Thyroid tumors represent 1.1% of all neoplasms in dogs and are the most commonly diagnosed endocrine neoplasm in this species.1–3 Historically, most thyroid tumors have been found to be malignant, with carcinomas and adenocarcinomas representing up to 90% of these tumors.1,3–6 However, investigators of 2 studies4,6 reported that 29 of 57 (51%) and 44 of 141 (31%) thyroid tumors found at necropsy were benign adenomas. Metastatic disease is present in 16% to 38% of dogs at the time of diagnosis, and 60% to 80% of affected dogs have evidence of metastatic disease at the time of death.1,4,6–8 The lungs are the most common sites of metastases, followed by regional lymph nodes; the risk of metastases increases proportionally with tumor size,6,8,9 and in 1 report,9 the risk in dogs with bilateral thyroid tumors was 16 times that of the risk in dogs that had a single tumor.
Thyroid tumors are most frequently reported for older, large-breed dogs and Beagles.1–3,7 In 1 study,3 569 of 638 (89%) dogs with thyroid tumors were between 7 and 15 years of age, and 270 (42%) were medium-sized to large-breed dogs. Siberian Huskies, Golden Retrievers, and Beagles are at an increased risk of developing thyroid neoplasia, compared with other breeds.1,3,4,6,7,10–14
The most common clinical sign is a ventral cervical mass, which can be an incidental finding on routine physical examination; cough, tachypnea, dyspnea, dysphagia, and dysphonia can also be present. These signs related to local disease are not surprising as < 25% of thyroid tumors reported in dogs in the United States are functional.1,6,8,15 Thyroid tumors are considered functional when T4 is hypersecreted and hyperthyroidism is identified in the presence of thyroid neoplasia. This has been described in several previous clinical reports.16–18
The treatment of choice for freely movable, nonmetastatic thyroid tumors is surgical excision. Historically, thyroidectomy has been associated with a low morbidity rate and an MST > 3 years.9,14 A recent report8 described an MST > 17 months for dogs that had mobile thyroid tumors treated with surgery alone; no significant difference in survival time was noted for those dogs, compared with dogs that underwent surgical excision and chemotherapy. Unfortunately, 25% to 50% of thyroid tumors are not amenable to surgical excision at the time of diagnosis owing to local invasiveness.2,9,10,14 For fixed, nonresectable thyroid tumors, radiation therapy is a treatment option for local disease control and palliation of clinical signs.
Iodine 131 has been used to treat primary thyroid tumors and metastatic disease, and survival times were similar to those obtained with external beam radiation therapy.19–21 Worth et al19 compared surgery, 131I, and a combination of both approaches as treatment for thyroid carcinomas in 65 dogs, of which 11 had hyperthyroidism. Three of the 11 dogs with hyperthyroidism underwent surgery alone, and 8 underwent 131I treatment alone. An MST for dogs undergoing surgery alone was not reached, and serum total T4 concentration was not reported to be significantly associated with MST for dogs in which outcome was known.19
It has been hypothesized that functional thyroid tumors are well differentiated, given that they synthesize secretory products. Alternatively, it may be that diagnoses are made earlier in the course of disease for dogs with functional tumors because of the presence of clinical signs associated with hyperthyroidism, and thus, the tumors are at an earlier stage and more amenable to surgical excision in those dogs. The objective of the study reported here was to describe the clinical findings and survival times in dogs with resectable functional thyroid tumors treated with surgery alone and to investigate potential prognostic factors for these patients. Our first hypothesis was that dogs with functional thyroid tumors treated with surgical excision alone would have survival times comparable to historically reported survival times for dogs with thyroid tumors (functional, nonfunctional, or status not specified). Our second hypothesis was that age, breed, preoperative clinical factors (hematologic values and time from diagnosis until treatment), administration of supplemental thyroid hormone after surgery, and histologic diagnosis (benign vs malignant tumor) would not be significantly associated with survival time for the sample of dogs included in this study.
