Pathology in Practice

Julie Piccione Texas A&M Veterinary Medical Diagnostic Laboratory, Texas A & M University, College Station, TX 77840.

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 DVM, MS
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Scott D. Reed Texas A&M Veterinary Medical Diagnostic Laboratory, 6610 W Amarillo Blvd, Amarillo, TX 79106.

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 DVM, PhD

History

An 8-year-old 5.3-kg (11.7-lb) neutered male domestic shorthair cat was evaluated because of inappetence and signs of neurologic disease. The cat was an indoor-outdoor barn cat from New Mexico that did not roam; its vaccination status was current. Signs of neurologic disease, including staring, ataxia, and 1 possible seizure, had been present for approximately 3 weeks. The clinical signs appeared to improve with corticosteroid administration but no improvement was evident following antimicrobial treatment.

Clinical, Clinicopathologic, and Cytologic Findings

On initial physical evaluation, the cat was severely ataxic with evidence of ptyalism and no menace response bilaterally. Results of an in-house ELISA for FeLV antigen and anti–FIV antibodies performed on a whole blood sample were negative. No overt abnormalities were detected by means of abdominal or thoracic radiography. An in-house CBC revealed only minimal anemia. Serum biochemical analysis revealed mild hyperglobulinemia and mildly low BUN concentration. The result of an immunofluorescent assay for feline coronavirus was negative (serum titer, < 1:400).

Treatment of the cat with broad-spectrum antimicrobials and a corticosteroid improved the cat's condition considerably. After approximately 2 weeks, the neurologic signs recurred and worsened. On physical examination, enlarged mandibular and popliteal lymph nodes were noted. Repeated hematologic analysis revealed moderate neutrophilia. Serum biochemical analysis revealed low BUN concentration and moderate hyperglycemia. Serum antibodies against systemic fungi (Coccidioides spp, Blastomyces spp, and Histoplasma spp) were not detected by agar gel immunodiffusion immunoglobulin tests. Fine-needle aspiration of an enlarged popliteal lymph node was performed (Figure 1).

Figure 1—
Figure 1—

Photomicrographs of a fine-needle aspirate specimen from an enlarged popliteal lymph node in a cat that was evaluated because of inappetence and signs of neurologic disease. Signs of neurologic disease, including staring, ataxia, and 1 possible seizure, had been present for approximately 3 weeks. Notice the large numbers of inflammatory cells. Small organisms are often arranged in packets (A [arrow]) and rarely phagocytized by inflammatory cells (B [arrow]). Aqueous Romanowsky stain; bar = 15 μm.

Citation: Journal of the American Veterinary Medical Association 252, 12; 10.2460/javma.252.12.1481

The smears from the popliteal lymph node were highly cellular and mildly hemodiluted in a densely proteinaceous background with occasional pyknotic cells. Throughout the background of the smears, there were many round to oval (2- × 3- to 4-μm) organisms that had a thin, nonstaining capsule, and a pale purple internal structure with a metachromatic nucleus. Aggregates of these organisms were often found in non-staining circular arrangements (Figure 1). Nucleated cells were predominantly composed of nondegenerate to degenerate neutrophils with fewer, but large numbers of macrophages (including epithelioid and multinucleated giant cells), lymphocytes, and presumed reactive fibroblasts. Macrophages and neutrophils contained phagocytized organisms, similar to those seen in the background of the smears. No overt neoplastic cells were observed.

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Clinicopathologic and Histopathologic Findings

The cytologic findings were suggestive of a protozoal infection; however, some consideration was given to fungal disease. No serum anti-Toxoplasma IgG and IgM were detected with specific immunofluorescent assays. Owing to the cat's worsening clinical signs and overall poor prognosis, euthanasia by means of IV administration of euthanasia solution was elected. An in-clinic necropsy revealed no overt abnormalities. Samples of a mandibular lymph node, spleen, liver, kidneys, lungs, and the head (cerebrum, cerebellum, thalamus, and brainstem) were submitted for histologic examination. On dissection of the head, 1 nodule on the medial aspect of the right olfactory bulb was identified. The nodule was raised, approximately 8 mm in diameter, yellow-white, and continuous with the meninges; it had caused a corresponding indentation on the medial aspect of the left olfactory bulb.

