Surgical Thyroidectomy: A Useful Treatment Option for Dogs with Thyroid Carcinoma?

Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994–2010)

Joanne L. Tuohy, Deanna R. Worley, and Stephen J. Withrow

Journal of the American Veterinary Medical Association 2012;241:95–103

Tumors of the thyroid gland are the most common endocrine neoplasm of the dog. Thyroid carcinomas, while responsible for approximately 50–70% of all thyroid tumors diagnosed at postmortem examination, account for up to 90% of thyroid tumors detected during life (1-3). Therefore, all thyroid masses detected upon physical examination must be presumed to malignant until proven otherwise.

In dogs suffering from thyroid carcinoma, the likelihood for metastasis is high, with up to 38% of dogs having gross metastatic disease at the time of initial evaluation (4,5). The most common site for metastasis is the lungs, with other sites being the regional lymph nodes, jugular veins, and heart (1-3). Tumor size appears to be predictive of metastasis; in 1 study, dogs with tumor volumes < 21 cubic cm had a significantly lower risk of metastasis (2). The finding of vascular invasion by neoplastic cells is also suggestive of potential metastasis (5). Bilateral thyroid tumors are typically larger than unilateral tumors. In accord with that, one study reported that bilateral tumors were 16 times more likely to metastasize than unilateral thyroid tumors (6).

Treatment options for canine thyroid carcinoma include surgical resection, external radiation therapy, radioiodine therapy, and chemotherapy (7). The choice of treatment for a particular dog with a thyroid gland tumor depends on tumor size, vascularity, and invasiveness; whether the tumor is fixed or mobile upon palpation; and most importantly, whether gross metastatic disease is present (7-10). External beam radiation and radioiodine treatment are indicated for dogs deemed to have nonresectable tumors, such as fixed, deeply invasive, or bilateral tumors (3,6,7,11-14). Metastatic disease can be potentially treated with radioiodine or chemotherapy (7,15-18). Surgical thyroidectomy can be considered in thyroid tumors that are not large or invasive, with no evidence of metastasis (8-10).

To date, however, there are no published guidelines for surgical management of dogs with freely movable thyroid gland tumors. The purpose of the study reported by Tuohy et al (10) was to evaluate the outcome of resection of simultaneous discrete bilateral mobile thyroid gland carcinomas in dogs.  The hypothesis of this study was that dogs with bilateral, mobile thyroid gland carcinoma would be amenable to a single bilateral thyroidectomy procedure, even when parathyroid glandular tissue was not preserved and hypoparathyroidism would be likely. A second hypothesis of this study was that bilateral tumor development does not always necessitate a need for adjuvant chemotherapy in order to obtain prolonged survival.

Objective of this study—To evaluate the outcome of resection of simultaneous discrete bilateral mobile thyroid gland carcinomas in dogs.

Design— Retrospective case series.

Animals— 15 dogs with resected simultaneous discrete bilateral mobile thyroid gland carcinomas. The dogs ranged in age from 7.6 to 11.9 years, with 10 breeds affected.  Seven of the dogs were females, and 8 were castrated males.

Procedures— Medical records (from 1994-2010) were searched for dogs with the appropriate diagnosis and treatment. Information collected included signalment, clinical signs, diagnostic test results, tumor mobility (mobile tumor identified by movement ≥ 1 cm in all planes during palpation), complications, adjuvant treatments, and outcome.

Results— Prior to surgery, serum thyroxine (T4) concentrations were assessed in 10 of the 15 dogs. Four dogs had low serum T4 concentrations (<1.0 μg/dL), and 2 dogs had high serum T4 concentrations (7.4 and 4.5 μg/dL); these dogs had no associated clinical signs. Four dogs were euthyroid (2.0 and 1.6 μg/dL). None of the dogs were treated with supplemental L-T4 prior to thyroidectomy.

Preoperatively, 6 dogs underwent ultrasound examination of the cervical region, 2 had thyroid scintigraphy, and 3 had computed tomographic (CT) scans.

