ADRENAL MASSES adrenal mass Incidental adrenal lesions Malignant/Benign/Functional/Non-Functional: How to decide?

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1 ADRENAL MASSES An adrenal mass is suspect when the maximum width of the adrenal gland exceeds 1.5 cm, there is loss of normal architecture/shape or there is asymmetry in shape/ size between the affected adrenal gland and the other adrenal gland. This is initial criteria however and many benign exceptions exist. Bulbous enlargement of the cranial or caudal pole of the adrenal gland is common in dogs with normal adrenal glands and can be misinterpreted as an adrenal mass. If the mass does not have obvious signs of aggressive behavior then an abdominal ultrasound should always be repeated to confirm that the mass is a repeatable finding before pursuing further diagnostics or surgery. Incidental adrenal lesions should be investigated clinically if they are diagnosed. Non-neoplastic adrenal lesions such as cysts or granulomas are very rare in dogs or cats and the high incidence of metastatic lesions justifies a thorough endocrinologic screening and evaluation for non-adrenal neoplasms. Incidental adrenal masses may appear to be nonfunctional at the time of diagnosis although it seems likely that they are actually subclinically functional. The diagnosis of functional adrenal tumors is discussed below but identification of a nonfunctional, incidental adrenal mass creates a management dilemma. Adrenal tumors are rare in cats and represent 0.2% of all feline tumors. In a retrospective study from UC Davis that included all cats that underwent complete necropsy over a 20-year period, 30% had adrenocortical tumors, 10% were pheochromacytomas, and 60% were metastatic tumors. Fewer than half of the metastatic tumors were seen grossly on necropsy. Primary adrenal tumors represent 1-2% of all canine tumors. In the same retrospective study, 41% had adrenocortical tumors, 32% were pheochromatcytomas, and 27% were metastatic lesions. Lymphoma was the most common cancer to spread to the adrenal glands in both species. In dogs, other metastatic tumours commonly identified included hemangiosarcoma, mammary carcinoma, histiocytic sarcoma, pulmonary carcinoma, and melanoma. The left and the right gland were affected equally, as were the cortex and medulla. The notable exception was that all metastatic melanomas remained confined to the medulla pp , Withrow and MacEwen s Small Animal Clinical Oncology, 4 th Ed, 2007, Saunders/Elsevier). Malignant/Benign/Functional/Non-Functional: How to decide? It may be difficult to determine if the mass is malignant/benign/functional/nonfunctional prior to surgical removal and histopathology in some cases. A thorough review of the clinical signs, physical examination findings, routine blood, urine tests and performance of appropriate hormonal tests should be done to determine the functional status of an incidental adrenal mass. Blood pressure must be measured. Malignancy is more often associated with larger masses, such as those that measure greater than 2 cm. Invasion of the mass into surrounding organs or blood vessels also supports malignancy as

2 does the detection of additional mass lesions with abdominal ultrasound and thoracic radiographs. Use of imaging modalities such as CT and MR will likely provide additional data on the characteristics of specific adrenal lesions for use in diagnosis and treatment planning, particularly as pertains to vascular or other invasion. However, CT scanning may not predict surgical resection potential, as this decision may be made in surgery, with gross inspection of the lesion. Calcification also suggests malignancy but may also be found as an age-related dystrophic change in both dogs and cats. Three-view thoracic radiographs must be performed in these patients to screen for metastatic disease. Ultrasonography is the primary instrument (mainly for diagnostic value, minimal cost, and general availability) for assessment of tumor size, aggressive non-capsulated vs. capsulated appearance, vascular invasion, and hepatic or other metastasis. NPO +/- low enema preparation of the patient is ideal to enhance visibility around the ascending and descending colon. US guided biopsy or FNA may be possible on the larger masses especially on the left side. However, adjacent vascular structures can