Canine Thyroid Carcinoma: Summary of Diagnosis and Conventional Treatment Options

This exclusive article is part of the MettaPets Veterinary Professional Blog Series

This article is the intellectual property of Dr. Erin Bannink, July 2021.

Distribution of this article in part or entirety without written permission from Dr. Bannink is prohibited.

Western Biomedicine Perspective

Most thyroid tumors diagnosed in dogs are malignant, as thyroid adenomas are usually small and clinically undetectable. A 2010 review of the Veterinary Medicine Database reported that of 545 thyroid tumors submitted, 90% were carcinoma or adenocarcinoma (Wucherer, 2010). Thyroid carcinoma has a high rate of metastasis, with the lungs and lymph nodes (prescapular, submandibular and retropharyngeal) the most common sites of metastasis. Tumor volume is associated with metastatic risk, with tumors exceed 23cm3 carrying a higher likelihood of metastasis and up to 100% incidence of metastasis with tumor volume over 100cm3 (Leav, 1976). Approximately 40% of dogs will present with metastasis at the time of initial diagnosis. Bilateral tumors occur in approximately 60% of patients and are 16 times more likely to metastasize (Theon, 2000). Without treatment, a median survival time (MST) of 3 months has been reported (Worth, 2005). Individual patient survivals can vary widely depending on individual tumor characteristics and behavior.

Molecular and Endocrine Aspects

The etiology of thyroid cancer in dogs is not well understood, although it is accepted that thyroid stimulating hormone (TSH) and TSH-receptors play a role in tumor development (Garcia-Jimenez, 2007) . Thyroid carcinomas retain thyroid stimulating hormone (TSH) receptors. Thyroid tumors occurred with greater frequency in hypothyroid beagles who did not receive thyroid hormone supplementation (Benjamin, 1996). Most thyroid carcinomas are nonfunctional, although about 30% of dogs will be hypothyroid and 10% hyperthyroid (Lunn, 2013) . Thyroid profile is recommended as part of routine staging to screen for imbalances in thyroid hormone regulation. Some patients who have normal thyroid levels will show high TSH levels. In these patients, thyroid hormone supplementation is often considered in order to lower TSH levels and decrease stimulation of tumor tissue by elevated TSH levels, although double blinded placebo controlled clinical trials evaluating the impact of this intervention have not been performed.

An understanding of the molecular mechanisms involved in tumor progression is helpful in informing new treatment approaches and may also be useful in elucidating the underlying mechanism of action for various herbal therapies. Molecular targets proposed for treatment of canine thyroid carcinoma include VEGF and COX-2 and p-53 (Campos, 2014) . Upregulation of gene expression has also been demonstrated for vascular endothelial growth factor receptors (VEGFR), AKT and epidermal growth factor receptor (EGFR), all associated with the PI3K/AKT pathway (Campos, 2014) . Additionally, platelet derived growth factor receptor-alpha (PDGFRα), VEGFR2, and KIT expression are receptors involved in tumor progression which have been documented in thyroid carcinoma (Urie, 2012) . Human Epidermal Growth Factor Receptor 2 (HER2) was also recently shown to be expressed in 48% of canine thyroid carcinoma samples (Yoshimoto, 2019) . Lastly, dysregulation of the Janus Kinase – Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway has been recognized in spontaneously-arising canine thyroid carcinoma tissue (Cletzer, 2020). These are important in the tumorigenesis of thyroid carcinoma and may be potential therapeutic targets for both pharmaceutical and herbal therapies.

Diagnosis

Differential diagnoses for a mass in the area of the thyroid gland include abscess, granuloma, salivary mucocele, sarcoma, carotid body tumor and metastatic lymph node from another type of cancer. Cytology is recommended to rule out other diagnoses but is only diagnostic for thyroid carcinoma or neuroendocrine tumor in about half of cases due to hemodilution (Lunn. 2013; Thompson, 1980). To increase diagnostic yield, ultrasound guidance and sampling using a needle without aspiration can be helpful to decrease blood contamination. Large core biopsies and wedge biopsies are cautiously recommended based on careful case selection in the author’s practice due to risk of hemorrhage, which can potentially be life-threatening and require blood transfusions. Diagnosis is most often made by the combination of cytology and supportive CT or cervical ultrasound findings. Approximately 80% of thyroid masses in dogs are malignant, with 70% of these being ultimately diagnosed as carcinomas. CT can be helpful in ruling in the likelihood of malignancy, as only malignant tumors exhibit mineralization, vascular invasion, and tissue invasion on CT imaging (Bertolini , 2017). Diagnosis is confirmed via histopathology when masses are amenable to surgical removal, or when there is question about the diagnosis and the recommended and elected treatments would change based on results, justifying the risks associated with the tissue biopsy procedure.

