JPC SYSTEMIC PATHOLOGY

ENDOCRINE SYSTEM

January 2025

E-N01

 

Signalment (JPC#1946890): 9-year-old male English springer spaniel

 

HISTORY: This dog had chronic pyoderma, alopecia, polyuria, polydipsia, rapid weight loss, and calcinosis cutis. 

 

HISTOPATHOLOGIC DESCRIPTION: Pituitary gland, pars distalis: Expanding and replacing the normal pituitary architecture and compressing the adjacent remaining rim of normal pars distalis is an 6 x 3 mm, unencapsulated, well circumscribed, moderately cellular neoplasm composed of polygonal cells arranged in nests, packets, and trabeculae supported by a fine fibrovascular stroma and separated by variably sized sinusoidal spaces. Neoplastic cells have indistinct cell borders, moderate amounts of microvacuolated to granular eosinophilic cytoplasm, and a round, occasionally vesiculate nucleus with finely stippled chromatin and one variably distinct nucleolus. Mitoses average less than 1 per 10 HPF (2.37mm²), and there is mild anisocytosis and anisokaryosis. Focally compressing a thin rim of remaining pars distalis is a 6 mm diameter cyst lined by attenuated to cuboidal, often ciliated epithelium and filled with hemorrhage, eosinophilic fibrillar material (fibrin), acicular clefts (cholesterol), basophilic granular material (mineral), bright golden-yellow amorphous material (hematoidin), hemosiderin-laden macrophages, and a moderate amount of fibrous connective tissue.

 

MORPHOLOGIC DIAGNOSES: 1. Pituitary gland, pars distalis: Adenoma, English springer spaniel, canine.

2. Pituitary gland: Cyst, craniopharyngeal duct origin.

 

GENERAL: 

• Secretory cells in the adenohypophysis are subdivided into acidophils, basophils, and chromophobes based on the staining of their secretory granules with pH-dependent histochemical stains (these cells, specifically basophils and chromophobes, cannot be reliably distinguished with standard hematoxylin & eosin stain)
• Adenomas can be further classified according to cell type and secretions:
  • Corticotroph and melanotroph adenomas: Corticotroph adenomas most common in domestic animals; pars intermedia (melanotroph) adenomas most common pituitary tumor in horses (E-N02); arise primarily in the pars distalis (especially in dogs) or pars intermedia; most common cause of clinical syndrome of cortisol excess in dogs; composed of chromophobe cells; secrete proopiomelanocortin (POMC), adrenocorticotrophic hormone (ACTH), melanocyte-stimulating hormone (MSH); boxers, Boston terriers, and dachshunds predisposed
    • Recent study showed corticotroph adenomas are larger, more proliferative, and associated with shorter survival than melanotroph adenomas; previous literature suggested the opposite (Miller, Vet Pathol. 2018)
  • Somatotroph adenomas: Occasional in cats and sheep, rare in dogs, report in budgerigars; usually cause acromegaly and diabetes mellitus; composed of acidophil cells; growth hormone (GH) secreting
  • Mammotroph/lactotroph adenomas: Most common in humans, non-human primates (NHP), rabbits, rats, and mice; rare in other species; composed of acidophilic cells; prolactin (Prl) secreting
  • Thyrotroph adenomas: Extremely rare; composed of basophil cells; Thyroid-stimulating hormone (TSH) secreting
  • Gonadotroph adenomas: Extremely rare; composed of basophil cells; follicle-stimulating hormone (FSH), luteinizing hormone (LH) secreting

 

PATHOGENESIS: 

• Functional corticotroph adenomas produce ACTH that stimulates the adrenal cortex causing hyperadrenocorticism (Cushing's disease)
• Pituitary tumors can compress and destroy the pituitary and adjacent brain

 

TYPICAL CLINICAL FINDINGS:

• ACTH secreting tumors: Polyuria, polydipsia, polyphagia, bilaterally symmetrical truncal alopecia, pot-bellied appearance, muscle wasting, stress leukogram, glucosuria in horses
• Any pituitary tumor: Hypopituitarism, atrophy of target organs, blindness, neurological signs, “pituitary cachexia” (lack of the anabolic effects of GH), possibly diabetes insipidus (damage to vasopressin-producing hypothalamic cells) or compression of cranial nerves 2, 3, and 4

 

TYPICAL GROSS FINDINGS: 

