Signalment:  

7-year-old, male castrated, Russian Blue cat (Felis cats).The cat had a history of weight loss for approximately one year, and left tarsal arthrodesis surgery five months prior. Clinical workup at the time of surgery revealed sternal lymphadenopathy, thick-walled intestines, mild anemia, thrombocytopenia and neutropenia. FIV/FeLV tests were negative.

More recent clinical presentation was for an ulcerated lip mass which had been noted for eight weeks. The owners also described that the cat had been wandering around the house, stuck in small spaces, was incoordinated, stumbling and vocalizing, with a decreased appetite. On physical exam, there were multifocal neurologic signs including decreased menace bilaterally, positional nystagmus and inappropriate mentation. Additional findings included left retinal detachment, heart murmur and thickened intestines with palpation.

Gross Description:  

On the lower left lip, there is a 1.0 x 0.5 x 0.5 cm ulcerated, firm red nodule. The left tarsal joint is fused (tarsal arthrodesis). Internally, subcutaneous and visceral fat stores are markedly reduced, with mild yellow discoloration of the adipose tissue (icterus).

The vermis of the cerebellum is focally compressed and flattened against the underlying brainstem at the foramen magnum (herniation). The leptomeninges of the rostral and dorsal cerebrum are thickened by granular, irregular, yellow to tan material (meningitis). When the fixed brain is sectioned, there is marked leptomeningeal expansion by similar granular material, with adherence of the right and left hemispheres of the rostral cerebrum at the longitudinal cerebral fissure. 

Histopathologic Description:

One section of rostral cerebrum is examined. The leptomeninges, including those along the longitudinal cerebral fissure, are markedly expanded up to 3 mm by large populations of inflammatory cells which extend into the brain parenchyma. Inflammatory populations consist of macrophages, neutrophils, lymphocytes and plasma cells. Multinucleate cells and occasional Mott cells are present. Multifocally, macrophages and multinucleate cells contain one or numerous (up to 20) 2-4 μm diameter, round to oval intracytoplasmic yeast characterized by a central, 1-2 μm, eosinophilic nucleus which is surrounded by clear space. Inflammatory cells similar to those described above are observed within Virchow-Robin spaces and infiltrate the adjacent neural parenchyma. Macrophages commonly contain enlarged nuclei with marginated chromatin and eosinophilic material (presumed reactive change). Small vessels in the regions of infiltration exhibit endothelial hypertrophy and there is regional rarefaction of the neuropil (edema). Gliosis is abundant, consisting of astrogliosis and numerous gemistocytic astrocytes. Fewer microglial cells are present, which exhibit rod cell morphology. Round, eosinophilic structures (spheroids) are also dispersed throughout the infiltrated brain parenchyma. 

Histoplasma immunohistochemistry (provided by the University of Connecticut Veterinary Medical Diagnostic Laboratory): Brain: Multifocally throughout the meninges, within macrophages, there are numerous positive staining, intracellular, spherical, 3-4 μm diameter organisms (Histoplasma capsulatum).

Similar, positive staining organisms are identified in the previous bone biopsy, lungs, adrenal glands and eye.

Morphologic Diagnosis:  

Brain (rostral cerebrum): Severe, chronic, pyogranulomatous, lymphoplasmacytic meningoencephalitis with intralesional, intracytoplasmic fungal yeast (consistent with Histoplasma capsulatum), regional edema, spheroids and gliosis with gemistocytic astrocytosis.

Lab Results:  

Normocytic, normochromic, nonregenerative anemia, mildly elevated ALT and AST, mild hypoalbuminemia and hyperglobulinemia.

Cytology: Aspirate of mass from the right lower lip region: All slides are examined and are found to be similar; the specimen is of moderate cellularity and contains moderate numbers of red blood cells with low to moderate numbers of nondegenerate neutrophils and activated macrophages. Rare tissue cells are identified and these are uniform fibrocytes showing no evidence of dysplasia or atypia. On several of the slides there are extremely low numbers of intracellular yeast structures; these are 1-3 microns in diameter, round to oval with a variably thick capsule and are primarily found within the cytoplasm of very few of the macrophages. The yeast organisms most resemble Histoplasma sp. 

Microscopic interpretation: Mild to moderate mixed (neutrophilic and histiocytic) inflammatory infiltrate associated with intracellular yeast organisms. 

Comment: Although the numbers of yeast structures are quite low, they provide unequivocal evidence of a primary fungal etiology and are most characteristic of Histoplasma capsulatum.

Condition:  

Histoplasma capsulatum

Contributor Comment:  

Histoplasma capsulatum is a dimorphic, soil-borne fungus, existing in the environment as a mycelial form, and in the host as a yeast.(2,3) Infections with this fungus are prevalent in the Midwest and southern United States, and regions along the Ohio, Missouri and Mississippi Rivers.(2,7,9) The organism grows best in soil containing nitrogen-rich organic matter, including bird and bat excrement.(3) Infection typically develops via inhalation or ingestion, and most animals clear the infection without developing clinical signs of disease.(1,2,6) In dogs and cats, macrophages phagocytize the organisms and can distribute them to other organ systems. Clinical signs are typically nonspecific and include weight loss, lymphadenopathy, lethargy, fever, and respiratory signs as well as cutaneous nodules, ocular disease, diarrhea, and lameness.(1-3,6) Histoplasmosis is the second most common fungal disease reported in cats after cryptococcosis.(1,3)

