Abstract
Client-owned cats underwent surgery to remove palpable cervical masses in cats with normal total T4 values and no clinical signs of hyperthyroidism, renal disease, or hyperparathyroidism. Non-functional thyroid and parathyroid adenomas were found and identified by histopathological examination. The significance of these findings is discussed in relation to palpating a goiterous mass in an asymptomatic cat.
In a previous paper, the authors described a sensitive palpation technique that permitted them to find a substantial number of client-owned cats with thyroid enlargement, no clinical signs of hyperthyroidism, and normal total thyroxine (TT4) values (Norsworthy et al 2002). The significance of this finding is the subject of this paper, which is to further study these cats at a histological level to determine the changes occurring in these enlarged cervical masses.
Thyroid adenomatous hyperplasia in cats with normal or low TT4 values has been reported (Chaitman et al 1999). The authors of this abstract identified 26 cats that had normal TT4 values on one or more occasions, no signs of hyperthyroidism, and a complete necropsy following euthanasia or spontaneous death. Although overt hyperthyroidism was not identified, 81% of these cats had cardiac disease at necropsy. The diseases included myocardial fibrosis (38%), hyaline arteriopathy (38%), endocardial fibrosis (19%), and myocarditis (12%). Only one had hypertrophic cardiomyopathy. The same authors continued their study with immunohistochemical staining of thyroglobulin in these cats, normal cats, and hyperthyroid cats (Chaitman et al 2000). They observed significant staining differences in the three groups of cats. Euthyroid cats with adenomatous hyperplasia showed little to no thyroglobulin production in their adenomatous tissue compared to significant production in the thyroid nodules of overtly hyperthyroid cats. They concluded that thyroid masses in euthyroid cats should be classified as non-functional.
Materials and methods
Palpation technique
Cats included in this study were palpated using a technique described by the authors (Norsworthy et al 2002). It permits identification of cervical masses that may elude convention palpation.
Thyroid size
Thyroid size was graded on a scale from 0 to 6. Lobes that were non-palpable were graded as ‘0’. A ‘1’ was assigned to a lobe that was barely palpable. A ‘6’ was assigned to a nodule that was approximately 2.5 cm longitudinally. The other values were assigned proportionally to measurements between ‘1’ and ‘6’. The limitations of this technique, in terms of subjectivity and consistency, were reported (Norsworthy et al 2002).
Data and tissue collection
The authors' previous paper reported on palpation findings in 155 cats presented for diseased, traumatised, and non-diseased or non-traumatised conditions. Many of them received thyroid palpation during an annual ‘wellness’ examination. Each of these cats received thyroid palpation, TT4 determination, and pertinent history collection (Norsworthy et al 2002).
Forty of the 155 cats were examined on more than one occasion, with data being recorded on up to seven occasions. In some instances, the sequential examinations were days apart; on others, they were months or years apart. During the course of the study, six of these patients developed overt hyperthyroidism and were subjected to thyroidectomy and histopathological examination of their enlarged thyroid lobe(s). Data from these cases are presented in Table 1.
Time lapse from initial palpation of goiter to onset of significant weight loss or elevated TT4
The reference range for TT4 concentrations is 13–67 nmol/l.
Abbreviations: L=left lobe; R=right lobe; Init=initial; y=year; Thy=thyroid; foll=follicular; hyperpl=hyperplasia; aden=adenoma; WL=weight loss; PU/PD=polyuria and polydipsia.
In 20 of the 155 cats, the mass palpated in the cervical region was surgically excised. These cats had no signs of hyperthyroidism, normal TT4 values, and thyroid palpation scores of ‘1’, ‘2’ or ‘3’. Histopathology was performed on the excised tissues (Table 2).
Results of surgery on 20 cats
Thyroid lobe size was determined on the day that surgery was performed. In several cases, it was larger at the time of surgery than when the cat was first entered into the study.
This cat had a ‘4’ lobe removed one month before removal of the ‘2’ lobe. The TT4 was 82.4 nmol/l at the time of initial diagnosis. The cat was pretreated with methimazole before the first thyroidectomy, but none was given in the 30 days between the two surgeries. A TT4 was not performed after the first thyroidectomy. Abbreviations: U=unilateral, B=bilateral, l/p=lymphoplasmacytic, DM=diabetes mellitus, WL=weight loss, PU/PD=polyuria/polydipsia, Hyperten=hypertension, PP=polyphagia.
Categories: 0=normal thyroid tissue, 1=thyroiditis, 2=non-inflammatory abnormalities, 3=changes typical of hyperthyroidism (usually thyroid adenoma), 4=parathyroid adenoma.
