How to Diagnose and Treat Adrenal Tumors Sandra Bechtel, DVM, DACVIM University of Missouri Columbia, MO Often, adrenal tumors are found incidentally upon imaging of the abdomen for other medical reasons. Once an adrenal mass is discovered, a thorough understanding of adrenal physiology will aid the veterinarian in guiding clients through diagnostic and therapeutic planning. The adrenal gland is divided into the cortex and medulla. The adrenal cortex has three functionally distinct layers that release different hormones under the control of separate stimulatory mechanisms: the zona glomerulosa releases mineralocorticoids under the control of the renin-angiotensin-aldosterone system, serum potassium and ACTH; the zona fasciculata releases glucocorticoids under the control of ACTH; and the zona reticularis secretes sex hormones. The adrenal medulla acts as a modified post ganglionic sympathetic neuron and releases epinephrine (EPI) and norepinephrine (NE). Adrenal masses may be benign or malignant, and functional or non-functional. Determining the functionality of an adrenal tumor is imperative to provide the most appropriate supportive care prior to definitive therapy. In canine necropsy studies, the most common adrenal masses were benign adrenocortical tumors, followed by - in decreasing frequency- adrenocortical carcinomas, adrenal medullary tumors (pheochromocytomas) and metastatic lesions to the adrenal gland. In cats, tumors metastatic to the adrenal glands the most common adrenal tumor, although cats can be diagnosed with adrenocortical tumors and pheochromocytomas.1-2 The most common metastatic tumor to the adrenal glands in both dogs and cats is lymphoma. Incidental adrenal tumors As an adrenal mass discovered during abdominal imaging for other reasons can be disruptive to the diagnostic and therapeutic decision making process, outlining differential diagnoses and prioritizing diagnostic tests is important for patient care. The first step is to determine whether or not the mass is functional (an adrenal cortical mass producing mineralocorticoids or glucocorticoids, or an adrenal medullary mass producing EPI or NE). Therefore, blood pressure, fundic exam, and endocrine testing as outlined below to rule out functional tumors should be considered. Determination of tumor functionality will also help determine pre-operative supportive care. Staging for other tumor types is also indicated since metastatic lesions to adrenal glands are common, particularly in cats. Therapy for incidentally found adrenal tumors is based on functionality, size, and evidence of invasion. If the mass is determined to be nonfunctional and is less than 2cm with no invasion, repeating an abdominal ultrasound regularly is recommended. Adrenalectomy should be considered for functional tumors, locally invasive tumors, or those larger than 2.5cm. Tumors of the adrenal cortex While hyperadrenocorticism (HAC) is a common endocrine disease in older dogs, it is most often pituitary dependent and the result of excess synthesis and secretion of ACTH, which results in bilateral adrenal cortical hyperplasia and resulting bilateral adrenal gland enlargement. Adrenal dependent HAC caused by a benign or malignant adrenal cortical tumor is relatively uncommon, representing only 15-20% of HAC cases. The result of a functional adrenal cortical tumor is usually excess glucocorticoid secretion leading to the typical HAC presentation. Dogs tend to be older with a median age of 11 years and clinical signs are consistent with HAC - polyuria, polydipsia, polyphagia, weakness, lethargy, dermatologic changes, abdominal enlargement, and panting.4-5 In addition to these clinical signs, dogs with HAC are prone to urinary tract infections, protein losing nephropathy, and a high percentage of dogs are reported to be hypertensive (complicating differentiation of cortical versus medullary adrenal tumors). To determine if an adrenal mass originates in the cortex resulting in adrenal dependent hyperadrenocorticism (ADH), endocrine testing should first confirm the presence of HAC. A urine cortisol-to-creatinine ratio from urine collected in the home environment is a good screening tool as it is very sensitive - a normal result rules out HAC but a positive requires further confirmation. Other tests for confirmation include the ACTH stimulation test and/ or low-dose dexamethasone suppression test. Endocrine tests used to differentiate ADH from pituitary dependent HAC include the low dose dexamethasone suppression test (in some cases), high dose dexamethasone suppression test, and endogenous ACTH. 3 Typical findings of HAC on minimum database include neutropenia, monocytosis, lymphopenia, thrombocytosis, hypercholesterolemia and elevated alkaline phosphatase. Abdominal imaging