JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

September 2023

P-N04

 

Signalment (JPC #1758838): 1‑year‑old Icelandic ewe

 

HISTORY: This ewe had dyspnea and mucopurulent nasal discharge of 4-5 months duration. 

 

HISTOPATHOLOGIC DESCRIPTION: Nasal cavity: Arising from the respiratory epithelium and infiltrating the underlying lamina propria and submucosa is an unencapsulated, poorly circumscribed, moderately cellular, multi-lobulated neoplasm forming papillary projections supported by a fine fibrovascular stalk as well as tubules and acini on fine fibrovascular stroma. Neoplastic cells are ciliated cuboidal to columnar epithelial cells with indistinct cell borders, a moderate amount of finely granular eosinophilic cytoplasm, a single round nucleus with moderately stippled chromatin, and one variably distinct nucleolus. Anisocytosis and anisokaryosis are mild and the mitotic rate is 1 per 2.37mm². Occasionally, neoplastic lumina contain flocculent, blue-gray material (mucin) admixed with low numbers of neutrophils and necrotic cellular debris. Multifocally separating neoplastic cells and expanding the adjacent submucosa there are ectatic lymphatics (edema), abundant mucin, and aggregates of lymphocytes and plasma cells with fewer macrophages, and neutrophils. Remaining respiratory epithelium is attenuated, mildly eroded, or occasionally hyperplastic. Neoplastic cells efface nasal turbinates and there is significant loss of pre-existing nasal bone with replacement by abundant fibrous connective tissue with reactive fibroblasts (fibrosis). 

 

MORPHOLOGIC DIAGNOSIS: Nasal cavity: Adenocarcinoma, Icelandic sheep, ovine.

 

CAUSE: Enzootic Nasal Tumor Virus (β-retrovirus: ENTV-1 in sheep, ENTV-2 in goats)

 

CONDITION: Endemic ethmoidal tumor; enzootic intranasal tumor; enzootic nasal adenocarcinoma; ethmoid tumor; infectious nasal adenopapilloma; ethmoid adenocarcinoma; tumor of the ethmoid olfactory mucosa; papillary adenoma of ethmoid origin

 

GENERAL DISCUSSION:  

• Worldwide distribution (except Australia, New Zealand, and the United Kingdom) infectious respiratory tract disease of sheep and goats

• ENTV-1: Sheep
• ENTV-2: Goats

• Ethmoturbinate tumor associated with a beta-retrovirus
• The neoplasm originates from the surface epithelium and glands of the ethmoidal conchae
• Typically, invasive but they do not metastasize
• Jaagsiekte sheep retrovirus (JSRV, P-V16) has been associated with nasal adenocarcinoma in sheep, indistinguishable from ENTV-1-induced adenocarcinoma 
• Sheep have multiple copies (~27) of an endogenous virus similar to JSRV (enJSRV), which is proposed to be the reason sheep lack a measurable immune response to the exogenous viruses (JSRV, ENTV-1, ENTV-2) (Jahns, J Vet Diagn Invest 2020)

 

PATHOGENESIS:  

• Infectious: Caused by ENTV-1 (or -2 in goats); neoplasms are experimentally induced in naive sheep and goats by transmission of nasal fluids from clinically affected animals; retrovirus-like particles have been demonstrated in neoplastic cells by electron microscopy in both sheep and goats
• ENTV-1 and -2 are genetically closely related to Jaagsiekte sheep retrovirus (JSRV), the causative agent of ovine pulmonary adenocarcinoma (OPA, P-V16) (Jahns, J Vet Diagn Invest, 2020)
• Viral envelope glycoprotein is thought to be responsible for tumor development (in mice); detectable in neoplastic cells but not adjacent normal tissue

 

TYPICAL CLINICAL FINDINGS:

• Insidious, progressive clinical symptoms including uni‑ or bilateral serous to mucopurulent nasal discharge, dyspnea, open mouth breathing, flared nostrils, respiratory stridor, and sneezing
• Facial deformities, exophthalmos, and lacrimation secondary to space occupying lesions
• Subclinical infection is common; most experimentally infected animals do not develop tumors

 

TYPICAL GROSS FINDINGS:  

• Unilateral or bilateral masses in the ethmoid turbinates, with compression of the surrounding structures
• Appear white, grey, pink, and/or dark red; soft, irregular, or friable with a granular surface covered by mucus
• Can extend into pharynx, sinuses, and/or infiltrate through the cribriform plate

