JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2055944): Sheep, breed not specified
HISTORY: Exhibited respiratory distress.
HISTOPATHOLOGIC DESCRIPTION: Lung: Multifocally arising from the alveolar epithelium, replacing 60% of normal pulmonary architecture and compressing adjacent alveoli (atelectasis) are variably-sized, up to 1mm diameter, unencapsulated, well-demarcated, expansile neoplastic foci composed of one or more layers of cuboidal to columnar epithelial cells which form acinar or papillary projections into alveolar lumina and are supported by a fine fibrovascular stroma. Neoplastic cells have distinct cell borders, a moderate amount of finely granular, occasionally vacuolated amphophilic to lightly eosinophilic cytoplasm, and round to oval nuclei with finely-stippled chromatin, and 1‑3 variably distinct nucleoli. The mitotic rate is less than 1 per 10 HPF. Multifocally, alveolar and bronchiolar lumina contain variable numbers of degenerate and nondegenerate neutrophils, foamy alveolar macrophages, fibrin, and edema. Multifocally, alveolar septa are mildly expanded by the previously-described inflammatory cells. Bronchiolar epithelium is frequently hyperplastic, piling up to 6 layers thick, and contains moderate numbers of goblet cells (goblet cell metaplasia). The pleura and interlobular septa are expanded up to 5 times normal by increased clear space and ectatic lymphatics (edema) and scattered previously-described inflammatory cells. Multifocally, there are increased numbers of bronchiole-associated lymphocytes, which occasionally form germinal centers (BALT hyperplasia).
MORPHOLOGIC DIAGNOSIS: Lung: Pulmonary adenocarcinoma, low-grade, breed unspecified, ovine
ETIOLOGIC DIAGNOSIS: Retroviral pulmonary carcinomatosis
CAUSE: Betaretrovirus (Jaagsiekte sheep retrovirus [JSRV])
CONDITION: Ovine pulmonary adenocarcinoma (OPA)
SYNONYMS: Jaagsiekte, ovine pulmonary carcinoma, pulmonary adenomatosis
- Contagious retroviral pulmonary carcinomoa of sheep, and rarely goats.
- caused by jaagsiekte sheep retrovirus (JSRV) (Betaretrovirus, ssRNA), which induces oncogenic transformation of alveolar and bronchiolar secretory epithelial cells
- Exists worldwide except Australia, New Zealand, Falkland Islands, and Iceland
- Significant problem in Scotland, South Africa, Peru; rare in North America
- Long incubation period (several months or years), therefore mostly seen in adult sheep (aged 2-4 years)
- Gottorp and merino sheep may have higher incidence
- Carriers may cause high flock infectivity -> high prevalence (some flocks 20%); most naturally infected animals don’t develop tumors
- Epizootic appearance (30-50% of flock mortality rate) which becomes endemic (1-5% mortality)
- JRSV spreads via aerosol or direct contact of young animals with infective nasal secretions; crowding/confinement increases spread
- Env glycoprotein (viral oncogene), which assists in cellular entry and also directly stimulates cellular neoplastic transformation
- Cell or origin is type II pneumocyte or Club cell (neoplastic cell express markers of both
- JSRV uses the membrane receptor Hyaluronidase-2 (Hyal2) present on many cell types, but replicates mostly in alveolar type II pneumocytes and club cells
- Specificity likely due to viral long terminal repeat (LTR), which contains enhancer elements that bind lung-specific transcription factors
- Characteristically, there is an absence of cellular and humoral immune response to viral proteins, likely due to immunotolerance from expression of enJSRV proteins in fetal thymus during T-lymphocyte development, ie central tolerance
- Virus-transformed cells proliferate, produce copious surfactant, and form intraalveolar and intrabronchiolar polypoid/papillary foci
- Small neoplastic foci expand, form large nodules, and compress and infiltrate pulmonary parenchyma
- Basic fibroblast growth factor (bFGF), platelet-derived growth factor-C (PDGF-C), vascular endothelial growth factor-C (VEGF-C) all play role in neoplastic transformation; bovine lactoferrin (bLF) activates macrophages and plasma cells
- Presence of bacterial pneumonia or Maedi-Visna may be present concurrently
TYPICAL CLINICAL SIGNS:
- The long incubation period and often lack of clinical signs with infected sheep facilitates viral transmission
- Pathognomonic sign is the production of copious amounts of fluid in the lung that is frothy, clear, milky or at times pinkish and drains from the sheep’s nostrils when it lowers its head or when its hindlimbs are elevated