Staging

Routine staging includes complete blood count, blood chemistry profile, urinalysis, thyroid profile, three view thoracic radiographs, and cytology of submandibular and/or prescapular lymph nodes. Extent of tumor invasion is initially assessed with cervical ultrasound and is confirmed prior to surgery on CT scan or MRI. Regional lymph nodes are also assessed with advanced imaging. Radioactive iodine (131I) or 99mPertechnetate have been used to identify ectopic tumors, residual local disease after surgery and, less reliably, metastatic disease.

Conventional Treatment Options

Complete surgical excision is the best treatment when small, freely movable, non-metastatic tumors are present, with median survival times (MST) of about 3 years. Surgical removal of small tumors with intracapsular invasion and minimal local invasion are associated with median survival times of 6-36 months (Reagan, 2019; Klein, 1995; Nadeau, 2011). MST up to 35 to 72 months has been reported for dogs with functional thyroid tumors treated with surgery (Frederick, 2020; Scharf, 2020). Only about 25-50% of thyroid carcinomas are amenable to surgical intervention at the time of diagnosis, as small tumors are often not palpable and clinical signs in euthyroid patients are uncommon when the tumors are small. Functional tumors may result in detection of small tumors, as only 36% of dogs reported with hyperthyroidism related to a functional thyroid tumor were reported to have palpable masses, whereas palpable or visible cervical mass is the most common reason for euthyroid patients who have a thyroid tumor to present for evaluation Scharf, 2020). This may account for better surgical outcomes in this subset of patients due to earlier detection. Surgery is often not advised when the tumor is large and deeply adhered to surrounding tissue or when it invades into surrounding tissues or vasculature. Involvement of local structures such as regional vasculature, recurrent laryngeal nerves, vagosympathetic trunk, larynx, trachea, and esophagus is common and surgery in these cases can result in severe and extensive hemorrhage (Lunn, 2013).

Full course radiation therapy is used for management of unresectable tumors and results in MST of between 1-3 years. Interestingly, the time to maximal tumor regression can be delayed and often occurs between 8 months to 2 years after radiation therapy is administered. Reported 1-year and 3-year progression free survival rates are 80% and 72% respectively (Pack, 2001; Théon, 2000). Radiation therapy is also used in a residual disease setting after incomplete excision, although survival times have not been thoroughly evaluated.

Course fraction radiation therapy (high dose per fraction, 4-5 total treatments) can be used as a palliative treatment in dogs presenting with metastatic disease. Complete (rare) and partial (common) responses resulting in reported time-to-progression (TTP) between 1-2 years and MST of 22 months (Brearley, 1999). A recent retrospective evaluation of 20 dogs undergoing palliative-intent course fraction radiation therapy at a single institution did not confirm these previously published survival times, reporting MST of only 5.6 months (Tsimbas, 2019).

Evaluation of Stereotactic Radiation Therapy was recently reported for 23 dogs as a treatment for thyroid carcinoma. Overall response rate was 70% with a median survival time of about 1 year. Metastasis was not a negative prognostic factor in the patients evaluated in this study. The treatment was well tolerated with 39% of dogs experiencing grade I acute radiation toxicity (Lee, 2020).

131I can be used for treatment of nonresectable, metastatic and incompletely resected thyroid tumors. Stage of disease impacts MST. Patients with stage II (2-5cm, fixed or unfixed) and stage III (>5cm, fixed or unfixed) have a MST over 2 years. Dogs with stage IV disease (metastatic) have a MST of about 1 year (Benjamin, 1996; Turrel, 2006). Hyperthyroid dogs with non-resectable ectopic thyroid carcinoma can be treated with 131I and may experience prolonged survivals if not presenting with metastasis (Lyssens, 2021). Adverse effects associated with 131I include bone marrow toxicity and hypothyroidism (all dogs need thyroid hormone supplementation after therapy). The dose is still empirical and based on tumor burden. High doses are typically needed for treatment of malignant thyroid tumors.

