Concurrent pituitary and adrenal tumors in dogs with hyperadrenocorticism: 17 cases (1978-1995)
Deborah S. Greco, DVM, PhD; Mark E. Peterson, DVM; Autumn P. Davidson, DVM; Edward C. Feldman, DVM; Kathianne Komurek, MA
Objective-To describe the clinicopathologic charac- teristics of dogs with hyperadrenocorticism and con- current pituitary and adrenal tumors.
Design-Retrospective study.
Animals-17 client-owned dogs.
Procedure-Signalment, response to treatment, and results of CBC, serum biochemical analysis, urinaly- sis, endocrine testing, and histologic examinations were obtained from medical records of dogs with hyperadrenocorticism and concurrent adrenal and chromophobe pituitary tumors.
Results-On the basis of results of adrenal function tests and histologic examination of tissue specimens collected during surgery and necropsy, concurrent pituitary and adrenal tumors were identified in 17 of approximately 1,500 dogs with hyperadrenocorticism. Twelve were neutered females, 5 were males (3 sex- ually intact, 2 neutered); and median age was 12 years (range, 7 to 16 years). Hyperadrenocorticism had been diagnosed by use of low-dose dexamethasone sup- pression tests and ACTH stimulation tests. During high-dose dexamethasone suppression testing of 16 dogs, serum cortisol concentrations remained high in 11 dogs but decreased in 5 dogs. Plasma concentra- tions of endogenous ACTH were either high or within the higher limits of the reference range (12/16 dogs), within the lower limits of the reference range (2/16), or low (2/16). Adrenal lesions identified by histologic examination included unilateral cortical adenoma with contralateral hyperplasia (10/17), bilateral cortical ade- nomas (4/17), and unilateral carcinoma with contralat- eral hyperplasia (3/17). Pituitary lesions included a chromophobe microadenoma (12/17), macroadenoma (4/17), and carcinoma (1/17).
Clinical Implications-Pituitary and adrenal tumors can coexist in dogs with hyperadrenocorticism, result- ing in a confusing mixture of test results that may com- plicate diagnosis and treatment of hyperadrenocorti- cism. (J Am Vet Med Assoc 1999;214:1349-1353)
H yperadrenocorticism is a recognized and common endocrine disorder in dogs.14 Most dogs with non- iatrogenic hyperadrenocorticism have bilateral adreno- cortical hyperplasia resulting from excessive ACTH secretion by the pituitary gland; however, approxi- mately 10 to 20% of dogs with hyperadrenocorticism suffer from autonomously functioning adrenocortical
From the Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 (Greco, Komurek); the Caspary Research Institute, The Animal Medical Center, New York, NY 10021 (Peterson); and the Department of Medicine and Epidemiology, University of California, Davis, CA 95616 (Davidson, Feldman).
adenomas or carcinomas.1,2 Diagnosis is based on appropriate clinical signs and laboratory abnormalities in concert with abnormal results of screening tests, such as the low-dose dexamethasone suppression (LDDS) test or ACTH stimulation test.1.4-7 Differ- entiating pituitary-dependent hyperadrenocorticism from hyperadrenocorticism caused by an adrenal tumor may be done by performing a high-dose dexa- methasone suppression (HDDS) test, measuring plas- ma concentrations of endogenous ACTH, or by per- forming imaging studies (eg, abdominal ultrasonogra- phy, computed tomography [CT], and magnetic reso- nance imaging) of the adrenal or pituitary glands.1,4,8-10
Characteristics of pituitary-dependent hyperadreno- corticism include high baseline serum cortisol concen- trations that remain high during LDDS testing and decrease during HDDS testing, increased or high refer- ence range values (high-normal) for plasma ACTH con- centrations, and 2 equally large adrenal glands, as revealed by adrenal imaging studies.1,4-10 Characteristics of hyperadrenocorticism caused by an adrenal tumor include high baseline serum cortisol concentrations that remain high during LDDS and HDDS testing, low or low reference range values (low-normal) for plasma ACTH concentrations, and a solitary, unilateral adrenal mass, as revealed by adrenal imaging studies.1.4-10 Differentiation of hyperadrenocorticism caused by either a functional pitu- itary tumor or adrenal tumor may be difficult in select patients. One explanation for this difficulty may be the coexistence of pituitary-dependent hyperadrenocorti- cism and functional adrenocortical tumors.1,11,12 The pur- pose of the study reported here is to describe the clinico- pathologic characteristics of dogs with hyperadrenocorti- cism and concurrent pituitary and adrenal tumors.
