Diagnosis and Management of Canine Cortisol-Secreting Adrenal Tumors

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ADRENAL DISORDERS

DIAGNOSIS AND MANAGEMENT OF CANINE CORTISOLSECRETING ADRENAL TUMORS Peter P. Kintzer, DVM, and Mark E. Peterson, DVM

Adrenocortical tumors are the underlying cause of approximately 15% of cases of naturally occurring canine hyperadrenocorticism. About one half of these tumors are malignant, and many have metastasized by the time of diagnosis. 1• 10 Hyperadrenocorticism caused by an adrenal tumor must be distinguished from pituitary-dependent hyperadrenocorticism before a course of treatment is contemplated, because the therapeutic strategy and prognosis for hyperadrenocorticism may differ according to cause. DIAGNOSIS OF HVPERADRENOCORTICISM CAUSED BY ADRENAL TUMOR

The diagnosis of hyperadrenocorticism is confirmed with a thorough history and physical examination and an adrenocorticotropic hormone (ACTH) stimulation test and/ or a low-dose dexamethasone suppression test (see the article on canine hyperadrenocorticism by Dr. Guptil and colleagues elsewhere in this issue). The high-dose dexamethasone suppression test, endogenous plasma ACTH determination, and various imaging procedures (radiography, ultrasonography, computed tomography, and magnetic resonance imaging) can all be used to differ-

From the Boston Road Animal Hospital, Springfield (PPK); and the Department of Medicine, Tufts University School of Veterinary Medicine, North Grafton (PPK), Massachusetts; and the Division of Endocrinology, The Animal Medical Center, New York, New York (MEP)

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entiate between pituitary-dependent and adrenocortical-dependent disease. However, none of these tests is completely reliable in differentiating the cause of the disorder, and we recommend the use of at least two procedures in most cases. The most definitive test (the "gold standard") is the histologic confirmation of an adrenal tumor or ACTH-secreting pituitary tumor, but this test is often not available antemortem. High-Dose Dexamethasone Suppression Test

In dogs with pituitary-dependent hyperadrenocorticism, high doses of dexamethasone usually suppress the exaggerated ACTH secretion and therefore decrease serum cortisol concentrations, whereas failure of suppression is seen in dogs with adrenal tumors. In our laboratory, serum cortisol values generally remain above 1.5 µ,g/dL (40 nmol/L) at all sampling times in dogs with adrenal tumors; therefore, suppression of the serum cortisol concentration below 1.5 µ,g/ dL is diagnostic for pituitary-dependent hyperadrenocorticism and excludes an adrenal tumor; additional diagnostic testing is not necessary. 7• 10 Approximately 20% of dogs with pituitary-dependent hyperadrenocorticism do not show adequate suppression during the high-dose dexamethasone suppression test using a dexamethasone dose of 1.0 mg/kg (an even higher percentage may not show suppression with a dexamethasone dose of 0.1 mg/kg).7· 10 Therefore, an individual dog showing inadequate suppression of serum cortisol values after 1.0 mg/kg dexamethasone has about a 50% chance of having an adrenal tumor as opposed to nonsuppressible pituitary-dependent hyperadrenocorticism. Because of the relatively high morbidity and mortality associated with surgical exploration of the adrenal glands, other less-invasive procedures to differentiate nonsuppressible pituitary-dependent hyperadrenocorticism from adrenocortical-dependent hyperadrenocorticism are necessary. Plasma Adrenocorticotropic Hormone Concentrations

Measurement of the endogenous plasma ACTH concentration is very useful in making this distinction. Little overlap in plasma ACTH concentrations is present between dogs with pituitary-dependent hyperadrenocorticism and those with adrenal tumors. Plasma ACTH concentrations are normal to high in dogs with pituitary-dependent hyperadrenocorticism (> 40 pg/mL or > 8 pmol/L}, whereas values are undetectable to low-normal in dogs with adrenal tumors (< 20 pg/ dL or < 4 pmol/L}. Obtaining accurate endogenous ACTH concentration readings is no longer difficult or expensive. As recent work has demonstrated, addition of the protease inhibitor aprotinin to ethylenediamine tetracetic acid (EDTA) tubes allows ACTH samples to be centrifuged at room temperature (within 30 minutes of collection), stored for a few days at below

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4°C, and shipped with frozen cold packs without significant loss of activity. 5 This increases the utility of this test for many practitioners.

