Adrenalectomy and Caval Thrombectomy in a Cat With Primary Hyperaldosteronism

Introduction

Primary hyperaldosteronism, also known as Conn’s syndrome, has been well described in humans but rarely reported in dogs and cats.^1–11 The condition is caused most often by an aldosterone-secreting adrenal gland tumor.^1–11 Humans with hyperaldosteronism may be asymptomatic or have nonspecific signs that are generally related to hypertension (e.g., headaches, dizziness, visual impairment) and hypokalemia (e.g., muscle weakness, polyuria, polydipsia, nocturia).^1–3 In the two reported canine cases, clinical signs were mild, lasted over a year, and included polyuria, polydipsia, polyphagia (without weight gain), nocturia, vomiting, and restlessness.^10,11 Clinical signs reported in cats with primary hyperaldosteronism have included episodic muscle weakness, cervical ventriflexion, hind-limb ataxia, polyuria, polydipsia, nocturia, vision loss, weight loss, and polyphagia.^4–9

Although adrenal gland tumors are uncommon in cats, the most common type are corticosteroid-secreting tumors, which occur in 16% of cats with hyperadrenocorticism.¹² Other adrenal gland tumors that have been reported in cats include pheochromocytomas, progesterone-secreting tumors, and nonfunctional tumors.^13–16 Twenty cats with hyperaldosteronism associated with an adrenal gland tumor have been previously reported.^4–9

Adrenal gland tumors cause caval thrombosis in humans, dogs, and cats.^{4,6,8,17–24} Caval thrombi develop in 6% to 17% of humans with adrenocortical tumors.^17–19 In dogs, thrombi in the caudal vena cava associated with adrenal gland tumors are well documented and are significantly more prevalent with pheochromocytomas (35%) compared to adrenocortical tumors (16%).^20–24 A single case report of a dog with an aldosteronoma has been published, and no caval thrombus was detected.¹¹

Successful removal of an adrenal gland tumor and associated thrombus has not been previously reported in cats.^4,7 In dogs, the thrombus usually invades the overlying phrenicoabdominal vein and extends into the caudal vena cava but can also infiltrate through the wall of the vessel. ^20–24 Thrombi extending from the phrenicoabdominal vein are pedunculated, which permits removal via venotomy around the junction of the phrenicoabdominal vein and vena cava.²⁰ Caval thrombectomy requires special anesthetic considerations because of the required caval occlusion. Deliberate hypothermia may protect vital organs from reduced oxygen delivery during temporary occlusion of the caudal vena cava to remove the thrombus.²⁵

The purpose of this report is to describe an aldosterone-producing adrenocortical carcinoma associated with a caval tumor thrombus in a cat that was successfully treated by adrenalectomy and caval thrombectomy.

Case Report

A 13-year-old, 5.4-kg, castrated male, domestic longhaired cat was examined by the referring veterinarian for cervical ventriflexion, lethargy, weakness, inappetence, and diarrhea. A serum biochemical panel revealed hypokalemia (2.6 mmol/L; reference range 3.6 to 4.9 mmol/L), normonatremia (153 mmol/L; reference range 151 to 158 mmol/L), hyperglycemia (166 mg/dL; reference range 73 to 134 mg/dL), hypophosphatemia (2.5 mg/dL; reference range 3.2 to 6.3 mg/dL), and increased creatine kinase activity (1585 IU/L; reference range 64 to 440 IU/L). A complete blood count (CBC) was unremarkable.

The cat was treated with intravenous (IV) lactated Ringer’s solution supplemented with 30 mEq/L of potassium chloride (KCl), potassium gluconate^a (2 mEq per os [PO] q 24 hours), and dexamethasone sodium phosphate^b (2 mg subcutaneously [SC] q 12 hours for 2 days, followed by a tapering dose). Hypokalemia was considered the most likely cause of the weakness and cervical ventriflexion.

Electrolytes were monitored periodically over the following 5 weeks. The potassium concentration remained below the reference range, despite increasing the frequency of potassium gluconate administration to q 12 hours, and the cat also developed hyponatremia. On days 18, 35, and 46 after initial examination, the potassium concentrations were 2.84, 3.01, and 2.86 mmol/L, respectively, while the sodium concentrations were 148, 142, and 148 mmol/L, respectively. Fifty-three days after initial examination, the serum creatinine, potassium, and sodium were 2.5 mmol/L (reference range 0.8 to 2.3 mmol/L), 3.0 mmol/L, and 154 mmol/L, respectively. The calculated urinary fractional clearance for potassium (FE_K) was 83% (reference range FE_K >6% indicates renal loss). The calculated urinary fractional clearance for sodium (FE_Na) was 0.97% (reference range FE_Na <1% indicates pre-renal azotemia; FE_Na >1% indicates tubular failure).²⁶ Other indicators of hydration status (i.e., blood urea nitrogen, packed cell volume, and skin turgor) were within normal limits. Hypomagnesemia was also present (1.5 mg/dL; reference range 1.8 to 2.4 mg/dL). The differential diagnoses for hypokalemia and kaliuresis included polyuric renal disease, renal tubular acidosis, hyperaldosteronism, and access to an acidifying feline diet.²⁷

