Adrenal Tumors

Adrenal tumors are neoplasms arising from the adrenal glands, which are paired endocrine organs located craniomedial to each kidney. They can originate from the adrenal cortex (producing cortisol, aldosterone, or sex steroids) or the adrenal medulla (producing catecholamines). In veterinary medicine, the most common adrenal tumors are cortisol-secreting adrenocortical adenomas and carcinomas (causing hyperadrenocorticism or Cushing's syndrome), aldosterone-secreting tumors (causing primary hyperaldosteronism), and pheochromocytomas (catecholamine-secreting tumors of the chromaffin cells). These tumors can be benign or malignant, functional (hormone-secreting) or non-functional, and may be unilateral or bilateral. Adrenal tumors are significant because they disrupt endocrine homeostasis, can invade local vasculature (especially the caudal vena cava), and may metastasize to distant organs. The clinical presentation varies widely depending on the tumor type, hormone secretion, and stage of disease.

The exact etiology of adrenal tumors in dogs and cats is largely unknown, but several factors are implicated. Chronic stimulation of the adrenal cortex by adrenocorticotropic hormone (ACTH) from a pituitary tumor is a well-known cause of bilateral adrenocortical hyperplasia, which can progress to adenoma or carcinoma in some cases. However, primary adrenal tumors often arise spontaneously without preceding pituitary disease. Genetic mutations, such as those in the p53 tumor suppressor gene or activation of oncogenes, have been suggested but not fully characterized in veterinary species. In humans, specific genetic syndromes (e.g., Li-Fraumeni, Beckwith-Wiedemann) predispose to adrenal tumors, but analogous syndromes are not well-defined in dogs and cats. Environmental factors, such as exposure to certain toxins or chronic inflammation, have been hypothesized but not proven. For pheochromocytomas, no specific etiologic agent is known, but they are more common in older dogs and may be associated with chronic hypoxia or other neuroendocrine stimuli. In cats, primary hyperaldosteronism is often due to unilateral adrenocortical adenoma or carcinoma, and the cause is similarly unknown.

Adrenal tumors are relatively uncommon in dogs and cats but are diagnosed with increasing frequency due to advanced imaging. In dogs, functional adrenocortical tumors account for approximately 15-20% of cases of hyperadrenocorticism, with pituitary-dependent hyperadrenocorticism being more common (80-85%). Adrenocortical tumors are more prevalent in older dogs, with a median age of 10-12 years. Certain breeds appear predisposed, including Poodles, Dachshunds, Boxers, and Boston Terriers, though any breed can be affected. There is no strong sex predilection, though some studies suggest a slight female predominance for adrenocortical tumors. Pheochromocytomas are rare, typically occurring in dogs older than 8 years, with no clear breed or sex predisposition. In cats, primary hyperaldosteronism is rare but increasingly recognized, usually affecting older cats (median age 11-13 years). Feline adrenocortical tumors causing hypercortisolism are extremely rare. Non-functional adrenal tumors (incidentalomas) are found in about 1-2% of dogs undergoing abdominal imaging for unrelated reasons, and the prevalence increases with age.

The pathophysiology of adrenal tumors depends on the cell type and hormone secretion. Adrenocortical tumors that secrete cortisol lead to hypercortisolism, which causes a cascade of systemic effects: increased gluconeogenesis and insulin resistance (leading to hyperglycemia and diabetes mellitus), protein catabolism (muscle wasting, poor hair coat, thin skin), immunosuppression (predisposing to infections), and hypertension. Excess aldosterone from aldosterone-secreting tumors causes sodium retention and potassium excretion, leading to hypertension, hypokalemia, and metabolic alkalosis. These electrolyte imbalances can cause muscle weakness, cardiac arrhythmias, and renal dysfunction. Pheochromocytomas secrete catecholamines (epinephrine, norepinephrine), which cause episodic or sustained hypertension, tachycardia, and arrhythmias. Catecholamine excess can also lead to myocardial damage and systemic vasoconstriction. Tumor invasion into the caudal vena cava can cause venous obstruction, hindlimb edema, and pulmonary thromboembolism. Malignant tumors can metastasize to the liver, lungs, lymph nodes, and other organs, further compromising organ function. The clinical signs are often insidious and progressive, reflecting chronic hormonal dysregulation.

Predisposing factors for adrenal tumors include advanced age, as most tumors occur in middle-aged to older animals. Breed predisposition has been noted for certain adrenocortical tumors, as mentioned. Chronic pituitary-dependent hyperadrenocorticism may predispose to the development of adrenocortical tumors due to prolonged ACTH stimulation. Obesity and metabolic syndrome may increase the risk of adrenal tumors, though evidence is limited. In cats, primary hyperaldosteronism is more common in older cats, and no breed predilection is clearly established. For pheochromocytomas, chronic hypoxia (e.g., in dogs with congenital heart disease) has been suggested as a risk factor. Immunosuppression or chronic inflammation might also play a role, but this is speculative. Genetic factors are likely important, but specific mutations have not been identified in veterinary medicine.

