Hypocalcemia after Surgical Removal of an Anal Sac Adenocarcinoma in a Dog

My patient is a 55 pound (25 kg), 11-year old, female English Springer who presented with polyuria,  polydipsia, and a decreased appetite.  Physical examination revealed a huge (apple-sized) anal sac mass and enlarged sublumbar lymph nodes on rectal palpation (presumably metastatic disease).

Routine blood work revealed severe hypercalcemia (16.5 mg/dl). Fortunately, the renal function still appeared to be adequate, as evidenced by the normal serum concentrations of both urea nitrogen and creatinine. However, the urine specific gravity was low at 1.007.

Hypercalcemia was confirmed by finding a very high serum ionized calcium concentration (2.1 mmol/L; reference interval, 1.25-1.45 mmol/L). A serum parathyroid hormone (PTH) concentration was suppressed (0.2 pmol/L; reference interval, 0.5 - 5.8 pmol/L), consistent with PTH-independent (e.g., malignant) hypercalcemia.

One week ago, I removed the anal sac tumor along with the enlarged sublumbar lymph nodes (lymphadenectomy). The dog did well in the immediate post-surgical period, but she started showing anxiety and facial itching 3 to 4 days ago. Yesterday, the owner finally brought her back for a recheck, and she was exhibiting severe signs of hypocalcemia, with muscle twitching, anxiety, and panting. We don't have the ability to measure ionized calcium in-house, but her total calcium value was low at 4.8 mg/dl.

I administered calcium gluconate slowly by intravenous injection "to effect," which resolved the sigs of hypocalcemia.  Over the next 2 hours, multiple IV doses were required to prevent return of her twitching and other signs of hypocalcemia. Therefore, we started her on a constant rate infusion (CRI) of calcium gluconate to maintain the serum calcium concentration in the low-normal range and prevent clinical signs.

We also started the dog on calcitriol (Rocaltrol) later that day as soon as she could swallow, using an initial dose of 0.5 µg, followed by a second dose of 0.25 µg 12 hours later. We also started oral calcium carbonate (Tums) at a dose of 3000 mg divided TID. This protocol worked well, bringing her serum calcium up to 8.4 mg/dl the following morning, with no return of clinical signs of hypocalcemia. She started eating within an hour of first infusion.

I weaned her off CRI throughout today. After 4 hours, the serum calcium concentration had fallen to 7.4 mg/dl, but she had no clinical signs and acted great. Now 18 hours later, she is still doing well clinically on twice daily oral calcium and calcitriol (0.25 µg).

So I assume I will be treating her with calcitriol for a few weeks at a tapering dose. I understand the standard maintenance is 5-15 µg/kg/day divided BID with food (1,2). Of course, that means that I'll have to have the drug compounded into that dosage by a compounding pharmacy, with its cost and delay. Is there an alternative dosing scheme that would work for her?

My Response:

Malignancies commonly associated with hypercalcemia in dogs include T cell lymphoma and adenocarcinomas derived from the apocrine glands of the anal sac (3,4). In a recent study, lymphoma accounted for ≈75% of the dogs with ionized hypercalcemia and cancer (5).

Tumors in the apocrine glands of the anal sac appear primarily in middle-aged dogs and commonly lead to hypercalcemia. Clinical signs are referable to hypercalcemia (polyuria, polydipsia, anorexia, and weakness), a mass in the perineum (tenesmus, ribbon-like stools, increased odor, and protruding mass), a mass in the sublumbar region, or more distant metastases (6-12).

In addition to anal sac carcinoma, humeral hypercalcemia of malignancy can also develop in dogs with thymoma, myeloma, melanoma, or carcinomas originating in the lungs, pancreas, thyroid gland, skin, mammary gland, nasal cavity or adrenal medulla (3.4).

Hypocalcemia after treatment of malignant hypercalcemia
It is very unusual to see post-operative hypocalcemia in a dog suffering from a malignant tumor that has resulted in hypercalcemia of malignancy, but it certainly is possible if you have removed most or all of the cancerous tissue (13). Severe hypercalcemia, no matter what the cause, will suppress normal parathyroid hormone secretion (1-4); so now that the underlying cause of the hypercalcemia has been removed (the anal sac tumor), the dog currently has iatrogenic hypoparathyroidism.