often prevent the feasibility of this procedure. Blood pressure must be measured and hypertension corrected prior to any FNA or biopsy of the mass. Controversy exists regarding the safety of US-guided FNA and particularly biopsy, as some consider this a relatively contraindicated procedure. Complications include hemorrhage, arrythmias, seeding of the needle tract, damage to adjacent organs and death. Diagnosis of the Functional Adrenal Mass: Cortisol-Secreting: Cortical adrenal tumors (adenoma, adenocarcinoma) are responsible for 15-20% of patients with hyperadrenocorticism. Cortisolsecreting tumours are usually unilateral (bilateral in 10-20%), may invade the aorta on the left or the vena cava on the right, and metastasize to the liver and lungs most frequently. History and clinical signs are typical for the suspected HAC patient. Work-up should consist of a CBC, chemistry panel, and urinalysis. Urine culture is recommended as many patients with HAC have occult urinary tract infections. UPC may be indicated. Further specific testing for the presence of HAC may include a LDDST or an ACTH stimulation test in addition to the abdominal ultrasound. Thoracic radiographs are recommended. A coagulation panel (PT and PTT) should be done to check for hypocoagulability and a D-dimer can help suggest hypercoagulability. TEG is helpful if available. Ultrasound usually reveals a small or atrophied contra lateral adrenal gland. The atrophy is a result of suppression of pituitary ACTH secretion % of cases have bilateral disease and patients with concurrent pituitary-dependent hyperadrenocorticism and an adrenal tumour have been reported.. Adenomas of the adrenal gland were generally < 2 cm in diameter and carcinomas were of any size, often > 2 cm. Calcification does not appear to be predictive for either adenoma or carcinoma. Catecholamine-Producing: Pheochromocytoma is a tumor derived from the chromaffin cells of the adrenal medulla that is relatively common in dogs but rare in cats. These should be considered malignant until proven otherwise. Invasion/entrapment/compression of the CVC is common. Mural invasion/luminal narrowing of the aorta, renal vessels, adrenal vessels, and

3 hepatic veins may also occur. Clinical signs associated with this type of tumor are usually related to invasion of local structures, metastases, or secretion of catecholamines. The most common clinical signs of excess catecholamines include generalized weakness, episodic collapse, tachypnea, panting, tachycardia, cardiac arrhythmias, and possibly neurological signs secondary to systemic hypertension. Catecholamine release and hypertension tends to be episodic so failure to document systemic hypertension does not rule out pheochromocytoma. Ultrasound: The contra lateral adrenal gland is usually normal in size and shape with a catecholamine-producing adrenal tumor. Pheochromocytomas uncommonly calcify. Specific hormonal tests (urinary catecholamine concentrations or their metabolites) are not routinely done. Since hypertension, tachycardia, and arrhythmias commonly occur during anesthesia induction and during surgical manipulation of the tumor, dogs must receive phenoxybenzamine (a non-competitive alpha-adrenergic antagonist) for 1-2 weeks prior to surgery. If tachycardia persists, it may also be necessary to employ a beta-blocker such as atenolol or propranolol. However, the beta-blockers can only be started AFTER alpha-adrenergic blockade has already been initiated, to prevent unopposed alpha-adrenergic stimulation and worsening hypertension. Aldosterone-Secreting: (rare in dog and cat). Clinical signs (Conn s Syndrome) are related to excessive secretion of aldosterone which causes sodium retention and potassium depletion. The resulting symptoms include lethargy, weakness, mild hypernatremia, severe hypokalemia (usually < 3.0 meq/l), and systemic hypertension. Ultrasound usually reveals a normal contra lateral adrenal gland, but may show normal adrenals (bilateral hyperplasia). Documenting increased plasma aldosterone concentrations prior to and after ACTH administration is used to confirm the diagnosis. If weakness and severe hypokalemia are present, plasma aldosterone concentrations can be measured in addition to plasma cortisol concentrations during the ACTH stimulation test. Surgery is usually the treatment of choice but medical management