Note: Several of these cats experienced mild weight loss. This is a very non-specific sign that could not be related to hyperthyroidism in these cats.
Another group of seven control cats were included (Table 3). These cats had ‘0’ thyroid palpation scores, normal TT4 values, and no significant signs of hyperthyroidism. Four were hospitalised cats that were euthanised for non-thyroid disease, and three were feral cats trapped by a local humane organisation and scheduled for euthanasia. One of the authors (GDN) euthanised each of these cats and immediately removed their thyroid and parathyroid glands. The tissues were placed in 10% buffered formalin and examined histologically.
Control cats
Bilat=bilateral; L/P=lymphocytic/plasmacytic; L=lymphocytic; y=year(s); est.=estimated.
Surgical technique
The 20 cats previously mentioned received exploratory ventral cervical surgery to expose, examine, and remove the palpable masses. Cats undergoing thyroidectomy were operated using the parathyroid transplant technique previously reported by one of the authors (Norsworthy 1995). All cats recovered without clinical evidence of hypocalcaemia.
Surgery was performed on these 20 cats for four reasons. First, the senior author had the clinical impression that cats with thyroid nodules monitored for 1–2 years would often become clinically hyperthyroid. Second, it was believed that surgery would carry less anaesthetic risk and fewer complications if performed on younger cats without clinical signs of hyperthyroidism. Third, delay in treating a goiterous cat until clinical signs of hyperthyroidism develop means the cat will likely experience significant weight loss and develop cardiac disease and hypertension. Fourth, for scientific purposes, it was necessary to document the histopathological changes in the thyroid lobes of cats with thyroid enlargement but no clinical signs of hyperthyroidism.
Histopathological examinations
Entire thyroid and parathyroid glands were removed during surgery and sent to a commercial veterinary laboratory for histopathological examination by veterinary pathologists certified by the American College of Veterinary Pathologists. The tissue samples for the early surgeries and controls were reviewed by one of the authors (MRM).
Results
Cats followed to overt hyperthyroidism
The six cats listed in Table 1 were clinically euthyroid at the time a palpable thyroid lobe was first detected. With time they either developed an elevated TT4 (three cats), lost ≥1 kg of body weight (six cats), or both. A thyroidectomy was performed on each with subsequent histopathological examination of the excised tissue. Their age range was 9 to 19 years (median 13.5 years), and the time from first detection of thyroid enlargement to surgery ranged from 11 to 31 months (median 15 months). Thyroid adenoma or thyroid follicular hyperplasia was diagnosed in all six cats.
Surgery and histopathologic findings
Twenty-three surgical procedures were performed on 20 cats, and the results are summarised in Table 2. Thyroidectomy permitted the histological examination of the thyroid tissue from asymptomatic cats. Thirteen of these cats (65%) had tissue changes typical of hyperthyroidism, namely areas of adenomatous hyperplasia and/or thyroid adenomas. Cats with lobes graded as ‘1’, ‘2’, and ‘3’ fell in this group. Four cats (20%) had non-proliferative changes of the thyroid (cysts, cystic follicles, etc.). Nine (45%) had thyroiditis with lymphocytic or lymphoplasmacytic infiltration [Fig 1(a,b)].
(a) An area of lymphocytic and plasmacytic inflammation adjoins a thyroid follicular cyst (top). 200x; H&E stain. (b) A thyroid follicular cyst with adjoining lymphocytic and plasmacytic inflammation. 100x; H&E stain.
Two cats (10%) had parathyroid abnormalities (hyperplasia and parathyroid adenoma), and one of these was bilateral [Fig 2(a,b)]. The cat with bilateral adenomas was without a history of hypercalcaemia, renal disease, or other signs or history suggestive of primary or secondary hyperparathyroidism (Feldman 1999). The cat with unilateral parathyroid adenoma did not have a history of hypercalcaemia or renal disease nor did it have an unbalanced diet. In addition, it was diagnosed with adenomatous thyroid hyperplasia in the contralateral thyroid lobe.
(a, b) A palpable ‘thyroid’ lobe was actually an enlarged parathyroid lobe in cats nine and 19. The pathologist reported both to be parathyroid adenomas and neither cat exhibited hypercalcaemia, renal disease, or clinical signs of hyperparathyroidism.
Only one (5%) of the 20 cats was reported to have normal thyroid tissue based on a lack of hyperplastic, neoplastic, inflammatory, or degenerative changes; it had a palpably enlarged thyroid lobe graded as a ‘2’ and a TT4 of 15.4 nmol/l.
