JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-N07

SLIDE A: Signalment (JPC #1697323):  An 11-year-old German shepherd dog

HISTORY:   Incidental finding

HISTOPATHOLOGIC DESCRIPTION:  Parathyroid gland:  Comprising 70% of this section, expanding the parathyroid gland, and compressing the surrounding parathyroid parenchyma, there is a partially encapsulated, 5 x 7mm, expansile, moderately well demarcated, densely cellular neoplasm composed of polygonal cells arranged in cords that often palisade around small caliber blood vessels (pseudorosettes), supported by a fine fibrovascular stroma.  Neoplastic cells have indistinct cell borders, a scant amount of finely granular, eosinophilic cytoplasm, and a round to oval, occasionally antibasilar nucleus with finely stippled chromatin and one distinct nucleolus.  There is mild anisocytosis and anisokaryosis, and mitotic figures average 0-1 in 2.37mm^2.

MORPHOLOGIC DIAGNOSIS:  Parathyroid gland:  Adenoma, German shepherd dog, canine.

SLIDE B: Signalment (JPC #1877305):  An 11-year-old German shepherd dog

HISTORY:   This dog was in chronic renal failure.

HISTOPATHOLOGIC DESCRIPTION:  Parathyroid gland:  All three parathyroid glands in section are hyperplastic, enlarged 2-3 times normal, minimally compressing the adjacent thyroid gland. These hyperplastic parathyroid glands are composed of a uniform population of densely packed chief cells arranged in nests and cords, supported by a fine fibrovascular stroma and surrounded by a fine fibrous capsule.  Chief cells have indistinct cell borders with a moderate amount of pale eosinophilic, finely granular cytoplasm with occasional distinct vacuoles.  Anisocytosis and anisokaryosis are minimal, and mitotic figures are rare.

Thyroid gland:  No significant lesions

Trachea:  There is extensive mineralization of the tracheal cartilage (old age change).

MORPHOLOGIC DIAGNOSIS:  Parathyroid glands:  Hyperplasia, diffuse, moderate, German shepherd dog, canine.

ETIOLOGIC DIAGNOSIS:  Secondary hyperparathyroidism

GENERAL DISCUSSION:

• The parathyroid glands are of endodermal origin and are derived from the 3^rd and 4^th pharyngeal pouches
• The glands contain:
  • Chief cells: Single purpose cells, produce parathyroid hormone (PTH); the majority of chief cells are inactive in healthy animals
  • Oxyphil cells: Do not have an active role in biosynthesis of PTH, purpose unknown
  • Transitional oxyphil cells: Have cytoplasmic characteristic of both chief and oxyphil cells, represent a transition of chief cells to oxyphil cells, and do not have an active role in biosynthesis of PTH; purpose is unknown
• Primary (idiopathic) hyperparathyroidism
  • Focal (nodular) or diffuse hyperplasia: increase in functioning chief cells, resulting in the secretion of excess amounts of parathyroid hormone (PTH)
• Secondary hyperparathyroidism results from increased production of PTH (stimulated by hypocalcemia) secondary to nutritional deficiencies or chronic renal disease
• Tertiary hyperparathyroidism refers to hyperplastic or hypertrophic chief cells that are autonomous/independent of blood calcium concentrations in humans and dogs; histologically similar to secondary hyperparathyroidism
• Neoplasm of parathyroid gland (chief cells):
  • Parathyroid gland adenoma – Older animals (mostly dogs); genetic predisposition in keeshounds; tumor development not related to secondary hyperparathyroidism; usually enlargement of a single parathyroid gland
  • Parathyroid gland carcinoma – Rare, but reported in dogs and cats; metastasis occur to the lung and regional lymph nodes, but is rare
• Persistently elevated PTH results in fibrous osteodystrophy

PATHOGENESIS:

