Canine Hyperadrenocorticism Due to Adrenocortical Neoplasia
Pretreatment Evaluation of 41 Dogs
Claudia E. Reusch, DVM, and Edward C. Feldman, DVM
This retrospective study identifies parameters that might separate dogs with hyperadrenocorticism caused by adrenocortical tumors from dogs with pituitary-dependent hyperadrenocorticism. Further, an attempt was made to identify factors that could separate dogs with adrenocortical adenomas from dogs with carcinomas. The records of 41 dogs with hyperadrenocorticism caused by adrenocortical neoplasia were reviewed. The history, physical examination, urinalysis, hemogram (CBC), chemistry profile adrenocorticotrophic hormone (ACTH) stimulation and low dose dexamethasone test results were typical of the nonspecific diagnosis of hyperadrenocorticism. The preceding information on the 41 dogs with adrenocortical tumors was compared with that from 44 previously diagnosed pituitary-dependent hyperadrenocorticoid dogs. There was no parameter which aided in separating these two groups of dogs.
Thirty dogs with adrenocortical tumors were tested with a high-dose dexamethasone test and none had suppressed plasma cortisol concentrations 8 hours after IV administration of 0.1 mg/kg of dexa- methasone. In 29 of the 41 adrenal tumor dogs, plasma endogenous ACTH was not detectable on at least one measurement (<20 pg/ml). The remaining 12 dogs from this group had nondiagnostic concentra- tions (20-45 pg/ml). Thirteen of 22 dogs (59%) with adrenocortical carcinomas had adrenal masses identified on abdominal radiographs and seven of 13 dogs (54%) with adrenocortical adenomas had radiographically visible adrenal masses. Thirteen of 17 adrenocortical carcinomas (76%) and five of eight adenomas (62%) were identified with ultrasonography. Radiographs of the thorax and ultrasonog- raphy of the abdomen identified most of the dogs (8 of 11) with metastatic lesions.
In conclusion, the most sensitive tests in distinguishing dogs with pituitary-dependent hyperadreno- corticism from dogs with adrenocortical tumors were the plasma endogenous ACTH concentrations, abdominal radiography, and abdominal ultrasonography. None of these three tests alone, however, were completely reliable, suggesting the potential need for review of several tests when attempting to sepa- rate dogs with pituitary-dependent hyperadrenocorticism from those with adrenocortical tumors. Recog- nition of metastatic lesions with radiography and/or ultrasonography was the only parameter that separated dogs with adenomas from dogs with carcinomas. (Journal of Veterinary Internal Medicine 1991; 5:3-10)
HYPERADRENOCORTICISM (Cushing’s syndrome) is a commonly diagnosed endocrine disorder in the dog and is most frequently associated with pituitary-depen- dent bilateral adrenocortical hyperplasia. Primary adre- nocortical neoplasia (adenoma or carcinoma) occurs in 10% to 20% of Cushing’s dogs.1,2 Recommended thera-
From the Department of Reproduction and the Small Animal Clinic, School of Veterinary Medicine, University of California, Davis, Cali- fornia. This study was completed while Dr. Reusch was on sabbatical leave from the I. Medizinische Tierulinik, der Universitat Munchen, Munich, Germany.
The authors thank Ms. Marsha Feldman of the Pituitary Function Laboratory, U.C. Davis, for her technical assistance, and Ms. Ruth Johnston for financial support in memory of “Teddy Bear.”
pies differ for the management of pituitary-dependent vs. primary adrenocortical tumor hyperadrenocorti- cism. Various tests, advocated as aids in distinguishing between these two forms of the syndrome, include high- dose dexamethasone suppression tests, endogenous plasma ACTH measurements, corticotrophin releasing hormone (CRH) stimulation tests, metyrapone tests, ra- diographs, ultrasound, computed tomography, and gamma camera imaging. Each of these diagnostic tools may have limitations since their results may not be con- clusive, they may provide inconsistent information, they can be expensive, some require sophisticated facili- ties, and several have yet to be studied in a large group of Cushing’s and non-Cushing’s dogs. It is difficult to per- form comparative studies on large numbers of dogs with functioning adrenocortical tumors, since these animals are not seen with great frequency. Therefore, the present
retrospective study was undertaken to provide an over- view of the signalment, history, clinical signs, and rou- tine laboratory test results in dogs with Cushing’s syn- drome caused by adrenocortical tumors. Several screen- ing and discriminating tests used in the diagnostic evaluation of these dogs were evaluated. The goals of this retrospective study were twofold: 1) to identify any features in dogs with functioning adrenocortical tumors that would distinguish them from dogs, with pituitary- dependent hyperadrenocorticism (PDH) and 2) these parameters were reviewed to determine whether any would aid in distinguishing dogs with adrenocortical carcinomas from those with adrenocortical adenomas.