Materials and Methods
Case selection criteria
The study was designed as a multicenter, retrospective cohort study. Paper and electronic medical record databases from 9 institutions (Pittsburgh Veterinary Specialty and Emergency Center, Pittsburgh, Pa; the University of Georgia, Athens, Ga; The Ohio State University, Columbus, Ohio; Texas A&M University, College Station, Tex; the University of Pennsylvania, Philadelphia, Pa; Auburn University, Auburn, Ala; Louisiana State University, Baton Rouge, La; Kansas State University, Manhattan, Kan; and Cornell University, Ithaca, NY) were searched to identify dogs that underwent surgical treatment for functional thyroid tumors between 2005 and 2015. These institutions were chosen on the basis of positive responses to an electronic mailing list or personal communications from study authors. Electronic search terms included hyperthyroidism, T4, thyroid tumor or mass, and thyroidectomy. Inclusion criteria included confirmation of hyperthyroidism on the basis of serum basal total T4 concentration, complete medical history, clinical staging, surgery for complete tumor excision, and histologic diagnosis of thyroid neoplasia. Tumor resectability was determined by clinicians responsible for the cases on the basis of preoperative physical examination and intraoperative findings. Dogs that had unresectable thyroid tumors, received adjunctive treatment (chemotherapy, 131I treatment, or radiation therapy) for the thyroid tumor, or had < 24 months' postoperative follow-up information were excluded from the study. One clinician or research associate at each institution performed a data search and completed a standardized abstract sheet for each included case. These forms were collected and data were compiled by 1 author (ANF).
Medical records review
Information obtained from medical records included signalment (breed, age, sex, reproductive status, and body weight), physical examination findings, date of diagnosis, results of diagnostic tests used for disease staging, time from diagnosis to treatment, surgical procedure, and histologic diagnosis. Date of diagnosis was defined as the first documentation of serum total T4 concentration greater than the upper limit of the applicable laboratory reference range in the absence of supplemental thyroid hormone administration.
Information including dates of local disease recurrence, detection of metastatic disease, and death or last follow-up was abstracted from the medical records. When necessary, the owner or referring veterinarian was contacted by telephone for additional information. Recurrence of clinical disease was identified when recrudescence of clinical signs, evidence of tumor recurrence, or detection of serum total T4 concentration above the reference range not attributed to iatrogenic causes (excessive thyroid hormone administration) was recorded. Survival time was defined as the time from surgery until death. Dogs that were alive at the end of the study period or for which cause of death or euthanasia was not tumor-related were censored at time of last contact or death. When the cause of death or euthanasia could not be determined, it was assumed to be tumor-related.
Statistical analysis
Descriptive statistics for dog age and time to treatment (after diagnosis) were computed to characterize the sample. Median survival time as well as 1-, 2-, and 3-year survival rates were estimated with the Kaplan-Meier method. Kaplan-Meier survival data were compared among dogs with various findings with log-rank tests. Cox proportional hazards models were fit to assess the importance of potential prognostic factors (breed, age [in years] at the time of diagnosis, serum total T4 concentration, serum ALT activity, serum ALP activity, administration of supplemental thyroid hormone [yes or no], and time to treatment [in days]) to the survival rate. Hazards ratios with 95% CIs and P values were reported to summarize the results of the Cox models. Similar analyses were performed to assess the potential influence of tumor type (benign vs malignant) on survival rates. All statistical analyses were performed with statistical software.a Values of P < 0.05 were considered significant.
Results
Twenty-seven dogs met the study criteria (2 at Pittsburgh Veterinary Specialty and Emergency Center, 8 at the University of Georgia, 8 at The Ohio State University, 2 at Texas A&M University, 2 at the University of Pennsylvania, 2 at Auburn University, 2 at Kansas State University, and 1 at Cornell University). Median age at the time of diagnosis was 10 years (range, 8 to 13 years). There were 10 females (all spayed) and 17 males (13 castrated and 4 sexually intact). The study sample comprised 5 Golden Retrievers, 5 Labrador Retrievers, 2 Siberian Huskies, 2 pit bull–type dogs, 2 Bichons Frises, 2 mixed-breed dogs, and 1 each of the following: American Water Spaniel, Whippet, Maremma Sheepdog, Cocker Spaniel, Welsh Corgi, Beagle, Shetland Sheepdog, Australian Shepherd, and Dachshund. Two dogs had no clinical signs and had hyperthyroidism detected on routine hematologic assessment. The most common clinical signs reported by owners at diagnosis were polyuria with polydipsia (15/27 [56%]) and weight loss (12 [44%]). Other signs included polyphagia (6/27 [22%]), alopecia (5 [19%]), excessive panting (5 [19%]), and a palpable cervical mass (5 [19%]). Prior to surgery, mean serum total T4 concentration (n = 27) was 6.3 ± 2.35 μg/dL (median, 5.8 μg/dL; range, 3.7 to 13.7 μg/dL), mean ± SD serum ALT activity (n = 21) was 75.2 ± 33.7 U/L (median, 65 U/L; range, 36 to 139 U/L), and mean serum ALP activity (n = 22) was 101.3 ± 81.0 U/L (median, 75.5 U/L; range, 30 to 308 U/L).
