JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

November 2023

U-F01 (NP)

 

Signalment (JPC #1807217): A killer whale

 

HISTORY: None provided

 

HISTOPATHOLOGIC DESCRIPTION: Slide A. Kidney: Markedly expanding and replacing both the cortical and medullary interstitium, separating, surrounding, and replacing tubules, and to a lesser extent filling the renal pelvis are multifocal to coalescing random aggregates of numerous viable and degenerate neutrophils, fewer macrophages, lymphocytes, plasma cells, and variable amounts of eosinophilic cellular and karyorrhectic debris (necrosis) and fibrin which is occasionally surrounded by fibrosis. These areas are often centered on numerous oval to round, 3-6 µm diameter, pale-staining, thin-walled blastospores and blastoconidia arranged in short chains (pseudohyphae), and slender, 3-4 µm wide, septate, parallel-walled hyphae. Tubules within and adjacent to affected areas are mildly ectatic, lined by attenuated epithelium, and are filled with sloughed epithelial cells, neutrophils, and necrotic cellular debris (cellular or granular casts). Tubule epithelium is undergoing various stages of degeneration (epithelial hypertrophy with cytoplasmic pallor and vacuolation) and necrosis (shrunken, bright eosinophilic cells with pyknotic nuclei) and occasionally tubules are lined by epithelial cells with increased cytoplasmic basophilia, prominent nucleoli, and rare mitoses (regeneration). Multifocally the urothelium in the renal pelvis is hyperplastic or eroded. There are few variably sized aggregates of neutrophils and debris within the renal pelvis (pyelitis).

 

Slide B: Kidney (PAS): Numerous PAS positive yeast, pseudohyphae, and hyphae.

 

Slide C: Kidney (Gridley): Numerous argyrophilic yeast, pseudohyphae, and hyphae.

 

MORPHOLOGIC DIAGNOSIS: Kidney: Nephritis, tubulointerstitial, necrosuppurative, subacute, multifocal to coalescing, moderate, with pyelonephritis and numerous PAS positive and argyrophilic hyphae, pseudohyphae, and yeast, Killer whale (Orcinus orca). 

 

ETIOLOGIC DIAGNOSIS: Renal Candidiasis

 

CAUSE: Candida spp.

 

GENERAL DISCUSSION: 

• Members of the family Candida spp. are ubiquitous, dimorphic, saprophytic fungi that normally inhabit the alimentary, upper respiratory and genital mucosa of mammals
• Most common species producing 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, and foals
• In marine mammals 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 
• Systemic (disseminated) candidiasis may involve any organ with the kidneys, heart valves, CNS and lungs most commonly affected
• 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:

 

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

 

CYTOLOGICAL FINDINGS:

• Yeast (3-6um) basophilic round to oval or elongated, clear cell wall, basophilic interior
• Pseudo-hyphae are chains of elongated yeast that remain attached end to end
• True hyphae are well-septated 3-5um wide structures with parallel walls with occasional branching

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Pseudohyphae (chains of blastoconidia which are distinguished from true hyphae by constriction at points of attachment of the individual yeast); hyphae 3-4 µm wide, parallel-walled, septate; and 2-6 µm round to oval narrow-based budding yeast 
• Systemic infections: Suppurative inflammation and necrosis; rarely granulomatous
• Inflammation may be minimal in severely immunosuppressed individuals
• Colonization of the keratinized stratified squamous epithelium of 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 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; septate hyphae with dichotomous branching; conidiophores
• Zygomycetes: Usually nonseptate, branching hyphae; bulbous enlargements
• 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; infections in mouth, esophagus, crop, proventriculus; hyperkeratosis due to vitamin A deficiency or anorexia can help propagate infection
• Pigs (piglets): Oral cavity – mycotic esophagitis (“thrush”), esophagus, and gastric squamous mucosa 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
• Dog: Mycotic stomatitis (“thrush”), peritonitis, cystitis, rare systemic disease or sepsis (usually in immunocompromised animals)
• Non-human primates: Lesions of the tongue, oral cavity (“thrush” or “moniliasis”), esophagus and intestine are most common

 

REFERENCES:

1. Cianciolo RE, Mohr FC.  Urinary system. In: Maxie MG, ed.  Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier; 2016:458-459.   
2. Lowenstine LJ, McManamon R, Terio KA. Apes. In Pathology of Wildlife and Zoo Animals, Cambridge, MA; Academic Press; 2018: 397.
3. Raskin, RE, Meyer, DJ, Boes KM.  Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide, St Louis, Missouri; Elsevier; 2023: 255, 310, 383.
4. Robinson WF, Robinson NA. Cardiovascular system. In: Grant Maxie M, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier; 2016:30-31.
5. Rodrigues Hoffmann A, 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.
6. Schmidt RE, Reavill DR, Phalen DN.  Pathology of Pet and Aviary Birds.  2nd ed.  Ames, IA: John Wiley & Sons, Inc; 2015:61-62.
7. Shivaprasad HL.  Fungal diseases.  In: Boulianne M, ed.  Avian Disease Manual. 7th ed.  Jacksonville, FL: American Association of Avian Pathologists, Inc; 2013:143-144.
8. Simmons J, Gibson S.  Bacterial and mycotic diseases of nonhuman primates. In: Nonhuman Primates in Biomedical Research. Vol 2. 2nd ed. San Diego, CA: Academic Press; 2012: 154-155.
9. 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: Mosby Elsevier; 2022:404;467.
10. Trupkiewicz J, Garner MM, Juan-Salles C. Passeriformes, Caprimulgiformes, Coaciiformes, Piciformes, Bucerotiformes, and Apodiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, Cambridge, MA; Academic Press; 2018: 806.
11. 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. Philadelphia, PA: Elsevier; 2016:202.   
12. Valenciano, AC.  Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat.  5^th edition.  St Louis, Missouri: Elsevier; 2020: 238-239; 290-294.
13. Welle, MM, Linder, KE. S. The integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St Louis, MO: Mosby Elsevier; 2022:1175.
14. Wunschmann A, Armien AG, Hofle U, Kinne J, Lowenstine LJ, Shivaprasad HL. Birds of Prey. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, Cambridge, MA; Academic Press; 2018: 731.

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