Criteria for Selection of Cases
The records of 41 dogs with hyperadrenocorticism caused by adrenocortical neoplasia, examined between 1977 and 1990, were reviewed. For inclusion in this study, each dog had to have clinical signs suggestive of hyperadrenocorticism (Cushing’s syndrome), an adre- nocortical tumor or tumors confirmed histologically and evidence that the tumor had been functional, i.e., atrophy of non-neoplastic adrenocortical tissue. The hyperadrenocorticism in each dog was initially sus- pected from the history, physical examination, routine laboratory test results (CBC, chemistry profile, urinaly- sis), and one or more endocrine screening test results (ACTH stimulation, low-dose dexamethasone).
Twenty-six of the 41 dogs had adrenocortical carci- nomas. Fourteen of the 26 dogs had adrenal tissue re- moved at surgery that was diagnosed as adrenocortical carcinoma. Eight of the 14 dogs underwent necropsy at a later date. Tissue was obtained during necropsy of 12 dogs that had not undergone surgery. Among the 26 dogs were two in which metastasis of tissue, thought to be adrenocortical carcinoma, was observed during nec- ropsy; whereas the solitary adrenal tumors, taken during surgery 1.5 years earlier in one dog and two years earlier in another dog, had been classified as adenomas. All 26 dogs had atrophied non-neoplastic adrenocortical tissue. In 11 dogs, the left adrenal was involved, in 14 dogs the right adrenal was involved and one dog had bilateral carcinomas. Twenty dogs were necropsied and none had pituitary abnormalities. Metastasis was confirmed on necropsy of 11 dogs (55%): in three dogs to both liver and lung, for dogs to the lungs only, two dogs to the liver only, one dog to the liver, lung, and kidney, and one dog to liver and kidney.
Adrenocortical adenomas were diagnosed in 15 of the 41 dogs. In nine of the 15 dogs adrenal tissue for histol- ogy was taken during surgery and three dogs eventually underwent necropsy. Tissue was obtained during nec- ropsy of six dogs that had not undergone surgery. Two surgeries, separated by 18 months, were performed on one dog, with a solitary adrenal adenoma removed at
each procedure. One dog had a right adrenal adenoma at surgery and a left adrenal adenoma identified at a later necropsy. In summary, six dogs had left-sided adreno- cortical adenomas, seven dogs had right-sided adreno- cortical adenomas, and two dogs had bilateral ade- nomas. Histology confirmed atrophy of nontumorous adrenocortical tissue in each dog. No pituitary abnor- malities were identified at necropsy or on subsequent histologic evaluation of tissue from nine of these dogs. Among these nine dogs were the two dogs with bilateral adrenocortical adenomas.
Materials and Methods
Hematologic, urine, and routine biochemical analyses were performed on the day of admission (day 1). Plasma for endogenous ACTH measurement was obtained on day 2, between 8:00 and 8:30 A.M. before any other endocrine testing. Three additional endocrine tests were done: ACTH stimulation, dexamethasone screening, and dexamethasone suppression. Any dog undergoing all three tests was studied on alternate days. The order of testing was randomized. Several dogs underwent only one or two of these tests and some dogs were studied during separate hospitalizations. Dogs in which several endogenous ACTH concentrations were evaluated, had samples obtained on separate hospitalizations. Ultraso- nography and/or radiography were performed on days in which no endocrine tests were done.
The ACTH stimulation test was performed by col- lecting heparinized blood samples before and 1 hour after IM injection of 0.25 mg of cosyntropin .* The “low-dose” or dexamethasone “screening” test con- sisted of collecting heparinized blood samples before and 8 hours after IV injection of 0.01 mg of dexametha- sonet/kg of body weight. The “high-dose” or dexameth- asone “suppression” test was performed by collecting heparinized blood samples before and 8 hours after IV injection of 0.1 mg of dexamethasone/kg of body weight. These tests were begun between 8:00 and 8:30 A.M. During the testing periods, each dog was kept as quiet as possible in its cage or run.
Blood samples for plasma cortisol determination were immediately centrifuged and the plasma was frozen. Plasma cortisol concentrations were assayed by use of a competitive protein-binding radioassay method.3 The assay is sensitive to a plasma cortisol concentration of 0.1 ug/dl. In 26 healthy dogs, the baseline cortisol con- centration was 3.4 + 2.3 ug/dl (mean ± standard devia- tion [SD]), and the post-ACTH cortisol concentration was 11.5 ± 2.6 ug/dl. A post-ACTH cortisol concentra- tion > 20 µg/dl (>3 SD greater than the mean) was
* Cosyntropin (Cortrosyn), Organon Pharmaceuticals, West Or- ange, NJ.
f Azium-SP, Schering Corporation, Kenilworth, NJ.
