JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-N05

Signalment (JPC #2237078):  A rat.

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION:  Thyroid gland:  Expanding and effacing 99% of the preexisting thyroid parenchyma is a partially encapsulated, multilobulated, moderately cellular, infiltrative neoplasm composed of polygonal cells arranged in variably sized, distinct nests, packets, and islands separated by thin to moderate fibrous septa; neoplastic cells often palisade along the stroma.  Neoplastic cells have variably distinct cell borders with a moderate amount of pale eosinophilic, granular cytoplasm and a round to oval nucleus with finely stippled chromatin and 0-1 indistinct nucleoli.  Anisocytosis and anisokaryosis are mild, the mitotic count is <1 per 2.37 sq mm, and there is multifocalsingle cell necrosis.  There is multifocal scattered hemorrhage, fibrin, and edema within nests of neoplastic cells, capsule, and septa, and there are few scattered mast cells and hemosiderin-laden macrophages.  Regionally extensively, the fibrous septa separating neoplastic cells are expanded by abundant, extracellular, amorphous, eosinophilic material (amyloid or sclerotic collagen). Few remaining intact follicles are variably ectatic, lined by attenuated epithelial cells, and filled with abundant eosinophilic secretory product (colloid).

MORPHOLOGIC DIAGNOSIS:  Thyroid gland:  C-cell carcinoma, strain not specified, rat, rodent.

SYNONYMS:  Medullary thyroid carcinoma; ultimobranchial tumor; parafollicular cell thyroid carcinoma

GENERAL DISCUSSION:

• Neoplasm of thyroid C (parafollicular) cells
• Common lesion in many strains of rats, bulls (not cows), humans, and occasionally horses and dogs
• There is a progression from C-cell hyperplasia to C-cell adenoma to carcinoma
  • Focal nodular C-cell hyperplasia often precedes C-cell neoplasm development
  • Histologic distinction between hyperplasia and adenoma may be difficult
• Diffuse C-cell hyperplasia is a physiologic response to chronic hypercalcemia
• C-cell tumors primarily secrete calcitonin but may also secrete somatostatin and neurotensin
• In humans and bulls, C-cell carcinoma is commonly found in association with other endocrine tumors, especially bilateral pheochromocytomas and occasionally pituitary adenomas; this familial cancer syndrome is known as multiple endocrine neoplasia (MEN1 [Mutation in MEN gene] and MEN2 [Mutation in receptor tyrosine kinase - RET gene]) in humans; it has been proposed but not confirmed in rats or other animals except for the horse
• Some families of Long-Evans rats are predisposed and have increased incidence of thyroid ganglioneuromas; may be part of MEN

PATHOGENESIS:

• Embryology: Calcitonin-secreting C-cells originate from neural crest cells and migrate and incorporate into the 5th (ultimobranchial) pharyngeal pouch; the ultimobranchial body migrates and fuses with the midline primordium that forms the thyroid gland in mammals; in submammalian species the ultimobranchial gland remains separate
• Ultimobranchial origin tumors may derive from:
  1. Proliferation of undifferentiated stem cell remnants of the ultimobranchial bodies (negative for calcitonin, somatostatin, and neurotensin)
  2. Parafollicular C cells (positive for calcitonin, somatostatin, and neurotensin)
• Etiology unknown; suggested relationship between long-term excess in dietary Ca²⁺ intake and high incidence of tumors in bulls; hypercalcemia may predispose to C-cell hyperplasia and neoplasia, and high levels of calcium absorbed from GI tract results in chronic C cell stimulation and has a role in pathogenesis of C-cell neoplasms
• Hypervitaminosis D is reported to increase frequency of C-cell neoplasms; vitamin D deficient rats have a reportedly lower incidence
• Amyloid produced by C cells is non-SAA amyloid, and is believed to be derived from calcitonin secreted by neoplastic C cells; the major fibril protein being A Cal

TYPICAL CLINICAL FINDINGS:

• Normal or slightly lowered levels of circulating calcium
• Sometimes palpable nodules in anteroventral cervical region in bulls and horses; may attain considerable size
• Increased incidence of vertebral osteosclerosis with ankylosing spondylosis deformans, ostophytes, vertebral fractures, and degenerative osteoarthrosis in bulls with C cell neoplasms

TYPICAL GROSS FINDINGS:

• C-cell hyperplasia: Usually not visible grossly
• C-cell adenoma: Discrete, encapsulated, usually unilateral but may be bilateral, single or multiple, gray to tan nodules; usually smaller than carcinomas (1-3 cm); often not visible grossly in rats
• C-cell carcinoma: Extensive, firm, multinodular, uni- or bilateral tumors that typically involve the entire gland; yellow, tan or white; may be divided into lobules by dense, white fibrous connective tissue; +/- hemorrhage and necrosis; metastasis usually to the cranial cervical lymph nodes; pulmonary metastasis less frequently

