What are the signs, symptoms, investigation, and treatment options for pheochromocytoma?

Pheochromocytoma: Signs, Symptoms, Investigation, and Treatment

Clinical Presentation

Pheochromocytoma presents with the classic triad of headache, palpitations, and sweating (particularly "cold sweat"), which when occurring together have 90% diagnostic specificity. 1

Key Signs and Symptoms

• Hypertension patterns: Either paroxysmal (episodic) or sustained hypertension (in up to 50% of cases with high norepinephrine production) 1
• Classic symptom tetrad: Headache, palpitations, pallor, and sweating occur in 95% of patients 1, 2
• At least 5% of patients are normotensive, making diagnosis challenging 2
• Significant blood pressure variability is a key clinical clue 1

High-Risk Populations Requiring Screening

• Early-onset hypertension (age <30 years) 1
• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) 1
• Paroxysmal hypertension with classic symptoms 1
• Family history of pheochromocytoma 1
• Incidentally discovered adrenal tumors (pheochromocytomas account for 6.5% of adrenal incidentalomas) 3

Diagnostic Investigation

Biochemical Testing (First-Line)

Plasma free metanephrines are the single best test with the highest sensitivity (96-100%) and specificity (89-98%) for diagnosing pheochromocytoma. 1, 4

Optimal Collection Technique

• Plasma free metanephrines should ideally be collected from an indwelling venous catheter after the patient has been lying supine for 30 minutes to limit false positive results 1
• Urinary fractionated metanephrines (24-hour collection) are an acceptable alternative with sensitivity of 86-97% and specificity of 86-95% 1, 4

Interpretation Algorithm Based on Results

• Levels ≥4 times upper limit of normal: Consistent with pheochromocytoma—proceed immediately to imaging 1, 4
• Levels 2-4 times upper limit of normal: Repeat testing in 2 months and consider genetic testing 1
• Marginally elevated levels: Repeat testing in 6 months and consider clonidine suppression test 1

Managing Equivocal Results

• If plasma testing is equivocal (less than fourfold elevation), perform 24-hour urine collection for catecholamines and metanephrines 1, 4
• Clonidine suppression testing has 100% specificity and 96% sensitivity for cases with equivocal results and strong clinical suspicion 1

Important Caveats About False Positives

• False positive elevations are usually <4 times the upper limit of normal 1
• Obesity, obstructive sleep apnea, and tricyclic antidepressants can cause elevated catecholamine metabolites 1
• Common antihypertensive medications (including alpha-1 blockers like doxazosin) do not affect plasma free metanephrine measurements when using LC-MS/MS analysis 1

Additional Biochemical Testing

• Plasma methoxytyramine measurement helps assess the likelihood of malignant disease with high accuracy 1, 4
• Elevated plasma methoxytyramine (>3x upper limit) is a risk factor for malignancy 4

Imaging Studies

Anatomical Localization

• CT or MRI of the abdomen is recommended after positive biochemical testing for anatomical localization 4
• MRI is preferred over CT due to risk of hypertensive crisis with IV contrast 1
• Chest CT should be included to evaluate for metastatic disease 4

Functional Imaging

• Meta-iodobenzylguanidine (MIBG) scintigraphy is helpful to detect multifocal disease 4, 3
• For patients with established pheochromocytoma, FDG-PET appears superior to MIBG for detecting malignant tumors, particularly in patients with SDHB mutation 1
• If initial imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck, and consider functional imaging 1

Critical Contraindication

Fine needle biopsy of suspected pheochromocytoma is absolutely contraindicated due to risk of hypertensive crisis. 1, 4

Genetic Testing

Genetic testing should be considered in all patients with pheochromocytoma, as approximately one-third of cases are inherited 1, 5, 6

Indications for Genetic Testing

• Family history of pheochromocytoma/paraganglioma 4
• Young age at diagnosis 4
• Bilateral or multifocal disease 4
• Extra-adrenal location 4

Associated Genetic Syndromes

• Multiple endocrine neoplasia type 2 (MEN2) 4, 3
• Von Hippel-Lindau syndrome (VHL) 4, 3
• Neurofibromatosis type 1 (NF1) 4, 3
• Hereditary paraganglioma syndromes (SDHB, SDHC, SDHD mutations) 4, 3

Special Considerations for SDHB Mutations

• SDHB mutations are associated with higher risk of aggressive behavior and metastatic disease 1
• Patients with SDHB mutations require more intensive surveillance due to higher risk of malignancy 1
• A PASS score ≥4, large primary tumor, and/or SDHB gene mutation should alert the clinician to carry out extended and prolonged (life-long) monitoring 1

Treatment

Preoperative Medical Management

All patients require preoperative alpha-adrenergic blockade for at least 10-14 days before surgery with gradually increasing dosages until blood pressure targets are achieved. 1, 5

FDA-Approved Medication

• Phenoxybenzamine hydrochloride is FDA-indicated for treatment of pheochromocytoma to control episodes of hypertension and sweating 7
• If tachycardia is excessive, it may be necessary to use a beta-blocking agent concomitantly 7

Alternative Agents

• Doxazosin (alpha-1 selective blocker) is commonly used, typically started 7-14 days before surgery 1
• Calcium channel blockers can be used as alternatives or adjuncts 5
• Beta-blockers should never be started before alpha-blockade is established to avoid unopposed alpha-stimulation and hypertensive crisis 5

Surgical Treatment

Complete surgical extirpation (R0 resection) is the mainstay of potentially curative treatment for pheochromocytoma. 4

Surgical Approach

• Laparoscopic surgery is the treatment of choice for pheochromocytomas <5 cm in diameter 2
• Larger tumors (≥5 cm) should be removed by open surgery 2
• Adrenal-sparing surgical intervention may be considered in appropriate cases 4
• Surgical resection is successful in 90% of cases 2

Postoperative Follow-Up

Biochemical testing should be performed approximately 14 days following surgery to check for remaining disease. 4

Long-Term Surveillance

• Long-term follow-up includes clinical evaluation, biochemical testing, and imaging with CT of thorax and abdomen as clinically indicated 4
• Annual follow-up with clinical and biochemical assessment is recommended in all cases after treatment 6

Management of Malignant/Metastatic Disease

Approximately 10% of pheochromocytomas are malignant, defined only by the presence of metastatic lesions at sites where chromaffin cells are normally absent. 4, 3

Risk Factors for Malignancy

• Tumor size ≥5 cm 4
• Extra-adrenal paraganglioma (20-50% malignancy rate vs. 10-15% for adrenal pheochromocytomas) 4, 6
• SDHB germline mutation 4
• Elevated plasma methoxytyramine (>3x upper limit) 4

Treatment Options for Inoperable Disease

• Disease and symptom control are the main treatment goals for patients with inoperable pheochromocytoma 4
• Cytoreductive surgery might be considered for malignant pheochromocytoma 4
• Radiopharmaceuticals, such as 131I-MIBG, for patients with sufficient MIBG uptake 4
• Chemotherapy is used for inoperable disease 3
• Molecular agents like sunitinib and everolimus may be useful in palliation 6
• Different ablation procedures may be considered 6

Prognosis

• Prognosis is good for benign disease with proper treatment 3
• Five-year survival is less than 50% in malignant disease 3