considered an abnormal response. In a second group of 22 healthy dogs, the mean plasma cortisol concentration 8 hours after administering the low dose of dexametha- sone (0.01 mg/kg intravenously [IV]) was 0.5 ± 0.29 ug/dl. A post-dexamethasone cortisol concentration ≥ 1.4 µg/dl (3 SD greater than the mean) was considered an abnormal response. In a third group of 20 healthy dogs, the mean plasma cortisol concentration 8 hours after IV injection of 0.1 mg of dexamethasone/kg was 0.27 µg/dl ± 0.18. All cortisol concentrations after ad- ministration of this dose of dexamethasone in the third group of control dogs were <50% of the baseline con- centration. Post-dexamethasone cortisol concentrations > 50% of baseline concentration were classified as no suppression, whereas concentrations < 50% of baseline values were regarded as being suppressed. Suppression is consistent with pituitary-dependent hyperadrenocorti- cism.3
Each blood sample for determination of plasma ACTH concentration was handled as previously de- scribed.4 The endogenous plasma ACTH concentrations were determined by radioimmunoassay.5 In 30 healthy dogs, the mean (±SD) baseline plasma ACTH concen- tration was 46 pg/ml ± 17, with a reference range of 20 to 100 pg/ml. A plasma ACTH concentration > 45 pg/ml in a dog with hyperadrenocorticism, as demon- strated by an abnormal screening test result was consid- ered consistent with pituitary dependency. A plasma ACTH concentration < 20 pg/ml in a dog with hyper- adrenocorticism was considered consistent with a func- tioning adrenal tumor.3,4
All other laboratory determinations were performed by the clinical pathology laboratories using standard methods.
Abdominal radiographs, including lateral and ventro- dorsal views, were evaluated for adrenal gland visualiza- tion, size, and calcification. Adrenomegaly was identi- fied by recognizing a discrete soft tissue opacity cranial and medial to the kidneys. Calcification was confirmed only if visualization of overlying structures could be eliminated. In a group of 30 age-matched control dogs and in greater than 100 dogs with pituitary-dependent hyperadrenocorticism, adrenomegaly and/or adrenal calcification was not identified.6 Thoracic radiographs were studied to identify lung metastasis.
Adrenal ultrasonographic examinations were per- formed using a commercially available, real-time me- chanical sector scanner. On animals weighing less than 5 kg, a 7.5 MHZ transducer was used, otherwise a 5.0 MHZ transducer was used. Transverse, longitudinal, and oblique scans were made from the ventral body wall to visualize the right and left perirenal regions, particularly the cranial and medial aspect of the cranial pole of each kidney. Normal-sized adrenal glands in healthy dogs are occasionally visualized and enlarged adrenals (unilateral
or bilateral) have been visualized in dogs with pituitary- dependent hyperadrenocorticism.”¿ However, identify- ing one large adrenal mass has been most consistent with the presence of an adrenal tumor .?
Statistical Analysis
All results are reported as mean + SD unless otherwise indicated. Statistical analysis was done using unpaired Students t-tests.8 P values < 0.05 were considered signif- icant.
Two comparison studies were performed using the information obtained from these 41 dogs with function- ing adrenocortical tumors. First, these dogs were com- pared with 44 dogs known to have pituitary-dependent hyperadrenocorticism.3 Second, the results of all param- eters obtained from the 15 dogs with adrenocortical ade- nomas were compared with those from the 26 dogs with adrenocortical carcinomas.
Results
Signalment, History, Clinical Signs
The age of the dogs with adrenocortical tumors ranged from six to 16 years with a mean age (+SD) of 11.3 ± 2.3 years. The mean age of PDH dogs (10.4 + 3.2 years) was not significantly different (P > 0.05) from that of the adrenal tumor dogs. Thirty-seven of the 41 adrenocorti- cal tumor dogs (92.5%) were ≥9 years of age versus 34 of 44 PDH dogs (77%). The mean age of the adrenal carci- noma group was 11.1 + 2.3 years versus the 11.4 ± 2.1 years of the adenoma groups. Twenty-six of the 41 dogs (63%) with adrenocortical tumors were female versus 25 of 44 dogs (57%) in the PDH group. If groups were established arbitrarily with dogs weighing less than or greater than 20 kg, 19 of the 41 adrenal tumor dogs (46%) were “large” versus 10 of the 44 PDH dogs (23%). Seven of 15 adrenocortical adenoma dogs (46%) and 12 of 21 carcinoma dogs (46%) weighed > 20 kg.
Polydipsia/polyuria (86%), abdominal enlargement (58%), polyphagia (56%), muscle weakness (53%), and hair loss (53%) were commonly reported owner con- cerns. Common abnormal physical examination find- ings were abdominal distention (67%), thin hair coat and/or bilateral symmetrical alopecia (64%), muscle weakness (56%), hepatomegaly (50%), and thin skin (39%). The history and physical examination findings were similar in the adenoma and carcinoma groups. The history and physical examination findings in the dogs with adrenocortical tumors were similar to those with PDH.
Laboratory Findings
Forty of 41 dogs (98%) had abnormal serum alkaline phosphatase (ALP) activity. The mean ALP value (±SD) in the carcinoma group was similar to the mean value in the adenoma group (1407 + 1272 IU/L vs. 1161 ± 1198). The ALT activities (33 of 41 dogs; 80%), serum cholesterol concentrations (30 of 41 dogs; 73%), and fasting plasma glucose concentrations (14 of 41 dogs; 34%) were frequently greater than the reference values. The blood urea nitrogen (BUN) concentration was ab- normally increased in four dogs (3 with carcinomas) and less than the reference range in 14 dogs (34%). These abnormalities were frequently identified in both the ad- renocortical adenoma dogs and the carcinoma dogs, as well as in the dogs with PDH.