Clinical signs of adrenal tumors vary depending on the hormone secreted and tumor size. For cortisol-secreting tumors (hyperadrenocorticism), common signs include polyuria, polydipsia, polyphagia, abdominal distension (pot-bellied appearance), bilateral symmetrical alopecia, thin skin, muscle weakness, lethargy, and panting. Calcinosis cutis may occur in dogs. For aldosterone-secreting tumors (primary hyperaldosteronism), signs are primarily due to hypokalemia and hypertension: muscle weakness, ventroflexion of the neck (in cats), lethargy, polyuria, polydipsia, and visual deficits due to hypertensive retinopathy. Pheochromocytomas cause episodic signs such as panting, restlessness, tachycardia, hypertension, and collapse. These episodes may be triggered by stress or exercise. Non-functional tumors may be asymptomatic or cause signs due to mass effect, such as abdominal discomfort, vomiting, or obstruction. In advanced cases, invasion of the caudal vena cava can cause hindlimb edema, ascites, and signs of pulmonary thromboembolism (acute dyspnea, collapse).

Differential diagnoses for adrenal tumors include: 1) Pituitary-dependent hyperadrenocorticism (PDH) – distinguished by ACTH stimulation test results (exaggerated response) and low-dose dexamethasone suppression test (suppression in PDH but not in adrenal tumors), and imaging showing bilateral adrenal enlargement in PDH vs. unilateral mass in adrenal tumors. 2) Other causes of polyuria/polydipsia, such as diabetes mellitus, chronic kidney disease, and diabetes insipidus – differentiated by blood glucose, urinalysis, and water deprivation test. 3) Hypertension from other causes, such as chronic kidney disease or hyperthyroidism – differentiated by endocrine testing and imaging. 4) Primary hyperaldosteronism must be differentiated from other causes of hypokalemia, such as gastrointestinal losses or renal tubular acidosis – aldosterone levels and imaging are key. 5) Pheochromocytoma must be differentiated from other causes of episodic weakness or collapse, such as cardiac arrhythmias, seizures, or hypoglycemia – plasma or urine metanephrines are specific. 6) Non-functional adrenal masses must be differentiated from other abdominal masses, such as renal tumors, pancreatic masses, or lymphadenopathy – imaging and biopsy are needed. 7) In cats, hyperthyroidism can cause similar signs and should be ruled out with thyroid hormone testing.

The diagnostic approach to adrenal tumors begins with a thorough history and physical examination. If hyperadrenocorticism is suspected, baseline screening tests include a urine cortisol:creatinine ratio (UCCR) – a normal result rules out hypercortisolism. If UCCR is elevated, an ACTH stimulation test or low-dose dexamethasone suppression test (LDDST) is performed to confirm hyperadrenocorticism. To differentiate PDH from adrenal tumor, an abdominal ultrasound is performed to assess adrenal gland size and symmetry. If a unilateral adrenal mass is found, an endogenous ACTH concentration can be measured – low ACTH suggests adrenal tumor, while high or normal ACTH suggests PDH. For suspected pheochromocytoma, measurement of plasma or urine metanephrines is the preferred screening test. For primary hyperaldosteronism, measurement of plasma aldosterone concentration and plasma renin activity (aldosterone:renin ratio) is diagnostic. Imaging with abdominal ultrasound, CT, or MRI is essential to characterize the tumor, assess vascular invasion, and detect metastases. Histopathology via ultrasound-guided fine-needle aspiration or surgical biopsy is the gold standard for definitive diagnosis, but is often avoided preoperatively due to risk of hemorrhage or catecholamine release. The diagnostic algorithm should be systematic, starting with endocrine screening and progressing to imaging and histopathology as needed.

Laboratory findings in adrenal tumors depend on the tumor type. In cortisol-secreting tumors, CBC may show a stress leukogram (neutrophilia, lymphopenia, eosinopenia), and serum biochemistry may reveal elevated alkaline phosphatase (ALP), alanine aminotransferase (ALT), hyperglycemia, hypercholesterolemia, and mild elevations in liver enzymes. Urinalysis may show low urine specific gravity (<1.020) and proteinuria. The ACTH stimulation test shows an exaggerated cortisol response (post-ACTH cortisol > 600 nmol/L in dogs), while the LDDST shows no suppression of cortisol (cortisol > 40 nmol/L at 8 hours post-dexamethasone). Endogenous ACTH is typically low (< 20 pg/mL) in adrenal tumors. In aldosterone-secreting tumors, serum biochemistry reveals hypokalemia, hypernatremia, and metabolic alkalosis. Plasma aldosterone concentration is elevated, and plasma renin activity is suppressed, resulting in a high aldosterone:renin ratio. In pheochromocytomas, plasma or urine metanephrines (normetanephrine and metanephrine) are elevated. Additionally, hypertension may be documented. Non-functional tumors may have normal laboratory findings, but may show mild non-specific changes such as elevated ALP due to mass effect.