Mitoxantrone, doxorubicin, actinomycin-D, cisplatin and carboplatin can result in tumor responses in individual cases and are used in a palliative setting. Response rates between 30%-50% have been reported. MST has not been adequately evaluated (Lunn, 2013). The role of adjuvant chemotherapy after surgical excision is not well defined. The most recently published study retrospectively evaluated 44 dogs treated with either surgery alone or surgery and chemotherapy. There was no statistically significant difference in MST between groups. Approximately half of the dogs presented with metastasis. Surprisingly, MST for dogs with metastasis was not significantly different than those without metastasis, suggesting the importance of local disease control in overall survival. The only factor approaching significance was duration of clinical signs prior to presentation (p=0.06), with those patients exhibiting clinical signs for more than 35 days having a MST of about 1 year, versus 4.5 years for those displaying clinical signs for less than 35 days (Nadeau, 2011). Although these results are interesting, they must be viewed in light of the low power of the study and the case selection bias for cases which are reasonable candidates for surgical intervention. A 2020 retrospective study specifically evaluating metastatic rate in patients with functional thyroid tumors reported metastatic rates of only 6% at the time of diagnosis and only 4% developing metastasis after diagnosis, suggesting that chemotherapy may not be indicated in this subset of patients when good local disease control is achieved (Scharf, 2020).

Palladia: Palladia (Toceranib) is a veterinary tyrosine kinase inhibitor which was originally developed to treat aggressive mast cell tumors. The primary mechanism of action is inhibition of KIT signaling, which is a key factor involved in mast cell tumor progression. Objective responses have been seen in various solid tumors, including thyroid carcinomas, treated with Palladia. A preliminary evaluation for biological activity in solid tumors showed a partial response in 4/15 (26%) dogs with thyroid carcinoma and stable disease in another 8/15 (53%), for a response rate of 80% in this small population of dogs (London, 2012). A recent retrospective evaluation of 42 dogs diagnosed with thyroid carcinoma and treated with Palladia in both treatment-naïve and prior-therapy settings reported clinical benefit in 88% of treatment-naïve patients and 75% of patients who had received prior therapy. Median survival time was 18 months and 36 months in the treatment-naive and previous-therapy groups respectively. The difference in survival was not statistically significant (Sheppard-Olivares, 2020).

Targets for Palladia are various receptor tyrosine kinases including KIT, platelet derived growth factor receptors-a and -b (PDFGRa/b), and vascular endothelial growth factor receptor 2 (VEGF2). Thyroid carcinomas were evaluated for expression of these receptors and, of the 15 samples evaluated, all expressed PDGFRa, 40% expressed VEGFR2, and 60% expressed KIT, providing some perspective behind the potential mechanisms of action related to the clinically observed therapeutic activity of Palladia in this tumor type (Urie, 2012). The precise mechanism of action of Palladia in thyroid carcinoma is, however, unknown at this time and requires future study to elucidate.

Benjamin SA, Stephens LC, Hamilton BF, et al. Association between lymphocytic thyroiditis, hypothyroidism, and thyroid neoplasia in beagles. Vet Pathol 1996; 33:486-494.

Bertolini G, Drigo M, Angeloni L, Caldin M. Incidental and nonincidental canine thyroid tumors assessed by multidetector row computed tomography: a single-centre cross sectional study in 4520 dogs. Vet Radiol Ultrasound. 2017 May;58(3):304-314.

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

Campos M, Ducatelle R, Kooistra HS, et al. Immunohistochemical expression of potential therapeutic targets in canine thyroid carcinoma. J Vet Intern Med 2014 Mar-Apr;28(2):564-70.

Campos M, Kool MM, Daminet S, et al. Upregulation of the PI3K/Akt pathway in the tumorigenesis of canine thyroid carcinoma. J Vet Intern Med 2014 Nov-Dec;28(6):1814-23.

Cletzer E, Klahn S, Dervisis N, LeRoith T. Identification of the JAK-STAT pathway in canine splenic hemangiosarcoma, thyroid carcinoma, mast cell tumor, and anal sac adenocarcinoma. Vet Immunol Immunopathol. 2020 Feb;220:109996.

Frederick AN, Pardo AD, Schmiedt CW, Hinson WD, Youk AO, Urie BK. Outcomes for dogs with functional thyroid tumors treated by surgical excision alone. J Am Vet Med Assoc. 2020 Feb 15;256(4):444-448.

