Clinical hypocalcemia following surgical resection of apocrine gland anal- sac adenocarcinomas in 3 dogs

Abstract

Three canine patients were presented with marked hypercalcemia secondary to an apocrine gland anal sac adenocarcinoma (AGASCA). Two of the patients underwent treatment for hypercalcemia before surgical resection of their tumors, including diuresis and the administration of bisphosphonates. All dogs developed clinically symptomatic hypocalcemia 2 to 4 days following surgery. Clinical signs included facial rubbing, muscle fasciculations, lameness, and collapse. The dogs each required calcium supplementation and close monitoring of serum ionized calcium, as inpatients and continuing after discharge. Hypocalcemia and associated clinical signs resolved with treatment in all cases.

Humoral hypercalcemia of malignancy (HHM) is a common cause of hypercalcemia in dogs. The pathophysiology behind HHM is related to tumor-cell production of parathyroid hormone-related peptide (PTHrP), a promoter of osteoclastic activity, and osteolysis secondary to bone metastasis (1,2). Tumor types known to commonly cause HHM include lymphosarcoma, apocrine gland anal sac carcinoma (AGASCA), and squamous cell carcinoma (3). Humoral hypercalcemia of malignancy has been reported in 27% to 53% of canine patients with AGASCA (1,2). The mainstay of treatment for AGASCA involves surgical resection of the primary tumor, with or without extirpation of nodal metastases. Adjuvant radiation and chemotherapy is elected in some cases (2,4–7).

Hypocalcemia following surgical resection of AGASCA in a previously hypercalcemic patient is rare. To the authors’ knowledge, there has only been 1 other reported case in the veterinary literature (8). The presumed mechanism of calcium dysregulation in these patients is secondary hypoparathyroidism. Parathyroid hormone-related peptide production by the tumor leads to high circulating calcium levels and hence, down regulation of PTH production by the parathyroid glands. Removal of the tumor can therefore lead to hypocalcemia due to a PTH deficiency in these patients. Hypocalcemia leads to neuromuscular hyperexcitability. Clinical signs are varied and can include seizures, muscle tremors and fasciculations, stiff gait, jaw “champing,” panting, facial rubbing, biting at paws, behavioral changes, vomiting, diarrhea, inappetence, and lethargy (9). The aim of this case report is to raise awareness of the potential for clinical hypocalcemia following resection of a PTHrP producing AGASCA, which is a rare but potentially life-threatening complication.

Case descriptions

Case 1

A 9-year-old neutered male border collie cross dog was referred for workup of a palpable caudal abdominal mass. The dog had a 6-week history of intermittent inappetence and vomiting. The owners also noted shaking hindlimbs at rest and polydipsia. Physical examination demonstrated a palpable dorso-caudal abdominal mass but was otherwise unremarkable. The anal sacs had no palpable abnormalities following evacuation.

Abdominal ultrasound was performed, and the mass was identified as severe bilateral medial iliac and hypogastric lymph node enlargement, measuring 58 × 27 mm on the left and 24 × 34 mm on the right (Figure 1). Fine-needle aspirate (FNA) of the lymph nodes was consistent with carcinoma. Complete staging was performed, consisting of complete blood (cell) count (CBC), biochemistry, and a computed tomography (CT) scan of the thorax, abdomen, and neck (pre- and post-contrast). Blood analysis demonstrated increased total calcium at 3.83 mmol/L [reference range (RR): 1.98 to 3.00 mmol/L]. The CT scan demonstrated severe enlargement of the medial iliac and hypogastric lymph nodes, causing compression of the caudal vena cava and iliac veins. Both anal sacs showed hypoechoic fluid content and no asymmetry in size. No definitive primary anal sac lesion was found on CT and there were no palpable abnormalities of either sac. Incidental findings included small hepatic nodules. Serum ionized calcium was markedly elevated at 2.41 mmol/L (RR: 1.00 to 1.40 mmol/L). Other serum chemistry and a CBC were within normal limits.

Figure 1.

Preoperative CT image (post contrast) showing enlarged sublumbar and hypogastric lymph nodes within the trifurcation of the aorta (red arrows) in Case 1: sagittal view (A), dorsal view (B), and transverse view (C).

