Pheochromocytoma

Pheochromocytoma is a neuroendocrine tumor of the adrenal medulla that secretes catecholamines (epinephrine, norepinephrine, and occasionally dopamine). It is the most common tumor of the adrenal medulla in dogs and cats, though it is relatively uncommon overall. These tumors can be benign or malignant, with malignancy defined by invasion into surrounding tissues or metastasis, not solely by histologic appearance. Pheochromocytomas may be functional (secreting catecholamines) or non-functional (incidental findings). They can cause a wide range of clinical signs due to the systemic effects of catecholamine excess, including hypertension, tachycardia, arrhythmias, and metabolic disturbances. In veterinary medicine, pheochromocytoma is often diagnosed incidentally during abdominal imaging for unrelated reasons, but it can also present as a life-threatening emergency due to hypertensive crises or catecholamine-induced cardiomyopathy.

The exact etiology of pheochromocytoma in dogs and cats is largely unknown. Most cases are sporadic, with no identifiable cause. However, a genetic predisposition is suspected in certain breeds, and there is evidence of familial clustering in some canine families. In humans, pheochromocytomas are associated with mutations in genes such as RET, VHL, NF1, and SDH genes, but similar genetic mutations have not been well-characterized in veterinary species. Chronic hypoxia has been suggested as a potential trigger in some cases, but this is not well-supported. No viral, bacterial, or environmental causes have been identified. In dogs, there is a possible association with chronic stimulation of the adrenal medulla, but this remains speculative. Overall, the etiology is considered idiopathic in the vast majority of veterinary cases.

Pheochromocytoma is an uncommon tumor in dogs and cats. It accounts for approximately 0.1% to 0.5% of all canine tumors and is even rarer in cats. The mean age at diagnosis in dogs is around 10-11 years, with a range of 2-15 years. No strong breed predisposition is recognized, but some reports suggest a higher incidence in Labrador Retrievers, Golden Retrievers, and German Shepherd Dogs. In cats, the mean age is around 12 years, and no breed predilection is noted. There is no clear sex predilection in either species. The tumor is more commonly diagnosed in older animals, likely due to the increased use of advanced imaging in geriatric patients. Pheochromocytomas are often found incidentally during abdominal ultrasonography or computed tomography (CT) performed for other reasons, which may contribute to the apparent increase in diagnosis in recent years.

Pheochromocytomas arise from chromaffin cells of the adrenal medulla, which are derived from the neural crest. These cells normally synthesize and secrete catecholamines (epinephrine, norepinephrine) in response to sympathetic stimulation. In pheochromocytoma, the tumor cells autonomously produce and release catecholamines, leading to excessive circulating levels. The pathophysiology is primarily driven by the effects of catecholamines on adrenergic receptors (alpha-1, alpha-2, beta-1, beta-2). Alpha-1 receptor activation causes vasoconstriction, leading to hypertension. Beta-1 receptor activation increases heart rate and myocardial contractility, potentially causing tachycardia and arrhythmias. Beta-2 receptor activation causes vasodilation and bronchodilation, but in the context of pheochromocytoma, the alpha-mediated effects usually predominate. Chronic catecholamine excess can lead to downregulation of adrenergic receptors, causing a blunted response over time. The tumor may also secrete other peptides, such as atrial natriuretic peptide or adrenomedullin, which can complicate the clinical picture. Sustained or paroxysmal hypertension can result in end-organ damage, including hypertensive retinopathy, renal injury, and cardiovascular remodeling. Catecholamine-induced cardiomyopathy can lead to myocardial necrosis, fibrosis, and congestive heart failure. Additionally, catecholamines can cause metabolic effects such as hyperglycemia, hyperlactatemia, and lipolysis. The tumor can also invade locally into the caudal vena cava, leading to vascular obstruction and potential tumor embolization.

Predisposing factors for pheochromocytoma in dogs and cats are not well-defined. Age is a significant factor, as the tumor is most commonly diagnosed in older animals (typically >8 years). There is no strong breed or sex predisposition, but some studies suggest a possible increased risk in certain breeds, such as Labrador Retrievers and Golden Retrievers. Genetic factors are suspected but not fully characterized; familial cases have been reported in dogs, suggesting a hereditary component in some instances. Chronic hypoxia, as seen in high-altitude environments, has been proposed as a risk factor in humans, but this has not been confirmed in veterinary patients. Other potential risk factors include chronic stress or chronic stimulation of the adrenal medulla, but these are speculative. Concurrent endocrine diseases, such as diabetes mellitus or hyperadrenocorticism, may be associated with pheochromocytoma, but this is likely due to the shared age group rather than a causal relationship.