Criteria for Selection of Cases
Approximately 1,500 medical records of dogs for which hyperadrenocorticism was diagnosed at Colorado State University College of Veterinary Medicine, The Animal Medical Center, or the University of California- Davis School of Veterinary Medicine between 1978 and 1995 were reviewed. Information on age, sex, response to treatment, endogenous ACTH concentrations, and results of CBC, serum biochemical analyses, urinalysis, ACTH stimulation, LDDS and HDDS tests, and surgery and necropsy were obtained from medical records of the 17 dogs that had concurrent adrenal tumors and chro- mophobe pituitary tumors.
Procedures
For the ACTH stimulation test, blood was collect- ed for determination of baseline serum cortisol con-
| Endogenous ACTHt | HDDS test results* | |
|---|---|---|
| Cortisol unaffected# (n = 10) | Cortisol decreased§ (n = 5) | |
| High and high-normal (> 40 pg/ml; n = 11) | Uni adenoma/microadenomall Uni adenoma/carcinoma Uni carcinoma/microadenoma Bi adenoma/macroadenoma Bi adenoma/macroadenoma Bi adenoma/microadenoma Bi adenoma/microadenoma | Uni adenoma/microadenoma Uni adenoma/microadenoma Uni adenoma/microadenoma Uni adenoma/macroadenoma |
| Low-normal (20 to 40 pg/ml; n = 2) Low (< 20 pg/ml; n = 2) | Uni adenoma/microadenoma | Uni adenoma/microadenoma |
| Uni adenoma/macroadenoma Uni adenoma/microadenoma | ||
| *Serum cortisol concentrations determined before and 8 hours after dexamethasone injection (1 mg/kg [0.45 mg/lb], IV). tReference range, 20 to 80 pg/ml. #Serum cortisol concentrations > 1.5 µg/dl 8 hours after dexamethasone injection. §Serum cortisol concentrations < 1.5 µg/dl 8 hours after dexamethasone injection. IlAdrenal lesion/pituitary lesion. Uni = unilateral. Bi = bilateral. | ||
centrations and ACTH gelª (2.2 U/kg [1 U/lb] of body weight, IM) or synthetic ACTHb (0.25 mg/dog, IV or IM) was then injected.1 One (synthetic ACTH) or 2 hours (gel) later, blood was collected again for determi- nation of serum cortisol concentrations. For the LDDS and HDDS tests, blood was collected for determination of baseline serum cortisol concentrations, and dexam- ethasone (low-dose, 0.01 or 0.015 mg/kg [0.005 or 0.007 mg/lb]; high-dose, 1 mg/kg [0.45 mg/lb], IV) was then injected.1,8,13 Eight hours later, blood was collected again for determination of cortisol concentrations.1,8,14 To obtain plasma samples for determination of endoge- nous ACTH concentrations, blood was collected in cold syringes coated with EDTA and transferred to cold glass tubes containing EDTA. Blood samples for all endocrine tests were centrifuged within 30 minutes of collection and plasma or serum were transferred to plastic tubes for storage at -20 C (-4 F) until assayed.
Serum cortisol concentrations were measured by use of a commercial cortisol radioimmunoassayª validated for use in dogs.7 Plasma ACTH concentrations were mea- sured by use of a human ACTH assay as described.15,16 Serum cortisol concentrations > 20 µg/dl 1 or 2 hours after administration of exogenous ACTH, and > 1.5 µg/dl 8 hours after injection of either high- or low-dose dex- amethasone, were considered diagnostic for hyper- adrenocorticism. On the basis of endogenous ACTH con- centrations and results of HDDS testing, dogs were clas- sified into 1 of the following 5 categories: high or high- normal plasma ACTH concentrations (> 40 pg/ml) and high serum cortisol concentrations (> 1.5 µg/dl), high or high-normal ACTH concentrations and a decrease in cor- tisol concentrations (< 1.5 µg/dl), low-normal ACTH concentrations (20 to 40 pg/ml) and high cortisol con- centrations, low-normal ACTH concentrations and a decrease in cortisol concentrations, and low ACTH con- centrations (< 20 pg/ml) and high cortisol concentra- tions. Results of histologic examinations of tissues col- lected during surgery, necropsy, or both were then tabu- lated for each dog in each category (Table 1).
