Functional ectopic adrenal carcinoma in a dog

Abstract

An 11-year-old spayed female pit bull terrier was presented with a 2-month history of polyuria, polydipsia, polyphagia, and panting. Serum chemistry, blood and urine analysis, and tests for hyperadrenocorticism suggested an adrenal tumor. Abdominal ultrasound identified a mass caudal to the right kidney. The mass was completely excised and histopathology was consistent with endocrine carcinoma. Three years later there was no evidence of recurrence or metastasis.

Case description

An 11-year-old spayed female pit bull terrier was presented with a 1.5-month history of progressive polyuria (PU), polydipsia (PD), panting, and polyphagia. Two weeks earlier the dog had been evaluated by the referring veterinarian for similar signs. At that time blood work and a urine analysis showed elevated alkaline phosphatase activity and a low urine specific gravity of 1.018 (Table 1). An adrenocorticotropic hormone (ACTH) stimulation test (Table 2) showed low pre- and post-stimulation values. The dog was referred for continued evaluation at our facility. The clinical signs of PU/PD, panting, and polyphagia were progressive. The owner also reported lethargy and mild abdominal distension. Carprofen for osteoarthritis had been discontinued 2 wk prior to presentation. The dog was currently taking tramadol (Amneal Pharmaceuticals, Patterson, New Jersey, USA), 2.2 mg/kg, PO, q8–12h, prn for pain and diphenhydramine (Baxter, Deerfield, Illinois, USA), 2.2 mg/kg, PO, q24h for allergies. Physical examination showed normal vital signs (temperature: 38.4°C, pulse: 138 beats/min, respiratory rate: 30 breaths/min, mucous membranes pink and moist) and body weight 26.5 kg. No alopecia was noted. Thoracic auscultation and abdominal palpation were within normal limits. Pain and crepitation were palpated in both elbows and the right hip. The remaining examination was within normal limits. An abdominal ultrasound revealed mildly small adrenal glands and a 4.4 cm × 2.5 cm mass in the right cranial quadrant of the abdomen, potentially within the root of the mesentery. Fine-needle aspiration of the mass under ultrasound guidance revealed suppurative and histiocytic inflammation with peripheral blood contamination. The dog was discharged from the hospital with instructions to return in 3 wk for a repeat abdominal ultrasound and to continue a workup for hyperadrenocorticism (HAC) through the referring veterinarian during the interim.

Table 1.

Values for alkaline phosphatase (ALP), alanine transaminase (ALT) in U/L and urine specific gravity over time

	6 mo pre-op	2 mo pre-op	Just before mitotane therapy	9 days post-op	6 mo post-op	36 mo post-op
ALP (5 to 131 U/L)a	559	2008	3318	2028	747	680
ALT (12 to 118 U/L)a	37	ND	179	ND	ND	48
Urine specific gravity	1.047	1.018	1.018	ND	ND	1.036

^aValues in brackets denote reference interval.

ND = not done.

Table 2.

Results of pre- and post-operative adrenocorticotropic hormone (ACTH) stimulation tests in nmol/L

	ACTH stimulation pre-op	ACTH stimulation 2 wk post-op
Prea	88.3	115.9
Posta	80.0	132.4

^aReference interval = 151.7 to 551.8 nmol/L.

A low dose dexamethasone suppression test (LDDST) performed by the referring veterinarian showed results consistent with HAC (Table 3). A high dose dexamethasone suppression test (HDDST) was then performed and showed results consistent with either pituitary dependent HAC or a functional adrenal tumor (Table 3). Recheck serum chemistry and complete blood (cell) count (CBC) values showed a progressive rise in alkaline phosphatase (ALP) [3,318 U/L; reference interval (RI): 5 to 131 U/L] and alanine transaminase (ALT) (179 U/L; RI: 12 to 118 U/L) (Table 1).

Table 3.