All dogs had thoracic radiography performed, and metastatic disease (in the lungs) was identified in 1 dog that had a unilateral thyroid tumor. Additional staging tests were clinician dependent and included scintigraphy (n = 5), cervical region ultrasonography (8), abdominal ultrasonography (5), and thoracic CT (2).
Median time from diagnosis to treatment was 15 days (range, 1 to 71 days). Two of 27 dogs underwent median sternotomy for mediastinal tumor excision, and 25 dogs underwent cervical thyroidectomy (unilateral in 20 and bilateral in 5). Owing to the retrospective nature of the study, details of surgery were not readily available for all dogs. Long-term care was variable, but most patients were monitored with routine physical examination and measurement of serum total T4 concentration. Thirteen (48%) dogs, including all 5 dogs that underwent bilateral thyroidectomy, required lifelong administration of supplemental thyroid hormone, 6 (22%) required temporary administration of such supplements, and 8 (30%) did not require supplemental thyroid hormone treatment.
One of 27 (4%) dogs developed local tumor recurrence, manifested as a ventral cervical mass in the region of the thyroid gland and high serum T4 concentration, 670 days after surgery. The only dog with metastasis detected at the time of diagnosis had static disease (as assessed by radiography) 3 months after surgery. On the basis of the long-term monitoring performed, no other dogs had evidence of recurrent disease or metastatic disease identified prior to death or the last follow-up visit.
Seven of 27 (26%) dogs were alive at the end of the study (median interval after surgery, 969 days; range, 700 to 1,751 days). Fifteen (56%) dogs died from or were euthanized because of disease unrelated to tumors. One dog's cause of death was unknown and was therefore assumed to be tumor-related. The dog with a recurrent functional thyroid tumor was euthanized 845 days after surgery. Three (11%) dogs were euthanized because of neurologic signs suggestive of metastatic disease (2 had seizures and 1 had signs of neck pain), although no dogs underwent necropsy. Survival time for the dog with metastatic disease at the time of diagnosis was 87 days.
Median survival time for the study sample was estimated to be 1,072 days after surgery (range, 87 to 2,067 days; Figure 1). The survival rates 1, 2, and 3 years after surgery were 24 of 27 (89%), 22 of 27 (81%), and 12 of 27 (45%), respectively. Age at the time of diagnosis (HR, 0.98; 95% CI, 0.71 to 1.35; P = 0.90), preoperative serum ALT (HR, 1.00; 95% CI, 0.86 to 1.26; P = 0.82) and ALP (HR, 1.00; 95% CI, 0.99 to 1.0; P = 0.40) activities, and time from diagnosis to surgery (HR, 1.00; 95% CI, 0.98 to 1.03; P = 0.80) were not associated with survival time. For every 1-unit increase in preoperative serum total T4 concentration, there was a slight but nonsignificant (P = 0.68) increase in the hazard of death (HR, 1.04; 95% CI, 0.86 to 1.26). The requirement for supplemental thyroid hormone treatment after surgery was not significantly (P = 0.29) associated with survival time (HR, 0.60; 95% CI, 0.23 to 1.55).
All tumors were submitted for histologic examination and reviewed by board-certified veterinary pathologists at the institution where the surgery was performed (n = 8) or a commercial pathology service laboratory (1). Dogs with bilateral thyroidectomies (ie, multiple tumors) had each thyroid gland evaluated individually, but had histologically similar findings reported for each gland. The most common tumor type reported was thyroid carcinoma (15/27 [56%]), followed by adenocarcinoma (8 [30%]) and adenoma (4 [15%]). Vascular invasion was reported for 12 dogs and noted to be absent for 9 dogs. The MSTs for dogs with malignant and benign tumors were 970 and 1,072 days, respectively; these were not significantly (P = 0.65) different.
Discussion
To the authors' knowledge, the present study was the first to evaluate outcomes and potential prognostic factors for dogs undergoing surgery for treatment of functional thyroid tumors. Hyperthyroidism is rare in dogs and typically associated with neoplasia or excessive supplemental thyroid hormone administration. Historically, thyroid tumors are most commonly diagnosed in older dogs (typically ≥ 10 years),2,7,8 in agreement with the findings of the present study. Golden Retrievers, Siberian Huskies, Boxers, and Beagles have previously been overrepresented in studies3,4,6,7,13 of dogs with all types of thyroid tumors, but our findings suggested many breeds can be affected. The most common clinical signs were polyuria and polydipsia, and the second most common sign was weight loss. These clinical signs attributable to hyperthyroidism may contribute to earlier detection of thyroid tumors in dogs, compared with nonfunctional thyroid tumors. However, some dogs in our study only had a palpable cervical mass, and for 2 dogs, the only sign was high serum total T4 concentration detected on routine hematologic analysis.