Results
Concurrent pituitary and adrenal tumors were confirmed in 17 of approximately 1,500 dogs with
hyperadrenocorticism. Twelve of the 17 dogs were neutered females, and 5 were males (3 sexually intact, 2 neutered). Median age of affected dogs was 12 years (range, 7 to 16 years). Most of the dogs were brought to veterinarians because of owner-observed clinical signs typical of severe and advanced hyperadrenocorti- cism, including pronounced polyuria and polydipsia (n = 16), pot-bellied appearance (15), excessive pant- ing (15), truncal alopecia (14), obesity (14), polypha- gia (14), and muscle wasting (12). Three dogs also had neurologic signs, such as anorexia and ataxia, that could be attributed to a large or expanding pituitary mass. Classic laboratory results suggestive of hyper- adrenocorticism included high serum alkaline phos- phatase activity (17), hyposthenuria (16), stress leuko- gram (15), increased serum cholesterol concentration (10), and erythrocytosis (8).
Hyperadrenocorticism was confirmed by abnormal results of LDDS tests, ACTH stimulation tests, or both. Serum cortisol concentrations remained high (median, 4.1 µg/dl; range, 1.6 to 22 µg/dl) in all 17 dogs 8 hours after administration of a low dose of dexamethasone. Fifteen of 17 dogs had exaggerated responses to injec- tion of exogenous ACTH, as indicated by an increase in serum cortisol concentrations (median, 30 µg/dl; range, 21 to 150 µg/dl) 1 to 2 hours after ACTH injec- tion. The 2 dogs that had equivocal ACTH stimulation test results had cortisol concentrations that remained high during LDDS testing.
To help determine the cause of the hyperadreno- corticism, HDDS tests were done in 16 of 17 dogs; serum cortisol concentrations remained high in 11 of these dogs but decreased in 5 dogs 8 hours after dex- amethasone injection. Endogenous ACTH concentra- tions were measured in 16 of 17 dogs; concentrations were high or high-normal (> 40 pg/ml; reference range 20 to 80 pg/ml) in 12 dogs, low-normal (20 to 40 pg/ml) in 2 dogs, and low (< 20 pg/ml) in 2 dogs (Table 1). None of the dogs had decreased cortisol con- centrations during HDDS testing and low concentra- tions of endogenous ACTH. Two of the 17 dogs were tested by use of either HDDS or determination of plas- ma ACTH concentrations and, therefore, could not be categorized by both tests.
Ultrasonography of the adrenal glands was per- formed in 7 of 17 dogs. Of these, 3 had a unilateral adrenal mass, 3 had large, asymmetric adrenal glands, and 1 had large, bilaterally symmetric adrenal glands. In addition, 5 of these 7 dogs had high-normal or high plasma ACTH concentrations and unilaterally, or bilat- erally and asymmetrically enlarged adrenal glands; the other 2 dogs had large, bilaterally symmetric adrenal glands with low plasma ACTH concentrations. Computed tomography of the pituitary and adrenal glands was done on an additional 2 of 17 dogs; both dogs had a unilaterally large adrenal gland, and 1 also had increased density in the region of the pituitary gland.
Two of the 17 dogs were euthanatized at the time of diagnosis because of the owners’ unwillingness to treat them. Of the remaining 15 dogs, 6 were treated by unilateral adrenalectomy because, on the basis of endocrine test results (cortisol concentrations remained high during HDDS testing and endogenous ACTH concentrations were low-normal), or evidence of a unilateral adrenal mass in dogs examined by abdominal ultrasonography or CT, the cause of hyper- adrenocorticism was believed to be an adrenal tumor. Three of these dogs died in the immediate postopera- tive period because of complications associated with hyperadrenocorticism. Of the 3 that survived, all had temporary improvement of clinical signs, but those signs were evident on reexamination 1, 6, and 8 months after surgery. Results of repeat testing of all 3 dogs at reexamination were consistent with pituitary- dependent hyperadrenocorticism (high-normal or high plasma ACTH concentrations, high cortisol concentra- tions during LDDS testing, and decreased cortisol con- centrations during HDDS testing). A second adrenalec- tomy was done on 1 of these 3 dogs, and it remained healthy with fludrocortisone acetate treatment for an additional 3 years, when it died of hemorrhagic gas- troenteritis. The other 2 dogs were treated successfully with mitotane, using a standard dosage regimen for treatment of pituitary-dependent hyperadrenocorti- cism17 for 6 and 8 months, after which they died of renal failure and hepatic carcinoma, respectively.