Mobile, discrete, bilateral thyroid gland carcinomas were removed in all dogs. Among the 15 dogs, complete parathyroidectomies were necessary in 9; parathyroid tissue was reimplanted in 4 and preserved in 2. Complications included hemorrhage and laryngeal nerve trauma, but without serious consequences. Thirteen dogs received calcitriol with or without supplemental calcium after surgery.

In the immediate postoperative period, hypocalcemia developed and was corrected in 11 dogs. At the last study followup, 7 dogs continued to receive calcitriol with or without supplemental calcium, and 8 dogs required long-term thyroid hormone treatment.

Serum total T4 concentrations, as assessed at the end of the immediate postoperative period, were low in 4 dogs, within reference range in 4 dogs, and slightly high in 2 dogs. Serum total T4 concentrations in 5 dogs were not determined. Eleven dogs received thyroid hormone treatment (ie, L-T4) whereas 3 dogs did not.

Six dogs received adjuvant chemotherapy. Local tumor recurrence or de novo distant metastasis was not detected at each dog’s last follow-up examination. Median survival time was 38.3 months. Three dogs were lost to follow-up, 8 survived (4.3 to 77 months after surgery), and 4 died of unrelated causes.

Thyroid hormone replacement therapy had a significant effect on overall survival time; median survival time was 38.3 months among  the 11 dogs that received L-T4 and 17.5 months among 3 dogs that did not receive L-T4 (Figure 1). Otherwise, there were no significant effects of chemotherapy or administration of supplemental calcitriol or calcium among the dogs.

Figure 1: Survival curve for dogs that were given L-T4 supplementation (dashed line; n = 11) and dogs that were not given L-T4 following surgery (solid line; 4)

Conclusions and Clinical Relevance— In dogs with thyroid gland carcinomas undergoing bilateral thyroid lobectomies, a successful outcome can be expected, even when parathyroid gland tissue cannot be preserved. The role of adjuvant chemotherapy in treatment outcome was not clearly defined.

My Bottom Line

This study by Tuohy et al (19) suggests that surgical resection is a viable treatment option for dogs with bilateral mobile thyroid gland carcinoma and that a good prognosis can be expected. Thyroid tumor mobility was the most important criterion for determining feasibility of successful resection in these dogs. The size of these tumors did not impact resection or patient survival, nor was preservation of parathyroid gland tissue critical.

Should adjunct chemotherapy or radiotherapy be given to dogs with thyroid carcinoma?
Vascular or lymphatic invasion (or both) by tumor cells was commonly detected during histologic examination of excised thyroid carcinomas (i.e., in 9 of the 15 dogs). This finding suggests that these affected dogs could benefit from adjuvant chemotherapy or external radiotherapy because such invasive tumors likely have a higher risk of metastasis.

None of the dogs in this study received adjuvant external radiotherapy or radioiodine therapy, so neither of these treatments could be evaluated. However, 6 dogs did undergo adjuvant chemotherapy (doxorubicin only or with carboplatin), but their survival time did not differ from the other dogs that did not receive any chemotherapy. This finding highlights the need for more definitive studies on the role of adjuvant chemotherapy in the treatment of thyroid gland carcinoma in dogs.

Postoperative thyroid hormone treatment for dogs with thyroid carcinoma?
After bilateral thyroidectomy, one would expect serum T4 and T3 levels to decrease into the subnormal  range within 1 to 2 days after surgery. If normal or high T4 values are found in the postoperative period (as reported in 6 dogs of this report), functional thyroid metastasis should be suspected and other follow-up tests of thyroid function (e.g., serum thyroid panel, thyroid uptake and scintigraphy) performed. Why 6 of the dogs of this study had normal to slightly high serum T4s in the "immediate" postoperative period is unclear since no additional follow-up information was reported. It is certainly possible — and even likely— that repeat thyroid testing done at a later date would have revealed low serum T4 values.

