Adrenal Pheochromocytoma With Contralateral Adrenocortical Adenoma in a Cat

Introduction

A pheochromocytoma is an endocrine tumor of the chromaffin cells within the adrenal medulla. Hormones produced in the medulla include epinephrine, norepinephrine, and occasionally dopamine.¹ Clinical signs associated with pheochromocytomas result from either excessive catecholamine production or a space-occupying mass. Observed clinical signs tend to be paroxysmal but occasionally can be persistent.¹ In humans, symptoms are typically episodic and include headache, sweating, anxiety, pallor, tachycardia, heart palpitations, and hypertension.²

In the cat, pheochromocytoma is an extremely rare tumor; only three previously reported cases appear to be published in the veterinary literature. ^3–5 In these cases, the clinical signs were nonspecific and included polyuria, polydipsia, lethargy, anorexia, seizure, and intermittent vomiting. ¹ The findings in the case described herein were consistent with pituitary-dependent hyperadrenocorticism, yet the cat was ultimately diagnosed with two distinct endocrine tumors: a pheochromocytoma and an adrenocortical adenoma. The occurrence of these two tumor types has previously been reported in humans and dogs,^6–14 but not in the cat.

Case Report

A 7-year-old, neutered male, domestic shorthair cat was presented for evaluation of a 6-month history of progressive polyuria, polydipsia, polyphagia, aggression, and weight gain. The cat previously weighed 6.9 kg and had gained 2.6 kg during the 6-month period prior to referral.

Three months prior to presentation, routine blood work and urinalysis were performed by the referring veterinarian (rDVM). The complete blood count (CBC) abnormalities included an increased hematocrit (49.9%; reference range 29% to 48%) and an increased mean corpuscular volume (62 fL; reference range 37 to 61 fL). Serum biochemical abnormalities included increased albumin (4.1 g/dL; reference range 2.5 to 3.9 g/dL), increased alanine aminotransferase (ALT, 170 U/L; reference range 10 to 100 U/L), increased serum sodium concentration (163 mEq/L; reference range 145 to 158 mEq/L), and an increased amylase (1754 U/L; reference range 100 to 1200 U/L). Urinalysis, which included dipstick and sediment analyses, revealed hematuria (2+), a pH of 6.0, calcium oxalate crystals, and a urine specific gravity of 1.031. Abdominal and thoracic radiographs were within normal limits. The cat was pre-scribed amoxicillin-clavulanic acid^a (6.6 mg/kg per os [PO] q 12 hours) for 14 days. A urinalysis was repeated 14 days later, revealing 1+ blood, a pH of 6.0, and a urine specific gravity of 1.035. A urine culture obtained by cystocentesis yielded no growth. The cat was then administered enrofloxacin^b (2.7 mg/kg PO q 24 hours) for 10 days, but the polyuria and polydipsia did not resolve.

Two weeks prior to presentation, the rDVMrepeated routine blood work and urinalysis. Abnormalities included an increased albumin (4.6 g/dL; reference range 2.5 to 3.9 g/dL), increased alkaline phosphatase (103 U/L; reference range 6 to 102 U/L), increased ALT (142 U/L; reference range 10 to 100 U/L), increased total calcium concentration (11.1 mg/dL; reference range 8.2 to 10.8 mg/dL), increased serum sodium concentration (169 mEq/L; reference range 145 to 158 mEq/L), increased amylase (2435 U/L; reference range 100 to 1200 U/L), and increased triglyceride level (503 mg/dL; reference range 25 to 160 mg/dL). A serum total thyroxine concentration was within normal limits (1.3 mg/dL; reference range 0.8 to 4.0 mg/dL). Urinalysis revealed proteinuria (1+), a pH of 7.5, a moderate amount of struvite crystals, and a urine specific gravity of 1.024. The cat was prescribed amoxicillin-clavulanic acid (9.9 mg/kg PO q 12 hours for 14 days) until presentation at Red Bank Veterinary Hospital.

On presentation, the cat was alert and extremely aggressive. The hair coat was generally rough and unkempt, with areas of mild alopecia on the thorax and proximal aspects of the front limbs. The cat was potbellied, had dorsal muscle wasting, and a body condition score of 8/9. A grade 2/6, left parasternal systolic heart murmur was present. The remainder of the physical examination was within normal limits.

