JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-N02

Signalment (JPC #1880198):  17-year-old horse

HISTORY:  This horse was hirsute. 

HISTOPATHOLOGIC DESCRIPTION:  Pituitary gland:  Expanding the pars intermedia and compressing the moderately congested pars distalis is a 1.5 x 2cm, unencapsulated, well-circumscribed, multilobulated, densely cellular neoplasm composed of polygonal to piriform to fusiform neoplastic cells arranged in indistinct nests and packets supported by fine fibrovascular stroma.  Frequently, cells palisade along the stroma and around blood vessels, forming pseudorosettes.  Neoplastic cells have indistinct cell borders, a moderate amount of granular to microvacuolated, eosinophilic cytoplasm, and round to oval, antibasilar nuclei with coarsely stippled chromatin and 1 to 2 nucleoli.  Anisocytosis and anisokaryosis are mild to moderate, and mitotic figures average less than one per 2.37mm².  Multifocally within the periphery of the neoplasm, neoplastic cells form follicules up to 3mm in diameter that are lined by low cuboidal cells and filled with homogeneous, eosinophilic material (colloid) and scant cellular debris.  The pars nervosa contains numerous vacuoles up to 1mm in diameter (spongiosis) and rare, scattered hemosiderin-laden macrophages. 

MORPHOLOGIC DIAGNOSIS:  Pituitary gland, pars intermedia:  Adenoma, breed unspecified, equine.

GENERAL DISCUSSION:

• Most common pituitary tumor in horses, second most common in dogs, rare in
• other species
• In horses, these are of melanotroph origin (i.e. produce MSH)
• Usually older horses; females > males; more common in ponies
• In horses, adenoma of the pars intermedia causes a syndrome of Pituitary Pars Intermedia Dysfunction (PPID), often inappropriately referred to as a “Cushing's-like disease” (total cortisol levels are not increased)
  • In horses, nearly all cases of clinical hyperadrenocorticism are due to a pituitary adenoma or hyperplasia
• The pituitary gland (hypophysis) is subdivided anatomically
• Neurohypophysis (posterior pituitary, pars nervosa):
• Oxytocin
• ADH (antidiuretic hormone/vasopressin)
• Adenohypophysis (anterior pituitary)
• Pars distalis:
• Lactotrophs (acidophils): PRL (prolactin)
• Somatotrophs (acidophils): GH (growth hormone)
• Thyrotrophs (basophils): TSH (thyroid-stimulating hormone)
• Gonadotrophs (basophils): FSH (follicle-stimulating hormone, LH (luteinizing hormone)
• Corticotrophs (chromophobes): ACTH (adrenocorticotrophic hormone)
• Pars tuberalis: Scaffold for the capillary network of the hypophyseal portal system; has secretory granules, stellate cells, and receptors for melatonin
• Pars intermedia:
• Melanotrophs: MSH (melanocyte-stimulating hormone), b-endorphin, and corticotropin-like intermediate lobe peptide (CLIP)

PATHOGENESIS:

• Thought to be an age-related neurodegenerative disease
  • Possibly due to oxidative injury to dopaminergic neurons in the hypothalamus
  • In horses, pars intermedia tumors are derived from melanotrophs
  • Melanotrophs lack glucocorticoid receptors and are controlled by dopaminergic inhibition from hypothalamus
  • Normally, shortened daylight in autumn decreases dopaminergic inhibition -> increased activity of the pars intermedia promotes hair growth and increased adipose tissue deposition
  • In PPID, pars intermedia dopamine concentrations are decreased year-round synthesize excessive pro-opiomelanocortins (POMC) and secrete excessive α-MSH, β-endorphins, and corticotrophin-like intermediate peptide (CLIP)
• Clinical signs in the horse with pars intermedia adenoma are the result of hypothalamic or neurohypophyseal dysfunction due to compression of the hypothalamus
• Over production of beta endorphin => unresponsive to pain, docile nature
• Compression of hypothalamus => hirsutism, polyphagia, hyperpyrexia
• Compression of neurohypophysis and decreased ADH secretion => polyuria

TYPICAL CLINICAL FINDINGS:

• Horses with pars intermedia dysfunction have a marked increase in MSH, CLIP, and b-endorphin (40 times or more)

• Since the hypothalamus regulates body temperature, appetite, and cyclic

shedding of hair; compression by large tumors can greatly diminish normal function

• Hirsutism (failure of seasonal shedding) - long, thick, wavy, and matted hair
• PU/PD, laminitis, polyphagia, muscle weakness, somnolence, intermittent pyrexia,

hyperhidrosis

• Hyperglycemia, glucosuria (down regulation of insulin receptors on target cells)
• Mildly elevated or normal cortisol and ACTH
• Cortisol lacks normal diurnal variation

TYPICAL GROSS FINDINGS:

• Well circumscribed, partially encapsulated; can be very large, extend out of the sella turcica, and may severely compress the overlying hypothalamus; often incorporate pars nervosa and compress pars distalis

