Introduction

The most common cause of Addison’s disease (ADD) in dogs is an immune-mediated destruction of the adrenal cortex. However, other causes including granulomatous disease, amyloidosis, hemorrhagic infarction, neoplasia, and iatrogenic intervention have also been identified.^1–4 Adrenal involvement has been reported in 21% of dogs with metastatic disease.¹ In humans, only 1% of patients with adrenal metastases develop ADD, and this low rate is mainly attributed to the fact that clinical symptoms associated with a loss of cortical function are often not identified until >90% of the parenchyma is damaged.^1,5 Only three cases of adrenal metastasis causing hypoadrenocorticism were found in the veterinary literature, including a 9 yr old intact male Doberman pinscher with disseminated lymphoma, a 12 yr old neutered male rottweiler—Labrador retriever mixed-breed with anaplastic bilateral adrenal neoplasia of an unknown origin, and a 2 yr old neutered male German shepherd dog with intravascular lymphoma.^1,6,7. A 7 yr old mixed-breed dog with adrenal and pituitary T-cell lymphoma was also reported to develop hypoaldosteronism instead of hypoadrenocorticism.⁸ To our knowledge, the present case is the first reported of a dog with ADD secondary to metastatic carcinoma describing the clinical presentation, complete diagnostic findings, treatment, outcome, and postmortem examination.

Case Report

A 12 yr old, 28.8 kg (63.5 lb) intact female Siberian husky was referred with a 2 wk progressive history of weakness, lethargy, anorexia, and panting. A 4 cm mass involving the fifth right mammary gland had been noticed 5 days before presentation and was removed by the referring veterinarian 2 days before. Biopsy results were compatible with a grade 3 solid carcinoma. Prior to surgery, the referring veterinarian had performed a complete blood test showing mild lymphocytosis (5.370 cells/µL; reference interval 1.060–4.950) and hyperkalemia (6.3 mmol/L; reference interval 3.6–5.8) with a low sodium (potassium ratio [22.86; reference interval 27–40]).

On presentation, physical examination revealed a decreased mental status, dry and pale mucous membranes, prolonged capillary refill time, weak peripheral pulse quality, panting, tachycardia (150 beats/min), and low systolic pressure (60 mm Hg). Popliteal lymph nodes were moderately enlarged but painless. The patient underwent emergency stabilization with 20 mL/kg of isotonic crystalloid solution^a administered over 20 min. Once the dog was hemodynamically stable, neurologic examination disclosed a moderate ambulatory paraparesis as well as proprioceptive deficits with decreased withdrawal reflexes on both pelvis limbs and severe hyperesthesia on lumbosacral palpation.

A complete blood count showed a leukocytosis (33.350 cells/µL; reference interval 5.050–16.760), lymphocytosis (8.210 cells/µL; reference interval 1.050–5.100), monocytosis (1.830 cells/µL; reference interval 160–1.120), and neutrophilia (22.430 cells/µL; reference interval 2.950–11.640) as well as a hematocrit of 38% (reference interval 37.3–61.7). Abnormal serum biochemistry findings included mild hypoalbuminemia (2.1 g/dL; reference interval 2.3–4.0), moderate azotemia (creatinine: 4.76 mg/dL, reference interval 0.5–1.9; blood urea nitrogen: 40.04 mg/dL, reference interval 8–28), and hyperkalemia (6.5 mmol/L; reference interval 3.6–5.8), with sodium concentration within the normal reference range and a low sodium: potassium ratio (22.46; reference interval 27–40).⁹ The remainder of the blood tests (including liver enzymes) were found to be within the normal reference ranges. Urine obtained by cystocentesis following fluid therapy showed a urine specific gravity of 1.012, whereas a sediment exam showed high numbers of white blood cells. Urine culture revealed Escherichia coli growth. Arterial blood gas analysis^b showed hypocapnia (26 mmHg; reference interval 36–44) and a low bicarbonate concentration (14.7 mmol/L; reference interval 24–26) consistent with mixed metabolic acidosis and respiratory alkalosis resulting in a normal pH (7.4; reference interval 7.36–7.44). Electrocardiogram did not show any morphological or rhythmic alterations. Abdominal radiographs were normal and thoracic radiographs revealed microcardia (vertebral heart score: 9.0; reference interval 9.2–10.5) with a narrow caudal vena cava (vena cava: fifth thoracic vertebra ratio: 0.5; reference interval 0.67–0.91).¹⁰ Radiographs of the cervical, thoracic, lumbar, and sacral spinal areas were normal. An abdominal ultrasound examination revealed that both adrenal glands were at the upper limit of normal size (left adrenal gland was 0.6 cm and right adrenal gland was 0.78 cm; reference interval <0.68 cm for dogs 10–30 kg), with a normal shape and echogenicity.¹¹ No other abnormalities were detected. Results of an adrenocorticotropic hormone (ACTH) stimulation test using a synthetic tetracosactide^c at 5 µg/kg were consistent with hypoadrenocorticism with baseline and post-ACTH serum cortisol concentrations^d of 0.6 µg/dL and 0.7 µg/dL, respectively.