• Variable size, white to brown, occasionally contain craniopharyngeal duct cysts
• Hemorrhage, necrosis, mineralization, and liquefaction in large tumors
• Compression or replacement of the hypothalamus and thalamus; in dogs, dorsal expansion via the incomplete diaphragma sellae causes neurologic signs
• Bilateral enlargement of the adrenal glands (zona fasciculata and reticularis) with ACTH secreting tumors

 

TYPICAL MICROSCOPIC FINDINGS: 

• Well-differentiated polygonal cells arranged in solid and sinusoidal patterns
• Moderate amounts of variably granular cytoplasm
• Low mitotic rate

 

ULTRASTRUCTURAL FINDINGS:

• Small (170 nm), spherical, electron dense secretory granules surrounded by a delicate limiting membrane; granules often peripheral in the cell
• Well-developed endoplasmic reticulum and Golgi apparatus

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Reticulin stain: Loss of normal reticulin fibers separating lobules differentiates adenomas from focal hyperplasia
• PAS-positive intracytoplasmic granules within adenomas
• Immunohistochemical staining for secretory activity (such as POMC, ACTH, MSH)
  • Note: Hyperplastic nodules and microadenomas would also label with these
• Insulinoma-associated protein I (INSMI) IHC: Positive in canine anterior pituitary, negative in posterior pituitary, and negative in (single) pituitary chromophobe adenoma (Yang, Vet Pathol 2024) 
• Clinical Pathology: 
  • Cortisol:Creatinine ratio – High sensitivity for hyperadrenocorticism, low specificity (in dogs)
  • ACTH concentration can help differentiate pituitary-dependent hyperadrenocorticism (PDH) from functional adrenocortical neoplasia (FAN) in dogs and cats
  • ACTH normal to increased in PDH, ACTH decreased in FAN
  • Plasma ACTH concentration in horses > 50 pg/ml supportive of pituitary adenoma or hyperplasia
  • Clinical use of ACTH often impractical due to instability 
  • Low-dose and high-dose dexamethasone suppression tests – expected results:
  • Healthy dogs: Cortisol concentration < 1.4 ug/dL in both tests (4h and 8h post-dexamethasone)
  • HAC due to PDH: Cortisol concentration < 1.4 ug/dL with HDDST and sometimes LDDST
  • HAC due to FAN: Cortisol concentration >/= 1.4 ug/dL in both tests (4h and 8h post-dexamethasone)

 

DIFFERENTIAL DIAGNOSIS: 

For gross pituitary mass: 

• Metastatic neoplasia: Lymphoma in cattle; melanoma in horses and dogs
• Sphenoid osteosarcomas, ependymomas, meningiomas, gliomas
• Craniopharyngiomas: Derived from oropharyngeal ectoderm, solid and cystic areas with mineralization, keratin, and colloid; present either in a suprasellar or infrasellar location; usually young adult dogs
• Suprasellar germ cell tumor

 

For histologic findings:

• Hyperplasia: Maintenance of normal reticulin fiber pattern with similar IHC labeling pattern (ACTH, MSH, POMC)
• Adenoma of the pars intermedia (E-N02): 
  • Moderate enlargement of the pituitary gland; may compress but does not invade pars distalis and should be separate from pars distalis; neurohypophysis may be incorporated into the tumor
  • Arise from lining epithelium of hypophyseal lumen
  • Smaller and not encapsulated
  • Distinctive feature includes PAS positive colloid filled follicles (lined by cuboidal to columnar cells) between nests of neoplastic cells
  • ACTH-secreting cells will have eosinophilic cytoplasm
  • May have prominent fibrous connective tissue
  • May or may not be active (i.e. secreting ACTH); active tumors result in similar clinical signs as corticotroph tumors in pars distalis and have variable labeling for ACTH and α-MSH (α-MSH indicates melanotroph)
  • Pituitary chromophobe carcinoma:
  • Uncommon compared to pituitary adenomas; seen in older dogs, cows and sheep
  • Usually endocrinologically inactive, but result in clinical disturbances due to destruction of adjacent tissue (panhypopituitarism, diabetes insipidus)
  • Large; invasive into skull, overlying brain, and sphenoid bone
  • +/- Metastasis to regional lymph nodes, liver, or spleen
  • Histo: Highly cellular, large areas of necrosis and hemorrhage; mitotic figures, nuclear pleomorphism, and giant cells more common than in chromophobe adenomas
  • Malignancy confirmed by invasion into sphenoid bone or metastasis (local invasion into adjacent brain or connective tissue can be seen with adenomas)
  • Other adenomas of the pars distalis (i.e. of somatotrophs) are uncommon and composed of columns of acidophils
  • Xanthogranulomatous pituitary adenoma: Recent report in a dog with hyperadrenocorticism (Fernandez-Gallego, J Comp Pathol. 2020); rare in humans; distinctive histologic features include cholesterol clefts surrounded by multinucleated giant cells, lymphoplasmacytic infiltrates, macrophages, and small epithelial cell clusters 
  • Nonfunctional tumors of the pars distalis (null cell adenoma / chromophobe adenoma) result in significant clinical signs due to compression of surrounding tissue

