Hyperadrenocorticism caused by bilateral adrenocortical neoplasia in dogs: Four cases (1983-1988)
Sara L. Ford, DVM; Edward C. Feldman, DVM; Richard W. Nelson, DVM
Summary: Hyperadrenocorticism caused by bilateral adrenocortical neoplasia was diagnosed in 4 dogs. Three dogs had bilateral adrenocortical adenomas, and 1 dog had bilateral adrenocortical carcinomas. The history, physical findings, clinicopathologic ab- normalities, and results of ACTH stimulation and low- dose dexamethasone suppression tests were compatible with diagnosis of hyperadrenocorticism. Adrenocorti- cal neoplasia was differentiated from pituitary-depen- dent hyperadrenocorticism on the basis of a combina- tion of test results, including lack of suppression of plasma cortisol after being given a high dose dexa- methasone (n = 4), undetectable (<20 pg/ml) plasma endogenous ACTH concentration (n = 4), iden- tification of a single mineralized adrenal mass by ab- dominal radiography (n = 2) and abdominal ultra- sonography (n = 1), and identification of bilateral nonmineralized adrenal masses by ultrasonography (n = 1).
A left adrenal mass was excised from 1 dog. Clin- ical signs persisted and administration of mitotane was initiated. One dog was treated only with mitotane. Treatment with ketoconazole was attempted in 2 dogs. All dogs died or were euthanatized because of persis- tent hyperadrenocorticism. Necropsy and histologic evaluation of the pituitary and adrenal tissue con- firmed bilateral adrenocortical neoplasia in all dogs. Bilateral adrenocortical neoplasia should be consid- ered as an uncommon, but possible, cause of bilater- ally large adrenal glands in dogs with hyperadreno- corticism.
N aturally developing hyperadrenocorticism is a multisystemic disorder resulting from exces- sive production of cortisol by the adrenal cortex. Hyperadrenocorticism is caused by excessive pitu- itary ACTH secretion (pituitary-dependent hypera- drenocorticism) or an autonomously functioning tumor of the adrenal cortex.1 Primary adrenocor- tical neoplasia has been diagnosed in 10 to 20% of dogs with hyperadrenocorticism.2,3 The preva-
From the Veterinary Medical Teaching Hospital (Ford), the Department of Reproduction (Feldman), and Department of Medicine (Nelson), School of Veterinary Medicine, University of California, Davis, CA 95616. Dr. Ford’s present address is Vet- erinary Specialty Hospital of San Diego, PO Box 9727, Rancho Santa Fe, CA 92067.
lence of adenoma and carcinoma in dogs with functional adrenocortical tumors is approximately equal, and the right and left glands appear to be involved with equal frequency.4 Bilateral adreno- cortical tumors resulting in hyperadrenocorticism are rare in dogs.2,3,5 In a retrospective study of 41 dogs with hyperadrenocorticism caused by adreno- cortical neoplasia, 3 dogs (7%) were found to have bilateral adrenocortical neoplasia.6 The purpose of the study reported here was to describe the clini- cal signs, laboratory findings, results of endocrino- logic testing, treatment, and outcome in 4 dogs with bilateral functional adrenocortical tumors.
Criteria for Selection of Cases
The records of 47 dogs with hyperadrenocor- ticism caused by adrenocortical neoplasia that were examined between 1980 and 1990 were re- viewed. Between 1983 and 1988, hyperadreno- corticism caused by bilateral adrenocortical neo- plasia was diagnosed and confirmed at necropsy in 4 dogs. For inclusion in the study, each dog had to have been determined to have hyperadreno- corticism caused by bilateral adrenocortical neo- plasia confirmed histologically, with no pituitary abnormalities identified at necropsy or with sub- sequent histologic evaluation. In addition, histo- logic evidence that the tumor had been functional, as evidenced by atrophy of the nonneoplastic adrenocortical tissue, was necessary. Bilateral adrenocortical adenomas were identified in 3 dogs. In 1 of these dogs, left adrenalectomy was done and an adenoma was identified histologically. At the time of adrenalectomy, the right adrenal gland ap- peared larger than normal, but was not removed. Two years later, an adenoma was confirmed in the right adrenal gland at necropsy. The other 2 dogs had histologic confirmation of bilateral adrenocor- tical adenomas at necropsy. One dog had bilateral adrenocortical carcinomas, with no evidence of metastatic disease confirmed at necropsy.
