JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-N04

SLIDE A: Signalment (JPC #2820685):  An old military working dog.

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION:  Thyroid gland:  Expanding 50% of the section and compressing remaining atrophic follicles is a 6 mm diameter, encapsulated, well-circumscribed, moderately cellular neoplasm composed of polygonal cells arranged in variably-sized follicles filled with pale eosinophilic homogenous material (colloid), nests, packets, and papillary projections extending into a central cystic space supported by a fine fibrovascular stroma.  Neoplastic cells are cuboidal to low columnar and have distinct cell borders, a moderate amount of eosinophilic, microvacuolated cytoplasm, and one round nucleus with finely-stippled chromatin and one indistinct nucleolus.  The mitotic count is 1 per 2.37mm² (10 hpf).  Multifocally, neoplastic cells contain a single, clear to pale eosinophilic, intracytoplasmic vacuole (incipient follicle).  Multifocally within the neoplasm and capsule are basophilic mineralized concretions that cometimes form concentric lamellations (corpora amylacea-like bodies).  Scattered throughout the neoplasm are low numbers of secretory-product laden macrophages.  The central cystic space contains a moderate amount of secretory product, numerous sloughed neoplastic cells, fibrin, and fewer macrophages. 

Prostate gland:  Diffusely, there is severe glandular atrophy with an increase in fibrous connective tissue and mature fibroblasts (fibrosis) that separate and surround atrophic glands (post-castration atrophy).

Parathyroid gland; kidney:  No significant findings.

MORPHOLOGIC DIAGNOSIS:  Thyroid gland:  Follicular adenoma, breed unspecified, canine.

SLIDE B: Signalment (JPC #2765024):  13-year-old-male English springer spaniel

HISTORY:  This dog had a mass in the ventral neck.

HISTOPATHOLOGIC DESCRIPTION:  Thyroid gland (per contributor):  Effacing and replacing 100% of the normal thyroid gland and infiltrating through the pre-existing capsule is an poorly-circumscribed, unencapsulated, multilobulated, moderately-cellular neoplasm composed of polygonal cells arranged in poorly-formed, variably-sized follicles filled with pale eosinophilic homogenous material (colloid), nests, packets, and solidly-cellular areas supported by a fine fibrovascular stroma.  Neoplastic cells have indistinct cell borders, a moderate amount of eosinophilic vacuolated cytoplasm, and one irregularly round to ovoid nucleus with finely-stippled chromatin and one to two distinct nucleoli.  There is moderate anisokaryosis and anisocytosis with occasional karyomegaly and cytomegaly.  The mitotic count is 5 per 2.37mm² (10 hpf).  There are few multinucleated neoplastic cells.  Multifocally, neoplastic cells contain a single, clear to pale eosinophilic, intracytoplasmic vacuole (incipient follicle).  Multifocally there are neoplastic emboli within blood vessels (vascular invasion).  Comprising 50% of the section is a 3 cm area of coagulative necrosis characterized by retention of cellular architecture and loss of differential staining, admixed with proteinaceous fluid, fibrin, hemorrhage, numerous acicular cholesterol clefts, and few hemosiderin-laden macrophages.  Adjacent to the area of necrosis are mineralized bony trabeculae with bone marrow formation (osseous metaplasia).  There is multifocal fibrosis.  Scattered throughout the neoplasm are low numbers of neutrophils and hemosiderin- and secretory product-laden macrophages.

MORPHOLOGIC DIAGNOSIS:  Thyroid gland (per contributor):  Follicular carcinoma, English springer spaniel, canine.

SLIDE C: Signalment (JPC #3106252):  8-year-old spayed female boxer

HISTORY:  This dog had a subcutaneous, fluid-filled sac in the ventral neck for one week.

HISTOPATHOLOGIC DESCRIPTION:  Fibrovascular tissue, ventral neck (per contributor):  Expanding the thin rim of fibrovascular tissue is an encapsulated, cystic, moderately-cellular neoplasm composed of polygonal cells arranged in papillae lined by simple columnar to stratified columnar epithelium and supported by a fine fibrovascular stroma.  Neoplastic cells have distinct cell borders, abundant pale eosinophilic, vacuolated cytoplasm which contains numerous yellow-green granules and one round, basilar nucleus with finely-stippled chromatin and one indistinct nucleolus.  There is mild anisocytosis and anisokaryosis, with occasional karyomegaly and cytomegaly.  The mitotic count is 1 per 2.37mm² (10 hpf).  There is acute hemorrhage within and at the periphery of the neoplasm.  Multifocally, neoplastic cells form variably-sized follicles filled with pale eosinophilic homogeneous material (colloid).  At the periphery of the neoplasm within the wall are multiple sheets of thyroid follicular cells with minimal colloid and numerous compressed, atrophic thyroid f,ollicles. The capsule is infiltrated by moderate numbers of lymphocytes, plasma cells and histiocytes.