An abdominal ultrasound on day 64 revealed an enlarged, irregularly lobulated, hypoechoic right adrenal gland measuring 16 × 14 × 22 mm, with an associated mass extending 15 mm into the lumen of the caudal vena cava. The left adrenal gland and both kidneys appeared normal. The mean systolic arterial blood pressure calculated from five consecutive Doppler readings was 200 mm Hg. Blood samples collected prior to and 1 hour after the intramuscular administration of 0.125 mg synthetic adrenocorticotropic hormone (ACTH)^c were submitted for determination of serum aldosterone concentration.^d Unfortunately, the baseline sample was lost, but post-ACTH aldosterone concentration was 3329 pmol/L (reference range 227 to 721 pmol/L). The clinical signs, ultrasound findings, blood pressure values, and increased post-ACTH aldosterone concentration were suggestive of an aldosterone-secreting tumor. The cat was prescribed benazepril^e (2.5 mg PO q 24 hours) to control the hypertension, and the potassium gluconate was increased to q 8 hours.

The cat was referred to the Veterinary Medical Teaching Hospital, University of California–Davis, 68 days after the initial examination. At presentation, the physical examination revealed a grade II/VI left systolic heart murmur and an irregular cardiac rhythm. An average of eight indirect blood pressure measurements^f yielded a systolic blood pressure of 167 mm Hg and a diastolic pressure of 120 mm Hg. Antihypertensive therapy was changed to amlodipine^g (0.625 mg PO q 24 hours), and the oral potassium gluconate (2 mEq PO q 8 hours) was continued.

Thoracic radiographs showed mild, generalized cardiomegaly and no evidence of pulmonary metastases. Abdominal ultrasonography identified the previously described multilobulated, hypoechoic right adrenal gland mass and apparent extension of the mass into the caudal vena cava [Figure 1]. In addition, thickening of the muscularis layer of a section of small intestine and enlarged hypoechoic regional lymph nodes were also detected. Echocardiography showed dynamic right ventricular outflow obstruction without valvular insufficiency. No arrhythmias were detected on electrocardiography.

Exploratory laparotomy was performed 1 week after initial examination. Preoperative potassium and sodium concentrations were 2.9 and 152 mmol/L, respectively. During surgery, moderate hypothermia (esophageal temperature 30° to 32°C) was induced using surface air cooling and cold water circulating blankets. The right adrenal gland mass was identified. The caudal vena cava adjacent to the adrenal gland was dilated and contained a 15-mm intraluminal mass that was attached to the right adrenal gland. Slight enlargement of the mesenteric lymph nodes and a mildly thickened section of jejunum were also observed.

The right adrenal gland was isolated, and dissection revealed the adrenal mass had invaded the overlying phrenicoabdominal vein and extended into the lumen of the caudal vena cava. The adrenal mass was dissected from surrounding tissue until the only remaining attachment was the thrombus extending through the phrenicoabdominal vein into the vena cava. Rumel tourniquets using umbilical tape were applied around the caudal vena cava, just cranial and caudal to the junction of the phrenicoabdominal vein. The caudal vena cava was incised around the base of the phrenicoabdominal vein, and the venotomy extended cranially until the thrombus could be removed without tearing the wall of the vein. The venotomy incision was closed with a simple continuous pattern of 4-0 silk suture.^h Total caval occlusion time was 8 minutes. Biopsies of the liver, jejunum, and mesenteric lymph nodes were also obtained.

Following surgery, the cat had a postoperative rectal temperature of 93°F, systolic blood pressure of 90 mm Hg, and a normal cardiac rhythm. He experienced two episodes of hypotension (systolic blood pressures of ≤85 mm Hg) that responded to a higher rate of IV fluid administration, and an episode of hypoglycemia (70 mg/dL; reference range 64 to 123 mg/dL) that was treated with the addition of 2.5% dextrose to the IV fluids.

Serum potassium concentration gradually increased from 1.5 mEq/dL (measured immediately after surgery) to 3.7 mEq/L (39 hours after surgery). Two days after surgery, the cat developed generalized subcutaneous edema and moderate pulmonary edema that were thought to result from iatrogenic fluid overload. These clinical signs resolved after administration of furosemideⁱ (2 mg/kg IV) and a reduction in the rate of IV fluid administration.

