Siamese mix cat (Felis
catus).Two-week history of cluster
seizures. No other previous medical history.
Upon presentation, the patient was hypothermic
(96 F), with a pulse of 120. She was
exhibiting open-mouthed breathing with a
respiratory rate of 45. Due to the anticipated
duration of intensive care, euthanasia was
elected. A postmortem MRI was performed,
which revealed a focal lesion in the left
caudate nucleus. Differential diagnoses
included infectious causes, a vascular event,
Central Nervous System:
The distal aspect of the cerebellar vermis can be observed from the foramen magnum.
Upon removal of the brain, the vermis is
flattened over the brainstem (cerebellar
coning). The brain is fixed whole and
sectioned, which reveals diffuse, mild
expansion of the leptomeninges and
widening of sulci by yellow to brown,
gelatinous material and a focal, 0.5 cm
diameter, gelatinous mass at the left caudate
Pulmonary: The lungs are mottled tan to medium red. Multiple nodules are present, and the tracheobronchial lymph nodes are markedly enlarged. The right cranial lung lobe has a large, firm to soft, smooth, tan to white mass that measures 2.5 x 2.5 x 1 cm. Within the left cranial lung lobe, at the junction between the cranial and caudal subsets, there is a focal, firm, 2 x 2 x 1 cm nodule. Smaller nodules are present at the distal aspect of the left cranial lung lobe that measure up to 1 cm in diameter. A large nodule is present with the accessory lobe that measures 2.5 x 1.3 by 1 cm.
Hemolymphatic: The mediastinal and tracheobronchial lymph nodes are markedly enlarged. All are soft to firm and pale tan to white. The largest of the mediastinal lymph nodes measures 1.7 x 2 x 1 cm and the tracheobronchial lymph nodes measure up to 1.5 x 1.0 x 1.0 cm.
Internal: In the omentum adjacent to the pancreas, there is a soft, smooth, tan to white mass that measures 1.6 x 1.6 x 1.3 cm. The regional omentum is hyperemic and thickened.
A section of
the cerebral cortex at the level of the caudate
nucleus or thalamus is examined. Diffusely,
the leptomeninges are expanded by
coalescing sheets of yeasts, interspersed by
multifocal inflammatory populations. Sulcal
widening is prominent. Yeasts are round to
oval, approximately 5-10 um in diameter,
with a thin, 1 um wall and are surrounded by a large, 10-20 um diameter clear capsule.
Occasional narrow-based budding is
observed. Inflammatory populations
interspersed by the yeasts are comprised
predominantly of lymphocytes, plasma cells,
and macrophages. The yeasts multifocally
extend into the regional cerebral cortical
parenchyma which exhibits white matter
vacuolation and gliosis. In some of the
sections, there is a focal nodule comprised
of yeasts at the level of the caudate nucleus.
Multifocally, scattered lymphocytes and
plasma cells are present within and
surrounding the nodule, both within
Virchow-Robin spaces and less frequently,
the regional parenchyma with mild
accompanying gliosis. Occasional yeasts are
observed within the lateral ventricles or
Virchow Robin spaces in some slides.
Throughout the cerebral cortex, there are
increased numbers of branched, small
caliber arterioles (edema) with increased
numbers of glial cells, as well as mild
vacuolation and gliosis of the centrum
semiovale. Small numbers of vessels
throughout the sections contain perivascular aggregates of Gitter cells with intracytoplasmic
brown pigment (lipofuscin).
Neurons throughout the sample also contain
intracytoplasmic brown pigment
Special stains: Gomori methenamine silver (GMS) and mucicarmine reveal positive staining of yeasts and highlights narrow based budding. The capsule is light pink with the mucicarmine stain.
Brain: Meningoencephalitis, lymphoplasmacytic,
histiocytic, multifocal to
coalescing, severe with myriad encapsulated
yeasts (etiology consistent with Cryptococcus
spp), rare parenchymal in-filtration
with regional spongiosis and gliosis;
cerebral edema, diffuse, mild.
