JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
August 2022
I-F04

Signalment (JPC# 1596989):  Adult female domestic shorthair cat.

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION:  

Slide A: Haired skin and subcutis:  Diffusely expanding the deep dermis and subcutis are multiple coalescing nodules of pyogranulomatous inflammation composed of numerous viable and degenerate neutrophils, epithelioid macrophages, scattered multinucleated giant cells, and rare lymphocytes and plasma cells admixed with moderate numbers of fibroblasts (fibrosis), eosinophilic cellular and karyorrhectic debris (lytic necrosis), fibrin, hemorrhage, and edema. Scattered throughout the nodules are many golden-brown pigmented fungal yeast and hyphae. Yeast are ovoid, 7 to 20µm in diameter, with 2-3µm-thick dark brown cell walls, and clear to pale brown cytoplasm with a central basophilic nucleus. Yeast occasionally form chains (pseudohyphae).  Hyphae are 5-10µm wide, septate, with irregular, dichotomous and non-dichotomous, acute angle to right angle branching and thin, pigmented, nonparallel walls.  Multifocally there are intact and degenerate fungal elements within the cytoplasm of macrophages and multinucleated giant cells.

Slide B (Periodic acid-Schiff stain):  Haired skin and subcutis:  The fungal elements are strongly PAS-positive.

MORPHOLOGIC DIAGNOSIS:  Haired skin and subcutis:  Dermatitis and panniculitis, pyogranulomatous, diffuse, severe, with many dematiaceous yeast and few hyphae, domestic shorthair, feline.

ETIOLOGIC DIAGNOSIS:  Cutaneous phaeohyphomycosis

CAUSE:  Pigmented (dematiaceous) fungi

CONDITION:  Phaeohyphomycosis

GENERAL DISCUSSION:

• Heterogenous group of opportunistic mycotic infections caused by pigmented (dematiaceous) fungi (hyphae and/or yeast) of many genera, including Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Ochroconis
• Worldwide in distribution and widespread in the soil, on wood, and in vegetation
• Uncommon opportunistic infection which usually affects the skin and/or subcutis, but central nervous system and disseminated infections may also occur (often associated with immune compromise)
• Subcutaneous fungal infection terms:
• Mycetoma – organism forms hyphae and is surrounded by Splendore-Hoeppli reaction; usually macroscopically visible
  • Eumycotic – fungal
  • Actinomycotic – Actinomyces or Nocardia (bacterial)
  • Chromomycosis – caused by dematiaceous fungi
    • Chromboblastomycosis – yeast morphology only and no hyphae; “sclerotic bodies”
    • Phaeohyphomycosis – yeast and hyphal morphology
  • Hyalohyphomycosis – subcutaneous and/or disseminated disease caused by non-dematiaceous fungi
• Pseudomycetoma – organism is present in tissue as granules and/or grains, but not of mycelial formation; caused by bacteria or dermatophytes

PATHOGENESIS:

• Infection occurs primarily by traumatic implantation or wound contamination
• Melanin synthesis in cell walls thought to be the main virulence factor
  • Contributes to ability to elude host immune response and protect the organism from oxidative burst
• Disseminated infection, but not subcutaneous infection, may be associated with immunosuppression

TYPICAL CLINICAL FINDINGS:

• Slow-growing, firm to fluctuant, dermal and subcutaneous nodules or plaques that coalesce, enlarge, ulcerate, and form fistulous tracts
• In cats and dogs, lesions are primarily on the face and distal extremities, and disseminated infections are rare
• Often non-painful and non-pruritic
• Disseminated infections often have a neutrophilic pleocytosis in cerebrospinal fluid

TYPICAL GROSS FINDINGS:

• Dermal or subcutaneous nodules (single or multiple) that are ulcerated or have fistulous tracts, and may form abscesses or thick-walled cysts
• Disseminated disease causes multifocal granuloma-like masses
• Lesion may be blue-gray or dark in color due to pigmented fungi – may be mistaken grossly for melanoma

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Diffuse or nodular granulomatous, pyogranulomatous, or lymphocyte-rich granulomatous dermatitis and panniculitis; diagnosis confirmed by presence of pigmented hyphae within tissue
• Hyphal characteristics include septate, non-parallel, 2-6um wide, branched or unbranched
• Curvularia produce characteristic C-shaped scrolls in tissue section
• While fungi always form pigment on culture, this may not be apparent in tissue sections (i.e. with Alternaria) and the special stains (Fontana-Masson) are necessary for differentiation