in cases of pituitary HAC may reveal bilaterally enlarged adrenal glands, but in the case of ADH, abdominal ultrasound or CT may reveal a unilateral adrenal mass. An adrenal adenoma tends to be small -less than 2cm- and well encapsulated or partially encapsulated. In contrast, adrenal carcinomas tend to be greater than 2cm in diameter and may invade into the cava. Fourteen -50% of adrenal carcinomas metastasize and the liver and lungs are the most commonly reported sites.4-5 Once HAC is confirmed via endocrine testing and imaging, the treatment of choice for tumors of the adrenal cortex is adrenalectomy; this should be considered in all cases with functional tumors, locally invasive tumors, or those larger than 2.5cm. Surgery is diagnostic, as histopathology will confirm benign versus malignant and determine if follow-up monitoring is required, and 501 therapeutic. Complications reported with surgery are cardiovascular events and hemorrhage. Potential post-operative abnormalities are adrenocortical insufficiency, pulmonary thromboembolism, pancreatitis, renal failure, and wound dehiscence. Perioperative mortality rates range from 9-60%. Post-operatively, ACTH stimulation testing within 24 to 48 hours should be considered as hypoadrenocorticism may result as the remaining adrenal gland may be atrophied, in addition to monitoring of glucose and electrolytes. Heparin and glucocorticoids may be indicated in addition to mineralocorticoid supplementation in some dogs. The median survival time in dogs with adrenocortical carcinomas treated with surgery alone is 778 days; in dogs that survive the peri-and post-operative period and are discharged from the hospital, the median survival time is reported as 992 days in one study and 17.5 months in another. If surgical excision is not an option, medical therapy should be considered for those cases with clinical signs of HAC. Medical therapy for functional adrenal tumors include mitotane, although much higher doses are required than when used for pituitary dependent HAC and relapses are common (up to 60% of dogs); untoward side effects of mitotane occur in greater than 50% of dogs, not including dogs that develop mineralocorticoid deficiencies. The median survival time reported is 16.4 months. Trilostane can also be used for medical management of HAC, where the quality of life improves and clinical signs decrease however the size of the adrenal tumor will remain the same or increase.3, 6 In dogs severely debilitated due to HAC medical therapy may be instituted as supportive care prior to consideration of surgery. Conn’s syndrome (primary aldosteronism) is an aldosterone secreting adrenocortical tumor increasingly recognized in cats. Cats tend to be middle-aged or older. Both adenomas and carcinomas can cause this syndrome and masses may be unilateral or bilateral. The most common clinical sign is muscle weakness resulting from hypokalemia; additional findings are arterial hypertension and, uncommonly, hypernatremia. A normal plasma aldosterone level in the face of hypokalemia is supportive of but not diagnostic for Conn’s syndrome and an oral fludrocortisone suppression test or aldosterone: renin ratio may be more useful for definitive diagnosis. Adrenalectomy is the treatment of choice with unilateral disease and outcomes reported are good, even if invasion into vena cava is present. Medical management with potassium supplementation, antihypertensive drugs, and spironolactone (an aldosterone antagonist) can be used for non-surgical patients.7-9 The adrenal cortex is also responsible for the secretion of sex hormones, and adrenal tumors with produce excessive sex hormones have been reported in the dog and cat with or without excessive glucocorticoid secretion. Tumors of the adrenal medulla Pheochromocytomas are functional tumors of the adrenal medulla derived from chromaffin cells. Normal chromaffin cells are stimulated by sympathetic nerve fibers to secrete epinephrine (EPI) and norepinephrine (NE) into the blood stream. Pheochromocytomas are not innervated, so catecholamine release is not initiated by neural impulses and therefore their release is variable and unpredictable. Pheochromocytomas are uncommon in dogs (0.01-0.1% of all canine tumors) and rare in cats. In dogs, the median age of diagnosis is 11 years with no sex predilection. Most often, pheochromocytomas are unilateral, slow growing, vascular, and malignant. Vascular invasion is reported in up to 82% of cases; and metastasis to the liver, spleen, lung, regional lymph nodes, bone, and central nervous system is reported in up to 40% of cases. Clinical signs are often absent or vague and episodic in nature due to the intermittent release of catecholamines. The most common clinical signs associated with pheochromocytoma