Adrenocortical Carcinoma in a Dog with Incomplete Excision Managed Long-term with Metastasectomy Alone

Introduction

Primary adrenal gland tumors can be either nonfunctional or secrete steroid hormones such as glucocorticoids, mineralocorticoids, sex hormones, or catecholamines. Adrenocortical tumors traditionally have been assumed to secrete a single hormone; however, the ability to secrete hormones with different functions (e.g., a glucocorticoid and a mineralocorticoid) must be considered. Secretory ability should be evaluated preoperatively to best manage the patient intraoperatively and to anticipate postoperative complications and therapeutic needs.

The following report documents a case of an adrenal tumor that had the ability to secrete both aldosterone and corticosterone (a glucocorticoid that is not typically measured). In addition, although the tumor was not completely resected, the patient had a long survival, and the response to metastasectomy was extremely positive. To date, metastasectomy has not been reported for treatment of a functional adrenocortical tumor, although it is done for a potentially similar endocrine tumor, insulinoma.

Case Report

A 10 yr old castrated male bichon frise weighing 9.5 kg presented to his primary veterinarian with a 3 mo history of polyuria, polydipsia, hind limb weakness, and lameness (day 0). Serum biochemistry revealed hypokalemia (2.9 mEq/L; reference range, 3.6–5.5 mEq/L) with serum Na at the upper end of normal (152 mEq/L; reference range, 139–154 mEq/L). Urine specific gravity was 1.018 with an elevated pH 7.5 (reference range, 5.5–7.0) and 2 + calcium oxalate crystalluria. Urine culture was negative for bacterial growth. Serum thyroxine concentration was also normal (41.2 nmol/L; reference range, 12.9–51.5 nmol/L), and a mild thrombocytosis was present (483,000/μL; reference range, 170,000–400,000/μL). The owner elected to monitor the condition without specific treatment, but decided to pursue further diagnostic testing after 2 wks because of progressive clinical signs.

On day 14, the dog returned to the primary veterinarian for further assessment. Serum biochemistry revealed a persistent hypokalemia (2.6 mEq/L) and a normal serum Na concentration (154 mEq/L). Serum creatinine kinase was elevated (4,863 IU/L; reference range, 59–895 IU/L). Hypertension was also present (systolic blood pressure was > 180 mm Hg). The complete blood count (CBC) was unremarkable. Differentials for the hypokalemia included fluid therapy, drug administration (e.g., diuretics), gastrointestinal fluid loss, hyperaldosteronism, renal disease, and renal failure. Given the profound hypokalemia, no history of administration of drugs that could cause the clinical signs, hypertension, or hypokalemia, no history of either vomiting or diarrhea, and the absence of azotemia, the primary differential diagnosis was hyperaldosteronism. On day 18, abdominal and thoracic radiographs were performed and were unremarkable (not shown). Abdominal ultrasonography revealed a left adrenal mass with right adrenal gland atrophy.

Endocrine testing was initiated on day 21 (Table 1). An adrenocorticotropic hormone (ACTH) stimulation test was performed. Cosyntropin^a (1 μg/kg IV) was administered and venous blood samples were collected 0 min and 60 min postinjection. Basal cortisol concentration was at the low end of normal (30 nmol/L; reference range, 30–140 nmol/L) and the stimulated cortisol concentration was low (199 nmol/L; reference range, 220–470 nmol/L). Basal serum 17-α-OH progesterone concentration was also low (0.03 ng/mL; reference range for a castrated male, 0.06–0.30 ng/mL). Basal serum aldosterone concentration was elevated (1,747 pmol/L; reference range 14–957 pmol/L) and the ACTH-stimulated aldosterone concentration was also high (> 3,329 pmol/L; reference range, 197–2,103 pmol/L).

Table 1 Basal and ACTH-stimulated Cortisol, Aldosterone, and Corticosterone Concentrations and Basal Endogenous ACTH Concentration

*

Based on ACTH stimulation test results in six normal greyhounds

ACTH, adrenocorticotropic hormone; N/A, not applicable; ND, not detected.

