Recombinant human thyrotropin in veterinary medicine: current use and future perspectives

Recombinant human thyrotropin (rhTSH) was developed after bovine thyrotropin (bTSH) was no longer commercially available. It was approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) as an aid to diagnostic follow-up of differentiated thyroid carcinoma in humans and for thyroid remnant ablation with radioiodine. In addition, rhTSH is used in human medicine to evaluate thyroid reserve capacity and to enhance radioiodine uptake in patients with metastatic thyroid cancer and multinodular goiter. Likewise, rhTSH has been used in veterinary medicine over the last decade. The most important veterinary use of rhTSH is thyroidal functional reserve testing for the diagnosis of canine hypothyroidism. Recent pilot studies performed at Ghent University in Belgium have investigated the use of rhTSH to optimize radioiodine treatment of canine thyroid carcinoma and feline hyperthyroidism. Radioiodine treatment optimization may allow a decreased therapeutic dosage of radioiodine and thus may improve radioprotection. This review outlines the current uses of rhTSH in human and veterinary medicine, emphasizing research performed in dogs and cats, as well as potential future applications.     

Association of Iatrogenic Hypothyroidism with Azotemia and Reduced Survival Time in Cats Treated for Hyperthyroidism

Background: Iatrogenic hypothyroidism can occur after treatment of hyperthyroidism, and is correlated with a reduced glomerular filtration rate in humans and dogs. Hypothesis: Cats with iatrogenic hypothyroidism after treatment for hyperthyroidism will have a greater incidence of azotemia than euthyroid cats. Animals: Eighty client owned cats with hyperthyroidism. Methods: Two retrospective studies. (1) Longitudinal study of 12 hyperthyroid cats treated with radioiodine (documented as euthyroid after treatment), to assess changes in plasma thyroid stimulating hormone (TSH) concentration over a 6‐month follow‐up period, (2) Cross‐sectional study of 75 hyperthyroid cats (documented as euthyroid) 6 months after commencement of treatment for hyperthyroidism to identify the relationship between thyroid status and the development of azotemia. Kaplan‐Meier survival analysis was performed to identify relationships between thyroid and renal status and survival. Results: Plasma TSH concentrations were not suppressed in 7 of 8 cats with hypothyroidism 3 months after radioiodine treatment. The proportion of cats with azotemia was significantly (P= .028) greater in the hypothyroid (16 of 28) than the euthyroid group (14 of 47). Twenty‐eight of 41 cats (68%) with plasma TT4 concentration below the laboratory reference range had an increased plasma TSH concentration. Hypothyroid cats that developed azotemia within the follow‐up period had significantly (P= .018) shorter survival times (median survival time 456 days, range 231–1589 days) than those that remained nonazotemic (median survival time 905 days, range 316–1869 days). Conclusions and Clinical Importance: Iatrogenic hypothyroidism appears to contribute to the development of azotemia after treatment of hyperthyroidism, and reduced survival time in azotemic cats.     

FELINE HYPERTHYROIDISM: EFFICACY OF TREATMENT USING VOLUMETRIC ANALYSIS FOR RADIOIODINE DOSE CALCULATION

Hyperthyroidism was diagnosed in 80 cats with thyroid scintigraphy using technetium pertechnetate. These cats were subsequently treated with radioiodine using a modified fixed dose method based on the volume of hyperfunctioning thyroid tissue calculated from the pertechnetate scans. The medical records and thyroid scintigrams were evaluated retrospectively. Follow-up was obtained on the cats to evaluate treatment success. Several parameters were evaluated in an attempt to identify a difference between treatment success and failure. Cats that failed to become euthyroid after one dose of radioiodine had a significantly higher pretreatment serum thyroxine level, had a significantly larger volume of hyperfunctioning thyroid tissue on scintigrams, and cats receiving oral versus intravenous radioiodine were over represented. Based on our results we conclude: 1) the administration of a dose of radioiodine based solely on the volume of hyperfunctioning thyroid tissue as estimated from the pertechnetate scan may be inadequate for those patients with extremely elevated serum thyroxine levels or large thyroid glands, and 2) oral administration of radioiodine is not recommended for the treatment of feline hyperthyroidism.     

