JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-N03

Signalment (JPC #1902422):  A domestic shorthair cat.

HISTORY:  This cat had high blood thyroxine levels.

HISTOPATHOLOGIC DESCRIPTION:  Thyroid gland: Comprising 90% of this section, expanding thyroid lobules, and effacing normal follicular architecture are multiple unencapsulated hyperplastic nodules up to 1 cm in diameter composed of cuboidal to polygonal epithelial cells arranged in trabeculae, cords, and occasional irregular follicles on a fine fibrovascular stroma. Cells have indistinct borders, a moderate amount of pale eosinophilic, granular to microvacuolated cytoplasm, and round nuclei with finely stippled chromatin and one distinct nucleolus.  There is less than 1 mitotic figure per 2.37 square millimeters. Remaining pre-existing follicles at the periphery of the hyperplastic nodules are lined by atrophied follicular epithelium and are filled with brightly eosinophilic colloid. There is a focal area of lytic necrosis characterized by loss of thyroid architecture with replacement by necrotic cellular debris and low numbers of macrophages which occasionally contain hemosiderin, lymphocytes, and plasma cells.

MORPHOLOGIC DIAGNOSIS:  Thyroid gland:  Adenomatous hyperplasia, multinodular, multifocal, chronic, marked, domestic shorthair, feline.

GENERAL DISCUSSION:

• Nodular hyperplasia (goiter) occurs in older cats, dogs, and horses.
• Thyroid gland hyperplasia/adenoma is more common in the cat, while carcinoma is more common in the dog
• In cats, hyperthyroidism may occur with encapsulated thyroid adenomas (usually single) or with bilateral multinodular adenomatous hyperplasia; adenomas may develop in hyperplastic thyroid glands
• 77% of hyperthyroid cats also had hyperparathyroidism and diffuse chief cell hyperplasia in the parathyroid glands
• Hyperthyroidism secondary to thyroid hyperplasia or neoplasia in cats closely resembles toxic nodular goiter in humans

PATHOGENESIS:

• Decreased G_i2 inhibitory protein expression à decreased inhibition of adenylyl cyclase à relative increase in stimulatory G protein expression à increased intracellular cAMP à upregulated mitogenesis and hormone production
• Overexpression of c-ras is highly associated with nodular follicular hyperplasia/adenomas in feline thyroid glands
• c-ras overexpression is associated with either activating point mutations (gain of function) or gene amplification; either case results in unregulated mitogenic stimuli
• Suspected mechanism of hyperparathyroidism: polyphagia à increased intestinal phosphorus absorption à reciprocal decline in blood ionized calcium à chief cell hyperplasia à elevated hyperparathyroidism
• Hyperphosphatemia may also be due to increased catabolism of muscle proteins, release of phosphorus due to gluconeogenic effects of elevated thyroid hormone, and increased bone resorption

TYPICAL CLINICAL FINDINGS:

• Older cats, females over-represented
• Weight loss, polyphagia, PU/PD, non-specific GI signs, increased activity, poor hair coat
• Palpable thyroid nodules
• Tachycardia, hypertension, heart murmur, gallop rhythm
• Hypertrophic cardiomyopathy from left ventricular hypertrophy; less commonly, dilatative
• High serum total T4 ([tT4)], but this fluctuates and may be normal at time of sampling
• Other minimum database changes may include: erythrocytosis; increased ALT, ALP, and/or creatine kinase; azotemia; hyperglycemia; decreased fructosamine concentrations
• Elevated phosphorus and parathyroid hormone with decreased serum ionized calcium (hyperparathyroidism)

TYPICAL GROSS FINDINGS:

• Hyperplasia: White to tan multiple nodules of various size that are sharply demarcated but not encapsulated; may not be visible grossly
• Adenomas: Normally a single adenoma per thyroid lobe; solid, multinodular; well demarcated, small, white to tan with a variably thick, white, fibrous capsule
• Carcinoma: Larger than adenomas, multinodular, poorly encapsulated with large central areas of hemorrhage and necrosis; locally invasive into the trachea, esophagus, larynx, etc.; often metastasizes to lungs before regional lymph nodes
• Left ventricular hypertrophy or less commonly, ventricular dilatation

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Hyperplasia:
  • Variable appearance ranging from small follicles with little colloid to large, irregular follicles with papillary projections into the lumen
  • Not encapsulated and no compression of adjacent thyroid tissue
  • Note there are no definitive criteria used to differentiate adenoma from hyperplastic nodule; in general hyperplastic nodules are usually multiple, not encapsulated, variable in structure, and do not cause as much compression of the adjacent normal thyroid as adenomas
  • May not be grossly visible
• Adenomas are classified as follicular or papillary; papillary pattern in domestic
• animals is rare
• Follicular adenomas: Contain neoplastic cells that form irregularly shaped
• follicles with occasional papillary infolding; they are partially to completely encapsulated and compress adjacent parenchyma; may cause atrophy of adjacent thyroid tissue; several different growth patterns exist:
  • Microfollicular adenomas - miniature follicles with little to no colloid
  • Macrofollicular adenomas - large, irregularly shaped follicles with abundant colloid
  • Cystic adenomas – one to two large cavities filled with proteinaceous fluid with neoplastic cells contained in the fibrous capsule
  • Oxyphilic adenomas – large cells with densely eosinophilic granular cytoplasm (granules are mitochondria)
• Adenomas commonly have concurrent diffuse chief cell hyperplasia and hyperparathyroidism