Imaging is crucial for the diagnosis and staging of adrenal tumors. Abdominal radiography may reveal a soft tissue mass in the cranial abdomen, but is not sensitive. Abdominal ultrasonography is the most commonly used modality: it can identify an adrenal mass (typically > 2 cm in diameter), assess the contralateral adrenal gland (which may be atrophied in cortisol-secreting tumors), and evaluate for invasion into the caudal vena cava or renal vessels. Doppler ultrasound can assess vascular flow. Computed tomography (CT) provides superior detail, allowing precise measurement of tumor size, extent of vascular invasion, and detection of metastases in the liver, lungs, and lymph nodes. CT is particularly useful for surgical planning. Magnetic resonance imaging (MRI) is less commonly used but can be helpful for evaluating vascular invasion and soft tissue contrast. In cases of suspected pheochromocytoma, imaging should be performed with caution, as manipulation of the tumor can precipitate a catecholamine crisis; premedication with phenoxybenzamine is recommended. Thoracic radiographs or CT are indicated to rule out pulmonary metastases. Echocardiography may be indicated if cardiac involvement is suspected, especially with vena caval invasion.

Cytology via ultrasound-guided fine-needle aspiration (FNA) of adrenal masses is controversial due to the risk of hemorrhage and potential for catecholamine release in pheochromocytomas. If performed, cytology may show clusters of epithelial cells with variable atypia, but cannot reliably distinguish benign from malignant tumors. Histopathology is the gold standard for diagnosis. Adrenocortical adenomas are well-circumscribed, encapsulated masses with uniform cells and low mitotic index. Adrenocortical carcinomas show capsular invasion, vascular invasion, and increased mitotic activity. Pheochromocytomas are composed of large polygonal cells with granular cytoplasm, and immunohistochemistry for chromogranin A and synaptophysin is positive. Histopathology also helps determine the cell of origin and malignancy. In cases of bilateral adrenal tumors, histopathology is essential to differentiate from pituitary-dependent hyperplasia. Biopsy can be obtained via surgery or ultrasound-guided core biopsy, but surgery is preferred for definitive treatment and diagnosis.

Treatment of adrenal tumors depends on the tumor type, stage, and clinical signs. For cortisol-secreting adrenocortical tumors, surgical removal (adrenalectomy) is the treatment of choice if the tumor is localized and resectable. Medical management with trilostane (Vetoryl) is an alternative for inoperable tumors or for stabilization before surgery. Trilostane is administered at an initial dose of 2-5 mg/kg PO q24h, with dose adjustments based on ACTH stimulation testing. For aldosterone-secreting tumors, surgical removal is also preferred; medical management with spironolactone (1-2 mg/kg PO q12h) and potassium supplementation may be used to control hyperaldosteronism. For pheochromocytomas, surgical removal is the definitive treatment, but preoperative medical management with phenoxybenzamine (0.25-1.5 mg/kg PO q12h for 10-14 days) is essential to control blood pressure and reduce the risk of intraoperative hypertensive crisis. Beta-blockers (e.g., propranolol 0.1-0.2 mg/kg PO q8h) may be added if tachycardia persists after alpha-blockade. For non-functional tumors, surgical removal may be recommended if the tumor is large, invasive, or causing clinical signs. In cases of metastatic disease, chemotherapy (e.g., mitotane for adrenocortical carcinoma) may be considered, but response is variable. Supportive care includes management of hypertension, electrolyte imbalances, and concurrent infections.

The prognosis for adrenal tumors varies widely. For benign adrenocortical adenomas that are completely excised, the prognosis is excellent, with resolution of clinical signs and long-term survival. For adrenocortical carcinomas, the prognosis is guarded, especially if there is vascular invasion or metastasis; median survival times of 1-2 years have been reported with surgery, but recurrence is common. For aldosterone-secreting tumors, surgical removal can be curative if the tumor is benign and completely excised; however, if malignant, the prognosis is poor. Pheochromocytomas have a guarded prognosis due to the risk of intraoperative complications and potential for metastasis; median survival times of 1-3 years have been reported with successful surgery. Negative prognostic factors include large tumor size (> 5 cm), invasion into the caudal vena cava, metastasis, and incomplete excision. The presence of clinical signs at diagnosis is also associated with a worse prognosis. Overall, early detection and complete surgical resection offer the best chance for long-term survival.