Gross pathology of the adrenal mass revealed four well-demarcated, round to oval nodules varying in size from 4 × 5 mm to 14 × 9 mm. One of the nodules contained a 3 × 2- mm region that was poorly demarcated, soft, and dark tan to brown in color [Figure 2]. The neoplasm occluded capsular vessels and extended into the vena cava. Histologically, the mass was composed of packets and nests of neoplastic cells separated by scant fibrovascular stroma and the occasional dilated blood vessel [Figure 3]. Rarely, the cells were arranged in lumen-like spaces filled with proteinaceous material. Neoplastic cells were polygonal, had distinct cell borders, abundant eosinophilic and finely vacuolated cytoplasm, round nuclei, vesiculated chromatin, and one prominent nucleolus. Minimal anisokaryosis and anisocytosis and few mitotic figures (<1 per 400× field) were seen. Small areas of necrosis were randomly distributed throughout the mass. The portion of the mass protruding into the vena cava had the same histological pattern as the intra-adrenal portion of the neoplasm. Based on histological appearance, the tumor was an adrenal cortical carcinoma.

The lamina propria of the jejunum was expanded by a monomorphic population of neoplastic lymphocytes that infiltrated the submucosa and dissected between smooth muscle bundles of the longitudinal and circular muscle layers. Similar lymphocytes expanded the paracortex of the mesenteric lymph node, displacing the prominent germinal centers. The neoplastic lymphocytes expressed cell markers of cluster of differentiation (CD)3 and CD18 by immunohistochemistry, but not CD45r or CD79a, indicating a small cell (T-cell) lymphoma.^28–31

Three days after surgery, the cat was discharged without any medications. Ten days after surgery, the serum potassium concentration was 5.5 mmol/L. The averaged systolic/diastolic blood pressures measured 34 and 66 days after surgery were 149/107 and 139/86 mm Hg, respectively. Periodic measurements of the electrolyte concentrations and arterial blood pressures were normal >14 months following surgery.

Although the cat had no clinical signs referable to the intestinal lymphoma, chlorambucil^j (2 mg PO q 3 days) and prednisone^k (5 mg PO q 12 hours) were initiated. The cat developed hematochezia after each of the first two chlorambucil treatments, so the protocol was interrupted for 1 month. The regimen was later restarted without any further complications, and it was continued for 6 months until the development of progressive signs (i.e., weight loss, thickened gut loops). The cat was then started on L-asparaginase^l (400 IU/kg SC), vincristine^m (0.025 mg/kg IV), cyclophosphamideⁿ (10 mg/kg IV), and doxorubicinⁱ (1 mg/kg IV), each administered once weekly.

The cat did well until a second relapse 14 months after surgery, when the cat was presented for weight loss, atrophied epaxial muscles, pale mucous membranes, and peripheral lymphadenopathy. Abdominal ultrasonography and thoracic radiography revealed mesenteric, ileocolic, and sternal lymphadenopathy. There was no obvious evidence of metastasis of the adrenal tumor. The cat died at home, and the owner declined a necropsy examination.

Discussion

Most of the clinicopathological abnormalities in this cat were also consistent with previous reports, where the most common abnormalities detected were hypokalemia, normo- to hypernatremia, hypomagnesemia, hypophosphatemia, increased kaliuresis, azotemia, elevated serum bicarbonate concentration, alkalemia, and elevated creatine kinase activity. ^4–9 Interestingly, the cat in this report did not have hypernatremia, and periodic sodium concentrations measured prior to surgery were normal or slightly below the reference range. The most likely explanation for the normonatremia was fluid expansion masking an elevation in total body sodium.⁷ The finding of mild hyponatremia after initiating treatment with potassium gluconate was unexpected and not easily explained, although it was presumably an indicator of fluctuations in fluid balance in the cat. Excess aldosterone leads to increased resorption of sodium primarily in the cortical collecting ducts of nephrons, stimulation of the thirst center, retention of water, and development of hypertension. ³² Retention of sodium and water is limited with hyperaldosteronism because of suppressed sodium resorption in nephron segments proximal to the collecting ducts in response to atrial natriuretic peptide; therefore, development of hypernatremia is variable and normonatremia is common.^33,34