Imaging Studies

We recommend performing survey abdominal radiography in all dogs that do not show suppression with the high-dose dexamethasone suppression test. A soft tissue mass or adrenal mineralization is observed in 30 to 50% of dogs with adrenal tumors, providing preoperative localization of the adrenal tumor. Mineralization, when evident, is in our experience usually indicative of malignancy. Adrenal mineralization may rarely be noted in pituitary-dependent disease. If radiographs are normal or inconclusive, further testing is necessary to differentiate pituitary-dependent from adrenal-dependent disease. If an adrenal tumor is evident on abdominal radiographs, thoracic films are indicated to search for pulmonary metastases. Ultrasound is a more sensitive means of identifying adrenal tumors in dogs than is radiography. It is, however, considerably more "userdependent" than is radiography (see the article by Dr. Tidwell and colleagues on "Imaging of Adrenal Gland Disorders" elsewhere in this issue). 1 An experienced ultrasonographer can identify a single enlarged adrenal gland in most dogs with adrenal tumors. Bilateral adrenal enlargement is usually, but not always, identified in dogs with pituitarydependent disease. In addition, ultrasonography can be useful in detecting the presence of liver metastasis or vascular invasion of an adrenal carcinoma. Computed tomography and magnetic resonance imaging can be useful in determining the cause of hyperadrenocorticism, especially in dogs that do not show adequate cortisol suppression after administration of high-dose dexamethasone. In approximately half of these dogs, computed tomography reveals a unilateral adrenal tumor. In the remaining dogs with nonsuppressible pituitary-dependent disease, computed tomography shows an approximately equal incidence of macroadenoma and microadenoma, whereas magnetic resonance imaging is more sensitive for detection of microadenoma. 1 Disadvantages include expense, limited availability at this time, and need for general anesthesia.

TREATMENT OF HYPERADRENOCORTICISM CAUSED BY ADRENAL TUMOR

Hyperadrenocorticism secondary to adrenocortical neoplasia can be treated with surgery, mitotane (o,p' -DDD), ketoconazole, or a combination of these modalities. Successful management of these patients requires careful evaluation and staging, an individualized approach to therapy, and close long-term follow-up.

