The essence in brief:
Pheochromocytoma and Paraganglioma are rare conditions with typical symptoms including excessive sweating, severe headaches, rapid heartbeat, and high blood pressure.
Diagnosis involves a biochemical test measuring free plasma metanephrines, with specific preparation requirements including abstaining from certain substances and medications. Normal metanephrines rule out pheochromocytoma
A clonidine test can be performed, if metanephrine values are in a gray zone, and it involves the administration of clonidine and subsequent blood collections.
The evaluation is based on the suppression of catecholamine levels, with different outcomes suggesting the presence or absence of pheochromocytoma.
The clonidine test can provide valuable diagnostic information in cases where the diagnosis is uncertain.
Imaging is essential for locating pheochromocytoma or paraganglioma after a biochemical diagnosis.
Ultrasound is the initial imaging choice but is often supplemented with computed tomography (CT) or magnetic resonance imaging (MRI) for better visualization.
Scintigraphy, such as 123I-MIBG, can be used, especially for large tumors or in cases of metastasis. PET scans are a superior alternative.
Genetic assessment may be considered for specific patient groups, but general genetic screening is not recommended.
Pheochromocytoma and Paraganglioma can be associated with other syndromes, including MEN 2A, MEN 2B, von Hippel-Lindau syndrome, and neurofibromatosis type 1.
Pheochromocytoma or paraganglioma should be surgically removed.
Most cases can be treated with minimally invasive adrenalectomy, but larger tumors may require open surgery.
Preoperative medication is essential to block alpha-receptors and prevent cardiovascular complications during surgery.
Follow-up includes monitoring plasma metanephrine levels after the operation and conducting annual checks of plasma and urinary metanephrines throughout the patient’s life to detect any recurrence or metastasis.
Patients with genetic mutations require annual MRI scans to identify hormonally inactive tumors.
Pheochromocytoma or paraganglioma are rare. Therefore, despite typical symptoms, appropriate evaluation is often not carried out.
The typical symptoms of pheochromocytoma or paraganglioma include excessive sweating, severe headaches, rapid heartbeat, and high blood pressure. Especially when these symptoms occur intermittently, one should consider the possibility of pheochromocytoma or paraganglioma.
Biochemistry:
The simplest test is the measurement of free plasma metanephrines. Blood collection should occur after 30 minutes of rest. On the day before the blood collection, one should avoid alcohol, coffee, cheese, fruits, nuts, and smoking. Medications that affect catecholamine release should be discontinued 14 days before if possible.
Reference values for metanephrines and normetanephrines vary with age.
Pheochromocytoma or paraganglioma is practically ruled out if metanephrine and normetanephrine levels are within the reference range.
Problems arise with values in the gray zone. If values persistently fall within the gray zone, a clonidine test can be performed.
Test Principle
Clonidine is an alpha-adrenergic agonist that inhibits the release of catecholamines by stimulating central presynaptic alpha-2 receptors (resulting in a decrease in catecholamines after clonidine administration).
Measurement Parameters
Adrenaline, noradrenaline, dopamine, metanephrine, and normetanephrine (in 2x 3 ml frozen EDTA plasma for each measurement time point)
1 red EDTA monovette per blood collection
EDTA blood samples must be centrifuged immediately after collection, and the plasma should be frozen. Special transport containers may be required, as requested by the laboratory.
Patient Preparation
Discontinue antihypertensive therapy (except for calcium channel blockers) at least 24 hours before the test. Patients should have high-normal or hypertensive blood pressure. Tricyclic antidepressants can also interfere with the test.
Test initiation is ideally in the morning (after rest, with alcohol, coffee, and nicotine abstinence). The patient should be fasting.
Blood collection and the entire test should be performed on a reclining patient using a continuous cannula, which should be placed approximately 30 minutes beforehand. Tubes should be pre-chilled in the refrigerator.
Adverse Effects: Significant drops in blood pressure in healthy individuals, hypertensive crises in patients with pheochromocytoma.
Procedure
90 minutes (2 x EDTA tubes)
180 minutes (2 x EDTA tubes)
Monitor blood pressure and pulse rate every 30 minutes!
Evaluation
Suppression of catecholamine levels into the reference range or a decrease to at least 50% of the baseline value suggests the absence of pheochromocytoma.
Lack of suppression of noradrenaline to below 500 ng/l suggests the presence of pheochromocytoma. Since some patients with primary hypertension and moderately elevated catecholamine levels do not show a drop into the reference range but instead a continuous decrease of more than 20%, a study also classified such catecholamine behavior as not indicative of pheochromocytoma. As a result, with a diagnostic sensitivity of 85% (upper reference value for the sum of adrenaline and noradrenaline: 550 ng/l), the diagnostic specificity increased from 73% to 100% for the clonidine test.
Imaging:
After a biochemical diagnosis has been made, imaging studies are conducted to locate the pheochromocytoma or paraganglioma. The simplest imaging is performed with an ultrasound of the adrenal region, which often helps localize a pheochromocytoma.
Image: Biochemically confirmed adrenal pheochromocytoma
Ultrasound alone is not sufficient as the sole imaging measure. A computed tomography (CT) scan provides excellent visualization of the thorax, abdomen, and pelvis. Alternatively, magnetic resonance imaging (MRI) can be performed, especially in cases of metastatic pheochromocytoma or paraganglioma, contrast agent allergies, or renal insufficiency.
Functional nuclear medicine imaging:
Large pheochromocytomas can also be visualized with scintigraphy. The sensitivity of a 123I-MIBG scintigraphy is not very high. In the presence of metastases, a 123I-metaiodobenzylguanidine (MIBG) scintigraphy is recommended, especially if radiotherapy with 131I-MIBG is planned. Alternatively to scintigraphy, PET scans can be conducted, which are superior to 123I-MIBG scintigraph
Genetic assessment:
If available, genetic assessment may be considered for specific patient groups. A general, non-targeted genetic screening is not recommended.
Pheochromocytoma or paraganglioma can be associated with the following conditions:
Multiple Endocrine Neoplasia Type 2A (MEN 2A):
Medullary thyroid carcinoma, primary hyperparathyroidism, cutaneous amyloidosis
Medullary thyroid carcinoma, skin and mucous membrane neurinomas, skeletal deformities, elastic joints
von Hippel-Lindau syndrome:
Hemangioblastomas, retinal angiomas, renal carcinoma, neuroendocrine tumors of the pancreas
Neurofibromatosis Type 1:
Neurofibromatosis, multiple café-au-lait spots, axillary and inguinal freckle-like spots, iris hamartomas, bone abnormalities, central nervous system gliomas, macrocephaly, and cognitive deficits.
A pheochromocytoma or paraganglioma should be surgically removed. Most pheochromocytomas can be removed using minimally invasive adrenalectomy. Larger tumors may require open resection. Small localized paragangliomas can also be removed laparoscopically, but larger ones necessitate open resection.
Preoperative Preparation:
Pheochromocytomas or paragangliomas require perioperative medication to prevent cardiovascular complications during surgery. Medication blockade can be achieved using the non-selective alpha-receptor blocker Phenoxibenzamine or the alpha-1 selective blocker Doxazosin. The therapy should begin 10-14 days before the operation. If tachycardia is present, a beta-blocker may be administered in addition, but the alpha-blocker should not be omitted.
Follow-up:
Plasma metanephrine levels are monitored at intervals of 2-4 weeks after the operation. Subsequently, annual checks of plasma and urinary metanephrines are conducted throughout the patient’s lifetime to detect any recurrence or metastasis.
For patients with a genetic mutation, annual MRI scans are also necessary to identify hormonally inactive tumo