The dog was administered pamidronate (Pamisol; Hospira, Victoria, Australia) 1.2 mg/kg body weight (BW), IV, and fluid diuresis with 0.9% sodium chloride for management of the hypercalcemia. Within 24 h the ionized serum calcium was reduced to 2.12 mmol/L. Surgical resection of the metastatic lesions in the medial iliac and hypogastric lymph nodes was performed without complications 48 h after administration of pamidronate (Figure 2). The surgeon opted to continue monitoring the anal sacs for palpable lesions and proceed with surgical resection if indicated in the future. The ionized serum calcium was reduced to 1.41 mmol/L 24 h following surgery and was 1.40 mmol/L 48 h after surgery. There were no complications in the immediate peri-operative period. Histopathology of the removed lymph nodes was consistent with metastatic anal sac adenocarcinoma.

Figure 2.

Intraoperative view of enlarged sublumbar lymph nodes (yellow arrows) (A) and following resection (B) in case 1.

The patient was presented 4 d after surgery due to apparent discomfort and a waxing-waning lameness. On re-examination he was distinctly painful on palpation of the caudal lumbar dorsal spinous processes with no apparent neurological deficits. He also had muscle fasciculations and intermittent pain responses on palpation of all limbs. The dog was also exhibiting episodes of recumbency with vocalization and hyperesthesia. Ionized serum calcium at this time was low at 0.69 mmol/L.

The patient was treated with methadone (Methone; Ceva Animal Health, New South Wales, Australia), 0.4 mg/kg BW, IM, q12h, tramadol (Tramal; Grunenthal, Germany), 2.5 mg/kg BW, PO, q8h, and gabapentin (Neurontin; Pfizer, New York, New York, USA), 10 mg/kg BW, PO, q12h, for analgesia, and intravenous fluid therapy with Hartmann’s solution (Compound Sodium Lactate; Baxter, New South Wales, Australia) before workup. Following the diagnosis of hypocalcemia, the patient was administered an intravenous calcium gluconate (Phebra, New South Wales, Australia) constant rate infusion (CRI), 10 mg/kg BW per hour for 4 d until normocalcemia was achieved, based on ionized serum calcium. Concurrently, oral calcitriol (Amneal Pharmaceuticals, Victoria, Australia), 0.01 mg/kg BW, q8h, and oral calcium carbonate (Caltrate; Pfizer), 60 mg/kg BW, q8h, were administered, and were continued following discharge. Additionally, the patient received oral diazepam (APO-Diazepam; Apotex, New South Wales, Australia), 0.1 mg/kg BW, q8h, for muscle relaxation, a fentanyl CRI (Fentanyl GH; Generic Health, Victoria, Australia), 4 μg/kg BW per hour and subsequent placement of a fentanyl patch (Durogesic; Janssen, New South Wales, Australia) 3.75 μg/kg BW per hour for ongoing analgesia.

Ionized serum calcium was closely monitored every 48 h for 2 wk following discharge. When mild hypercalcemia occurred, with ionized serum calcium of 1.54 mmol/L (2 wk following initial hypocalcemia diagnosis), oral calcitriol and calcium gluconate dosages were weaned off gradually over a period of 10 wk. The dog made a full recovery and was normocalcemic following cessation of supplementation over a follow-up time of 22 wk, with ionized calcium ranging from 1.25 to 1.37 mmol/L. The dog’s anal sacs remained palpably normal over this time.

Six months after surgery the dog had a repeat abdominal ultrasound and CBC, and serum biochemistry. There were no hematological abnormalities, but recurrence of hypercalcemia was evident, with a total calcium of 3.1 mmol/L (RR: 2.2 to 2.8 mmol/L) and an ionized serum calcium of 1.46 mmol/L. Ultrasonography demonstrated a large (52 × 39 mm) ovoid lesion in the region of the hepatic lymph nodes in the midcranial abdomen (suspect lymph node) and another smaller lesion, similar in appearance, arising from the periphery of the right medial liver lobe. No abnormalities were seen at the site of medial iliac lymph node resection or in any other regions of the abdomen. Fine-needle aspirates from the larger mass were obtained for cytology using ultrasound guidance. Cytology was consistent with a small cell adenocarcinoma. The owner also reported some mild deterioration in the patient’s exercise tolerance and appetite, increased lethargy, and frequent diarrhea. The owner declined further surgery and opted for palliative care with pamidronate 1.5 mg/kg BW to manage the dog’s hypercalcemia. Within 2 d of pamidronate administration the patient was clinically doing well with improved energy levels and appetite.

At 8 to 9.5 mo after surgery, the patient remained persistently hypercalcemic (2.02 to 2.41 mmol/L) which was managed with 2 further pamidronate infusions at 1.5 to 2.25 mg/kg BW. At 10.5 mo after surgery, despite persistent hypercalcemia, further pamidronate infusions were declined. The patient was euthanized 11 mo after surgery due to lethargy and declining quality of life.