Initial treatment included amoxicillin/clavulanic acid^e (25 mg/kg IV q 8 hr) to treat a suspected pyelonephritis, methadone^f (0.3 mg/kg subcutaneously q 4 hr) and gabapentin^g (10 mg/kg per os q 12 hr) for lumbosacral pain, omeprazole^h (1 mg/kg IV q 12 hr), and fluid therapy. Hydrocortisone sodium phosphateⁱ was initiated at 0.5 mg/kg/hr IV as a constant rate of infusion.¹²

Serial measurements of plasma electrolyte concentrations were performed q 4–12 hr to adjust fluid therapy. Serum potassium concentrations decreased to normal range within the first 12 hr of treatment. Treatment using hydrocortisone sodium phosphate was stopped after 24 hr, at which point, a treatment program of oral prednisolone^j was commenced (0.2 mg/kg per os q 12 hr) and desoxycorticosterone pivalate^k at 2.2 mg/kg intramuscularly as a single dose was initiated.¹³ At this time, supplemental feeding^k was delivered through a nasoesophageal feeding tube. Serial blood tests revealed an increase in white blood cells count (leukocytes: 49.410 cells/µL, reference interval 5.050–16.760; lymphocytes: 9.280 cells/µL, reference interval 1.050–5.100; monocytes: 3.840 cells/µL, reference interval 600–1.120; and neutrophils: 36.190 cells/µL, reference interval 2.950–11.640), moderately nonregenerative normocytic normochromic anemia (hematocrit: 29.7%; reference interval 37.3–61.7), thrombocytopenia (126,000/µL; reference interval 148,000–484,000), and persistent hypoalbuminemia (2.0 g/dL; reference interval 2.3–4.0), with improvement of the azotemia (creatinine: 1.8 mg/dL, reference interval 0.5–1.9; blood urea nitrogen: 25.04 mg/dL, reference interval 8–28).

On the third day following admission, the patient showed a stuporous mental status, bilateral epistaxis, hematuria, and hypotension. Blood tests revealed moderate anemia (hematocrit: 20% reference interval 37.3–61.7). Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged (PT >100 s, reference interval 11.0–17.0; aPTT >300 s, reference interval 72–102). Unfortunately, a cardiac arrest occurred over the next hour. Cardiopulmonary resuscitation was attempted but was unsuccessful.

The patient’s adrenal glands, popliteal lymph nodes, L4–L7 vertebral body and sacrum were submitted for postmortem examination. Microscopically, both adrenal subcapsular cortices were completely replaced by multifocal aggregates of polygonal cells, with undefined cell borders, eosinophilic cytoplasm, round nuclei, and slightly granular basophil nucleoli, with anisocytosis and anisokaryosis noted, forming nests compatible with neoplastic epithelial cells (Figure 1). Both adrenal medullas were also infiltrated by desmoplastic stroma, with areas of necrosis associated with neoplastic nests. Atypical cells were found in the adjacent adipose tissue and were infiltrating the sympathetic nervous ganglions and fascicules of the peripheral nerve. Neoplastic cells of the right adrenal gland extended to the caudal vena cava. Within the popliteal lymph nodes, small aggregates of polygonal atypical cells, mainly in the subcapsular sinuses, were observed. Emboli of atypical cells were also found in the lumen of afferent lymphatic vessels and vessels of the fibrous trabeculae supporting the lymph node (Figure 2). Neoplastic foci were detected in the medullary cavity of the vertebral bodies and paralumbar musculature. Histopathological diagnosis consisted of a diffuse infiltrate of neoplastic cells in both adrenal glands, popliteal lymph nodes, vertebral bodies and paralumbar musculature, consistent with mammary metastatic carcinoma.

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Discussion

The most common cause of ADD in dogs is an immune-mediated destruction of the adrenal cortices, but other causes include granulomatous disease, amyloidosis, hemorrhagic infarction, neoplasia, and iatrogenic intervention.^1–4 To the authors’ knowledge, this is the first case report of a dog with ADD secondary to metastatic carcinoma describing the clinical presentation, complete diagnostic findings, treatment, outcome, and postmortem examination.