Clinical and pathologic features of thyroid tumors in 26 dogs

Thyroid tumors were diagnosed in 26 dogs between 1977 and 1984. A total of 23 of the 26 tumors were carcinomas, and 3, detected as incidental findings at necropsy, were adenomas. The median patient age was 9.5 years. Dogs of the Beagle breed were affected most commonly (5 dogs). The most common physical abnormalities in carcinoma patients were cervical swelling, dyspnea, and coughing. A total of 25 of 26 dogs were clinically euthyroid. Aspiration cytology provided diagnostic information in 8 of 17 cases. In dogs with thyroid carcinoma, a cervical soft tissue lesion was identified consistently by use of radiography and scintigraphy with sodium pertechnetate. Pulmonary metastases were detected radiographically in 8 of 21 dogs with thyroid carcinoma. Thoracic nuclear imaging confirmed the radiographic findings in 11 of 14 dogs. Surgical excision of the thyroid mass was the primary treatment for 17 dogs with carcinoma. Eight dogs died within 2 years (median, 7 months) of surgery because of primary tumor regrowth or metastases. Four dogs were alive at a range of 3 to 48 months after surgery, and 4 dogs died from unrelated causes. Necropsy of 7 dogs with thyroid carcinoma revealed neoplastic infiltration of the cervical blood vessels and pulmonary metastases in each dog. The most common histologic patterns of thyroid carcinoma were solid or compact cellular (11 dogs) and mixed solid-follicular tumors (8 dogs). Dogs with a solid carcinoma had a median survival time of 10.5 months (6 dogs), and dogs with a mixed solid-follicular tumor had a median survival time of 8 months (3 dogs).     

Nuclear imaging and radiation therapy in canine and feline thyroid disease.

The indications, techniques, and expectations for radionuclide diagnostic studies on canine and feline thyroid glands are presented. In addition, the considerations surrounding radioiodine or external beam radiotherapy for benign and malignant thyroid disease are reviewed. The intent of this article is to familiarize primary care veterinarians with the utility of and outcome of the ionizing radiation-based diagnostic and therapeutic techniques for assessing and treating canine and feline thyroid disease.     

Radioactive Iodine Treatment of a Functional Thyroid Carcinoma Producing Hyperthyroidism in a Dog

Radioactive iodine (131I) was used in the treatment of a 12-year-old female dog with hyperthyroidism resulting from a large, unresectable (and metastatic) thyroid carcinoma associated with signs of severe inspiratory stridor and dyspnea. Hyperthyroidism was diagnosed on the basis of clinical signs (polyuria, polydipsia, polyphagia, weight loss, nervousness) and high basal serum thyroxine (T4) concentrations, as well as thyroid radioiodine kinetic studies that showed a high radioiodine uptake into the thyroid (% thyroid uptake) and markedly increased serum concentrations of protein-bound iodine-131 (PB131I) after 131I tracer injection. Thyroid imaging revealed diffuse radionuclide accumulation by the tumor, which involved both thyroid lobes. The dog was treated with three large doses of radioiodine (131I), ranging from 60 to 75 mCi, given at intervals of 5 to 7 months. The dog became euthyroid, and the size of the tumor decreased by approximately 25% after each 131I treatment, improving the severe inspiratory stridor and dyspnea, but both the hyperthyroid state and breathing difficulty recurred within a few months of each treatment. The dog was euthanatized 5 months after the last treatment because of progressive tracheal compression and pulmonary metastasis.     