Additionally, to be included in this study, each dog must have been suspected to have hypera- drenocorticism on the basis of history and results of physical examination, initial CBC, serum bio- chemical analysis, and urinalysis. The diagnosis must have been supported with results of 1 or more endocrine screening test (ACTH stimulation, low-
dose dexamethasone suppression of plasma corti- sol). The diagnosis of adrenocortical neoplasia must have been suspected on the basis of high-dose dexamethasone suppression of plasma cortisol, plasma endogenous ACTH (EACTH) test results, and review of abdominal radiographs or ultrasono- grams.
Diagnostic evaluation
Laboratory analyses for all dogs included a CBC, serum biochemical analysis, and urinalysis. Plasma was obtained for measurement of EACTH concen- tration from all 4 dogs, using a previously validated assay.7,8 The protocols for the ACTH stimulation test (plasma obtained before and 1 hour after adminis- tration of 0.25 mg of synthetic ACTH,ª IM; 4 dogs), low-dose dexamethasone suppression test (plasma obtained before and 8 hours after administration of 0.01 mg of dexamethasoneb/kg of body weight, IV; 3 dogs), and high-dose dexamethasone suppres- sion test (plasma obtained before and 8 hours after administration of 0.1 mg of dexamethasone/kg, Iv; 4 dogs) have been reported.6,9 Plasma cortisol concentrations were determined using an assay previously validated in dogs.9 All endocrine studies were initiated before 10 AM. During endocrine testing, other procedures were not performed, and all dogs were kept as quiet as possible.
Thoracic radiographs (lateral and dorsoventral views) were assessed for each dog as a screening test for pulmonary metastasis. Standard lateral and ventrodorsal abdominal radiographic views were reviewed for visualization and measurement of the adrenal glands and to determine whether there was evidence of mineralization. Abdominal ultrason- ography was performed by use of a real-time sec- tor scanner” to evaluate adrenal size.10 The right and left perirenal areas were examined in trans- verse, longitudinal, and oblique scanning sections, with particular attention to the region cranial and medial to the cranial pole of each kidney. The ab- domen was evaluated for changes in intrabdominal echogenicity compatible with metastasis.10
Results
Clinical evaluation-The 4 dogs in this study were 10 to 14 years old (mean, 11.5 years) at the time of diagnosis of hyperadrenocorticism. Two of the 4 dogs were spayed female Poodles, the other 2 dogs (1 Viszula, 1 Beagle) were castrated males. Historic problems were consistent with hyper- adrenocorticism and included polyuria and poly- dipsia (n = 4), polyphagia (n = 3), abdominal enlargement (n = 3), hair loss (n = 3), muscle weakness (n = 2), and panting (n = 1). Physical examination abnormalities included abdominal enlargement (n = 4), hepatomegaly (n = 4), bi- lateral symmetric alopecia (n = 3), cutaneous hy-
perpigmentation (n = 2), thin skin (n = 2), calci- nosis cutis (n = 1), and panting (n = 1).