• Primary hyperparathyroidism:
• Due to functional parathyroid adenomas, carcinomas or primary parathyroid hyperplasia (nodular or diffuse)
• Described in German Shepherd puppies (inherited as an autosomal recessive trait)
• All secrete excess PTH, resulting in persistent hypercalcemia
• Nutritional secondary hyperparathyroidism:
• Common in horses (“bran disease” or “big head disease”), dogs & cats fed imbalanced meat diets, some primates, goats on high concentrate diets, birds, reptiles, and pigs fed unsupplemented grain rations
  • Horse typically fed grain diet and low quality roughage
  • “Bran disease”: Bran is the source of excess phosphorus in equine diet
  • “Big head disease”: hyperosteotic fibrous osteodystrophy more severe in the mandible and maxilla
• Induced by:
  • Diets low in calcium (results in osteoporosis and less severe fibrous osteodystrophy)
  • Diets high in phosphorus (most frequent dietary cause of secondary hyperparathyroidism) with normal or low calcium (more severe fibrous osteodystrophy)
  • Diets with excessive oxalate content
  • Inadequate vitamin D3 (more severe fibrous osteodystrophy)
• All of the above cause hypocalcemia, resulting in parathyroid stimulation and PTH secretion
• With chronicity, stimulated chief cells undergo hypertrophy and eventually hyperplasia
• Renal secondary hyperparathyroidism (renal osteodystrophy):
• Mechanisms of hypocalcemia in chronic renal disease (hypocalcemia > increased PTH secretion):
  • Significantly decreased number of functional nephrons > GFR <25% of normal (significant reduction in GFR) > phosphorus retention > hyperphosphatemia > increased formation of hydroxyapatite crystals (mass law) > hypocalcemia > increased secretion of PTH > chief cell hypertrophy and hyperplasia (most important mechanism)
  • Decreased number of renal tubular cells with 1-α-hydroxylase activity > decreased active vitamin D (1,25-hydroxycholecalciferol, calcitriol) > decreased intestinal and renal absorption of calcium > hypocalcemia > increased secretion of PTH > diffuse chief cell hypertrophy and hyperplasia
  • Decreased GFR à metabolic acidosisà ↑iCaà ↓serum Caà ↑PTH secretion > ↑Ca and PO4 release from bone
• Serum FGF23 (from osteocytes and osteoblasts) increases early in CKD process > decreased renal 1-α-hydroxylase activity (before the renal cells producing 1-α-hydroxylase have actually decrease in number); FGF23 also acts in the parathyroid gland where it decreases secretion of PTH
• Increased PTH stimulates increased 1-α-hydroxylase in attempt to maintain normal calcitriol (active vitamin D levels)
• Neoplasm of parathyroid gland
• Functional adenoma or carcinoma will cause primary hyperparathyroidism; overactive parathyroid gland > release too much parathyroid hormone (PTH) regardless of serum calcium levels > stimulate calcium resorption from bones > hypercalcemia
• PTH increases blood calcium levels through 3 mechanisms:
  • Bone: bone resorption via increased osteoclast activity (direct)
    • With chronic hyperparathyroidism, reabsorption of bone through osteoclastic activity can result in fibrous osteodystrophy of mandible/maxilla (“rubber jaw”) or osteoporosis of skull
  • Kidney: Increased reabsorption of calcium in the distal convoluted tubules and decreased reabsorption of phosphorus in the proximal convoluted tubules (direct)
  • Intestine: Increased absorption of calcium from the intestine by regulating hydroxylation of 25-hydroxycholecalciferol to 1, 25-dihydroxycholecalciferol (active Vitamin D) by 1-α-hydroxylase in the kidney (indirect)
• Metastatic and dystrophic mineralization incorporating the hydroxyapatite crystal in multiple tissues occurs
  • Mass Law: Total Ca x inorganic P (expressed in mg/dL) = >70 often results in metastatic mineralization of tissues (e.g. lungs, kidneys)

TYPICAL CLINICAL FINDINGS:

• Primary hyperparathyroidism:
  • Increased parathyroid hormone (PTH)
  • Hypercalcemia
    • Anorexia, vomiting, constipation, depression, PU/PD, generalized muscular weakness
  • Hypophosphatemia
  • Increased fractional clearance of inorganic phosphate in the urine
    • Prone to developing nephrocalcinosis and urolithiasis
  • Stunted growth
  • Diffuse reduction in bone density > lameness caused by fractures of long bones, compression fractures of vertebral bodies
• Nutritional secondary hyperparathyroidism:
  • Increased PTH
  • Normocalcemia or hypocalcemia
  • Variable phosphorus (depends on underlying dietary cause)
  • Clinical signs of fibrous osteodystrophy include lameness and pathologic fractures
• Renal secondary hyperparathyroidism:
  • Signs of kidney failure predominate: Increased BUN and creatinine, hyperphosphatemia, nonregenerative anemia (end-stage renal failure and decreased erythropoietin production)
  • Low serum bicarbonate
  • Hypocalcemia to normocalcemia with increased PTH
  • Clinical signs of fibrous osteodystrophy include lameness and pathologic fractures
• Primary or secondary hyperparathyroidism: Elevated alkaline phosphatase - bone isoenzyme (bone resorption)
• Enlarged parathyroid glands are rarely palpable, except in the cat

TYPICAL GROSS FINDINGS:

• Primary hyperparathyroidism:
  • Facial hyperostosis due to extensive osteoblastic proliferation and deposition of poorly mineralized osteoid (dogs)
  • Loosening or loss of teeth from alveolar sockets (dogs)
  • Nodular hyperplasia: Mineralization of multiple organs (lung, kidney, GI mucosa)
• Nutritional secondary hyperparathyroidism:
  • All parathyroid glands are uniformly enlarged
  • Soft or pliable, sometimes thickened bones, often in maxilla, mandible, and subperiosteal areas of long bones; bilateral swelling of bones of the head (hyperostosis), especially dogs and horses (big head); loose teeth; increased fractures; osteopenia; detachment of ligaments & tendons
• Renal secondary hyperparathyroidism:
  • All parathyroid glands are uniformly enlarged
  • Shrunken, pale kidney characteristic of chronic renal disease
  • Calcification of the subpleural intercostal musculature, gastrointestinal mucosa, lung, and vascular subintima
  • Soft or pliable bones, often in maxilla, mandible (“rubber jaw”), and subperiosteal areas of long bones; loose teeth; increased fractures; osteopenia; detachment of ligaments & tendons
• Neoplasm of parathyroid gland:
  • +/- multiple white foci in thyroid gland of dogs
  • Adenoma: Nodule up to 1cm, single/unilateral enlarged red to light brown parathyroid gland in the cervical neck or at the base of heart; atrophied remaining glands
  • Carcinoma: Larger, unencapsulated, invasive

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Primary hyperparathyroidism:
  • Nodular hyperplasia: multiple nodules of uniform cellularity, minimal compression, no fibrous encapsulation; unilateral or bilateral
  • Diffuse hyperplasia: uniform cellularity and cells extend to capsule of the gland; no compressed atrophic parathyroid parenchyma at the periphery
• Nutritional secondary hyperparathyroidism:
  • Hyperplasia and hypertrophy of chief cells with crowding and narrowing of perivascular spaces with light eosinophilic vacuolated cytoplasm; chief cells are crowded, diffusely hypertrophied, with compression of the fibrovascular stroma and capsule
• Renal secondary hyperparathyroidism:
  • Combined with histologic lesions of chronic renal disease there is hyperplasia and hypertrophy of parathyroid chief cells with narrowing of perivascular spaces, cytoplasmic vacuolation and clearing; chief cells are crowded, diffusely hypertrophied with compression of the fibrovascular stroma and capsule
  • Mineralization of the subpleural intercostal musculature, gastrointestinal mucosa, lung, and vascular subintima
• Neoplasm of parathyroid gland
  • Adenomas: Cuboidal to polyhedral closely packed chief cells often arranged in nests and packets with moderate, lightly eosinophilic cytoplasm, enlarged nucleus, pseudorosettes, delicate fibrovascular stroma, thin fibrous partial to complete capsule, few mitosis, compression of adjacent parathyroid parenchyma and +/- thyroid gland
    • Compressed/atrophy of nonneoplastic chief cell at periphery of functional adenomas
      • Small, irregular shape, small amount of densely eosinophilic cytoplasm, +/- lipofuscion or lipid
    • +/- oxyphil cells (water clear cytoplasm) scattered throughout or may predominate in some adenomas
    • +/- mast cells and adipocytes
  • Carcinoma: Larger, destructive and invasive (i.e., capsule, thyroid glands, periglandular connective tissues and cervical muscles), unencapsulated, more cellular, nuclear atypia and increased mitosis compared to adenomas
    • Malignant chief cells may form follicles
    • Cats may have large cystic spaces lined by cuboidal to flattened chief cells
  • Fibrous osteodystrophy: Osteoclastic resorption, fibrous replacement and failure of mineralization of woven bone