Clinical Features and Treatment Outcomes of 41 Dogs with Sublingual Ectopic Thyroid Neoplasia

Background

Thyroid neoplasia is common in dogs, but there are few reports of dogs with ectopic, sublingual thyroid tumors.

Objectives

To describe clinical features and outcomes of dogs with ectopic, sublingual thyroid neoplasia.

Animals

Five hundred and forty‐four dogs with thyroid neoplasia.

Methods

This retrospective study reviewed the medical records of dogs referred for thyroid neoplasia between 1995 and 2013. Data extracted included signalment, extent of thyroid disease (eutopic or ectopic; metastasis), serum thyroxine (T₄) concentration, treatment, and survival.

Results

Of 544 dogs with thyroid neoplasia, 41 (7.5%) dogs had ectopic sublingual thyroid tumors. The clinical features of these 41 dogs were similar to the cohort group of 503 dogs with eutopic or ectopic mediastinal thyroid tumors, but dogs with sublingual tumors were younger and less likely to have metastatic disease (15% versus 30%, P < .05). Of the 41 dogs, 28 received treatment: 21 with surgery (which included partial hyoidectomy in 13), 7 with radioiodine alone, and 13 with surgery followed by administration of radioiodine. Overall median survival was 562 days (range, 1‐1,850 days).

Conclusions and Clinical Importance

When compared with eutopic thyroid carcinomas, ectopic sublingual thyroid tumors generally have a less aggressive biologic behavior. Many dogs have prolonged survival, even without treatment, although death because of local tumor invasiveness or metastasis can develop in some dogs. Surgical thyroidectomy, including partial hyoidectomy, is generally effective for control of local disease. Administration of radioiodine, alone or in combination with surgical treatment, is recommended for multifocal disease or metastasis.     

Clinical factors determining the efficacy of urinary bladder tumour treatments in dogs: surgery, chemotherapy or both?

In a study of 44 canine patients suffering from histopathologically proven urinary bladder tumour with a high incidence of transitional cell carcinoma (TCC) (n = 35), a close relationship was found either between the disease-free period and the age (r = -0.40) of animals or between the survival times and the age (r = -0.62) of animals after treatment. In addition to the dog breeds known to be prone to have urinary bladder tumour, we found an additional potentially sensitive breed, the Hungarian Vizsla. The median survival times obtained by the applied treatment types were as follow: 'surgery and chemotherapy' (n = 8/44) 475 days, 'surgery alone' (n = 19/44) 240 days, 'chemotherapy alone' (n = 7/44) 31 days, and 'no treatment' (n = 10/44) 7 days (P < 0.001). According to the findings, chemotherapy combined with surgery completed in time is the most effective protocol in the treatment of urinary bladder tumour cases in dogs. A rational and more effective procedure for the assessment and treatment of urinary bladder tumour cases is presented.     

Radiographic and Scintigraphic Evidence of Focal Pulmonary Neoplasia in Three Cats With Hyperthyroidism: Diagnostic and Therapeutic Considerations

Three cats were diagnosed as hyperthyroid based on clinical signs, historical findings, laboratory abnormalities, and basal serum thyroxine (T₄) concentrations, and/or nuclear thyroid scans. Additionally, a presumptive diagnosis of thyroid carcinoma with pulmonary metastasis was made in each cat based on radiographic or scintigraphic evaluation. All three cats had solitary pulmonary nodules 1.5 to 2 cm in diameter on survey thoracic radiographs; one cat also had chylous pleural effusion and pulmonary lobar consolidation. Focal pulmonary accumulation of sodium pertechnetate (^99mTcO₄ -) and/or radioiodine (¹³¹I) corresponding to radiographic lesions were seen in all cats. Two cats were treated with single ablative doses (1111 to 1480 MBq) of¹³¹I; the remaining cat was euthanatized.
One of the treated cats died 8 days later; the other cat was euthanatized 22 weeks following treatment. Histopathologic examination of tissue obtained at necropsy confirmed metastatic thyroid carcinoma in one cat and bronchogenic adenocarcinoma in two cats. Our findings indicate that increased radionuclide uptake in focal pulmonary lesions and cytologic evaluation of tissue obtained by fine-needle aspiration are not specific for thyroid tissue. (Journal of Veterinary Internal Medicine 1993; 7:303–308. Copyright © 1993 by the American College of Veterinary Internal Medicine.)     