View Fullscreen

On day 24, the patient was referred to Veterinary Surgical Specialists of Orange County for further evaluation. On physical exam, the dog weighed 7.9 kg and he was bright, alert, and responsive. Temperature, pulse, and respiration were within normal limits. Cardiac and pulmonary auscultation and abdominal palpation were unremarkable. An orthopedic exam revealed a mild lameness of the left pelvic limb. A mild cranial drawer sign was present on palpation of the left stifle and medial patellar luxation (grade 2 of 4) was present in the right stifle. Systolic blood pressure was > 180 mm Hg.

Given the previous diagnostic test results, an aldosterone-secreting adrenal tumor was suspected. Secondary hyperaldosteronism due to overactivity of the renin-angiotensin system appeared less likely based on the clinical information available. Unfortunately, primary hyperaldosteronism could not be confirmed due to the lack of a commercially available plasma renin activity assay. No additional endocrine testing was performed. Left adrenalectomy was recommended and phenoxybenzamine^b was prescribed (2.5 mg per os [PO] q 12 hr for 3 wk) in preparation for surgery in the event the mass was a pheochromocytoma. Because phenoxybenzamine can have hypotensive effects, other antihypertensive agents were not prescribed.

On day 46, the patient underwent exploratory laparatomy. The preoperative systolic blood pressure, before administration of any medications, was 81 mm Hg. A left adrenalectomy was performed. Because the mass invaded the left phrenicoabdominal vein and the kidney, a left nephrectomy was also performed. The left adrenal mass (measuring approximately 4 cm × 3 cm × 2 cm) extended intraluminally into the vena cava. The remainder of the abdomen appeared unremarkable on visual inspection. The resection appeared to be complete (grossly) during surgery; however, histopathology of the resected tissue confirmed a left adrenal cortical carcinoma with incomplete excision. The tumor was comprised of nests and packets of eosinophilic vacuolated cells with mildly pleomorphic round nuclei and few mitotic figures. The cells invaded through the capsule and extended to the edge of the section. Immunohistochemistry for chromagranin and synaptophysin was negative, which ruled out a tumor originating from the medulla of the adrenal gland.

One day postoperatively (day 47), hypokalemia (1.5 mEq/L) was present; however, the serum potassium concentration subsequently (and consistently) increased and was within the reference interval within 72 hr of surgery. Systolic and diastolic blood pressures (three separate measurements) were normal. An ACTH stimulation test was performed using 2.2 U/kg corticotrophin gel^c. A persistent basal hypocortisolemia (8 nmol/L) was noted, but the ACTH-stimulated concentration was normal (300 nmol/L). Baseline aldosterone concentration was undetectable, whereas the ACTH-stimulated aldosterone concentration was normal (384 pmol/L). Because the patient was in the intensive care unit and a low baseline cortisol was considered inappropriate, prednisone^d was prescribed (5 mg PO q 12 hr for 7 days then 5 mg PO q 24 hr).

On day 57, serum biochemistry and a CBC revealed elevated concentrations of potassium (6.5 mEq/L), phosphorus (8.5 mg/dL; reference range, 2.1–6.3 mg/dL), blood urea nitrogen ([BUN] = 67 mg/dL; reference range, 7–27 mg/dL), and creatinine (2.1 mg/dL; reference range, 0.4–1.8 mg/dL), elevated alkaline phosphatase ([ALP] = 544 U/L; reference range, 10–150 U/L) and elevated alanine aminotransferase (188 U/L; reference range 5–107 U/L), a monocytosis (1,666/μL; reference range, 150–1,350/μL), and thrombocytosis (621,000/μL). A urinalysis revealed a urine specific gravity of 1.035 and a benign sediment.

Endocrine testing was repeated on day 58. Both basal and ACTH-stimulated cortisol concentrations were low (8 nmol/L and 86 nmol/L, respectively). The decreased cortisol concentrations were believed to be due to the negative feedback by the prednisone administration on the pituitary, diminishing ACTH secretion and leading to adrenocortical atrophy. As azotemia can be due to glucocorticoid and/or mineralocorticoid deficiency and hypokalemia can be due to mineralocorticoid deficiency, concern arose regarding an aldosterone deficiency either with or without possible underdosing of glucocorticoid supplementation. As prednisone possesses both glucocorticoid and mineralocorticoid activity, the prednisone dose was increased on day 58 to 5 mg PO q 12 hr. The plan was to maintain that dose of prednisone until day 70 before being tapered to 5 mg PO q 24 hr for 14 days then 5 mg PO q 48 hr for approximately 6 wk.