In human patients, administration of large doses of thyroid hormone is commonly used as an adjunct treatment after surgery, with the goal of inducing mild hyperthyroidism and completely suppressing circulating TSH to low or undetectable levels (20-22). Circulating TSH can serve as a growth factor to stimulate growth of residual tumor cells; therefore, suppression of TSH may prevent or slow the regrowth of carcinoma tissue in patients with residual neoplastic disease.

In this study, it was interesting that thyroid hormone supplementation appeared to improve survival time in the 11 dogs treated (see Figure 1). Unfortunately, it is not known if TSH suppression was achieved in these dogs since the dose(s) of L-T4 given to these dogs was not provided, and follow-up post-pill serum thyroid hormone or TSH values were not reported. However, two things are very clear— it can be difficult to produce iatrogenic hyperthyroidism in dogs with L-T4 supplementation and that high doses would be needed to completely suppress TSH secretion (23,24).

In the end, it's really impossible to know if the L-T4 therapy really had any true suppressive effect on thyroid carcinoma regrowth or on the dog's survival.  That all said, it remains an interesting observation, and high-dose thyroid hormone suppressive therapy certainly deserves to be investigated as an adjuvant  treatment for dogs with thyroid carcinoma.

References

1. Brodey RS, Kelly DF. Thyroid neoplasms in the dog. A clinicopathologic study of fifty-seven cases. Cancer 1968;22:406-416. 
2. Leav I, Schiller AL, Rijnberk A, et al. Adenomas and carcinomas of the canine and feline thyroid. Am J Pathol 1976;83:61-122.  
3. Barber LG. Thyroid tumors in dogs and cats. Vet Clin North Am Small Anim Pract 2007;37:755-773. 
4. Birchard SJ, Roesel OF. Neoplasia of the thyroid gland in the dog—a retrospective study of 16 cases. J Am Anim Hosp Assoc 1981;17:369–372. 
5. Harari J, Patterson JS, Rosenthal RC. Clinical and pathologic features of thyroid tumors in 26 dogs. J Am Vet Med Assoc 1986;188:1160-1164.  
6. Theon AP, Marks SL, Feldman ES, et al. Prognostic factors and patterns of treatment failure in dogs with unresectable differentiated thyroid carcinomas treated with megavoltage irradiation. J Am Vet Med Assoc 2000;216:1775-1779.  
7. Peterson ME: Hyperthyroidism and thyroid tumor in dogs. In: Melian C, Perez Alenza MD, Peterson ME, Diaz M, Kooistra H (eds): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Multimedica, Barcelona, Spain, 2008, pp 113-125. 
8. Klein MK, Powers BE, Withrow SJ, et al. Treatment of thyroid carcinoma in dogs by surgical resection alone: 20 cases (1981-1989). J Am Vet Med Assoc 1995;206:1007-1009. 
9. Liptak JM. Canine thyroid carcinoma. Clin Tech Small Anim Pract 2007;22:75-81. 
10. Radlinsky MG. Thyroid surgery in dogs and cats. Vet Clin North Am Small Anim Pract 2007;37:789-798, viii.  
11. Pack L, Roberts RE, Dawson SD, et al. Definitive radiation therapy for infiltrative thyroid carcinoma in dogs. Vet Rad Ultrasound 2001;42:471-474. 
12. Brearley MJ, Hayes AM, Murphy S. Hypofractionated radiation therapy for invasive thyroid carcinoma in dogs: a retrospective analysis of survival. J Small Anim Pract 1999;40:206-210. 
13. Brearley MJ. Radiation therapy for unresectable thyroid carcinomas. J Am Vet Med Assoc  2000;217:466-467. 
14. Mayer MN, MacDonald VS. External beam radiation therapy for thyroid cancer in the dog. The Can Vet J 2007;48:761-763.  
15. Worth AJ, Zuber RM, Hocking M. Radioiodide (131-I) therapy for the treatment of canine thyroid carcinoma. Aust Vet J 2005;83:208-214. 
16. Turrel JM, McEntee MC, Burke BP, et al. Sodium iodide I 131 treatment of dogs with nonresectable thyroid tumors: 39 cases (1990-2003). J Am Vet Med Assoc 2006;229:542-548. h 
17. Fineman LS, Hamilton TA, de Gortari A, et al. Cisplatin chemotherapy for treatment of thyroid carcinoma in dogs: 13 cases. J Am Anim Hosp Assoc 1998;34:109-112. 
18. Jeglum KA, Whereat A, Young K. Chemotherapy of canine thyroid carcinoma. Compend Contin Educ Pract Vet 1983;5:5:96–98. 
19. Tuohy JL, Worley DR, Withrow SJ. Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994-2010). J Am Vet Med Assoc 2012;241:95-103. 
20. Clark OH. TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 1981;5:39-47. 
21. Deasy J, Prichard RS, Evoy D, et al. The role of thyrotropin suppression in patients with differentiated thyroid carcinoma. Ir Med J 2010;103:202-205. 
22. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid 2010;20:135-146. 
23. Piatnek DA, Olson RE. Experimental hyperthyroidism in dogs and effect of salivariectomy. Am J Physiol 1961;201:723-728. 
24. Kaptein EM, Hays MT, Ferguson DC. Thyroid hormone metabolism. A comparative evaluation. Vet Clin North Am Small Anim Pract 1994;24:431-466. 