Adrenal involvement has been reported in 21% of dogs with metastatic disease.¹ The most common tumors that metastasize to the adrenal glands in dogs are pulmonary, mammary, prostatic, gastric, and pancreatic carcinomas and melanomas.¹ Carcinomas account for >40% of metastasis to the adrenal glands.¹ In humans, only 1% of patients with adrenal metastases develop ADD, and the most common cause of death in these individuals is the primary tumor rather than the adrenal dysfunction.⁵ This low rate of ADD in patients with adrenal metastases is attributed mainly to the fact that clinical symptoms associated with the loss of cortical function are not observed until >90% of the parenchyma is damaged.^1,5

Dogs with ADD have significantly thinner adrenals on abdominal ultrasound in comparison with healthy dogs and ill non-Addisonian dogs affected by other conditions.¹⁴ However, normal size adrenal glands on abdominal ultrasound do not rule out hypoadrenocorticism.¹⁴ The presence of a highly malignant metastatic tumor in a patient with signs compatible with hypoadrenocorticism increases the likelihood of a metastatic adrenal disease.^15,16 Percutaneous ultrasound-guided fine-needle aspiration of bilateral adrenal glands should be considered; however, a final diagnosis should be performed with an ACTH stimulation test and histological evaluation.^16,17

We suspect that the acute adrenal crisis in the present case was triggered by a stressful event, as mammary surgery was performed 2 days prior to presentation. In addition, we suspect that the clinical signs reported by the owners (weakness, lethargy, anorexia, and panting) prior presentation were possibly a result of the hypoadrenocorticism. The patient developed disseminated intravascular coagulation (DIC) supported by the presence of tumor involvement of the caudal vena cava and a hemorrhagic phenotype with multiple bleeding events, thrombocytopenia, and prolonged coagulation times (aPTT and PT).¹⁸ Functional tissue factors have been reported to be overexpressed in canine mammary tumors, which possibly triggered the emergence of DIC.^19,20 Overall, the metastatic disease progression, hypovolemic decompensated shock on presentation, ADD, DIC and the urinary infection probably contributed to the deterioration of the patient.

One of the main differential diagnoses of ADD considered in this case was critical illness related corticosteroid insufficiency (CIRCI). CIRCI is characterized by an inadequate production of cortisol in response to critical illness. In patients with this syndrome, the basal cortisol concentration is usually normal or high, with a blunted cortisol response to ACTH administration.^21,22 Consequently, the absolute change in cortisol concentration (Δcortisol) after ACTH administration is low. The most significant problem associated with CIRCI is the presence of hypotension refractory to fluid therapy.⁴ Despite the fact that we cannot rule out this syndrome completely, it seems unlikely that this was present because the basal cortisol was low and hypotension at the time of presentation resolved with the administration of a bolus of isotonic crystalloid fluid therapy with normal pressure maintained during the following days.

This case emphasizes the importance of evaluating Na:K ratio and lymphocyte count when hypoadrenocorticism is suspected.²³ As a result of the risk of metastasis associated with mammary tumors, staging prior to initiating therapy is strongly recommended. Clinical staging includes complete blood test, three-view thoracic radiographs, and fine-needle aspiration of regional lymph nodes, even if they appear normal on palpation. An abdominal ultrasound may also be indicated, especially in dogs with suspected regional lymph node involvement or changes on preoperative blood work.²⁴

The fifth neoplastic mammary gland usually drains into the inguinal and popliteal lymph nodes and into a lymphatic network at the medial aspect of the ipsilateral thigh.²⁵ Unfortunately, the owners did not authorize a complete necropsy and only the adrenal glands, popliteal lymph nodes, L4–L7 vertebral body, and sacrum were available for pathological examination. As a full postmortem examination was not performed, the involvement of other organs or lymph nodes consequently remained unknown. Another limitation of the present study was that aldosterone and endogenous ACTH levels were not measured. However, electrolyte disturbances and histopathological findings were suggestive of ADD, making secondary hypoadrenocorticism unlikely.

Conclusion

To the authors’ knowledge this represents the first reported case of metastasis from a carcinoma causing ADD in a dog. Tumor staging should be performed prior to initiating therapy including AUS. In dogs with a known highly metastatic tumor with nonspecific signs compatible with ADD, infiltrative metastatic adrenal disease should be considered. Further diagnostic tests should include percutaneous ultrasound-guided fine-needle aspiration of the adrenal glands, with definitive diagnosis made by ACTH stimulation test and histological evaluation.