Ultrasonographic imaging of the abdomen revealed bilateral adrenal gland enlargement. The short axis measurement of the left adrenal gland was 0.76 cm [Figure 1], and the right adrenal was 1.33 cm [Figure 2]. The reported normal size for the feline adrenal gland ranges between 0.29 cm and 0.53 cm along the short axis.¹⁵ The left adrenal had a normal echogenicity and shape, whereas the right adrenal had a decreased echogenicity and a generalized thickening, especially at each pole. The remainder of the ultrasound examination was within normal limits.

A blood pressure measurement was attempted but could not be obtained because of the cat’s aggressive disposition. A low-dose dexamethasone suppression test (LDDST) was performed by giving 0.1 mg/kg of dexamethasone^c intravenously. Results of the LDDST revealed a baseline cortisol concentration of 11.3 μg/dL (reference range 0 to 5 μg/dL) and inadequate suppression of cortisol at both the 4-hour (10.3 μg/dL; reference range <1.4) and 8-hour samplings (6.3 μg/dL; reference range <1.4). The clinical signs, LDDST results, and bilateral adrenal gland enlargement were consistent with pituitary-dependent hyperadrenocorticism. Medical and surgical therapies were discussed with the owners, and the decision was made to pursue exploratory surgery and bilateral adrenalectomy.

The day prior to surgery, 10 mg (1.05 mg/kg intramuscularly [IM]) of prednisone acetate^d was administered to prevent a perioperative hypoadrenal crisis. The day of surgery, 20 mg (2.1 mg/kg) of desoxycorticosterone pivalate^e (DOCP) and 10 mg of prednisone acetate were administered IM. At surgery, a ventral midline celiotomy was performed, and the entire abdomen was explored. Bilateral adrenal gland enlargement was noted during surgery, and the remainder of the abdomen was unremarkable. Ligaclips^f were used to ligate the phrenicoabdominal veins. Hemostasis was achieved using gelatin sponges^g and cautery. The right adrenal gland was removed, followed by the left adrenal gland. Care was taken to ensure the entire capsule of the right adrenal gland was removed because of its large size. The abdomen was flushed with sterile saline and closed routinely.

The systolic blood pressure remained at 150 mm Hg until the right adrenal gland was removed. The cat then became hypotensive with a systolic blood pressure of 50 mm Hg. The fluid infusion rate was increased from 10.5 mL/kg per hour to 15.7 mL/kg per hour for the next 20 minutes (which coincided with the end of surgery). The systolic blood pressure remained between 50 and 60 mm Hg until the end of surgery. The blood pressure then increased, and the cat recovered uneventfully.

The packed cell volume, total solids, and electrolytes were within normal limits the day of surgery and for the first 2 days postoperatively. The cat was administered 5 mg of prednisone acetate IM once a day for 3 days and was discharged 3 days postoperatively with prednisone^h (0.52 mg/kg PO q 24 hours indefinitely) and with instructions to return to the veterinarian for DOCP (2.1 mg/kg IM) therapy once monthly.

The adrenal glands were analyzed histopathologically. Sections from the right adrenal gland were composed almost entirely of a nodular mass of plump, polygonal cells that compressed the remnant adrenal medullary tissue [Figure 3]. The cells within the nodular mass were arranged in sheets, trabeculae, and scattered nests supported by a fine fibrovascular stroma. The cells had abundant, finely granular to vacuolated eosinophilic cytoplasms and indistinct cell borders. Nuclei were round, oval, or reniform with dispersed chromatin and one or two prominent nucleoli. Rare binucleated nuclei were also seen. Mild anisocytosis and anisokaryosis were present, but mitoses were not observed. Scattered fibrin thrombi and focal hemorrhage bordered by areas of necrosis were also seen. The neoplastic cells were immunonegative to antibodies against leuenkephalin, chromogranin A (CGA), synaptophysin (SYN), protein gene product 9.5 (PGP 9.5), pancytokeratin, and adrenocorticotropic hormone (ACTH). Together, these findings were consistent with an adrenocortical adenoma.