Iatrogenic Hyperthyroidism in a Boxer Treated with Massive Doses of L-T4

My problem case is a 9-year-old F/S Boxer (weighing 30 kg) that was diagnosed as hypothyroid by another veterinarian about a year ago. She has been on 1.2 mg of levothyroxine (L-T4) every 12 hours. Clinically, the dog is doing very well, but she has mild polyuria and polydipsia. I have never had a dog on this high of a L-T4 dose, so I'm worried about thyroid hormone overdose and cardiac complications.

I did a complete thyroid profile at Michigan State University's Endocrine Laboratory (see results of the panel, below). The sample was collected about 6 hours after the morning L-T4 was administered. As you can see, the free T3 is extremely high, but the total T3 is undetectable.

I'm really confused. My questions include the following:

1. Why the discordant results between the total and free T3 levels in this dog?
2. Do I need to worry about the high FT3?
3. Is the high T3 autoantibody value significant?
4. Is this dog now hyper- or hypothyroid?
5. Does this dog have a T4 to T3 conversion defect?
6. Should I lower the L-T4 dose or add L-T3 to this dog's treatment regimen?

My Response:

Your dog has very high serum levels of T3 autoantibodies, together with lower, but detectable, levels of both T3 and thyroglobulin autoantibodies.  When thyroid hormone autoantibodies are present, they can interfere with immunoassays used to measure the serum concentrations of either T4 or T3 (or both) (1-4). In the radioimmunoassays used at the Michigan State Endocrine Laboratory, the presence of high T3 autoantibodies will cause a false elevation of the serum FT3 concentration and a false lowering of the total T3 (the value of "0" in this dog). These thyroid hormone values are spurious —they represent a laboratory artifact because it is difficult to accurately measure the true hormone concentration when these autoantibodies are present (1-4).

Thyroid autoantibodies in dogs with hypothyroidism
Lymphocytic thyroiditis is a frequent cause of hypothyroidism in dogs and is generally accepted to have an autoimmune pathogenesis. Part of the immune response is reflected by production of thyroid autoantibodies (1-4).

The most common thyroid autoantibody detected in dogs are thyroglobulin autoantibodies (2-5). These autoantibodies do not interfere with the standard measurement of serum total or free thyroid hormone concentrations. Thyroid hormone autoantibodies that bind to T3 or T4 are seen less frequently (2-6); however, when high T4 or T3 autoantibody titers are reached, the antibodies may interfere with the hormone immunoassay measurements to produce erroneous thyroid test results.

