JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
August 2022
I-F06

Signalment (JPC# 3104239):  14-month-old Newfoundland dog

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION: SLIDE A:  Haired skin: Expanding the dermis, separating and surrounding adnexal structures, extending into the markedly hyperplastic and hyperkeratotic epidermis are multifocal to coalescing nodules composed of epithelioid macrophages, viable and necrotic neutrophils, fewer lymphocytes, plasma cells, rare eosinophils, scant hemorrhage, eosinophilic filamentous beaded material (fibrin), clear space (edema), and are surrounded by loosely arranged fibroblasts. Admixed within the inflammatory nodules are numerous extracellular and rarely intrahistiocytic, round, 10-20µm yeast that have a 2µm double-contoured refractile wall and a basophilic nucleus; yeast occasionally exhibit broad-based budding. The overlying epithelium is markedly hyperplastic with anastomosing rete ridges, abundant basilar mitoses, moderate acanthosis, and an 800µm thick layer of orthokeratotic and parakeratotic hyperkeratosis. The stratum spinosum and stratum corneum are expanded by multifocal nodules composed of previously described inflammatory cells, yeast, eosinophilic and karyorrhectic cellular debris, hemorrhage, fibrin, and edema (intraepidermal and intracorneal abscesses, respectively). Multifocal apocrine glands are mildly ectatic and small caliber blood vessels are lined by hypertrophied endothelial cells (reactive endothelium).

Slide B (PAS):  Haired Skin:  Within the dermis and epidermis there are multifocal PAS positive, 10-20µm diameter, oval yeasts with double contoured walls that exhibit broad based budding.

MORPHOLOGICAL DIAGNOSIS:  Haired Skin:  Dermatitis, pyogranulomatous, multifocal to coalescing, marked, with intraepidermal abscesses, epidermal hyperplasia, hyperkeratosis, and yeast, etiology consistent with Blastomyces dermatitidis, Newfoundland, canine.

ETIOLOGIC DIAGNOSIS:  Cutaneous blastomycosis

CAUSE:  Blastomyces dermatitidis

CONDITION:  Blastomycosis

SYNONYMS:  Gilchrist’s disease, Chicago disease, North American blastomycosis

GENERAL DISCUSSION:

• Dimorphic fungus (thermally dependent) that exists in the mycelial (mold) form in cooler temperatures and converts to yeast form above 37^oC
• Infectious, non-contagious disease most frequently reported in humans, dogs, cats, and horses; however, numerous cases in many mammalian species have been documented
• Endemic in the U.S., especially in the Mississippi, Ohio, and St. Lawrence river valleys; northern Ontario in Canada; Great Lakes and the mid-Atlantic states in the Unites States; but also found in Europe, Asia, Africa, and Central & South America
• Recently disturbed soil is a recognized factor in some outbreaks
• 3 disease forms: pulmonary (most common) (P-F05), disseminated, and cutaneous (rare)
• The lung is the most consistently affected site; most common cause of intraocular mycosis in dogs

PATHOGENESIS:

• Mycelial spores (conidia) inhaled à trapped in mucus layer of terminal bronchioles via centrifugal and inertial turbulence à conidia bind to alveolar macrophages via surface adhesins (e.g. BAD1) à conidia are either rapidly phagocytized and killed by macrophages/neutrophils (conidia readily phagocytized/killed), or they rapidly convert to yeast form (yeast are resistant to phagocytosis/killing) à proliferate in lungs à may disseminate systemically via leukocyte trafficking (macrophages) via blood and lymphatics
• In dogs, the most common sites of extrapulmonary dissemination are the lymph nodes, eyes (S-F02), skin, subcutaneous tissues, bones, and joints; less common are the central nervous system, urogenital tract, spleen, and mammary gland
• Short macrophage lifespan (6-16 days) à intrahistiocytic yeast and yeast-derived debris released upon macrophage death à chemokines/cytokines recruit more macrophages and neutrophils (repetitive cycle)
• Localized cutaneous infection: Should be considered a manifestation of underlying disseminated visceral disease; rarely can be caused by direct inoculation
• Virulence factors:
  • BAD-1 (Blastomyces adhesion factor 1, formerly WI-1) surface protein mediates adhesion to alveolar macrophages (CR3 and CD14 receptors) and suppresses TNF-α production
  • Alpha-1,3-glucan within yeast cell wall and melanin are protective against phagocytosis/killing

 TYPICAL CLINICAL FINDINGS:

• Systemic disease: Anorexia, weight loss, ocular disease, lameness, skin disease; may have hypercoagulability with elevations in plasma fibrinogen concentration
• Hypercalcemia of granulomatous disease due to the excessive production of 1,25 dihydroxycholecalciferol by macrophages

TYPICAL GROSS FINDINGS: 

• Skin lesions include granulomatous papules, nodules, plaques, ulcers, draining tracts with a serosanguinous to purulent exudate, and abscesses in the subcutis; usually multiple, frequently found on nasal planum, face, and nail beds
• Occasional generalized lymphadenopathy
• The lung is the most consistently affected site with diffuse, multifocal distribution of variably sized grey-white nodules

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Mixed granulomatous to pyogranulomatous inflammatory reaction depending on site and chronicity; may have discrete granulomas/pyogranulomas; necrosis is often present
• Epidermis is often acanthotic or ulcerated and exudative and may contain abscesses
• Yeast: 5-15 um (rarely up to 30um), round, non-encapsulated, with a distinct wall and granular protoplasm; exhibit broad based budding; free in tissue and in macrophages often at the center of inflammatory focus

ADDITIONAL DIAGNOSTIC TESTS:

• Histochemical stains: Grocott methenamine silver (GMS), Periodic-Acid Schiff (PAS)
• Cytology: Organisms seen on transtracheal wash or lymph node aspirate; double contour wall
• PCR
• Enzyme immunoassays:
  • BAD-1
  • Galactomannan: widely used clinically; sensitivity in urine 94%, serum 87%
• AGID, ELISA: commercial kits available for demonstration of capsular A-antigen
• Culture: NOT recommended due to the danger of infection from the mycelial form

DIFFERENTIAL DIAGNOSIS:

• For gross finding of multinodular lesions within the lung and other organs:
• Metastatic neoplasia: Nodules often larger and more variable in size
• For histological findings:
  • Cryptococcus neoformans: 2‑20 um in diameter, thick 2‑10 um mucopolysaccharide capsule that is mucicarmine positive, narrow- based budding
  • Coccidioides immitis: Spherules 20‑200 um diameter; endospores 2‑5 um in diameter
  • Paracoccidioides brasiliensis (South American blastomycosis): 5‑60 um diameter, exhibit multiple narrow based budding giving the appearance of a “spoke wheel”
  • Histoplasma capsulatum var. duboisii: 8‑15 um diameter, size is similar but bud from a narrow base, hourglass shape, uninucleate, vacuolated cytoplasm
  • Histoplasma capsulatum var. capsulatum: 2‑5 um diameter; intracellular
  • Sporothrix schenckii: Smaller and generally more pleomorphic than dermatitidis; often “cigar-shaped”
  • Prototheca: Algae; larger with characteristic “Mercedes Benz” endospore morphology
  • Lacazia (Loboa) loboi: Yeast often associate to produce “string of pearls” appearance

COMPARATIVE PATHOLOGY:

• Cutaneous form occasionally reported in cats
• Has been reported (mostly disseminated) in the following species: Rhesus macaque, lemur, horse, alpaca, African and Asian lions, Siberian tiger, cheetah, snow leopard, polar bear, wolves, Indian fruit bat, ferret, Atlantic bottlenose dolphin, Steller’s and California sea lions; uncommon in captive and free ranging bears; frequent in coyotes in certain parts of the United States; recent report of Blastomyces dermatitidis pneumonia in a llama (Jankovsky Jour Vet Diagn Invest. 2018)
• Humans: Most frequently occurs in North America, but has been reported worldwide

References:

1. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:580-582.
2. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018:511.
3. Jankovsky JM, Donnell RL. Blastomyces dermatitidis pneumonia in a llama. J Vet Diagn Invest. 2018; 30(4):576-579.
4. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, and Ailuridae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018:245.
5. Raskin RE, Meyer DJ, eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023: 49-50, 53, 80-81, 175, 261, 371-373.
6. Stockham SL, Scott MA. Calcium, phosphorus, magnesium, and their regulatory hormones. In: Fundamentals of Veterinary Clinical Pathology. 2nd ed. Blackwell Publishing; 2008: 599.
7. Valenciano AC, Cowell RL, eds. Diagnostic Cytology and hematology of the dog and cat. 5th ed. St. Louis, MO: Elsevier; 2020: 50-51, 189, 219-221, 254, 312, 394, 490, 503, 545 .
8. Welle MW, Linder, KE. The integument. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1178.
9. Wilcock BP, Njaa BL. Special senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th, St. Louis, MO: Elsevier; 2016:449.

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