Sections from the left adrenal gland contained a nodular mass and a fragment of normal cortical tissue [Figure 4]. The mass was composed of nests and trabeculae of polygonal cells separated by a delicate fibrovascular stroma. The cells in the mass had a moderate amount of granular to vacuolated basophilic cytoplasm and variably distinct cell borders. Nuclei were oval to elongate and often hyperchromatic with central nucleoli. Anisocytosis and anisokaryosis were moderate, but mitotic figures were not observed. Several vascular profiles contained fibrin thrombi. The neoplastic cells were immunoreactive to antibodies against leuenkephalin [Figure 5], CGA, SYN, and PGP 9.5, and they were immunonegative to antibodies against pancytokeratin and ACTH. These findings were consistent with a pheochromocytoma. Staining for ACTH was performed to determine if ectopic ACTH from the pheochromocytoma could have caused the hyperadrenocorticism.

After discharge, the cat continued to be anorexic, and episodes of vomiting occurred at home. A CBC, packed cell volume, total solids, and electrolytes were within normal limits 5 days postoperatively. The cat was hospitalized, started on intravenous fluid therapy, and administered 5 mg of prednisone acetate (0.52 mg/kg IM q 24 hours) for 2 days. The clinical signs continued over the next week despite the supportive care, so a 12-French esophagostomy tube was surgically placed 12 days postoperatively. Additionally, 20 mg (2.1 mg/kg subcutaneously [SC]) of methylprednisolone acetateⁱ was administered. Over the next 2 weeks, the cat slowly improved and the anorexia resolved.

The cat continued to improve over the next few months. The polyuria and polydipsia resolved, and the aggression dramatically subsided. Serial physical examinations were unremarkable except for the previously noted heart murmur. The cat’s body weight decreased from 9.55 kg to 7.1 kg within 10 months following surgery. At 36 months postsurgically (at the time of writing this report), the cat was receiving 15 mg methylprednisolone acetate (2.1 mg/kg SC q 30 days) and 15 mg of DOCP (2.1 mg/kg IM q 30 days).

Discussion

Pheochromocytomas are extremely rare tumors in the cat. To our knowledge, only three reported cases have been published in the veterinary literature. The first case was an 18-year-old, spayed female, domestic shorthair cat with an extra-adrenal pheochromocytoma (i.e., paraganglioma).³ The cat was presented with polydipsia, lethargy, and intermittent vomiting. A midabdominal mass was noted on physical examination. Blood urea nitrogen (50 mg/dL) and serum creatinine (2.2 mg/dL) were elevated on routine blood work prior to surgery. Surgery confirmed the presence of an abdominal mass located adjacent to the left kidney and left adrenal, but it was not directly associated with either structure. The mass and left kidney were removed. Following surgery, the cat developed renal failure. Despite aggressive medical management, the cat continued to decline and was euthanized 2 days postoperatively. The gross, histological, and electron microscopic findings were consistent with an extra-adrenal pheochromocytoma.

The second case was an 11-year-old, spayed female, domestic shorthair cat that was presented with a 3-month history of polyuria, polydipsia, and a palpable abdominal mass cranial to the left kidney.⁴ Hyposthenuria (1.004), hypokalemia, hypercarbia, hypertriglyceridemia, increased lactate dehydrogenase, increased ALT, and increased creatine kinase were identified in the affected cat. The ACTH stimulation test and LDDST results were not consistent with hyperadrenocorticism. Abdominal ultrasound revealed a 2 × 2.1-cm mass in the area of the left adrenal gland. The plasma epinephrine concentration (0.592 ng/mL) was elevated when compared to that (0.29 ng/mL) of an age-matched cat with no clinical signs of disease and compared to the plasma epinephrine level (0.048 ng/mL) in the affected cat 5 days postadrenalectomy. During surgery, the cat experienced a significant decrease in blood pressure (systolic pressure decreased from 180 mm Hg to 45 mm Hg) when the adrenal mass was removed. A dopamine infusion was instituted, which maintained the systolic blood pressure between 65 and 75 mm Hg for the duration of surgery. Following surgery, the cat’s clinical signs (of polyuria and polydipsia) completely resolved. The diagnosis of pheochromocytoma was based on clinical signs, the decrease in blood pressure during surgery, elevated plasma epinephrine level prior to surgery, reduction in plasma epinephrine level following surgery, and histopathology.