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Surgery

Surgical removal is the treatment of choice in a dog with an adrenal adenoma or small carcinoma, because surgery is often curative in these cases. Surgical adrenalectomy, however, is a difficult procedure with several potential complications. It may be associated with a high rate of intra- and postoperative complications, including death. 12 If adrenalectomy is performed, we prefer the ventral midline approach in most cases for several reasons: inspection of both adrenal glands and a thorough search for metastatic lesions is readily accomplished, anesthesia time is not substantially lengthened when compared to the retroperitoneal approach (especially in dogs in which preoperative lateralization of the tumor was inconclusive), and dehiscence of the ventral incision has not been a problem in our experience. Whichever surgical approach is undertaken, careful surgical technique as well as and close intraoperative and postoperative monitoring is extremely important. During and after surgery, large doses of glucocorticoids must be administered to prevent the rapid development of adrenocortical insufficiency that transpires with successful adrenalectomy (the contralateral adrenal gland is atrophied). We prefer to administer dexamethasone (0.1 to 0.2 mg/kg) intravenously inunediately before surgery, immediately after surgery, and then every 6 to 8 hours in the immediate postoperative period. An isotonic electrolyte solution such as lactated Ringer's should be administered at 10 mL/kg/h throughout anesthesia, surgery, and the postoperative period. Several serious complications can occur during and after adrenalectomy.12 These include, but are not limited to, cardiac arrest, pulmonary thromboembolism, acute renal failure, pneumonia, pancreatitis, and acute adrenal insufficiency. Intensive postoperative monitoring is mandatory to prevent, recognize, and treat these potential complications. Renal function and fluid, electrolyte, and acid-base status should be closely monitored, with abnormalities and complications managed as they occur. If hyperkalemia and hyponatremia occur, oral fludrocortisone (.01 to .02 mg/kg daily) is administered. Therapy is rarely necessary for more than several days. To evaluate adrenal reserve and exclude occult metastasis or incomplete resection, ACTH stimulation testing is performed 24 to 48 hours after surgery. Only after completion of the test is glucocorticoid therapy switched to prednisone at a dosage of 0.5 mg/kg twice daily for 3 to 4 days. In dogs with adrenal insufficiency, this dose is tapered over 10 to 14 days to a daily maintenance dose of 0.2 mg/kg. Prednisone is continued at this dosage until the remaining adrenal gland has regained function, as determined by ACTH stimulation testing. Prednisone supplementation can usually be discontinued within 2 to 3 months. Prednisone supplementation is unnecessary if the results of the postoperative ACTH stimulation test reveal a low-normal, normal, or exaggerated serum cortisol response to ACTH administration, indicating residual tumor. 6• 12

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Ketonconazole

Ketoconazole inhibits adrenal and gonadal steroidogenesis through enzymatic blockade, thereby blocking cortisol production and rapidly lowering serum cortisol concentrations in most dogs with hyperadrenocorticism. The drug can be effective in both pituitary- and adrenaldependent disease. 2 In most dogs, hyperadrenocorticism can be controlled with a dose of 10 mg/kg given twice daily, and therapy is often initiated at this dosage. The initial response to treatment is assessed with an ACTH stimulation test after 14 days of therapy. Both basal and post-ACTH serum cortisol levels should be lowered to within the normal resting range to ensure adequate control of hyperadrenocorticism. Should serum cortisol levels remain outside this range, the dose is increased to 15 mg/kg twice daily and an ACTH response test is repeated after 10 to 14 days. Although further dosage increases can be tried if an inadequate response is seen, they are more likely to be associated with adverse reactions. Adverse effects associated with ketoconazole administration are uncommon and include anorexia, vomiting, diarrhea, transient liver enzyme elevations, and idiosyncratic hepatopathy. Hypocortisolism can also be induced, but it is reversible with discontinuation of the medication. After the establishment of adequate control, follow-up ACTH response tests are performed at 3- to 6-month intervals to ensure that both basal and post-ACTH serum cortisol concentrations remain in the normal resting range. Drawbacks of ketoconazole include high cost, twice-daily administration, and lack of effectiveness in at least one half of dogs. 8 At this time, the primary use for ketoconazole in dogs with adrenal-dependent hyperadrenocorticism is preoperative preparation for 4 to 8 weeks before adrenalectomy, because amelioration of the cortisol excess diminishes anesthetic and surgical risks for the patient. Ketoconazole can also be used as palliative therapy in dogs with unresectable or metastatic adrenal carcinomas.8 Ketoconazole is not adrenocorticolytic like mitotane, however, and would be expected to have no effect on tumor progression (although clinical signs may be controlled). Therefore, a trial with moderate-to high-dose mitotane is warranted in these dogs before palliative therapy with ketoconazole can be recommended. Mitotane

Indications for mitotane therapy include gross metastatic disease evident before surgery, an unresectable or incompletely resectable tumor, residual disease after adrenalectomy, unacceptable anesthetic and surgical risks to the patient, and refusal of surgery by the owner. Mitotane is considered the treatment of choice for nonresectable or recurrent adrenocortical carcinoma, at least in humans. 4• 9• 13 Mitotane is

