JPC SYSTEMIC PATHOLOGY
NERVOUS SYSTEM
January 2023
N-F04
Signalment (JPC #2023496): 6-year-old female African elephant (Loxodonta africana)
HISTORY: Located in the left superior temporal lobe was a focal, circumscribed (2.3 cm), grayish‑white, firm mass.
HISTOPATHOLOGIC DESCRIPTION: Brain, cerebrum: Effacing 70% of the tissue, affecting both gray and white matter, and compressing the adjacent neuroparenchyma is a 1.5 cm diameter granuloma composed of a large central area of eosinophilic cellular and karyorrhectic debris (necrosis) interspersed with small, primarily extracellular clusters of brown pigmented yeast, pseudohyphae, and hyphae, further surrounded by low numbers of epithelioid macrophages and rare multinucleated giant cells. At the periphery of the granuloma, internal to a thick, 400µm wide band of dense, mature fibrous connective tissue, there are multiple foci of deeply basophilic mineral admixed with epithelioid macrophages, few foamy gitter cells, and low numbers of multinucleate giant cells that occasionally contain intracytoplasmic fungal hyphae. Yeasts are round to oval, 8‑10 µm in diameter, and occasionally form chains (pseudohyphae). Hyphae are septate, with parallel 4-6µm walls, with occasional bulbous dilatations up to 25µm in diameter. The fibrous capsule and surrounding neuroparenchyma are multifocally infiltrated by few lymphocytes, plasma cells, and neutrophils, which multifocally form perivascular cuffs around small vessels and minimally infiltrate the meninges. There is multifocal mild gliosis in the adjacent, spongiotic neuropil including few gemistocytes and rod-shaped microglia.
MORPHOLOGIC DIAGNOSIS: Cerebrum: Granuloma, focal, with extracellular and rare intrahistiocytic pigmented fungal yeast, pseudohyphae, and hyphae, African elephant (Loxodonta africana), proboscid.
ETIOLOGIC DIAGNOSIS: Cerebral phaeohyphomycosis (chromomycosis)
CAUSE: Presumed Cladosporium sp.
GENERAL DISCUSSION:
· Phaeohyphomycosis: Uncommon; infection with dematiaceous (pigmented) fungi
· Vs. hyalohyphomycosis (paecilomycosis): infection with non-pigmented, saprophytic fungi
· Dematiaceous fungi are widespread saprophytes and cause opportunistic infections; species include Alternaria, Bipolaris, Cladosporium, Curvularia, Exophila, Phialophora, Wangiella, Drechslera
· Cladophialophora is the most common cause of cerebral phaeohyphomycosis in dogs and cats (Grooters, Infectious Diseases of the Dog and Cat, 2012)
· Reported most commonly in horses, cattle, dogs, birds, and cats; German shepherd dogs may be predisposed
PATHOGENESIS:
· Two forms of phaeohyphomycosis are described:
· Cutaneous (usually subcuticular): Colonization of epidermis, hair follicles, and subcutis following traumatic implantation
· Systemic infection:
· Hypothesized as inhalationàpulmonary infectionàhematogenous spread; however, primary pulmonary infection not always identified
· Hematogenous spread to CNS from fungal otitis has been documented
· Cell mediated immunity is necessary to prevent infection; immunosuppression is common in affected animals
· The mechanism of neurotropism is unknown
· Melanin synthesis in cell walls thought to be main virulence factor, blocking effects of hydrolytic enzymes and scavenging free radicals released by phagocytes
TYPICAL CLINICAL FINDINGS:
· Variable or no CNS signs including proprioceptive deficits, nystagmus, lethargy, ataxia, paralysis, weakness, neck pain
TYPICAL GROSS FINDINGS:
· Focal or multifocal, variably discrete areas of malacia to well-defined microabscesses
· Pigmentation may be grossly visible
· Meninges may be thickened and opaque
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Discrete abscesses with thick fibrous encapsulation
· Hyphae are septate, 2-6um (often variable in width), with variably present branching, and are often individualized or in small aggregates scattered throughout lesion; pigmentation may not be apparent in tissue sections
· Necrosis may be extensive
· Vascular invasion with thrombosis possible
· Skin lesions contain variably discrete abscesses to less discrete pyogranulomatous dermatitis and panniculitis
ADDITIONAL DIAGNOSTIC TESTS:
· Special fungal stains (eg. GMS, Gridley's) are not normally necessary
· Fontana-Masson method will highlight the pigment of sparsely pigmented fungi (such as Alternaria spp.)