All clinical signs resolved within 14 days postoperatively (day 60). Reexamination on day 61 revealed normokalemia. Serum creatinine was normal; however, the following parameters were elevated: phosphorus (6.2 mg/dL), BUN (68 mg/dL), alanine aminotransferase (195 IU/L), and ALP (449 IU/L). The patient had a leukocytosis with a total WBC count of 30,300/μL (reference range, 4,000–15,500/μL) due to a neutrophilia (26,900/μL; reference range, 2,000–10,000/μL) and a monocytosis (1,800/μL; reference range, 0–840/μL). A thrombocytosis was present (estimated to be >600,000/μL) which could be attributed to glucocorticoid administration. The elevated BUN concentration could have been due to either mild dehydration or gastrointestinal bleeding, but the packed cell volume was normal and therefore did not support the latter. Diet may have also played a role in the elevated BUN. The cause of the leukocytosis was unclear, possibly attributable to either the prednisone therapy (and the recent dose increase) or postoperative inflammation. The degree of leukocytosis was greater than expected for either explanation. Given that the patient did not have a fever and was clinically stable, the decision was made to reexamine the dog in approximately 5–7 days.

On day 70, the dog had an increased serum phosphorus concentration (7.3 mg/dL) and an elevated ALP (322 IU/L). All other previous laboratory abnormalities had resolved. A partial CBC showed a leukocytosis of 19,920 μL (reference range, 6,000–17,000 μL) with a thrombocytosis of 626,000/μL, which were both consistent with glucocorticoid administration. The cause of the hyperphosphatemia was unclear given the dog was fed a commercial diet, was not being supplemented with phosphorus, had a normal serum Ca concentration, and was not azotemic.

Reexamination on day 92 revealed normal serum potassium (4.5 mEq/L) and phosphorus (5.5 mg/dL) concentrations. Systolic blood pressure was within normal limits. Serum ALP remained mildly elevated (160 IU/L). Basal and ACTH-stimulated cortisol concentrations were within normal limits (144 nmol/L and 295 nmol/L, respectively). The patient was still receiving 5 mg prednisone PO q 48 hr at that time, but the owners were instructed to discontinue the prednisone therapy approximately 8 wk after surgery.

Approximately 2 yr (day 740) after initially presenting to the primary veterinarian, the patient re-presented with a 2 mo history of polyuria and polydipsia. The reappearance of clinical signs was suspected to be related to regrowth and/or metastasis of the original tumor. Blood work again revealed hypokalemia (2.6 mEq/L) and thoracic radiographs were unremarkable. Abdominal computed tomography showed no evidence of local recurrence, but two hypoattenuating mass lesions within the left side of the liver were noted that had heterogenous contrast-enhancement (Figures 1A, B). Contrast-enhancing nodules were also present within the spleen. No evidence of a caudal vena cava filling defect was seen. Systolic and diastolic blood pressures were 140 mm Hg and 80 mm Hg, respectively.

View Figure

• Download as Powerpoint
• Download Figure

An ACTH stimulation test was performed. Basal and ACTH-stimulated aldosterone concentrations were elevated (both > 3,329 pmol/L). Basal and ACTH-stimulated cortisol concentrations were 86 nmol/L and 326 nmol/L, respectively. Although the cortisol concentrations at recurrence were within normal limits, the mildly suppressed ACTH-stimulated cortisol concentration prior to the left adrenalectomy and a low baseline cortisol concentration on postoperative day 1 were suggestive of right adrenal gland cortex suppression by hormones with glucocorticoid activity. Corticosterone concentrations were measured^e with an assay validated for measurement of canine corticosterone.¹ The sensitivity of the assay was 10 nmol/L. Basal serum corticosterone concentration was 227 nmol/L and ACTH-stimulated corticosterone was > 1,320 nmol/L, which were comparable to concentrations reported previously in dogs with corticosterone-secreting tumors.^2,3 As the findings were suggestive of an aldosterone- and corticosterone-secreting metastatic adrenal carcinoma of the liver, an exploratory laparotomy was scheduled.