• Yellow to white, multinodular neoplasm
• On cut surface, pars distalis is compressed
• Adrenal glands are usually normal

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Partially encapsulated, compresses the pars distalis
• Large, spindle shaped to polygonal cells with granular eosinophilic cytoplasm and an oval hyperchromatic nucleus
• Form packets separated by fine fibrovascular septae
• Occasional follicles lined by cuboidal cells, filled with dense eosinophilic colloid
• May appear more sarcomatous, with spindled cells palisading around vessels
• Microadenomas are between 1 and 5 mm in diameter; macroadenomas are at least 5 mm (but in horses often are 1 to 3 cm) in diameter

ULTRASTRUCTURAL FINDINGS:

• Well-developed rough endoplasmic reticulum and Golgi apparatus (indicates synthesis and packaging of secretory proteins)

• Numerous membrane-bound cytoplasmic secretory granules

ADDITIONAL DIAGNOSTIC TESTS:

• Clinical diagnostics:
• Measurement of serum α-MSH
• Baseline ACTH concentration, TRH stimulation test
• Immunohistochemistry:
• Diffuse, moderate to strong immunoreactivity for POMC, α-MSH, and b-endorphin
• Variable immunoreactivity to ACTH, CLIP, and b-lipotropin

DIFFERENTIAL DIAGNOSIS:

• Other pituitary neoplasms:
  • Corticotroph (chromophobe) adenoma: Most common pituitary tumor in dogs; higher incidence in Boxers, Boston Terriers, Dachshunds
  • Hormonally inactive chromophobe adenoma: Dogs, cats, lab rodents, and parakeets; may cause problems through compression of adjacent tissue
  • Acidophil adenoma: Uncommon in domestic species; fairly common in various strains of older rats
  • Basophil adenoma: Rare in all animal species
  • Chromophobe carcinoma: Older dogs and cows; usually hormonally inactive;  pleomorphic, highly cellular, hemorrhage, necrosis, more mitoses, invasive growth into adjacent bone or brain
• Neoplasms metastatic to the pituitary gland:
  • Malignant lymphoma: Cattle and dogs
  • Malignant melanoma: Horses and dogs
  • Transmissible venereal tumors: Dogs
  • Mammary adenocarcinoma: Dogs
• Neoplasms in the region of the pituitary gland:

• Craniopharyngioma:  Benign tumor derived from Rathke’s pouch remnants(epithelial); usually younger animals; may cause dwarfism in puppies (reduced secretion of somatotropin and other trophic hormones before growth plate closure); alternating solid epithelial nests and cystic areas with focal mineralization

• Granular cell tumor of the pituitary – uncommon; reported in dogs, horses, and cats
• Suprasellar germ cell tumor: Dogs and (one) calves. pleomorphic round cells resembling seminoma with larger vacuolated cells, glandular formations, and squamous differentiation; positive for alpha fetoprotein

• Osteosarcoma of sphenoid bone
• Ependymoma:  Infundibular recess of third ventricle
• Meningiomas and gliomas of the infundibular stalk

COMPARATIVE PATHOLOGY:

Dogs (Adenoma of the pars intermedia):

• Second most common pituitary neoplasm in dogs; more common in non-brachycephalic breeds
• Moderately enlarges the pituitary; may compress pars distalis, usually doesn’t
• invade
• Neoplastic cells arise from lining epithelium of the residual hypophyseal lumen
• Well circumscribed, not encapsulated
• Numerous large, colloid-filled follicles lined by partially ciliated, simple columnar epithelium interspersed between nests of large chromophobic cells
• Usually but not always endocrinologically inactive; may cause hypopituitarism and diabetes insipidus (due to compression of the hypothalamus); may secrete ACTH and cause bilateral adrenal cortical hyperplasia

References:

1. Burns TA, McFarlane D, Toribio RE. Pituitary pars intermedia dysfunction. In: Reed SM, Bayly WM, Sellon DC, eds. Equine Internal Medicine, 4th ed. St. Louis, MO: Elsevier; 2018:1100-1109.
2. Hart KA, Woechle DM, Norton D, et al. Effects of age, season, body condition, and endocrine status on serum free cortisol fraction and insulin concentration in horses. J Vet Intern Med. 2016;30(2):653-663.
3. Karikoski NP, McGowan CM, Singer ER, et al. Pathology of natural cases of equine endocrinopathic laminitis associated with hyperinsulinemia. Vet Pathol. 2015;52(5):945-956.
4. Miller MA, Moore GE, Bertin FR, Kritchevsky JE. What’s new in old horses? Postmortem dignoses in mature and aged equids. Vet Pathol. 2016;53(2):390-398.
5. Miller MA. Endocrine system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Elsevier; 2017:695-699,715-716.
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; 2016:281-285. Stockham SL, Scott, MA. Fundamentals of Veterinary Clinical Pathology. Ames, Iowa: Blackwell Publishing, 2008:809.

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