- Email: [email protected]
Canine Thyroid Carcinoma
Canine Thyroid Carcinoma Julius M. Liptak, BVSc, MVetClinStud Malignant thyroid carcinomas are relatively common in dogs. The majority of tumors are unilateral and nonfunctional. Before deciding on treatment options, it is important to determine whether the tumor is freely moveable or fixed and invasive into adjacent tissues. Thyroidectomy is recommended for unilateral, mobile thyroid carcinomas. Radiation therapy or radioactive iodine therapy are recommended for dogs with invasive or bilateral thyroid carcinomas. The role of adjunctive chemotherapy is poorly defined, but should be considered in dogs with high-risk tumors, such as large or bilateral thyroid carcinomas. The prognosis is good following surgical treatment of mobile thyroid tumors and irradiation of fixed thyroid carcinomas, with median survival times greater than 3 years. Clin Tech Small Anim Pract 22:75-81 © 2007 Elsevier Inc. All rights reserved. KEYWORDS thyroid, carcinoma, thyroidectomy, radiation therapy,
T
umors of the thyroid gland are relatively common in dogs and account for 1.2 to 3.8% of all canine tumors.1-3 The etiopathogenesis of thyroid carcinomas is unknown, although iodine deficiency and prolonged lymphocytic thyroiditis and hypothyroidism have been implicated, and sufficient exposure to radiation can induce tumors in the thyroid glands in all species, including dogs.1,2,4,5 Malignant thyroid tumors are more common than benign tumors and account for up to 88% of all thyroid masses.1,6 Malignant thyroid tumors can arise from either follicular or parafollicular cell lineages. Follicular thyroid carcinomas are more common.1 These have been histologically classified as follicular, compact, and mixed, although this has no prognostic significance. Parafollicular carcinomas, which are also known as medullary or C-cell carcinomas, represent 36% of all thyroid carcinomas, and these may have a slightly different gross appearance and prognosis compared with follicular carcinomas.7 Benign adenomas and adenomatous hyperplastic lesions are usually incidental findings at necropsy (Fig. 1).6,8 Malignant thyroid tumors are frequently large and poorly encapsulated and may invade into adjacent normal tissues, such as the trachea, larynx, esophagus, cervical musculature, and regional neurovascular structures.1,2 Early invasion into the cranial and caudal thyroid veins (Fig. 2), with subsequent tumor thrombi formation, is associated with the development of pulmonary metastasis and cranial vena cava syndrome.8 Approximately 67 to 75% of thyroid carcinomas are unilateral and 25 to 33% are bilateral.6,9 Bilateral tumors are usually large and extensive and it can be difficult to determine whether these tumors have developed simultaneously,
131iodine,
dog
extended across the isthmus, or metastasized from one side to the other. Unlike cats, thyroid tumors in dogs are usually nonfunctional with less than 25% of dogs having clinical or biochemical evidence of hyperthyroidism.1,7,10,11 Hypothyroidism is also possible and may be caused by the neoplastic destruction of normal thyroid tissue, suppression of pituitary thyroid-stimulating hormone secretion (TSH), and subsequent atrophy of normal thyroid tissue, or the suppressive effects of nonspecific illnesses on circulating thyroid hormone concentrations.1,3 Metastasis is relatively common in dogs with malignant thyroid carcinomas. Up to 33% of dogs have evidence of metastatic disease at the time of diagnosis and 65 to 90% of untreated dogs are diagnosed with regional and distant metastasis at necropsy.6-8,12 The lungs and the regional lymph nodes are the most common metastatic sites.1,2 The regional lymph nodes are the submandibular, medial retropharyngeal, and parotid lymph nodes because lymph drains cranially from the thyroid glands in dogs.13 Other metastatic sites include the adrenal glands, brain, kidneys, heart, liver, and bone.3 The formation of accessory thyroid tissue is common during thyroid development in dogs.13 Islets of rapidly proliferating cells of the thyroid primordial separate from the main mass and become incorporated in the developing structures of the branchium and thorax.13 As a result, thyroid carcinomas can arise from ectopic thyroid tissue in the tongue, along the trachea distant to the thyroid glands, and in the thoracic inlet, cranial mediastinum, and pericardium, and along the descending aorta and heart base.1,2
Anatomy Alta Vista Animal Hospital, Ottawa, Ontario, Canada. Address reprint requests to Alta Vista Animal Hospital, 2616 Bank Street, Ottawa, Ontario K1T 1M9, Canada, E-mail: [email protected].
1096-2867/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.ctsap.2007.03.007
The paired normal thyroid glands are elongated, dark red structures attached to fascia along the right and left ventro75
J.M. Liptak
76
Figure 1 An intraoperative image of a thyroid adenoma in a dog. Thyroid adenomas are often smaller than thyroid carcinomas and are usually an incidental finding at necropsy. Note the prominent cranial (left) and caudal thyroid vessels and extensive vasculature network between these two vessels supplying this benign thyroid tumor. SH, sternohyoideus muscle.
lateral surfaces of the proximal trachea (Fig. 3).13 The right thyroid gland is located further cranially than the left thyroid gland, with the right thyroid gland extending from the caudal cricoid cartilage to the fifth tracheal ring and the left thyroid gland extending from the third to eighth tracheal rings.13 The thyroid glands are covered by the sternocephalicus and sternohyoideus muscles ventrally and the sternothyroideus muscle laterally.13 The common carotid artery, internal jugular vein, and vagosympathetic trunk course along the dorsolateral surface of the right thyroid gland, while the esophagus borders the dorsolateral surface of the left thyroid gland and the caudal laryngeal nerve courses along its dorsal surface.13 The esophagus displaces the common carotid sheath on the
Figure 3 A diagrammatic representation of the ventral view of the thyroid and parathyroid glands in the dog and their anatomic relationship with adjacent structures such as the trachea, esophagus, carotid artery, internal jugular vein, vagosympathetic trunk, and cervical musculature. Reprinted with permission.13
left side and hence these structures are not in contact with the left thyroid gland. The parathyroid glands are intimately associated with the thyroid glands. The external parathyroid gland is located on the dorsolateral surface of the cranial pole, and the internal parathyroid gland is located within the parenchyma of the caudal pole of the thyroid gland.13 The thyroid glands have an extensive vascular supply. The cranial and caudal thyroid arteries provide the principal blood supply.13 The cranial thyroid artery is the first major branch of the common carotid artery that also supplies segments of the larynx and trachea. The cranial thyroid artery anastomoses with the caudal thyroid artery along the dorsal surface of the thyroid gland. The caudal thyroid artery is a branch of the brachiocephalic artery and courses along the lateral surface of the trachea.13 These anastomosing arteries then form a rich vascular network along the dorsal and ventral surface of the thyroid glands, which bifurcate to supply the lateral and medial aspects of the thyroid glands and then anastomose to form a vascular network at the surface and within the capsule of the thyroid glands.13 The venous drainage parallels the arterial system, with the cranial thyroid vein draining into the internal jugular vein.13
Signalment The median age at diagnosis in dogs with thyroid tumors is 9 to 10 years.8,12,14 A consistent sex predisposition has not been identified.1 Boxers are predisposed to both benign and malignant thyroid tumors,12,14 while beagles and golden retrievers also have an increased risk for developing malignant thyroid carcinomas.14
Clinical Signs and Diagnosis Figure 2 An intraoperative image of a well-encapsulated thyroid carcinoma in a dog that has gross evidence of vascular invasion and tumor thrombi within the cranial and caudal thyroid veins (arrows). This finding is frequently associated with pulmonary metastasis.