Six days later (day 746), an exploratory laparotomy, splenectomy, and left lateral and left medial liver lobectomies were performed (Figure 2). The liver lobes and spleen were submitted for histopathology. A nodule < 2 cm in diameter was present in each resected lobe. The biopsy results confirmed metastatic endocrine carcinoma of the liver with complete excision for both nodules. The metastases were identical in appearance to the original tumor, and immunohistochemistry results were the same. There was no evidence of neoplasia within the spleen. On the first day postoperatively, an ACTH stimulation test was performed. All corticosteroid hormone concentrations were decreased compared to preoperatively. Basal and ACTH-stimulated cortisol, aldosterone, and corticosterone concentrations were 17 nmol/L and 132 nmol/L, 472 pmol/L and 418 pmol/L, and undetectable and 18 nmol/L, respectively. The plasma endogenous ACTH concentration was low (5.5 pmol/L; reference range, 6.7–25.0 pmol/L), most likely due to negative feedback on the pituitary gland by corticosterone secretion from the tumor. The patient recovered without complication from surgery and was again prescribed prednisone (5 mg PO q 12 hr).

View Figure

• Download as Powerpoint
• Download Figure

Clinical signs again resolved within 2 wk of surgery. The dog was clinically stable, and the aldosterone concentrations were within normal limits (basal and ACTH-stimulated aldosterone concentrations were 663 pmol/L and 1262 pmol/L, respectively). A partial CBC showed a thrombocytosis (798,000/μL) with a mild granulocytosis (13,050/μL). Serum ALP activity was elevated (290 U/L), most likely associated with the exogenous glucocorticoid administration. Basal cortisol (116 nmol/L) and ACTH-stimulated concentrations (353 nmol/L) were within normal limits. The dog was reportedly doing well 1,353 days (3.5 yr) after initial presentation.

Discussion

To the authors’ knowledge, this is the first report of a dog with a metastatic adrenal carcinoma successfully managed with surgical management as the only therapy. Less than 1% of all canine neoplasms are estimated to occur in the adrenal glands, and four main types of secretory adrenal tumors exist.⁴ Adrenocortical tumors may secrete mineralocorticoids, glucocorticoids, or sex hormones. Adrenal medullary tumors (i.e., pheochromocytomas) secrete catecholamines. The most common canine adrenal gland tumors are adrenocortical adenomas and carcinomas secreting glucocorticoids (i.e., Cushing’s syndrome). A search of the Veterinary Medical Database from 1985 to 1996 found that adrenocortical adenomas comprised 58% of canine adrenal tumors, adrenocortical carcinomas comprised 20%, and pheochromocytomas or other neuroendocrine medullary tumors comprised 22% of all canine primary adrenal tumors.⁴

Adrenal carcinomas reportedly metastasize to multiple locations including, but not limited to, the liver, spleen, kidneys, lungs, and tricuspid valve.^3,5 Adrenocortical tumors that secrete multiple hormones are rare. To the authors’ knowledge, there have been only two previous case reports of an adrenocortical tumor producing both mineralocorticoids and glucocorticoids.^2,3

Hyperaldosteronism is a rare endocrine disorder affecting cats more commonly than dogs.⁶ To the authors’ knowledge, only four cases of canine hyperaldosteronism have been reported.^2,3,7,8 Aldosterone is a mineralocorticoid produced within the adrenocortical zona glomerulosa. The hallmark of primary hyperaldosteronism is suppression of plasma renin activity. Excess circulating aldosterone concentrations lead to sodium retention and an expansion of the extracellular fluid and plasma volume. That expansion is registered by stretch receptors in the renal juxtaglomerular apparatus and renin secretion is suppressed.⁹ In the dog described herein, plasma renin activity was not measured due to lack of a commercially available assay. Other general diagnostic and endocrine results consistent with a diagnosis of primary hyperaldosteronism include persistent hypokalemia, systemic hypertension, metabolic alkalosis, normal to elevated serum Na concentrations, and the presence of an adrenal tumor. Causes of secondary hyperaldosteronism such as cardiovascular or renal failure and severe generalized hepatocellular dysfunction were ruled out in this case.