Does this dog have a T4 to T3 conversion defect?
The short answer is no —a dog with an undetectable serum T3 concentration despite a normal T4 concentration (before or after L-T4 treatment) is not a dog with a T4 to T3 conversion defect. Again, in this dog, the presence of T3 autoantibodies has resulted in an artefactual low T3 result (5,6). The true serum T3 concentration may actually be normal, and we certainly do not have to supplement with L-T3 in this dog.

Such a T4 to T3 conversion defect has not ever been recognized in either normal dogs or dogs with hypothyroidism (2-4).

How common are thyroid hormone autoantibodies in dogs suffering from hypothyroidism?
Investigators have reported that 35% of dogs with hypothyroidism will have T3 autoantibodies whereas 14% have T4 autoantibodies (5-7). Almost all dogs with T3 or T4 autoantibodies will also have positive titers for thyroglobulin autoantibodies; thus, positive results are evidence of thyroid autoimmunity. The relatively high incidence of positive T3 autoantibodies may explain why the diagnostic accuracy of T3 measurements is poor in dogs suffering from hypothyroidism.

The 10 breeds with the highest prevalence of thyroid hormone antibodies, many of those with a propensity for autoimmune thyroiditis, were the Pointer, English Setter, English Pointer, Skye Terrier, German Wirehaired Pointer, Old English Sheepdog, Boxer, Maltese, Kuvasz, and Petit Basset Griffon Vendeen (3).

My Bottom Line: Adjusting the thyroid hormone dose in this dog
It is important to recognize that these antibodies have no influence on the choice or dosage of thyroid medication, because the capacity of the antibodies to bind thyroid hormone is relatively small and can be saturated with administered thyroid hormone (5,6).

In this dog, you are going to have to regulate the L-T4 dose based upon the dog's clinical signs and serum concentrations of total T4, free T4, and TSH. Serum total or free T3 should not be measured because the T3 autoantibodies will only produce spurious test results that will confuse diagnostic interpretation.

At this time, this dog is showing clinical signs consistent with mild hyperthyroidism (i.e., polyuria and polydipsia). This finding, together with the borderline high serum T4 and completely suppressed TSH concentrations, suggests that the dog's current L-T4 dose is too high.

Dogs are quite resistant to developing iatrogenic hyperthyroidism, but this dog's current dose of 2.4 mg per day is extremely high. Almost all dogs respond quite nicely to doses of 20 µg/kg, administered either once or twice daily, which calculates into a dose of only 25-50% of the current L-T4 dose given to this dog.

For this dog, I'd try cutting the L-T4 dosage in half and monitoring again in another 4 weeks. Remember that thyroid hormone supplementation is best give on an empty stomach to enhance absorption (8).

References:

1. Kemppainen RJ, Young DW. Canine triiodothyronine autoantibodies. In: Kirk RW, Bonagura JD, editors. Current Veterinary Therapy XI: Small Animal Practice. Philadelphia: W.B. Saunders Co; 1992. p. 327-330.
2. Graham PA, Refsal KR, Nachreiner RF. Etiopathologic findings of canine hypothyroidism. Vet Clin North Am Small Anim Pract 2007;37:617-631. 
3. Ferguson DC. Testing for hypothyroidism in dogs. Vet Clin North Am Small Anim Pract 2007;37:647-669.   
4. Mooney CT. Canine hypothyroidism: a review of aetiology and diagnosis. N Z Vet J 2011;59:105-114.
5. Nachreiner RF, Refsal KR, Graham PA, et al. Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. J Am Vet Med Assoc 2002;220:466-471. 
6. Nachreiner RF, Refsal KR, Thacker EL, et al. Incidence of T3 and T4 autoantibodies in dogs using a sensitive binding assay (abstract). J Vet Intern Med 1990;4:114.
7. Refsal KR, Nachreiner RF. Thyroid hormone autoantibodies in the dog: their association with serum concentrations of iodothyronines and thyrotropin and distribution by age, sex, and breed of dog. Canine Pract 1997;22:16–17.
8. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther 2008;31:95-101. 

