History

A 9-year-old 5.5-kg (12.1-lb) neutered male Pixie-Bob Cat with a history of medically managed megacolon of several years’ duration was evaluated at the Oregon State University Veterinary Teaching Hospital because of a multiday episode of nonresolving lethargy, anorexia, vomiting, and icterus.

Clinical and Gross Findings

Initially, the cat was hospitalized for a 48-hour period. Clinicopathologic analyses revealed normocytic, normochromic, nonregenerative anemia; lymphopenia; markedly high alanine aminotransferase activity; marked hyperbilirubinemia; and mildly high alkaline phosphatase activity. Whole blood γ-glutamyltransferase activity was within the reference range; whole blood aspartate aminotransferase activity was not measured. Prothrombin time and partial thromboplastin time were markedly prolonged. The cat was provided supportive care. Abdominal ultrasonography revealed a small gallbladder with a thickened, markedly hyperechoic wall (0.3 cm in thickness in all regions); a cystic, tortuous common bile duct (0.5 cm in diameter); and a moderate amount of free peritoneal fluid. Despite treatment, the cat's icterus progressively worsened and its condition deteriorated. Approximately 3 weeks after the initial evaluation, exploratory laparotomy was performed. Clear serous fluid was present in the abdominal cavity. No normal gallbladder tissue was identified; instead, a firm, 3 × 2 × 2-cm mass was located between the medial lobes of the liver. A red rubber catheter was placed in the duodenal papilla but could not be passed into the common bile duct. Owing to the cat's poor prognosis, euthanasia by IV injection of pentobarbital was performed during anesthesia.

On gross postmortem examination, the body was in fair condition with severe, generalized icterus. The gallbladder was replaced with a 3 × 2 × 2-cm, ovoid, poorly demarcated mass of firm, pale—tan tissue, the center of which was composed of a narrow lumen filled with yellow—tan caseous, necrotic material (Figure 1). Intra- and extrahepatic biliary ducts had markedly thickened walls. The common bile duct was not patent at 1 cm proximal to the major duodenal papilla, and its wall measured ≤ 0.3 cm in thickness. The pancreas was firm, and the surrounding adipose tissue had white, chalky foci of fat necrosis ≤ 0.5 cm in diameter. The descending colon was markedly dilated and filled with soft white-gray feces.

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Photograph of the liver (A), gallbladder (B), and intra- and extrahepatic bile ducts (C) of a 9-year-old neutered male Pixie-Bob Cat with a history of nonresolving anorexia, vomiting, lethargy, and icterus. Following diagnostic testing and surgical exploration, the cat was euthanized. In the liver (upper right-hand area of panel A), there are a few small, sub-capsular cysts. The liver has an enhanced reticular pattern. Necropsy revealed a firm mass in place of the gallbladder (B) and severely thickened intra- and extrahepatic bile ducts (C).

Citation: Journal of the American Veterinary Medical Association 255, 8; 10.2460/javma.255.8.899

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Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Histopathologic Findings

On histologic examination, the thick-walled mass corresponded to the gallbladder wall that had been expanded by abundant fibrous connective tissue stroma separating and often whirled around single to small clusters of epithelial cells that occasionally formed small-diameter lumens (Figure 2). The ratio of neoplastic epithelium to desmoplastic connective tissue was approximately 1:10. Neoplastic epithelial cells were cuboidal with marked atypia, anisocytosis, and anisokaryosis; high nuclear-to-cytoplasmic ratio; and infrequent mitotic figures. Nuclei were large and round to oval, with open chromatin and a single prominent nucleolus. Large areas of liquefactive necrosis involved approximately 50% of the gallbladder mass. The small cavitation filled with debris on gross examination corresponded to the gallbladder lumen and lacked an epithelial lining. Small to moderate numbers of mononuclear cells and neutrophils were scattered throughout areas with and without necrosis. Demarcation of the mass from the surrounding hepatic parenchyma was poor owing to infiltration of surrounding liver parenchyma by tumor cells and the marked, associated desmoplastic response. In the surrounding liver tissue, portal triads had mild to moderate accumulation of neutrophils and lymphocytes with fewer plasma cells and moderate biliary hyperplasia with ≤ 6 biliary profiles/portal field (Figure 3). The cytoplasm of the periacinar hepatocytes was expanded with pigmented granules (presumed to be bile and lipofuscin) and scattered discrete vacuoles (lipidosis). Pigment granules were also present in some Kupffer cells and rare macrophages in portal triads. Rare bile casts were present in biliary canaliculi, and there was marked congestion with occasional fibrin thrombi in dilated hepatic and, less commonly, portal veins. Aerobic bacterial culture of a swab specimen of the gallbladder lumen revealed 3+ hemolytic Escherichia coli and 1+ Enterococcus spp; anaerobic bacterial culture and culture for salmonellae resulted in no growth.