A retrospective study of 22 cases of feline histoplasmosis found that amongst three categories (disseminated, pulmonary and gastrointestinal), disseminated was the most common manifestation, occurring in 68% of cases. The most frequent sites of infection were listed as the lungs, lymph nodes, liver, spleen, kidney, adrenal glands, eyes, bone marrow and the gastrointestinal tract.(1) Disseminated infection with involvement of the brain is rarely reported in cats and dogs.(4,7,9) In this case, the brain was the most severely affected organ, and the cat re-presented for its neurologic signs. Immunohistochemistry for Histoplasma was performed at the University of Connecticut Veterinary Medical Diagnostic Laboratory. The combination of H&E, silver stains and IHC confirmed Histoplasma organisms in the brain, eye, lungs, adrenal glands, bone marrow at site of previous surgery (taken at the time of surgery) and the ulcerated lip lesion. Demonstrable organisms in the ulcerated lip lesion correlated with the cytologic results. In one report, a review of cases from the authors institution revealed that several cats with oral histoplasmosis presented with focal or multifocal exophytic or ulcerative lesions within the oral cavity, with no apparent systemic involvement.(6) Osseous lesions with associated soft tissue swelling or joint effusion and lameness have been described with feline histoplasmosis.(3) Histoplasma organisms were immunohistochemically identified in the bone marrow biopsy obtained 5 months before euthanasia, indicating a long time frame of infection. Although the intestines were palpably thickened, neither granulomatous enteritis nor intralesional organisms were identified at postmortem examination; however, the intestines displayed mucosal fibrosis, which may indicate previous infection. 

The cat in this case had a history of being indoor-only for 3 years, and prior to this had intermittent access to the outdoors in rural Pennsylvania. Other reports of histoplasmosis in indoor only cats without travel to endemic regions suggest that household dust or potting soil are possible sources of infection.(3) Some studies found a high prevalence of FeLV in cats with the disseminated form of histoplasmosis, whereas others found a low prevalence.(1,4) In our case, the cat was negative for both FIV and FeLV. Typical clinicopathologic changes in cats with disseminated histoplasmosis include normochromic, normocytic, nonregenerative anemia, hypoalbuminemia, and thrombocytopenia, with variable leukocyte counts.(3,4) Nonregenerative anemia is suspected to result from chronic inflammatory disease, Histoplasma infection of the bone marrow, and intestinal blood loss in gastrointestinal disease. Some cats have been reported to have hyperproteinemia, hyperglobulinemia, mild hyperglycemia or hyperbilirubinemia, and elevations of alanine aminotransferase activities. Hypercalcemia has been reported in several cats and is likely due to granulomatous disease.(3) In our case, mild elevations of ALT and AST may be explained by concurrent chronic cholangiohepatitis.

JPC Diagnosis:  

Cerebrum: Meningoencephalitis, pyogranulomatous, multifocal, moderate with intrahistiocytic yeast.

Conference Comment:  

The contributor provided a very good summary of histoplasmosis caused by Histoplasma capsulatum var. capsulatum in dogs and cats. Conference participants reviewed two other variants of H. capsulatum: H. capsulatum var. farciminosum (also referred to as H. farciminosum) and H. capsulatum var. duboisii. H. farciminosum causes equine epizootic lymphangitis in horses and mules, characterized by ulcerated discharging cutaneous nodules located along thickened lymphatic vessels, and regional lymphadenopathy, resembling farcy. H. capsulatum var. duboisii causes African histoplasmosis in humans and nonhuman primates.(5,8)

References:

1. Aulakh HK, Aulakh KS, Troy GC. Feline histoplasmosis: a retrospective study of 22 cases (1986-2009). J Am Anim Hosp Assoc. 2012;48(3):182-187.
2. Br+�-�mel C, Greene CE: Histoplasmosis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. St Louis, MO: Elsevier Saunders; 2012:614-621.
3. Br+�-�mel C, Sykes JE. Histoplasmosis in dogs and cats. Clin Tech Small Anim Pract. 2005;20(4):227-32. Review.
4. Clinkenbeard KD, Cowell RL, Tyler RD. Disseminated histoplasmosis in cats: 12 cases (1981-1986). J Am Vet Med Assoc. 1987;190(11):1445-1448.
5. Gades NM, Marler RJ. Pathology in practice. J Am Vet Med Assoc. 2009;234(12):1535-1537.
6. Lamm CG, Rizzi TE, Campbell GA, Brunker JD. Pathology in practice. Histoplasma capsulatum infections. J Am Vet Med Assoc. 2009;235(2):155-7.
7. Lavely J, Lipsitz D. Fungal infections in the central nervous system in the dog and cat. Clin Tech Sm Anim Prac. 2005;20:212-219.
8. Quinn PJ, Markey BK, Leonard FC, FitzPatrick ES, Fanning S, Hartigan PJ. Dimorphic fungi. In: Veterinary Microbiology and Microbial Disease.  2nd ed. Ames, Iowa: Blackwell Science Ltd; 2011: Kindle edition. 
9. Schaer M, Johnson KE, Nicholson AC. Central nervous system disease due to histoplasmosis in a dog: a case report. J Am Anim Hosp Assoc. 1983;19:311-315.

Click the slide to view.

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2-1. Cerebral cortex, telencephalon

2-2. Cerebral cortex, telencephalon

2-3. Cerebral cortex, telencephalon

2-4. Cerebral cortex, telencephalon

2-5. Cerebral cortex, telencephalon

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