 

COMPARATIVE PATHOLOGY: 

• Pituitary adenomas are most common in the dog, but also common in rats, mice (B6 and Swiss), horses, and cats
• Pituitary adenoma in cats: In a recent study (Miller, Vet Pathol. 2021), the most common adenomas were somatotroph, followed by melanotroph and gonadotroph, and rarely thyrotroph adenomas; somatotroph and melanotroph adenomas resulted in pituitary-dependent clinical disease, but gonadotroph and thyrotroph adenomas did not; diabetes mellitus most common associated clinical endocrine disorder (insulin-resistant with somatotroph adenoma). 
• Pituitary adenoma in rats: Very common in older rats, esp. Sprague-Dawley and Wistar strains; usually chromophobic, prolactin-producing and associated with mammary hyperplasia/neoplasia and chronic progressive neuropathy; arise in the pars distalis; decreased incidence/age of onset with dietary restriction; genetic factors and breeding history may also play a role in occurrence
• Pituitary adenoma in mice: FVB/N mice prone; more frequent in females; mostly prolactin secreting; expansile with compression of the overlying brain; sinusoidal or cystic (appearing bloody grossly), or solidly cellular
• Equine adenomas of the pars intermedia (E-N02) may produce a unique clinical syndrome resulting in diabetes insipidus, hyperglycemia, glucosuria, polyphagia, pyrexia, hyperhidrosis and hirsutism
• Rabbit pituitary adenomas are commonly prolactin secreting and an associated pathologic finding is mammary dysplasia (in primiparous New Zealand white does)
• Pituitary adenomas and carcinomas in birds: Very common in budgerigars; typically chromophobic pituitary adenomas and less frequently carcinomas; strongly reactive for growth hormone; extend beyond gland into skull, brain, and retrobulbar space; carcinomas more anaplastic with numerous giant cells bizarre, hyperchromatic, karyomegalic nuclei, increased mitotic figures; +/- neurologic signs, exophthalmos, blindness, bilateral hyperplasia of adrenal glands
• Incidence of ferrets with hyperadrenocorticism has increased from 30% to 70% in two decades; due to inbreeding, altered photoperiods, and gonadectomy at an early age, ferrets with hyperadrenocorticism are rarely pituitary dependent, normal cortisol levels, hyperestrogenism
• Cynomolgus macaques most commonly develop lactotroph pituitary adenomas; pituitary adenomas less frequent in rhesus macaque, gorilla, chimpanzee, golden lion tamarin; often incidental findings
• Pituitary adenoma reported in llamas and alpacas, shrew and elephant
• Fish: true prevalence hard to determine, but reported cases of pituitary adenomas are rare
• Chinchillas: 4 pituitary adenomas described; two confined to pars distalis and two invading brain; all weak to strong IHC + for GH (somatotroph adenomas) (Lee, Vet Pathol, 2023)

 

REFERENCES: 

1. Abdul-Aziz T, Fletcher OJ. Chapter 12: Endocrine System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 549.
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7. Fernandez-Gallego A, Del-Pozo J, Boag A, et al. Xanthogranulomatous pituitary adenoma in a dog with typical hyperadrenocorticism. J Comp Pathol. 2020;180:115-121. 
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17. Yang F, Chang Y, Chang Y, et al. Insulinoma-associated protein I (INSMI) immunohistochemical expression in normal, hyperplastic, and neoplastic canine neuroendocrine tissues. Vet Pathol. 2024. doi: 10.1177/03009858241279127. Epub ahead of print.

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