Values (nmol/L) for pre-operative low dose dexamethasone suppression test (LDDST) and high dose dexamethasone suppression test (HDDST)

	LDDST pre-op	HDDST pre-op	LDDST 3 y post-op
Pre	102.1	110.4	149.0
Post 4 h	80.0	99.3	< 19.3
Post 8 h	80.0	91.0	82.8

The dog was presented to our facility for a repeat abdominal ultrasound 3 wk later as previously instructed. Clinical signs of PU, PD, polyphagia, and panting were still apparent to the owner. The mass in the region of the right mesentery had the same appearance, yet appeared to have increased in size to 4.7 cm × 3.7 cm, the rest of the abdomen was as previously reported. The owner was given treatment options and elected trial therapy with mitotane. The dog was started on a loading dose of mitotane (Henry Schein, Melville, New York, New York, (West-Ward Pharmaceutical, Eatontown, New Jersey, USA), 0.5 mg/kg BW, to be kept in case of crisis. Three days into the loading phase of mitotane, the owner elected to pursue surgical exploration of the abdomen. Mitotane was discontinued and surgery was performed the following day. Further endocrine testing was not performed before surgery.

Anesthetic pre-medication included morphine (Hospira, Lake Forest, Illinois, USA), 0.5 mg/kg BW, IM, acepromazine (Vedco, Shawnee Mission, Kansas, USA), 0.04 mg/kg BW, IM and glycopyrrolate (West-Ward Pharmaceutical), 0.02 mg/kg BW, IM. The dog was induced with propofol (Abbott Labs, North Chicago, USA) to effect and an endotracheal tube was placed. Anesthesia was maintained with isoflurane (Henry Schein) delivered in oxygen. A ventral midline celiotomy was performed and the abdomen explored. The liver appeared mildly enlarged but normal in color and architecture. Both adrenal glands were equally small to normal in size. A cystic glandular mass was found caudal to the right kidney and originating from the right ovarian pedicle (Figure 1). The surgical staples from the previous ovariohysterectomy were found proximal to the mass. The mass was completely excised proximal to the surgical staples to ensure adequate margins and that it was clear of the right ureter. The rest of the abdomen was within normal limits and the dog recovered uneventfully from anesthesia in the intensive care unit for the next 3 d until discharge. During recovery, serial electrolyte panels showed no signs of hyperkalemia. Inappetance was noted during the first 2 d which improved by day 3. Hypoalbuminemia (15 to 17 g/L; RI: 22 to 39 g/L) was noted during the postoperative hospital stay and was treated with a hetastarch constant rate infusion at 20 mL/kg BW per day until discharge. There was no vomiting or diarrhea during recovery. The dog was discharged from the hospital on the third postoperative day with the following medications: amoxicillin clavulanate (Zoetis, Kalamazoo, Michigan), 375 mg PO, q12h, tramadol (Anneal Pharmaceuticals), 100 mg PO, q8h, famotidine (Wockhardt Pharmaceuticals, Parsippany, New Jersey, USA), 20 mg PO, q12h, and metoclopramide (Hospira), 10 mg PO, q8h. A tapering dose of corticosteroids was not administered post-operatively; however, a single dose of dexamethasone sodium phosphate (Bimeda, Meridian, Idaho, USA), 0.1 mg/kg BW, IV, was administered on day 3 after surgery for peri-incisional inflammation.

Figure 1.

Intra-operative photograph showing the cystic glandular mass caudal to the right kidney at the site of the previous right ovary. The mass was excised deep to the surgical staples left from the previous spay procedure.

At 7 d after surgery, the dog was seen at the referring veterinarian for 12 h duration of anorexia, lethargy and 1 episode of vomiting. Vital signs were within normal limits, as was a physical examination. The dog was treated supportively as an outpatient and the owner reported the dog to be back to normal the next day. On day 9 after surgery, the dog was seen for a recheck examination at our facility. Physical examination was normal and the owner reported improvement in all clinical signs. Recheck serum chemistry and CBC values showed an improving ALP of 2028 U/L (Table 1), the remaining values were normal. A repeat ACTH stimulation test (Table 2) was found to be mildly low (Table 2). The incision had healed and all sutures were removed.

Sections of tissue from the mass lesion showed tumor consisting of nests and packets of cells separated from one another by a fine fibrovascular stroma. Nuclei were mildly pleomorphic, round, and had prominent nucleoli. Mitoses were occasionally present and the cells were vacuolated. Hemorrhage was present throughout. The tumor extended to but not beyond the margins of the submitted tissue samples. The histopathologic diagnosis was endocrine carcinoma, likely adrenal in origin. Histopathology of the liver sample showed severe, diffuse cloudy type cellular swelling consistent with a steroid induced hepatopathy.