Top Endocrine Publications of 2012: The Canine Thyroid Gland

In my fifth compilation of the canine and feline endocrine publications of 2012, I’m moving on to disorders of the canine thyroid gland. Listed below are 27 research papers written in 2012 that deal with a variety of thyroid gland topics and issues of clinical importance.

These range from use of recombinant human thyrotropin for diagnosis and an an aid to treatment in dogs with hypothyroidism and thyroid tumors (1,2) to case reports of congenital hypothyroidism in dogs (3,5,9); from studies of the effects of hypothyroidism on glucose metabolism (6) or aggression (20) to studies of thyroid carcinoma (7,11,17,19,25,26,27).

Other studies included dietary hyperthyroidism in a dog (8) to the reproductive effects of hypothyroidism in dogs (16); and finally, from ectopic thyroid tissue (7,22) to an evaluation of quantitative thyroid scintigraphy as a diagnostic test for dogs (24).

References:

1. Campos M, Peremans K, Vandermeulen E, et al. Effect of recombinant human thyrotropin on the uptake of radioactive iodine (123-I) in dogs with thyroid tumors. PLoS One 2012;7:e50344. 
2. Campos M, van Hoek I, Peremans K, et al. Recombinant human thyrotropin in veterinary medicine: current use and future perspectives. J Vet Intern Med 2012;26:853-862. 
3. Dodgson SE, Day R, Fyfe JC. Congenital hypothyroidism with goiter in Tenterfield terriers. J Vet Intern Med 2012;26:1350-1357. 
4. Fyfe JC, Lynch M, Olsen J, et al. A thyroid peroxidase (TPO) mutation in dogs reveals a canid-specific gene structure. Mamm Genome 2012. 
5. Gal A, Raetzman LT, Singh K. Congenital adenohypophyseal hypoplasia associated with secondary hypothyroidism in a 2-week-old Portuguese water dog. Can Vet J 2012;53:659-664. 
6. Hofer-Inteeworn N, Panciera DL, Monroe WE, et al. Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs. Am J Vet Res 2012;73:529-538. 
7. Kang MH, Kim DY, Park HM. Ectopic thyroid carcinoma infiltrating the right atrium of the heart in a dog. Can Vet J 2012;53:177-181. 
8. Köhler B, Stengel D, Neiger R. Dietary hyperthyroidism in dogs. J Small Anim Pract 2012;53:182-184.
9. Kuczynski LA, Schwartz P, Peddle G, et al. Goiter with vascular anomalies in a litter of Polish Lowland sheepdogs. J Am Anim Hosp Assoc 2012;48:278-283. 
10. Lowrie M, De Risio L, Dennis R, et al. Concurrent medical conditions and long-term outcome in dogs with nontraumatic intracranial hemorrhage. Vet Radiol Ultrasound 2012;53:381-388. 
11. Metivier KS, Deitz K, Xu WW, et al. Gene expression profiling demonstrates differential expression of osteopontin in follicular thyroid carcinomas compared to normal thyroid tissue in dogs. Vet Comp Oncol 2012;doi: 10.1111/j.1476-5829.2012.00348:1-17. 
