Pheochromocytomas (Proceedings)

The adrenal gland consists of two distinct regions, the outer cortex and inner medulla. The cortex consists of three distinct layers that produce mineralocorticoids (aldosterone), glucocorticoids and androgens. Collectively these hormones are sometimes referred to as corticosteroids. The medulla produces catecholamines including epinephrine, norepinephrine and dopamine. The synthesis and release of catecholamines is stimulated by stressful stimuli such as exercise, hemorrhage, hypotension, hypoxemia, and hypoglycemia amongst others.1,2 The normal adrenal medulla converts most norepinephrine to epinephrine which is the primary product excreted.1 Once released into circulation, catecholamines are bound to proteins such as albumin and quickly metabolized by various tissues into inactive metabolites such as metanephrine, normetanephrine and vanillymandelic acid. 1,2 The intact catecholamines and their metabolites are excreted in the urine.2 Excess intracellular catecholamines are also metabolized within the adrenal medulla. This explains why pheochromocytomas excrete a large number of metabolites directly into circulation.1,2 Catecholamines stimulate adrenergic receptors on various tissues. Some effects include vasoconstriction, vasodilation, increased heart rate and force of contraction, increased renin release, decreased intestinal motility, increased glycogenolysis in the liver, bronchiolar dilatation and lipolysis.2

Signalment

Pheochromocytomas are uncommon but found in dogs much more often than in cats. In fact there have only been 4 reports of pheochromocytomas causing clinical signs to the author's knowledge.3,4,5,6 Animals are usually older at the time of diagnosis.1,7,8

Etiology

Neuroendocrine tumors are tumors of organ systems that utilize both hormones and chemical messenger systems. Neuroendocrine tumors of the adrenal medulla that produce excess catecholamines are called pheochromocytomas. Pheochromocytomas arise from chromaffin cells in the adrenal medulla. Unilateral involvement occurs in most all animals but bilateral disease has been reported.7,8 Rarely, concurrent adrenocortical disease is present.9,10,11 Approximately 50% of pheochromocytomas are considered malignant based on their behavior.7,8,12 These tumors may invade adjacent vessels (caudal vena cava, phrenicoabdominal artery/vein, adrenal artery/vein, renal artery/vein and hepatic vein) or metastasize to the regional lymph nodes, liver, spleen, kidneys, pancreas, peritoneum, lungs, heart, spinal cord, bone and brain.7,8,12,13,14

Clinical Signs

These tumors may be an incidental finding and in a previous report was found in up to 60% of dogs at necropsy so most animals with pheochormocytomas exhibit no clinical signs.7,8 In animals with signs, they may be non-specific and intermittent. Signs include lethargy, weight loss, anorexia, panting, polydispia, polyuria, abdominal distention, and collapse.1 Additional clinical findings may include pale mucous membranes, tachycardia and hypertension.1

General Laboratory Findings

Routine laboratory abnormalities are uncommon but may include a non-regenerative anemia of chronic disease, regenerative anemia (if hemorrhage), hyperglycemia, and elevated liver enzymes.1 Proteinuria and variable concentration might be found on urinalysis due to the effects of catecholamines on hypertension and vasopressin secretion, respectively.1

Diagnostic Imaging

Thoracic radiographs are typically unremarkable unless pulmonary metastases are noted. Abdominal radiographs may be normal or a soft tissue mass noted in the region of the adrenal gland. If hemorrhage has occurred then decreased serosal detail might be seen. Abdominal ultrasound will usually reveal a mass and is a sensitive tool for evaluating for local invasion or concurrent thrombosis. Dogs with clinical signs are more likely to have larger tumors than those in which the pheochromocytoma is found incidentally.1 Cross-sectional imaging (CT, MRI) can also be used to detect the tumor and metastatic disease.15 Nuclear scintigraphy utilizing radiolabeled metaiodobenzylguanidine (123 I-MIBG) has been used in humans to image neuroendocrine tumors.16 The radioisotope is taken up by cells of neural crest origin (neuroendocrine cells) because of its structural similarity to norepinephrine. There is a single report of one dog with a pheochromocytoma that was visualized with 123 I-MIBG.17 There is another report of a dog with a pheochromocytoma identified using positron emission tomography (PET) and fluorinated MIBG.18

Diagnosis

A presumptive diagnosis is often made in dogs and cats with adrenal masses that display clinical signs consistent with a pheochromocytoma and rule out a corticosteroid producing tumor.