ADDITIONAL DIAGNOSTIC TESTS:

• [tT4] is screening test of choice, usually accompanied by elevated total T3 concentration ([tT3])
• Elevated free T4 concentration ([fT4]) may support the diagnosis in cases where total T3/T4 levels are within reference range, however sick euthyroid cats can have elevated [fT4] and low or normal [tT4]
• In borderline cases, T3 suppression test may be useful; normally administration of exogenous T3 inhibits TSH secretion causing decreased [tT4]; in hyperthyroid cats T4 is independent of TSH regulation and will remain elevated
• Thyrotropin-releasing hormone (TRH) will have little or no effect on [TSH] and [tT4] in hyperthyroid cats; in euthyroid cats, [tT4] should double
• Thyroid imaging (radionuclide uptake)

DIFFERENTIAL DIAGNOSIS:

• Thyroid carcinoma: Difficult to distinguish histologically because carcinomas can be well differentiated with low mitotic rates; key findings are vascular invasion or metastasis to lymph node or lung; fixed in position because of tissue invasion; very rare in cats
• Thyroid C-cell tumor: Discrete, single or multiple, gray-tan nodules; most common in aged bulls (may be in association with multiple endocrine neoplasms, especially bilateral pheochromocytomas and pituitary adenomas in Guernsey bulls) and Long-Evans rats 

ADDITIONAL DIAGNOSTIC TESTS:

• Immunohistochemistry: thyroid follicular epithelium in cats is positive for thyroglobulin, pancytokeratin, PAX-8, TTF-1; negative for vimentin and calcitonin; weak positivity for S100; uncommonly positive for NSE and chromogranin A

COMPARATIVE PATHOLOGY:

• Non-neoplastic hyperplasia of the thyroid gland (goiter) is caused by 4 main mechanisms:
• Diets with an excess or deficiency in iodine
• Diets with goitrogenic substances (Brassica , white clover, couch grasses, broccoli) which interfere with hormone synthesis
• Enzyme deficiencies in thyroid hormone synthesis; clinically hypothyroid
• Corriedale, Dorset Horn, Merino, and Romney March sheep; Afrikander cattle; and Saanen dwarf goats; rarely reported in dogs and cats
• Dogs (E-N04): Non-functioning carcinomas most common; Beagle, Boxer, and Golden Retriever predisposed; dogs have much more efficient enterohepatic excretory mechanism to process excess thyroid hormone; only 25% of thyroid neoplasms produce clinical signs of hyperthyroidism
• Birds: have naturally lower circulating T4 levels; TRH triggers growth hormone (not TSH) release from the anterior pituitary; growth hormone causes increase of T3 which triggers release of TSH from anterior pituitary and subsequently T4 from the thyroid
• Budgerigars and other pet/non-pet species develop hyperplastic goiter due to iodine deficiency (from grain grown on iodine-deficient soil)
• Macaws may develop hyperplastic goiter associated with sudden death
• Fish (osteichthyes): Goiter is a problem with managed fish populations; it is associated with iodine deficient diets and with elevated nitrates and ozonation in the aquaria; thyroid gland hyperplasia results in mass(es) typically in the branchial arch or glossal area but as thyroid tissue can be located in various organs in teleost fish, masses can develop in many potential locations
• Humans: Toxic nodular goiter (homologue to feline hyperthyroidism) is associated with mutations in the thyroid-stimulating hormone (TSH) receptor gene

REFERENCES:      

1. Angenta FF, de Mello LS, Slaviero M, et al. Pathological and Immunohistochemical Characterization of Thyroid Neoplasms in Cats. Comp. Path. 2021;184:44-55.
2. Frasca S Jr., Wolf JC, Kinsel MJ, Camus AC, Lombardini ED. Osteichthyes. In: Terio KA, McAloose D, St. Leger J, eds.  Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier, 2018:954-955.
3. Miller MA. Endocrine system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease, 6th ed. St. Louis, MO: Elsevier; 2017:720-721.
4. Reavill DR, Dorrestien G. Psittacines, Coliiformes, Musophagiformes, Cuculiformes. In: Terio KA, McAloose D, St. Leger J, eds.  Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier, 2018, 769-792.
5. Rich AF, Piviani M, Swales H, et a. Bilateral Thyroid Carcinosarcoma in a Cat. Comp. Path. 2019; 171: 24-29.
6. Rosol TJ, Grone A. Endocrine Glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016; 319-332.
7. Stockham, SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2^nd Ames, IA; 2008; 783-803.

Click the slide to view.

---