Histopathological controls
One cat had thyroid hyperplasia, and none had thyroid adenoma. Interestingly, six of the seven control cats had histopathologic changes of mild thyroiditis and follicular cyst formation as detailed in Table 3.
Discussion
Non-functional goiters are defined here as thyroid lobes that histologically contain areas with adenomas or adenomatous hyperplasia but occur in cats with normal total T4 values and no clinical signs of hyperthyroidism. The palpation technique cited in this paper has permitted the authors to document non-functional adenomas in live cats.
The authors acknowledge that TT4 values fluctuate over time and cats with borderline hyperthyroidism may periodically have TT4 values in the reference range (Peterson 1987). Sequential TT4 testing could better identify the nonfunctional state. Other tests, including the T3 suppression test and scintigraphy, would have also better defined this state. However, cats in this study were from the private practice of two of the authors (GDN, JAM). The limitations of private veterinary practice dictated that a substantial number of cats could be included in the study if the costs of testing were borne by the owners and the inconvenience of testing be minimised. The use of more in-depth testing could refine the definition of non-functional goiters and should be employed in future studies.
The six cats followed sequentially allowed an observation of the progression from a state of asymptomatic thyroid enlargement to a state of clinical hyperthyroidism. It appears from these cats, and from those receiving early surgery, that certain cats have non-functional or minimally functional adenomas for all or most of that time. It seems logical to assume that large, functional thyroid adenomas do not develop in a short period of time since the weight loss that occurs in hyperthyroid cats is gradual enough that many clients do not detect it until several kilograms have been lost. Therefore, it also seems reasonable to assume that the non-functional adenomas found in this study and in that of Chaitman, et al (2000) could potentially progress to a functional state. Further studies that include larger numbers of cats are needed to determine the likelihood of non-functional thyroid adenomas progressing to functional thyroid adenomas.
The surgery group allowed us to document that adenomatous hyperplasia, adenoma, and other histological lesions occur in euthyroid cats. Well over half of those cats were histologically confirmed to have one of these conditions, while most of the others had non-proliferative abnormalities of unknown significance.
Thyroiditis has been previously reported in cats and is particularly interesting in light of possible aetiologies of hyperthyroidism (Kennedy & Thoday 1988). Subacute thyroiditis in humans, deQuervain's disease, is a nonsuppurative granulomatous inflammatory process that may affect all or part of the thyroid. The aetiology is unproved but is suspected to be viral (Thrall & Ziessman 1995). Graves' disease is an autoimmune disease that begins as thyroiditis. Thyroid stimulating antibodies are produced that attach to TSH receptors on the thyroid follicular cells and cause uncontrolled thyroid stimulation (Greenspan 1997). It is possible that either of these mechanisms could occur in hyperthyroid cats and this speculation opens various channels of further investigation. In fact, circulating thyroid immunoglobulins have been demonstrated in 34% of hyperthyroid cats, but they have not been proven to stimulate growth of follicular cells in vivo or to increase thyroid hormone synthesis (Brown 1992).
Other possible causes of thyroiditis include bacterial, fungal, or viral infections, toxins, and allergy. Because much of the inflammation was immediately adjacent to the expanding thyroid cysts, it is also possible that cystic expansion per se is responsible for much of the observed inflammation and its relevance to etiology may be minimal or nil. The control cats seem to validate the latter position, as these changes were common in otherwise normal thyroid glands. Further studies are needed to determine what truly constitutes normal for feline thyroid gland histology.
Parathyroid disease was found in two cats. Only nine cases of hyperparathyroidism have been reported in cats (Kallet 1991, den Hertog 1997). It is thus possible that non-functional parathyroid adenomas are more common than currently thought. It is also possible that this is another disease process or a variation of normality.
Feline practitioners must confront the issue of what to do with a euthyroid cat with thyroid enlargement. It is the authors' belief that any thyroid enlargement is potentially pathological. The finding by Chaitman et al (2000) of an extremely high incidence (81%) of cardiac disease in the euthyroid cats with adenomatous hyperplasia is troubling. This may indicate that cardiac disease is a very early accompaniment of occult hyperthyroidism. If so, the earlier the cat is diagnosed and treated, the more the cat will be spared further cardiac damage. Similar considerations could apply also to other organ systems.
This study did not determine if all euthyroid cats with thyroid enlargement ultimately develop hyperthyroidism. Rechecking these cats every 4–6 months for clinical signs of hyperthyroidism, notably weight loss, or TT4 elevation would currently appear to be the most sensible clinical option at this time. Future recommendations may include periodic scintigraphy, T3 suppression testing, or pre-emptive surgery as utilised in the present study.