JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

November 2024

D-V21

 

Signalment (JPC #1782714): 3-month old Hereford calf

 

HISTORY: This calf had a history of severe chronic diarrhea and oral erosions for a 1-week period prior to death. 

 

MICROSCOPIC DESCRIPTION: 

Slide A: Rumen: There is a 5mm long focally extensive thickening of the mucosal epithelium up to 2mm thick (hyperplasia) with acanthosis and markedly swollen squamous epithelial cells with abundant clear to light eosinophilic, flocculent, vacuolated cytoplasm (ballooning degeneration) that often contain a single, round to irregular, often large (up to 20 µm), eosinophilic, intracytoplasmic viral inclusion body. Multifocally, vacuolated cells coalesce to form clear spaces up to 200 µm in diameter which often contain numerous viable and degenerate neutrophils admixed with fibrin, hemorrhage, edema, and necrotic debris (intraepithelial pustules), and there is scattered single cell necrosis. The epithelium is multifocally eroded or ulcerated and replaced by eosinophilic fluid and fibrin with enmeshed cellular and karyorrhectic debris, abundant viable and degenerate neutrophils, and scattered colonies of superficial cocci (serocellular crust). The remaining epithelium is hyperplastic with moderate parakeratotic hyperkeratosis. The lamina propria and submucosa contains abundant degenerate neutrophils, fewer macrophages, lymphocytes, and plasma cells, and hemorrhage, fibrin, edema with ectatic lymphatics, and blood vessels are often lined by hypertrophied endothelial cells (reactive endothelium). Muscle bundles of the tunica muscularis are mildly separated by increased clear space (edema).

 

Tongue: Few multifocal, random myocytes are mildly hypereosinophilic with loss of cross-striations and pyknotic nuclei (necrosis), with small cytoplasmic aggregates of basophilic globular to granular material (mineralization).

 

Slide B: Esophagus: Affecting 80% of the section, the mucosal epithelium is thickened up to 1 mm (hyperplasia) and there is extensive, severe intracellular edema (ballooning degeneration) with similar formation of intraepithelial pustules and numerous previously described eosinophilic intracytoplasmic viral inclusion bodies. There is a focally extensive area of ulceration and replacement with a moderate amount of granulation tissue, eosinophilic cellular and karyorrhectic debris, viable and degenerate neutrophils, hemorrhage, abundant fibrin, edema, and many superficial cocci (serocellular crust). In the adjacent subepithelial connective tissue, there is granulation tissue, diffuse mild congestion and many viable and necrotic neutrophils, fewer macrophages, lymphocytes, and plasma cells. Blood vessels are often lined by hypertrophied endothelial cells (reactive endothelium). 

 

MORPHOLOGIC DIAGNOSIS: 1. Rumen: Rumenitis, proliferative and necrotizing, subacute, focally extensive, severe, with ballooning degeneration, intraepithelial pustules, and numerous epithelial intracytoplasmic viral inclusion bodies, Hereford, bovine.

2. Esophagus: Esophagitis, proliferative and necrotizing, subacute, diffuse, severe, with ballooning degeneration, intraepithelial pustules, and numerous epithelial intracytoplasmic viral inclusion bodies.

3. Tongue, myocytes: Necrosis and mineralization, multifocal, mild.

 

ETIOLOGIC DIAGNOSIS: Parapoxviral esophagitis and rumenitis

 

CAUSE: Bovine papular stomatitis virus (bovine parapoxvirus)

 

CONDITION: Bovine papular stomatitis; infectious ulcerative stomatitis and esophagitis

 

GENERAL DISCUSSION:

• Bovine popular stomatitis virus (BPSV) is an enveloped DNA virus of the genus Parapoxvirus, family Poxviridae 
• Most common in young calves or immunosuppressed adults; frequently associated with deficient colostrum administration
• Typically not a clinically significant infection; important to differentiate from other more serious diseases causing oral lesions (e.g. foot and mouth, vesicular stomatitis, etc.)
• Mild papular and necrotizing disease of the skin and oral cavity of cattle; udders/teats may be affected in adults from nursing; esophagus and forestomaches occasionally affected; non-vesicle forming
• Zoonotic; causes papules located on fingers and arms of humans that may persist for several weeks
• Chronic form is reported but less common, causing exudative necrotic dermatitis of the trunk and oral cavity; death occurs within 4-6 weeks

 

PATHOGENESIS:

• Direct contact with fomites or crust (lesion from other animal) -> virus enters Langerhans and endothelial cells -> local replication and trafficking -> endothelial cell dysfunction/death -> epithelial damage (vesicles and pustules) -> epithelial proliferation -> proliferative and erosive stomatitis/dermatitis
• Virus shed in nasal secretions and saliva
• Infection does not confer immunity; relapses can occur

 

TYPICAL CLINICAL FINDINGS:

• Morbidity approaches 100% within a group, but signs are mild to inapparent
• Occasional transient anorexia, weight loss, ptyalism, +/- slight fever 
• Most infections acute and resolve within approximately 1 week
• Chronic form: Stomatitis