The referring veterinarian reported all clinical signs resolved by 4 to 6 wk after surgery; however, the dog’s allergies had begun to worsen steadily since surgery. The next serum chemistry panel 6 mo after surgery showed an ALP of 747 U/L, other values were within normal limits. At that time, the dog was taking prednisone (West-Ward Pharmaceutical), 0.1 mg/kg BW, PO, q48h, for recurrence of severe allergies.

The owner and referring veterinarian were contacted 3 y after surgery for long-term follow-up. The owner was interviewed and reported a continued lack of PU, PD, polyphagia, and panting. The only problem reported was chronic osteoarthritis of both thoracic limbs for which the dog was taking tramadol (2.2 mg/kg BW, PO, q12h prn). The owner consented to repeat blood work and urine analysis, abdominal ultrasound, LDDST (Table 3) and survey thoracic (three view) and abdominal (two view) radiographs. No evidence of local recurrence or distal metastasis was evident on abdominal ultrasound or survey radiographs. Serum chemistry values showed mildly elevated ALP (680 U/L), cholesterol (3.87 g/L; RI: 0.92 to 3.24 g/L) and low glucose (3.66 mmol/L; RI: 3.89 to 7.66 mmol/L). The LDDST showed normal suppression at the 4 h post sample; however, a rebound effect was observed at the 8 h sample.

Discussion

This report describes the clinical course and response to surgical treatment alone for a dog with an ectopic adrenal carcinoma causing signs consistent with Cushing’s disease. Clinical signs were resolved by 6 wk after surgery and remained silent at long-term follow-up 36 mo later. Because specific hormonal assays were not performed prior to surgery, we are unable to report if the tumor excised was responsible for secreting glucocorticoids, mineralocorticoids, or other hormones.

In the immediate post-operative period, serial electrolyte panels were run in an effort to monitor for signs of typical Addison’s disease; however, none were observed. A repeat ACTH stimulation test was not done until 2 wk after surgery and may have aided in the diagnosis of atypical Addison’s disease in the immediate post-operative period, as well as defining the need for a tapering dose of corticosteroids after surgery. An Addisonian crisis was not observed during the post-operative period; however, mild clinical signs of lethargy and inappetance were noted. Sufficient up-regulation of normal adrenal tissue function was shown to have been present at 2 wk after surgery. Glucocorticoids were not administered immediately after surgery because pre-operative ACTH stimulation test results did not show high levels of glucocorticoids.

Long-term follow-up LDDST showed normal suppression at the 4 h interval; however, a rebound effect was seen at 8 h. This increase could be due to laboratory error, early onset of pituitary-dependent HAC, or non-adrenal illness. Should the initial tumor have recurred, no suppression would have been expected. The dog showed no clinical signs consistent with Cushing’s disease at home; therefore, this value will be rechecked by the referring veterinarian in the future. Long-term follow-up chemistry values showed a persistent mild elevation in ALP which has been present in this dog since surgery and presumed to be due to underlying non-clinical hepatopathy based on previous pathology results and repeat ultrasonographic imaging. The hypoglycemia is artifact due to the blood sample sitting an extended period of time before being spun down.

The authors are unaware of any previous reports describing Cushing’s disease secondary to an ectopic adrenal carcinoma in a dog. Therefore, survival rates and disease free intervals do not exist for such clinical problems. The dog described here was free of clinical signs and evidence of local or distant metastasis at 36 mo after surgery.

