September 2024

D-F05 (NP)

SIGNALMENT (JPC Accession #3165184): A 4-year-old male owl monkey (Aotus sp.)

HISTORY: This monkey had experienced weight loss and anemia of an undetermined cause over the last six months. Treatments for the latter had been unsuccessful. Recently, the animal was treated with an antibiotic for suspected sepsis. Subsequently, the monkey developed white plaques on the tongue and was euthanized.

HISTOPATHOLOGIC DESCRIPTION: Esophagus: There is diffuse marked hyperplasia of the mucosal epithelium characterized by deep rete ridge formation and acanthosis, and there is increased intercellular clear space with prominent intercellular bridging (spongiosis) and intracellular edema (hydropic degeneration). There are frequent areas of erosion and rare ulceration with replacement by viable and necrotic neutrophils, macrophages, sloughed nucleated squamous epithelial cells, necrotic debris, and numerous fungi of varying morphologies. There are also frequent intramucosal pustules filled with similar inflammatory cells. Fungi morphologies include oval to round, 3-6 µm diameter, pale-staining, thin-walled yeast arranged either in short chains (pseudohyphae), individual yeast, and slender, 3-4 µm wide, septate, parallel-walled, non-branching hyphae. The lamina propria and submucosa are expanded by neutrophils, macrophages, and fewer lymphocytes and plasma cells. Within the muscularis mucosa, these inflammatory cells which surround, and separate smooth muscle myocyte that are variably disorganized, degenerate (vacuolated sarcoplasm with vesiculate nuclei), and necrotic (shrunken, angular, hypereosinophilic sarcoplasm with pyknotic nuclei). There is mildly increased clear space and ectatic lymphatic vessels (edema) within the lamina propria and submucosa.

Tongue: There is diffuse marked hyperplasia of the mucosal epithelium characterized by deep rete ridge formation and acanthosis, and there is increased intercellular clear space with prominent intercellular bridging (spongiosis), and intracellular edema (hydropic degeneration). The superficial mucosa contains pockets of viable and degenerate neutrophils admixed with eosinophilic and karyorrhectic cellular debris (intramucosal pustules). The overlying mucosa is eroded and replaced by viable and necrotic neutrophils, sloughed nucleated keratinocytes, necrotic debris, and numerous oval to round, 3-6 µm diameter, pale-staining, thin-walled yeast arranged in short chains (pseudohyphae), as individual yeast, and as slender, 3-4 µm wide, septate, parallel-walled, non-branching hyphae. Adjacent epithelial cells are degenerate (swollen epithelial cells with vacuolated cytoplasm and vesiculate nucleus) or necrotic (shrunken epithelial cells with hypereosinophilic cytoplasm and pyknotic nucleus). Rarely, there is transmigration of neutrophils across the mucosa. Within the superficial submucosa there are numerous lymphocytes and plasma cells with fewer neutrophils admixed with increased clear space and ectatic lymphatic vessels (edema).

MORPHOLOGIC DIAGNOSIS: Esophagus and tongue: Esophagitis and glossitis, erosive, neutrophilic, multifocal to coalescing, moderate, with mucosal hyperplasia and numerous fungal yeast, pseudohyphae, and hyphae, Owl monkey, non-human primate.

ETIOLOGIC DIAGNOSIS: Oral Candidiasis

CAUSE: Candida alibicans

CONDITION: “Thrush”

GENERAL DISCUSSION:

Candida spp. are ubiquitous, dimorphic, saprophytic fungi that normally inhabit the alimentary, upper respiratory, and genital mucosa of mammals and poultry
Two main forms: Commensal, non-pathogenic yeast, and pathogenic filamentous hyphae and pseudohyphae; Candida spp. will undergo phenotypic switching to become pathogenic and invasive.
Most common species associated with candidiasis are C. albicans and C. tropicalis; other species include C. glabrata, C. krusei, and C. parasillosis
Candidiasis is mainly a disease of keratinized epithelium in young animals, especially pigs, calves, foals, and poultry
In marine mammals, the disease is speculated to be associated with prolonged antibiotic use, immunosuppression, concurrent disease, and environmental stress/contamination

PATHOGENESIS:

Superficial (localized) candidiasis produces relatively mild lesions in skin and mucous membranes

Non-human primates: lesions of the tongue, oral cavity (“thrush” or “moniliasis”), esophagus, and intestine are most common

Systemic (disseminated) candidiasis may involve any organ, but most commonly affect the kidneys, heart valves, CNS, and lungs
All of the following can increase the risk of both localized and systemic candidiasis: immunosuppression, cytotoxic chemotherapy causing neutropenia, diabetes mellitus, long-term glucocorticoid therapy, prolonged use of broad-spectrum antibiotics (alters normal protective flora), or disruption of mucosal barriers (trauma, surgery, indwelling catheters, neoplasia)
Candida spp. produce a large number of functionally distinct adhesins that are important determinants of virulence; Candida yeast mainly bind mannose receptors, while Candida hyphae primarily bind complement receptor 3 (CR3) and the Fc-gamma receptor
Adherence and persistence of many Candida species is facilitated by biofilm formation; biofilm formation also increases adherent Candida resistance to antifungal drugs
Candida produce enzymes including aspartyl proteinases (degrades extracellular matrix proteins) and catalases (resists oxidative killing by phagocytic cells) as well as adenosine (blocks neutrophil oxygen radical production and degranulation)
Cell-mediated immunity appears to be an important limitation to the pathologic spread of Candida spp.
Accumulation of keratin in the upper digestive tract due to anorexia may also contribute to the extensiveness of lesions in all species by increasing the substrate available to the fungus

TYPICAL CLINICAL FINDINGS:

Often nonspecific; related to the organ system(s) most severely affected

TYPICAL GROSS FINDINGS:

Cutaneous/mucous membrane form (i.e. oral cavity, esophagus): White pseudomembranes that are peeled easily from the mucosal surface; reveal ulcerated or erythematous tissue underneath

Systemic form: Multiple white foci in affected organs

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Yeast (3–6 µm basophilic round to oval or elongated, clear cell wall, basophilic interior), pseudohyphae (chains of elongated yeast that remain attached end to end without distinct segmentation), true hyphae (well septate 3–5 µm wide with parallel walls occasional branching)
Blastospores are round basophilic yeast of asexual fungal reproduction produced via budding from hyphae that are occasionally seen
Systemic infections: Suppurative inflammation and necrosis; rarely granulomatous
Inflammation may be minimal in severely immunosuppressed individuals
Colonization of the keratinized stratified squamous epithelium of the oral, crop, and esophageal mucosa is typically limited to the stratum corneum but may extend into the superficial stratum spinosum
Fibrinosuppurative membrane with necrotic debris, yeast, pseudohyphae, hyphae, and sloughed epithelial cells often covers the mucosal surface

ADDITIONAL DIAGNOSTIC TESTS:

PAS, Gridley, and Gomori methenamine silver stains
Culture results should be correlated with histology since C. albicans can be normal flora

DIFFERENTIAL DIAGNOSIS:

Geotrichum candidum: Yeast, pseudohyphae, and septate hyphae; may cause granulomatous inflammation
Aspergillus sp: A. fumigatus most common; parallel, septate hyphae with dichotomous acute angle branching; conidiophores at air interfaces
Zygomycetes: Usually nonseptate, branching hyphae; bulbous enlargements
Paracoccidioides brasiliensis (previously named Lacazia loboi and Loboa loboi): Granulomatous dermatitis in Atlantic bottlenose dolphins; yeast in branching chains
Candida glabrata (previously Torulopsis glabrata): Do not form hyphae; 2-3µm diameter yeast; now considered part of the Candida genus
Histoplasma capsulatum: 2-4µm yeast, intrahistiocytic
Blastomyces dermatitidis: 7-17µm yeast with single, broad-base budding

COMPARATIVE PATHOLOGY:

Birds: Common opportunistic infections in the mouth, esophagus, crop, proventriculus, ventriculus (finches); hyperkeratosis due to vitamin A deficiency or anorexia can help propagate infection
Pigs (piglets): Oral cavity – mycotic esophagitis (“thrush”), esophagus and the gastric squamous mucosa (pars esophagea) are most often affected
Ox: Systemic infections; mastitis, and abortion
Calves: Lesions are present in the ventral sac of the rumen, omasum, or reticulum following prolonged antibiotic therapy
Horse: Squamous epithelial ulceration typically adjacent to the margo plicatus (foal); valvular endocarditis (adult)
Mice: Gastritis reported in immunocompromised mice; Candida pintolopesii inhabits surface glandular stomach mucosa of normal mice
Rats: Systemic infection of Sprague-Dawley rats is used to evaluate antifungal therapies
Dog: Mycotic stomatitis (“thrush”), peritonitis, cystitis, rare systemic disease or sepsis (usually in immunocompromised animals)
Pinnipeds: Opportunistic fungal dermatitis occurs due to water quality issues and pre-existing mechanical disruption of the skin.

REFERENCES:

Barthold SW, Griffey SM, Percy DH. Rabbits. In: Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016:79.
Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St Louis, MO: Elsevier; 2016:458-459.
Colegrove KM, Burek-Huntington KA, Roe W, Siebert U. Pinnipediae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:583.
Farina LL, Lankton JS. Chiroptera. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:623.
Fletcher OJ, Abdul-Aziz T. Chapter 7: Alimentary System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 273, 286, 292, 297.
Haddad JL, Marks Stowe DA, Neel JA. The Gastrointestinal Tract. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:290-294.Hoffmann AR, Ramos MG, Walker RT, Stranahan LW. Hyphae, pseudohyphae, yeasts, spherules, spores, and more: A review on the morphology and pathology of fungal and oomycete infections in the skin of domestic animals. Vet Pathol. 2023;60(6):812-828.
Hostetter SJ. Chapter 7: Oral Cavity, Gastrointestinal Tract, and Associated Structures. In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022: 376, 381 – 382.
Leger JA, Raverty S, Mena A. Cetacea. In: Terio KA, McAloose D, St. Leger JA, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:559-560.
Lowenstine LJ, McManamon R, Terio KA. Apes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:397.
McAdam AJ, Milner DA, Sharpe AH. Infectious diseases. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:386-387.
Robinson WF, Robinson NA. Cardiovascular system. In: Grant Maxie M, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St Louis, MO: Elsevier; 2016:30-31.
Schmidt RE, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc; 2015:61-62.
Shivaprasad HL. Fungal Diseases. In: Boulianne M ed. Avian Disease Manual. 7^th ed. Madison, WI: Omnipress; 2013.
Spagnoli ST, Gelberg HB. Alimentary System and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:396-485.
Simmons J, Gibson S. Bacterial and Mycotic Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2nd ed. San Diego, CA: Elsevier; 2012: 151, 154-156.
Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St Louis, MO: Elsevier; 2016:32, 202.
Wunschmann A, Armien AG, Hofle U, Kinne J, Lowenstine LL, Shivaprasad HL. Birds of Prey. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:737.
Young KM, Teixeira LBC. Eyes and Associated Structures. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:149, 151.
Zachary JF. Fungal Diseases of Organ Systems Alimentary System and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, Pathologic Bases of Veterinary Disease. 7^th ed. St. Louis, MO: Mosby Elsevier; 2022: 280-281.