The complete blood counts in the dogs with adreno- cortical tumors often revealed absolute lymphopenia (20 of 41; 49%) and eosinopenia (22 of 41; 54%). These values were similar comparing PDH and adrenocortical tumor dogs as well as in comparing results from the two tumor-type groups. Urine specific gravity was less than 1.015 in 27 of the 41 dogs and the mean was 1.0128. The carcinoma group’s mean urine specific gravity was not significantly different (P > 0.05) from the adenoma group’s mean urine specific gravity (1.0114 vs. 1.0154).
Endocrine Screening Tests
The ACTH stimulation test was performed in all 41 adrenocortical tumor dogs. The basal (5.6 ug/dl ± 2.2) and poststimulation (27.9 ug/dl ± 19.5) plasma cortisol concentrations were not significantly different (P > 0.05) when compared with those obtained from dogs with PDH (4.7 ug/dl ± 1.8 and 25.5 ug/dl ± 6.9, respec- tively). Twenty-six of 41 test results (63%) were consid- ered diagnostic of hyperadrenocorticism in the adrenal tumor group versus 23 of 26 test results (88%) in the PDH group. The basal cortisol concentrations were not different (P> 0.05) in comparing the results from adre- nal adenoma dogs (5.0 µg/dl ± 2.2) with those from the carcinoma group (5.7 ug/dl + 2.1) but a significant dif- ference (P < 0.05) was observed in poststimulation values: 36.6 ug/dl + 21.6 in the carcinoma group and 20.2 ug/dl ± 12.0 in the adenoma group (Tables 1 and 2). Additionally, the carcinoma group had a higher inci- dence of diagnostic (plasma cortisol concentration > 20 ug/dl) test results than the adenoma dogs (77% vs. 47%).
The “low-dose” or “screening” dexamethasone test was performed in 28 of the adrenocortical tumor dogs. The basal (5.1 µg/dl + 2.2) and post-dexamethasone (4.6 ug/dl ± 2.0) plasma cortisol concentrations were not significantly different (P > 0.05) when compared with values from dogs with PDH (4.7 ug/dl ± 1.9 and 4.2 ug/dl ± 2.1, respectively). All 28 test results were consid- ered diagnostic of hyperadrenocorticism in the adrenal
tumor group versus 25 of 26 in the PDH group (96%). The basal and post-dexamethasone plasma cortisol values (Tables 1 and 2) were not statistically different (P > 0.05) in the carcinoma dogs (5.2 µg/dl + 1.9 basal, 4.6 ug/dl ± 1.7 post) versus the adenoma dogs (4.8 ug/dl ± 2.5 basal, 4.4 ug/dl ± 2.6 post).
Endocrine Discrimination Tests
Thirty of the 41 adrenocortical tumor dogs were evalu- ated with the “high-dose” dexamethasone “suppres- sion” test (Tables 1 and 2). Using either an absolute cortisol concentration of <1.4 ug/dl or >50% suppres- sion from basal concentrations as definition of suppres- sion, none of the plasma cortisol concentrations from adrenal tumor dogs suppressed. The mean basal and post-dexamethasone cortisol concentrations were 4.6 ug/dl ± 1.6 and 4.4 µg/dl + 1.7, respectively. There was no statistical difference (P > 0.05) comparing the basal and post-dexamethasone plasma cortisol concentrations from the carcinoma dogs (5.0 ug/dl ± 1.4 and 4.6 ug/dl ± 1.5) with those of the adenoma dogs (4.0 µg/dl + 1.8 and 3.9 ug/dl ± 1.9). In contrast, post-dexamethasone suppression in plasma cortisol concentration was dem- onstrated in 18 of 30 PDH dogs (60%) using an absolute cortisol value as a criterion of suppression, and 23 of those 30 dogs (77%) suppressed using >50% as the crite- rion.
A total of 62 endogenous ACTH concentrations were evaluated from the 41 dogs with adrenocortical tumors. In 36 of these samples the ACTH concentration was undetectable (<20 pg/ml), 21 were considered nondiag- nostic (>20, <40 pg/ml), and five were ≥40 pg/ml (40, 42, 43, 44, 44 pg/ml, respectively). Twenty-nine dogs (71%) had at least one undetectable plasma endogenous ACTH concentration and these dogs were suspected as having an adrenocortical tumor. In 14 of those 29 dogs, multiple (2 or 3) samples were obtained. Six dogs had two or three plasma samples with no detectable ACTH, four dogs had one undetectable level and one detectable result, and four dogs had one undetectable level and two detectable results. Nine dogs had one ACTH determina- tion and three dogs had two endogenous ACTH deter- minations of 20 to 45 pg/ml, with no undetectable test results. Twenty-two of 39 ACTH concentrations (56%) in dogs with carcinomas were undetectable versus 14 of 23 ACTH concentrations (61%) from the adenoma group (Tables 1 and 2). Fifty plasma ACTH concentra- tions from 45 dogs with confirmed PDH had a mean of 132 ± 68 pg/ml, and a range of 29 to 340 pg/ml. Three samples (6%) were <40 pg/ml (29, 38 and 39 pg/ml) and three samples were ≥40 pg/ml but <45 pg/ml (40, 42, 43 pg/ml).
