JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

August 2025

I-M05

Signalment (JPC 1906446): Horse, breed, age, and sex unspecified

HISTORY: This horse presented with multiple cutaneous nodules.

HISTOPATHOLOGIC DESCRIPTION: Slide A: Subcutis (per contributor): Diffusely expanding and effacing the subcutis are multifocal to coalescing, variably sized deposits of extracellular amorphous, homogenous, eosinophilic material (amyloid) that measure up to 1 mm in diameter. Deposits of amyloid are surrounded by large numbers of lymphocytes and epithelioid macrophages, moderate numbers of multinucleated giant cells (Langhans and foreign body type), and fewer eosinophils and plasma cells. Multinucleated giant cells often contain up to 30 nuclei and a moderate amount of ingested intracytoplasmic amyloid. In the less affected adipose tissue deep to the panniculus carnosus, there are dense perivascular infiltrates of primarily lymphocytes and plasma cells, with fewer macrophages and multinucleated giant cells. There is moderate fibrosis throughout the affected areas.

Slide B: Congo red: The previously described amorphous deposits stain orange-red (congophilic) and demonstrate apple‑green birefringence under polarized light.

MORPHOLOGIC DIAGNOSIS: Subcutis (per contributor): Amyloidosis, multifocal to coalescing, marked, with granulomatous dermatitis, breed unspecified, equine.

CONDITION: Cutaneous amyloidosis

GENERAL DISCUSSION:

• Amyloid is a pathogenic proteinaceous substance composed of polypeptides arranged in beta-pleated sheets
• Amyloidosis is considered a protein-misfolding disorder in which the proteins biologic function is lost
• Amyloid is deposited between cells of various tissues and organs in response to a variety of pathologic conditions; produces pressure atrophy in adjacent tissues; may be systemic or localized to a single organ
• Three most common types of amyloid:
  • AL: amyloid light chain; derived from plasma cells; contains immunoglobulin light chains
  • AA: amyloid-associated; an acute phase protein produced in excess, predominantly by hepatocytes, result of chronic antigenic stimulation such as occurs in persistent infections, inflammation, or neoplasia
  • Aβ Amyloidosis: cerebral cortex of aged dogs with canine cognitive disorder or human beings with Alzheimer’s disease
  • Islet Amyloid Polypeptide: amyloid secreting β cells of the pancreatic islets; associated with insulin-resistant Type 2 diabetes mellitus, but may be seen in cats with normal glucose tolerance
  • Cutaneous amyloidosis occurs rarely in horses, dogs, and cats

PATHOGENESIS:

• There are several mechanisms of amyloidosis:
  • Propagation of misfolded proteins that serve as a template for self-replication (e.g. prion diseases)
  • Accumulation of misfolded precursor proteins due to a failure to degrade them
  • Genetic mutations that promote precursor protein misfolding
  • Protein overproduction because of an abnormality or proliferation in the synthesizing cells (e.g. plasma cell dyscrasia or neoplasia)
  • Loss of chaperoning molecules or other essential protein assembly components
• Primary systemic amyloidosis: characterized by AL immunoglobulin light chains derived from plasma cells; in AL amyloidosis, abnormal plasma cells secrete the light chain fragments into circulation, and amyloid can be deposited almost anywhere in the body
  • Considered primary when dyscrasias or neoplastic proliferations of plasma cells are the source of the amyloid
  • Canine/feline cutaneous amyloidosis: derived from monoclonal immunoglobulin light chains (AL); has been associated with monoclonal gammopathy, dermatomyositis, or plasmacytomas of skin and oral cavity
  • Equine cutaneous amyloidosis: pathogenesis is unclear, but is morphologically related to cells of the mononuclear phagocytic system and plasma cells
• Reactive systemic amyloidosis (secondary amyloidosis): Occurs secondary to a variety of chronic inflammatory diseases; the protein deposited is AA, which is formed from SAA (serum amyloid-associated), a protein synthesized in the liver under the influence of IL-6 and IL-1 during prolonged tissue damage and inflammation
• Familial amyloidosis (systemic): AA amyloid in Abyssinian (glomerular) and Siamese (liver) cats, as well as Shar-Pei dogs (renal medullary interstitium)
• Localized amyloidosis: Less common in animals; affects a single organ (reported with extramedullary plasmacytoma and amyloid-producing odontogenic tumors)
• Cutaneous amyloidosis can be the localized or systemic type
  • Dogs and cats:
    • Localized primary nodular cutaneous form is the most common type of cutaneous amyloidosis and is associated with plasma cell proliferation, discrete cutaneous extramedullary plasmacytoma, monoclonal gammopathy, dermatomyositis
    • Systemic amyloidosis can affect the skin and often accompanies multiple myeloma
  • Horses:
    • Localized amyloidosis (unknown underlying cause) can affect the skin, nasal cavity, upper respiratory tract
    • Systemic amyloidosis with AA amyloid due to chronic infections (glanders, strangles, tuberculosis, osteomyelitis)