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of limited effectiveness in most dogs with cortisol-secreting adrenal tumors when administered at dosages used to treat dogs with pituitarydependent hyperadrenocorticism. 3, 6 We recently reported the results of a study of the effectiveness and safety of higher doses of mitotane administered for long periods in 32 dogs with adrenal tumors. 6 Overall, this study showed that medical adrenalectomy with mitotane is an effective and relatively safe therapeutic alternative for most dogs with cortisol-secreting adrenocortical tumors. When treating dogs with adrenocortical neoplasia, mitotane should be used as a true chemotherapeutic agent, with the goal of destruction of all tumor tissue (as indicated by undetectable basal and post-ACTH serum cortisol concentrations). Although complete destruction of neoplastic adrenocortical tissue is unnecessary in the treatment of adrenal adenomas, most dogs have either known adrenal carcinoma or have not been surgically explored (and therefore have about a 50% chance of having adrenal carcinoma). Thus, the induction of overt hypoadrenocorticism is not discouraged and may improve the long-term prognosis. Unfortunately, in many dogs the development of direct mitotane toxicity limits the induction of complete adrenocortical insufficiency and precludes use of this approach. Initially, mitotane should be given at a dosage of 50 to 75 mg/kg daily for 10 to 14 days. Concurrent prednisone supplementation at 0.2 mg/kg daily is indicated throughout the period of mitotane administration. At the completion of this initial period of daily therapy, an ACTH response test is performed. Glucocorticoid supplementation must be withheld on the morning of the test to avoid interference with the cortisol assay. Although not correlated with tumor response in all dogs, serum cortisol determinations are a practical and relatively reliable means of assessing response to therapy, with the therapeutic objective being undetectable to low basal and post-ACTH serum cortisol concentrations. Additionally, periodic re-evaluation with abdominal ultrasonography can be extremely useful in monitoring tumor response. Should serum cortisol concentrations decrease but remain within or above the normal resting range, mitotane is continued (50 to 75 mg/kg/ d) and ACTH response testing is repeated every 10 to 14 days until serum cortisol concentrations fall below normal. If this initial daily dose is essentially ineffective and the serum cortisol response to ACTH remains unchanged from pretreatment values, the daily dosage of mitotane should be increased by 50-mg/kg/ d increments every 10 to 14 days, if necessary, until an ACTH test demonstrates some decrease in serum cortisol concentrations or drug intolerance occurs. In these dogs, daily mitotane is continued at the dosage at which some response was seen or at the highest tolerated dosage, and ACTH stimulation testing is continued at 10- to 14-day intervals until circulating cortisol concentrations fall below the normal resting range. Dogs with adrenal tumors require higher daily induction dosages of mitotane than those generally needed by dogs with pituitary-dependent hyperadrenocorticism. More importantly, a longer period of induction (> 2 weeks) is necessary in about half of the dogs to satisfactorily