Histologic examination of sections of the cerebrum and lymph node revealed abnormalities. Greater than 80% of the mandibular lymph node was effaced and expanded by pyogranulomatous inflammation characterized by large numbers of epithelioid macrophages with viable and degenerate neutrophils and lesser numbers of lymphocytes and plasma cells. Rare foreign body-type multinucleated giant cells were also present along with moderate neovascularization and fibroplasia. Multifocally within areas of pyogranulomatous inflammation were 30- to 150-μm-diameter spherules with a 1- to 2-μm-thick eosinophilic to basophilic double-contoured wall surrounding large numbers of 2- to 4-μm diameter endospores (Figure 2). Occasional free endospores and intracytoplasmic endospores in macrophages were also seen.

Figure 2—
Figure 2—

Photomicrographs of a section of a nodular mass on the medial aspect of the right olfactory bulb in the cat in Figure 1. Classic Coccidioides spherules (A) and macrophages with phagocytized Coccidioides endospores (B) are visible. Similar findings were observed in sections of a mandibular lymph node (image not shown). H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 252, 12; 10.2460/javma.252.12.1481

The nodule of the right olfactory bulb of the frontal lobe of the cerebrum was composed of large numbers of viable and degenerate neutrophils with macrophages and gitter cells that had effaced and expanded the brain parenchyma. Within the dense infiltrate of inflammatory cells were frequent spherules similar to those detected in the lymph node.

Some of the serum sample collected for anti-Toxoplasma antibody titers was used to test for Coccidioides-specific antibodies by complement fixation after the histologic examinations. This test result was also negative.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: severe subacute focal pyogranulomatous encephalitis and severe chronic focally extensive pyogranulomatous lymphadenitis with intralesional spherules consistent with Coccidioides spp.

Case summary: coccidioidomycosis in a cat.

Comments

Coccidioidomycosis is caused by the soil-dwelling dimorphic fungus Coccidioides immitis or Coccidioides posadasii. Many species, including cats, have been affected by this systemic fungal disease.1 Infections occur more commonly by inhalation of Coccidioides arthrospores, and rarely by inoculation of the skin.2 Coccidioides organisms are considered endemic in the southwestern United States.1 In otherwise dry seasons, infection rates are increased by heavy rainfall that increases the dispersion of arthrospores.1

Once Coccidioides arthrospores are introduced into the body, classic spherules develop. In environments with phagocytic leukocytes and high carbon dioxide concentration, arthrospores develop into spherules that have internal endospores.1 Endospores replicate until the spherules rupture, thereby releasing endospores into the extracellular matrix. These endospores can then form more spherules.1

Coccidioidomycosis has been considered uncommon in cats.3 There are several reports that characterize the disease in low to moderate numbers of cats.3–5 Infections with Coccidioides spp in cats are predominantly characterized by skin lesions, with fewer cases of ocular and neurologic diseases.3–5 Currently, there appears to be no correlation between retrovirus status and Coccidioides infections in cats.3

Clinical signs in domestic animals with coccidioidomycosis can vary dramatically. Infected cats most commonly develop dermatologic disease; however, respiratory, musculoskeletal, ocular, and neurologic signs have also been reported.3 Ocular manifestations of coccidioidomycosis in cats include periocular swelling, anterior uveitis, and blindness.4 In cats with CNS infections, granulomas can mimic the appearance of neoplastic lesions on MRI images.5

Definitive diagnosis of coccidioidomycosis is often based on the microscopic visualization of spherules in cytologic and histologic preparations. Positive results of serologic tests can be helpful in cases with clinical signs and findings consistent with Coccidioides infection. With regard to serologic testing, it has been reported that the sensitivity of agar gel immunodiffusion immunoglobulin testing for detection of anti-Coccidioides antibodies can be less than that of Coccidioides-specific ELISA.1 Fungal culture of Coccidioides spp from appropriate specimens can be a helpful diagnostic tool; however, given the risk of infection among personnel, not all laboratories are equipped to perform this testing.

Definitive treatment protocols are lacking for cats with coccidioidomycosis. Treatment often depends on anatomic location and severity of the infection, and on owners' financial constraints. Common drug options include amphotericin B and azoles.1 Thorough follow-up care is indicated including repeated CBCs, serum biochemical analyses, physical examinations, and potentially Coccidioides-specific serologic or antigen testing. Prognosis for affected cats is highly variable, but lifelong treatment and infection relapses are common.