may consist of potassium supplementation, antihypertensive therapy, and spironolactone (aldosterone antagonist). Progesterone-Secreting: Although a functional tumor arising from the zona reticularis of the adrenal cortex could secrete excessive amounts of estrogen, progesterone or testosterone, to date, only progesterone-secreting adrenocortical tumors in cats have been documented. Clinical signs can include: diabetes mellitus and feline fragile skin syndrome, which is characterized by progressively worsening dermal and epidermal atrophy, patchy endocrine alopecia, and easily torn skin. Ultrasound usually notes a normal contra lateral adrenal gland. Diagnosis requires documenting an increased plasma progesterone concentration with the adrenal panel from the Univerisity of Tennessee panel.. The clinical features mimicked feline hyperadrenocorticism, which is the primary differential diagnosis. Results of

4 tests of the pituitary-adrenocortical axis are normal to suppressed in cats with progesterone-secreting adrenal tumors. Deoxycorticosterone (precursor of aldosterone)-secreting: (rare) Clinical signs are related to the mineralocorticoid activity and include weakness, marked hypokalemia, and systemic hypertension. Tests: Increased plasma deoxycorticosterone and non detectable plasma aldosterone concentrations were documented in the dog. 17-OH-progesterone (precursor of cortisol)-secreting: (rare) Clinical signs are similar to hyperadrenocorticism. Tests: Pre- and post-acth stimulation plasma 17-OH-progesterone concentrations will be increased. To Cut or Not to Cut? If endocrine testing has ruled out the presence of a functional cortical tumor, and pheochromocytoma is confirmed by eliminating the other possibilities and aggressive sonographic characteristics are present, the phenoxybenzamine should be initiated prior to adrenalectomy. If a cortisol producing adrenal tumor has been documented then surgical resection or medical therapy with trilostane or mitotane should be considered. Mitotane has direct cytotoxic effects and has been shown both to decrease tumor size and to decrease metastatic burden. However, it may be necessary to use high dosages. Trilostane may also be efficacious. Earlier studies comparing trilostane vs mitotane yielded conflicting results. However, a recent paper (JR Helm et al, 2011) compared survival times and factors that influence survival in dogs with adrenal-dependent HAC treated with mitotane or trilostane. The overall median survival time was 277 days. The MST for dogs without evidence of metastatic disease was 402 days; it was 61 days for dogs with evidence of metastatic disease (statistically significant). The median survival time for dogs treated with trilostane was 353 days and 102 days for mitotane. This difference was not considered statistically significant in this study. The MST for mitotane in this study differed from other studies that reported 320 days MST for mitotane. Either mitotane or trilostane appear to be reasonable choices in medical management for cortisol-producing adrenal tumours. Indications for medical therapy include gross pulmonary metastatic disease evident before surgery, an unresectable or incompletely respectable tumour, residual disease after adrenalectomy, unacceptable anesthetic and surgical risk to the patient, and refusal of surgery by the owner. The biggest dilemma is whether to perform an adrenalectomy if hormonal tests for hyperadrenocorticism and serum electrolyte concentrations are normal and clinical signs and systemic hypertension suggestive of pheochromocytoma are not present. Further non-invasive work-up for a potential pheochromocytoma may be possible in the future. An abstract at ACVIM 2011 (EN-9) suggests that measurement of plasma free metanephrines (catecholamine breakdown products) may show promise as a diagnostic test for pheochromocytomas. A study from JVIM 2010 reported that urinary epinephrine, norepinephine and metanephrine to creatinine ratios did not differ between dogs with hyperadrenocorticism and pheochromacytomas. The urinary normetanephrine to creatinine ratio was significantly higher in dogs with