Garcia-Jimenez C, Santisteban P. TSH signaling and cancer. Arq Bras Endocrinol Metabol 2007;51:654-671.

Klein MK, Powers BE, Withrow SJ, Curtis CR, Straw RC, Ogilvie GK, Dickinson KL, Cooper MF, Baier M. Treatment of thyroid carcinoma in dogs by surgical resection alone: 20 cases (1981-1989). J Am Vet Med Assoc. 1995 Apr 1;206(7):1007-9.

Leav I, Schiller AL, Rijnberk A, et al. Adenomas and carcinomas of the canine and feline thyroid. Amer J Pathol 1976;83:61-122.

Lee BI, LaRue SM, Seguin B, Griffin L, Prebble A, Martin T, Leary D, Boss MK. Safety and efficacy of stereotactic body radiation therapy (SBRT) for the treatment of canine thyroid carcinoma. Vet Comp Oncol. 2020 Dec;18(4):843-853.

London C, Mathie T, Stingle N, et al. Preliminary evidence for biological activity of toceranib phosphate (Palladia) in solid tumors. Vet Comp Oncol 2012 Sept;10(3):194-205.

Lunn KF, Page RL. Tumors of the Endocrine System. In: Withrow SJ, Vail DM, Page RL. Small Animal Clinical Oncology. 5th ed. St. Louis: Saunders Co, 2013;513-515.

Lyssens A, van den Berg MF, Peremans K, et al. 131 treatment in dogs with hyperthyroidism caused by a non-resectable ectopic thyroid tumour: 5 cases (2008-2019). J Small Anim Pract. 2021 Feb;62(2):137-144.

Nadeau ME, Kitchell BE. Evaluation of the use of chemotherapy and other prognostic variables for survigally excised canine thyroid carcinoma with and without metastasis. Can Vet J 2011 Sept;52(9):994-998.

Pack L, Roberts RE, Dawson SD, et al. Definitive radiation therapy for infiltrative thyroid carcinoma in dogs. Vet Radiol Ultrasound 2001;42:471-474.

Reagan JK, Selmic LE, Fallon C, et al. Complications and outcomes associated with unilateral thyroidectomy in dogs with naturally occurring thyroid tumors: 156 cases (2003-2015). J Am Vet Med Assoc. 2019 Oct 15;255(8):926-932.

Scharf VF, Oblak ML, Hoffman K, et al. Clinical features and outcome of functional thyroid tumours in 70 dogs. J Small Anim Pract. 2020 Aug;61(8):504-511.

Sheppard-Olivares S, Bello NM, Wood E, et al. Toceranib phosphate in the treatment of canine thyroid carcinoma: 42 cases (2009-2018). Vet Comp Oncol. 2020 Dec;18(4):519-527.

Théon AP, Marks SL, Feldman ES, Griffey S. Prognostic factors and patterns of treatment failure in dogs with unresectable differentiated thyroid carcinomas treated with megavoltage irradiation. J Am Vet Med Assoc. 2000 Jun 1;216(11):1775-9.

Thompson EJ, Stirtzinger T, Lumsden JH, Little PB. Fine needle aspiration cytology in the diagnosis of canine thyroid carcinoma. Can Vet J. 1980 Jun;21(6):186-8.

Tsimbas K, Turek M, Christensen N, et al. Short survival time following palliative-intent hypofractionated radiotherapy for non-resectable canine thyroid carcinoma: A retrospective analysis of 20 dogs. Vet Radiol Ultrasound. 2019 Jan;60(1):93-99.

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.

Urie BK, Russell DS, Kisseberth WC, et al. Evaluation of expression and function of vascular endothelial growth factor receptor 2, platelets derived growth factor receptors-alpha and –beta, KIT and RET in canine apocrine gland anal sac adenocarcinoma and thyroid carcinoma. BMC Vet Res 2012 May 25;8:67.

Worth A.J, Zuber R.M, Hocking M. Radioiodide (I131) therapy for the treatment of canine thyroid carcinoma. Aust. Vet. J. 2005;83:208–214.

Wucherer KL, Wilke V. Thyroid cancer in dogs: an update based on 638 cases (1995-2005). J Am Vet Med Assoc 2010; 46:249-254.

Yoshimoto S, Kato D, Kamoto S, et al. Immunohistochemical evaluation of HER2 expression in canine thyroid carcinoma. Heliyon. 2019 Jul 17;5(7):e02004.