of lung nodules, lymph nodes, omental
nodule: Impression smears are similar and
consist of mixed inflammatory cell
populations including foamy macrophages,
lymphocytes, and plasma cells. Inflammatory
cells are intermixed with
numerous yeast organisms which are surrounded by a large, clear capsule, and
occasionally exhibit narrow based budding
cytologic and histologic findings are
consistent with disseminated Cryptococcus
spp. infection of the respiratory tract and
central nervous system (CNS). Cryptococcosis
is the most common systemic
mycosis of cats,3,5 infection of which is
thought to be acquired from the
environment.5 Infection is not contagious or
zoonotic, as is typical for the systemic
mycoses.3 Cryptococcosis in dogs and cats
is primarily caused by two encapsulated,
dimorphic, basidiomycetous fungi, Cryptococcus
neoformans and Cryptococcus
5,7 The yeast phase is found under
routine laboratory conditions and within
mammalian host tissues.5 Infection can
occur from inhalation of the basidiospore
stage or desiccated yeasts from the
environment.1 The infectious form can be
found in soil, pigeon or other avian guano,
and decaying organic matter.3,5 The initial
site of infection is hypothesized to be the
nasal cavity, lungs, and/or gastrointestinal
tract.4,7 The skin, lymph nodes, CNS, and
eyes are frequently affected.7 Additional testing for species identification was not
performed in this case.
Pathogenesis is dependent upon the amount of organism present upon exposure, virulence of the strain and immune status of the host. Cryptococcus has been called a sugar-coated killer with designer genes,5 due to its virulence factors.5 The four main virulence factors include the ability to grow at 37 degrees C, its polysaccharide capsule, melanin production and secretion of degradative enzymes.2,5 The polysaccharide capsule provides protection from the environment and host, 5 is comprised of negatively charged glucuronoxylomannan and enlarges after infection of the host.5 The capsule is chemotactic for neutrophils, however, inhibits phagocytosis via its negative charge and blocks the antibody Fc receptor from communicating with host phagocytes. It interferes with leukocyte migration, can deplete complement and inhibits T cell responses. Resolution of infection in immunocompetent animals requires a T-helper cell 1 (Th1) pattern of cytokine and lymphocyte-mediated adaptive immune response.2,4 Tumor necrosis factor, IL-12, IL-18, GM-CSF and IF-? among others play a role in host defense.2 Humoral factors are thought to aid in clearance via antibodies and complement.2 Melanin or a melanin-like compounds are produced from diphenolic compounds via the enzyme laccase (phenoloxidase)2,5 which help protect the organism from oxidative damage7 and may modulate the host immunoinflammatory response.3 Interestingly, rare Cryptococcus spp without a capsule can be easily phagocytized and incite a strong granulomatous response.3
Yeasts were more prominent than inflammation in the majority of the sample. Cryptococcus infection in cats has been shown to have relatively less inflammation than infections in dogs, which may reflect differences in infecting strains and/or underlying unrecognized defects in the immune or inflammatory response.6-8 The cat, in this case, had no significant previous medical history, however, FIV/FeLv status was unknown. In one Australian study, Siamese, Birman and Ragdoll cats were found to be predisposed to Cryptococcus infection.5 This cat was described as a Siamese mix.
After infection of the respiratory tract, fungal organisms are thought to spread hematogenously via macrophages, frequently to the CNS.5 Extension of nasal cavity infection across the cribriform plate, frontal sinus or along cranial nerves into the brain may also occur.5,7,8 Histologic evaluation of samples from the nasal cavity did not reveal any fungal organisms, and the frontal sinus was grossly normal. Ocular abnormalities can occur in up to one-third of affected cats,5 however, no histologic evidence of infection of the eye or optic nerves was present in this case. Neurologic signs vary depending upon the location of the lesions. Obtundation, behavioral changes, hyperesthesia, tremors, seizures, circling, head pressing, ataxia, paresis, head tilt, vestibular signs, and blindness are common clinical signs.5 The cat, in this case, exhibited obtundation and cluster seizures. Meningeal involvement is common, as in this case, and is considered a predilection site.6 Grossly, the leptomeninges may be unremarkable, or cloudy to thickened, with gelatinous mucoid material and sulcal widening.
Histologically, tightly packed yeasts give a soap bubble appearance.3,6The leukocytic response can consist of neutrophils, macrophages, multinucleate giant cells, lymphocytes, plasma cells and eosinophils, which is dependent upon host immune status.8 In humans, CNS involvement manifests as meningitis, meningoencephalitis, or Cryptococcomas, which are tumor-like intraparenchymal masses containing yeasts and inflammatory cells,7 similar to the focal nodule observed with imaging and evaluation of the gross specimen in this case. Gelatinous pseudocysts are cystic extensions of VirchowRobin spaces with collections of yeasts, and can also be detected with imaging modalities.7 One study of cats and dogs with CNS Cryptococcus infection identified three histopathologic patterns: 1) Pseudocyst formation with expansion of cryptococcal organisms along Virchow-Robin spaces with multifocal intraparenchymal pseudocysts, 2) Diffuse meningitis only without pseudocysts or parenchymal involvement and 3) meningoencephalitis without pseudocyst formation.7 These patterns were not found to correlate with the type of Cryptococcus sp. or treatment.7
Meningitis, lymphoplasmacytic and
histiocytic, diffuse, moderate, with
numerous narrow based budding and
encapsulated yeasts, etiology consistent with
Cerebrum, cat. There is marked expansion of the leptomeninges with numerous 3-6um budding yeasts with a prominent clear
capsule. In the 400X image at left, there low numbers of plasma cells at the periphery, attesting to the chronicity of the lesion.