In the case described in the present report, a rare and underreported morphological variation of Coccidioides spp was identified in the cytologic preparations. Typically, the microscopic diagnosis of coccidioidomycosis is almost exclusively based on the identification of large spherules in tissue and cytologic samples. To the authors' knowledge, there is only 1 case report of coccidioidomycosis in which endospores were predominant in cytologic preparations.6 For the cat of the present report, the original cytologic preparation was reviewed by several veterinary clinical pathologists, and protozoal disease was considered a primary concern with less consideration given to fungal disease. Typical Coccidioides spherules were not observed in the smears of the popliteal lymph node fine-needle aspirate specimen. The immunofluorescent assay for anti-Toxoplasma IgG and IgM yielded negative results; in addition, the result of serologic testing for Coccidioides-specific antibodies by complement fixation performed after the histologic examinations was also negative.

Coccidioidomycosis should be considered a differential diagnosis in cats with neurologic disease that reside or have traveled to areas endemic for Coccidioides spp. Serologic testing may provide support for diagnosis, but such tests can have poor sensitivity for detection of active infections, especially early infections. Although fungal infections in general can be diagnostic challenges, knowledge of the morphological variation of Coccidioides spp in infected animals is imperative for rapid, accurate diagnosis.

Acknowledgments

The authors thank Dr. Olin Dawkins for clinical assistance.

References

  • 1. Graupmann-Kuzma A, Valentine BA, Shubitz LF, et al. Coccidioidomycosis in dogs and cats: a review. J Am Anim Hosp Assoc 2008;44:226235.

  • 2. Kirkland TN, Fierer J. Coccidioidomycosis: a reemerging infectious disease. Emerg Infect Dis 1996;2:192199.

  • 3. Greene RT, Troy GC. Coccidioidomycosis in 48 cats: a retrospective study (1984–1993). J Vet Intern Med 1995;9:8691.

  • 4. Tofflemire K, Betbeze C. Three cases of feline ocular coccidioidomycosis: presentation, clinical features, diagnosis, and treatment. Vet Ophthalmol 2010;13:166172.

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  • 5. Bentley RT, Heng HG, Thompson C, et al. Magnetic resonance imaging features and outcome for solitary central nervous system coccidioides granulomas in 11 dogs and cats. Vet Radiol Ultrasound 2015;56:520530.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Beaudin S, Rich LJ, Meinkoth JH, et al. Draining skin lesion from a desert poodle. Vet Clin Pathol 2005;34:6568.

  • Figure 1—

    Photomicrographs of a fine-needle aspirate specimen from an enlarged popliteal lymph node in a cat that was evaluated because of inappetence and signs of neurologic disease. Signs of neurologic disease, including staring, ataxia, and 1 possible seizure, had been present for approximately 3 weeks. Notice the large numbers of inflammatory cells. Small organisms are often arranged in packets (A [arrow]) and rarely phagocytized by inflammatory cells (B [arrow]). Aqueous Romanowsky stain; bar = 15 μm.

  • Figure 2—

    Photomicrographs of a section of a nodular mass on the medial aspect of the right olfactory bulb in the cat in Figure 1. Classic Coccidioides spherules (A) and macrophages with phagocytized Coccidioides endospores (B) are visible. Similar findings were observed in sections of a mandibular lymph node (image not shown). H&E stain; bar = 100 μm.

  • 1. Graupmann-Kuzma A, Valentine BA, Shubitz LF, et al. Coccidioidomycosis in dogs and cats: a review. J Am Anim Hosp Assoc 2008;44:226235.

  • 2. Kirkland TN, Fierer J. Coccidioidomycosis: a reemerging infectious disease. Emerg Infect Dis 1996;2:192199.

  • 3. Greene RT, Troy GC. Coccidioidomycosis in 48 cats: a retrospective study (1984–1993). J Vet Intern Med 1995;9:8691.

  • 4. Tofflemire K, Betbeze C. Three cases of feline ocular coccidioidomycosis: presentation, clinical features, diagnosis, and treatment. Vet Ophthalmol 2010;13:166172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Bentley RT, Heng HG, Thompson C, et al. Magnetic resonance imaging features and outcome for solitary central nervous system coccidioides granulomas in 11 dogs and cats. Vet Radiol Ultrasound 2015;56:520530.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Beaudin S, Rich LJ, Meinkoth JH, et al. Draining skin lesion from a desert poodle. Vet Clin Pathol 2005;34:6568.

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