MORPHOLOGIC DESCRIPTION:  Ventral neck (per contributor):  Papillary carcinoma (thyroglossal duct tumor), boxer, canine.  

GENERAL DISCUSSION:

• Thyroid follicular carcinoma is more common than adenoma/hyperplasia in dogs; typically not metabolically active due to the liver’s ability to metabolize the hormone
• Thyroid follicular adenoma or hyperplasia is more common than carcinoma in adult cats; these are metabolically active, resulting in hyperthyroidism
• Types of primary thyroid tumors:
  • Follicular cell adenoma
  • Follicular cell carcinoma
  • C-cell adenoma/carcinoma (ultimobranchial tumors)
  • Thyroglossal duct tumor (well-differentiated papillary carcinoma)
• Adenomas are classified as follicular, papillary, trabecular, or oxyphilic; type most likely has no clinical significance
  • Follicular type preserves ability to form follicles and is more common than papillary
• Carcinomas often arise from follicular cells in thyroid lobes, but also ectopic thyroid tissue within the mediastinum
• In dogs, 90% of clinically apparent thyroid tumors are carcinomas; however thyroid adenomas are common incidental findings in older dogs
• More common in older animals; no sex predilection; beagles, boxers and golden retrievers and predisposed
• The most frequent site of thyroid carcinoma metastasis is the lungs through the thyroid vein; less frequently, retropharyngeal and caudal cervical lymph nodes and rarely, bone (focal osteolysis and persistent hypercalcemia)
• Thyroglossal duct: connection formed after dorsolateral migration of branched cords of pharygenal plate (thyroid origination site); remnants lead to cyst or neoplasm formation; thyroid originates from the epithelial cells from the floor of the pharynx
  • Thyroglossal duct tumors are rare in animals; identified as well-differentiated papillary carcinomas; develop de novo from the epithelium of the thyroglossal duct and are NOT a cystic metastasis from a primary carcinoma in the thyroid gland; slow growth with minimal peripheral invasion

PATHOGENESIS:

• Reported potential risk factors for the high incidence of cats: indoor environment, flea powder treatment regularly, fertilizer and herbicide exposure, goitrogenic elements of food (e.g. bisphenol-A), non-Siamese breed, high to deficient iodine diets
• Persistence of follicular cell function despite absence of TSH
  • Neoplastic follicular cells overexpress c-ras (oncogene) in cats with hyperthyroidism
  • TSH receptor and G-protein (Gsα) genes à TSH receptor activation and cAMP over production by neoplastic cells
• One study of beagles reports a strong association between the prevalence of progressive lymphocytic thyroiditis, hypothyroidism and thyroid follicular neoplasia and hypothesize this may be due to chronic excess thyrotropin stimulation

TYPICAL CLINICAL FINDINGS:

• Hyperthyroidism can be linked to adenomas, adenocarcinomas, and multinodular hyperplasia of follicular cells
• Swelling or mass in the ventral neck
• +/- coughing, respiratory distress, polydipsia, polyuria, listlessness, weight loss, vomiting, regurgitation, dysphagia, anorexia, facial edema and changes in voice
• Usually euthyroid, occasionally hypothyroid, rarely hyperthyroid in dog
• Carcinomas are typically invasive and not freely moveable on palpation
• Thyroglossal duct tumors are slow growing, expansile masses

TYPICAL GROSS FINDINGS:

• Adenoma: Small, white or tan, well-demarcated nodules with distinct white capsule, may be cystic; usually single nodule
  • Cystadenoma: smooth surface with elaborate network of vessels
• Carcinoma: Large, multinodular, with areas of hemorrhage and necrosis; usually unilateral; invades surrounding tissues including the trachea and blood vessels
• Tumors of ectopic thyroid tissue typically can occur anywhere from the neck to the mediastinum to the heart base
• Thyroglossal duct tumors: Well-demarcated, fluctuant, movable masses that range from 2 to 4 cm in diameter along the ventral midline in the anterior cervical region; multiloculated cystic areas containing clear proteinaceous fluid alternating with white solid areas on cut section; thyroid glands appear normal