Abdominal radiographs were performed in 22 of the 26 dogs with adrenocortical carcinomas, including the dog with bilateral carcinomas. Thirteen tumors were
| Dog | ACTH Stimulation (cortisol µg/dl) | Low-Dose Dexamethasone (cortisol µg/dl) | High-Dose Dexamethasone (cortisol ug/dl) | Endogenous ACTH (pg/ml) | |||
|---|---|---|---|---|---|---|---|
| Pre | Post | Pre | Post | Pre | Post | Basal | |
| 1 | 5.3 | 23.1 | 4.0 | 3.8 | 5.7 | 4.9 | + |
| 2 | 4.3 | 8.5 | 3.1 | 2.4 | 1.3 | 2.1 | + |
| 3 | 10.3 | 35.3 | ND | ND | ND | ND | + |
| 4 | 3.1 | 21.0 | 4.9 | 5.9 | 3.2 | 3.0 | t. + |
| 5 | 5.7 | 13.4 | ND | ND | ND | ND | 42 |
| 6 | 6.7 | 23.2 | 3.9 | 3.3 | 2.9 | 2.4 | 1, 1, 25 |
| 7 | 4.3 | 10.5 | 2.4 | 2.6 | 3.4 | 2.2 | + |
| 8 | 3.2 | 13.2 | 1.8 | 1.6 | 2.2 | 3.6 | 25 |
| 9 | 5.2 | 10.9 | ND | ND | 5.1 | 5.2 | 37 |
| 10 | 5.6 | 27.9 | 5.0 | 4.8 | 4.6 | 4.1 | + |
| 11 | 5.3 | 53.0 | 9.8 | 9.6 | 6.8 | 8.4 | 1, 24, 33 |
| 12 | 4.8 | 25.3 | 8.7 | 7.4 | 4.8 | 4.1 | 39, 44 |
| 13 | 7.4 | 14.2 | 5.8 | 6.0 | 5.7 | 5.8 | 22 |
| 14 | 1.0 | 14.5 | ND | ND | ND | ND | + |
| 15 | 3.0 | 9.2 | 3.0 | 1.6 | 1.7 | 1.5 | t. t. + |
| # Samples | 15 | 15 | 11 | 11 | 12 | 12 | 23 |
| Mean | 5.0 | 20.2 | 4.8 | 4.4 | 4.0 | 3.9 | |
| ±1 SD | 2.2 | 12.0 | 2.5 | 2.6 | 1.8 | 1.9 | |
| # Dogs tested | 26 | 26 | 22 | 22 | 20 | 20 | 30 |
| Reference mean | 3.4 | 11.5 | 3.4 | 0.5 | 3.4 | 0.3 | 46 |
| ±1 SD | 2.3 | 2.6 | 2.3 | 0.3 | 2.3 | 0.2 | 17 |
ND: not done.
* Blood samples were obtained before and 1 hour after IM administration of synthetic ACTH, and before and 8 hours after IV administration of 0.01 mg/kg and 0.1 mg/kg dexamethasone (low and high dose, respectively).
t <20 pg/ml.
identified. One was visualized as a large soft tissue mass and 12 adrenocortical carcinomas were identified due to calcification within each mass, visualized as radio- opaque areas. Ten of the 11 left adrenal carcinomas were seen radiographically and nine were calcified. Only three of the 13 right-sided carcinomas were calcified and detected radiographically. The dog with bilateral carci- nomas had calcification of the right adrenal tumor, the left adrenal carcinoma was not visible. One noncalcified carcinoma was found during an IV urogram. Abdomi- nal radiographs were obtained on 13 dogs with a total of 15 adrenocortical adenomas. Two dogs had bilateral ad- renal adenomas. Radiographs revealed a solitary calci- fied mass in seven dogs (4 left-sided and 3 right-sided) of the 13 dogs (54%). In the initial evaluation of the two dogs with bilateral adrenal adenomas, radiographs re- vealed one left-sided calcified mass in each. In sum- mary, radiology identified adrenocortical tumors in 20 of the 35 dogs studied (57%).
Evidence of an adrenal mass was detected on abdomi- nal ultrasonography in 18 of 25 dogs with adrenocortical tumors (72%); 13 of 17 dogs with adrenocortical carci- nomas (76%) and five of eight dogs with adenomas (62%). In the one dog with bilateral carcinomas, both adrenals were visualized, in contrast to the two dogs with bilateral adenomas, in each of which a solitary mass was visualized and thought to be enlarged. Ultraso- nography was performed in five of the dogs with abdom-
inal metastasis. In three dogs, the liver was nonhomo- geneous with one or multiple masses identified. These masses were histologically confirmed to be metastatic from an adrenal carcinoma. One of these dogs was also suspected to have a splenic mass, however, pathology revealed metastasis in the left kidney. Ultrasound iden- tified a mass in the caudal vena cava in one dog but the liver metastasis discovered at necropsy was not detected. All seven dogs with abdominal metastasis were radio- graphed. Two of those dogs were suspected to have liver masses.
