Skip to main content

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

Abstract

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-aged-to-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.

Table 1 Complete blood count and serum biochemical results of a dog with pheochromocytoma, atypical Cushing’s syndrome, and diabetes mellitus
Fig. 1
figure1

Cytology from the fine-needle aspiration biopsy of a right adrenal mass diagnosed as pheochromocytoma in a dog. Neuroendocrine cells, with naked nuclei, anisokaryosis, prominent nucleoli, and coarse chromatin are seen (a). Polygonal cells containing moderate amounts of slightly basophilic granular cytoplasm are predominant (b). Diff-Quick stain; Bar = 25 μm (a & b)

Cytologic evaluation of the mass suggested that it could be originated from the adrenal medulla. Computed tomography (CT) was performed to confirm the origin of the mass, evaluate local or distant metastasis, and prepare the therapeutic plan. CT revealed an enlarged, mineralized right adrenal mass (width × height × length, 28 × 26 × 48 mm3) with CVC invasion and a nodule in the right lung lobe, indicating suspected distant metastasis from the malignant adrenal tumor (Fig. 2). An adrenocorticotropin hormone (ACTH; Synacthen; Dalim Bio Tech, Korea) stimulation test was performed to identify the presence of adrenal-dependent hyperadrenocorticism (University of Tennessee, Knoxville, TN, USA). The adrenal hormone panel showed elevated adrenal hormones (androstenedione [pre-stimulation, 4.53 ng/mL; reference interval, 0.05–0.36 ng/mL; post-stimulation, 6.18 ng/mL; reference interval, 0.24–2.90 ng/mL], estradiol [pre-stimulation, 87.7 pg/mL; reference interval, 23.1–65.1 pg/mL; post-stimulation, 72.4 pg/mL; reference interval, 23.3–69.4 pg/mL], progesterone [pre-stimulation, < 0.20 ng/mL; reference interval, < 0.20 ng/mL; post-stimulation, 2.44 ng/mL; reference interval, 0.22–1.45 ng/mL], and 17-OH progesterone [pre-stimulation, 1.40 ng/mL; reference interval, 0.08–0.22 ng/mL; post-stimulation, 11.14 ng/mL; reference interval, 0.25–2.63 ng/mL]) with normal cortisol (pre-stimulation, 3.4 μg/dL; reference interval, < 1.0–5.6 μg/dL; post-stimulation, 9.1 μg/dL; reference interval, 7.1–15.1 μg/dL) in both pre- and post- ACTH stimulation tests (Table 2). Table 3 shows the results of plasma fMN and fNMN, which were measured to investigate adrenal medullary involvement. The findings were consistent with PCC in dogs (fMN, > 4.18 nmol/L; fNMN, > 5.52 nmol/L) [3]. Based on the laboratory and clinical examinations, DM concurrent with PCC and atypical Cushing’s syndrome were suspected. Additionally, an echocardiograph revealed mitral valve degeneration and regurgitation, indicating myxomatous mitral valve degeneration (MMVD).

Fig. 2
figure2

Computed tomography (CT) showing dorsal (a), sagittal (b), and transverse (d) images and a dorsal view of the 3D volume reconstructed renderings created from the CT images (c) of a dog diagnosed with pheochromocytoma. Heterogenous attenuation and multiple mineralization of the mass (arrow heads) are observed (a & b). The size of the right adrenal mass (arrow heads) is width × height × length = 28 × 26 × 48 mm3 (a & c) and that of the left adrenal gland (an arrow) is width × height × length = 5.6 × 2.3 × 14 mm3 (a). Prominent caudal vena cava invasion (an arrow) is also revealed (b). A small nodule (an arrow) in the right caudal lobe is observed (d)

Table 2 Adrenal hormone concentrations before and after adrenocorticotropin hormone stimulation in a dog with atypical Cushing’s syndrome
Table 3 Plasma free metanephrine and free normetanephrine levels in a dog with pheochromocytoma

Furosemide (1 mg/kg orally q12h; Handok, Korea) and trilostane (1 mg/kg orally q12h; Dechra, UK) were initiated to control MMVD and atypical Cushing’s syndrome. Clopidogrel (3 mg/kg orally q24h; Sinil, Korea) was additionally prescribed as an anti-coagulant. Insulin therapy (isophane insulin; 0.35 IU/kg; Humulin, Lilly, USA.) and irbesartan (5 mg/kg orally q24h; Sanofi Winthrop Industrie, France) were continued to control DM and hypertension.

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 non-resectable 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 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 up-regulation 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.

Availability of data and materials

All the data are presented in the main paper and accompanying figures.

Abbreviations

ACTH:

Adrenocorticotropin hormone

BP:

Blood pressure

CT:

Computed tomography

CVC:

Caudal vena cava

DM:

Diabetes mellitus

fMN:

Free metanephrine

fNMN:

Free normetanephrine

HbA1c:

Glycosylated hemoglobin

MMVD:

Mitral valve degenerative disease

PBZ:

Phenoxybenzamine

PCC:

Pheochromocytoma

PU/PD:

Polyuria/polydipsia

References

  1. 1.

    Bertazzolo W, Didier M, Gelain ME, Rossi S, Crippa L, Avallone G, et al. Accuracy of cytology in distinguishing adrenocortical tumors from pheochromocytoma in companion animals. Vet Clin Pathol. 2014;43:453–9.