- Dyspnea is accentuated by exercise (thus the Afrikaans name jaagsiekte, “chasing sickness”); this is not a specific sign
TYPICAL GROSS FINDINGS:
- Heavy, wet lungs with multifocal small, firm, gray nodules; progresses to large coalescing gray masses with associated atelectasis
- Ooze fluid on cut section
- More severe cranioventrally, with caudodorsal areas often normal
- In severe disease, lungs fail to collapse and are heavy and firm due to fibroplasia
- Abundant clear, frothy or mucoid fluid in bronchi, trachea and nasal cavity
- Bronchial and mediastinal lymph nodes are often enlarged
- +/- chronic pleuritis (due to expansile nature), secondary bronchopneumonia, abscess, pleural adhesions, tumor necrosis
- “Atypical OPA” form with hard, pearly-white tumor nodules and a dry cut surface; fluid is absent and lymphoid proliferations are common
- Subclinical, therefore incidental finding at necropsy, though atypical lesions can occur in conjunction with the “classical” form
- Extrathoracic metastasis may occur in liver, kidneys, skeletal muscle, digestive tract, spleen, skin and adrenal glands; reported to be rare
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Multiple neoplastic foci emanating from alveolar and bronchiolar epithelium which form which expand into adjacent structures; well differentiated pulmonary carcinoma
- Fibrovascular stroma can dominate center of tumor nodules
- Cuboidal or columnar neoplastic cells are type II pneumocytes with fewer club cells
- The following patterns may be observed: lepidic, papillary, acinar, myxomatous, polypoid – (arising from brohchioles)
- Adjacent alveoli: compression (atelectasis), +/- fibrosis, +/- lymphohistiocytic alveolar infiltrate; most often poorly demarcated and extend into adjacent alveoli
- +/- lymphocytic interstitial pneumonia, peribronchiolar lymphoid hyperplasia (OPP) or cranioventral suppurative bronchopneumonia (e.g., multocida pneumonia)
- Predominance of alveolar type II pneumocyte morphology: surface microvilli, basal or centrally located nuclei, desmosomes, intracellular lamellar bodies
- Contain variable numbers of secretory granules, which can appear as electron-dense structures or are filled with myelinoid whorls, in comparison with the electron-lucent granules found in normal granular pneumocytes
- May also have Club cell differentiation: cytoplasmic dense core granules
- Betaretrovirus is 100nm diameter, enveloped, ss-RNA
ADDITIONAL DIAGNOSTIC TESTS:
- IHC: retrovirus antigen (Jaagsiekte Sheep Retrovirus Capsid Protein, JSRV CA) demonstrated in cytoplasm of tumor cells in the lung and lymph nodes
- PCR on blood samples to detect JSRV-infected cells (high false negatives)
- PCR testing of bronchoalveolar lavage samples most successful method
- IHC to distinguish cell of origin: type II pneumocyte (pulmonary surfactant proteins: SP-A and SP-B in apical cytoplasm, and SP-C in perinuclear area of tumor cells), Club cell (Club cell 10-kd protein [CC-10])
- OPP is induced by another retrovirus (genus Lentivirus, species visna/maedi virus); both may have type II pneumocyte hyperplasia +/- interstitial fibrosis, but OPP has prominent peribronchiolar and perivascular lymphocytic inflammation and lacks papillary growths characteristic of OPA
- Non-viral pulmonary carcinoma of sheep (rare): Cannot be distinguished from JSRV associated pulmonary carcinoma without additional testing (IHC for JSRV)
- Dual infection with JSRV and visna/maedi virus is common
- Gross lesions: lungworms, bacterial bronchopneumonia (primary or secondary)
- Coexistence of JSRV and the betaretrovirus (enzootic nasal tumor virus-1) that causes enzootic nasal adenocarcinoma in sheep suggests a synergistic relationship
- Goat: frequently infected with JSRV, but rarely develop an associated BAC; recent case report of a spontaneous BAC not related to JSRV (tumor lacked bronchiolar involvement and acinar/papillary patterns characteristic of OPA; IHC revealed type II pneumocyte origin; animal was JSRV-negative by PCR)
- Mouse: BAC is a common primary respiratory tumor of aged mice with higher incidence in males
- Dog: BAC is the most common primary lung tumor in the dog but occurs infrequently
- Human: BAC is rare; JSRV is expressed in tumor tissue depending on patients’ geographical origin; causal relationship not proven, but JSRV may increase susceptibility to development of BAC
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