Thoracic radiographs of 17 dogs with adrenocortical carcinomas were reviewed. In four of the six dogs with lung metastasis, soft tissue nodules consistent with met- astatic neoplasia were seen in the lungs.
Discussion
No characteristics in age, sex, or breed distinguished dogs with adrenocortical adenomas from dogs with car- cinomas, nor were they different from those reported in dogs with pituitary-dependent hyperadrenocorticism.9,10 According to previous reports,3,11-13 adrenocortical tumors causing hyperadrenocorticism were recognized in dogs six to 16 years of age, as was observed in the 41 dogs reported herein. Breed and/or body weight are nei- ther definitive nor specific when distinguishing between dogs with PDH and those with adrenocortical tumors.
| Dog | ACTH Stimulation (cortisol µg/dl) | Low-Dose Dexamethasone (cortisol ug/dl) | High-Dose Dexamethasone (cortisol ug/dl) | Endogenous ACTH (pg/ml) | |||
|---|---|---|---|---|---|---|---|
| Pre | Post | Pre | Post | Pre | Post | Basal | |
| 1 | 3.4 | 59.4 | 5.4 | 6.6 | 6.6 | 4.5 | 7,43 |
| 2 | 2.8 | 14.2 | 2.8 | 2.8 | 3.7 | 4.8 | 1. 44 |
| 3 | 7.2 | 63.7 | ND | ND | ND | ND | + |
| 4 | 9.4 | 38.0 | ND | ND | ND | ND | + |
| 5 | 5.9 | 32.1 | ND | ND | ND | ND | 36 |
| 6 | 4.5 | 4.3 | 4.0 | 4.4 | 4.1 | 2.7 | 31 |
| 7 | 5.1 | 8.9 | 4.3 | 4.1 | 4.8 | 4.0 | 30 |
| 8 | 5.2 | 12.4 | 7.1 | 5.7 | 6.4 | 6.3 | 33, 28 |
| 9 | 5.1 | 53.0 | 5.5 | 5.3 | 5.4 | 6.1 | 1. 30, 40 |
| 10 | 3.0 | 31.0 | 3.8 | 4.1 | 4.3 | 5.1 | t. t |
| 11 | 3.6 | 20.0 | ND | ND | 3.1 | 3.3 | + |
| 12 | 3.1 | 11.3 | 2.8 | 1.8 | 2.6 | 1.5 | 1, 28 |
| 13 | 4.4 | 31.2 | 2.7 | 1.6 | 2.7 | 2.4 | 1, 20 |
| 14 | 7.5 | 37.6 | 5.1 | 3.1 | 5.1 | 5.8 | t.t |
| 15 | 5.8 | 26.4 | 6.4 | 5.9 | ND | ND | + |
| 16 | 4.4 | 22.7 | ND | ND | ND | ND | + |
| 17 | 5.0 | 18.5 | 4.3 | 4.4 | 5.5 | 4.4 | t. + |
| 18 | 6.0 | 21.9 | ND | ND | 5.3 | 4.8 | + |
| 19 | 5.7 | 48.0 | 4.7 | 4.3 | 5.5 | 6.3 | 20,21 |
| 20 | 5.5 | 36.6 | ND | ND | ND | ND | + |
| 21 | 12.2 | 106.0 | ND | ND | ND | ND | 26 |
| 22 | 4.8 | 23.5 | ND | ND | ND | ND | + |
| 23 | 6.0 | 37.0 | 7.5 | 5.6 | 6.2 | 4.1 | 1, 28, 43 |
| 24 | 9.0 | 50.5 | 9.9 | 7.0 | 7.5 | 5.7 | + |
| 25 | 5.2 | 20.6 | 7.2 | 7.4 | 6.7 | 7.4 | 30 |
| 26 | 7.5 | 20.2 | 4.6 | 4.4 | 4.6 | 4.0 | 1, 32 |
| # Samples | 25 | 25 | 16 | 16 | 18 | 18 | 39 |
| Mean | 5.7 | 36.6 | 5.2 | 4.6 | 5.0 | 4.6 | - |
| ±1 SD | 2.1 | 21.6 | 1.9 | 1.7 | 1.4 | 1.5 | |
| # Dogs tested | 26 | 26 | 22 | 22 | 20 | 20 | 30 |
| Reference mean | 3.4 | 11.5 | 3.4 | 0.5 | 3.4 | 0.3 | 46 |
| ±1 SD | 2.3 | 2.6 | 2.3 | 0.3 | 2.3 | 0.2 | 17 |
ND: not done.
* Blood samples were obtained before and 1 hour after IM administration of synthetic ACTH, and before and 8 hours after IV administration of 0.01 mg/kg and 0.1 mg/kg dexamethasone (low and high dose, respectively).
៛ <20 pg/ml.
Problems identified by owners and clinical findings described by veterinarians included abnormalities that were typical of hyperadrenocorticism, but not specific for either pituitary or adrenal dependency.9,10,12.14 No difference in history or clinical findings were revealed when comparing the dogs with adrenocortical carci- nomas to those with adenomas. Although it has been suggested that many dogs with adrenocortical carci- nomas have too rapid an onset and progression of their disease to develop prominent dermatologic signs,9 most of the dogs (78%) in this series had at least one typical skin and/or hair coat alteration. Based on the results of the present study there are no clinical features that readily distinguish dogs with adrenocortical carcinomas from dogs with adenomas, nor are there clinical features that allow separation of dogs with pituitary-dependent adrenocortical hyperplasia from dogs with adrenocorti- cal tumors.