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• C-cell hyperplasia
  • Diffuse or focal increase in morphologically normal C-cells which have indistinct cell borders, increased amount of lightly eosinophilic granular cytoplasm, and a round to ovoid nuclei with finely stippled chromatin
  • Nodular hyperplasia consists of aggregates of C-cells less in diameter than the size of equal to or less than five colloid-filled follicles
• C-cell adenomas
  • Discrete nests of well-differentiated to mildly atypical C-cells with abundant lightly eosinophilic, amphophilic, or clear cytoplasm; some cells may have large nuclei with coarsely clumped chromatin and prominent nucleoli
  • Compresses but does not invade adjacent thyroid
  • Connective tissue septa may contain amyloid deposits (likely originates from the neoplastic C-cells); septa are often sclerotic in bulls
  • Adenomas often contain multiple entrapped thyroid follicles which should not be interpreted as a thyroid follicular adenoma
• C-cell carcinomas
  • More cellular, pleomorphic, and infiltrative than an adenoma
  • Cells are polyhedral to spindle with amphophilic, finely granular cytoplasm and an oval to elongate nucleus with vesiculate chromatin; mitoses more numerous than in adenomas; often subdivided into small groups by fine connective tissue septa containing capillaries
  • Similar to the C-cell adenoma, C-cell carcinomas may also contain amyloid within the connective tissue septa separating neoplastic cells
  • Most likely to metastasize to the cranial cervical lymph nodes; less frequently metastasize to the lungs

ULTRASTRUCTURE FINDINGS:

• Many small, argyrophilic, membrane-bound cytoplasmic secretory granules which contain calcitonin
• Large perinuclear aggregates of concentric or interwoven microfilaments, often near the Golgi apparatus and partially indenting the nucleus (distinctive for polypeptide hormone-secreting cells of the APUD series)
• Distended rough endoplasmic reticulum, free ribosomes, prominent Golgi apparatus
• May see amyloid fibrils interspersed in the stroma between bundles of collagen fibers

ADDITIONAL DIAGNOSTIC TESTS:

• Immunohistochemistry
  • Calcitonin is the most reliable immunohistochemical marker for canine and bovine C-cells
  • Neuron specific enolase (NSE), calcitonin gene-related peptide (CGRP), and thyroid transcription factor-1 may be positive (C cell tumors are usually negative for thyroglobulin which distinguishes from thyroid follicular carcinomas)
  • Napsin A typically will label thyroid C-cells (as well as thyroid follicular cells)
• Plasma calcitonin level is the preferred assay for C-cell carcinoma in humans

DIFFERENTIAL DIAGNOSIS:

• C-cell clusters (dogs only): Dogs frequently have prominent C-cell nodules along the course of major vessels and this should not be over interpreted as multifocal C- cell hyperplasia
• Follicular adenomas or carcinomas of the thyroid gland: More hyperchromatic cytoplasm, better defined cell boundaries, and more coarse chromatin; calcitonin negative
• Oxyphilic follicular cell carcinoma: Tendency to form small follicles; not yet reported in the rat; calcitonin negative
• Parathyroid adenomas or carcinomas: Calcitonin negative
• Chemodectoma (carotid body tumors, aortic body tumors): Calcitonin negative

COMPARATIVE PATHOLOGY:

• Ox: 30% of aged bulls have C-cell tumors; 15-20% have hyperplasia; these may present as part of MEN syndrome (may include pheochromocytomas and/or pituitary adenomas); autosomal dominant pattern suggested in Guernsey bulls; rare in cows; ultimobranchial origin tumors in the thyroid gland of bulls have a more complex structure than neoplasms in other species; may contain less differentiated areas and areas with follicular and C cell differentiation resembling an unusual type of thyroid carcinoma in humans termed ‘intermediate type of differentiated thyroid carcinoma’
• Horse: C-cell hyperplasia and adenomas much more common (most common thyroid neoplasm in the horse); carcinomas rare; MEN-like syndrome described in a horse
• Man: Sporadic entity; often has a genetic predisposition; unlike the rat, amyloid deposition is common; approximately 15-20% are part of a syndrome of multiple endocrine neoplasia (MEN), which is inherited as an autosomal dominant trait
• Dog: Occasionally reported; C-cell neoplasms more likely to be malignant
• Domestic and nondomestic felids: Medullary (C-cell) thyroid neoplasms are rare
• Mouse: Unlike the rat these tumors are rare in mice; only four tumors (1 adenoma, 3 carcinomas) reported in the literature
• Rat: C-cell adenoma is common in aged Fischer 344, Wistar Han, and Sprague-Dawley rats; C-cell carcinomas occur frequently and are similar to what is described above
• Exotic species: Reported in an African pygmy hedgehog and in a red fox

REFERENCES:

1. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, and Ailuridae. In: Terio KA, McAloose D, St. Leger J eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier Inc. 2018:235.
2. Mense MG, Boorman GA. Thyroid gland. In: Suttie AW, Leininger JR, Bradley AE, eds. Boorman’s Pathology of the Rat. 2nd ed. San Diego, CA: Elsevier; 2018:681-683.
3. Miller MA. Endocrine system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:702.
4. 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.
5. 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.
6. Rosol TJ, Grone A. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6^th St. Louis, MO: Elsevier; 2015:296-7, 333-336.
7. 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.; 2017:776, 803-809, 812.

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