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decrease serum cortisol concentrations. In dogs with pituitary-dependent hyperadrenocorticism, the cumulative induction dose of mitotane is usually 400 to 500 mg/kg, whereas we found that dogs with adrenal tumors often require a cumulative induction dose up to 10 times higher. Once undetectable to low-normal serum cortisol concentrations are documented, an initial maintenance mitotane dose of 75 to 100 mg/kg/ wk, in divided doses, together with daily maintenance glucocorticoid supplementation, is recommended. To ensure that serum cortisol concentrations remain suppressed to desired levels, an ACTH stimulation test should be repeated one to two months after initiation of maintenance therapy. The original maintenance mitotane dose should be continued if basal and post-ACTH serum cortisol concentrations remain at undetectable to low levels. If serum cortisol concentrations rise into the normal resting range, however, the weekly maintenance dose should be increased by 50%. If basal or post-ACTH serum cortisol concentrations rise above the normal resting range, daily mitotane treatment is reinstituted (usually at 50 to 100 mg/kg/ d) until cortisol concentrations fall to low or undetectable values. The weekly maintenance dose is then increased by 50%. Such dosage adjustments are followed by repeat ACTH-stimulation testing in 1 month to ensure an adequate response to the new maintenance dose. Subsequent dosage adjustments are based on periodic ACTH stimulation tests at 3- to 6-month intervals, as well as the dog's tolerance of the medication itself. Relapses are not uncommon and can be expected in one half to two thirds of dogs during maintenance mitotane therapy. Although a low initial mitotane dosage is an obvious cause, continued adrenal tumor growth or metastasis, or both, contribute to relapse in some dogs. For the most part, dogs with known metastatic disease will not be as well controlled on a long-term basis as will dogs without evidence of metastasis, presumably because of progression of disease. In general, dogs with adrenal tumors require higher maintenance dosages of mitotane than those needed by dogs with pituitary-dependent hyperadrenocorticism. We have found the mean final maintenance dosage of dogs with adrenal tumors (159.l mg/kg/wk) to be almost double the final maintenance dosage required in dogs with pituitarydependent hyperadrenocorticism (70.9 mg/kg/wk). About one fourth of dogs with adrenal tumors can be expected to need a maintenance dose of over 150 mg/kg, a dose necessary in only about 5% of dogs with pituitary-dependent hyperadrenocorticism. Moreover, some dogs would be given even higher doses of mitotane in an attempt to control clinical signs or tumor growth save for adverse reactions becoming a limiting factor. Some dogs do, however, respond to mitotane dosages used to treat pituitary-dependent hyperadrenocorticism. Of the 32 dogs we studied, 6 (18.8%) were treated successfully with the protocol most commonly recommended for pituitary-dependent hyperadrenocorticism (an induction dosage of 40 to 50 mg/kg/ d for 7 to 10 days, followed by a maintenance dosage of 50 mg/kg/wk). Most dogs that respond to these comparatively low dosages of mitotane probably have either an adenoma or a small carcinoma without widespread metastasis. Although

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a decrease of serum cortisol concentrations into or below the normal resting range indicates successful control of disease, we have seen some dogs nevertheless succumb to tumor progression. Such progression is presumably due to drug-resistant nonfunctional neoplastic cells. Adverse effects including anorexia, lethargy, weakness, and diarrhea develop in about 60% of dogs with adrenal tumors treated with mitotane. In some cases, adverse reactions result from the development of subnormal serum cortisol concentrations, as has been reported in dogs with pituitary-dependent hyperadrenocorticism overtreated with mitotane. In about half of the dogs, however, these adverse reactions result from a direct drug toxicity independent of mitotane's effect on cortisol secretion. In such cases, side effects do not appear to be related to low circulating cortisol concentrations for the following reasons: (1) the dogs are receiving at least maintenance daily glucocorticoid supplementation, (2) no resolution in adverse signs occurs when the glucocorticoid dose is increased, and (3) post-ACTH cortisol concentrations are not undetectable to low when adverse effects develop. Moreover, a similar drug reaction develops in up to 80% of human patients with adrenal carcinoma treated with large dosages of mitotane. If severe side-effects occur, mitotane should be stopped, glucocorticoid supplementation continued, and the dog reevaluated as soon as possible to exclude glucocorticoid and mineralocorticoid deficiency (with an ACTH stimulation test and serum electrolyte determinations). In dogs with normal serum electrolyte concentrations and subnormal serum cortisol concentrations, the daily glucocorticoid supplementation is increased (to 0.4 mg/kg/ d) to exclude cortisol deficiency as the cause of the adverse side effects. If the adverse side effects recur when maintenance mitotane is reinstituted despite such an increase in daily glucocorticoid dosage, a direct drug toxicity is likely. In dogs suspected of suffering such direct drug toxicity, maintenance mitotane is reinstituted at a 25 to 50% lower dose after signs of toxicity have resolved. As a result, cortisol concentrations usually rise to within or above the normal resting range on repeat ACTH stimulation testing. The resting and postACTH cortisol concentrations must, however, be kept in the normal resting range to prevent recurrence of signs of hyperadrenocorticism. Restitution of the higher weekly maintenance dosage can be attempted at a later date; unfortunately, recurrence of adverse signs is likely. Complete glucocorticoid and mineralocorticoid deficiency {Addison's disease), although rare, can develop in some dogs given high doses of mitotane. If iatrogenic Addison's disease does develop, mitotane is discontinued and appropriate supplementation with glucocorticoid and fludrocortisone acetate is instituted. Additional mitotane is not necessary unless hypoadrenocorticism resolves and cortisol concentrations again increase into or above the normal resting range. Unfortunately, one cannot predict in which dogs Addison's disease will occur. Neither high maintenance mitotane dosage nor the tumor's status as benign or malignant is an unequivocal portent of the development of Addison's disease. We have treated one dog with adrenal carcinoma and pulmo-