Prognostic factors and patterns of treatment failure in dogs with unresectable differentiated thyroid carcinomas treated with megavoltage irradiation

OBJECTIVE: To determine quality and duration of progression-free survival (PFS) time in dogs with unresectable thyroid carcinomas treated with definitive megavoltage irradiation and analyze prognostic factors of PFS and patterns of failure (local recurrence vs metastasis). DESIGN: Prospective clinical trial. ANIMALS: 25 dogs with locally advanced thyroid carcinomas and no evidence of metastasis. PROCEDURE: Dogs were treated with 48 Gy during 4 weeks on an alternate-day schedule of 4 Gy/fraction. RESULTS: Irradiation was safe and effective for treatment of large unresectable thyroid carcinomas. Progression-free survival rates were 80% at 1 year and 72% at 3 years. Time to maximum tumor size reduction ranged from 8 to 22 months. Factors affecting PFS were not found. Twenty-eight percent (7/25) of dogs developed metastasis. Dogs with bilateral tumors had 16 times the risk of developing metastases, compared with dogs with a single tumor. Dogs with no evidence of tumor progression had 15 times less risk of developing metastases. Radiation-induced hypothyroidism was suspected in 2 dogs 13 and 29 months after irradiation. CONCLUSIONS AND CLINICAL RELEVANCE: Irradiation is effective for local control of thyroid tumors, despite their slow regression rate. Results provided evidence that local tumor control affects metastatic outcome in dogs with thyroid carcinomas and is a strong basis for the development of new approaches that include irradiation in the management of dogs with advanced thyroid carcinomas. Improvements in local tumor control alone may be insufficient to improve survival times because of the high risk of metastatic spread before an initial diagnosis is made, which warrants initiation of early systemic treatment.     

Radiotherapy of pituitary tumours in five cats

Five cats tentatively diagnosed with pituitary adenoma (four cases) or pituitary carcinoma (one case), based on computed tomography (CT) or magnetic resonance imaging, were treated with radiotherapy. Electrons were applied in four cats and electrons and photons in the fifth. Ten to 12 fractions of 3.5 to 4.0 Gy each were delivered on a Monday/Wednesday/Friday schedule. The mean total dose applied was 39 Gy. No severe acute side effects to treatment were seen. Follow-up CT examination was performed in four cats; the mass had disappeared in one cat and remained stable or slightly decreased in size in the other three. The survival times were 5.5, 8.0, 15.0, 18.0 and 20.5 months, with two cats dying of causes unrelated to the tumour. Based on these cases, radiotherapy appears to be a valuable treatment option for feline pituitary tumours.     

Radioiodine treatment of hyperthyroidism

Radioactive iodine provides a simple, effective, and safe treatment for cats with hyperthyroidism and is regarded by most authorities to be the treatment of choice. It is a particularly useful treatment for cats with bilateral thyroid involvement (found in approximately 70% of cats), cats with ectopic (intrathoracic) thyroid tissue, and the rare patient with thyroid carcinoma. Treatment with radioiodine avoids the inconvenience of daily, oral administration of an antithyroid drug, as well as the side effects commonly associated with these drugs. Use of radioiodine also avoids the risks and perioperative complications associated with anesthesia and surgical thyroidectomy. Radioiodine treatment involves a single, nonstressful procedure that is without associated morbidity or mortality. A single treatment restores euthyroidism in most cats with hyperthyroidism. Whereas the therapy is simple and relatively stress-free for cats, it does require special licensing and hospitalization facilities, nuclear medicine equipment, and extensive compliance with local and state radiation safety laws.     