Clinical signs of pheochromocytoma are highly variable and can be paroxysmal or persistent. Many animals are asymptomatic, and the tumor is discovered incidentally. When signs are present, they are often related to the cardiovascular effects of catecholamine excess. Common signs include: weakness, lethargy, panting, restlessness, anxiety, and episodic collapse. Hypertension is a hallmark finding, but it may be intermittent. Tachycardia and arrhythmias (e.g., premature ventricular contractions, supraventricular tachycardia) are common. Some animals may present with signs of congestive heart failure, such as cough, dyspnea, and exercise intolerance. Other signs include polyuria, polydipsia, polyphagia, weight loss, and vomiting. Neurologic signs, such as seizures or ataxia, can occur secondary to hypertensive encephalopathy. In cases of tumor invasion into the caudal vena cava, signs of hindlimb edema, ascites, or acute collapse due to tumor embolization may be observed. Physical examination may reveal a palpable abdominal mass in some cases, but this is not always possible. The clinical signs can be triggered by stress, exercise, or abdominal palpation, which can cause a catecholamine surge.

Differential diagnoses for pheochromocytoma include: 1) Hyperadrenocorticism (Cushing's syndrome) - both can cause polyuria, polydipsia, panting, and abdominal distension; however, Cushing's is associated with characteristic skin changes, hepatomegaly, and a typical cortisol profile (elevated cortisol on ACTH stimulation or low-dose dexamethasone suppression). Pheochromocytoma may cause hypertension, which is less common in Cushing's. 2) Chronic kidney disease - can cause hypertension, polyuria, polydipsia, and lethargy; however, renal disease is characterized by azotemia, isosthenuria, and abnormal renal imaging. 3) Hyperthyroidism (in cats) - can cause tachycardia, hypertension, polyphagia, and weight loss; however, hyperthyroidism is associated with elevated T4 and characteristic thyroid gland enlargement. 4) Diabetes mellitus - can cause polyuria, polydipsia, polyphagia, and weight loss; however, diabetes is characterized by persistent hyperglycemia and glucosuria. 5) Primary hypertension (essential hypertension) - can cause similar signs but is a diagnosis of exclusion after ruling out secondary causes. 6) Cardiac disease (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy) - can cause tachycardia, arrhythmias, and signs of heart failure; however, echocardiography will reveal structural abnormalities. 7) Anxiety or behavioral disorders - can cause episodic weakness, panting, and restlessness; however, these are diagnoses of exclusion. 8) Other adrenal tumors (e.g., adrenocortical carcinoma) - can cause similar abdominal mass and hormonal signs; however, adrenocortical tumors typically produce cortisol or sex hormones, and imaging may show a different pattern (e.g., mineralization). 9) Pheochromocytoma can also mimic acute abdomen due to tumor rupture or hemorrhage. Definitive diagnosis requires measurement of catecholamines or their metabolites, and imaging.

The diagnostic approach to pheochromocytoma should be systematic. 1) Clinical suspicion: Consider pheochromocytoma in any older dog or cat with hypertension, tachycardia, arrhythmias, or episodic weakness, especially if an adrenal mass is detected on imaging. 2) Baseline laboratory tests: Complete blood count, serum biochemistry, urinalysis, and blood pressure measurement. These may reveal non-specific changes such as hemoconcentration, hyperglycemia, or elevated liver enzymes. 3) Imaging: Abdominal ultrasonography is often the first imaging modality. It can identify an adrenal mass and assess for invasion into the caudal vena cava. Doppler ultrasound can evaluate vascular invasion. Computed tomography (CT) or magnetic resonance imaging (MRI) provides more detailed assessment of the mass, its relationship to surrounding structures, and the presence of metastasis. 4) Confirmatory testing: The gold standard for diagnosis is the measurement of urinary catecholamines or their metabolites (metanephrines, normetanephrines) via a urine metanephrine-to-creatinine ratio. In dogs, a urine metanephrine-to-creatinine ratio > 0.3 is highly suggestive of pheochromocytoma. Plasma metanephrine levels can also be measured, but urine testing is more commonly used. 5) Additional tests: If pheochromocytoma is suspected, a clonidine suppression test or a glucagon stimulation test may be performed, but these are less commonly used in veterinary medicine. 6) Histopathology: Definitive diagnosis requires histologic examination of the tumor after surgical excision or biopsy. Immunohistochemistry for chromogranin A, synaptophysin, and neuron-specific enolase can confirm the neuroendocrine origin. 7) Staging: If malignancy is suspected, thoracic radiographs and abdominal imaging should be performed to check for metastasis. The diagnostic algorithm should be tailored to the individual patient, and if pheochromocytoma is strongly suspected, surgical resection is often recommended, with histopathology confirming the diagnosis.