Clinical signs associated with mineralocorticoid excess include polyuria/polydipsia, anorexia, and retinal hemorrhage or detachment secondary to systemic hypertension.⁶ Hypokalemia is a common clinical manifestation because increased aldosterone levels promote potassium excretion into the urine. In addition, total potassium stores decrease as potassium shifts from the intracellular to the extracellular storage site in an attempt to maintain serum potassium concentration. The movement of potassium to the extracellular environment results in a reverse shift of hydrogen ions with an increased renal excretion of hydrogen ions leading to metabolic alkalosis. If potassium depletion is severe enough, alkalosis, thirst, and polyuria may develop with compensatory polydipsia. Potassium depletion is also thought to cause a resistance to vasopressin, leading to polyuria.⁹ Systemic hypertension is believed to initially be secondary to increased vascular volume due to sodium retention. With chronicity, the systemic hypertension is more closely associated with increased systemic vascular resistance.¹⁰

Medical management of mineralocorticoid excess includes use of spironolactone (an aldosterone antagonist), oral potassium supplementation, and antihypertensive agents such as amlodipine. Interestingly, the dog described in this case report apparently responded to phenoxybenzamine as an antihypertensive agent, at least based on the finding of a single preoperative blood pressure that was approximately normal. Ideally, blood pressure would have been monitored once or more between initiation of phenoxybenzamine therapy and the surgery to ensure the hypertension was controlled. Spironolactone may have been a better choice of therapy given the identification of hyperaldosteronism; however, the dog could have been in a more chronic phase of increased systemic vascular resistance allowing for the response to an α-adrenergic blocker.

In a suspected case of a functional adrenal tumor, preoperative endocrine evaluation may aid in confirming a diagnosis. This case report emphasizes the importance of preoperative endocrine testing to not only arrive at a definitive diagnosis but also to establish a baseline for postsurgical monitoring, to better prepare for endocrine imbalances that may occur postoperatively, and to determine appropriate intra- and postoperative medical management. Adrenal tumors can secrete multiple hormones, and the effects of one hormone may dominate over the clinical signs of other hormones. Diagnostic testing can reveal evidence of secretion of additional hormones. For example, elevated circulating concentration of aldosterone precursors, particularly deoxycorticosterone, can produce a similar clinical presentation to that seen in the dog of this case report.^10,11 Because corticosterone is a precursor of aldosterone, it may have contributed to the mineralocorticoid effects noted in this case, although likely to a lesser degree than aldosterone. Relative to cortisol, corticosterone, deoxycorticosterone, and aldosterone have 15 ×, 100 ×, and 3,000 × as much mineralocorticoid activity, respectively.²

To the authors’ knowledge, this is the first report of a dog with prolonged survival with an adrenocortical carcinoma treated surgically with an original adrenalectomy followed by removal of hepatic metastases. Reported survival postadrenalectomy for dogs with adrenocortical carcinoma has varied greatly.^6,10,12–15 Survival can be prolonged, with some dogs living approximately 54 mo postoperatively.^12,13,16 Clinical signs do not always recur, so surgery is potentially curative. If signs recur, either due to assumed or proven recurrence or metastasis, subsequent reported survival in cases with or without medical therapy and in which the dog had died or euthanized were 15 days, 3 mo, up to 5 mo, up to 7 mo, and 7–8 mo (in three dogs).^{11–13,15,16} To the authors’ knowledge, surgery has never been reported to remove adrenocortical metastases, although such practice does occur with other endocrine tumors with good success (such as insulinomas). In comparison with previously reported survivals postrecurrence, the dog of this case was alive 1.5 yr after the second surgery and was reportedly doing well.

Weaknesses associated with this case report include the lack of a commercially available assay to measure plasma renin activity to prove that primary hyperaldosteronism was present. However, all possible criteria of the diagnosis were met, and the aldosterone concentrations decreased greatly postoperatively. In addition, corticosterone was not measured before the first surgery, so whether the original tumor secreted corticosterone remains unknown. Considering the metastases did secrete corticosterone, the original tumor likely did as well.

Conclusion

For dogs with an adrenocortical tumor, the possibility that the tumor is secreting more than one hormone needs to be considered, and secretory ability may need to be evaluated with appropriate testing both pre- and postoperatively to identify therapeutic needs. Hormones not typically measured may be the cause of some clinical signs or clinicopathologic abnormalities (e.g., corticosterone or desoxycorticosterone), and additional testing may need to be sought. Even with incomplete resection of an adrenal mass, survival may be long, and additional surgery without chemotherapy can be a beneficial option for palliation.