CASE 19 Pheochromocytoma – All the glitters is not gold !

Original case by Mohammed Z. Ansari et al

A 40-year-old male with a history of hypertension of 5-years duration presented with acute right upper abdominal pain associated with shortness of breath. His blood pressure (BP) was reported to be controlled at home with diet and exercise. He was evaluated at an independent emergency facility because of acute abdominal pain. The abdominal CT scan at that facility revealed a right adrenal mass encapsulating the IVC. He was transferred to our facility for acute surgical care.

Q What would be your approach to evaluating this case ?

This could be treated as an adrenal incidentaloma. I would look for the following things :

  1. Size of the adrenal mass
  2. What is the attenuation of the mass on CT scan what are the washout characteristics
  3. I would see if the mass is functioning adrenal mass of not. I would ask for
    1. Overnight dexamethasone suppression test
    2. 24 hour urinary metanephrine and normetanephrine
    3. Serum aldosterone / renin ration (since the patient is hypertensive)

His initial physical examination revealed an obese male (body mass index of 36 kg/m2) in moderate respiratory distress while breathing 50% oxygen through a Venturi mask. The patient’s oral temperature was 101.0°F; his initial BP range without antihypertensive treatment was 119 to 133/63 to 83 mm Hg with a heart rate of 107 to 144 beats per minute. There was mild right upper quadrant tenderness despite receiving intravenous hydromorphone via a patient-controlled analgesia pump.

Repeat CT imaging of the chest, abdomen, and pelvis with and without contrast confirmed a large right adrenal mass measuring 23.2 × 18.9 cm. The tumor was composed of fat with areas of calcification and hemorrhage. The tissue density was variable, between −100 to +61 Hounsfield units (HU). There was an associated right lung basilar atelectasis and minimal right pleural effusion present. Significant displacement of the right kidney and elevation of the right hemi-diaphragm with mass effect on the liver and pancreas combined with narrowing of both the IVC and portal vein (Fig. 2) was also seen.

The left adrenal gland appeared normal. The blood hemoglobin was 7.8 g/dL (normal, 14 to 18 g/dL). He underwent embolization of the right inferior suprarenal artery due to a suspicion of an active hemorrhage into the mass. Postembolization, the BP increased significantly. An intravenous nicardipine infusion with oral doxazosin was begun. The compressive effects of the adrenal mass resulted in severe hypoxia, with lung atelectasis and infiltrates that required support with bilevel positive airway pressure.

Forty-eight hours following embolization, a venous sample was obtained and placed on ice until plasma was separated and frozen. It was then submitted for metanephrine (free) assay by quantitative high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) and for fractionated catecholamines by quantitative HPLC. A 24-hour urine sample was collected and maintained in a refrigerated state. Fractionated urinary free metanephrine by HPLC-MS/MS and catecholamines by HPLC were completed.

The findings were as follows: serum norepinephrine, 1,422 pg/mL (normal, 80 to 520 pg/mL); epinephrine, 71 pg/mL (normal, 10 to 200 pg/mL); dopamine, 64 pg/mL (normal, 0 to 20 pg/mL); plasma normetanephrine, 2.17 nmol/mL (normal, 0 to 0.89 nmol/mL); metanephrine, 0.1 nmol/mL (normal, 0 to 0.49 nmol/mL); 24-hour urine norepinephrine, 558 μg/24 hours (normal, 0 to 100 μg/24 hours); urine epinephrine, 40 μg/24 hours (normal, 0 to 25 μg/24 hours); urine normetanephrine, 2,846 μg/24 hours (normal, 50 to 650 μg/24 hours); metanephrine, 284 μg/24 hours (normal, 30 to 350 μg/24 hours); and serum chromogranin-A, 45 ng/mL (normal, 0 to 95 ng/mL). Table  

Q What is your interpretation of the urinary cathecholamine reports ?

It seems to be a predominantly norepinephrine secreting pheochromocytoma.

Surgery was imminent, and as endocrine consultants, we recommended an oral clonidine suppression test. It was performed in the surgical intensive care unit by administering a single dose of clonidine (0.4 mg). The plasma norepinephrine concentration decreased by 60% 3 hours after administration of the clonidine. There was a concordant decline in BP and heart rate.

Q What kind of a drug is clonidine ?

It is a centrally acting alpha2 adrenergic agonist. It suppress the central sympathetic outflow.

Q What is the usual protocol for clonidine suppression test ?

  1. Blood is drawn for cathecholamines before giving clonidine
  2. Clonidine is given
  3. Catecholamines are repeated after 3 hours

Q What is the interpretation of clonidine suppression test ?

Catecholamines generally fall in patients not having pheochromocytoma while they donot fall in patients with pheochromocytoma. In patients not having pheochromocytoma there is fall in plasma metanephrine by 40% from baseline.

Q What is the interpretation in this case ?

There is about 60% fall in norepinephrine value from baseline after giving clonidine. This goes against pheochromocytoma.

Patient underwent urgent exploratory laparotomy. Based on the endocrine diagnostic test findings, there was a low probability of pheochromocytoma. Surgery proceeded under general anesthesia without the customary preparation done for pheochromocytoma surgery. A 3.07-kg mass was resected in multiple pieces. This was described as adrenal myelolipoma. The largest section (32 × 25 × 13.5 cm) had a well-circumscribed tan-green and partially necrotic area (5.5 × 4 × 3 cm) that was completely encompassed by adipose tissue, with multiple hemorrhagic and necrotic areas that comprised the majority of the specimen. Microscopic examination of the mass disclosed extensively necrotic (approximately 80%) with focal viable areas characterized by trilineage hematopoietic elements, mature adipose tissue, and thick fibrous bands. Only small areas of residual adrenal gland were identified. Immunohistochemistry for chromogranin was diffusely negative in the tumor and adrenal gland. Postsurgery, the BP normalized without the administration of antihypertensive therapy.

Q What was the evidence of false positive in this case ?

False positive in plasma metanephrine and catecholamines is no unusual.  False positive is less likely if

  1. Both plasma metanephrine and normetanephrine are elevated
  2. Either of them is elevated 3 fold above normal

In this case only the plasma normetanephrine was elevated and it was not 3 fold above normal. Also the Chromogranin was not elevated. The stress of the critical illness and other issue led to the raise in the plasma normetanephrine values.

Q What are adrenal myelolipoma ?

They are benign tumors of the adrenal often incidentally detected. Low density on CT is characteristic.

Q Can they be functioning ?

Functioning adrenomyelolipoma are often reported in literature.

Learning points from this case

  1. ‘All that glitters is not gold’. Elevated plasma normetanephrine may not always suggest a pheochromocytoma. Stress can often lead to increase in plasma normetanephrine values which must be interpreted carefully.
  2. Clonidine suppression test is a useful adjuvant in cases where the diagnosis is in doubt.
  3. Suppression of Plasma metanephrine by >40% , 3 hours after clonidine goes against the diagnosis of pheochromocytoma.
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