JPC SYSTEMIC PATHOLOGY
SIGNALMENT (JPC 1930834): Adult woodchuck (Marmota monax)
HISTOPATHOLOGIC DESCRIPTION: Liver: Infiltrating and replacing approximately 70% of the normal hepatic architecture is an unencapsulated, multilobulated, densely cellular neoplasm composed of polygonal cells arranged in disorganized, 5 to 6-cell- layer-thick trabeculae and fewer acini on a moderate fibrovascular stroma. Neoplastic cells have variably-distinct cell borders, abundant eosinophilic granular to vacuolated cytoplasm, round nuclei with finely stippled chromatin and one to two distinct magenta nucleoli. Anisocytosis and anisokaryosis are moderate and there are low to moderate numbers of cytomegalic, multinucleated neoplastic cells with occasional bizarre nuclei. The mitotic rate averages 1 per 10 HPF. There are multifocal areas of lytic necrosis with loss of normal hepatic architecture and replacement by eosinophilic cellular and karyorrhectic debris, hemorrhage, fibrin and fibrosis. Within the adjacent compressed hepatic parenchyma, portal areas are expanded by numerous lymphocytes and plasma cells and fewer neutrophils that occasionally bridge portal areas and are admixed with increased small biliary duct profiles (ductal reaction), and fibrosis. Frequently, the cytoplasm of adjacent hepatocytes is expanded by granular material, imparting a microvacuolated appearance (vacuolar degeneration, glycogen type). Multifocally neoplastic cells contain discrete clear cytoplasmic vacuoles (vacuolar degeneration, lipid type).
- Liver: Hepatocellular carcinoma, woodchuck (Marmota monax), rodent.
- Liver: Hepatitis, portal, lymphoplasmacytic and neutrophilic, chronic, diffuse, moderate, with biliary hyperplasia, bridging fibrosis, and hepatocellular degeneration and necrosis.
ETIOLOGY: Woodchuck hepatitis virus (WHV)
ETIOLOGIC DIAGNOSIS: Hepadnaviral hepatitis and hepatocellular carcinoma
- Family Hepadnaviridae: Partially dsDNA virus; hepatotrophic family of virusus
- Genus Orthohepadnavirus (infects mammals):
- Ground squirrel hepatitis virus
- Hepatitis B virus
- Woodchuck hepatitis virus
- Woolly monkey hepatitis B virus
- Genus Avihepadnavirus (infects birds):
- Duck hepatitis B virus
- Heron hepatitis B virus
- Causes hepatitis in wild American woodchucks; strongly associated with the development of hepatocellular carcinoma
- Hepadnaviruses also cause hepatitis and increased incidence of hepatocellular carcinoma in other species, including humans and chimpanzees (human hepatitis B virus)
- The woodchuck is a valuable animal model for studying the pathogenesis of viral hepatitis and viral hepatocarcinogenicity
- Genus Orthohepadnavirus (infects mammals):
- Classifications of hepatocellular carcinoma
- Most common form
- More differentiated (closely resembles normal liver)
- Thickened trabeculae are a frequent feature
- Pseudoglandular (adenoid)
- Neoplastic hepatocytes have a lobular arrangement within a scant connective tissue stroma
- Crude acini formed by neoplastic hepatocytes
- Solid sheets of poorly differentiated, pleomorphic neoplasic hepatocytes, do not form sinusoids
- Multiple foci of ductular formation and associated extracellular matrix (the ducts stain immunohistochemically with CD 7 and 19)
- The majority of hepatocellular damage caused by WHV is induced by immunologic mechanisms, particularly through cytotoxic CD8+ T lymphocytes
- Viral DNA is integrated into the host cell genome at the c-myc or n-myc2 locus
- Normal growth control of infected hepatocytes is disrupted by transcriptional activation of host proto-oncogenes
- Venous invasion is typical of hepatocellular carcinomas
TYPICAL GROSS FINDINGS:
- Usually single primary tumor (non-pedunculated, no clear demarcation, varied coloration on cut surface d/t hemorrhage and necrosis, friable mass)
- Small intrahepatic metastases can surround the primary tumor and invade portal vessels and lymph nodes
- Spontaneous rupture can cause fatal hemoperitoneum
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Hepatocellular carcinoma growth patterns: Cords, trabeculae, acinar (adenoid) or large solid structures; multiple patterns may occur within the same neoplasm; trabecular carcinomas are the most common histologic pattern
- Invasive, poorly demarcated growth
- Disorganized, thick hepatic cords (often >4 hepatocytes thick)
- Necrosis, hemorrhage, dilated sinusoids and cystic blood and/or serum filled spaces
- Atypical or bizarre cells and/or neoplastic giant cells are a common feature in some hepatocellular carcinomas (large, multilobed, or multiple nuclei)