On the basis of endocrine test results (cortisol con- centrations decreased during HDDS testing and high- normal to high endogenous ACTH concentrations), or evidence of bilateral adrenal gland enlargement in dogs that were examined by use of abdominal ultrasonogra- phy, the remaining 9 of 15 dogs not euthanatized immediately after the diagnosis of hyperadrenocorti- cism was made were believed to have pituitary-depen- dent hyperadrenocorticism. These dogs were initially treated medically with cyproheptadine (n = 1) or mitotane (8). Clinical response to treatment was not detected in the dog given cyproheptadine; eventually a unilateral adrenalectomy was performed, but the dog died because of postoperative renal failure. Of the 8 dogs treated with mitotane, 4 were euthanatized or died (intestinal strangulation [n = 1], neurologic dis- ease [1], congestive heart failure [1], and thyroid car- cinoma [1]) within 3 months of initiating treatment. Because of the short amount of time that these 4 dogs were treated with mitotane, their response to treatment
could not be adequately evaluated. Clinical signs of hyperadrenocorticism resolved, and serum cortisol concentrations decreased to within reference range17 in the remaining 4 mitotane-treated dogs. However, these dogs died or were euthanatized (splenic hemangiosar- coma [1], neurologic disease caused by a pituitary macroadenoma [1], ruptured chordae tendineae [1], and neurologic disease of unknown cause [1]) 1 to 3 years after diagnosis.
Results of histologic examination of specimens of adrenal glands collected during surgery, necropsy, or both revealed unilateral cortical adenoma with con- tralateral hyperplasia (n = 10) with additional areas of nodular hyperplasia reported in 4 of these dogs, bilat- eral cortical adenoma (4), and carcinoma with con- tralateral hyperplasia (3). In specimens from 2 dogs, cortical necrosis secondary to treatment with mitotane was also detected. Pituitary lesions detected by histo- logic examination of tissue specimens collected at necropsy included a chromophobe microadenoma (n = 12), pituitary macroadenoma (4), and pituitary carci- noma (1).
Discussion
In dogs, noniatrogenic hyperadrenocorticism may be either ACTH-dependent (ie, pituitary-dependent with resultant bilateral adrenocortical hyperplasia) or ACTH-independent (ie, unilateral cortisol-secreting adrenal tumor).1.4 The dogs in this study differed from most dogs with hyperadrenocorticism, because there was evidence of concurrent pituitary- and adrenal- dependent disease. Because this was a retrospective study, it was impossible to determine whether both pituitary and adrenal tumors were secretory or, alter- natively, if 1 or the other was nonfunctional.
Autonomous secretion of cortisol by a functional adrenocortical tumor suppresses pituitary secretion of ACTH to low or undetectable concentrations, resulting in atrophy of the contralateral adrenal cortex.1,4,18 Because all of the dogs in our study that had a unilat- eral adrenal tumor (n = 13) also had evidence of con- tralateral adrenal hyperplasia rather than hypoplasia or atrophy, it is likely that the pituitary tumors in these dogs were secreting ACTH. Alternatively, the adrenal tumors may have been nonfunctional; however, clini- cal signs of hyperadrenocorticism temporarily improved in the 3 dogs of this report that were treated by unilateral adrenalectomy, suggesting that, at least in these dogs, the adrenal and pituitary masses were secretory. It is also possible that the adrenal tumors were medullary (eg, pheochromocytoma) and not cor- tical in origin. Concurrent hyperadrenocorticism and pheochromocytoma has been described in dogs19 but, on the basis of results of histologic examination, this is an unlikely diagnosis for the dogs in our study.
In the 4 dogs with bilateral adrenocortical tumors, the concurrent pituitary tumor may have been non- functional.20 Hyperadrenocorticism caused by bilateral adrenocortical tumors is rare but has been reported in dogs.21 As opposed to the dogs of our study that, in general, responded well to treatment with mitotane, others1,21 report that dogs with bilateral adrenal tumors have a poor response to medical treatment. However,
none of those dogs had evidence of a pituitary tumor. In addition, the 4 dogs in our study had high-normal to high plasma ACTH concentrations, suggestive of a functional pituitary tumor, rather than the low con- centrations expected if adrenal tumors were the sole cause of hyperadrenocorticism.