The most common presentation is a palpable mass in the ventral to ventrolateral neck.7-9 Occasionally larger tumors may descend toward to thoracic inlet. Differential diagnoses for masses in this region include abscesses, granulomas, sal-
Canine thyroid carcinoma ivary mucoceles, other primary tumors (such as carotid body tumors, soft-tissue sarcomas, etc), lymphoma, and nodal metastasis from head and neck tumors.1 Other clinical signs include coughing, gagging, retching, regurgitation, and dysphonia.7-9 Fixed thyroid carcinomas invade into adjacent structures and cause a variety of clinical signs, such as dyspnea, dysphonia, dysphagia, Horner’s syndrome, and cranial vena caval syndrome.6 Dogs with functional thyroid tumors have similar clinical signs to hyperthyroid cats, but these symptoms are usually less severe.2,3,11 Physical examination is important to determine the size and degree of fixation of the thyroid mass, assess for metastasis to the regional lymph nodes, and determine the presence of comorbid conditions that may affect anesthetic and surgical management. Malignant thyroid carcinomas will either be freely moveable or be fixed and invasive, with 24 to 55% of thyroid carcinomas classified as mobile and up to 67% classified as fixed.7,9 This is an important distinction because the treatment options for the primary tumor are determined by the degree of fixation. Occasionally, determining whether a thyroid tumor is mobile or fixed can be difficult in a conscious dog and, in these cases, palpation under anesthesia, imaging tests, or exploratory surgery are required to assess the degree of invasion. Ultrasonography is a valuable and relatively inexpensive imaging modality to differentiate thyroid tumors from other ventral neck masses, to assess the vascularity and degree of invasion of thyroid masses, to assess the presence of bilateral thyroid disease, and perhaps to guide fine-needle aspirates or needle-core biopsies for diagnostic purposes.15 Advanced imaging techniques, using contrast-enhanced computed tomography or magnetic resonance imaging, have been described for the diagnosis of thyroid tumors,1 but their principal indication is for planning radiation treatment of invasive or incompletely resected malignant thyroid tumors. These techniques have also been recommended for evaluating the surgical resectability of thyroid tumors,1 but surgical exploration is often a more accurate, rapid, and cost-effective method of determining tumor invasiveness and resectability, especially compared with magnetic resonance imaging. Radionuclide imaging using either 99mtechnetium pertechnetate or 131iodine has been described for the diagnosis of thyroid neoplasia in dogs.8,10 Thyroid tumors do not need to be functional for an abnormal scintigraphic study, although hyperthyroid dogs have a more intense uptake than euthyroid dogs.10 This imaging modality is particularly useful for identifying malignant ectopic tissue, which can be difficult to detect using conventional imaging modalities, and regional lymph node metastasis, but not pulmonary metastasis.10 Scintigraphy can also be used to determine the functional status of normal nonneoplastic thyroid tissue, likelihood of responding to radioactive iodine treatment, and response to radiation therapy.1,3,16,17 A biopsy is required for definitive diagnosis. Fine-needle aspiration should be performed because it is minimally invasive and does not require sedation or general anesthesia; however, the diagnostic accuracy of this technique is low because of frequent blood contamination.8,18 Ultrasound guidance of fine-needle aspirates or needle-core biopsies may improve the diagnostic accuracy by reducing the risk of blood contamination. Incisional biopsies are recommended
77 for definitive diagnosis of fixed and invasive thyroid masses, but are rarely indicated for mobile thyroid tumors because the surgical approach is the same as for thyroidectomy. Furthermore, because of the highly vasculature nature of thyroid tumors, surgical biopsy procedures are also associated with a high risk of hemorrhage and this complication should be considered when deciding whether to perform a biopsy of a thyroid mass.
Clinical Staging The clinical staging for dogs with thyroid tumors includes hematology, serum biochemistry, serum thyroxine, and TSH concentrations, evaluation of the characteristics of the local tumor, assessment of the regional lymph nodes, and threeview thoracic radiographs.1 The majority of dogs diagnosed with thyroid tumors are middle to older aged and hence it is important to assess their health status with hematology, serum biochemistry, urinalysis, and abdominal ultrasonography to evaluate their ability to tolerate curative-intent treatment options. Thyroxine and TSH levels are used to determine the thyroid status of dogs. Hypothyroidism may increase the anesthetic risk for treated dogs and indicate the need for thyroid hormone supplementation following, and perhaps before, curative-intent treatment. Dogs with hyperthyroidism may be more responsive to treatment with 131iodine, although radioactive iodine can be effective regardless of whether a thyroid tumor is functional or not.19,20 Palpation and imaging modalities, as described above, are used to assess the size of the tumor and degree of invasiveness. The regional lymph nodes and lungs are the two most common metastatic sites in dogs with thyroid carcinomas.1 Lymph drains cranially from the thyroid glands and hence the regional lymph nodes for dogs with thyroid tumors are the mandibular, parotid, and medial retropharyngeal lymph nodes.1,13 However, recent studies in cats and dogs with oral tumors have shown that the parotid and medial retropharyngeal lymph nodes are not palpable and only 55% of 31 animals with metastasis to the regional lymph nodes had metastasis to the palpable mandibular lymph node.21 Although similar studies have not been performed in dogs with thyroid tumors, it would be prudent to aspirate each of these lymph nodes under ultrasound guidance or, alternatively, excise the regional lymph nodes en bloc at the time of thyroidectomy for clinical staging purposes.22 Three-view thoracic radiographs, involving right lateral, left lateral, and either ventrodorsal or dorsoventral projections, are recommended in nonanesthetized dogs for evaluation of pulmonary metastasis. Following these staging tests, dogs with thyroid tumors are clinically staged according to the World Health Organization’s TNM staging system (Table 1).23
Treatment The treatment options for dogs with thyroid carcinomas depend on the size of the tumor, extent of invasion, availability of therapeutic modalities, such as radiation therapy and nuclear medicine, and presence of metastatic disease (Fig. 4).1 For dogs with no evidence of metastasis, treatment is primarily directed at control of the local tumor. The most important
J.M. Liptak
78 Table 1 The World Health Organization’s Clinical Staging System for Canine Thyroid Carcinomas23 Primary Tumor T0 T1 T2 T3
Node N0 N1 N2 Metastasis M0 M1
No evidence of neoplasia Tumor <2 cm in diameter, superficial, and exophytic Tumor 2-5 cm in diameter or with minimal invasion irrespective of size Tumor >5 cm in diameter or with invasion of subcutis irrespective of size No evidence of regional lymph node involvement Ipsilateral regional lymph node involvement Bilateral regional lymph node involvement No evidence of metastasis Evidence of distant metastasis with site specified
Figure 5 An intraoperative image of a mobile, well-encapsulated thyroid carcinoma in a dog. Note the prominent large blood vessel on the cranial aspect of the thyroid tumor (arrow). Despite being noninvasive, mobile thyroid carcinomas still have an extensive blood supply and prominent tumor neovasculature that can result in significant hemorrhage if disturbed during thyroidectomy.
The local tumor (T) is subclassified as “a” for mobile tumors, and “b” for fixed tumors.
factor in determining the best treatment option is whether the thyroid tumor is mobile or fixed.