TYPICAL CLINICAL FINDINGS:

• Horse: Epistaxis, dyspnea, poor performance if upper respiratory lesions are present
• Dogs and cats: Often purpuric; cutaneous hemorrhage easily induced by minor trauma

TYPICAL GROSS FINDINGS:

• Small animals: Solitary, firm, non-pruritic, dermal or subcutaneous nodules often on ear
• Horse
• Multiple, firm, 0.5 – 10 cm in diameter, nonpruritic, well circumscribed, papules, nodules, and plaques most commonly seen on the head, neck, shoulders, and pectoral region with normal overlying skin and haircoat
• Cutaneous lesions are rarely associated with upper respiratory lesions (nasal amyloidosis), with unilateral or bilateral nodular to plaque-like lesions in the nasal cavity

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Nodular to diffuse granulomatous dermatitis and panniculitis, with extracellular homogenous amorphous hyaline eosinophilic material which may contain clefts or fractures; multinucleated histiocytic giant cells are usually numerous
• Dog and cats: Cutaneous amyloidosis often seen in association with plasma cell tumors; Superficial dermis contains amorphous, homogenous eosinophilic substance; walls of blood vessels in involved area are thickened by deposits of same substance

ADDITIONAL DIAGNOSTIC TESTS:

• Amyloid stains a light orange-red with Congo Red and exhibits apple green birefringence with polarized light; however, not all forms of amyloid are congophilic
• With pre-treatment with potassium permanganate, AL amyloid retains congophilia & apple green birefringence
• With pre-treatment with potassium permanganate, AA amyloid is no longer stained by Congo Red & apple green birefringence is lost
• Amyloid exhibits a bright yellow fluorescence with thioflavin-T staining
• Historically, iodine was used on the gross floor to identify amyloid; iodine reacts with amyloid, producing a mahogany color that changes to blue when sulfuric acid is subsequently added

DIFFERENTIAL DIAGNOSIS:

• Grossly, cutaneous nodules could also be formed in horses by mast cell tumors, collagenolytic (eosinophilic) granulomas, habronemiasis, sarcoids/soft tissue sarcomas, and pythiosis
• In small animals, cutaneous neoplasms, infectious and noninfectious granulomas, eosinophilic granulomas

COMPARATIVE PATHOLOGY:

• Canine (Kobayashi 2022)
• Amyloid deposits can be found in the stroma of hair follicle tumors and in the margins of keratin debris around normal hair follicles
• This can occur without systemic involvement
• Cytokeratin 5 is thought to be the precursor protein
• Systemic amyloidosis occurs in non-human primates (NHPs), domestic and wild cats, cattle and mice, often associated with inflammation
• NHPs
• New and Old World NHPs develop age-related cerebrovascular amyloid angiopathy (CAA) within vessels of the cortex and leptomeninges, which may be easily missed on routine H&E sections
• Macaques, African Green Monkeys, Common marmosets, cotton-top tamarins all develop amyloid plaques with age
• NHPs most commonly develop secondary amyloidosis (SAA), small intestinal amyloidosis within the lamina propria, and often with co-infections of Mycobacterium sp.

REFERENCES:

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2. Buckles, Elizaneth A. et al. Pheonicopteriformes In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:691.
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9. Kobayashi K, Iwaide S, Sakai H, Kametani F, Murakami T. Keratinic amyloid deposition in canine hair follicle tumors. Veterinary Pathology. 2022;60(1):60-68.
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