment.

Symptoms of Pheochromocytoma

Pheochromocytoma has earned a reputation as the “great masquerader” in medicine, as its symptoms can mimic common conditions like anxiety, panic attacks, or hypertension. Many patients present with episodic symptoms, while others are discovered by chance during imaging for unrelated reasons. Early recognition is vital, as undiagnosed pheochromocytoma can have fatal outcomes.

Symptom	Frequency/Significance	Notes/Presentation	Source
Hypertension	Most common (60–80%)	Sustained or paroxysmal; may be absent	1 2 4 5 14
Headache	~60%	Often severe, episodic	1 2 3 4 5 14
Palpitations	~59%	Fast heart rate, pounding	1 2 3 4 5 14
Diaphoresis	~52%	Profuse, trunk-predominant sweating	1 2 3 4 5 14
Anxiety/Panic	Variable	May mimic panic disorder	1 3 14
Pallor	Common	Due to vasoconstriction	1 14
Flushing	Less common	May occur in some cases	1 2
Weakness	Occasional	Non-specific	2 5
Asymptomatic	Up to 25% in screening group	Found incidentally	4

Table 1: Key Symptoms

Classic and Common Symptoms

The most recognizable signs of pheochromocytoma arise from catecholamine excess, which overstimulates the cardiovascular system:

• Hypertension: This is the hallmark, present in most patients. It can be constant (sustained) or occur in sudden bursts (paroxysmal). Interestingly, some patients (especially those found incidentally or with hereditary syndromes) may be normotensive or asymptomatic 1 2 4 5 14.
• Classic Triad: Headache, palpitations, and diaphoresis (profuse sweating) are the classic triad. The presence of all three in a hypertensive patient should raise strong suspicion for pheochromocytoma 2 3 4.
• Other Symptoms: Anxiety, panic attacks, pallor, flushing, and weakness are also reported. Palpitations may be accompanied by tachycardia, and headaches are often intense and episodic 1 2 3 5 14.

Modern Presentation

With increasing use of imaging, many pheochromocytomas are discovered as “adrenal incidentalomas.” In these cases, classic symptoms may be absent or subtle. Up to 25% of patients identified through genetic screening are asymptomatic at diagnosis 4.

Paroxysmal vs. Sustained Symptoms

Symptoms often occur in sudden episodes, triggered by stress, surgery, or certain foods and medications. These paroxysms can be dangerous, leading to hypertensive crises, arrhythmias, and even stroke 1 4 14.

Diagnostic Challenges

No single symptom is diagnostic. The combination of the classic triad and hypertension is the most predictive, but normotensive and asymptomatic cases exist. Diagnosis often relies on a high index of suspicion and biochemical testing 2 4 5.

Types of Pheochromocytoma

Pheochromocytomas are not a uniform group of tumors. Advances in genetics and molecular biology have revealed multiple distinct types, each with unique clinical and biological behaviors. Understanding these subtypes is essential for prognosis, management, and familial screening.

Type	Distinguishing Features	Genetic Link/Cluster	Source
Sporadic	Most cases; no family history	Variable	1 3 11 16
Familial (Hereditary)	Early onset, multiple/bilateral	MEN2, VHL, NF1, SDHx	1 3 6 10 11 16
Kinase-type (Cluster 2)	Adrenergic, episodic symptoms	RET, NF1, TMEM127, MAX	9 16
Metabolism-type (Cluster 1)	Noradrenergic, aggressive	VHL, SDHB/C/D, FH, EPAS1	9 10 16
Wnt-signaling (Cluster 3)	Poorly characterized, aggressive	MAML3, CSDE1	16
Malignant	Metastatic at diagnosis/recurrence	More common in SDHB, extra-adrenal	11 13 16
Extra-adrenal (Paraganglioma)	Outside adrenal gland	Often SDHx mutations	3 10 11