The third case was a 15-year-old, domestic shorthair cat with a recurrent apocrine gland adenocarcinoma.⁵ Presurgical abdominal radiographs revealed a 2-cm midabdominal mass ventral to the second lumbar vertebra. The ALT was elevated at 573 IU/L (reference range 26 to 84 IU/L). An abdominal ultrasound revealed a mass, measuring 2 cm × 2.2 cm, in the area of the right adrenal gland. An aspirate and core biopsy of the mass were performed. Cytology was consistent with a mass of neuroendocrine origin, and the biopsy results were consistent with a pheochromocytoma. The adrenal mass was removed surgically. Postoperatively, the cat developed respiratory distress, and a blood clot was identified in the caudal vena cava cranial to the kidneys. An arterial blood gas was consistent with hypoxia and hypercapnia. Thoracic radiographs were within normal limits. Based on the presumed diagnosis of a pulmonary thromboembolism secondary to a vena caval thrombus, streptokinase was administered. The cat continued to deteriorate despite supportive care, and euthanasia was performed. A diagnosis of pheochromocytoma was based on cytology and histopathology of the excised adrenal gland.

The cat presented in this article appears to be only the fourth reported case of a pheochromocytoma in this species. The cat in this case report had clinical signs of hyperadrenocorticism, a positive LDDST, and bilaterally enlarged adrenal glands. Prior to surgery, pituitary-dependent hyper-adrenocorticism was suspected; however, the histopathology and immunohistochemistry both supported the diagnosis of a pheochromocytoma in the left adrenal gland.

In human medicine, a test with adequate sensitivity and specificity to definitively diagnose pheochromocytomas is currently lacking. This is likely related to the fact that prevalence of this disease in the general population is low, and individual pheochromocytomas can produce different types and amounts of hormones.^1,2 For example, catecholamine production tends to be episodic over time.² Thus, clinical diagnosis can be challenging. In veterinary medicine, tests for pheochromocytomas are not commercially available. Available techniques for diagnosing pheochromocytomas are expensive and technically difficult. Also, they typically lack an established reference range, so their use is limited. ^16,17 In the case described herein, the index of suspicion for a pheochromocytoma was low, and suspicion was high for pituitary-dependent hyperadrenocorticism, so testing was not performed.

In humans, presurgical diagnosis of a pheochromocytoma is based on documenting abnormal regulation of catecholamines and localizing a tumor within the adrenal gland. One of the initial tests performed in humans is direct measurement of catecholamines (such as epinephrine) or catecholamine breakdown products (such as metanephrines or urine vanillylmandelic acid) in the blood or urine via high-performance liquid chromatography (HPLC).^2,16 This test generally has a high sensitivity, but even a small number of false negatives are of concern. The HPLC test also has a high specificity, but the low prevalence of disease in the general population makes false positives a troublesome occurrence.¹⁸

Catecholamine levels have rarely been evaluated in dogs and cats. A preliminary reference range for urine catecholamines has been determined in healthy dogs.¹⁹ Urine catecholamines were measured in three dogs with a pheochromocytoma; however, the results were inconclusive in two of the three cases.^19,20 Plasma epinephrine levels were determined in one cat and were supportive of the diagnosis.⁴

In humans, nuclear imaging via nuclear scintigraphy or positron emission tomography can also be performed to achieve a presurgical diagnosis of pheochromocytoma. Nuclear imaging measures the uptake of a radioactive isotope, such as m-iodobenzylguanidine, m-flourobenzylguanidine, or p-flourobenzylguanidine by the adrenal medulla. Nuclear imaging has been explored in dogs,^21–23 but this technique is typically only available in a research setting. The main advantage of nuclear imaging over measuring catecholamine levels is that it combines functional activity with anatomical localization, and the presence of metastasis and multifocal disease can be identified.²

Finally, the catecholamine suppression test can also be performed in humans to diagnose pheochromocytomas. This test is performed by administering an alpha agonist and subsequently measuring metanephrine or normetanephrine levels. The main advantage of the catecholamine suppression test is that it can differentiate sympathetic stimulation from a pheochromocytoma. This test, however, lacks sensitivity and specificity, and adverse effects have been observed following administration of the alpha agonist. As a result, catecholamine suppression tests are not commonly utilized in humans,¹⁶ and this test has not been evaluated in domestic animals.

In order to confirm the presence of a pheochromocytoma, an adrenal tumor needs to be detected. This is typically achieved with radiography, ultrasonography, computed tomography, or magnetic resonance imaging. Each of these modalities has been utilized in the dog.²⁴ In cats, radiography and ultrasonography were used in two of the three previous case reports, as well as in the case described here.