In humans the diagnosis is typically made by identification of catecholamines (norepinephrine, epinephrine, dopamine) and/or metabolites (metanephrine, normetanephrine, vanillymandelic acid) in the urine or plasma utilizing HPLC.2,19 Measurement of catecholamines and metabolites is not routinely performed in dogs and cats because of limited availability of test sites, episodic excretion of catecholamines/metabolites (explains poor sensitivity of this test), and a lack of normal ranges in dogs and cats. In a recent study, urinary catecholamine and metabolite ratios were evaluated in a small number of dogs and urinary normetanephrine:creatinine ratios were significantly higher in dogs with pheochromocytomas compared to healthy controls.20 There was a recent study in a small number of cats that looked at plasma metanephrine and normetanephrine levels in healthy and sick cats as well as one cat with a pheochromocytoma and the cat with the pheochromocytoma had significantly higher levels of normetanephrine in the plasma but metanephrine levels overlapped between this cat and the sick cats.3 The Royal Veterinary College is currently studying plasma metanephrine levels in dogs and actively recruiting cases of suspected pheochromocytoma.21

In humans they also measure chromagranin A, a peptide stored and released with numerous hormones, including catecholamines.2,19 A human ELISA has been used on canine plasma samples to measure chromogranin A with good results but more studies are needed.22

Currently, definitive diagnosis is often made with tumor removal and immunohistochemical staining for chromogranin A and synaptophysin. Chromogranin A was discussed previously. Synaptophysin is a membrane glycoprotein found in the pre synaptic vesicles of neurons and neuroendocrine tumors.23,24

Treatment

Adrenalectomy is the treatment of choice for dogs and cats with clinical signs attributable to a pheochromocytoma.25 Venotomy can be performed to remove thrombi.25 Vascular resection can be performed for tumors that invade the vessels.25 The most common pre-surgical concerns are hypertension and tachyarrhythmias. For animals with hypertension the non-specific alpha antagonist, phenoxybenzamine, is given until 14 to 21 days of normal blood pressure has occurred prior to surgery. If tachycardia is present a beta blocker, such as atenolol or propanolol, are also given. It is important to start the beta blocker several days after the phenoxybenzamine in order to avoid severe hypertension that can result from unopposed stimulation of alpha adrenergic receptors. A retrospective study of 48 dogs that had undergone adrenalectomy for pheochromocytoma revealed a significant decrease in mortality in those dogs treated with phenoxybenzamine preoperatively for a median of 20 days.26 Regarding anesthesia, morphine is avoided because of its effects on histamine release and possible hypotension.27 Ketamine is sympathomimetic so it is avoided.27 Halothane may sensitize the myocardium to arrhythmias. Intra-operative and post-operative concerns include arrhythmias, hypertension, hypotension, and hemorrhage.27

In animals with local invasion or metastatic disease, surgical debulking can be performed. Phenoxybenzamine and beta blockers can also be given as needed when complete resection is not possible.

Prognosis

The prognosis with complete resection is good. Even with incomplete resection survival times of several years have been reported.1,28

References

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Wimpole JA, Adagra CF, et al. Plasma free metanephrines in healthy cats, cats with non-adrenal disease and a cat with suspected pheochromocytoma. J feline Med Surg 2010 June; 12(6):435-40.

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Thuroczy J, van Sluijs FJ, et al. Multiple endocrine neoplasia in a dog: corticotrophic tumor, bilateral adrenocortical tumors, and pheochromocytoma. Vet Q. 1999 Apr;20(2):56-61.

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Jacobson AF, Deng H, et al. 123I-meta-iodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of meta-analysis. J Clin Endocrinol Metab 2010 Jun;95(6):2596-606.

Wright KM,N, Breitschwerdt EB, et al. Diagnostic and therapeutic considerations in a hypercalcemic dog with multiple endocrine neoplasia. J Am Anim Hosp Assoc 1995 Mar-Apr;31(2):156-62.

Berry CR, DeGrado TR, et al. Imaging of pheochromocytoma in 2 dogs using p-[18F] fluorobenzylguanidine. Vet Radiol Ultrasound 2002 Mar-Apr;43(2):183-6.

Lenders JW, Pacak K, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002 Mar 20;287(11):1427-34.

Kook PH, Grest PL, et al. Urinary catecholamine and metadrenaline to creatinine ratios in dogs with phaeochromocytoma. Vet Rec 2010 Feb 6;166(6):169-74.

Gostelow R, Syme H. Plasma metadrenalines in canine pheochromocytoma. Vet Rec 2010 Apr 24;166(17):538.

Akiyoshi H, Aoki M, et al. Measurement of plasma chromogranin A concentrations for assessment of stress responses in dogs with insulin-induced hypoglycemia. Am J Vet Res 2005 Oct;66(10):1830-5.

Doss, JC, Grone A, et al. Immunohistochemical localization of chromogranin A in endocrine tissues and endocrine tumors of dogs. Vet Pathol 1998 Jul;35(4):312-25.

Gould VE, Wiedenmann B, et al. Synaptophysin expression in neuroendocrine neoplasms as determined by immunocytochemistry. Am J Pathol 1987 Feb;126(2):243-57.

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Herrara MA, Mehl ML, et al. Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma. J Vet Int Med 2008 Nov-Dec;22(6):1333-9

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