Surgery Surgery is recommended for dogs with mobile thyroid tumors or thyroid tumors with invasion limited to the superficial tissues (Fig. 5).1,7,9 Surgical exploration may be necessary to determine the level of invasion if this distinction is unable to be made preoperatively. Surgical resection is not indicated for dogs with deeply invasive and fixed thyroid carcinomas or bilateral thyroid tumors.1 In addition to the clinical staging tests described above to evaluate the health status, dogs in which surgery is planned should also have a coagulation profile, cross-matching, and
Figure 4 An algorithm for the treatment of dogs with nonmetastatic and metastatic thyroid carcinomas. Treatment of the local tumor is the most important consideration in dogs with nonmetastatic thyroid carcinomas. Surgery is recommended for dogs with mobile tumors and either radiation therapy or radioactive iodine therapy for dogs with fixed and invasive thyroid carcinomas. (Color version of figure is available online.)
blood typing performed. Blood loss can be significant during surgery because of regional coagulopathies, and disruption of the rich vascular supply to the thyroid glands, extensive and fragile tumor vascularity, and vascular invasion.1 As a result, the surgeon should be prepared to administer matched blood products if required. The anesthetic management of dogs with thyroid tumors is usually uncomplicated because hyperthyroidism, and its systemic effects, is rare in dogs.1-3 Following induction of anesthesia, the dog is positioned in dorsal recumbency with the neck extended by placing a towel under the neck. A ventral midline skin incision is made from the larynx to the manubrium and this is continued through subcutaneous tissue and oblique fibers of sphincter coli muscle. The sternohyoideus muscles are separated in the midline to expose the cervical trachea. The thyroid glands are normally located immediately caudal to the larynx on the medial aspect of the sternothyroideus muscles, but abnormal thyroid glands can be located ventral or lateral to the trachea anywhere between the larynx and thoracic inlet. Following identification of the thyroid tumor, the contralateral thyroid gland should be located and examined to rule out bilateral disease. Intraoperative aspiration and cytology should be performed if the contralateral thyroid gland has an abnormal gross appearance. Thyroidectomy should be performed if the thyroid tumor is unilateral and is either mobile or superficially invasive. Handling of the thyroid tumor should be minimized to reduce the risk of disrupting the fragile tumor vessels as hemorrhage from these vessels can be very difficult to control (Fig. 6). The cranial and caudal thyroid arteries and veins should be identified and ligated. Ligation or cauterization of many other vessels may also be necessary during thyroidectomy because of the extensive vascular network of the thyroid gland and neovasculature of thyroid carcinomas. The use of an automatic stapling device, such as ligaclips, facilitates this process. Following ligation of the major vessels, thyroidectomy is completed using a combination of careful blunt and sharp dissection to separate the thyroid tumor from its fascial attachments to the trachea. The plane
Canine thyroid carcinoma
79
Radiation Therapy
Figure 6 An intraoperative image of a mobile thyroid carcinoma in a dog. Note the fascial attachments to the trachea with prominent vasculature. These vessels should be either ligated or cauterized and the fascia carefully dissected to complete the thyroidectomy. Note that the thyroid tumor is being manipulated with hemostats attached to the fascia rather than directly handling the tumor. Direct handling of the tumor can disrupt the fragile tumor neovasculature and result in hemorrhage, which is difficult to control.
of dissection is usually close or adjacent to the pseudocapsule of the thyroid tumor. It is important to note that wide resection of noninvasive thyroid tumors is rarely possible or indicated because the rate of local tumor recurrence is relatively low following marginal resection and the morbidity associated with wide resection is unacceptably high.9 If the thyroid carcinoma is invasive into adjacent neurovascular structures, then the ipsilateral jugular vein, carotid artery, and vagosympathetic trunk can be sacrificed with minimal morbidity.1 There are no vascular consequences following this procedure, but the dog will develop unilateral Horner’s syndrome.1 Thyroidectomy also involves removal of the ipsilateral internal and external parathyroid glands. Preservation of the ipsilateral external parathyroid gland is not necessary because this may increase the risk of local tumor recurrence and calcium homeostasis will not be disrupted provided that the contralateral parathyroid glands are not compromised. Following thyroidectomy, the sternohyoideus muscle, subcutaneous, and cutaneous tissues are closed routinely. Postoperative management is usually uncomplicated following unilateral thyroidectomy. Thyroxine supplementation is usually unnecessary, but thyroxine and TSH concentrations should be assessed at regular intervals.
Radiation therapy is recommended for dogs with fixed and invasive thyroid carcinomas. A number of different protocols have been described, including a hypofractionated protocol (9 Gy once weekly for 4 weeks for a total dose of 36 Gy24) and fractionated protocols (4 Gy per fraction on a MondayWednesday-Friday schedule for 12 fractions and a total dose of 48 Gy17,25) or 2.7 to 3.0 Gy on a Monday-to-Friday schedule for 18 to 20 fractions and a total dose of 54 Gy (LaRue SM, personal communication, 2006). Acute radiation effects include esophageal, tracheal, and laryngeal mucositis resulting in mild and self-limiting dysphagia, dysphonia, and coughing.17,24,25 Hypothyroidism is a rare late effect following irradiation of thyroid tumors.17,24 The outcome following treatment with either hypofractionated or fractionated radiation therapy is encouraging. The majority of tumors will respond to radiation therapy with complete responses observed in 8% of dogs (eg, resolution of palpable tumor) and partial responses in 69% of dogs (eg, tumor volume decreases in size by greater than 50%).24,25 However, it can take between 6 to 22 months to achieve the maximal reduction in tumor size.17,25 Importantly, the duration of this response is excellent with no tumor progression in 80% of dogs at 1 year and 72% at 3 years after irradiation.17 Radiation therapy can be used to downstage large invasive thyroid carcinomas and make them more amenable to surgical excision. Although this has not been investigated, surgical removal or debulking of residual tumor burden following irradiation may provide a survival benefit because local tumor progression accounts for a significant proportion of mortality in dogs treated with radiation therapy.17
Radioactive Iodine Therapy Radioactive iodine is the preferred treatment for cats with thyroid lesions and either as an adjunct to surgery or as a primary treatment for unresectable malignant thyroid tumors in people.1,3,26 Thyroid tumors do not need to be functional to respond to radioactive iodine therapy.10,17,20 Pretreatment radionuclide scans are recommended as it has been suggested that tumors which do not adequately concentrate the radioisotopes are less likely to respond to radioactive iodine therapy.16,17 Radioactive iodine is not effective for the treatment of large tumors, which limits its clinical applicability in many dogs with thyroid tumors.17 However, a recent study of 43 dogs treated with one to three doses of 131I, either alone (n ⫽ 32) or as an adjunct to surgery (n ⫽ 11), to a total dose of 555 to 1850 MBq resulted in very encouraging median survival times (MSTs) of 30 and 34 months, respectively.20 The major logistical disadvantages of radioactive iodine therapy in dogs are the need for multiple doses to maintain therapeutic levels and prolonged hospitalization.16,19
Chemotherapy The role of chemotherapy in the treatment of dogs with thyroid tumors remains to be defined. The use of either doxorubicin or cisplatin results in response rates of 30 to 50% in dogs with thyroid carcinomas, which suggests that chemotherapy may have a role in the management of canine thyroid
J.M. Liptak
80 Table 2 The Prognosis for Dogs with Thyroid Carcinomas Following Curative-Intent Treatment9,17,24
Mobile thyroid carcinomas Surgery Fixed thyroid carcinomas Surgery Radiation therapy Radioactive iodine
Median Survival Time
1-Year Progression-Free Survival Rate
2-Year Progression-Free Survival Rate
>36 months
75%
70%
10 months 24.5 to >45 months 30 months
25% 80% —
10% 72% —
carcinomas.27-29 However, improved survival times have not been reported with the use of adjuvant chemotherapy. Similar findings have been reported in people with thyroid tumors.26 The major indication for chemotherapy in people, usually in combination with hypofractionated radiation therapy, is for the treatment of thyroid tumors which are not amenable to surgical resection and unresponsive to radioactive iodine therapy.26 Chemotherapy, using either doxorubicin or cisplatin, should be recommended following either surgery or radiation therapy in dogs with a high risk for the developing metastatic disease, such as large and bilateral thyroid carcinomas.7,17 In dogs with small, unilateral, and perhaps medullary thyroid carcinomas, the choice to proceed with chemotherapy should be dependent on an informed discussion with the owners of the risks and benefits of treatment.
