57 Pathophysiology, Evaluation, and Medical Management of Adrenal Disorders

These extra-adrenal pheochromocytomas

At least 5 genes - 

• REarranged Transfection protooncogene (RET),
• Von Hippel–Lindau (VHL),
• Neurofibromatosis type 1 (NF1), and
• Mitochondrial succinate dehydrogenase subunits D and B genes (SDHD, SDHB),

Malignancy can only be defined by the presence of clinical metastases.

Pathologic appearance and even local invasion are of only limited value in determining metastatic potential of a given lesion

• 10% extra-adrenal,
• 10% familial,
• 10% bilateral,
• 10% pediatric, and
• 10% malignant

 However, this rule has been challenged repeatedly, up to 25% of pheochromocytomas can be extraadrenal

Similarly, familial cases account for up to 30% of tumors at presentation

• Headache
• Episodic sudden perspiration
• Tachycardia

Given their rich vascularity and low lipid content, pheochromocytomas typically measure an attenuation of greater than 10 HU on unenhanced CT (mean ≈35 HU). This property affords the ability to differentiate them from lipid-rich adenomas. 

Furthermore, pheochromocytomas can be distinguished from lipid-poor adenomas using CT contrast washout strategies. Although nonspecific, pheochromocytomas, unlike adenomas, do not exhibit rapid contrast washout on delayed imaging.

• Extra-adrenal,
• Metastatic,
• Recurrent pheochromocytoma.
• To localize diseases in patients with biochemical evidence of pheochromocytoma but negative cross-sectional imaging.

Plasma concentration of metanephrines is a much more sensitive means of tumor detection than the measurement of rises in plasma catecholamines. Vast majority of metanephrine synthesis occurs within the adrenal medulla and/or pheochromocytoma and only then do they enter the bloodstream. 

Sensitivity of urine VMA levels is  low. 

Cloniodine suppression test - Clonidine, an α2 agonist, suppresses catecholamine (specifically norepinephrine) production by the sympathetic nervous system but not by pheochromocytoma. Comparison of normetanephrine levels before and after clonidine administration has been shown to yield results with favorable test characteristics. 

Chromogranin A–level evaluation has a role for confirmatory testing in patients who have mild or moderate (less than a fourfold) elevation in free-plasma metanephrine levels

Together normetanephrine and metanephrine are known as metanephrines

All patients with pheochromocytoma and an abnormal metabolic evaluation undergo preoperative catecholamine blockade, including patients who do not exhibit evidence of blood pressure elevation and lack classic symptomatology.

Phenoxybenzamine is the most common α blocker used for preoperative catecholamine blockade of pheochromocytoma.

Phenoxybenzamine is started 7 to 14 days prior to surgery. Oral dosing of 10 mg twice daily is initiated and titrated by increases of 10 to 20 mg to a blood pressure of 120 to 130/80 mm Hg in a seated position.

In children, 0.2 mg/kg (maximum dose of 10 mg) four times daily with increases in 0.2 mg/kg increments is recommended.

Selective reversible α1 blockers, such as terazosin, doxazosin, or prazosin if phenoxybenzamine.

 β blockade should never be started prior to appropriate α blockade. Indeed, in the absence of α blockade, β antagonists cause a potentiation of the action of epinephrine on the α1 receptors, due to blockade of the arteriolar dilation at the β2 receptor.

• Intake of salt and fluid is encouraged once catecholamine blockade has been initiated 
• Admit patients the day before surgery and initiate aggressive intravenous fluid resuscitation.
• The last dose of phenoxybenzamine and/or metyrosine is usually given on the night prior to surgery, and the next morning’s dose is held. This approach minimizes potentially prolonged hypotension following tumor resection

If phenoxybenzamine was employed for preoperative α blockade, hypotension is common, given the lasting effects of the agent. 

Moreover, in a high catecholamine state, α2-adrenoreceptor stimulation inhibits insulin release. The withdrawal of this adrenergic stimulus following tumor resection, may result in rebound hyperinsulinemia and subsequent hypoglycemia

Repeat metabolic testing 2 weeks after adrenalectomy to document normalization of chromaffin cell function. 

In patients in whom metanephrine levels remain elevated, MIBG imaging may be helpful. MIBG uptake by previously unseen metastases may now be unveiled following resection of the primary tumor. 

Lifelong screening for recurrence is recommended by some experts, because 10-year recurrence rates are as high as 16% in some series of fully resected lesions.  Biochemical testing at 6 months after surgery, followed by annual testing. Need for subsequent imaging should be guided by results of biochemical testing

Given that for patients with MEN-2 and VHL, the risk of malignancy is low while risk of bilateral disease is significant, partial cortical-sparing adrenalectomy has been advocated. This strategy is employed to avoid lifelong hormonal replacement, with its associated morbidity

• Largely palliative
• Surgical metastatectomy of resectable disease is the standard of care.
• Given selective uptake of MIBG by pheochromocytoma cells, systemic treatment of metastatic patients with radioactive 131I-MIBG may be instituted.