Canine Pheochromocytoma

Pheochromocytoma is a rare endocrine tumor derived from chromaffin cells.  It is the most common neoplasm of the adrenal medulla and develops often in dogs and cattle.  The tumor can be unilateral or bilateral, infrequently functional and has no reported breed or sex predilection.  Pheochromocytomas in dogs are usually benign, however, with potential for local invasion.  Occasionally, they are malignant with metastasis to distant organs, especially the liver, regional lymph nodes or lungs.  This neoplasm is considered malignant when metastasis is present in non-chromaffin cells.  Affected dogs are usually older, with a mean age of 11 years.  Pheochromocytomas are of neuroectodermal origin, arising from chromaffin cells,  which produce and secrete catecholamines.  Epinephrine and nor-epinephrine are the catecholamines most commonly produced, with dopamine produced less frequently.  Catecholamine release in functional pheochromocytomas is usually paroxysmal.  This may be attributed to changes in blood flow, chemicals, or drugs, or direct pressures on the tumor (abdominal palpation) since the tumors have no innervation.

  Clinical signs associated with pheochromo-cytoma are often vague and intermittent, and may mimic more common disorders such as hyperadrenocortisism, diabetes mellitus, hepatic or renal disease, or other neoplasms.  Clinical signs frequently observed include weakness, collapse, lethargy, anorexia, vomiting, panting, weight loss, anxiety, restlessness, polyuria, polydipsia, diarrhea, abdominal distention, hind limb edema, epistaxis, seizures or acute blindness.  The clinical signs are generally associated with catecholamine excess and systemic hypertension.  Elevation of blood pressure induced by sudden release of catecholamines can precipitate acute congestive heart failure, pulmonary edema, myocardial infarction, ventricular fibrillation and cerebral hemorrhage.  Nonfunctional tumors can also produce clinical signs by their space occupying nature.

  Pheochromocytomas occasionally result in secondary conditions including invasion and thrombosis of the caudal vena cava, aortic thromboembolism, spontaneous rupture of the tumor, paresis secondary to spinal cord compression, arrhythmias, cardiac hyper-trophy, arteriolar sclerosis, systemic hyper-tension, or hyperadrenocortisism.  About 15-38% of pheochromocytomas invade the caudal vena cava, causing clinical signs of ascites, hind limb edema, or distention of the caudal epigastric veins.  Ultrasound and Doppler imaging can be used to identify obstruction of the caudal vena cava.  Aortic thrombo-embolism is fairly uncommon in dogs, and occurs due to endothelial damage, vascular stasis, and hypercoagulable states.  Rarely, pheochromocytomas may rupture spon-taneously and cause retroperitoneal hemorrhage or periumbilical ecchymoses (Cullen's sign).  Systemic hypertension occurs in 43-70% of canine patients with pheo-chromocytoma, and concurrent hyperadreno-cortism has been found in 12% of reported cases.

  Antemortem diagnosis of pheochromocytoma can be difficult because the tumors are often non-functional or episodic in nature.  Abnormalities in routine laboratory testing are often non-specific, but may be useful to rule out concurrent disease.  The CBC may reveal anemia (from chronic disease or blood loss) or a transient thrombocytopenia if the patient has platelet consumption from episodic hemorrhage.  The leukogram often reveals leukocytosis characterized by a mature neutrophilia due to either catecholamine induced by demargination of neutrophils or necrosis/inflammation within the tumor.  Serum blood chemistry occasionally reveals a mild azotemia, hypercholesterolemia, hypoalbumi-nemia, and elevated ALT and ALP.  Abdominal radiographs and ultrasound can be used to detect abdominal masses, and thoracic radiographs should be taken to detect distant metastasis.  A pneumoperitoneogram may aid in tumor visualization.  Caudal abdominal venography can be useful to diagnose local tumor invasion or tumor related thrombosis, and contrast urography can identify invasion into the cranial pole of the kidney.  Human medicine frequently uses advanced imaging techniques (CT, MRI, or metaiodo-benzylguanidine scanning) and serum or urine catecholamine metabolite assays to obtain a diagnosis.  These methods are of limited use in veterinary medicine because of their unavailability, expense, the need for general anesthesia, and lack of reference ranges.  A definitive diagnosis of pheochromocytoma can only be obtained through histopathology; therefore, the diagnosis is often obtained post-mortem.

  Grossly, pheochromocytomas are often large (10 cm or greater in diameter), multilobular, firm, and encapsulated, and typically replace most of the affected adrenal gland.  A thin rim of adrenal cortex may surround smaller neoplasms.  Large tumors are often locally invasive into the tissues surrounding the affected adrenal gland, most notably the caudal vena cava where they may form a thrombus.  Pheochromocytomas may also be located at extra-adrenal sites where they are called paragangliomas.  On cross section, the tumors are often red-brown to yellow (as a result of areas of hemorrhage and necrosis), and are calcified in approximately 10% of cases.  Histologically, the cells vary from small, round or polyhedral cells to large pleomorphic cells with multiple hyperchromatic nuclei.  Tumor cells are often arranged in irregular cords that are separated by fine fibrovascular septae.  The cytoplasm is usually pale eosinophilic and finely granular.  Cytoplasmic granules can be observed by techniques using Muller, Zenker, Orth, or other dichromate-containing fixatives.  A valuable diagnostic aid is the Henle chromoreaction, which can be performed by applying Zenker's solution to the flat-cut surface of a freshly resected tumor.  In a pheochromocytoma, the catecholamines will be oxidized, forming a dark brown pigment within 20 minutes of application.

  The treatment of choice for canine pheochromocytoma is surgical removal.  Medical therapy can be used for nonresectable or metastatic disease, or to stabilize the patient prior to surgical excision.  Medical therapy is generally aimed at correcting systemic hypertension and cardiac arrhythmias.  The prognosis is guarded; however, survival of up to one year has been reported in 50% of dogs with uncomplicated cases following surgical removal of the tumor.  Pheochromo-cytoma should be considered in cases which have vague clinical signs and concurrent hypertension.  Perhaps with more awareness of this condition, it can be diagnosed and managed more successfully.

-by Dr. Kelly Baete, Class of 2004

-edited by Dr. Gopa Gopalakrishnan, ADDL Graduate Student

References:

1. Jones TC, BD Hunt and NW King: 1997.  Veterinary Pathology.  Baltimore: Williams and Wilkens

2. Jubb KVF, PC Kennedy, N Palmer (Eds): 1993.  Pathology of Domestic Animals, 4th ed.  San Diego: Academic Press, 1993.

3. Locke-Bohannon LG and GE Mauldin: 2001.  Canine Pheochromocytoma: diagnosis and management.  Compendium on Continuing Education for the Practicing Veterinarian 23: 807-814.

4. McGavin MD, WW Carlton, JF Zachary: 2001.  Thompson's Special Veterinary Pathology, 3rd ed.  St. Louis: Mosby

5. Santamarina et al: 2003.  Aortic Thromboembolism and Retroperitoneal Hemorrhage Associated with a Pheochromo-cytoma in a Dog.  J Vet Int Med.  17(6): 917-922.

6. Williams JE and SG Hackner: 2001.  Pheochromocytoma Presenting as Acute Retroperitoneal Hemorrhage in a Dog.  J Vet Emerg and Critical Care. 11(3): 221-227