Prognosis The prognosis for dogs with malignant thyroid carcinomas is good to excellent with appropriate treatment (Table 2). The MST for untreated dogs with thyroid carcinomas is only 3 months.20 The MST for dogs with mobile thyroid carcinomas treated with surgery alone is greater than 36 months, with 1and 2-year survival rates of 75 and 70%, respectively.9 In contrast, the MST for dogs with fixed thyroid carcinomas treated with surgery alone is only 10 months, with 1- and 2-year survival rates of 25 and 10%, respectively.7 Radiation therapy is recommended for the treatment of dogs with fixed thyroid carcinomas because survival outcome is superior to surgery alone with a MST of 24.5 to greater than 45 months and 1- and 2-year progression-free survival rates of 80 and 72%, respectively.17,25 The MST of 32 dogs treated with 131I alone is 30 months.20 Interestingly, in 13 dogs treated with a hypofractionated protocol, there was no difference in survival time for dogs with (n ⫽ 5) and without (n ⫽ 8) metastasis at the time of radiation therapy.24 Histologic evidence of capsular or vascular invasion does not correlate with poor survival in dogs with thyroid carcinoma,11 but tumor thrombi extending into the cranial thyroid vein is associated with a high risk of metastasis.8 Local recurrence or progression is reported in up to 30% of dogs following thyroidectomy and 24% after radiation therapy.11,17 The metastatic rate for dogs with treated thyroid carcinomas is less than 40%.11,17,25 The risk of metastasis increases in dogs with tumor volume greater than 20 cm3 or diameter greater than 5 cm,6 bilateral thyroid tumors,17 and perhaps follicular thyroid carcinomas.7 Dogs with thyroid tumors smaller than 20 cm3 have a metastatic rate less than 20%, whereas the majority of dogs with tumors larger than
100 cm3 develop metastases.6 Dogs with bilateral thyroid carcinomas have a 16 times greater risk of developing metastatic disease than dogs with unilateral tumors.17 The risk of metastatic disease is significantly decreased with good local tumor control as dogs with no evidence of tumor progression have a 15 times decreased risk of developing metastasis.17
References 1. Page RL: Tumors of the endocrine system, in Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology (ed 3). Philadelphia, PA, Saunders, 2001, pp 423-427 2. Capen CC: Tumors of the endocrine glands, in Meuten DJ (ed): Tumors in Domestic Animals (ed 4). Ames, IA, Iowa State Press, 2002, pp 638-664 3. Mooney CT: Hyperthyroidism, in Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (ed 6). St. Louis, MO, Elsevier Saunders, 2005, pp 1544-1560 4. Benjamin SA, Saunders WJ, Angleton GM, et al: Radiation carcinogenesis in dogs irradiated during prenatal and postnatal development. J Radiat Res 32:86-103, 1991 (suppl 2) 5. Benjamin SA, Stephens LC, Hamilton BF, et al: Associations between lymphocytic thyroiditis, hypothyroidism, and thyroid neoplasia in beagles. Vet Pathol 33:486-494, 1996 6. Leav I, Schiller AL, Rihnberk A, et al: Adenomas and carcinomas of the canine and feline thyroid. Am J Pathol 83:61-122, 1976 7. Carver JR, Kapatkin A, Patnaik AK: A comparison of medullary thyroid carcinoma and thyroid adenocarcinoma in dogs: a retrospective study of 38 cases. Vet Surg 24:315-319, 1995 8. Harari J, Patterson JS, Rosenthal RC: Clinical and pathologic features of thyroid tumors in 26 dogs. J Am Vet Med Assoc 188:1160-1164, 1986 9. 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 206:1007-1009, 1995 10. Marks S, Koblik P, Hornof W, et al: 99mTc-pertechnetate imaging of thyroid tumors in dogs: 29 cases (1980-1992). J Am Vet Med Assoc 204:756-760, 1994 11. Kent MS, Griffey SM, Verstraete FJM, et al: Computer-assisted image analysis of neovascularization in thyroid neoplasms from dogs. Am J Vet Res 63:363-369, 2002 12. Brodey RS, Kelly DF. Thyroid neoplasms in the dog: a clinicopathologic study of fifty-seven cases. Cancer 22:406-416, 1968 13. Hullinger RL. The endocrine system, in Evans HE, Christensen GC (eds): Miller’s Anatomy of the Dog (ed 2). Philadelphia, PA, Saunders, 1979, pp 602-631 14. Hayes HH: Canine thyroid neoplasms: epidemiologic features. J Natl Cancer Inst 55:931-934, 1975 15. Wisner ER, Nyland TG: Ultrasonography of the thyroid and parathyroid glands. Vet Clin North Am Small Anim Pract 28:973-991, 1998 16. Peterson ME, Kintzer PP, Hurley JR, et al: Radioactive iodine treatment of a functional thyroid carcinoma producing hyperthyroidism in a dog. J Vet Intern Med 3:20-25, 1989 17. Théon 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 216:1775-1779, 2000 18. Thompson EJ, Stirtzinger T, Lumsden JH, et al: Fine needle aspiration cytology in the diagnosis of canine thyroid carcinoma. Can Vet J 21: 186-188, 1980
Canine thyroid carcinoma 19. Adams WH, Walker MA, Daniel GB: Treatment of differentiated thyroid carcinoma in 7 dogs utilizing 131I. Vet Radiol Ultrasound 36:417424, 1995 20. Worth AJ, Zuber RM, Hocking M: Radioiodide (131I) therapy for the treatment of canine thyroid carcinoma. Aust Vet J 83:208-214, 2005 21. Herring ES, Smith MM, Robertson JL: Lymph node staging of oral and maxillofacial neoplasms in 31 dogs and cats. J Vet Dent 19:122-126, 2002 22. Smith MM: Surgical approach for lymph node staging of oral and maxillofacial neoplasms in dogs. J Am Anim Hosp Assoc 31:514-518, 1995 23. Owen LN: TNM classification of tumours in domestic animals. Geneva, World Health Organization, 1980 24. Brearley MJ, Hayes AM, Murphy S: Hypofractionated radiation therapy for invasive thyroid carcinoma in dogs: a retrospective analysis of survival. J Small Anim Pract 40:206-210, 1999
81 25. Pack LA, Roberts RE, Dawson SD, et al: Definitive radiation therapy for infiltrative thyroid carcinoma in dogs. Vet Radiol Ultrasound 42:471474, 2001 26. Carling T, Udelsman R: Thyroid tumors, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 7). Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp 1502-1520 27. Jeglum KA, Whereat A: Chemotherapy of canine thyroid carcinoma. Compend Contin Educ Pract Vet 5:96-98, 1983 28. Post GS, Mauldin GN: Radiation and adjuvant chemotherapy for the treatment of thyroid adenocarcinoma in dogs. Vet Cancer Soc Conf 12:43-44, (abstr) 29. Fineman LS, Hamilton TA, de Gortari A: Cisplatin chemotherapy for treatment of thyroid carcinoma in 13 dogs: 13 cases. J Am Anim Hosp Assoc 34:109-112, 1998
T