- Mitotic figures are more frequent in carcinomas than adenomas
- Focal to widespread lipidosis or glycogen accumulation within neoplastic hepatocytes
- Acute hepatitis: Inflammatory infiltrate confined by the limiting plate, with little or no hepatocellular necrosis and minimal fibroplasia and biliary ductular reaction
- Chronic hepatitis: Numerous inflammatory cells expanding portal areas and extending beyond the limiting plate into the parenchyma, with proliferation of bile ducts, fibroplasia, and hepatocellular necrosis
ULTRASTRUCTURE: Woodchuck hepatitis virion (aka “Dane particle”) is 42-48 nm, spherical, double-layered, with an electron-dense, 27-30 nm, slightly hexagonal or icosahedral core (nucleocapsid) surrounded by a closely adhered outer capsid or surface envelope
ADDITIONAL DIAGNOSTIC TESTS:
- Electron microscopy to demonstrate the virus is definitive
- IHC staining for canine/feline HCC – HepPar1 (binds a hepatocyte specific antigen); CK19 (marker of hepatic progenitor cells, immature hepatocytes, and biliary epithelial cells)
- Major histologic features of common hepatocellular hyperplastic and neoplastic lesions:
- Nodular hyperplasia: Middle-aged to old dogs, rare other species; variable sized 2 mm to 3 cm; usually multiple, randomly distributed, well-circumscribed, non-encapsulated, sharply distinct from surrounding parenchyma often fatty and pale with well-differentiated cords (1-2 cells thick) with focal or diffuse lipidosis or glycogen accumulation; sinusoids are often dilated with foci of hematopoiesis; the hallmark of the hyperplastic nodule is retention of normal liver architecture with maintenance of recognizable central vein and portal areas
- Regenerative nodules: Usually found in damaged, fibrotic livers, process occurs with significant fibrosis and disruption of normal parenchyma
- Hepatocellular adenoma: Usually single, may be greater than 15 cm in diameter, well-demarcated, mostly non-encapsulated, compressive with occasional markedly dilated sinusoids and cystic blood and/or serum filled spaces; usually lack central veins, bile ducts, hepatic venules, multiple portal tracts, or cholangioles; cells arranged in cords or trabelculae but typical acinar structures are absent; occasional foci of extramedullary hematopoiesis and Fe-pigment containing macrophages
- Hepatoblastoma: Rare benign neoplasm, reported in sheep, dogs, horses and a bull; cells similar to fetal hepatocytes, extramedullary hematopoiesis within mass; alpha-fetoprotein positive and some are positive for neuroendocrine markers (S100, chromogranin A and NSE)
- Hepatic carcinoids: Rare aggressive neoplasms arising from neuroendocrine cells; recognized in both extrahepatic and intrahepatic sites with metastasis to lymph nodes and peritoneum; form nests and packets with frequent mitotic figures on a fine fibrovascular stroma; diagnosis is based on the following: Neuroendocrine cell markers chromogranin A, NSE, or neurosecretory products such as glucagon or serotonin; presence of neurosecretory granules with electron microscopy or argyrophilic cytoplasmic granules detected by silver stains
- Cholangiocellular tumors can be distinguished from hepatocellular tumors by their multiplicity, firmness, white color (abundant stroma) and umbilicated appearance of those involving the capsule
- Hepatocellular carcinomas reported in many species, including humans, dogs, cats, cows, sheep, pigs, horses, fowl, woodchucks, prairie dogs, and trout
- Hepatocellular neoplasms are reportedly more common in dogs with left lateral liver lobe often affected while cholangiocellular neoplasia is more common in cats
- Chronic inflammation and hepatitis virus are associated with hepatocellular carcinoma in humans, ducks (DHBV), prairie dogs, and woodchucks
- Viral or chemical (aflatoxin, nitrosamines) etiologies are suggested in laboratory and domestic animals
- Hepadnaviruses cause hepatitis in man and chimpanzees (HBV), Beechey ground squirrels, tree squirrels, ducks (Pekin and others) and herons
- In man, HBV infection produces a wide spectrum of hepatic disease, including fulminant hepatitis and an asymptomatic carrier state
- Hepatocellular neoplasia is the most common spontaneous neoplasm in prosimians, with lung most common site of metastasis; NOT associated with hepadnaviral infection nor high iron levels and not likely due to aflotoxin B1 nor chronic inflammation
- Helicobacter hepaticus infection is associated with increased incidence and earlier onset of hepatocellular tumors in A strain mice; preceded by foci of cellular alteration
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