Diagnostic evaluation-Abnormalities detected in the CBC and results of serum biochemical anal- ysis and urinalysis were compatible with the diag- nosis of hyperadrenocorticism. The CBC abnormal- ities included neutrophilic leukocytosis (total WBC, 17,300/ul and 21,400/ul; 2 dogs), monocytosis (1,900/ul and 1,500/ul, 2 dogs), lymphopenia (650/pl, 1 dog), and eosinopenia (O/pl, 1 dog) identified on the hemogram. Abnormalities in the serum biochemical values included high serum al- kaline phosphatase activity (mean, 2,194 IU/L; range, 542 to 4,389 IU/L; reference, 15 to 127 IU/ L), high serum alanine transaminase activity (mean, 435 IU/L; range, 274 to 420 IU/L; reference, 19 to 70 IU/L), and hypercholesterolemia (mean, 337 mg/dl; range, 296 to 420 mg/dl; reference, 135 to 270 mg/dl). Mean urine specific gravity was 1.011 (range, 1.007 to 1.017). Protein was detected in 2 of 4 urine specimens.
Abdominal radiography performed in 3 dogs on initial examination revealed hepatomegaly in all 3 dogs, and a mineralized adrenal mass craniome- dial to the left kidney in 1 dog and craniomedial to the right kidney in another dog. Abdominal ultra- sonography was performed in all 4 dogs at the time of initial examination. Bilateral adrenomegaly was identified in 2 dogs, unilateral adrenomegaly in 1 dog, and the adrenal glands were not visualized in 1 dog. Bilateral adrenomegaly was symmetric in 1 dog and asymmetric in 1 dog. The 2 adrenal masses identified with abdominal radiography were iden- tified with ultrasonography. Ultrasonography in 1 of these dogs also revealed a 3-cm diameter non- mineralized mass involving the contralateral adre- nal gland. Thoracic radiography failed to reveal pulmonary metastasis in any dog.
Endocrinologic evaluation-Results of the ACTH stimulation test were consistent with hyperadreno- corticism in 3 of 4 dogs (Table 1). Plasma cortisol concentration did not suppress in any dog after IV administration of a low or high dose of dexameth- asone. Plasma EACTH concentration was undetect- able (ie, < 20 pg/ml) in the dogs. In 2 dogs, plasma EACTH concentration was measured 4 and 14 months later, and was again undetectable.
Patient management-Therapy was attempted in all dogs. A mineralized left adrenal gland mass was removed surgically in 1 dog. The histologic di- agnosis was adrenocortical adenoma. At the time of surgery, the right adrenal gland was larger than ex- pected, but smaller than the left adrenal mass. The right adrenal gland was not removed. The clinical signs and clinicopathologic abnormalities did not improve after surgery. Hormonal assessment of the pituitary-adrenocortical axis performed 3 months after surgery revealed an exaggerated response to ACTH stimulation, failure of the plasma cortisol concentration to suppress after IV administration of
aCortrosyn, Organon Inc, West Orange, NJ.
bDex-A-Vet, Anthony Products, Arcadia, Calif. “ALT Ultramark 8, Advanced Laboratories Inc, Bothell, Wash.
| ACTH stimulation test (cortisol, ug/dl) | Low-dose dexamethasone screening test (cortisol, µg/dl) | High-dose dexamethasone suppression test (cortisol, µg/dl) | Endogenous ACTH (pg/ml) | Histologic diagnosis | ||||
|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | Basal | Biopsy | Necropsy |
| 3.0 | 21.0 | 4.9 | 5.9 | 3.2 | 3.0 | <20 | Left AA | Right AA |
| 4.3 | 10.5 | 2.4 | 2.6 | 3.4 | 2.2 | <20 | ND | Bilateral AA |
| 3.6 | 20.0 | ND | ND | 3.1 | 3.3 | <20 | ND | Bilateral AC |
| 5.3 | 53.3 | 5.3 | 6.4 | 6.8 | 8.4 | <20 | ND | Bilateral AA |
| Ref range: | ||||||||
| 0.5 to 6.0 | 5.5 to 17.0 | 0.5 to 6.0 | <1.4 | 0.5 to 6.0 | <1.4 | 20 to 100 | - | - |
| Adrenocortical | ||||||||
| tumor | ≥17.0 | NA | >1.4 | NA | >50%* | <20 | - | - |
*Pretreatment DEX value.
