JPC SYSTEMIC PATHOLOGY

SPECIAL SENSES SYSTEM

April 2024

S-F01 (NP)

 

Signalment (JPC #1743577): Labrador mix dog

 

HISTORY: This Labrador mix developed neurological signs including papillitis, which eventually progressed to blindness. At necropsy, the animal also had meningitis.

 

HISTOPATHOLOGIC DESCRIPTION: Eye: Diffusely expanding the optic nerve meninges up to 1mm and extending into perineural adipose tissue are numerous epithelioid macrophages, fewer lymphocytes and plasma cells, occasional multinucleated giant cells, and rare neutrophils. Admixed with the inflammatory cells are numerous extracellular and intrahistiocytic, round to crescentic, non-staining, 5-20 µm diameter yeast with thin, birefringent walls and rare narrow-based budding. Yeasts are surrounded by a clear, 5-10 µm wide halo. Focally within the choroid, there is a single, 70 x 80 µm nodule composed of moderate numbers of previously described inflammatory cells and yeast that elevates the retinal pigmented epithelium.  

 

MORPHOLOGIC DIAGNOSIS: Eye, optic nerve: Meningitis, granulomatous, diffuse, moderate, with focal choroiditis, perineural steatitis, and numerous yeast, Labrador mix, canine.

 

ETIOLOGIC DIAGNOSIS: Ocular cryptococcosis

 

CAUSE: Cryptococcus neoformans

 

SYNONYM: European blastomycosis, torulosis

 

GENERAL DISCUSSION:  

• Cryptococcus neoformans is a worldwide cause of subacute to chronic mycotic infections in a wide variety of animals (especially cats) and humans; C. neoformans and C. gattii are the most common cause of fungal rhinitis in cats
• C. neoformans is a saprophytic, 5-20 µm wide, yeast-like basidiomycete fungal organism that reproduces by narrow-based budding; in tissues, organisms are round to crescentic, thin walled, and surrounded by a thick, 5-10 µm wide, mucopolysaccharide capsule forming a clear halo that imparts the characteristic “soap bubble” microscopic appearance
• C. neoformans (C. neoformans var. neoformans and C. neoformans var. grubii) is associated with pigeon and other bird droppings, and Cryptococcus gattii is found primarily in organic material (particularly tropical plants)
• Infections occur primarily in immunocompromised animals and may be localized or disseminated; there is a predilection for the respiratory (particularly the nasal region) and central nervous systems; cutaneous and ocular lesions occur less frequently
• C. gattii is a primary pathogen than can cause disease in immunocompetent hosts

 

PATHOGENESIS:

• C. neoformans and C. gatti exist in the environment as a filamentous form (teleomorph), named Filobasidiella neoformans and F. bacillosporus, respectively; this form of the organism undergoes both sexual as well as asexual reproduction in the environment
• Transmission generally occurs via inhalation of basidiospore-contaminated dust or soil enriched with pigeon droppings
• Basidiospores settle in the nasal mucosa or alveoli and rapidly germinate to yeast in the mucosa to resist phagocytosis/killing.
• Yeast have several virulence factors:
  1. Glucosylceramide is essential for survival in mucosa.
  2. Phospholipase causes type II pneumocyte injury and inhibition of surfactant production, and improving adhesion.
  3. Melanin acts as an antioxidant and modulates the host immunoinflammatory response, production attributed in part to the enzyme phenoloxidase (laccase)
  4. Urease inhibits acidification of the phagolysosome
  5. Thick capsule: 
     • Composed primarily of glucuronoxylomannan and galactoxylomannan
     • Impairs phagocytosis, activates complement, and may suppress T-cell response
     • The yeast produces additional capsule once in the phagolysosome to dilute hydrolases and other degenerative products and ultimately causes gross distension of macrophages and the gelatinous matrix of cryptococcomas
• Direct (from nasal cavity/sinuses) or hematogenous dissemination (via leukocyte trafficking) causes secondary infection of other organs, such as the CNS, eyes (choroid, optic nerve), lymph nodes, mammary glands, skin, and bone
• Ocular infection may occur through hematogenous spread or extension from the brain via optic nerves
• Rupture of short-lived macrophages leads to liberation of antigens and capsular material and recruitment of additional macrophages