12. Muntener T, Schuepbach-Regula G, Frank L, et al. Canine noninflammatory alopecia: a comprehensive evaluation of common and distinguishing histological characteristics. Vet Dermatol 2012;23:206-e244. 
13. Nakamura RK, Russell NJ, Shelton GD. Adult-onset nemaline myopathy in a dog presenting with persistent atrial standstill and primary hypothyroidism. J Small Anim Pract 2012;53:357-360. 
14. Narula HS. Accidental thyrotoxicosis caused by inadvertent ingestion of levothyroxine "dog-tabs" by a veterinarian with hypothyroidism. Am J Med 2012;125:e3. 
15. Nelson LL, Coelho JC, Mietelka K, et al. Pharyngeal pouch and cleft remnants in the dog and cat: a case series and review. J Am Anim Hosp Assoc 2012;48:105-112. 
16. Panciera DL, Purswell BJ, Kolster KA, et al. Reproductive effects of prolonged experimentally induced hypothyroidism in bitches. J Vet Intern Med 2012;26:326-333. 
17. Pessina P, Castillo V, Araujo M, et al. Expression of thyroid-specific transcription factors in thyroid carcinoma, contralateral thyroid lobe and healthy thyroid gland in dogs. Res Vet Sci 2012;93:108-113. 
18. Piechotta M, Jens R, Rick M, et al. Serum transthyretin concentration is decreased in dogs with nonthyroidal illness. Vet Clin Pathol 2012;41:110-113. 
19. Proverbio D, Spada E, Perego R, et al. Potential variant of multiple endocrine neoplasia in a dog. J Am Anim Hosp Assoc 2012;48:132-138. 
20. Radosta LA, Shofer FS, Reisner IR. Comparison of thyroid analytes in dogs aggressive to familiar people and in non-aggressive dogs. Vet J 2012;192:472-475. 
21. Ricci R, Bevilacqua F. The potential role of leptin and adiponectin in obesity: a comparative review. Vet J 2012;191:292-298. 
22. Roth DR, Perentes E. Ectopic thyroid tissue in the periaortic area, cardiac cavity and aortic valve in a Beagle dog - a case report. Exp Toxicol Pathol 2012;64:243-245. 
23. Scott-Moncrieff JC. Thyroid disorders in the geriatric veterinary patient. Vet Clin North Am Small Anim Pract 2012;42:707-725.
24. Shiel RE, Pinilla M, McAllister H, et al. Assessment of the value of quantitative thyroid scintigraphy for determination of thyroid function in dogs. J Small Anim Pract 2012;53:278-285. 
25. Tuohy JL, Worley DR, Withrow SJ. Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994-2010). J Am Vet Med Assoc 2012;241:95-103.
26. Urie BK, Russell DS, Kisseberth WC, et al. Evaluation of expression and function of vascular endothelial growth factor receptor 2, platelet derived growth factor receptors-alpha and -beta, KIT, and RET in canine apocrine gland anal sac adenocarcinoma and thyroid carcinoma. BMC Vet Res 2012;8:67.
27. Lane AE, Wyatt KM. Paraneoplastic hypercalcemia in a dog with thyroid carcinoma. Can Vet J 2012;53:1101-1104. 