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nary metastases whose disease resolved after administration of mitotane and subsequent development of adrenal insufficiency. Iatrogenic Addison's disease is not undesirable and may enhance the dog's longterm prognosis, because all functional neoplastic adrenocortical tissue (as well as any remaining normal adrenal tissue) has probably been destroyed. References 1. Feldman EC: Hyperadrenocorticism. In Textbook of Veterinary Internal Medicine, ed 4. Philadelphia, WB Saunders, 1995, pp 1538-1578 2. Feldman EC, Bruyette OS, Nelson RW, et al: Plasma cortisol response to ketoconazole administration in dogs with hyperadrenocorticism. J Vet Med Assoc 197:71, 1990 3. Feldman EC, Nelson RW, Feldman MS, et al: Comparison of mitotane treatment for adrenal tumor versus pituitary-dependent hyperadrenocorticism in dogs. J Am Vet Med Assoc 200:1642, 1992 4. Hutter AM, Kayhoe DE: Adrenal cortical carcinoma: Results of treatment with o,p'DDD in 138 patients. Am J Med 41 :581, 1966 5. Kemppainen RJ, Clark TP, Peterson ME: Aprotinin preserves imrnunoreactive adrenocorticotropin in canine plasma (abstract). In Proceedings of the Annual Veterinary Medical Forum (American College of Veterinary Internal Medicine). 1994 6. Kintzer PP, Peterson ME: Mitotane (o,p' -DDD) treatment of dogs with cortisol-secreting adrenocortical neoplasia: 32 cases (1980--1992). J Am Vet Med Assoc 205:54-61, 1994 7. Kintzer PP, Peterson ME: Mitotane (o,p'-DDD) treatment of cortisol-secreting adrenocortical neoplasia. In Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp 1034-1037 8. Kintzer PP, Peterson MP: Management of cortisol-secreting adrenal tumors. In Proceedings of the Annual Veterinary Medical Forum (American College of Veterinary Internal Medicine). 1992 9. Nader S, Hickey RC, Sellin RV, et al: Adrenal cortical carcinoma: A study of 77 cases. Cancer 52:707-711, 1983 10. Peterson MP: Hyperadrenocorticism. Vet Clin North Am Small Anim Pract 14:731, 1986 11. Peterson ME, Orth DN, Halmi NS, et al: Plasma imrnunoreactive proopiomelanocortin (POMC) peptides and cortisol in normal dogs and dogs with Addison's disease and Cushing's syndrome: Basal concentrations. Endocrinology 119:720, 1986 12. Scavelli TD, Peterson ME, Matthiesen DT: Results of surgical treatment for hyperadrenocorticism caused by adrenocortical neoplasia in the dog: 25 cases (1980--1984) . J Am Vet Med Assoc 189:1360--1364, 1986 13. Schteingart DE: Cushing's syndrome. Endocrinol Metab Clin North Am 18:311

Address reprint requests to Peter P. Kintzer, DVM Staff Internist Boston Road Animal Hospital 1235 Boston Road Springfield, MA 01119