umors of the thyroid gland are relatively common in dogs and account for 1.2 to 3.8% of all canine tumors.1-3 The etiopathogenesis of thyroid carcinomas is unknown, although iodine deficiency and prolonged lymphocytic thyroiditis and hypothyroidism have been implicated, and sufficient exposure to radiation can induce tumors in the thyroid glands in all species, including dogs.1,2,4,5 Malignant thyroid tumors are more common than benign tumors and account for up to 88% of all thyroid masses.1,6 Malignant thyroid tumors can arise from either follicular or parafollicular cell lineages. Follicular thyroid carcinomas are more common.1 These have been histologically classified as follicular, compact, and mixed, although this has no prognostic significance. Parafollicular carcinomas, which are also known as medullary or C-cell carcinomas, represent 36% of all thyroid carcinomas, and these may have a slightly different gross appearance and prognosis compared with follicular carcinomas.7 Benign adenomas and adenomatous hyperplastic lesions are usually incidental findings at necropsy (Fig. 1).6,8 Malignant thyroid tumors are frequently large and poorly encapsulated and may invade into adjacent normal tissues, such as the trachea, larynx, esophagus, cervical musculature, and regional neurovascular structures.1,2 Early invasion into the cranial and caudal thyroid veins (Fig. 2), with subsequent tumor thrombi formation, is associated with the development of pulmonary metastasis and cranial vena cava syndrome.8 Approximately 67 to 75% of thyroid carcinomas are unilateral and 25 to 33% are bilateral.6,9 Bilateral tumors are usually large and extensive and it can be difficult to determine whether these tumors have developed simultaneously,
131iodine,
dog
extended across the isthmus, or metastasized from one side to the other. Unlike cats, thyroid tumors in dogs are usually nonfunctional with less than 25% of dogs having clinical or biochemical evidence of hyperthyroidism.1,7,10,11 Hypothyroidism is also possible and may be caused by the neoplastic destruction of normal thyroid tissue, suppression of pituitary thyroid-stimulating hormone secretion (TSH), and subsequent atrophy of normal thyroid tissue, or the suppressive effects of nonspecific illnesses on circulating thyroid hormone concentrations.1,3 Metastasis is relatively common in dogs with malignant thyroid carcinomas. Up to 33% of dogs have evidence of metastatic disease at the time of diagnosis and 65 to 90% of untreated dogs are diagnosed with regional and distant metastasis at necropsy.6-8,12 The lungs and the regional lymph nodes are the most common metastatic sites.1,2 The regional lymph nodes are the submandibular, medial retropharyngeal, and parotid lymph nodes because lymph drains cranially from the thyroid glands in dogs.13 Other metastatic sites include the adrenal glands, brain, kidneys, heart, liver, and bone.3 The formation of accessory thyroid tissue is common during thyroid development in dogs.13 Islets of rapidly proliferating cells of the thyroid primordial separate from the main mass and become incorporated in the developing structures of the branchium and thorax.13 As a result, thyroid carcinomas can arise from ectopic thyroid tissue in the tongue, along the trachea distant to the thyroid glands, and in the thoracic inlet, cranial mediastinum, and pericardium, and along the descending aorta and heart base.1,2
Anatomy Alta Vista Animal Hospital, Ottawa, Ontario, Canada. Address reprint requests to Alta Vista Animal Hospital, 2616 Bank Street, Ottawa, Ontario K1T 1M9, Canada, E-mail: [email protected].
1096-2867/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.ctsap.2007.03.007
The paired normal thyroid glands are elongated, dark red structures attached to fascia along the right and left ventro75
J.M. Liptak
76
Figure 1 An intraoperative image of a thyroid adenoma in a dog. Thyroid adenomas are often smaller than thyroid carcinomas and are usually an incidental finding at necropsy. Note the prominent cranial (left) and caudal thyroid vessels and extensive vasculature network between these two vessels supplying this benign thyroid tumor. SH, sternohyoideus muscle.
lateral surfaces of the proximal trachea (Fig. 3).13 The right thyroid gland is located further cranially than the left thyroid gland, with the right thyroid gland extending from the caudal cricoid cartilage to the fifth tracheal ring and the left thyroid gland extending from the third to eighth tracheal rings.13 The thyroid glands are covered by the sternocephalicus and sternohyoideus muscles ventrally and the sternothyroideus muscle laterally.13 The common carotid artery, internal jugular vein, and vagosympathetic trunk course along the dorsolateral surface of the right thyroid gland, while the esophagus borders the dorsolateral surface of the left thyroid gland and the caudal laryngeal nerve courses along its dorsal surface.13 The esophagus displaces the common carotid sheath on the
Figure 3 A diagrammatic representation of the ventral view of the thyroid and parathyroid glands in the dog and their anatomic relationship with adjacent structures such as the trachea, esophagus, carotid artery, internal jugular vein, vagosympathetic trunk, and cervical musculature. Reprinted with permission.13
left side and hence these structures are not in contact with the left thyroid gland. The parathyroid glands are intimately associated with the thyroid glands. The external parathyroid gland is located on the dorsolateral surface of the cranial pole, and the internal parathyroid gland is located within the parenchyma of the caudal pole of the thyroid gland.13 The thyroid glands have an extensive vascular supply. The cranial and caudal thyroid arteries provide the principal blood supply.13 The cranial thyroid artery is the first major branch of the common carotid artery that also supplies segments of the larynx and trachea. The cranial thyroid artery anastomoses with the caudal thyroid artery along the dorsal surface of the thyroid gland. The caudal thyroid artery is a branch of the brachiocephalic artery and courses along the lateral surface of the trachea.13 These anastomosing arteries then form a rich vascular network along the dorsal and ventral surface of the thyroid glands, which bifurcate to supply the lateral and medial aspects of the thyroid glands and then anastomose to form a vascular network at the surface and within the capsule of the thyroid glands.13 The venous drainage parallels the arterial system, with the cranial thyroid vein draining into the internal jugular vein.13
Signalment The median age at diagnosis in dogs with thyroid tumors is 9 to 10 years.8,12,14 A consistent sex predisposition has not been identified.1 Boxers are predisposed to both benign and malignant thyroid tumors,12,14 while beagles and golden retrievers also have an increased risk for developing malignant thyroid carcinomas.14
Clinical Signs and Diagnosis Figure 2 An intraoperative image of a well-encapsulated thyroid carcinoma in a dog that has gross evidence of vascular invasion and tumor thrombi within the cranial and caudal thyroid veins (arrows). This finding is frequently associated with pulmonary metastasis.
