PC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
August 2022
I-M03

Signalment (JPC# 1963156):  Parakeet

HISTORY:  Cutaneous mass from the wing.

HISTOPATHOLOGIC DESCRIPTION:  Feathered skin (2 sections):  Diffusely expanding the dermis and subcutis and widely separating and replacing feather follicles are multiple coalescing lipid granulomas (xanthogranulomas) centered on aggregates of lipid, scant eosinophilic cellular debris, and numerous linear, up to 300um long, clear, acicular clefts (cholesterol clefts).  Cholesterol clefts are surrounded by numerous tightly packed epithelioid macrophages with abundant eosinophilic cytoplasm that contains many small, clear, discrete vacuoles (lipid).  These are further surrounded by multinucleate giant cells with up to 80 nuclei that are arranged centrally (foreign body type), peripherally (Langhan’s type), or have a central area of dense eosinophilic cytoplasm bordered by multiple nuclei arranged in a circle that are surrounded by a peripheral rim of clear cytoplasm (Touton’s type). Multifocally there are low numbers of perivascular lymphocytes, heterophils, and fewer plasma cells. There is mild epidermal hyperplasia with minimal orthokeratotic hyperkeratosis and mild epidermal intercellular edema.

MORPHOLOGIC DIAGNOSIS:  Feathered skin:  Lipid granulomas (xanthogranulomas), multifocal to coalescing, severe, with Touton type multinucleate giant cells and acicular cholesterol clefts, parakeet, avian.

ETIOLOGIC DIAGNOSIS:  Cutaneous xanthoma

SYNONYM:  Xanthomatosis, xanthogranulomas

GENERAL DISCUSSION:

• Non-neoplastic, yellow to white, nodular masses composed of large accumulations of lipoprotein-laden macrophages, multinucleate giant cells, free cholesterol, and variable amounts of connective tissue; invasive and difficult to excise
• Occurs in the skin, subcutaneous tissues, and internal organs
• Occurs in gallinaceous and psittacine birds, New Zealand White rabbits, rarely in the cat (Siamese), and very rarely in the dog and horse
• An accumulation of excess lipids in the body probably due to disturbances of lipid metabolism and marked by formation of fatty masses
• Significant chicken flock problem in the 1960s, primarily affecting white leghorns
• Lesions take their name from the Greek “xanthos”, meaning yellow

PATHOGENESIS:

• Idiopathic in birds and Siamese cats; likely some type of disturbance in lipid metabolism
• Other disorders involving lipid metabolism such as diabetes mellitus, hyperlipidemia in cats, or diets high in fats
• Trauma may predispose to formation
• Idiopathic lesions in chickens have been linked to diets with high levels of chlorinated hydrocarbons
• Abnormal plasma concentrations of cholesterol, triglycerides, or lipoproteins (dyslipoproteinemias); dyslipoproteinemias can be inherited or acquired
  • Acquired dyslipoproteinemias include diabetes mellitus and hyperadrenocorticism; lesions abate with resolution of primary disease

TYPICAL CLINICAL FINDINGS:

• Birds are bright and active with normal egg production and feed consumption
• The skin may be featherless, ulcerated, or hemorrhagic
• No sex predilection, except more frequently seen in female budgerigars; typically identified in older (~10 years old) psittacines, and more common in budgerigars and cockatiels
• Lesions can be painful or pruritic
• Hypercholesterolemia and hyperlipidemia, occasionally

TYPICAL GROSS FINDINGS:

• Yellow to white, single to multiple, discrete subcutaneous nodules, plaques, or papules with erythematous margins
• Initially lesions are soft, fluctuant, and contain a pale-yellow transudate, but can become firm with chalky white areas of cholesterol
• Nodules are interfollicular and occur anywhere on the skin; may overlie other neoplasms, especially lipomas
• In birds they are found on the breast, abdomen, feathered portion of the leg, or wattles, eyelid and third eyelid, bone marrow, ventriculus, liver; infrequently they are periarticular or involve the oral cavity, bone marrow, or internal organs

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Nodular-to-diffuse infiltration of foamy macrophages, lipid lakes, acicular cholesterol clefts, and multinucleate giant cells (Touton’s type)
• Granulomatous inflammation and fibroplasia may occur

ADDITIONAL DIAGNOSTIC TESTS:

• Oil-red-O stained frozen sections have positive staining of lipid within macrophages, giant cells and in extracellular lakes
• Polarized frozen sections have birefringent rhombic crystals with typical "Maltese cross" of cholesterol esters

DIFFERENTIAL DIAGNOSIS:

For gross findings:

• Infectious and noninfectious granulomas – differentiate on histology
• Gout - differentiate on histology; gouty tophi
• Atypical mycobacterial infection
• Neoplasms - especially histiocytic or fibrohistiocytic; Marek’s disease associated cutaneous lymphoma (usually affect feather follicles)

COMPARATIVE PATHOLOGY:

• Secondary to acquired or inherited dyslipoproteinemias in other animals
• Dogs and cats:
  • Reported as secondary lesion with diabetes mellitus, hypothyroidism, hyperadrenocorticism, and high-lipid diets
  • Seen in the kidneys, among other organs, of cats with inherited hyperlipoproteinemia and dogs with hypothyroidism and severe atherosclerosis
  • Seen most commonly on the distal extremities, head, bony prominences, or paws
  • Intraocular xanthomas are rare in dogs (Miniature Schnauzers) and appear as a tan mass-like lesion filling the entire globe
  • Recent report of a xanthogranulomatous pituitary adenoma with concurrent hyperadrenocorticism in a Labrador retriever (J Comp Pathol., 2020)
• Lizards: Reported in green (Chinese) water dragons and geckos (coelomic surfaces, brain, and spinal cord affected)
• Horses: Xanthomas occur on the thorax of horses with hyperadrenocorticism and have been described along with equine pituitary pars intermedia dysfunction (PPID)
• Watanabe heritable hyperlipidemic rabbits (WHHL):
  • Develop xanthomatosis secondary to hypercholesterolemia due to a single genetic defect for low-density-lipoprotein (LDL) receptors leading to decreased cell uptake and increased production of LDL
  • Seen in the muscle, heart, lung, choroid plexus, kidney, gastrointestinal tract, eye and endocrine organs

• Captive frogs: Reported in pituitary gland, brain, nerves, lung, stomach, ovaries, arteries, and periarticular soft tissues in captive frogs associated with corneal lipid deposition (lipid keratopathy, corneal lipidosis); suspected to be due to captive-fed diets that differ in cholesterol or other lipid composition

REFERENCES:

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2. Crespo R, Franca MS, Fenton H and Shivprasad HL. Galliformes and Columbiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018: 750-751.
3. Fernandez-Gallego A, Del-Pozo J, Boag A, Maxwell S, and Perez-Acino J. Xanthogranulomatous Pituitary Adenoma in a Dog with Typical Hyperadrenocorticism. J Comp Pathol. 2020; 180:115-121.
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