January 2017



Signalment (JPC #1602214):  Age and breed unspecified dog


HISTORY:  Two-year history of progressive ataxia and posterior paresis


HISTOPATHOLOGIC DESCRIPTION (Slide A):  Cerebral cortex and diencephalon:  Multifocally infiltrating and effacing normal gray and white matter architecture and often elevating the overlying ependyma and infiltrating the ventricle are multiple, random, up to 3mm diameter, well-demarcated, nodular aggregates of numerous macrophages, lymphocytes, plasma cells and fewer neutrophils.  Macrophages occasionally contain one to ten, 2‑4um diameter, round to oval intracytoplasmic yeast with a central 1um basophilic nucleus surrounded by a clear zone.   Nodular areas contain scant remaining gliovascular strands and neurons that are often shrunken, hypereosinophilic and angular (neuronal necrosis).  Small blood vessels are often lined by hypertrophied endothelium (reactive).  Within the adjacent neuropil there is scattered spongiosis, occasional dilated myelin sheaths with swollen axons (spheroids) and mild gliosis.  Multifocally, Virchow-Robin space is expanded by cuffs of low to moderate numbers of lymphocytes and fewer plasma (perivascular cuffing). 


Slide B:  Cerebral cortex and diencephalon (GMS):  There are numerous intrahistiocytic yeast with argyrophilic walls.  


MORPHOLOGIC DIAGNOSIS:  Cerebral cortex and diencephalon:  Encephalitis, granulomatous, multifocal, moderate, with intrahistiocytic yeast, breed unspecified, canine.


ETIOLOGIC DIAGNOSIS:  Cerebral histoplasmosis


CAUSEHistoplasma capsulatum var. capsulatum


CONDITION:  Histoplasmosis



·     Common, soil-born, facultative intracellular, dimorphic fungus that infects macrophages and is a cause of granulomatous pneumonia and systemic disease affecting many organ systems in many domestic and wild animal species and humans; CNS involvement is rare

·     Worldwide occurrence but predominately found in the United States along the St. Lawrence, Ohio, and Mississippi River valleys

·     Dogs and cats are most susceptible to infection; second most common fungal disease in cats in North America

·     Persian cats, weimaraners, pointers, terriers, Brittany spaniels, sporting and working dogs predisposed

·     Thrives in moist, high nitrogen-rich organic matter such as bird and bat excrement



·     Dimorphic fungus with free-living, mycelial stages (macroconidia that are 5-18 um diameter) and infectious microconidia (2-3um diameter) as well as yeast stage

·     Infection is not contagious and is transmitted by inhalation of airborne conidia and rarely by ingestion or skin contact with infective spores

·     Inhalation or ingestion of microconidia > phagocytosis by neutrophils or macrophages > converted to yeast forms > yeast synthesizes proteins that inhibit acidification of phagolysosome > dissemination via lymphatic and hematogenous routes to target organs

·     May become dormant, persist for years in immunocompetent hosts

·     Infection normally limited to respiratory system and local lymph nodes but dissemination may occur quickly in the immunocompromised or those with a high dose exposure

·     When histoplasmosis becomes clinically apparent, the infection is disseminated and rapidly progressive and fatal

·     Target organs contain high numbers of reticular cells (macrophages) and include lungs, lymph nodes, spleen, liver, bone marrow, gastrointestinal tract, adrenal glands and mucous membranes of the oral cavity



·     Dogs: Often targets GI tract therefore will have emaciation, persistent large-bowel diarrhea, voluminous watery diarrhea with protein losing enteropathy, tenesmus, fresh blood in stool, splenomegaly, lymphadenopathy, hepatomegaly with icterus

·     Cats: Non-specific signs: weight loss, mental depressions, anorexia, dyspnea, tachypnea, pale mucous membranes, along with splenomegaly, lymphadenopathy, hepatomegaly with icterus splenomegaly, lymphadenopathy, hepatomegaly with icterus 