The most common presentation is a palpable mass in the ventral to ventrolateral neck.7-9 Occasionally larger tumors may descend toward to thoracic inlet. Differential diagnoses for masses in this region include abscesses, granulomas, sal-
Canine thyroid carcinoma ivary mucoceles, other primary tumors (such as carotid body tumors, soft-tissue sarcomas, etc), lymphoma, and nodal metastasis from head and neck tumors.1 Other clinical signs include coughing, gagging, retching, regurgitation, and dysphonia.7-9 Fixed thyroid carcinomas invade into adjacent structures and cause a variety of clinical signs, such as dyspnea, dysphonia, dysphagia, Horner’s syndrome, and cranial vena caval syndrome.6 Dogs with functional thyroid tumors have similar clinical signs to hyperthyroid cats, but these symptoms are usually less severe.2,3,11 Physical examination is important to determine the size and degree of fixation of the thyroid mass, assess for metastasis to the regional lymph nodes, and determine the presence of comorbid conditions that may affect anesthetic and surgical management. Malignant thyroid carcinomas will either be freely moveable or be fixed and invasive, with 24 to 55% of thyroid carcinomas classified as mobile and up to 67% classified as fixed.7,9 This is an important distinction because the treatment options for the primary tumor are determined by the degree of fixation. Occasionally, determining whether a thyroid tumor is mobile or fixed can be difficult in a conscious dog and, in these cases, palpation under anesthesia, imaging tests, or exploratory surgery are required to assess the degree of invasion. Ultrasonography is a valuable and relatively inexpensive imaging modality to differentiate thyroid tumors from other ventral neck masses, to assess the vascularity and degree of invasion of thyroid masses, to assess the presence of bilateral thyroid disease, and perhaps to guide fine-needle aspirates or needle-core biopsies for diagnostic purposes.15 Advanced imaging techniques, using contrast-enhanced computed tomography or magnetic resonance imaging, have been described for the diagnosis of thyroid tumors,1 but their principal indication is for planning radiation treatment of invasive or incompletely resected malignant thyroid tumors. These techniques have also been recommended for evaluating the surgical resectability of thyroid tumors,1 but surgical exploration is often a more accurate, rapid, and cost-effective method of determining tumor invasiveness and resectability, especially compared with magnetic resonance imaging. Radionuclide imaging using either 99mtechnetium pertechnetate or 131iodine has been described for the diagnosis of thyroid neoplasia in dogs.8,10 Thyroid tumors do not need to be functional for an abnormal scintigraphic study, although hyperthyroid dogs have a more intense uptake than euthyroid dogs.10 This imaging modality is particularly useful for identifying malignant ectopic tissue, which can be difficult to detect using conventional imaging modalities, and regional lymph node metastasis, but not pulmonary metastasis.10 Scintigraphy can also be used to determine the functional status of normal nonneoplastic thyroid tissue, likelihood of responding to radioactive iodine treatment, and response to radiation therapy.1,3,16,17 A biopsy is required for definitive diagnosis. Fine-needle aspiration should be performed because it is minimally invasive and does not require sedation or general anesthesia; however, the diagnostic accuracy of this technique is low because of frequent blood contamination.8,18 Ultrasound guidance of fine-needle aspirates or needle-core biopsies may improve the diagnostic accuracy by reducing the risk of blood contamination. Incisional biopsies are recommended
77 for definitive diagnosis of fixed and invasive thyroid masses, but are rarely indicated for mobile thyroid tumors because the surgical approach is the same as for thyroidectomy. Furthermore, because of the highly vasculature nature of thyroid tumors, surgical biopsy procedures are also associated with a high risk of hemorrhage and this complication should be considered when deciding whether to perform a biopsy of a thyroid mass.
Clinical Staging The clinical staging for dogs with thyroid tumors includes hematology, serum biochemistry, serum thyroxine, and TSH concentrations, evaluation of the characteristics of the local tumor, assessment of the regional lymph nodes, and threeview thoracic radiographs.1 The majority of dogs diagnosed with thyroid tumors are middle to older aged and hence it is important to assess their health status with hematology, serum biochemistry, urinalysis, and abdominal ultrasonography to evaluate their ability to tolerate curative-intent treatment options. Thyroxine and TSH levels are used to determine the thyroid status of dogs. Hypothyroidism may increase the anesthetic risk for treated dogs and indicate the need for thyroid hormone supplementation following, and perhaps before, curative-intent treatment. Dogs with hyperthyroidism may be more responsive to treatment with 131iodine, although radioactive iodine can be effective regardless of whether a thyroid tumor is functional or not.19,20 Palpation and imaging modalities, as described above, are used to assess the size of the tumor and degree of invasiveness. The regional lymph nodes and lungs are the two most common metastatic sites in dogs with thyroid carcinomas.1 Lymph drains cranially from the thyroid glands and hence the regional lymph nodes for dogs with thyroid tumors are the mandibular, parotid, and medial retropharyngeal lymph nodes.1,13 However, recent studies in cats and dogs with oral tumors have shown that the parotid and medial retropharyngeal lymph nodes are not palpable and only 55% of 31 animals with metastasis to the regional lymph nodes had metastasis to the palpable mandibular lymph node.21 Although similar studies have not been performed in dogs with thyroid tumors, it would be prudent to aspirate each of these lymph nodes under ultrasound guidance or, alternatively, excise the regional lymph nodes en bloc at the time of thyroidectomy for clinical staging purposes.22 Three-view thoracic radiographs, involving right lateral, left lateral, and either ventrodorsal or dorsoventral projections, are recommended in nonanesthetized dogs for evaluation of pulmonary metastasis. Following these staging tests, dogs with thyroid tumors are clinically staged according to the World Health Organization’s TNM staging system (Table 1).23
Treatment The treatment options for dogs with thyroid carcinomas depend on the size of the tumor, extent of invasion, availability of therapeutic modalities, such as radiation therapy and nuclear medicine, and presence of metastatic disease (Fig. 4).1 For dogs with no evidence of metastasis, treatment is primarily directed at control of the local tumor. The most important
J.M. Liptak
78 Table 1 The World Health Organization’s Clinical Staging System for Canine Thyroid Carcinomas23 Primary Tumor T0 T1 T2 T3
Node N0 N1 N2 Metastasis M0 M1
No evidence of neoplasia Tumor <2 cm in diameter, superficial, and exophytic Tumor 2-5 cm in diameter or with minimal invasion irrespective of size Tumor >5 cm in diameter or with invasion of subcutis irrespective of size No evidence of regional lymph node involvement Ipsilateral regional lymph node involvement Bilateral regional lymph node involvement No evidence of metastasis Evidence of distant metastasis with site specified
Figure 5 An intraoperative image of a mobile, well-encapsulated thyroid carcinoma in a dog. Note the prominent large blood vessel on the cranial aspect of the thyroid tumor (arrow). Despite being noninvasive, mobile thyroid carcinomas still have an extensive blood supply and prominent tumor neovasculature that can result in significant hemorrhage if disturbed during thyroidectomy.
The local tumor (T) is subclassified as “a” for mobile tumors, and “b” for fixed tumors.
factor in determining the best treatment option is whether the thyroid tumor is mobile or fixed.