Why do we commonly see postoperative hypocalcemia after removal of a parathyroid tumor (primary hyperparathyroidism) but only rarely see postoperative hypocalcemia after removal of a tumor associated with hypercalcemia of malignancy? Most likely, the difference is due to the fact that it is usually difficult to remove enough of the malignant, metastatic tissue responsible for the dog's hypercalcemia, whereas it's relatively easy to remove a parathyroid tumor(s) — at least once it's identified— since most of these parathyroid nodules are benign.

Protocol for treating postoperative (iatrogenic) hypocalcemia
With severe postoperative hypocalcemia, as seen in this dog, it's generally best to just go straight to a constant rate infusion of 10% calcium gluconate after initial stabilization (1,2).  To that end, 10% calcium gluconate should initially be given 0.5–1.5 ml/kg, IV, slowly over 20–30 minutes until clinical signs have subsided. An ECG should be used to monitor cardiac effects and the infusion stopped if there is ST segment elevation, QT shortening, or if arrhythmias develop. Thereafter, a continuous rate infusion should be used at 10–15 mg/kg/h (10–15 ml/kg over 24 hours) until oral therapy allows better control.

If you use intermittent injections of calcium gluconate, these must be be given via the intravenous route. Calcium salts should never be used subcutaneously, as this can lead to sterile abscess formation and skin sloughing in dogs (2).

Longer-term treatment for postoperative hypocalcemia includes the use of oral calcium and vitamin D (calcitriol) supplementation.  Successful management of this condition is rather expensive and requires intense monitoring, with serum total or ionized calcium measured at least once weekly and dose adjustment made as needed (1,2).

Eventually, this dog can be tapered off of both the calcium and vitamin D supplementation, but how quickly this will occur is impossible to predict. It could be days to many months, but recovery will likely occur within the next 2 to 3 months.This could be a good sign, indicating that the parathyroid glands are functioning again. On the other hand, this may also be a bad prognostic indicator, since this could also mean that the cancer (and humeral hypercalcemia) is recurring.

So it's not likely that you will need to keep this dog on the standard maintenance dosage (5-15 ng/kg/day divided bid) of calcitriol for very long (perhaps a couple weeks to a month) before you can try weaning completely off the drug.  In most of these dogs, the sizes of the Rocaltrol oral capsules (0.25 µg and 0.5 µg) are too large for maintenance. In these cases, an oral solution of calcitriol (Rocaltrol Oral Solution; 1 µg/ml) is available (14), or the calcitriol can be reformulated to the required concentration by a compounding pharmacy to assure accurate dosing.

References:

1. Chew D, Nagode L. Treatment of hypoparathyroidism. In: Bonagura JD, ed. Kirk’s Current Veterinary Therapy: XIII: Small Animal Practice. Philadelphia: Saunders; 2000:340–345.
2. Skelly BJ. Hypoparathyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012.
3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
4. Bergman PJ. Paraneoplastic hypercalcemia. Top Companion Anim Med  2012;27:156-158.
5. Messinger JS, Windham WR, Ward CR. Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003). J Vet Intern Med 2009;23:514-519.
6. Hause WR, DVM, Stevenson S, DVM, MS, Meuten DJD, et al. Pseudohyperparathyroidism associated with adenocarcinomas of anal sac origin on four dogs. J Am Anim Hosp Assoc 1981;17:373-379.
7. Meuten DJ, Cooper BJ, Capen CC, et al. Hypercalcemia associated with an adenocarcinoma derived from the apocrine glands of the anal sac. Vet Pathol 1981;18:454-471. 
8. Goldschmidt MH, Zoltowski C. Anal sac gland adenocarcinoma in the dog: 14 cases. J Small Anim Pract 1981;22:119-128. 
9. Ross JT, Scavelli TD, Matthiesen DT, et al. Adenocarcinoma of the apocrine glands of the anal sac in dogs: a review of 32 cases. J Am Anim Hosp Assoc 1991;27:349 - 355.
10. Bennett PF, DeNicola DB, Bonney P, et al. Canine anal sac adenocarcinomas: clinical presentation and response to therapy. J Vet Intern Med 2002;16:100-104. 
11. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995). J Am Vet Med Assoc 2003;223:825-831.
12. Hobson HP, Brown MR, Rogers KS. Surgery of metastatic anal sac adenocarcinoma in five dogs. Vet Surg 2006;35:267-270.
13. Saba C, Ellis A, Cornell K. Hypocalcemia following surgical treatment of metastatic anal sac adenocarcinoma in a dog. J Am Anim Hosp Assoc 2011;47:e173-177. 
14. Rocaltrol (calcitrol) web site. Assessed April 30, 2014.

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