Favorable outcome of pheochromocytoma in a dog with atypical Cushing’s syndrome and diabetes mellitus following medical treatment: a case report

Background Pheochromocytoma (PCC) has poor prognosis and adrenalectomy is hard to be performed, in case of caudal vena cava invasion. The long-term administration of phenoxybenzamine in PCC has not been reported in dogs. Case presentation A 14-year-old castrated male Poodle dog presented with an abdominal mass. On physical examination, hypertension, increased lens opacity, calcinosis cutis, generalized alopecia, and systolic murmur were observed. Serum chemistry and urinalysis profiles revealed hyperglycemia, hypercholesterolemia, elevated liver enzymes, and glucosuria. Abdominal ultrasonography showed a right adrenal mass with invasion of the caudal vena cava, which was cytologically diagnosed as suspected PCC. An adrenal mass (width × height × length, 28 × 26 × 48 mm3) was found on computed tomography and diagnosed as PCC with increased plasma metanephrines and normetanephrines. An adrenocorticotropin hormone stimulation test showed elevated adrenal hormones (androstenedione, estradiol, progesterone, and 17-OH progesterone) with normal cortisol, compatible with atypical Cushing’s syndrome. The dog was managed with trilostane, phenoxybenzamine, and insulin therapy. Glycosylated hemoglobin and fructosamine levels gradually decreased, and hypertension resolved. In the 10-month follow-up period, the liver enzymes levels gradually decreased, and the clinical signs of the dog were well-controlled without deterioration. Conclusions This case report describes long-term medical management without adrenalectomy of PCC complicated with atypical Cushing’s syndrome and DM.


Background
Adrenal tumors are common in dogs, functionally active, and may secrete an excessive amount of one or more type of hormones, causing tumor-related syndromes [1]. Among them, pheochromocytoma (PCC) is a rare tumor, which is derived from chromaffin cells in the adrenal medulla [2][3][4][5][6]. PCC typically affects middle-agedto-old dogs with over 50% of cases involving local invasion to the caudal vena cava (CVC) and surrounding soft tissues [2,3,7]. Metastases to the local lymph nodes, lungs, and liver have been reported in dogs [4,5]. The clinical signs of PCC are typically nonspecific but can be acute and life threatening [2,3,5], including lethargy, tachyarrhythmias, hypertension, polyuria/polydipsia (PU/ PD), and collapse [4,7]. Excessive secretion of catecholamines from tumor tissues manifests these clinical features [2,8]. The definitive diagnosis of PCC relies on histopathology of the adrenal mass [3,7], but plasma free metanephrine (fMN) and normetanephrine (fNMN) concentrations can be useful to identify PCC in both humans [7] and dogs [3,9]. Moreover, cytology of the primary adrenal tumor is helpful in distinguishing the cortical tumors from the medullary ones [1]. In general, PCC is more aggressive in dogs than in humans [2]. This is a case report that describes the clinical manifestations and favorable outcome following intensive medical treatment of PCC in a dog complicated with atypical Cushing's syndrome and diabetes mellitus (DM).

Case presentation
A 14-year-old castrated male Poodle dog was referred for evaluation of an abdominal mass. The dog had a history of PU/PD and hypertension and was diagnosed with DM 6 months before. Irbesartan, an anti-hypertensive agent, and intermediate acting insulin for controlling DM were administered before the visit.
Physical examination revealed hypertension (systolic/ diastolic blood pressure [BP], 155/108), increased lens opacity, calcinosis cutis, generalized alopecia, and systolic murmur (grade 3). Hematologic and serum biochemical profiles showed hyperglycemia, elevated liver enzymes, and hypercholesterolemia (Table 1). DM was poorly controlled, with a glycosylated hemoglobin (HbA1c) of 8.4% (68 mmol/mol; reference interval, 0.6-2.7%) [10]. Urinalysis showed glucosuria (4+, 1000 mg/ dL). Radiograph showed cardiomegaly (vertebral heart score, 11.5v), a mild bronchointerstitial pattern on the overall lung field, and hepatomegaly. Abdominal ultrasonography showed a right adrenal mass with invasion of CVC and increased hepatic parenchymal echogenicity with gall bladder sludge. Differential diagnosis for the adrenal mass included adrenal-dependent hyperadrenocorticism, hyperaldosteronism, and PCC. Fine-needle aspiration biopsy of the adrenal mass showed predominant naked nuclei, suspected as neuroendocrine cells, and polygonal cells containing a moderate amount of slightly basophilic and finely granular cytoplasm, which originated from the adrenal medulla (Fig. 1). There were a few clusters of adrenal cortical cells with cytoplasmic vacuolation.
On day 19, the liver enzyme levels abruptly increased, and trilostane dosage was increased to twice that of the initial dosage. Moreover, irbesartan was switched to hydralazine (0.5 mg/kg orally q12h; Samjin, Korea), considering the risk of hyperkalemia. On day 25, systolic BP was 163 mmHg, and glucose maximum and nadir were 328 mg/dL and 242 mg/dL, respectively. Therefore, the hydralazine dosage was increased to 1 mg/kg, orally, q12h, and isophane insulin was switched to caninsulin (1 unit twice a day; MSD, Korea). Until day 90, the caninsulin dosage was 1.8 units, but the glycemic curve was not well-controlled, and the fructosamine level was over 343 μmol/L, indicating poor response to the medical treatment. Therefore, phenoxybenzamine (PBZ; 0.25 mg/ kg orally q12h; Aristo, German) was added to control hypertension and improve glucose intolerance. One week later, systolic BP decreased to 131 mmHg, and glucose maximum and nadir also decreased to 265 mg/dL and 169 mg/dL, respectively. One month after the start of PBZ, fructosamine decreased to 314 μmol/L, and HbA1c decreased to 6.6% (49 mmol/mol), showing a favorable outcome ( Table 1, day 125). The treatment was continued for 10 months, and the liver enzyme levels gradually decreased, with well-controlled DM and hypertension. Moreover, the owner perceived increased activity of the dog, and the general condition of the dog improved with no other side effects.