ND = Not done; NA = Not applicable; DEX = Dexamethasone; AA = Adrenocortical adenoma; AC = Adrenocortical carcinoma.
low and high doses of dexamethasone, and plasma EACTH concentration that was undetectable. Ultra- sonographic examination in the region of the right adrenal gland failed to reveal adrenomegaly.
The owners declined a second exploratory ce- liotomy. The dog was treated with mitotaned for 25 months, at a mean dosage of 25 mg/kg/d. The owners reported improvement in the clinical signs. The post-ACTH stimulation plasma cortisol concen- tration, however, remained higher than the basal reference range (0.5 to 5 µg/dl) throughout treat- ment. Repeat diagnostic evaluation 24 months af- ter left adrenalectomy revealed a 2-cm mineralized right adrenal mass via abdominal radiography and ultrasonography. One month later, the dog was euthanatized because of an acute onset of respira- tory distress. Necropsy confirmed a right adreno- cortical adenoma, steroid hepatopathy, chronic membranoproliferative glomerulonephritis, and multifocal metastatic soft tissue calcification.
Mitotane was administered to another dog for 22 months at a mean dosage of 30 mg/kg/d. Clin- ical signs improved in this dog, but post-ACTH plasma cortisol concentration remained greater than the basal reference range. The dog was eutha- natized after an acute onset of depression, an- orexia, and vomiting. Necropsy revealed bilateral adrenocortical adenomas and steroid hepatopathy.
Ketoconazolee was administered (10 mg/kg, q 12 h) to 2 dogs. Clinical signs improved and post- ACTH plasma cortisol concentration decreased to within the basal reference range in both dogs. One dog was treated with ketoconazole for 4 months, at which time an oral melanoma with metastasis to regional lymph nodes was diagnosed. The dog was euthanatized 2 months later. Necropsy revealed bilateral adrenocortical adenomas, steroid hepat- opathy, and malignant oral melanoma with lymph node and pulmonary metastasis. The other dog was treated with ketoconazole for 2 months, at which time the owner had the dog euthanatized because of severe progressive osteoarthritis. Necropsy find- ings included bilateral adrenocortical carcinomas
with no evidence of metastasis, steroid hepatopa- thy, and hepatic nodular hyperplasia.
Discussion
There was no information in the initial evalu- ation of these 4 dogs to suggest bilateral adreno- cortical neoplasia. The history, physical findings, clinical pathologic abnormalities, and results of ACTH stimulation and low-dose dexamethasone suppression tests were typical of a nonspecific di- agnosis of hyperadrenocorticism.1-3,5
Endocrine discriminating tests that identified these dogs as having functional adrenocortical tu- mors included the high-dose dexamethasone sup- pression test, EACTH concentration, abdominal ul- trasonography, and radiography. Failure of plasma cortisol concentration to suppress plasma cortisol concentrations during the high-dose dexametha- sone suppression test correctly identified adreno- cortical-dependent disease in all 4 dogs. Uniform nonsuppressibility has been demonstrated with adrenocortical tumors, however, 20 to 30% of dogs with pituitary-dependent hyperadrenocorticism have similar test results. 2,3,9,1’1
The plasma EACTH concentration is less than the sensitivity of the radioimmunoassay (< 20 pg/ ml) or in the low normal range (20 to 45 pg/ml) in prior studies of dogs with adrenocortical neoplasia. Low normal results are not diagnostic. 7,9 However, when undetectable, the plasma EACTH concentra- tion is consistent with an autonomously function- ing adrenocortical tumor or iatrogenic hypera- drenocorticism.6,9 All 4 dogs reported herein had EACTH concentration that was undetectable. In 2 dogs, these test results were repeatable.
