JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-N09

SIGNALMENT (JPC #2064150):  A dog; age, sex and breed unknown 

HISTORY:  This dog had clinical signs of hyperadrenocorticism.

HISTOPATHOLOGIC DESCRIPTION:  Adrenal gland: Infiltrating and effacing normal adrenal gland architecture and compressing the remaining adrenal cortex is an unencapsulated, poorly demarcated, multilobular, densely cellular neoplasm composed of polygonal cells arranged in cords, nests, and packets on a fine fibrovascular stroma which forms lobules separated by dense reticulations of collagen. Neoplastic cells have indistinct borders, a moderate amount of microvacuolated eosinophilic cytoplasm, and a round to oval nucleus with finely stippled chromatin and one magenta nucleolus. There is mild to moderate anisocytosis and anisokaryosis and the mitotic count is 3 per 0.237sq mm (individual 40x HPF). Multifocally, neoplastic cells and adrenocortical cells contain large, clear cytoplasmic vacuoles and have hyperchromatic to pyknotic nuclei (lipoidal degeneration).  Within the neoplasm there is multifocal single cell necrosis and larger areas of lytic necrosis, hemorrhage, fibrin, edema, and mineral deposition.

MORPHOLOGIC DIAGNOSIS:  Adrenal gland: Adrenocortical carcinoma, breed unspecified, canine.

GENERAL DISCUSSION:

• Adrenal gland adenomas are more common than carcinomas
• Adrenocortical carcinomas (ACC) are reported most often in cattle and older dogs
• Adrenocortical neoplasms are occasionally functional and most often secrete excessive cortisol causing hypercortisolism/ hyperadrenocorticism (Cushing’s disease)
  • 15% of dogs with hyperadrenocorticism have function adrenal tumors

PATHOGENESIS:

• Carcinoma: PI3 kinase activation through insulin growth factor-1 (IGF-1) is thought to be associated with malignancy in dogs and humans
• Clinical signs are caused by invasion, metastasis, and compression of adjacent tissue
• Hypercortisolism if tumor is functional

TYPICAL CLINICAL FINDINGS:

• Hypercortisolism:
  • Polyuria/polydipsia, polyphagia, pendulous abdomen, muscle weakness, lethargy
  • Mature neutrophilia, lymphopenia, monocytosis, eosinopenia (steroid stress leukogram)
  • Increased serum alkaline phosphatase (levamisole-resistant steroid isoenzyme), elevated cortisol, decreased urine specific gravity, hyperglycemia, lipemia, hypercholesterolemia
  • Skin lesions: bilateral, symmetric alopecia; skin fragility syndrome in cats with chronic hyperadrenocorticism
  • Increased susceptibility to bacterial infections

TYPICAL GROSS FINDINGS:

• Adenoma: < 2 cm diameter, well circumscribed, solitary yellow to red nodule which expands the cortex and compresses adjacent normal cortex and medulla
• Carcinoma: > 2 cm, more likely to be bilateral, variegated, yellow to red, friable with poorly circumscribed areas of necrosis and cystic degeneration, +/- vascular invasion of caudal vena cava or aorta, tumor cell thrombi, mineralization or ossification; metastasis to the liver and lungs is most common
• Contralateral adrenal cortex atrophy (of the zonae fasciculata and reticularis, E-M04) occurs with functional adrenal tumors
  • Elevated blood cortisol causes negative feedback inhibition of pituitary ACTH
• Skin (if tumor is functional): severe mineralization of skin (calcinosis cutis) with crystals protruding from an atrophic epidermis

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Adenoma: Single discrete nodule, partially or completely encapsulated, composed of polygonal cells resembling zonae fasciculata or reticularis with cytoplasmic vacuolation; nodular hyperplasia may also be present
  • Areas of telangiectasis, hematopoiesis, mineralization, hemosiderosis, adipose, and fibrosis may be present
• Adenocarcinoma: Indiscrete nodules, capsular and peripheral invasion, peripheral fibrosis, trabecular growth pattern, cells are highly pleomorphic with decreased cytoplasmic vacuolation
  • Hemorrhage, swathes of necrosis, and single cell necrosis
  • Anaplasia may lead to spindling of neoplastic cells
  • Differentiation from adenoma on histology alone is challenging
• Indicators of metastatic potential include: Diffuse growth pattern, vascular invasion, single cell necrosis, and fibrous bands within the tumor
• Skin (secondary to hyperadrenocorticism, I-M23): cutaneous mineralization (calcinosis cutis)
  • Epidermal and adnexal atrophy; collagen and elastin fiber loss in the dermis and subcutis
• Mineralization of other tissues: lungs, skeletal muscle, stomach wall

ADDITIONAL DIAGNOSTIC TESTS:

Parameter	Adrenal dependant	Pituitary dependant
Tests to confirm hyperadrenocorticism regardless of cause include:
Resting cortisol	Normal to Elevated	Normal to Elevated
ACTH stimulation	Normal to exaggerated (up to 50% normal)	Normal to exaggerated
Low dose dex suppression	Will not suppress	Will not suppress
Urine cortisol:creatinine (best to rule OUT cushings)	Increased (may also increase with stress)	Increased (may also increase with stress)
Tests to distinguish the cause:
Low dose dex suppression at 4 and 8 hours	No suppression (escape) at 4 hours	Most (75-98%) escape by 8 hours (so if suppressed at 4hrs and escape by 8 hrs= PDH)
High dose dex suppression	No suppression	75% suppress
Endogenous ACTH	Low	Normal to high
Corticotrophin releasing hormone test	No response in either cortisol or ACTH	Increase in cortisol and ACTH