This case report is unusual, because two discrete endocrine tumors were detected: a pheochromocytoma and an adrenocortical adenoma. In humans and dogs, an association between the presence of a pheochromocytoma and concurrent neoplasia has been reported.^{2,6–9,17,20,25,26} For example, concurrent neoplasia was found in 50%²⁰ and 54%²⁵ of the canine pheochromocytoma cases in two large retrospective studies. Therefore, a correlation between neoplasia and pheochromocytomas may also exist in cats. In one of the published reports, an apocrine gland adenocarcinoma was diagnosed in a cat with a pheochromocytoma.⁵

Further, hyperadrenocorticism has also been associated with pheochromocytomas in dogs.^{6–8,17,20,25} Specifically, hyperadrenocorticism was documented in 13 out of 61 dogs with pheochromocytomas in one report²⁵ and in six dogs with hyperadrenocorticism from a case series of dogs with concurrent pheochromocytoma and hyperadrenocorticism. ¹⁷ This may be caused by a direct association between the adrenomedullary and adrenal cortical tissues. Normally, some cells within the adrenal medulla are directly exposed to the cortical venous blood.⁹ Consequently, this would expose the medullary tissue to increased concentrations of cortisol in the presence of an adrenal tumor. Elevated cortisol has been shown to activate catecholamine secretion and may lead to either hyperplasia or neoplasia.⁷

Hyperadrenocorticism caused by ectopic ACTH production by the pheochromocytoma was also considered a possibility; but this theory was ruled out, because the pheochromocytoma did not react to ACTH antibodies in the immunohistopathology studies. Hyperadrenocorticism resulting from ectopic ACTH production has been reported in humans with a pheochromocytoma^{10–12,26–28} and in one dog with a neuroendocrine tumor.²⁹ If this occurred in our case, however, we would also have expected cortical hyperplasia in both adrenals, not just in the right adrenal gland as was observed in this case.

The generalized enlargement of both adrenals was surprising, given the presence of bilateral solitary tumors. Focal enlargement of each adrenal gland would be expected with two discrete tumors. This was not observed during either the ultrasound examination or surgery. Reasons for this are likely related to the location of the tumors within the adrenal glands, the subsequent alteration of the surrounding parenchyma, and the relatively small size of the adrenal gland making changes difficult to detect grossly.

Although the signs were possibly from either one of the tumors or both tumors simultaneously, the clinical signs were more likely to be from the hypercortisolemia than from an excess catecholamine production. This hypothesis is based mainly on the positive results of the LDDST. That is, the likelihood is greater of having a nonproductive tumor present and a subsequent development of a functional tumor than having two functional tumors develop simultaneously. In the human literature, only one report has documented a functional cortical adenoma and a functional pheochromocytoma being present at the same time.⁹ Nonetheless, the LDDST might have yielded a false-positive result, and the affected cat’s clinical signs may have been related to the pheochromocytoma, since the specificity of the LDDST has not been completely evaluated in cats. Evidence to support this supposition is the lack of atrophy in the contralateral adrenal cortex, which would be expected with a cortisol-secreting tumor.

The presenting signs of the cat described herein were also more likely to be from the hyperadrenocorticism than from the catecholamine excess. The clinical signs of polyuria, polydipsia, polyphagia, the potbelly appearance, and alopecia have all been associated with hyperadrenocorticism in cats.³⁰ Despite the fact that some of these signs have not been associated with a pheochromocytoma, it is plausible that a pheochromocytoma could have been the cause. Ultimately, knowing which adrenal tumor caused the clinical signs leading to presentation is not possible, because catecholamine testing was not performed.

Conclusion

This is the first report of a pheochromocytoma and concurrent cortical tumor in the cat. Despite its rarity, a pheochromocytoma should be considered as a differential diagnosis for an enlarged adrenal gland in the cat. Further, pheochromocytoma should not be completely ruled out by the presence of bilateral adrenal gland enlargement or a positive LDDST. In two of the four cases of feline pheochromocytomas reported to date, the cats died postoperatively.^3,5 Two of the cats that survived surgery had perioperative hypotension during removal of the adrenal, as was observed in the cat reported here.⁴ Thus, an increased risk may accompany surgery in cats with pheochromocytomas, but a favorable outcome may be achieved without perioperative mortality. Thirty-six months have passed since surgery, and the cat described in this report remains free of clinical signs. The cat has been maintained on both methylprednisolone acetate and DOCP every 30 days without further incident.