 

TYPICAL GROSS FINDINGS:

• Papular lesions occur on the muzzle and in the rostral nares, inner aspect of the lips, gingiva, buccal papillae, dental pad, hard palate, ventral and lateral (not dorsal) surfaces of the tongue, udders and teats in nursing animals, and occasionally the esophagus and forestomaches
• Most common lesion: Sharply demarcated, 2mm to 2cm diameter, erythematous, round macule that develops rapidly into a raised papule, then undergoes central necrosis

• These circular, coin-shaped lesions often have a hyperemic, thickened periphery
• Lesions often coalesce

• Lesions heal quickly (4-7 days) and leave a reddish brown area after regression
• Vesicles are not present
• Chronic form: Necrotizing and proliferative dermatitis and stomatitis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Epithelial hyperplasia up to two times normal depth, acantholysis, and ballooning degeneration in deeper layers 
• Dense eosinophilic intracytoplasmic inclusion bodies in vacuolated cytoplasm of keratinocytes, especially in cells at active margin of lesions
• Basilar epithelium unaffected
• Congestion and edema in the lamina propria and submucosa, with low numbers of macrophages, lymphocytes and plasma cells 
• Chronic form: Parakeratotic hyperkeratosis, pseudoepitheliomatous hyperplasia, fewer intracytoplasmic inclusion bodies

 

ULTRASTRUCTURE:

• Virions have a regular spiraled filamentous surface pattern (resembles ball of yarn or coil of rope) and are 320 x 125 nm
• Slightly smaller and more ovoid than other poxviruses

 

ADDITIONAL DIAGNOSTIC TESTS:

• Electron microscopy of the saliva
• Virus isolation, indirect immunofluorescence, PCR
• Neutralizing antibodies not readily produced

 

DIFFERENTIAL DIAGNOSIS:

Oral lesions in cattle

• Foot-and-mouth disease (D-V17; Picornaviridae, aphthovirus): Vesicles, mucosal sloughing, necrosis, and ulceration
• Vesicular stomatitis (D-V11; Rhabdoviridae, vesiculovirus): Vesicles, mucosal sloughing, necrosis and ulceration
• Bovine virus diarrhea/mucosal disease (D-V09; Flaviviridae, pestivirus): Mucosal epithelial erosions, blunting of buccal papillae
• Rinderpest (D-V28; Paramyxoviridae, morbillivirus): Necrotizing foci and oral erosions; syncytia, intranuclear and intracytoplasmic inclusion bodies
• Malignant catarrhal fever (D-V15; alcelaphine herpesvirus 1 or ovine herpesvirus 2): Oral erosions, scabs on muzzle; fibrinoid vascular necrosis
• Bluetongue (D-V16; Reoviridae, orbivirus): Clinical disease rare in cattle; insect vector, seasonal
• Infectious bovine rhinotracheitis (bovine herpesvirus type 1, alphaherpesvirus): Hyperemia of muzzle ("red nose"), pustules on nasal mucosa that later develop into plaques; eosinophilic intranuclear inclusions; outbreaks in newborn calves

 

COMPARATIVE PATHOLOGY:

Other Parapoxviruses

• Ovine parapoxvirus (D-V22): Contagious ecthyma (orf) in sheep and goats and other ruminants; orf in humans

• Oncogenic role suggested by activation of CD163+ macrophages that express EGFR and VEGFR2 (synergestic action with vVEGF signaling) (Pintus, Vet Pathol 2022)

• Parapoxvirus of red deer in New Zealand: Genomically distinct parapoxvirus isolated from red deer in New Zealand; pustular dermatitis on the muzzle, face, ears, and sometimes neck and limbs
• Pseudocowpox virus: Lesions usually confined to the udder and rarely the medial thighs or scrotum; usually no systemic signs of illness; causes “milker’s nodules” in humans
• Red squirrel parapoxvirus: Suspected to be factor in severe population declines of red squirrels in United Kingdom and Ireland; exudative dermatitis; large percentage of grey squirrels are positive for virus and are likely maintenance hosts
• Parapoxviruses also isolated from harbor seals, northern fur seals, gray seals, northern elephant seals, South American sea lions, reindeer, chamois, muskoxen, camels, gazelles, wild Japanese serows, and pygmy chimpanzees
• Humans: Parapoxviruses from multiple animal species produce erythematous papules on the hands, fingers, or forearms

 

REFERENCES:

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2. Cheville NF. Ultrastructural Pathology, the Comparative Cellular Basis of Disease. 2nd ed. Ames, IA: Wiley-Blackwell; 2009:324-325. 
3. 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; 2018:576. 
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6. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:125-126.
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8. Pintus D, Cancedda MG, Puggioni G, et. al. ORF virus causes tumor-promoting inflammation in sheep and goats. Vet Pathol. 2022;61(5):803-814.
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: Elsevier; 2022:465. 
10. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1224.
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