Surgery Surgery is recommended for dogs with mobile thyroid tumors or thyroid tumors with invasion limited to the superficial tissues (Fig. 5).1,7,9 Surgical exploration may be necessary to determine the level of invasion if this distinction is unable to be made preoperatively. Surgical resection is not indicated for dogs with deeply invasive and fixed thyroid carcinomas or bilateral thyroid tumors.1 In addition to the clinical staging tests described above to evaluate the health status, dogs in which surgery is planned should also have a coagulation profile, cross-matching, and
Figure 4 An algorithm for the treatment of dogs with nonmetastatic and metastatic thyroid carcinomas. Treatment of the local tumor is the most important consideration in dogs with nonmetastatic thyroid carcinomas. Surgery is recommended for dogs with mobile tumors and either radiation therapy or radioactive iodine therapy for dogs with fixed and invasive thyroid carcinomas. (Color version of figure is available online.)
blood typing performed. Blood loss can be significant during surgery because of regional coagulopathies, and disruption of the rich vascular supply to the thyroid glands, extensive and fragile tumor vascularity, and vascular invasion.1 As a result, the surgeon should be prepared to administer matched blood products if required. The anesthetic management of dogs with thyroid tumors is usually uncomplicated because hyperthyroidism, and its systemic effects, is rare in dogs.1-3 Following induction of anesthesia, the dog is positioned in dorsal recumbency with the neck extended by placing a towel under the neck. A ventral midline skin incision is made from the larynx to the manubrium and this is continued through subcutaneous tissue and oblique fibers of sphincter coli muscle. The sternohyoideus muscles are separated in the midline to expose the cervical trachea. The thyroid glands are normally located immediately caudal to the larynx on the medial aspect of the sternothyroideus muscles, but abnormal thyroid glands can be located ventral or lateral to the trachea anywhere between the larynx and thoracic inlet. Following identification of the thyroid tumor, the contralateral thyroid gland should be located and examined to rule out bilateral disease. Intraoperative aspiration and cytology should be performed if the contralateral thyroid gland has an abnormal gross appearance. Thyroidectomy should be performed if the thyroid tumor is unilateral and is either mobile or superficially invasive. Handling of the thyroid tumor should be minimized to reduce the risk of disrupting the fragile tumor vessels as hemorrhage from these vessels can be very difficult to control (Fig. 6). The cranial and caudal thyroid arteries and veins should be identified and ligated. Ligation or cauterization of many other vessels may also be necessary during thyroidectomy because of the extensive vascular network of the thyroid gland and neovasculature of thyroid carcinomas. The use of an automatic stapling device, such as ligaclips, facilitates this process. Following ligation of the major vessels, thyroidectomy is completed using a combination of careful blunt and sharp dissection to separate the thyroid tumor from its fascial attachments to the trachea. The plane
Canine thyroid carcinoma
79
Radiation Therapy
Figure 6 An intraoperative image of a mobile thyroid carcinoma in a dog. Note the fascial attachments to the trachea with prominent vasculature. These vessels should be either ligated or cauterized and the fascia carefully dissected to complete the thyroidectomy. Note that the thyroid tumor is being manipulated with hemostats attached to the fascia rather than directly handling the tumor. Direct handling of the tumor can disrupt the fragile tumor neovasculature and result in hemorrhage, which is difficult to control.
of dissection is usually close or adjacent to the pseudocapsule of the thyroid tumor. It is important to note that wide resection of noninvasive thyroid tumors is rarely possible or indicated because the rate of local tumor recurrence is relatively low following marginal resection and the morbidity associated with wide resection is unacceptably high.9 If the thyroid carcinoma is invasive into adjacent neurovascular structures, then the ipsilateral jugular vein, carotid artery, and vagosympathetic trunk can be sacrificed with minimal morbidity.1 There are no vascular consequences following this procedure, but the dog will develop unilateral Horner’s syndrome.1 Thyroidectomy also involves removal of the ipsilateral internal and external parathyroid glands. Preservation of the ipsilateral external parathyroid gland is not necessary because this may increase the risk of local tumor recurrence and calcium homeostasis will not be disrupted provided that the contralateral parathyroid glands are not compromised. Following thyroidectomy, the sternohyoideus muscle, subcutaneous, and cutaneous tissues are closed routinely. Postoperative management is usually uncomplicated following unilateral thyroidectomy. Thyroxine supplementation is usually unnecessary, but thyroxine and TSH concentrations should be assessed at regular intervals.
Radiation therapy is recommended for dogs with fixed and invasive thyroid carcinomas. A number of different protocols have been described, including a hypofractionated protocol (9 Gy once weekly for 4 weeks for a total dose of 36 Gy24) and fractionated protocols (4 Gy per fraction on a MondayWednesday-Friday schedule for 12 fractions and a total dose of 48 Gy17,25) or 2.7 to 3.0 Gy on a Monday-to-Friday schedule for 18 to 20 fractions and a total dose of 54 Gy (LaRue SM, personal communication, 2006). Acute radiation effects include esophageal, tracheal, and laryngeal mucositis resulting in mild and self-limiting dysphagia, dysphonia, and coughing.17,24,25 Hypothyroidism is a rare late effect following irradiation of thyroid tumors.17,24 The outcome following treatment with either hypofractionated or fractionated radiation therapy is encouraging. The majority of tumors will respond to radiation therapy with complete responses observed in 8% of dogs (eg, resolution of palpable tumor) and partial responses in 69% of dogs (eg, tumor volume decreases in size by greater than 50%).24,25 However, it can take between 6 to 22 months to achieve the maximal reduction in tumor size.17,25 Importantly, the duration of this response is excellent with no tumor progression in 80% of dogs at 1 year and 72% at 3 years after irradiation.17 Radiation therapy can be used to downstage large invasive thyroid carcinomas and make them more amenable to surgical excision. Although this has not been investigated, surgical removal or debulking of residual tumor burden following irradiation may provide a survival benefit because local tumor progression accounts for a significant proportion of mortality in dogs treated with radiation therapy.17
Radioactive Iodine Therapy Radioactive iodine is the preferred treatment for cats with thyroid lesions and either as an adjunct to surgery or as a primary treatment for unresectable malignant thyroid tumors in people.1,3,26 Thyroid tumors do not need to be functional to respond to radioactive iodine therapy.10,17,20 Pretreatment radionuclide scans are recommended as it has been suggested that tumors which do not adequately concentrate the radioisotopes are less likely to respond to radioactive iodine therapy.16,17 Radioactive iodine is not effective for the treatment of large tumors, which limits its clinical applicability in many dogs with thyroid tumors.17 However, a recent study of 43 dogs treated with one to three doses of 131I, either alone (n ⫽ 32) or as an adjunct to surgery (n ⫽ 11), to a total dose of 555 to 1850 MBq resulted in very encouraging median survival times (MSTs) of 30 and 34 months, respectively.20 The major logistical disadvantages of radioactive iodine therapy in dogs are the need for multiple doses to maintain therapeutic levels and prolonged hospitalization.16,19
Chemotherapy The role of chemotherapy in the treatment of dogs with thyroid tumors remains to be defined. The use of either doxorubicin or cisplatin results in response rates of 30 to 50% in dogs with thyroid carcinomas, which suggests that chemotherapy may have a role in the management of canine thyroid
J.M. Liptak
80 Table 2 The Prognosis for Dogs with Thyroid Carcinomas Following Curative-Intent Treatment9,17,24
Mobile thyroid carcinomas Surgery Fixed thyroid carcinomas Surgery Radiation therapy Radioactive iodine
Median Survival Time
1-Year Progression-Free Survival Rate
2-Year Progression-Free Survival Rate
>36 months
75%
70%
10 months 24.5 to >45 months 30 months
25% 80% —
10% 72% —
carcinomas.27-29 However, improved survival times have not been reported with the use of adjuvant chemotherapy. Similar findings have been reported in people with thyroid tumors.26 The major indication for chemotherapy in people, usually in combination with hypofractionated radiation therapy, is for the treatment of thyroid tumors which are not amenable to surgical resection and unresponsive to radioactive iodine therapy.26 Chemotherapy, using either doxorubicin or cisplatin, should be recommended following either surgery or radiation therapy in dogs with a high risk for the developing metastatic disease, such as large and bilateral thyroid carcinomas.7,17 In dogs with small, unilateral, and perhaps medullary thyroid carcinomas, the choice to proceed with chemotherapy should be dependent on an informed discussion with the owners of the risks and benefits of treatment.