ADDITIONAL DIAGNOSTIC TESTS:

• Stain positive with Gomori methenamine silver (GMS) or periodic acid Schiff (PAS) (Note: fungal stains mask the natural color)
• Fontana-Masson staining method highlights melanin pigment that might not be evident on H&E sections, thereby differentiating it from nonpigmented fungi
• Culture necessary for a definitive diagnosis
• Cytology: Pale staining, oval to round, septate hyphae 7-14µm wide with eosinophilic internal stippling (Alternaria)

DIFFERENTIAL DIAGNOSIS:

• Gross differential (pigmented mass): Melanocytic neoplasm
• Two additional presentations of dematiaceous (pigmented) fungal infections:
  • Dematiaceous eumycotic “black grained” mycetomas have macroscopic tissue grains composed of entangled mass of pigmented hyphae embedded in cement-like material; may be surrounded by Splendore-Hoeppli material; forms discrete extracellular organized granules whereas phaeohomycosis is in small aggregates and individual hyphae throughout the lesion that can be intracellular within macrophages or multinucleate giant cells
  • Chromoblastomycosis – Causative fungi are pigmented, but don't form hyphae in tissue and their division by septation is distinctive; form large (4-15 um), round, thick and dark-walled yeast-like cells (sclerotic bodies, chromo bodies, Medlar bodies)

COMPARATIVE PATHOLOGY:

• Emerging disease in domestic and wild animals and invertebrates; more common in cats than other domestic mammals, but also occurs in horses (multiple lesions at different locations), cattle, goats, dogs (multiple extensive lesions, German shepherds may be predisposed), as well as fish, reptiles, amphibians, and birds (and humans)
• Reported in Grevy’s zebra with pyogranulomatous pneumonia, myocarditis, and pericardial effusion
• Reported in a Pudu (Curvularia spicifera)à usually affects skin, but has been reported in a 2021 publication causing a pyogranulomatous meningoencephalitis
• Ochroconis and Exophiala species identified in granulomatous lesions in box turtles, radiated tortoise, Aldabra tortoise, and Galapagos tortoise
• Veroneas identified in stranded green sea turtles with obstructive tracheitis
• Exophiala spp in freshwater and marine bony fish, where angioinvasion was commonly seen
• Systemic necrotizing lesions seen in seadragons infected with Exophiala angulospora and aquamarina
• Phomamycosis – phaeohyphomycosis of hatchery raised fish caused by Phoma herbarum

REFERENCES:

1. Boes KM . Respiratory system. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023: 191.
2. Duncan M. Perissodactyls. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018: 449.
3. Frasca Jr. S, Wolf JC, Kinsel MJ, Camus AC, Lombardini ED. Osteichthyes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018: 974.
4. Levine GJ, Cook JR. Cerebrospinal fluid and central nervous system cytology. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and hematology of the dog and cat. 5th ed. St. Louis, MO: Elsevier; 2020: 217.
5. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Saunders Elsevier; 2016: 654-655.
6. McCann RS, Cole GA, LaDouceur EEB, McAloose D, Sykes JM, Dennison-Gibby S, D’Agostino J. Mycotic pneumonia and encephalitis in southern Pudu (Pudu puda). J Zoo Wildl Med. 2021; 52(1):379-388.
7. More SN, Hernandez O, Castleman WL. Mycotic rhinitis and sinusitis in Florida horses. Vet Pathol. 2019; 56(4):586-598.
8. Plumlee Q, Meason-Smith C, Dieterly A, Gomez G, Porter BF, Rodrigues Hoffmann A. Chaetomiaceae fungi, novel pathogens of equine neurotropic phaeohyphomycosis. Vet Pathol. 2017; 54(5):813-819.
9. Rodriguez CE, Duque AMH, Steinberg J, Woodburn DB. Chelonia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018: 839.
10. Velazquez-Jimenez Y, Hernanadez-Castro R, Romero-Romero L, Salas-Garrido CG, Martinez-Chavarria LC. Feline phaeohyphomycotic cerebellitis caused by Cladosporium cladosporioides-complex: Case report and review of literature. J Comp Pathol. 2019; 170:78-85.
11. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1176.

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