Metastatic disease at the time of diagnosis was identified in only 1 of 27 (4%) dogs in our study sample, which is a lower proportion than previously reported.2,7,8 Results of a previous study9 indicated a higher risk of metastatic disease is associated with bilateral thyroid tumors, but the only dog in the present study with metastatic disease had a unilateral thyroid tumor. Survival time for the dog with metastatic disease (87 days) was less than the overall MST (1,072 days) in the present study. Local recurrence was identified in 1 dog in our study almost 2 years after surgery, and this dog was euthanized because of progressive disease 6 months after recurrence; survival time for this dog (845 days) was also less than the MST.
The survival rates for dogs 1, 2, and 3 years after surgery were 89%, 81%, and 45%, respectively. Median survival time was 1,072 days (35.8 months), with 7 of 27 (26%) dogs still alive at the end of the study. Median survival time for dogs with malignant thyroid tumors (carcinoma or adenocarcinoma) was 970 days (32.3 months); this was not significantly different from dogs with benign tumors (1,072 days [35.7 months]). Previous studies8,14 that evaluated outcomes for dogs with thyroid tumors treated with surgical excision revealed survival times of approximately 1.5 to 3 years. Klein et al14 evaluated 20 dogs with thyroid carcinomas (functional vs nonfunctional status not specified) treated with surgery alone, and the estimated MST was > 36 months. Nadeau et al8 evaluated 28 dogs that had thyroid tumors treated with surgery alone (functional vs nonfunctional status not specified) and found a higher rate of metastatic disease (9/28 [32%]) than in the cohort of the present study. In that study,8 several tumors were considered fixed or invasive, so some dogs only underwent cytoreductive surgery. The MST was 17 months for 22 of 28 dogs with and without metastatic disease for which outcome was known. This supported our hypothesis that dogs with functional thyroid tumors treated with surgical excision alone have survival times comparable to historically reported survival times for dogs with all thyroid tumors.
The statistical evaluation of association between preoperative serum total T4 concentration and the outcome of death in the present study suggested a 4% increased hazard of death for every 1-unit increase in the T4 concentration; however, the finding was not statistically significant. Similarly, results that suggested dogs requiring supplemental thyroid hormone administration after surgery had longer survival times did not meet the significance criteria. In fact, none of the potential prognostic indicators that were investigated were significantly associated with survival time. The results should be viewed cautiously because the small sample size (27 dogs) likely yielded insufficient power to detect significant differences. Although results of a recent study8 indicated that tumor size does not affect outcome, this factor could not be assessed in the present study, as medical records available were insufficient for computation of tumor size.
The limitations of the present study were mostly inherent to its retrospective nature and the small sample size. The diagnostic tests performed and treatment recommendations were clinician dependent, making selection of patients treated with surgery alone potentially biased because the dogs could have been selected as surgical candidates on the basis of the clinician's determination that a tumor was not highly aggressive. Clinical follow-up was variable, and in some cases, evaluation for recurrence of disease was an assumption made on the basis of physical examinations performed and clinical signs noted by owners. The lack of necropsy evaluations also limited definitive diagnosis of recurrent or metastatic disease. Finally, histologic samples were reviewed by different pathologists, and no standard reporting format was followed for these evaluations; the variation in recording the degree of differentiation, vascular or capsular invasion, and completeness of excision prevented further comparison of histologic diagnoses (other than benign vs malignant disease) with clinical outcome. In human medicine, the current recommendations for histologic reporting for thyroid carcinomas includes tumor type, degree of differentiation, evaluation of surgical margins, angiolymphatic or perineural invasion, and extrathyroidal extension.22 In veterinary medicine, future studies are warranted to investigate whether following a standard method for reporting histologic findings impacts prognosis and recommendations for adjunctive treatments.
Acknowledgments
No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.
The authors thank Kathleen Tidd (University of Pennsylvania), Megan E. Brown (The Ohio State University), Bonnie B. Boudreaux (Louisiana State University), Annette N. Smith (Auburn University), James A. Flanders (Cornell University), and Misty Bear (Kansas State University) for their contributions to data collection.
ABBREVIATIONS
ALP | Alkaline phosphatase |
ALT | Alanine aminotransferase |
CI | Confidence interval |
HR | Hazard ratio |
MST | Median survival time |
T4 | Thyroxine |
Footnotes
Stata, version 15, StataCorp, College Station, Tex.
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