Approximately 15% of dogs diagnosed with HAC have excessive cortisol levels due to a function adrenal cortical tumor. Adrenocortical adenomas cannot be differentiated from a carcinoma by blood tests; however, adrenal carcinomas tend to be larger than adenomas and are usually > 50% normal kidney size at the time of diagnosis (1). In addition, roughly 50% of these tumors show some degree of mineralization, none of which was observed in this patient on ultrasonography or radiography. Along with cortisol, mineralocorticoids, aldosterone, and adrenal androgens are products of the adrenal gland that can be secreted in excess with a functional adrenal tumor; however, cortisol is by far the most common (2). Blood tests could have been performed to quantify the levels of these hormones prior to and following surgery to more clearly diagnose this dog’s problem. While the adrenal panel might have provided additional information regarding the dog’s condition, this test was not necessary in light of the hypercortisolism, with LDDST and HDDST being both abnormal. An endogenous ACTH test was offered to the clients but declined. The laboratory’s normal baseline cortisol level is 27.6 to 137.9 nmol/L. This meant that the baseline cortisol level found on the ACTH stimulation was within the normal range, but the post Cortrosyn cortisol level (80.0 nmol/L) was lower than the post-Cortrosyn laboratory reference range of 151.7 to 551.8 nmol/L. Baseline cortisols are of little value in the diagnosis of HAC. The cause for this low post-Cortrosyn cortisol level is uncertain. Use of oral or topical exogenous steroids can cause suppression of the adrenal axis. The client was interviewed regarding history of steroid therapy; however, none was reported.

Although the histopathologic diagnosis of the tumor in this dog was an adrenocortical tumor, the location of the tumor at the previous right ovariectomy site may also suggest the possibility of an ovarian-derived tumor in this dog, despite the lack of heat cycles over the preceeding 10 y. A previous report (3) of an ovarian steroid cell tumor resembling a luteoma was reported in a 6.5-year-old, intact female Rottweiler presenting with a 2-month history of PU, PD, muscle wasting, weight loss, and the development of a pot-bellied appearance. Similar to our patient, elevation in ALP (533 U/L) and ALT (242 U/L) was observed on a serum chemistry panel. A LDDST showed no suppression at 0, 6, and 8 h. This dog was taken to surgery and a 13-cm encapsulated cystic mass caudal to the right kidney was found in place of the right ovary. This mass was excised and a left ovariectomy was performed. After surgery, the dog experienced an Addisonian crisis which was treated supportively and with a tapering dose of corticosteroids over the following 3 wk. Repeat LDDST and urine cortisol:creatinine ratios performed 33 d after surgery showed a normal pituitary-adrenal axis. Ectopic adrenal tissue (4–6) and adrenocortical carcinoma (7) have been documented in the human literature. These ectopic tissues and neoplasms are suggested to arise along the gonadal descent and at adrenocortical rests (7). A non-functional adrenocortical neoplasm was described in a 5-month-old girl (7) who was presented for asymmetric paresis and increased crying at night. An MRI of the spinal column and abdomen showed a heterogeneously enhancing mass measuring 6 cm × 1.5 cm, in an intradural, extramedullary location at T10-L2. The mass was surgically removed without complication, but recurred 6 mo later. A second excision was performed and she underwent adjuvant chemotherapy at 5 mo post-surgery. Histopathology and immunohistochemistry of the initial tumor were consistent with an adrenocortical tumor of intermediate malignant potential. Ectopic adrenocortical tumors affecting the central nervous system of humans have shown a 5:1 predominance for females (7). Insulin-like growth factor-2, identified by fluorescent in-situ hybridization, is overexpressed in human adrenocortical carcinomas compared with adenomas (8). This could be a consideration for further investigation of future veterinary cases in which histopathology alone may not be definitive.

Ectopic ACTH Syndrome has been reported to occur in dogs; however, only in primary lung tumors (2). The active molecules responsible could be ACTH precursors, ACTH, endorphins, enkephalins, or melanocyte-stimulating hormone resulting in excessive cortisol production/secretion from both adrenal glands, in which case one would expect bilateral adrenal hypertrophy as seen in pituitary dependent HAC. Those types of tumors do not tend to show suppression on LDDST or HDDST. The lack of pulmonary masses or metastases observed on pre-operative and 3-year post-operative radiographs, and the resolution of clinical signs after abdominal mass excision argue against this clinical scenario in the case report described in this paper.

In conclusion, the HAC in this case was due to functional ectopic adrenal tissue located within the glandular mass removed during surgery. This patient had complete resolution of all clinical signs related to HAC after mass excision with no evidence of recurrence 3 y later based on repeat imaging. Curative treatment was achieved with surgery alone. CVJ