In humans, coexisting pituitary- and adrenal- dependent hyperadrenocorticism has been reported but is rare.22,23 As in dogs, the most common cause of hyperadrenocorticism in humans is a pituitary tumor, characterized by increased secretion of ACTH and development of diffuse, bilateral adrenocortical hyper- plasia.18,24 A subset of patients with hyperadrenocorti- cism, however, develop multiple large nodules of vari- ous sizes within the adrenal cortex, forming an entity called macronodular adrenal hyperplasia.18,24-26 The clinical manifestations of hyperadrenocorticism in patients with macronodular adrenal hyperplasia does not differ from hyperadrenocorticism associated with diffuse bilateral adrenal hyperplasia; however, patients with the former usually have a more chronic and severe disease.18 Moreover, results of biochemical tests assessing the hypothalamic-pituitary-adrenal axis are variable in these patients.18,24-26 A few appear to have typical pituitary-dependent hyperadrenocor- ticism with normal or high plasma ACTH concentra- tions and a decrease in serum cortisol concentrations during HDDS testing. Others have low to unde- tectable plasma ACTH concentrations and, in as many as 75% of these patients, serum cortisol con- centrations remain high after HDDS testing.26 Radiologic imaging usually reveals bilateral nodular and large adrenal glands but, in a few patients, uni- lateral nodular hyperplasia with diffuse hyperplasia of the contralateral gland is detected.27,28 Because cortisol concentrations may not decrease during HDDS test- ing and plasma ACTH concentrations may be low in patients with macronodular adrenal hyperplasia, a few of these patients have erroneously been thought to have an adrenal tumor.
Classification of abnormal adrenal tissue on the basis of histologic examination is a diagnostic chal- lenge1; it can be difficult to distinguish macronodular hyperplasia from adenoma and the term “adenomatous hyperplasia” has been suggested to describe such lesions.29 Further, it can be difficult to distinguish ade- noma or adenomatous hyperplasia from carcinoma. Therefore, it is possible that most if not all dogs in this study had macronodular adrenal hyperplasia rather than adrenal adenoma or carcinoma, especially because none of the dogs had metastases. As in humans with macronodular adrenal hyperplasia, all of our dogs had evidence of severe, chronic hyperadrenocorticism. Again, because this was a retrospective study, we could not determine unequivocally whether these dogs had macronodular adrenal hyperplasia, true concurrence of pituitary-dependent hyperadrenocorticism and a func- tional adrenocortical tumor, or alternatively, pituitary- dependent hyperadrenocorticism associated with a nonfunctional adrenal tumor.
Although concurrent pituitary-dependent hyper- adrenocorticism and adrenal tumors in dogs is rare, this condition has been described by others.1,11,12,30 In 1
report from a European veterinary college,30 concomi- tant pituitary- and adrenal-dependent hyperadrenocor- ticism was identified during necropsy in 12 of 97 dogs. Compared with our study, in which the prevalence of adrenal tumors in dogs with pituitary-dependent hyperadrenocorticism was approximately 1%, a preva- lence of approximately 12% seems high. In the European study, however, results of tests assessing the hypothalamic-pituitary-adrenal axis were not provid- ed, and it is not clear how the diagnosis of pituitary- and adrenal-dependent hyperadrenocorticism was made. Diagnoses made on the basis of necropsy cannot assess the secretory nature of these concurrent tumors and, again, the adrenal tumors identified by the European group may actually have been macronodular hyperplasia.
In summary, results of this report confirm that apparently functional adrenal tumors can be identified in dogs with pituitary-dependent hyperadrenocorti- cism. This can result in a confusing mixture of test results that may complicate diagnosis and treatment of hyperadrenocorticism. Moreover, these dogs may have true concurrence of pituitary-dependent hyperadreno- corticism and functional or nonfunctional adrenocorti- cal tumors or, alternatively, they may have macronodu- lar adrenal hyperplasia.
“ACTH gel, Anthony Pharmaceuticals, Arcadia, Calif. “Cortrosyn, Organon Inc, West Orange, NJ.
“Coat-a-Count, Cortisol assay, Diagnostic Products Corp, Los Angeles, Calif.
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