· Culture or molecular diagnostics is required for a specific fungal species diagnosis due to similar morphologic appearance between etiologic agents
DIFFERENTIAL DIAGNOSIS:
Cerebral mycoses:
· Other pigmented lesions:
· Chromoblastomycosis: Pigmented fungi, histologically lacks presence of hyphae; bulbous forms termed “sclerotic bodies”
· Melanocytic neoplasms
· Other fungal encephalidities:
· Chromoblastomycosis: Pigmented fungi, histologically lacks presence of hyphae; bulbous forms termed “sclerotic bodies
· Cryptococcus neoformans (N-F02)
· Common saprophyte; often systemic infection
· Grossly, gelatinous foci in the brain
· Large (up to 20 um); thick carminophilic capsule
· Blastomyces dermatitidis: Yeasts with broad-based budding
· Aspergillus sp., Mucor sp., Candida sp.: Hyphae are not pigmented
· Fungal skin lesions:
· Dog, case report: Cutaneous-lymphatic form of sporotrichosis
· Eumycotic mycetomas (eumycetoma): discrete organized (often) extracellular granules (fungi) with Splendore-Hoeppli reaction forming “tissue grains”
COMPARATIVE PATHOLOGY:
· Dogs: Often multiple lesions; ulceration, draining nodules, and/or plaques on paws and legs
· Cats: Lesions most often single, involving the nose or pinnae (face), and paws; ulceration, draining tracts
· Feline Phaeohyphomycotic cerebellitis caused by Cladosporium cladosporioides-complex; zonally extensive dark soft areas of the left cerebellar flocculus; Fontanna Masson positive staining hyphae; leptomeningeal pyogranulomatous exudate admixed with dark brown hyphae (J. Comp. Path 2019)
· Horses: Lesions often multifocal, though can be generalized
· Phaeohyphomycosis rhinitis and sinusitis caused by Alternaria sp., Cladophialophora sp. in 16 Florida horses (Vet Pathol 2018)
· Cattle: Multiple ulcerate cutaneous nodules; may involve nasal mucosa
· Chickens and turkeys: Epizootic encephalitis caused by Ochroconis gallopavum (a dematiaceous fungus)
· Zoo/exotic species
· Amphibians: Pigmented fungi, including Cladosporium, Philalophora, and Fonsecaea species, among others, cause chromoblastomycosis and phaeohyphomycosis, more often in captive amphibians
· Chelonia: Phaeohyphomycosis infections associated with granulomatous to ulcerative skin lesions on the feet and tail (box turtles), oral granuloma (radiated tortoise), deep ulcerative shell lesions (Aldabra tortoise), and unilateral ocular infection and systemic disease (Galapagos tortoise)
· Bony fish species (Osteichthyes): Phaeohyphomycosis lesions may be cutaneous, subcutaneous, or systemic
· Weedy and leafy seadragons: Disseminated phaeohyphomycosis (Exophiala angulospora, E. aquamarina) infection characterized by systemic necrotizing lesions, angioinvasion, and vascular necrosis, with/without cutaneous ulcers
· Atlantic salmon: Infection with E. pisciphila, with hyphal invasion of the cranial structures, semicircular canals and lateral line, with granulomatous inflammation
· Phomamycosis causes phaehypomycosis of hatchery-reared fish, especially salmonids in intensive aquaculture
· Sumatran Tiger: Curvularia sp. disseminated phaeohyphomycosis; large subcutaneous axillary mass, draining tracts containing numerous small black grains; affecting various lymph nodes, the nasal cavity, mesenteric adipose tissue, abdominal aorta, pericardium, and kidney (JVDI 2021)
References:
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2. Crespo R, et al. Galliformes and Columbiformes. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 765.
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