Laboratory findings in pheochromocytoma are often non-specific but may include: 1) Complete blood count: Hemoconcentration due to dehydration or polycythemia (rare). Stress leukogram (neutrophilia, lymphopenia, eosinopenia) may be present. 2) Serum biochemistry: Hyperglycemia due to catecholamine-induced glycogenolysis and insulin resistance. Elevated liver enzymes (ALT, ALP) may be seen due to hepatic congestion or concurrent disease. Azotemia may occur if hypertension has caused renal damage. Electrolyte abnormalities are uncommon but may include hypokalemia due to stress or hyperaldosteronism. 3) Urinalysis: Proteinuria may be present due to hypertension-induced glomerular damage. Urine specific gravity may be low if there is concurrent renal disease. 4) Blood pressure measurement: Hypertension (systolic > 180 mmHg) is common, but blood pressure may be normal or even low in some cases. 5) Urine metanephrine-to-creatinine ratio: This is the most specific and sensitive test for pheochromocytoma. A ratio > 0.3 in dogs is considered diagnostic. In cats, a ratio > 0.3 is also suggestive. 6) Plasma metanephrine levels: Can be measured, but urine testing is preferred due to ease of collection. 7) Other biomarkers: Chromogranin A levels may be elevated, but this test is not widely available. 8) Thyroid function tests: May be performed to rule out hyperthyroidism in cats. 9) Adrenal function tests: ACTH stimulation test or low-dose dexamethasone suppression test may be performed to rule out hyperadrenocorticism, as concurrent disease is possible.

Imaging plays a crucial role in the diagnosis and staging of pheochromocytoma. 1) Abdominal radiography: May reveal a soft tissue mass in the cranial abdomen, but this is not sensitive. Calcification of the adrenal gland may be seen in some cases. 2) Abdominal ultrasonography: This is the most commonly used imaging modality. It can identify an adrenal mass (usually hypoechoic or mixed echogenicity) and assess for invasion into the caudal vena cava. Doppler ultrasound can detect blood flow within the mass and evaluate vascular invasion. Ultrasonography can also identify metastasis to the liver or other abdominal organs. 3) Computed tomography (CT): CT provides excellent anatomical detail and is superior to ultrasound for detecting vascular invasion and metastasis. It can also characterize the mass (e.g., heterogeneity, necrosis, calcification). CT is recommended for surgical planning. 4) Magnetic resonance imaging (MRI): MRI is less commonly used but can provide detailed soft tissue contrast and is useful for evaluating vascular invasion. 5) Thoracic radiography: Should be performed to check for pulmonary metastasis. 6) Echocardiography: May be indicated if cardiac signs are present, as catecholamine-induced cardiomyopathy can cause myocardial thickening or dilation. 7) Scintigraphy: Metaiodobenzylguanidine (MIBG) scintigraphy is used in human medicine but is rarely available in veterinary practice.

Cytology and histopathology are essential for definitive diagnosis. 1) Fine needle aspiration (FNA) of the adrenal mass: This can be performed under ultrasound guidance. Cytologic examination may reveal clusters of polygonal cells with abundant granular cytoplasm, but FNA is not always diagnostic and carries a risk of triggering a catecholamine crisis. Therefore, FNA is often avoided if pheochromocytoma is suspected. 2) Histopathology: After surgical excision or biopsy, histologic examination is the gold standard. Pheochromocytomas are composed of nests or cords of polygonal cells with eosinophilic cytoplasm and round to oval nuclei. Malignancy is determined by invasion into the capsule, blood vessels, or surrounding tissues, or by the presence of metastasis. Immunohistochemistry for chromogranin A, synaptophysin, and neuron-specific enolase can confirm the neuroendocrine origin. 3) Special stains: Silver stains (e.g., Grimelius) can highlight neurosecretory granules. 4) Electron microscopy: Can demonstrate dense-core granules, but this is rarely needed. 5) If the tumor is non-functional, histopathology is the only way to diagnose it.