Documentation of an increased baseline serum aldosterone concentration and an adrenal mass on abdominal ultrasonography support the diagnosis of primary hyperaldosteronism. ⁷ In the current case, an ACTH stimulation test was performed to assess the responsiveness of the adrenal tumor to ACTH, but based on other prior case reports, this test is not necessary to establish the diagnosis. Abdominal ultrasonography was used to detect the presence of an adrenal gland mass and the associated caval thrombus in this cat. Ultrasonography is a sensitive and noninvasive method for detecting and localizing adrenal lesions and vascular thrombi. ^35–37 In dogs, the sensitivity and specificity of abdominal ultrasonography for detecting caval thrombus associated with tumor has been 80% and 90%, respectively.²⁰ In prior reports of ultrasonography being performed in cats with adrenal gland tumors and hyperaldosteronism, an adrenal gland mass was detected in all 18 cats, and the presence of caval extension was detected in both cats with confirmed tumors.^4,6–9

Histopathological examination of the adrenal tumor was done in 18 of the 20 cats reported with primary hyperaldosteronism. Similar to the cat in this report, nine had an adrenocortical carcinoma.^5,7,8 Eight cats had an adrenal adenoma (two of which were bilateral).^7,8 One tumor was reported only as an epithelial tumor.⁴ One cat with an adenoma underwent a successful adrenalectomy, but signs recurred 2 years later; subsequently an adrenocortical carcinoma with thrombus formation was identified on ultrasonography, and the cat was euthanized during the exploratory laparotomy.⁸ Distant metastases were found at necropsy in two of four cats with postmortem examinations. ^4,5

Thrombus formation associated with adrenal gland tumors is uncommon in the cat. Three of 20 cats with an aldosterone-secreting adrenal gland tumor had caval thrombosis. ^4,6,8 To the authors’ knowledge, this is the first documented successful surgical excision of an adrenal gland tumor and associated caval thrombus in a cat. Ash et al. found tumor involvement of the caudal vena cava by direct extension through an adjoining vessel in two of 13 cats, and those cats were euthanized because of extensive intraoperative hemorrhage.⁷ Clinical signs associated with invasion of an adrenal gland tumor into the caudal vena cava can result from obstruction of venous blood flow and lymphatic drainage, which may result in a Budd-Chiari-like syndrome (e.g., hind-limb weakness, pitting edema, and ascites).^20,22,24 Most dogs with caval thrombi associated with an adrenal gland tumor, however, do not have clinical signs of caval obstruction.²⁰ Similarly, the cat in this report and other reported cats with a caval thrombus have not shown clinical signs referable to a caval thrombus.^4,6,8 It is probable that signs only develop when the thrombus is large enough to completely obstruct venous flow in the caudal vena cava.

In most dogs with adrenal gland tumors and associated caval thrombus, the tumor did not directly invade the vena cava.²⁰ Instead, the tumor invaded the lumen of the phrenicoabdominal vein overlying the adrenal gland and extended down the lumen of the phrenicoabdominal vein into the caudal vena cava. This pattern of invasion was also evident in the cat reported here. Consequently, surgical removal of the caval thrombus involved a venotomy around the insertion site of the phrenicoabdominal vein. Only a minimal portion of the caval wall was removed, and surgical closure of the caval venotomy had minimal effect on the luminal diameter of the caudal vena cava. One previous report exists of adrenalectomy and caval thrombectomy in a cat in which a section of the caval wall was excised, and primary caval reconstruction resulted in marked narrowing of the vena cava, leading to venous congestion, renal failure, and death.¹¹

Deliberate hypothermia may be used to protect vital organs from decreased oxygen delivery when venous occlusion is anticipated for removal of a mass invading the vena cava.³⁹ Moderate hypothermia (30° to 32°C) has been used in dogs for these purposes, but deliberate intraoperative hypothermia has not yet been reported in cats.⁴⁰ Hypothermia in this case was induced using cold water circulating blankets and forced air cooling, and body temperature was measured in the lower third of the esophagus. Progressive rewarming was performed under general anesthesia to prevent the development of hypothermia-induced cardiac arrhythmias and to prolong the protective effects of hypothermia.^40,41

Adrenalectomy is the method of choice for long-term treatment of primary hyperaldosteronism.^7,9 Medical therapy aimed at correcting hypokalemia and controlling systemic hypertension should be considered prior to adrenalectomy. The cat in this report was treated with oral potassium supplements and antihypertensive drugs over a 5- week period, with minimal improvement in clinical signs, serum potassium concentrations, or systemic hypertension.

Conclusion

Primary hyperaldosteronism was diagnosed in a 13-year-old cat with an adrenal cortical carcinoma. Adrenalectomy resolved the hypokalemia, hypertension, and other electrolyte abnormalities. Surgical excision of a tumor thrombus from the caudal vena cava was accomplished without any pathological narrowing of the vena cava. Deliberate intraoperative hypothermia with progressive rewarming was utilized to protect vital organs during the caval occlusion. Further studies are needed to examine the safety and efficacy of this technique in cats.