    Article  Google Scholar 

  2. 2.

    Barthez PY, Marks SL, Woo J, Feldman EC, Matteucci M. Pheochromocytoma in dogs: 61 cases (1984-1995). J Vet Intern Med. 1997;11:272–8.

    CAS  Article  Google Scholar 

  3. 3.

    Gostelow R, Bridger N, Syme HM. Plasma-free metanephrine and free normetanephrine measurement for the diagnosis of pheochromocytoma in dogs. J Vet Intern Med. 2013;27:83–90.

    CAS  Article  Google Scholar 

  4. 4.

    Musser ML, Taikowski KL, Johannes CM, Bergman PJ. Retrospective evaluation of toceranib phosphate (palladia®) use in the treatment of inoperable, metastatic, or recurrent canine pheochromocytomas: 5 dogs (2014-2017). BMC Vet Res. 2018;14:272.

    Article  Google Scholar 

  5. 5.

    Galac S, Korpershoek E. Pheochromocytomas and paragangliomas in humans and dogs. Vet Comp Oncol. 2017;15:1158–70.

    CAS  Article  Google Scholar 

  6. 6.

    Mak G, Allen J. Simultaneous pheochromocytoma and third-degree atrioventricular block in 2 dogs. J Vet Emerg Crit Care (San Antonio). 2013;23:610–4.

    Article  Google Scholar 

  7. 7.

    Herrera MA, Mehl ML, Kass PH, Pascoe PJ, Feldman EC, Nelson RW. Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma. J Vet Intern Med. 2008;22:1333–9.

    CAS  Article  Google Scholar 

  8. 8.

    Green B, Frank EL. Comparison of plasma free metanephrines between healthy dogs and 3 dogs with pheochromocytoma. Vet Clin Pathol. 2013;42:499–503.

    Article  Google Scholar 

  9. 9.

    Salesov E, Boretti FS, Sieber-Ruckstuhl NS, Rentsch KM, Riond B, Hofmann-Lehmann R, et al. Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs. J Vet Intern Med. 2015;29:597–602.

    CAS  Article  Google Scholar 

  10. 10.

    Oikonomidis IL, Tsouloufi TK, Soubasis N, Kritsepi-Konstantinou M. Validation, reference intervals and overlap performance of a new commercially available automated capillary electrophoresis assay for the determination of the major fraction of glycated haemoglobin (HbA1c) in dogs. Vet J. 2018;234:48–54.

    CAS  Article  Google Scholar 

  11. 11.

    Beninato T, Kluijfhout WP, Drake FT, Lim J, Kwon JS, Xiong M, et al. Resection of Pheochromocytoma improves diabetes mellitus in the majority of patients. Ann Surg Oncol. 2017;24:1208–13.

    Article  Google Scholar 

  12. 12.

    Mesmar B, Poola-Kella S, Malek R. The physiology behind diabetes mellitus in patients with pheochromocytoma: a review of the literature. Endocr Pract. 2017;23:999–1005.

    Article  Google Scholar 

  13. 13.

    Williams DT, Dann S, Wheeler MH. Phaeochromocytoma-views on current management. Eur J Surg Oncol. 2003;29:483–90.

    CAS  Article  Google Scholar 

  14. 14.

    Pappachan JM, Raskauskiene D, Sriraman R, Edavalath M, Hanna FW. Diagnosis and management of pheochromocytoma: a practical guide to clinicians. Curr Hypertens Rep. 2014;16:442.

    Article  Google Scholar 

  15. 15.

    Syme HM, Scott-Moncrieff JC, Treadwell NG, Thompson MF, Snyder PW, White MR, et al. Hyperadrenocorticism associated with excessive sex hormone production by an adrenocortical tumor in two dogs. J Am Vet Med Assoc. 2001;219:1725–8.

    CAS  Article  Google Scholar 

  16. 16.

    Davison LJ. Diabetes mellitus and pancreatitis-cause or effect? J Small Anim Pract. 2015;56:50–9.

    CAS  Article  Google Scholar 

  17. 17.

    Hill KE, Scott-Moncrieff JC, Koshko MA, Glickman LT, Glickman NW, Nelson RW, et al. Secretion of sex hormones in dogs with adrenal dysfunction. J Am Vet Med Assoc. 2005;226:556–61.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Ian Animal Diagnostic (Imaging Center, Seoul, Republic of Korea) for the production of the CT and 3D reconstructed images of the dog.

Funding

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2016M3A9B6903437).

Author information

Affiliations

Authors

Contributions

GWL was involved in case analysis and was responsible for writing the manuscript. CRY and DL were involved in the draft preparation and case analysis. HMP was involved in the coordination of the case and was responsible for interpretation of results. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hee-Myung Park.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written consent was obtained from the present owners of the dogs for publication of this case report and any accompanying images.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, GW., Yoo, CR., Lee, D. et al. Favorable outcome of pheochromocytoma in a dog with atypical Cushing’s syndrome and diabetes mellitus following medical treatment: a case report. BMC Vet Res 16, 3 (2020). https://doi.org/10.1186/s12917-019-2225-x

Download citation

Keywords

  • Adrenal tumor
  • Atypical Cushing’s syndrome
  • Dog
  • Diabetes mellitus
  • Pheochromocytoma