Medical Treatment of Insulinomas

Dietary or medical management of insulinoma is recommended for animals that are showing signs of hypoglycemia and have previously undergone surgery and in those whose owners have declined surgery (1-6).

Specific chemotherapy can also be considered in animals in which all of the tumor cannot be resected and in those that have undergone previous surgery and again are showing signs of hypoglycemia. Just over half of dogs with insulinoma have metastases at the time of diagnosis (1-4), so it is reasonable to discuss the possibility of follow-up chemotherapy after surgery. Chemotherapy should be given only to patients with a confirmed histologic diagnosis of insulinoma.

Dietary management of hypoglycemia
Animals with insulinoma should be fed a diet that is high in protein, fat, and complex carbohydrates. Simple sugars, often contained in semimoist pet foods, should be avoided. Dogs should be fed small meals three to four times daily. Cats and ferrets may be fed free choice if they do not become obese. Exercise should be controlled and owners should attempt to limit excitement in these pets.

Glucocorticoids
Glucocorticoids are recommended when frequent feedings are no longer successful in controlling clinical signs of hypoglycemia. These drugs raise blood glucose by inhibiting glucose uptake in the peripheral tissues (creating insulin resistance) and stimulating hepatic glucose production (7-9).

Oral prednisone (or prednisolone) is started at the dosage of 0.25 mg/kg, twice daily (1-6). This dosage may be increased gradually as needed to control clinical signs or may be decreased if the disease is well controlled at the initial dosage. We should remember, however, that dosages of 1.1 mg/kg or higher given twice daily are considered immunosuppressive.

Diazoxide
Diazoxide (Proglycem, Teva Pharmaceuticals) is a nondiuretic benzothiadiazide that decreases insulin secretion, promotes gluconeogenesis and glycogenolysis, and inhibits the cellular uptake of glucose (10-12). Diazoxide can be difficult to obtain in the United States; however, reputable compounding pharmacies can often supply this drug.

The recommended starting dosage of diazoxide is 5 mg/kg, given orally twice daily (1-6,13). As with prednisone, the dosage may be increased as needed to control clinical signs. The maximal recommended dosage is 30 mg/kg twice daily.

The most common side effects of diazoxide are anorexia, vomiting, and diarrhea (1-6,13). These signs may be avoided or lessened by giving the medication with food. Ferrets find the diazoxide suspension distasteful, but because only small volumes are required, owners usually are able to administer it. Other potential side effects of diazoxide are hyperglycemia, bone marrow suppression, and sodium retention.

Octreotide acetate
Somatostatin is a polypeptide hormone that inhibits the secretion of insulin, glucagon, gastrin, secretin, and motilin. Octreotide acetate (Sandostatin, Novartis) is a long-acting somatostatin analogue that can be used in the management of patients with insulinoma (14).

Reports on the use of octreotide acetate in veterinary patients are limited and the response is mixed (4,12,15). About half of dogs with refractory hypoglycemia will show a response to octreotide acetate.  Ferrets refractory to other forms of treatment may show improvement in clinical signs in some, but certainly not all, cases.

The recommended dosage is 1 to 2 μg/kg given subcutaneously two to three times daily. This drug is relatively expensive, but may be practical for use in small dogs, cats, or ferrets due to their small size.

Currently, there is no way of predicting which patients will respond to octreotide acetate. Metastatic lesions may express fewer somatostatin receptors than the primary mass, so octreotide may be less effective in patients with advanced disease. This agent does appear to be safe and can be administered by owners at home. Thus, it should be considered for the treatment of animals with insulinoma that are refractory to or unable to tolerate traditional medical or surgical therapy (4,12).

Streptozotocin
Streptozotocin (Zanosar, Teva Pharmaceuticals) is a chemotherapeutic drug that selectively destroys pancreatic beta cells (16-19). When given alone, this drug may cause severe, acute renal failure in dogs. However, the drug can be administered safely if given with aggressive saline diuresis (17-19). Treatment is discontinued if there is clear tumor progression, resistant or recurrent hypoglycemia, or drug toxicity.

Streptozotocin may induce diabetes in some dogs, but the chemotherapy drug may be given along with appropriate insulin therapy if gross disease is still present.  No reports have described the use of streptozotocin in cats or ferrets with insulinoma. Further study of this agent is needed in all species.

Prognosis

The short-term prognosis for dogs with insulinoma is good, although most will eventually die of this disease. While survival time depends on the stage of the disease and the success of surgery, it also depends on the owners’ willingness to treat aggressively and follow up with symptomatic therapy once signs of hypoglycemia return.

Approximately two-thirds to three-quarters of dogs survive 6 months or longer after surgery (often over a year) before intractable hypoglycemia recurs. Reported median survival time is much longer in dogs initially treated with surgery than in those treated with medical management alone (1-5,20,21). Individualizing therapy with the use of combinations of medical and surgical therapy based on the stage and extent of disease may improve prognosis and survival time in any given patient.  

References:

1. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
2. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
3. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
4. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
5. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
6. Nelson RW, Foodman MS. Medical management of canine hyperinsulinism. J Am Vet Med Assoc 1985;187:78-82. 
7. Olefsky JM, Kimmerling G. Effects of glucocorticoids oncarbohydrate metabolism. Am J Med Sci 1976;271:202-210. 
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