Post-treatment follow-up is essential for monitoring recurrence and managing complications. After adrenalectomy, patients should be re-evaluated at 1-2 weeks for surgical site healing and histopathology results. Hormonal status should be assessed at 1-3 months post-surgery: for cortisol-secreting tumors, an ACTH stimulation test should be performed to ensure resolution of hypercortisolism; for aldosterone-secreting tumors, serum electrolytes and blood pressure should be monitored. For pheochromocytomas, blood pressure and catecholamine levels should be checked. Long-term monitoring includes abdominal ultrasound or CT every 3-6 months for the first year, then every 6-12 months thereafter to detect recurrence or metastasis. For patients on medical therapy (e.g., trilostane), ACTH stimulation tests should be performed at 10-14 days after starting therapy, then every 3-6 months to adjust dosing. Owners should be educated on signs of recurrence, such as polyuria, polydipsia, weakness, or collapse, and advised to seek immediate veterinary care if these occur.

Pearls: 1) Always measure blood pressure in any dog or cat with suspected adrenal tumor, as hypertension is common and can cause severe complications. 2) In dogs with hyperadrenocorticism, a low endogenous ACTH concentration (< 20 pg/mL) strongly suggests an adrenal tumor, while a high or normal ACTH suggests pituitary-dependent disease. 3) For pheochromocytomas, always premedicate with phenoxybenzamine before any surgical or interventional procedure to prevent hypertensive crisis. 4) In cats with hypokalemia and hypertension, consider primary hyperaldosteronism even if the cat is otherwise healthy. 5) Non-functional adrenal masses (incidentalomas) should be evaluated for malignancy and vascular invasion; if small (< 2 cm) and non-invasive, monitoring may be an option. Pitfalls: 1) Do not perform FNA of an adrenal mass without first ruling out pheochromocytoma, as this can precipitate a fatal catecholamine release. 2) Avoid using trilostane in animals with primary aldosteronism, as it will not correct hypokalemia. 3) Do not administer beta-blockers before alpha-blockade in pheochromocytoma, as this can cause unopposed alpha-mediated vasoconstriction and severe hypertension. 4) Failure to assess for vascular invasion preoperatively can lead to intraoperative hemorrhage and death. 5) Do not assume that a unilateral adrenal mass is always functional; always perform endocrine testing to determine hormone secretion.

For cortisol-secreting tumors: Trilostane (Vetoryl) – initial dose 2-5 mg/kg PO q24h, adjust based on ACTH stimulation test (target post-ACTH cortisol 40-150 nmol/L). Mitotane (Lysodren) – for adrenocortical carcinoma, loading dose 50 mg/kg/day PO divided q12h for 7-10 days, then maintenance 50 mg/kg/week, with monitoring of cortisol. For aldosterone-secreting tumors: Spironolactone – 1-2 mg/kg PO q12h, and potassium supplementation (potassium gluconate 2-4 mEq/kg/day PO divided). For pheochromocytomas: Phenoxybenzamine – 0.25-1.5 mg/kg PO q12h, starting at low dose and titrating up over 10-14 days; Propranolol – 0.1-0.2 mg/kg PO q8h, only after adequate alpha-blockade. For hypertension: Amlodipine – 0.05-0.1 mg/kg PO q24h, titrate to effect. For supportive care: Fluid therapy with 0.9% NaCl for hypercalcemia or hypernatremia, but avoid potassium-containing fluids in hyperkalemia. All dosages are based on Plumb's Veterinary Drug Handbook, and should be adjusted for renal or hepatic impairment. Contraindications: Trilostane should not be used in animals with primary hepatic disease or renal insufficiency; mitotane is contraindicated in animals with severe hepatic dysfunction. Drug interactions: Trilostane may interact with potassium-sparing diuretics; phenoxybenzamine may potentiate the effects of other antihypertensives.

Key studies and consensus guidelines: 1) ACVIM consensus statement on the diagnosis and treatment of hyperadrenocorticism in dogs (2018) recommends trilostane as the first-line medical therapy, with monitoring via ACTH stimulation tests. 2) A study by Behrend et al. (2013) reported that dogs with adrenal tumors have a median survival of 2 years after surgical removal, with a 10% perioperative mortality rate. 3) A retrospective study by Herrera et al. (2019) on pheochromocytomas in dogs found that preoperative phenoxybenzamine significantly reduced intraoperative complications. 4) For feline primary hyperaldosteronism, a case series by Javadi et al. (2005) demonstrated that surgical removal of the affected adrenal gland resolves hypokalemia in most cats. 5) A meta-analysis by Bennaim et al. (2019) on the use of mitotane for adrenocortical carcinoma showed a response rate of 50%, but with significant adverse effects. 6) The IRIS (International Renal Interest Society) guidelines recommend monitoring blood pressure and proteinuria in animals with adrenal tumors to prevent renal damage. These studies and guidelines support the current diagnostic and therapeutic approaches, emphasizing the importance of early detection, surgical resection when feasible, and careful medical management.