 

TYPICAL CLINICAL FINDINGS:

• Ocular: Optic neuritis, chorioretinitis, anterior uveitis, blindness, mydriasis, posterior synechia, retinal hemorrhage and detachment, exophthalmos due to retrobulbar abscess
• CNS: Disorientation, circling, ataxia, paresis/paralysis, Horner’s syndrome
• Respiratory: Unilateral or bilateral rhinitis, nasal swelling, mucopurulent discharge, sneezing

 

TYPICAL GROSS FINDINGS:

• Typical presentation is of rapidly growing, often multiple, pale, gelatinous to mucoid, granulomatous or tumor-like masses in the affected organs
• The retina, choroid, optic nerve, and/or meninges, may be diffusely or multifocally thickened by gelatinous material that may displace surrounding structures
• In the CNS, the meninges are similarly thickened, and organisms and inflammation may displace underlying cerebral tissues or invade adjacent bone
• In the skin, ulcerated nodules with draining tracts +/- lymphadenopathy
• Respiratory system: Nasal mass or swelling that may involve frontal sinus, granulomatous pneumonia

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Numerous ovoid or spherical, 4-10µm, thick-walled, yeast-like organisms surrounded by a 1-30 µm thick gelatinous capsule with occasional narrow-based budding and forming “soap bubble” masses
• Ocular lesions are typically bilateral but not always symmetric
• Rough coated variants may lack capsule
• Minimal to moderate mononuclear, granulomatous, or pyogranulomatous inflammation with yeast in affected organs

 

ADDITIONAL DIAGNOSTIC TESTS:

• Cytology: Mucicarmine, India ink (negative staining) of capsule
• Special histochemical stains:
  • Yeast bodies stain with PAS and GMS
  • Melanin can be demonstrated with Fontana Masson
  • Capsule stains with mucicarmine, PAS, and Alcian blue, giving it a radiating, spoke-wheeled appearance
• CSF tap shows pleocytosis (elevated nucleated cell count) and elevated protein concentrations; inflammatory population is variable; organisms present in majority of CSF samples
• BAL may demonstrate yeast in granulomatous pneumonia
• Culture (esp. to differentiate C. neoformans and C. gattii), PCR
• Serum and CSF can be used for capsular antigen detection via latex agglutination

 

DIFFERENTIAL DIAGNOSIS:

Causes of Fungal/Algal Intraocular Infections:

• Blastomyces dermatitidis (S-F02): Most common cause of intraocular mycosis in dogs and causes diffuse granulomatous to pyogranulomatous endophthalmitis with retinitis, exudative retinal separation, and granulomatous optic neuritis; exhibits broad-based budding; yeast walls may demonstrate mild mucicarmine staining, but there is no capsule
• Histoplasma capsulatum: Rarely causes ocular disease and is less destructive than Cryptococcus or Blastomyces, with lesions centered on the choroid and dominated by plasma cells and macrophages
• Coccidioides immitis: Large, 5-50 µm wide, non-encapsulated yeast with reproduction via endosporulation; rarely affects the eye, causing pyogranulomatous inflammation that is more destructive than Cryptococcus or Blastomyces
• Prototheca zopfii (S-M03): Colorless, refractile, 2-20 µm wide, endosporulated algal organisms with tripartite cell wall division; argyrophilic and PAS-positive; causes minimal to intense granulomatous inflammation
• Aspergillus terreus: Disseminated granulomatous infection in young to middle-aged German Shepherds with chronic anterior and posterior uveitis and diskospondylitis

 

COMPARATIVE PATHOLOGY:

• Cats: The most common systemic mycosis in cats; causes primarily nasal lesions with direct extension to the CNS
• Horses: Primarily nasal lesions with direct extension to the CNS; also causes placentitis and abortions
• Cattle: C. neoformans can cause granulomatous mastitis, associated with intractable mastitis with supramammary lymphadenopathy and rare dissemination to other regions 
• Rabbits: Have been used as a model for chronic cryptococcal meningitis; normally highly resistant to C. neoformans infection
• Humans: Usually localized in the meninges with pulmonary lesions less common; often underlying immunodeficiency
• Documented in a variety of wildlife and zoo animals: Koalas, cetaceans, apes, cheetahs

 

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