·     Clin Path: Normocytic, normochromic, nonregenerative anemia; leukopenia with left shift, toxic changes, and Döhle bodies; lymphopenia with eosinopenia

·     Cytology: Organisms readily recognizable in macrophages on FNA of liver, spleen, lymph nodes, marrow, or skin



·     CNS: Moderately well-demarcared, expansile yellow-brown foci that displace normal tissue

·     Lungs: Grey, round nodules up to 2cm

·     Intestine: Chiefly in lower small intestine, nodular thickening of mucosa or corrugations similar to Johne’s disease from lymphocytes, plasma cells, and macrophages

·     Lymph nodes: Enlarged with grey nodular lesions effacing architecture

·     Spleen and liver: Enlarged, grey, and firm



·     Enlargement of tissues is due to proliferation and infiltration by monocytes and epithelioid macrophages often forming granulomas

·     Yeast:  Intrahistiocytic 2-4um diameter, oval to round, with a central 1-2um basophilic center surrounded by a 2um clear halo; narrow-based budding



·     Cytology:  Rectal scrapings, organ/lymph node fine needle aspirates, pleural and peritoneal fluids, bone marrow and CSF

·     IHC, PAS, GMS and Giemsa:  Stains as an empty red (PAS), black (GMS) or pale light blue ring (Giemsa)

·     Fungal culture:  Zoonotic potential for lab workers from inhalation of microconidia




·     Histoplasmacapsulatumvar. duboisii (African histoplasmosis):  Only reported in baboons and humans, larger (8-15um), narrow base budding

·     Blastomyces dermatitidis:  Larger (7-15 um), multinucleated, thick “doubly contoured” walls, broad-based budding

·     Cryptococcus neoformans: Variably-sized yeast (2-20 um), uninucleate, pleomorphic shape, single narrow based budding, thin mucicarmine-positive capsule, rare hyphae

·     Candida (Torulopsis) glabrata: Slightly larger (2-5 um), variably sized, oval to elongate, broad-based budding, amphophilic, stain entirely with H&E, no “halo” or pseudocapsule

·     Leishmania sp. (amastigotes within macrophages): 2-4um, kinetoplasts perpendicular to nuclei

·     Toxoplasma gondii: 2-6um crescentic bradyzoites, stain entirely with H&E, no “halo”, develops pseudocysts, usually found in somatic cells instead of phagocytic cells

·     Neospora caninum: Similar to Toxoplasma gondii, in CNS often within tissue cysts

·     Pneumocystis carinii (intra-alveolar cyst form): 4-6um, primarily extracellular, lack budding, GMS-positive

·     Sporothrix schenckii: 2-6 um, pleomorphic, mainly single narrow based budding, thin cell wall, rare hyphae, uninucleate, few yeast found in macrophages



·     Horses: Histoplasma farcinosum (epizootic lymphangitis of horses): Causes a chronic suppurative lymphadenitis of solipeds

·     Baboons:Histoplasma capsulatum var. duboisii; only reported in baboons and humans



1.  Greene CE, Broemel C. Histoplasmosis. In: Stringer S, ed. Infectious Diseases of the Dog and Cat, 4th ed. St. Louis, MO: Elsevier; 2012:614-621.

2.  Jensen ED, Lipscomb T, Van Bonn B, et al. Disseminated histoplasmosis in an Atlantic bottlenose dolphin (Tursiops truncatus). J Zoo & Wildl Med. 1998;29:456-460.

3.  Miller AD, Zachary JF. Nervous system. In: Zachary JF ed. Pathologic Basis of Veterinary Disease. St. Louis, MO: Elsevier; 2017:841.

4.  Morita T, Kishimoto M, Shimada A, et al. Disseminated histoplasmosis in a sea otter (Enhydra lutris). J Comp Path. 2001;125:219-223.

5.  Valli VEO, Kiupel M, Bienzle D.  Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:186-187.

6.  Zachary JF. Mechanisms of microbial infections. In: Zachary JF ed. Pathologic Basis of Veterinary Disease. St. Louis, MO: Elsevier; 2017:233.

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