Radiographic detection of adrenomegaly with or without mineralization aids the diagnosis of functional adrenocortical neoplasia in approxi- mately half of affected dogs, as was true in 2 of 4 dogs in this report that had mineralized adrenal masses.12,13 A second mineralized adrenal mass was identified 24 months after the first calcified adrenal mass was surgically removed in 1 dog. Thus, abdominal radiography represents a means of potentially identifying an adrenocortical tumor. Bilateral adrenocortical neoplasia, however, was
not suspected in any dog after examination of ab- dominal radiographs.
Abdominal ultrasonography to assess adrenal gland size, shape, and echogenicity has been used in the evaluation of hyperadrenocorticism.10 In another study,6 ultrasonography correctly detected adrenocortical tumors in 76% of adrenal carcino- mas and 62% of adrenal adenomas. In this study, abdominal ultrasonography was an inconsistent diagnostic aid. Ultrasonography correctly detected contralateral adrenomegaly in 1 dog in which radi- ography revealed only unilateral adrenomegaly. Bilateral adrenomegaly in another dog was recog- nized only by ultrasonography. Unilateral adrenomegaly in 1 dog was detected by use of ra- diography and ultrasonography, but the enlarge- ment of the opposite gland was only identified during exploratory surgery. In 1 dog, bilateral adrenomegaly was only detected at necropsy.
Identification of bilateral adrenomegaly is most consistent with of pituitary-dependent hypera- drenocorticism. Additional causes of bilateral ad- renal enlargement include bilateral (macronodular or micronodular) hyperplasia, functional adreno- cortical neoplasia (adenoma or carcinoma), ad- renomedullary neoplasia, metastasis to the adrenal glands, hemorrhage into the adrenal glands, and nonfunctional adrenal tumors.14 Bilateral adrenal neoplasia in a dog with hyperadrenocorticism could result from bilateral adenomas or carcinomas of the adrenal cortex, as described in this report, adrenocortical neoplasia in 1 adrenal gland with adrenomedullary neoplasia in the opposite adrenal gland, or unilateral adrenocortical carcinoma with metastasis to the opposite adrenal gland.
Adrenocortical tumors are almost always uni- lateral and solitary. Adrenalectomy is the treatment of choice for adrenocortical neoplasia. If both ad- renal glands appear to be affected, however, bilat- eral adrenalectomy with subsequent mineralocor- ticoid and glucocorticoid supplementation should be considered. Bilateral adrenalectomy affords the advantages of a potential cure as well as a histologic diagnosis. Histologic evaluation is the only means of confidently separating hyperplasia from ade- noma or carcinoma.º Persistent nonsuppressible steroid secretion after surgery indicates residual or metastatic tumor, as was detected in 1 dog of this report. In that dog, the smaller adrenal adenoma was not removed at surgery and continued to cause clinical signs of hyperadrenocorticism. Bilateral adrenalectomy may have proved curative in this as well as the other 3 dogs in this report.
Medical treatment is a viable option when metastatic disease or other complicating factors preclude surgery. Dogs with functional adrenal tu- mors are more resistant to the effects of mitotane than dogs with pituitary-dependent hyperadreno- corticism.15 Clinical and biochemical control is more difficult when mitotane is being adminis- tered, as was true for 2 dogs in this report treated
for 22 and 24 months with high dosages of mito- tane (25 and 30 mg of mitotane/kg/d, respective- ly). Although improvement in clinical signs was achieved, the post-ACTH plasma cortisol concen- trations consistently remained greater than the basal reference range (ie, > 5 µg/dl) for the dura- tion of treatment.
Ketoconazole is an alternative treatment for adrenocortical neoplasia. Ketoconazole is effective in suppressing glucocorticoid secretion by the adrenocortical tumor, it has low toxicity, the inhi- bition of steroidogenesis is reversible, and it has a minimal effect on mineralocorticoid produc- tion.2,16 Ketoconazole was used successfully in the short-term treatment of 2 dogs in this report.
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