ADDITIONAL DIAGNOSTIC TESTS:

• IHC: Chief cells (normal, adenoma, carcinoma) are immunoreactive for PTH (1-34 or 1-84), chromogranin A, and synaptophysin; negative for thyroglobulin
• The appearance and number of affected glands is helpful in distinguishing adenoma from hyperplasia

DIFFERENTIAL DIAGNOSIS:

• Causes of hypercalcemia:
  • Hyperparathyroidism
  • Acidosis, Addison’s (Hypoadrenocorticism)
  • Renal Failure: in the horse and in young dogs with familial renal disease (e.g. lhasa apso)
  • Excess vitamin D due to:
    • Ingestion of: calciferol containing rodenticides, excess vitamin D-containing diets, vitamin D glycoside-containing plants (Cestrum, Solanum sp., and Trisetum sp.) or
    • Granulomatous disease: macrophage secretion of activated Vitamin D, such as with blastomycosis, histoplasmosis, cryptococcosis, pulmonary angiostrongylosis
  • Thiazide diuretics
  • Immobilization
  • Osteolytic lesions (e.g.- osteomyelitis)
  • Increased PTH or PTHrp activity:
    • Primary hyperparathyroidism (i.e., parathyroid neoplasia)
    • Humoral hypercalcemia of benign disorders (i.e., canine schistosomiasis)
    • Neoplasia: (CLAP)
      • Carcinoma metastasis to the bone (i.e., squamous cell carcinoma in the horse)
      • Lymphoma: due to production of PTHrP
      • Apocrine cell adenocarcinoma of the anal sac: due to production of PTHrP
      • Plasma cell myeloma
    • Spurious: Hemoconcentration, Hyperproteinemia (including paraproteinemia), and Granulomatous disease

COMPARATIVE PATHOLOGY:

• Primary and secondary hyperparathyroidism are described in most domestic and exotic species
• Leopards, tigers, cougars - Parathyroid adenoma and nodular hyperplasia associated with CRD reported in nondomestic felids (Pope et at., J Vet Diagn Invest. 2017)
• Nutritional hypocalcemia with secondary hyperthyroidism reported rabbits fed calcium deficient diet; may also have dental abnormalities
• Dromedary camel: Fibrous osteodystrophy due to nutritional secondary hyperparathyroidism was diagnosed with bilateral enlarged parathyroid glands (Hines et al., J Vet Diagn Invest. 2021)
• Nutritional secondary hyperparathyroidism suspected in juvenile red foxes; microscopic lesions consistent with fibrous osteodystrophy
• NWM and OWM: Secondary hyperparathyroidism due to low calcium and excess phosphorus; chronic kidney failure (loss of functional nephrons) induces renal secondary hyperparathyroidism
• Possums: Lesions consistent with renal secondary hyperthyroidism reported a single animal with idiopathic progressive renal disease
• Lizards:
  • Kyphosis, lordosis, and scoliosis are common findings in young animals that develop nutritional or renal secondary hyperparathyroidism early in life
  • Secondary hyperparathyroidism is a common sequela of chronic insufficiency resulting in fibrous osteodystrophy
• Birds: Nutritional secondary hyperparathyroidism can result from diets low in calcium and vitamin D3 (i.e. seed diets, peanuts, and corn)
• Parathyroid adenoma are reported in snakes and turtles

REFERENCES:

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