Table 2: Types and Subtypes of Pheochromocytoma

Sporadic vs. Hereditary

• Sporadic: The majority (60–70%) of pheochromocytomas occur without a family history or identifiable genetic mutation 1 3 11 16.
• Hereditary: Up to 40% are linked to germline mutations. These often present at a younger age, may be multiple or bilateral, and strongly associate with certain syndromes 1 3 6 10 11 16:
  • Multiple Endocrine Neoplasia type 2 (MEN2): RET mutations; often with medullary thyroid carcinoma and parathyroid disease.
  • Von Hippel-Lindau (VHL) Syndrome: VHL gene mutations; associated with kidney, CNS, and retinal tumors.
  • Neurofibromatosis type 1 (NF1): Characterized by café-au-lait spots, neurofibromas, and increased tumor risk.
  • Succinate Dehydrogenase (SDHx) Mutations: SDHB, SDHC, SDHD; often linked to paragangliomas and higher malignancy risk 10 11.

Molecular Clusters

Modern classification divides pheochromocytomas and paragangliomas into three molecular clusters based on genetic alterations and biochemical profiles 9 16:

• Cluster 1 (Pseudohypoxia/Metabolism): VHL, SDHx, EPAS1. Noradrenergic phenotype, higher metastatic risk.
• Cluster 2 (Kinase Signaling): RET, NF1, TMEM127, MAX. Adrenergic phenotype, more episodic symptoms, generally less aggressive.
• Cluster 3 (Wnt Signaling): Rare; often aggressive, but not yet well defined.

Malignant Pheochromocytoma

Malignancy is defined by the presence of metastases, not by histology. Malignant forms are more common in extra-adrenal and SDHB-mutated tumors, and may be more aggressive and harder to treat 13 16.

Extra-Adrenal Tumors (Paragangliomas)

If arising outside the adrenal gland, the tumor is called a paraganglioma (PGL). These are more likely linked to hereditary mutations and have a higher propensity for malignancy 3 10 11.

Causes of Pheochromocytoma

Pheochromocytomas are ultimately caused by genetic and molecular changes that drive abnormal growth of chromaffin cells. Understanding these causes is vital for early detection, genetic counseling, and targeted therapy.

Cause/Factor	Role in Pathogenesis	Notes/Associated Syndrome	Source
Germline Mutations	Major cause (up to 40%)	MEN2 (RET), VHL, NF1, SDHx	1 3 6 10 11 16
Somatic Mutations	Additional 35–40% cases	Various genes; sporadic cases	16
Proto-oncogene Activation	Drives cell proliferation	RET in MEN2	1 16
Tumor Suppressor Loss	Loss of growth control	VHL, SDHB/SDHC/SDHD	1 10 16
Environmental/Unknown	Likely minor	No clear external risks	1 11

Table 3: Causes and Genetic Factors

Genetic Mutations

A significant proportion of pheochromocytomas are linked to germline (inherited) mutations. Key genes and associated syndromes include:

• RET: Proto-oncogene; activating mutations cause MEN2, leading to pheochromocytoma and medullary thyroid carcinoma 1 16.
• VHL: Tumor suppressor gene; loss-of-function mutations cause VHL syndrome, with pheochromocytoma among other tumors 1 16.
• NF1: Tumor suppressor gene; mutations cause neurofibromatosis type 1 1 11.
• SDHB, SDHC, SDHD: Genes encoding succinate dehydrogenase; mutations predispose to familial pheochromocytoma/paraganglioma and are associated with higher malignancy risk 10 16.
• Others: TMEM127, MAX, EPAS1, FH, and more; the number of identified susceptibility genes continues to increase 6 16.

Molecular Pathways

These genetic disruptions lead to abnormal cell signaling and growth. For instance:

• RET mutations lead to continuous cell proliferation (oncogenic activation).
• VHL and SDHx mutations impair cellular metabolism and oxygen sensing, promoting tumorigenesis (pseudohypoxia pathway) 16.
• Kinase and Wnt pathway mutations drive other subtypes 9 16.

Hereditary Patterns and Family Screening

Hereditary pheochromocytoma often runs in families, with variable expressivity and penetrance. Family members should undergo genetic counseling and, if indicated, genetic testing 1 6 16.