Routine urinalysis, hemogram, and serum chemistry profiles revealed alterations that were only helpful in
supporting the nonspecific clinical suspicion of hyper- adrenocorticism.15,16 These alterations were not of ben- efit in distinguishing between adrenocortical adenomas and carcinomas nor in separating dogs with adrenocorti- cal tumors from dogs with pituitary-dependent hyper- adrenocorticism.
Both ACTH stimulation and “low-dose” dexametha- sone screening tests are accepted as reliable in identify- ing dogs with hyperadrenocorticism.9,17 Neither test has been found to be helpful in differentiating dogs with adrenocortical tumors from those with pituitary-depen- dent hyperadrenocorticism.3 In the present study, com- parison was made in the diagnostic accuracy of ACTH stimulation versus dexamethasone screening test results. Twenty-eight dogs were studied with both tests. All dogs with adrenocortical tumors had at least one abnormal test result since the low-dose dexamethasone test results were abnormal in each of the 28 dogs. Eighteen of the 28 dogs had abnormal ACTH stimulation test results. Al- though the post-ACTH stimulation mean plasma corti-
sol concentration was significantly higher in the carci- noma group (36.6 ug/dl ± 21.6) than in the adenoma group (20.2 µg/dl + 12.0), abnormal test results on an individual dog remains a nonspecific finding. Approxi- mately two thirds of the dogs (63%) in this study had ACTH stimulation test results that were consistent with a diagnosis of hyperadrenocorticism.11,17 According to previous reports, dexamethasone screening test results were diagnostic more often than ACTH stimulation test results.17,18 Since 100% of the dogs with hyperadreno- corticism due to adrenocortical tumors in this study had abnormal low-dose dexamethasone test results, this pro- cedure remains the more sensitive screening test.
The high-dose dexamethasone suppression test may be used as an aid in distinguishing pituitary-dependent from adrenal tumor hyperadrenocorticism.3,9 All the dogs with adrenocortical tumors failed to exhibit sup- pression of plasma cortisol concentration after the ad- ministration of a “high dose” of dexamethasone. Al- though results from the dogs in this series indicate uni- form nonsuppressibility, it is known that approximately 20% to 30% of the dogs with PDH are also resistant to dexamethasone suppression.19 All test results in which the plasma cortisol concentration fails to suppress, therefore, must be regarded as inconclusive and further testing is recommended.
In a previous study, the majority of dogs with adreno- cortical tumors had endogenous plasma ACTH concen- trations less than detectable limits of the assay, whereas the remaining dogs had results in the low normal range.3 The present study revealed undetectable endogenous ACTH concentrations in 29 of 41 dogs, but 14 of those 29 dogs had multiple samples evaluated. The endoge- nous ACTH concentration, when undetectable, is con- sistent with the presence of an autonomously function- ing adrenocortical tumor or iatrogenic hyperadrenocor- ticism. Therefore, this test alone does not confirm a diagnosis of an adrenocortical tumor and since 26 of 62 results were >20 and <45 pg/ml, there was a 42% inci- dence of nondiagnostic test results. In 12 dogs with non- diagnostic ACTH concentrations, further discriminat- ing tests needed to be performed. In eight dogs radiology revealed an adrenal tumor and in four of these dogs tumors were visualized with ultrasonography. It is in this context that the various “discrimination” tests complement each other as diagnostic aids.
Ultrasound evaluation of the abdomen aided in the identification of more adrenocortical tumors than radi- ology (72% vs. 57%). With either procedure, carcinomas were identified with greater frequency than adenomas, in contrast to the results of a previous study.6 The ad- vantages of radiography are that it is widely available and identification of calcified adrenal masses can be straightforward. Evaluation of the abdomen with ultra- sonography might result in detection of more noncalci- fied tumors and right-sided adrenal tumors. Addition-
ally, ultrasonography appears superior to radiology in detecting abdominal metastasis. On the other hand, ul- trasound evaluation may occasionally result in visual- ization of adrenals in normal dogs as well as dogs with adrenal enlargement secondary to other causes, includ- ing pituitary-dependent hyperplasia.7 Therefore, adre- nal enlargement detected with ultrasonography is not specific for the presence of an adrenocortical tumor.