Discussion and conclusions
DM is a common complication of PCC in humans, resulting from impaired glucose tolerance due to catecholamine excess [11]. Glucose intolerance or DM can occur in 35-50% of patients with PCC, as increased catecholamine levels induce downregulation of insulin secretion and upregulation of insulin resistance [12]. Moreover, glucose uptake decreases, and gluconeogenesis and glycogenolysis increase as sequelae of excessive catecholamine levels [11,12]. Hyperglycemia changes to normoglycemia after resection of PCC in 79% of patients with PCC and DM [11]. In humans, prevalence of DM concurrent with PCC correlates to large and symptomatic tumors [11], but until recently, there was no information about the risk factors of DM in dogs with PCC.
PBZ is an α-adrenergic antagonist, which irreversibly and noncompetitively binds to both α-1 and α-2 adrenergic receptors, thereby blocking the α-adrenergic effect to the circulating epinephrine and norepinephrine [5,7]. In humans with PCC, most patients receive PBZ for days to weeks before adrenalectomy to control BP in the perioperative period [13], which also decreases perioperative mortality in dogs with PCC [7]. In cases of nonresectable PCC, medical treatment with PBZ is indicated to manage hypertension [5,14]. The adverse effects of PBZ include nasal stuffiness and postural hypotension in humans [13], and hypotension, miosis, and tachycardia in dogs [15]. Although the accurate dose, frequency, and duration of PBZ administration to adequately achieve  D days after first examination, fMN free metanephrine, fNMN free normetanephrine the desired effects have not been defined for dogs [7], the dog in this case showed a favorable outcome in 10 months after start of low-dose PBZ.
Hypertension is a serious sign of PCC and the principal cause of death from a tumor in humans [13]. In this case, the possible causes of hypertension included DM, atypical Cushing's syndrome, and PCC. To manage the dog's hypertension, trilostane and hydralazine were administrated. However, there was no response to the treatment; therefore, PBZ was administered additionally. In humans, blocking the α-adrenergic receptors can not only control hypertension but also improve glucose intolerance and insulin release [12,14]. In this case, after PBZ administration, the dog's glycemic curve was well-controlled, and HbA1c had remarkably improved. Moreover, hypertension was resolved. Considering the history of poorly controlled DM and a clinically favorable response to PBZ, PCC could have led to glucose intolerance, which progressed to DM. Similarly, if glycemic control is difficult in dogs with DM, other possible causes, including insulin resistance, should be considered, such as PCC, hyperadrenocorticism, and obesity [16].
In this case, the definitive diagnosis of PCC could not be made without histologic examination of the dog's adrenal gland. However, the increased plasma fMN and fNMN levels, normal-sized left adrenal gland, clinical presentation, and cytologic findings led to the presumptive diagnosis of PCC. Moreover, a complete adrenal panel was helpful in diagnosing atypical Cushing's syndrome. Increased adrenal sex hormone concentrations have been reported in dogs with non-cortisol-secreting adrenocortical tumors [17]; thus, non-cortisol-secreting adrenocortical tumor could be concurrent with PCC, inducing atypical Cushing's syndrome in this case. However, ectopic ACTH secretion from PCC could have occurred, triggering atypical Cushing's syndrome by upregulation of ACTH secretion. Although the etiopathogenesis of atypical Cushing's syndrome is unknown, this report describes a rare case of combined PCC and atypical Cushing's syndrome in a dog.
PCC has poor prognosis in both humans and dogs [2,14], and the definitive treatment of PCC requires adrenalectomy [4]. However, in this case, adrenalectomy could not be performed because of CVC invasion, and the dog had poor prognostic factors, such as a large-sized tumor and suspected pulmonary metastasis [7]. However, in the 10-month follow-up period, the clinical signs gradually improved, and there were no side effects from the administered drugs, thereby increasing the quality of life.
In conclusion, plasma fMN and fNMN levels could aid in the diagnosis of PCC, allowing appropriate and rapid targeted therapy in cases of an adrenal mass by differentiating between an adrenal cortex tumor and PCC. Although the dog had severe multiple endocrine diseases including PCC, atypical Cushing's disease and DM, the diseases were managed successfully with medical therapy and without surgery. In particular, PBZ lead to clinical improvement in hypertension and glycemic control in the dog. This is a case report that describes the clinical manifestations and favorable outcome following intensive medical treatment of PCC in a dog with atypical Cushing's syndrome and DM.