Radioiodide (131I) therapy for the treatment of canine thyroid carcinoma

OBJECTIVE: To assess the efficacy of radioactive iodine treatment (131I) for canine thyroid carcinoma, as both the sole therapeutic modality and as an adjunct to surgery. DESIGN: Retrospective analysis of case records from the Gladesville Veterinary Hospital Nuclear Medicine Service, Sydney, between August 1988 and December 2001. CASE DETAILS: The records of 65 dogs with thyroid carcinoma were analysed according to therapy and outcome. Forty-three dogs received radioiodide therapy, either as the sole therapeutic modality (32) or as an adjunct to surgery (11). Radioisotope therapy consisted of one to three doses of 131I with a dose range of 555 to 1850 MBq. For analysis, dogs were divided into groups according to therapy: no treatment, surgery alone, surgery with radioiodide therapy or radioiodide therapy alone. Mode of therapy, dosage of 131I, clinical staging and age were all independently analysed according to survival to compare efficacy or predictive value respectively. RESULTS: When radioiodide therapy was used as an adjunct to surgery, median survival was 34 months. Censored median survival time for dogs that received radioiodide alone was 30 months. Dogs that did not receive treatment had a median survival of only 3 months. Log rank statistical analysis indicated that mode of therapy was significantly correlated with survival but that clinical stage of disease was not. CONCLUSION: The authors conclude that 131I therapy is effective at extending survival time, both as a sole therapeutic modality and as an adjunct to surgery, in dogs with invasive canine thyroid carcinoma. Incomplete surgical resection may not prolong survival in dogs also receiving 131I therapy, however surgical resection with curative intent should be recommended as the first line of therapy for mobile thyroid carcinomas. Radioisotope therapy can be recommended for cases where surgery alone is considered unlikely to be curative because of metastatic disease or local invasion, or for cases where surgery has been attempted but complete surgical removal has not been achieved.     

Computed tomographic densitometry of normal feline thyroid glands

We studied the computed tomographic (CT) appearance and determined Hounsfield units (HU) for normal thyroid tissue in eight cats. Helical CT images (2 mm collimation) were acquired from cranial aspect of the second cervical vertebra (C2) through caudal aspect of the fourth cervical vertebra (C4). Data were acquired before contrast medium administration (n = 7), after delayed contrast medium enhancement (n = 8), and immediately after contrast medium enhancement after a second dose of contrast medium (n = 8). Attenuation of thyroid tissue was compared with surrounding tissues. Before contrast medium enhancement, thyroid tissue was hyperattenuating to the surrounding soft tissues. After delayed contrast medium enhancement, thyroid tissue was hyperattenuating to surrounding soft tissues and isoattenuating to contrast medium-laden blood vessels. Immediately after contrast medium enhancement, thyroid tissue was hyperattenuating to surrounding soft tissues and hypoattenuating to contrast medium-laden blood vessels. The thyroid glands were dorsolateral to the trachea, ovoid, and displayed homogenous contrast medium enhancement. Circular regions of interest were drawn on the right and left thyroid lobes. Densitometric data of thyroid tissue were as follows: precontrast medium enhancement, 123.2 HU (95% CI: 119.4-127.1 HU); delayed contrast medium enhancement, 132.1 HU (95% CI: 127.4-136.8 HU); immediate postcontrast medium enhancement, 168.5 HU (95% CI: 163-173.9 HU). Normal feline thyroid tissue is easily detected using CT without contrast medium enhancement. This information may be useful for CT evaluation of abnormal feline thyroid glands.     