Environmental Factors

No consistent environmental risk factors have been identified. The vast majority of cases are due to spontaneous or inherited genetic changes 1 11.

Treatment of Pheochromocytoma

Pheochromocytoma is one of the few potentially curable causes of hypertension. However, management is complex, requiring careful preoperative preparation, skilled surgery, and close follow-up for recurrence or malignancy.

Treatment Modality	Indication/Goal	Key Points	Source
Surgical Resection	First-line, curative for most	Laparoscopic preferred; adrenal-sparing in bilateral cases	1 3 13 14 15
Preoperative Medical	Prevent intraoperative crisis	Alpha-blockade, beta-blockade as needed	14 15
Genetic Counseling	Hereditary cases	Screen family, inform management	1 6 16
Radiotherapy	Malignant/metastatic cases	MIBG therapy, external beam	13 14
Chemotherapy	Malignant/metastatic cases	CVD regimen, other protocols	13 14
Targeted/Immunotherapy	Experimental, advanced cases	Kinase inhibitors, immunotherapy	16 17

Table 4: Treatment Strategies

Surgical Management

• Definitive Therapy: Surgical removal of the tumor is the only curative option for most patients 1 3 13 14 15.
• Laparoscopic Adrenalectomy: Minimally invasive and preferred for most cases. Adrenal-sparing surgery is considered for bilateral tumors, especially in hereditary cases, to preserve adrenal function 1 14.
• Preoperative Preparation: Essential to prevent potentially lethal catecholamine surges during surgery. Alpha-blockers are started 7–14 days before surgery, and beta-blockers may be added for tachycardia (but only after adequate alpha-blockade) 14 15.

Management of Malignant and Metastatic Disease

• Radiotherapy: Iodine-131 meta-iodobenzylguanidine (MIBG) therapy is commonly used for metastatic or inoperable tumors 13.
• Chemotherapy: Cyclophosphamide, vincristine, and dacarbazine (CVD) regimen is standard; other agents may be considered 13 14.
• Other Local Therapies: Surgical debulking, external radiation, and sometimes embolization may be used for symptom relief 13.

Emerging and Experimental Treatments

• Targeted Therapy: Drugs targeting specific molecular pathways (kinase inhibitors) and immune checkpoint inhibitors are under investigation, particularly for advanced disease and specific subtypes 16 17.
• Personalized Medicine: Ongoing research aims to match therapy to the tumor’s molecular cluster, offering hope for more effective and less toxic treatments in the future 16.

Long-term Follow-up and Genetic Counseling

• Surveillance: Lifelong follow-up with biochemical testing and imaging is necessary due to the risk of recurrence or new tumors, especially in hereditary cases 1 16.
• Family Screening: Genetic counseling and testing for family members are crucial in hereditary cases to detect tumors early and reduce morbidity 1 6 16.

Conclusion

Pheochromocytoma, though rare, poses significant diagnostic and therapeutic challenges. Its protean symptoms, genetic complexity, and potential for malignancy require a multidisciplinary approach and high clinical suspicion. Advances in genetics and molecular biology are transforming the understanding and management of this condition.

Key Points:

• Symptoms: Classic triad (headache, palpitations, diaphoresis) and hypertension are most common, but presentations are variable and can be subtle or even absent, especially in screened or incidental cases.
• Types: Pheochromocytomas are classified as sporadic or hereditary, with further subdivision into molecular clusters that impact clinical behavior and management.
• Causes: Genetic mutations account for a substantial proportion of cases. Testing and family screening are vital, particularly in hereditary syndromes.
• Treatment: Surgical excision is curative for most, with preoperative medical management essential. Malignant cases require multimodal therapy, and research into targeted and immunotherapies is ongoing.
• Future Directions: Personalized, genetics-driven management will play an increasingly important role, offering hope for improved outcomes in this challenging disease.

Recognizing and treating pheochromocytoma promptly is crucial—not just for symptom relief, but for saving lives.