 

• No biochemical or clinical features can distinguish between adenomas and carcinomas
• Immunohistochemistry: Adenomas and carcinomas are variably positive for the normal adrenal cortical immunohistochemical antigens: steroidogenic factor-1, calreticulin, α-inhibin, melan-A, and S-100
  • Typically negative for cytokeratin and chromogranin

DIFFERENTIAL DIAGNOSIS: 

• For gross finding of adrenal cortical masses:
  • Nodular cortical hyperplasia: Multiple expansile nodules of unencapsulated hyperplastic cells often in both adrenal glands and often outside of the adrenal capsule
  • Myelolipoma: A benign lesion of adipose cells and hematopoietic tissue; most common in cattle and NHPs
  • Pheochromocytoma: Cells with darker, granular cytoplasm with hyperchromatic nuclei; Henle chromaffin reaction on gross sections using Zenker’s solution; immunohistochemical profile may include Chromogranin A, synaptophysin, protein gene product 9.5 (PGP 9.5), neuron-specific enolase, catecholamines, catecholamine-synthesizing enzymes, and opioid peptides (met-enkephalin, leu-enkephalin, beta-endorphin, dynorphin B)
  • Metastatic neoplasia: The adrenal corticomedullary junction is a common site of tumor metastasis

COMPARATIVE PATHOLOGY:

• Ferrets: Adrenal-associated endocrinopathy (AAE) is a common metabolic disease of ferrets
  • Functional proliferative lesions of the adrenal cortex in order of frequency in ferrets: hyperplasia > carcinoma > adenoma; AAE occurs with all and is specific to none
    • Note: ectopic adrenocortical tissue is common in ferrets (do not interpret as metastasis)
  • In ferrets, hyperplastic and neoplastic cells of the zona fasciculata (ZF) and zona reticularis (ZR) release sex steroids instead of cortisol
  • Pathogenesis of AAE is linked to early neutering: early gonadectomy disrupts negative feedback of hypothalamic–pituitary–gonadal axis à persistently elevated levels of luteinizing hormone (LH) à proliferation of primitive adrenocortical cells and upregulation of LH receptors in ZF and ZR à secretion of estradiol or its intermediates à hyperestrogenism
  • Hyperestrogenism: vulvar enlargement, bilaterally symmetric alopecia, PU/PD, anemia, thrombocytopenia, pyometra, endometrial hyperplasia, squamous metaplasia of prostatic ductular epithelium, cystic prostatic disease (can cause urinary obstruction), return of sexual behavior
  • No hypercortisolism and no atrophy of the contralateral cortex
  • Adrenal cortical carcinomas with myxoid differentiation are associated with increased malignancy and metastasis
  • Transcription factor GATA-4 is a marker of anaplasia in ferret adrenocortical tumors
  • AAE testing panel for confirmation: estradiol, 17-hydroxyprogesterone, and androstenedione
• Cattle: adenomas may approach 10cm or more in diameter with areas of ossification and mineralization
• Hamster: Adrenocortical tumors are one of the most common tumors in hamsters and a common cause of hyperadrenocorticism
• Cats: Functional neoplasms arising from the aldosterone-secreting cells of the zona glomerulosa are rarely reported in cats
• Gonadectomy increases incidence of adrenal tumors in mice and goats

REFERENCES:

1. Baktavatchalu V, Muthupalani S, Marini RP, et al. Endocrinopathy and Aging in Ferrets. Vet Pathol. 2016; 53(2):349-365.
2. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. West Sussex, UK. John Wiley & Sons, Inc.; 2016: 193.
3. Ferguson DC, Hoenig M. Endocrine system. In: Latimer KS, ed. Duncan & Prasse’s Veterinary Laboratory Medicine: Clinical Pathology. 5th ed. Ames, IA: Iowa State University Press; 2011:318-23.
4. Fox JG, Muthupalani S, Kiupel M, Williams B. Neoplastic diseases. In: Fox JG, Marini RP, eds. Biology and Diseases of the Ferret. 3^rd Ames, IA: John Wiley & Sons, Inc.; 2014:591-594.
5. Miller CL, Marini RP, Fox JG. Diseases of the endocrine system. In: Fox JG, Marini RP, eds. Biology and Diseases of the Ferret. 3^rd Ames, IA: John Wiley & Sons, Inc.; 2014:377-384.
6. Miller MA. Endocrine system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:706-708.
7. Rosol TJ, Grone A. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Saunders Elsevier; 2016:337-348.
8. Stockham SL, Scott MA. Adrenocortical function. In: Fundamentals of Clinical Pathology, 2^nd ed, Ames, IA: Blackwell; 2008:806-830.
9. Williams BH, Burek Huntington KA, Miller M. Mustelids. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:288-289.

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