Immunohistochemical analysis of cyclin A, cyclin D1 and P53 in mammary tumors, squamous cell carcinomas and basal cell tumors of dogs and cats

The involvement of cyclin A, cyclin D1 and p53 proteins in canine and feline tumorigenesis was analyzed immunohistochemically. In the present study, a total of 176 cases were examined, among which there were 108 canine cases (75 mammary lesions, 16 squamous cell carcinomas and 17 basal cell tumors) and 68 feline cases (43 mammary lesions, 20 squamous cell carcinomas and 5 basal cell tumors). Speckled nuclear staining for cyclin A was observed in 19/38 (50%) canine malignant mammary tumors and 18/37 (48.6%) feline mammary carcinomas, while this was not seen in benign mammary tumors of either dogs or cats. Marked intense nuclear cyclin A staining was seen in 7/16 (43.8%) canine squamous cell carcinomas and 18/20 (90.0%) feline squamous cell carcinomas. Only 3/17 (17.6%) canine basal cell tumors showed slight and scattered staining for cyclin A. Expression of cyclin D1 was very rare in both canine and feline tumors. Nuclear staining of p53 was found in 7/37 (18.9%) feline mammary carcinomas. Intense immunoreactivity for p53 was found in 6/16 (37.5%) canine squamous cell carcinomas and 8/20 (40%) feline squamous cell carcinomas. These results suggest that cyclin A may have a role in the proliferation of canine malignant mammary tumors, feline mammary carcinomas and squamous cell carcinomas of dogs and cats, and p53 may associate with the tumorigenesis of feline mammary carcinomas and squamous cell carcinomas of dogs and cats.     

Scintigraphic findings in 120 hyperthyroid cats

The aim of this study was to characterise the scintigraphic findings in a large population of hyperthyroid cats in order to determine the location of thyroid pathology in newly diagnosed hyperthyroid cats and those that had previously undergone thyroidectomy. A specific aim was to identify the proportion of cats with ectopic hyperfunctional thyroid tissue and characterise the scintigraphic and clinical features of this subset of cats. Nearly one in five hyperthyroid cats was identified to have multiple areas of hyperfunctional thyroid tissue and/or intrathoracic hyperfunctional thyroid tissue where surgical thyroidectomy would not be curative. In addition, this study demonstrated that scintigraphy cannot reliably distinguish between thyroid carcinoma and adenoma. Owners should always be warned about the possibility of ectopic thyroid tissue before thyroidectomy is performed. In this study, intrathoracic hyperfunctional thyroid tissue and multiple areas of increased radionuclide uptake (IRU) were a common feature of benign thyroid disease and responded well to treatment with low dose radioiodine.     

Interference of iohexol with radioiodine thyroid uptake in the hyperthyroid cat

Absorbed thyroid dose and effective half-life were determined in 46 hyperthyroid cats after treatment with a low dose (mean 111MBq) of radioiodine intravenously. Thirteen of these cats had received iohexol for glomerular filtration rate (GFR) measurement within 24h before treatment with radioiodine in view of another ongoing study at our institution. Pre-therapy values were obtained for total thyroxine (TT(4)) and for the thyroid to salivary gland ratio with sodium pertechnetate gamma-camera imaging. All cats underwent post-therapy scans at 24, 48 and 120 h for evaluation of radioactive iodine uptake (RAIU) and the effective half-life of radioiodine. The absorbed dose was calculated from the cumulative activity with Olinda software. Both groups were comparable in age, TT(4) and the ratio of thyroid activity to salivary gland activity. Statistical analysis revealed a significant decreased absorbed dose in the thyroid in the iohexol group. This decreased uptake was not accompanied by an decreased effective half-life of the radioiodine. The variation of inter-individual RAIU decreased in this group and more homogenous absorbed doses were obtained. No significant difference in outcome could be demonstrated. However, a tendency towards a higher number of residual hyperthyroidism in the iohexol group was noted (15 versus 6% in control group). This study demonstrates that iohexol interferes with the uptake of radioiodine in the hyperthyroid cat but does not provoke increased turnover. In this study, albeit including a small number of cats, outcome did not seem to be significantly affected.