Right- and left-sided adrenal tumors were found at surgery and/or necropsy in nearly equal frequency. Bi- lateral adrenocortical tumors have been previously re- ported,9 but the incidence in this study (3 of 41 dogs; 7%) is surprising. Only one dog had bilateral masses identified on initial evaluation and this 16-year-old dog (with carcinomas) rapidly deteriorated, died, and was necropsied within three months of diagnosis. The two dogs with bilateral adenomas had a solitary mass surgi- cally removed and the second adenoma (on the contra- lateral side in each) was identified more than 12 months and 18 months later, respectively. Necropsy results did not reveal pituitary or hypothalamic abnormalities in any of these dogs. The two dogs initially believed to have adrenocortical adenomas and subsequently shown to have had carcinomas illustrate the difficulty occasion- ally encountered in assigning a histopathologic diagnosis to some endocrine gland tumors. 13.20
In looking for the most reasonable and reliable diag- nostic aids in confirming presence of an adrenocortical tumor or in distinguishing between adrenocortical ade- nomas and carcinomas, no test is totally reliable. The low-dose dexamethasone test appears to be the most consistent screening test. However, considering the ad- vantages (short duration of time, recognition of iatro- genic Cushing’s, use during treatment) the ACTH stim- ulation test still has value. The practitioner should be aware, however, of the incidence of false negative results with ACTH stimulation. As plasma ACTH concentra- tions become more available, they remain good, but not foolproof. Radiographically visible adrenal calcification in a dog with hyperadrenocorticism is highly suggestive of adrenocortical neoplasia, but only 50% to 60% of these tumors calcify.6 Discrimination between hyperad- renocorticism resulting from pituitary dependency and that caused by adrenocortical tumors typically demands review of several studies. Histologic evaluation is the only means of separating carcinomas from adenomas unless metastatic lesions are obvious on radiographs or ultrasonography.
References
1. Owens, JM, Drucker WD. Hyperadrenocorticism in the dog: Ca- nine Cushing’s syndrome. Vet Clin North Am (Small Animal Practice) 1977; 7:583-602.
2. Meijer JC. Canine Hyperadrenocorticism. In: Kirk RW, ed. Cur- rent Veterinary Therapy. Philadelphia: WB Saunders, 1980; 975-979.
3. Feldman EC. Distinguishing dogs with functioning adrenocortical tumors from dogs with pituitary-dependent hyperadrenocorti- cism. J Am Vet Med Assoc 1983; 183:195-200.
4. Feldman EC, Bohannon NV, Tyrrell JB. Plasma adrenocortico- tropin levels in normal dogs. Am J Vet Res 1977; 38:1643- 1645.
5. Nelson RW, Feldman EC, Shinsako J. Effect of o,p’DDD therapy on endogenous ACTH concentrations in dogs with hypophy- sis-dependent hyperadrenocorticism. Am J Vet Res 1985; 46:1534-1537.
6. Penninck DG, Feldman EC, Nyland TG. Radiological features of canine hyperadrenocorticism caused by autonomously func- tioning adrenocortical tumors: 23 cases (1978-1986). J Am Vet Med Assoc 1988; 192:1604-1608.
7. Kantrowitz BM, Nyland TG, Feldman EC. Adrenal ultrasonogra- phy in the dog. Detection of tumors and hyperplasia in hyper- adrenocorticism. Vet Radiol 1986; 27:91-96.
8. Snedecor GW, Cochran WG. Statistical Methods. 7th ed. Ames, IA: Iowa State University Press, 1980; 39-102.
9. Peterson ME. Hyperadrenocorticism. Vet Clin North Am (Small Animal Practice). 1984; 14:731-749.
10. Ling GV, Stabenfeldt GH, Comer KM, et al. Canine hyperadre- nocorticism: Pretreatment clinical and laboratory evaluation of 117 cases. J Am Vet Med Assoc 1979; 174:1211-1215.
11. Peterson ME, Gilbertson SR, Drucker WD. Plasma cortisol re- sponses to exogenous ACTH in 22 dogs with hyperadrenocor- ticism caused by adrenocortical neoplasia. J Am Vet Med Assoc 1982; 180:542-544.
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 1986; 189:1360-1364.
13. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction. Philadelphia: WB Saunders, 1987; 137-194.
14. Scott DW. Hyperadrenocorticism (Hyperadrenocorticoidism, Hyperadrenocorticalism, Cushing’s Disease, Cushing’s Syn- drome). Vet Clin North Am (Small Animal Practice) 1979; 9:3-28.
15. Hoffmann WE. Diagnostic value of canine serum alkaline phos- phatase and alkaline phosphatase isoenzymes. Journal of the American Animal Hospital Association 1977; 13:237-241.
16. Rogers WA, Ruebner BH. A retrospective study of probable glu- cocorticoid-induced hepatopathy in dogs. J Am Vet Med Assoc 1977; 170:603-606.
17. Feldman EC. Comparison of ACTH response and dexamethasone suppression as screening test in canine hyperadrenocorticism. J Am Vet Med Assoc 1983; 182:506-510.
18. Feldman EC. Evaluation of a combined dexamethasone suppres- sion/ACTH stimulation test in dogs with hyperadrenocorti- cism. J Am Vet Med Assoc 1985; 187:49-53.
19. Kemppainen RJ, Zenoble RD. Non-dexamethasone-suppressible, pituitary-dependent hyperadrenocorticism in a dog. J Am Vet Med Assoc 1985; 187:276-278.
20. Kruth SA, Feldman EC, Kennedy PC. Insulin secreting islet all tumors: Establishing a diagnosis and the clinical course of 25 days. J Am Vet Med Assoc 1982; 181:54-58.
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