Treatment of pheochromocytoma involves surgical resection, medical management of catecholamine effects, and supportive care. 1) Preoperative stabilization: The primary goal is to control blood pressure and heart rate before surgery to reduce the risk of intraoperative hypertensive crises. Alpha-adrenergic blockade is the cornerstone. Phenoxybenzamine (0.25-1.5 mg/kg PO q8-12h) is the most commonly used alpha-blocker. It should be started 10-14 days before surgery. Beta-blockers (e.g., propranolol 0.2-1.0 mg/kg PO q8h) should only be used after adequate alpha-blockade to prevent unopposed alpha-mediated vasoconstriction. 2) Surgical resection: Adrenalectomy is the treatment of choice. The tumor and the entire adrenal gland should be removed. If there is invasion into the caudal vena cava, a cavotomy may be necessary. Surgery should be performed by an experienced surgeon, and intraoperative monitoring of blood pressure and ECG is essential. 3) Postoperative care: Blood pressure should be monitored closely, as hypotension may occur after tumor removal due to downregulation of adrenergic receptors. Supportive care includes intravenous fluids, pain management, and monitoring for arrhythmias. 4) Medical management of inoperable tumors: If surgery is not possible, long-term alpha-blockade with phenoxybenzamine can be used to control clinical signs. Other drugs such as amlodipine (0.05-0.1 mg/kg PO q24h) may be added for hypertension. 5) Chemotherapy: There is limited evidence for the efficacy of chemotherapy in pheochromocytoma. Mitotane has been used in some cases, but results are variable. 6) Radiation therapy: May be considered for palliative treatment of non-resectable tumors, but it is not commonly used. 7) Dietary management: A low-sodium diet may be beneficial for managing hypertension. 8) Emergency treatment: If a hypertensive crisis occurs, intravenous nitroprusside (0.5-10 mcg/kg/min CRI) or phentolamine (0.02-0.1 mg/kg IV) can be used. Arrhythmias should be treated with appropriate antiarrhythmic drugs.

The prognosis for pheochromocytoma is variable and depends on several factors. 1) Benign tumors that are completely excised have a good prognosis, with many animals living for years after surgery. 2) Malignant tumors with vascular invasion or metastasis have a guarded to poor prognosis. The median survival time for dogs with malignant pheochromocytoma is reported to be around 1-2 years, but some may live longer with medical management. 3) The presence of clinical signs at diagnosis is associated with a poorer prognosis compared to incidentally discovered tumors. 4) Intraoperative complications, such as hypertensive crises or arrhythmias, can increase morbidity and mortality. 5) The overall perioperative mortality rate is reported to be around 10-20%. 6) Recurrence is possible if the tumor is incompletely excised. 7) In cats, the prognosis is similar, with a median survival time of around 1-2 years for malignant tumors. 8) Regular monitoring is essential to detect recurrence or metastasis.

Follow-up care for pheochromocytoma is crucial. 1) Postoperative monitoring: Blood pressure should be checked regularly, as hypertension may persist or resolve. 2) Serial urine metanephrine-to-creatinine ratios: These should be measured every 3-6 months for the first year, then every 6-12 months thereafter, to detect recurrence or metastasis. 3) Imaging: Abdominal ultrasound or CT should be repeated every 6-12 months to monitor for local recurrence or metastasis. 4) Blood pressure monitoring: If hypertension persists, antihypertensive therapy should be adjusted. 5) Cardiac monitoring: If the animal had cardiac complications, an echocardiogram should be repeated as needed. 6) General health: Routine physical examinations and blood work should be performed every 6-12 months. 7) If the tumor was non-functional and completely excised, follow-up may be less intensive, but still recommended. 8) Owners should be educated about the signs of hypertensive crisis and when to seek emergency care.