(Photo courtesy of the Animal Medical Center, 510 East 62nd St. New York, NY 10065 www.amcny.org) (HE, 10X and 40X)
Cryptococcus sp., Siamese cat mix, Felis
provides an outstanding summary of the
epidemiology, pathogenesis, clinical signs,
gross and histologic patterns associated with
disseminated cryptococcosis in dogs and
cats. Cryptococcosis is a fungal disease with
worldwide distribution and is the most
common systemic mycotic disease in cats. Dogs, horses, cattle, and humans are also
affected by this dimorphic, basidiomycete,
yeast-like fungi.1,3,8,9 The diagnosis is
typically based on identifying the organism
and its characteristic thick capsule on
histologic sections or cytologic preparations.
Cryptococcus sp. is the only pathogenic
mycotic organism with a thick capsule making the histopathologic diagnosis
relatively straightforward; especially when
there is a myriad of organisms, as in this
2 The thick polysaccharide capsule
gives lesions a gelatinous appearance seen in
the gross photograph and noted by the
contributor. Distention of the leptomeninges
by the organism is commonly observed in
cats and occurs through a repetitive process
of macrophage phagocytosis, cell lysis, and
taxis of additional
accumulation of the
budding in their
The contributor noted that the distal aspect of the cerebellar vermis could be observed from the foramen magnum and upon removal of the brain, the vermis was flattened over the brainstem interpreted as cerebellar coning indicating cerebellar herniation. In humans, prognostic indicators for cryptococcosis include abnormal mental status, history of seizures, high antigen titers within serum and cerebral spinal fluid (CSF), poor host inflammatory response, and high CSF pressure.7 This animal likely had increased intracranial pressure secondary to infection leading to herniation of the cerebellum, altered mental state, and seizure activity. Increased intracranial pressure secondary to Cryptococcus sp. infection of the central nervous system is a negative prognostic indicator in humans and animals.3,7
Conference participants discussed different histochemical stains to highlight the thick capsule of this organism. The capsule can by highlighted by mucicarmine and in wet mounts, it stains with India ink. In addition to the periodic acid-Schiff and Grocott's methenamine silver stain run by the contributor, the yeasts also stain with Fontana-Masson stains due to their pro- duction of melanin via a virulence factor, laccase. A positive culture is required for definitive diagnosis.3 Participants also noted the relative lack of inflammation within the neuropil of this animal. As mentioned by the contributor, in contrast to other mycotic infections, such as Blastomyces sp, Coccidioides sp, and Histoplasma sp, the host inflammatory reaction is often quite minimal, likely due the polysaccharide capsular component glucuronoxylomannan, preventing yeast recognition by phagocytes, induction of IL-10, and disruption of dendritic cell activation and maturation.2,5
1. Burns RE and Mohr, CF. Pathology
in Practice. J Am Vet Med Assoc.
2. Carroll SF, Guillot L, Qureshi ST. Mammalian model hosts of cryptococcal infection. Comp Med. 2007; 57(1):9-17.
3. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier; 2016:582-583.
4. Lorente-Méndez C, Martínez CM, Corpa JM. Pathology in practice. J Am Vet Med Assoc. 2009; 235:1407- 1409.
5. Malik R, Krockenberger M, OBrien CR, Martin P, Wigney D, Medleau L. Cryptococcosis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis, MO: Elsevier Inc; 2006:584-598.
6. Summers BA: Inflammatory diseases of the central nervous system. In: Cummings JF, de Lahunta A, eds. Veterinary Neuropathology. St. Louis, MO: Mosby-Year Book, Inc.; 1995:151-155.
7. Sykes JE, Sturges BK, Cannon MS, et al. Clinical signs, imaging features, neuropathology, and outcome in cats and dogs with central nervous system crypto- coccosis from California. J Vet Intern Med. 2010; 24:14271438.
8. Zachary JF: Nervous system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Mosby, Inc.; 2012:891-893.
9. Uchiumi K, Stowe DM, DeVanna JC, Wilcox JL, Neel JA. Pathology in practice. Cryptococcus sp in a dog. J Am Vet Med Assoc. 2014; 245:893-895.