Case 2

A 10-year-old spayed female Labrador retriever dog was presented for a presumptive AGASCA and refractory hypercalcemia. Five days before presentation, the dog was evaluated by the referring veterinarian for excessive twitching in her sleep. A right anal sac mass was palpated and cytology was consistent with a carcinoma. A CBC was unremarkable, but a chemistry panel revealed a total calcium of 5 mmol/L (RR: 2.3 to 2.9 mmol/L). Calcium diuresis with intravenous 0.9% sodium chloride was initiated. The total calcium remained elevated 48 h following initiation of fluid therapy so pamidronate (Pamidronate Disodium Injection; Pfizer Medical, Bridgewater, New Jersey, USA), 1.6 mg/kg BW, IV, was given. The dog was then referred for refractory hypercalcemia 48 h after initial presentation.

On presentation the dog’s vital parameters were within normal limits. On physical examination a firm nodular right anal sac mass was palpated along with an abdominal mass in the caudal abdomen. The ionized serum calcium was 2.15 mmol/L (RR: 1.18 to 1.37 mmol/L). The remainder of the physical examination and preoperative blood analysis were unremarkable. Abdominal ultrasound revealed lymphadenomegaly of the right medial iliac lymph node and the internal iliac lymph nodes. Calcium diuresis was initiated with intravenous fluid therapy (0.9% NaCl), furosemide (Furosemide injection; MWI, Boise, Idaho, USA), 0.7 mg/kg BW per hour, IV, and a single dose of dexamethasone (Dexamethasone sodium phosphate; Bimeda-MTC Animal Health, Cambridge, Ontario), 0.05 mg/kg BW, IV. Twenty-four hours later the dog’s ionized serum calcium was decreased (1.84 mmol/L) and surgery was performed to remove the primary anal sac mass and the metastatic nodes. No complications were recorded during surgery. Twenty-four hours after surgery the ionized serum calcium was 1.49 mmol/L, at 48 h it was 1.33 mmol/L. The dog was discharged to the care of her owners.

Four days following discharge the dog was taken to the referring veterinarian for panting excessively, trouble walking, and pain. Total calcium was decreased at 1.65 mmol/L (RR: 2.3 to 2.9 mmol/L). The dog was administered a single dose of calcium gluconate (Cal-Nate 1069; Grand Island, Nebraska, USA), 5 mg/kg BW, IV, which resolved the clinical signs. Calcium supplementation was not initiated. Four days following the initial crisis, the dog was again presented to the referring veterinarian for panting, tremors, and collapse. Ionized calcium was 0.74 mmol/L.

The dog was treated with 2 injections of calcium gluconate (0.5 mg/kg BW, IV) and started on supplementation with calcitriol (calcitriol oral solution; West-Ward Pharmaceuticals, Eatontown, New Jersey, USA), 0.015 μg/kg BW, PO, q12h, and calcium carbonate (Tums; GlaxoSmithKline Consumer Healthcare, Moon Township, Pennsylvania, USA), 750 mg PO, q12h. The dog was monitored in hospital for 3 d then discharged with close observation. Following an episode of hypercalcemia, oral supplementation of calcitriol and calcium was discontinued. On recheck examination 3 wk following surgery, ionized serum calcium was 1.41 mmol/L and the dog was doing well.

Four months after surgery the dog was presented for a rapid onset of muscle tremors. On physical examination the dog had a frequent cough and pain on palpation of the cervical region. The dog’s ionized serum calcium was elevated at 2.0 mmol/L (RR: 1.18 to 1.37 mmol/L) and thoracic radiographs revealed evidence of thoracic metastases. The owner elected euthanasia.

Case 3

A 10-year-old neutered male bichon frise dog was presented because of a 3-cm perirectal mass that was incidentally found on routine physical examination. A CBC was unremarkable and a serum chemistry panel revealed hypercalcemia (3.7 mmol/L; RR: 2.3 to 2.9 mmol/L) and hypophosphatemia (0.74 mmol/L; RR: 0.9 to 1.7 mmol/L). Ionized calcium was significantly elevated at 1.82 mmol/L (RR: 1.18 to 1.37 mmol/L). Cytology of the mass was consistent with an AGASCA. Chest radiographs were unremarkable. Abdominal ultrasound revealed urinary cystic calculi but no other abnormalities. Sublumbar lymph nodes were reported to be within normal size.