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Originate from olfactory mucosa of the turbinates in sheep and respiratory or olfactory mucosa in goats
• Morphologic features do not distinguish between viral and sporadic neoplasms
• Locally aggressive, destructive, and space-occupying
• Appearance is of an adenoma or low-grade adenocarcinoma

• Adenocarcinoma if there is invasion of bone

• Cuboidal or pseudostratified non-ciliated epithelial cells form orderly acinar, tubular, or papillary arrangements
• Occasionally have abundant mucus production, and rarely squamous metaplasia
• May be accompanied with nasal inflammatory polyps and glandular hyperplasia
• Metastasis to regional lymph nodes has been reported in cattle

 

ULTRASTRUCTURAL FINDINGS:

• Intracytoplasmic or extracellular viral particles  
• Viral particles are 90-135 nm in diameter with a core surrounded by an electron dense or translucent zone enveloped by a spiked unit membrane
• Viral particles occasionally bud from apical microvilli of neoplastic cells
• Neoplastic cells have characteristic proteinaceous-like secretory granules, rough endoplasmic reticulum, and many mitochondria

 

ADDITIONAL DIAGNOSTIC TESTS: 

• IHC, electron microscopy to search for virus
• PCR - important to distinguish between viruses, since ENTV-1 and JSRV can produce identical lesions (Jahns, J Vet Diagn Invest 2020)

 

DIFFERENTIAL DIAGNOSIS:

• Sporadic (nonviral) nasal tumor (IHC, PCR, EM to differentiate)
• Fungal granulomas
• Nasal polyp: Fibrous/myxomatous core covered by hyperplastic epithelium with inflammatory cell infiltrate

 

COMPARATIVE PATHOLOGY:   

• Goats:  Retrovirus-associated nasal carcinoma also seen in goats (ENTV-2)
• Bighorn sheep:

• Paranasal sinus tumors of unknown causative agent, similar to enzootic nasal tumor of sheep:

• Seromucinous nasal discharge, soft white mass in the sinus cavity
• While some masses are classified as adenocarcinomas, a more robust mesenchymal component differentiates this from enzootic nasal adenocarcinoma in domestic sheep

• Nasal tumors in other species:

• Enzootic nasal adenocarcinomas have been identified in cattle, horses, and pigs, but a clear viral etiology has not been established
• Main site for nasal neoplasms is nasal passages for dogs, tip of nose and nasal passages for cats, and maxillary sinus and nasal passages for horse

• In dogs, nasal neoplasms occur in Collies, Airedale terrier, basset hound and German Shepherd dogs

• Virus-associated tumors in wildlife

• Atlantic salmon: Retrovirus, leiomyosarcoma
• Deer: Deltapapillomavirus, cutaneous fibropapillomas and cutaneous fibromas (I-V02)
• Giraffe: Deltapapillomavirus, fibropapillomas (sarcoids)
• Koala: Koala retrovirus B, lymphoma
• Mountain gorilla: Gbb lymphocryptovirus 1, B cell lymphoma
• Northern fulmar: Papillomavirus, mesenchymal neoplasm
• Raccoon: Raccoon polyomavirus, brain neuroglial tumor
• Sea turtle: Suspected alphaherpesvirus (Chelonid herpesvirus 5), fibropapillomas
• South American fur seal: Otarine herpesvirus 1, urogenital carcinoma
• Tapir: Deltapapillomavirus, fibropapillomas (sarcoids)
• Walleye fish: Epsilon retrovirus, dermal sarcoma
• Water buffalo: Deltapapillomavirus, fibropapillomas (sarcoids)
• Western barred bandicoot: Bandicoot papillomatosis carcinomatosis virus type 1, papillomas and squamous cell carcinoma
• Zebra: Deltapapillomavirus, fibropapillomas (sarcoids)

 

REFERENCES:  

1. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed.  Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016: 560.
2. De Las Heras M, Reséndiz RA, González-Sáinz JM, Ortín A. Exogenous Small Ruminant Betaretrovirus Envelope Protein Is Detected in Draining Lymph Nodes in Contagious Respiratory Tumors of Sheep and Goats. Vet Pathol. 2021 Mar;58(2):361-368
3. Jahns H, Cousens C. Nasal adenocarcinoma associated with jaagsiekte sheep retrovirus infection in a sheep. Jour Vet Diagn Invest. 2020;32(1):152-155.
4. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: ed. Terio KA, McAloose D, St. Leger, J. Pathology of Wildlife and Zoo Animals. San Diego, CA:Elsevier. 2018:124.
5. Lopez A. Martinson, SA. Respiratory system, mediastinum, and pleurae.  In: Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2022:619-620.

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