JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2237078): A rat.
HISTOPATHOLOGIC DESCRIPTION: Thyroid gland: Expanding and effacing 90% of thyroid parenchyma is a partially encapsulated, multilobulated, moderately cellular, infiltrative neoplasm composed of polygonal cells arranged in variably sized, distinct nests and islands surrounded by thin fibrous septa. Neoplastic cells have variably distinct cell borders with a moderate amount of pale eosinophilic granular cytoplasm and often palisade along the stroma. Nuclei are round to oval with finely stippled chromatin and indistinct nucleolus. The mitotic rate is < 1 per 10 HPF. Multifocally, there is single cell necrosis, hemorrhage within the nests of neoplastic cells and within the capsule and septa, there are few mast cells and hemosiderin-laden macrophages. Neoplastic cells are multifocally separated and surrounded 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
- Neoplasm of thyroid C (parafollicular) cells
- Common lesion in many strains of rats, bulls (not cows), humans, and occasionally in horses, and dogs
- There is a progression from C-cell hyperplasia to C-cell adenoma to carcinoma
- Secrete primarily 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
- 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:
- Proliferation of undifferentiated stem cell remnants of the ultimobranchial bodies (negative for calcitonin, somatostatin, and neurotensin)
- 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 anterioventral 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:
- Carcinomas are more cellular, pleomorphic, and infiltrative than an adenoma and may have evidence of metastases into cranial cervical lymph nodes
- Form small nests divided by fine connective tissue septa or is solidly cellular; occasional ducts, follicles or cysts; variable stromal amyloid; vascular invasion; metastasis; capsular invasion; may involve the entire lobe of the thyroid gland
- Polygonal to spindled cells with eosinophilic, finely granular cytoplasm
- Nuclei vesicular, oval to elongate; frequent to variable mitoses
- Some C-cells form acinar-like structures that have a lumen containing colloid-like material (due to their ultimobranchial origin); most prominent in bulls
- Similarly, C-cell tumors often contain entrapped normal follicles
ADDITIONAL DIAGNOSTIC TESTS:
- 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)
- Plasma calcitonin level is the preferred assay for C-cell carcinoma in humans
- Recent study in the Journal of Comparative Pathology indicates that napsin A is as sensitive as calcitonin for C-cell tumors
- 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)
- Many small argyrophilic membrane-bound cytoplasmic secretory granules which contain calcitonin
- Distended rough endoplasmic reticulum, free ribosomes, prominent Golgi apparatus
- May see amyloid fibrils interspersed in the stroma between bundles of collagen fibers
- C-cell hyperplasia: Diffuse or focal increase in morphologically normal C-cells which have increased amount of lightly eosinophilic granular cytoplasm; nodular hyperplasia consists of aggregates of C-cells less in diameter than the size of one colloid-filled follicle; occurs as a response to chronic hypercalcemia; note: 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; focal nodular C cell hyperplasia often precedes C cell neoplasm development and histologic distinction between hyperplasia and adenoma may be difficult
- Adenoma: Discrete nests of well-differentiated C-cells, fill contiguous follicles
- Expansile, well circumscribed/may be partially encapsulated; may be subdivided into pockets
- Adjacent thyroid compressed but not invaded; sometimes amyloid deposits; often sclerotic in bulls
- Mild cellular atypia consisting of enlarged or more fusiform-shaped cells and enlarged nuclei; numerous membrane bound secretory granules
- Contain multiple entrapped thyroid follicles which should not be interpreted as thyroid follicular adenoma
- 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
- 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: Few reports of C-cell adenomas and carcinomas (adenomas more common); 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
- 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
- Ferret: Has been reported as part of MEN-like syndrome in a ferret
- Exotic species: Reported in an African pygmy hedgehog and in a red fox
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