Resection of the anal sac mass was performed and the patient recovered uneventfully from surgery. The dog was treated with hydromorphone (Hydromorphone hydrochloride; Sandoz Canada, Boucherville, Quebec), 0.1 mg/kg BW, IV, q6h, meloxicam (Metacam; Boehringer Ingelheim, Duluth, Georgia, USA), 0.1 mg/kg BW, PO, q24h, and intravenous fluids (0.9% NaCl + 20 mEq KCl/L). Forty-eight hours after surgery the dog was noted to have muscle fasciculations and was exhibiting face rubbing. An ionized calcium level revealed hypocalcemia (0.82 mmol/L). This was treated with a 2 mg/kg BW, IV injection of calcium gluconate followed by a CRI at 1 mg/kg BW per hour. Oral calcium carbonate (25 mg/kg BW, PO, q12h) and calcitriol (0.025 μg/kg BW, PO, q 24h) supplementation was initiated. The dog was discharged 8 d after surgery and slowly weaned off calcium supplementation over the following months. He was euthanized 4 y later secondary to intractable seizures, the cause of which was not investigated.

Discussion

Humoral hypercalcemia of malignancy is a common sequela of AGASCA, with hypercalcemia at presentation historically associated with reduced survival (1,2). Return to normocalcemia is generally seen following successful surgical tumor excision, and tumor recurrence or progression is generally associated with recurrence of hypercalcemia (10). Normal homeostatic mechanisms tightly regulate calcium levels. In healthy animals parathyroid hormone (PTH) acts to regulate extracellular calcium levels through its influence on bone resorption, renal reabsorption of calcium and phosphorus and formation of the active metabolite of vitamin D, calcitriol. A negative feedback loop exists whereby increased calcium levels downregulate the production of PTH and lower calcium levels increase PTH secretion (9).

Subsequent to removal of a PTHrP secreting neoplasm, ionized serum calcium levels drop. In most cases, a return to normocalcemia is considered a marker of successful treatment of AGASCA, indicating the body’s return to a state of homeostasis (10). However, in the cases reported here, despite lowered ionized calcium levels, the parathyroid glands appeared unable to produce sufficient endogenous PTH to maintain appropriate serum calcium levels. Saba et al (8) hypothesized that chronic suppression of the parathyroid glands from high circulating calcium levels in HHM subsequently led to glandular atrophy. This was based on inappropriately low PTH levels in combination with hypocalcemia, following removal of a PTHrP secreting anal sac adenocarcinoma. Similar rebound hypocalcemia is reported following induction of chemotherapy in patients with HHM related to lymphosarcoma (11,12). In order to accurately assess the pathophysiology of the hypocalcemic episodes in the cases described in this paper, measurement of PTH and PTHrP during treatment would be ideal.

In 2 cases described herein, pamidronate was administered before surgery. This may have further contributed to dysregulation of calcium homeostasis in these patients. Pamidronate primarily acts to inhibit calcium resorption from bone, and has been demonstrated to have a median duration of effect of 8.5 wk in canine patients (13). This indicates that these patients were likely to be under the effects of pamidronate at the time they developed clinical signs of hypocalcemia. There is a possibility that the reduction in resorption of calcium from the bones contributed to the patients’ episodes of severe hypocalcemia. The other single reported case of rebound hypocalcemia (8) did not receive pamidronate as treatment. Pamidronate should, however, be used with caution for pre-operative management of these patients, and serial ionized serum calcium measurements should be employed after surgery to monitor for evidence of rebound hypocalcemia.

Interestingly, in case 1, the primary tumor was not identified. It was presumed that the neoplastic disease noted in the medial iliac and hypogastric lymph nodes was secondary to an anal sac adenocarcinoma, based on both location and histopathology results. Another similar case has been reported, in a dog with a retroperitoneal mass with a histopathological diagnosis of apocrine gland adenocarcinoma. This patient had no evidence of primary anal sac disease (14). Due to the rarity of this presentation, it is difficult to speculate on the significance of our inability to identify the primary tumor in this case. In a study of 21 dogs with metastatic cancer of unknown primary origin, 57% were carcinoma (15).

It is reasonable to believe that rebound hypocalcemia following surgical treatment of anal sac adenocarcinoma is relatively rare, and therefore not a significant risk consideration for most clinicians treating these patients. However, when it does occur it can lead to significant increases in hospitalization time and costs for owners and can be life-threatening to the patient. The authors believe it is essential to categorize this syndrome as an important post-operative complication to increase awareness and vigilance in monitoring patients for clinical hypocalcemia. In addition, caution should be exercised in regard to the use of pre-operative bisphosphonates to decrease circulating calcium levels when removal of a PTHrP secreting tumor is planned.