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Adenoma (expansile and encapsulated): classified into two types
• Follicular (microfollicular, macrofollicular, trabecular and oxyphilic) types; follicular type demonstrates a consistent growth pattern:
  • Microfollicular thyroid adenoma: mini-follicles
  • Macrofollicular thyroid adenoma: irregular, large follicles
  • Cystic: 1-2 large cavities containing proteinaceous material, debris, and blood with progression to cystic degeneration
  • Trabecular/solid thyroid adenoma: considered the most poorly differentiated; tumor cells in narrow columns
  • Oxyphilic (“Huerthle”) oncocytic thyroid adenoma: large cells with eosinophilic granular cytoplasm
• Papillary: columnar to cuboidal cells palisading along a thin fibrovascular stalk; protrude into variably sized cysts that contain sloughed neoplastic cells, colloid, blood, and infrequently laminated mineral
• Carcinoma (increased cellularity, pleomorphism, infiltration through fibrous capsule, tumor cell thrombi in longer standing carcinomas, pulmonary metastases due to cranial and caudal thyroid vein invasion):
• Follicular cell carcinoma
  • Well-differentiated thyroid carcinoma
    • Follicular thyroid carcinoma: recognizable follicular pattern
    • Compact (solid) carcinoma: solid sheets of cells
    • Follicular-compact thyroid carcinoma: most common in dogs
    • Variably sized follicles; some may be cystic
    • Papillary thyroid carcinoma: uncommon
  • Undifferentiated (anaplastic) thyroid carcinoma: little to no architectural pattern of neoplastic cells
    • Spindle cell thyroid carcinoma
    • Small cell thyroid carcinoma
    • Giant cell thyroid: marked pleomorphism; may exhibit syncytial cells
  • Malignant mixed tumor: Contain both malignant thyroid follicular cells and mesenchymal components; can include osteogenic or cartilagenous; rarely reported in the dog
• Thyroglossal duct tumor: Well-differentiated papillary carcinoma; numerous papillary outgrowths lined by several layers of tall cuboidal to columnar epithelial cells that extend from the wall into the lumen
• Key finding: Non-neoplastic, small follicles in the fibrous capsule and adjacent connective tissue
• Thyrogenic epithelium in the form of follicles and cell cords and lined by low cuboidal epithelium and contain colloid; often present within the fibrous capsule and in the surrounding connective tissue
• Cyst wall is lined by a dense fibrous capsule with multifocal hemorrhage and cholesterol clefts; may undergo squamous metaplasia with keratinization

ADDITIONAL DIAGNOSTIC TESTS:

Immunohistochemistry:

• Follicular cell tumors: Thyroglobulin, TTF-1 (thyroid transcription factor), Pax8
• C-cell carcinomas: Calcitonin, CGRP (calcitonin gene-related peptide), NSE (neuron specific enolase), chromogranin A; +/- TTF-1
• Mixed thyroid tumors: Thyroglobulin and calcitonin +
• Pax8 and Napsin may be positive in follicular and C-cell tumors
• Thyroglossal duct tumor: duct-lining epithelium and follicles in the wall are positive for thyroglobulin

DIFFERENTIAL DIAGNOSIS:

• Other neoplasms
  • Heart base tumor differential: Aortic and carotid body tumors, thyroid gland tumors, thymoma, lymphoma, and hemangiosarcoma
  • C-cell tumors: Adenoma and carcinoma  
  • Thyroglossal duct tumor
  • Adenomatous follicular hyperplasia: often bilateral; lobes are not appreciably enlarged
• Non-neoplastic mass lesion: Ectopic thyroid, thyroglossal duct cyst, abscess, or granuloma

COMPARATIVE PATHOLOGY:

• Cats (Argenta, J Comp Pathol, 2021):
• Follicular adenomas – more common, unilateral, multinodular
  • Thyroglobulin expressed more commonly than thyroid transcription factor 1
• Carcinomas are less common
  • Immunopositive for thyroglobulin, pancytokeratin, chromogranin A, synaptophysin
• Nondomestic felids: retrospective study of thyroid neoplasms identified thyroid adenomas in 7 out 12 neoplasms utilizing thyroglobulin (positive), calcitonin (negative), and chromogranin A (negative) immunohistochemical stains (Pope, J Vet Diagn Invest. 2017)
• C-cell adenoma/carcinoma: Aged bulls (frequently) and horses (less frequently); non- functional C-cell adenoma occurs in aged horses
• Multiple endocrine neoplasms (MEN) have been described in dogs, horses, a ferret, bulls and Guernsey cattle; mutation in MEN1 or RET have never been documented in these cases
• MEN-1: Mutation in the MEN1gene, characterized by primary hyperparathyroidism, pancreatic islet cell tumors and pituitary tumors; other associated lesions are duodenal gastrinomas, carcinoids, thyroid adenomas, adrenocortical tumors and lipomas
• MEN-2: Mutation in the receptor tyrosine kinase RET; there is MEN-2A and MEN-2B and both are associated with C-cell tumors, primary hyperparathyroidism, and pheochromocytomas
• Macrofollicular thyroid adenomas, thyroid cystadenomas, papillary thyroid adenomas, follicular thyroid carcinomas, follicular-compact thyroid carcinomas, and small-cell thyroid carcinomas have been described in Guinea pigs (Gibbons, Vet Pathol. 2013)
• Mouse models for human disease include:
• In B6C3F1 mice: Xenobiotics (hepatic Cyp2B inducers, thyroperoxidase and 5’-deiodinase inhibitors, and sodium/iodide symporter inhibitors) lead to follicular cell tumors
• Transgenic mice expressing Ret/PTC1, Ret/PTC3 TRK-T1, BRAF, or ras offer a reasonable approximation of the features of papillary thyroid carcinoma in humans
• Follicular thyroid carcinoma has been primarily investigated using a single mouse model, TrB^PV/PV
• There is only one transgenic model of anaplastic carcinoma, Tg-Sv40 LT
• Reproduction of the MEN 2A syndrome using CGRP-Ret^C634R is successful, but there is a significant contribution of background strain to the development of medullary thyroid carcinomas; these models develop several extrathyroidal neoplasms common to the MEN2A syndrome, while only the CGRP-v-Ha-ras model mimics the presence of medullary thyroid carcinoma alone, which is the most common in humans
• Thyroglossal duct tumor: Rare in animals; most commonly reported in dogs

REFERENCES:

1. Argenta FF, de Mello LS, Slaviero M, Cony FG, Bandinelli MB, Pavarini SP, Driemeier D, Sonne L. Pathological and Immunohistochemical Characterization of Thyroid Neoplasms in Cats. J Comp Pathol. 2021;184:44-55.
2. Bakthavatchalu V, Muthupalani S, Marini RP, Fox JG. Endocrinopathy and aging in ferrets. Vet Pathol. 2016;53(2):349-365.
3. Gibbons PM, Garner MM, Kiupel M. Morphological and immunohistochemical characterization of spontaneous thyroid gland neoplasms in Guinea gigs (Cavia porcellus). Vet Pathol. 2013;50(2):334-342.
4. Jankovic J, Dettwiler M, Fernández MG, et. al. Validation of Immunohistochemistry for Canine Proteins Involved in Thyroid Iodine Uptake and Their Expression in Canine Follicular Cell Thyroid Carcinomas (FTCs) and FTC-Derived Organoids. Vet Pathol. 2021;58(6):1172-1180.
5. Kiupel M, Capen C, Miller M, Smedley R. Histological Classification of Tumors of the Endocrine System of Domestic Animals. 2nd series. Volume XII. Washington, DC: Armed Forces Institute of Pathology; 1998.
6. Lopez A, Martinson SA: Respiratory system, mediastinum, and pleurae. In: Zachary JF. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2017:554-555.
7. Miller MA. Endocrine system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:701-703.
8. Pope JP, Steeil J, Ramsay EC, Reel D, Newman SJ. Spontaneous proliferative and neoplastic lesions in thyroid and parathyroid glands of nondomestic felids. J Vet Diagn Invest. 2017;29(1):8-13.
9. Ramos-Vara JA, Frank CB, DuSold D, Miller MA. Immunohistochemical detection of Pax8 and Napsin A in canine thyroid tumours: comparison with thyroglobulin, calcitonin and thyroid transcription factor 1. J Comp Pathol. 2016;155(4):286-298
10. 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: Elsevier; 2016:326-336.
11. Rosol TJ, Meuten DJ. Tumors of the endocrine glands. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. Ames, IA: John Wiley & Sons, Inc.; 2017:791-799,803.
12. Soares LMC, Pereira AHB, de Campos CG, et. al. Histopathological and Immunohistochemical Characteristics of Thyroid Carcinoma in the Dog. J Comp Pathol. 2020;177:34-41.

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