Pearls: 1) Always measure blood pressure in any older dog or cat with an adrenal mass. 2) If pheochromocytoma is suspected, avoid fine needle aspiration of the adrenal gland, as it can precipitate a fatal catecholamine surge. 3) Preoperative alpha-blockade is essential to reduce surgical risk. 4) Beta-blockers should never be used without prior alpha-blockade. 5) Pheochromocytoma can be a cause of sudden death due to arrhythmias or tumor rupture. 6) In cats, pheochromocytoma is rare but should be considered in any cat with hypertension and an adrenal mass. 7) Urine metanephrine-to-creatinine ratio is the most reliable diagnostic test. Pitfalls: 1) Failing to recognize that hypertension may be intermittent, so a single normal blood pressure reading does not rule out pheochromocytoma. 2) Misinterpreting clinical signs as hyperadrenocorticism, as both can cause polyuria, polydipsia, and panting. 3) Performing surgery without adequate alpha-blockade, leading to intraoperative hypertensive crisis. 4) Overlooking the possibility of concurrent pheochromocytoma and hyperadrenocorticism. 5) Assuming that a non-functional pheochromocytoma is benign; malignancy is determined by invasion and metastasis, not by hormone secretion. 6) Not monitoring blood pressure postoperatively, as hypotension can occur.

Based on Plumb's Veterinary Drug Handbook, the following drug protocols are recommended for pheochromocytoma: 1) Phenoxybenzamine (Dibenzyline): Dogs: 0.25-1.5 mg/kg PO q8-12h, starting at the low end and titrating up based on blood pressure. Cats: 0.25-0.5 mg/kg PO q12h. It is an irreversible alpha-blocker. Side effects include hypotension, tachycardia, and gastrointestinal upset. It should be started 10-14 days before surgery. 2) Propranolol (Inderal): Dogs: 0.2-1.0 mg/kg PO q8h. Cats: 0.2-0.6 mg/kg PO q8h. It is a non-selective beta-blocker. It should only be used after adequate alpha-blockade. Side effects include bradycardia, hypotension, and bronchoconstriction. 3) Amlodipine (Norvasc): Dogs: 0.05-0.1 mg/kg PO q24h. Cats: 0.625-1.25 mg/cat PO q24h. It is a calcium channel blocker used for hypertension. It can be used in addition to alpha-blockade. 4) Nitroprusside (Nipride): For hypertensive crisis: 0.5-10 mcg/kg/min IV CRI, titrated to effect. It is a direct vasodilator. It should be used with caution and blood pressure monitored continuously. 5) Phentolamine (Regitine): For hypertensive crisis: 0.02-0.1 mg/kg IV, given slowly. It is a short-acting alpha-blocker. 6) Lidocaine: For ventricular arrhythmias: 2 mg/kg IV bolus, then 25-80 mcg/kg/min CRI. 7) Esmolol: For supraventricular tachycardia: 0.5 mg/kg IV over 1 minute, then 50-200 mcg/kg/min CRI. 8) Supportive care: Intravenous fluids (e.g., 0.9% NaCl) at maintenance rates, but avoid overhydration. 9) Pain management: Opioids (e.g., buprenorphine 0.01-0.02 mg/kg IV/IM q8-12h) or NSAIDs (e.g., carprofen 2.2 mg/kg PO q12h) as appropriate. 10) If chemotherapy is considered, mitotane (Lysodren) has been used at 50 mg/kg/day PO, but its efficacy is unproven.

Evidence-based literature on pheochromocytoma in veterinary medicine is limited, but several key studies provide guidance. 1) A retrospective study by Barthez et al. (1997) evaluated 50 dogs with pheochromocytoma and found that clinical signs were non-specific, and hypertension was present in only 50% of cases. The study emphasized the importance of urine metanephrine-to-creatinine ratio for diagnosis. 2) A study by Kyles et al. (2003) reported on 20 dogs with pheochromocytoma that underwent adrenalectomy. The perioperative mortality rate was 15%, and the median survival time was 30 months. The study highlighted the importance of preoperative alpha-blockade. 3) A study by Gilson et al. (1994) compared dogs with pheochromocytoma to those with adrenocortical tumors and found that pheochromocytomas were more likely to invade the caudal vena cava. 4) A consensus statement from the ACVIM (2014) on hypertension in dogs and cats recommends that pheochromocytoma be considered as a secondary cause of hypertension, and that urine metanephrine-to-creatinine ratio be measured in suspected cases. 5) A study by Herrera et al. (2008) evaluated the use of CT for surgical planning in dogs with adrenal tumors and found that CT was superior to ultrasound for detecting vascular invasion. 6) A recent study by Arenas et al. (2020) reported on the use of laparoscopic adrenalectomy for pheochromocytoma in dogs, showing that it is feasible and associated with lower morbidity compared to open surgery. 7) Overall, the evidence supports surgical resection as the treatment of choice, with medical management for inoperable cases. The use of alpha-blockers is strongly recommended based on clinical experience and extrapolation from human medicine.