Prognosis The prognosis for dogs with malignant thyroid carcinomas is good to excellent with appropriate treatment (Table 2). The MST for untreated dogs with thyroid carcinomas is only 3 months.20 The MST for dogs with mobile thyroid carcinomas treated with surgery alone is greater than 36 months, with 1and 2-year survival rates of 75 and 70%, respectively.9 In contrast, the MST for dogs with fixed thyroid carcinomas treated with surgery alone is only 10 months, with 1- and 2-year survival rates of 25 and 10%, respectively.7 Radiation therapy is recommended for the treatment of dogs with fixed thyroid carcinomas because survival outcome is superior to surgery alone with a MST of 24.5 to greater than 45 months and 1- and 2-year progression-free survival rates of 80 and 72%, respectively.17,25 The MST of 32 dogs treated with 131I alone is 30 months.20 Interestingly, in 13 dogs treated with a hypofractionated protocol, there was no difference in survival time for dogs with (n ⫽ 5) and without (n ⫽ 8) metastasis at the time of radiation therapy.24 Histologic evidence of capsular or vascular invasion does not correlate with poor survival in dogs with thyroid carcinoma,11 but tumor thrombi extending into the cranial thyroid vein is associated with a high risk of metastasis.8 Local recurrence or progression is reported in up to 30% of dogs following thyroidectomy and 24% after radiation therapy.11,17 The metastatic rate for dogs with treated thyroid carcinomas is less than 40%.11,17,25 The risk of metastasis increases in dogs with tumor volume greater than 20 cm3 or diameter greater than 5 cm,6 bilateral thyroid tumors,17 and perhaps follicular thyroid carcinomas.7 Dogs with thyroid tumors smaller than 20 cm3 have a metastatic rate less than 20%, whereas the majority of dogs with tumors larger than
100 cm3 develop metastases.6 Dogs with bilateral thyroid carcinomas have a 16 times greater risk of developing metastatic disease than dogs with unilateral tumors.17 The risk of metastatic disease is significantly decreased with good local tumor control as dogs with no evidence of tumor progression have a 15 times decreased risk of developing metastasis.17
References 1. Page RL: Tumors of the endocrine system, in Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology (ed 3). Philadelphia, PA, Saunders, 2001, pp 423-427 2. Capen CC: Tumors of the endocrine glands, in Meuten DJ (ed): Tumors in Domestic Animals (ed 4). Ames, IA, Iowa State Press, 2002, pp 638-664 3. Mooney CT: Hyperthyroidism, in Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (ed 6). St. Louis, MO, Elsevier Saunders, 2005, pp 1544-1560 4. Benjamin SA, Saunders WJ, Angleton GM, et al: Radiation carcinogenesis in dogs irradiated during prenatal and postnatal development. J Radiat Res 32:86-103, 1991 (suppl 2) 5. Benjamin SA, Stephens LC, Hamilton BF, et al: Associations between lymphocytic thyroiditis, hypothyroidism, and thyroid neoplasia in beagles. Vet Pathol 33:486-494, 1996 6. Leav I, Schiller AL, Rihnberk A, et al: Adenomas and carcinomas of the canine and feline thyroid. Am J Pathol 83:61-122, 1976 7. Carver JR, Kapatkin A, Patnaik AK: A comparison of medullary thyroid carcinoma and thyroid adenocarcinoma in dogs: a retrospective study of 38 cases. Vet Surg 24:315-319, 1995 8. Harari J, Patterson JS, Rosenthal RC: Clinical and pathologic features of thyroid tumors in 26 dogs. J Am Vet Med Assoc 188:1160-1164, 1986 9. 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 206:1007-1009, 1995 10. Marks S, Koblik P, Hornof W, et al: 99mTc-pertechnetate imaging of thyroid tumors in dogs: 29 cases (1980-1992). J Am Vet Med Assoc 204:756-760, 1994 11. Kent MS, Griffey SM, Verstraete FJM, et al: Computer-assisted image analysis of neovascularization in thyroid neoplasms from dogs. Am J Vet Res 63:363-369, 2002 12. Brodey RS, Kelly DF. Thyroid neoplasms in the dog: a clinicopathologic study of fifty-seven cases. Cancer 22:406-416, 1968 13. Hullinger RL. The endocrine system, in Evans HE, Christensen GC (eds): Miller’s Anatomy of the Dog (ed 2). Philadelphia, PA, Saunders, 1979, pp 602-631 14. Hayes HH: Canine thyroid neoplasms: epidemiologic features. J Natl Cancer Inst 55:931-934, 1975 15. Wisner ER, Nyland TG: Ultrasonography of the thyroid and parathyroid glands. Vet Clin North Am Small Anim Pract 28:973-991, 1998 16. Peterson ME, Kintzer PP, Hurley JR, et al: Radioactive iodine treatment of a functional thyroid carcinoma producing hyperthyroidism in a dog. J Vet Intern Med 3:20-25, 1989 17. Théon 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 216:1775-1779, 2000 18. Thompson EJ, Stirtzinger T, Lumsden JH, et al: Fine needle aspiration cytology in the diagnosis of canine thyroid carcinoma. Can Vet J 21: 186-188, 1980
Canine thyroid carcinoma 19. Adams WH, Walker MA, Daniel GB: Treatment of differentiated thyroid carcinoma in 7 dogs utilizing 131I. Vet Radiol Ultrasound 36:417424, 1995 20. Worth AJ, Zuber RM, Hocking M: Radioiodide (131I) therapy for the treatment of canine thyroid carcinoma. Aust Vet J 83:208-214, 2005 21. Herring ES, Smith MM, Robertson JL: Lymph node staging of oral and maxillofacial neoplasms in 31 dogs and cats. J Vet Dent 19:122-126, 2002 22. Smith MM: Surgical approach for lymph node staging of oral and maxillofacial neoplasms in dogs. J Am Anim Hosp Assoc 31:514-518, 1995 23. Owen LN: TNM classification of tumours in domestic animals. Geneva, World Health Organization, 1980 24. Brearley MJ, Hayes AM, Murphy S: Hypofractionated radiation therapy for invasive thyroid carcinoma in dogs: a retrospective analysis of survival. J Small Anim Pract 40:206-210, 1999
81 25. Pack LA, Roberts RE, Dawson SD, et al: Definitive radiation therapy for infiltrative thyroid carcinoma in dogs. Vet Radiol Ultrasound 42:471474, 2001 26. Carling T, Udelsman R: Thyroid tumors, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 7). Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp 1502-1520 27. Jeglum KA, Whereat A: Chemotherapy of canine thyroid carcinoma. Compend Contin Educ Pract Vet 5:96-98, 1983 28. Post GS, Mauldin GN: Radiation and adjuvant chemotherapy for the treatment of thyroid adenocarcinoma in dogs. Vet Cancer Soc Conf 12:43-44, (abstr) 29. Fineman LS, Hamilton TA, de Gortari A: Cisplatin chemotherapy for treatment of thyroid carcinoma in 13 dogs: 13 cases. J Am Anim Hosp Assoc 34:109-112, 1998