5 pheochromacytoma than with HAC, especially if the cut-off level used was 4 times the level for normal dogs. An aggressive approach (i.e., adrenalectomy) is based on the assumption that the mass is malignant until proven otherwise and should be removed before metastasis has occurred. In theory, this approach would offer the best chance for long-term survival. However, the age of the patient, the size of the mass, the presence of concurrent diseases, the level of invasion into other organs, and the probability that metastases already exist should weigh into the decision. Poor surgical candidates generally include: dogs compromised from effects of hypercortisolemia, older animals, those with concurrent disease, those in which invasion is aggressive and surgical or post surgical complications are likely, those with very large masses which have likely already metastasized, and those with documented potential metastatic disease. In addition, adrenalectomy may not be indicated when the mass is small (< 3 cm diameter) and nonfunctional, and the patient is healthy. Anderson et al. recently reported an approximate 45% success rate of surgical resection in 102 cases of adrenal masses with positive prognosis inversely proportionate to tumor size. In cases of concurrent hepatic nodular changes identified by ultrasound, hepatic biopsy assessment can be performed prior to surgery to rule out metastatic disease in cases of suspicious lesions visualized by ultrasound. Often Cushings disease causes benign nodular hyperplasia of the liver which should NOT be automatically interpreted as a sign of hepatic metastasis during an ultrasound exam. Alternatively, suspicious lesions should be confirmed and biopsied at surgery. Post operative complications include delayed wound healing due to excessive corticoid circulation and wasting, hemorrhage, sepsis, and thromboembolism. A recent paper examined pre-operative prognostic factors in the surgical treatment of adrenal gland tumors in 41 dogs (J Am Vet Med Assoc 2008; 232; 77-84). Similar to other studies (up to 51%), this study reported high perioperative complication rate (35%). Intraoperative mortality rate was 4.8% and perioperative mortality rate was 22%. Like the patients in other studies, if the patient survived to discharge from the hospital, however, he/she had a long survival time. Other studies have found that removal of caval thrombi is not associated with higher morbidity and mortality rates. In this study, pre-operative factors that were associated with a shorter survival time included weakness or lethargy, thrombocytopenia, increased BUN, increased PTT, increased AST and hypokalemia. Intra-operative hemorrhage and/or the need for a concurrent nephrectomy were associated with shorter survival times. From this perspective, pre-operative imaging with CT may help determine if nephrectomy is indicated. Post-operative complications included adrenal gland insufficiency, acute renal failure, pancreatitis, septic peritonitis, and suspected pulmonary thromboembolism. Post-operative complications associated with a shorter survival included pancreatitis and acute renal failure. Tumour type, completeness of surgical excision, and microscopic vascular invasion were NOT significantly associated with survival time. Detection of gross lesions at surgery and histological evidence of metastatic disease were not significantly associated with survival time. Many dogs had gross lesions in other organs, but most did not prove metastatic on

6 histopathology. survival time. Tumor size and volume were not significantly associated with References: Diagnostic Approach to the Incidental Adrenal Mass, WSAVA 2002 Congress, Richard W. Nelson, DVM, Diplomate ACVIM,School of Veterinary Medicine, University of California,Davis, CA, USA\Management of Endocrine Neoplasia, World Small Animal Veterinary Association World Congress Proceedings, 2001, Steven Withrow, United States. ACVIM Ettinger s Textbook of Veterinary Internal Medicine Proceedings of the 2011 ACVIM Forum (Abstract EN-9) JR Helm et al. A Comparison of Factors that Influence Survival in Dogs with Adrenal-Dependent Hyperadrenocorticism Treated with Mitotane or Trilostane JVIM 2011; 25: S. Quante et al. Urinary catecholamine and metanephrine to creatinine ratios in dogs with hyperadrenocorticism or pheochromocytoma, and in normal dogs. JVIM 2011; 24 (5): Johanna Frank DVM DVSc Diplomate ACVIM (Internal Medicine) New Jersey Mobile Eric Lindquist DMV (Italy), DABVP K9 & Feline Practice Cert. IVUSS Director NJ Mobile Associates, Founder SonoPath.com