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Photomicrographs of a section of the firm mass in the location of the gallbladder in the cat in Figure 1. A—Atypical, pleomorphic, cuboidal cells are visible individually and arranged in haphazard ductules separated by abundant fibrous connective tissue that forms whorls around cells and tubules. H&E stain; bar = 100 μm. B—The morphology of the cells is characterized by marked anisocytosis and anisokaryosis, a high nuclear-to-cytoplasmic ratio, and infrequent mitotic figures. H&E stain; bar = 25 μm.

Citation: Journal of the American Veterinary Medical Association 255, 8; 10.2460/javma.255.8.899

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Photomicrographs of sections of the liver (A) and duodenum (B) from the cat in Figure 1. The histologic changes are indicative of triaditis. Inflammatory infiltration and fibrosis consistent with cholangiohepatitis are present in the portal regions of the liver (A). The neutrophilic infiltrate suggests ascending infection. H&E stain; bar = 25 μm. The lamina propria of the duodenum is expanded by lymphocytes and scattered plasma cells and eosinophils, consistent with inflammatory bowel disease (B). H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 255, 8; 10.2460/javma.255.8.899

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The peripancreatic adipose tissue contained a focus of neoplastic cells similar to those described in the liver; cells were surrounded by dense fibrous tissue (desmoplasia). Approximately 30% of the pancreatic lobules and a rim of peripancreatic adipose tissue were necrotic, and there was occasional saponification of the adipocytes. Neither an inflammatory cell infiltrate nor fibrosis was present in areas of necrosis.

All segments of the small intestines had mild to moderate expansion of the lamina propria by lymphocytes and plasma cells and rare eosinophils, as well as hyperplasia of crypt epithelium (Figure 3). The colon had mild expansion of the lamina propria and submucosa by lymphocytes and plasma cells; occasional crypts were dilated and filled with karyorrhectic debris. Additional microscopic findings included multifocal areas of hemorrhage in the cardiac muscle attributed to a combination of hypocoagulability and terminal disseminated intravascular coagulation. There were no notable findings in any other tissues including the kidneys, brain, and hemolymphatic system.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: cholangiocarcinoma of intra- and extrahepatic bile ducts and gallbladder, extensive neutrophilic to lymphoplasmacytic cholangiohepatitis, diffuse lymphoplasmacytic enterocolitis, and acute multifocal necrotizing pancreatitis.

Case summary: extrahepatic biliary obstruction (EHBO) as a result of cholangiocarcinoma in a Pixie-Bob Cat with suspected triaditis.

Comments

In the cat of the present report, cholangiocarcinoma resulted in EHBO. We speculated that the development of cholangiohepatitis and pancreatitis was secondary to ascending bacterial infection that resulted from a combination of reduced bile flow and chronic enteritis. In cats, cholangiocarcinomas are rare but nevertheless the most common primary hepatic tumor.¹ Cholangiocarcinomas arise from the epithelium of intra- or extrahepatic bile ducts; they may appear nodular or papillary and be locally invasive or may spread superficially along the biliary mucosa. Invasive forms commonly metastasize to regional lymph nodes. Although intrahepatic forms are more common,² extrahepatic forms of cholangiocarcinomas may develop, as highlighted by the case described in the present report. All forms of cholangiocarcinomas cause biliary obstruction to some degree, but biliary stasis is much more severe in association with extrahepatic forms as a result of global rather than regional cholestasis.^2,3 Extrahepatic bile obstruction and resulting bile stasis can lead to ascending infection and icterus.^4–6 Icterus is observed when serum bilirubin concentrations exceed 2 mg/dL and is classified as having prehepatic, hepatic, or posthepatic causes.⁴ The cat of the present report had severe primarily posthepatic icterus attributable to obstruction of bile outflow secondary to biliary cholangiocarcinoma.

Bile stasis resulting from an obstructive process such as EHBO neoplasia, pancreatitis, inflammatory bowel disease (IBD), or dysfunction of the sphincter of Oddi, is thought to predispose a patient to secondary bacterial infection of the biliary tree.^3,5 Bile stasis allows opportunistic pathogens to ascend and colonize the gallbladder and increases intestinal absorption of endotoxins, thereby exacerbating hepatocellular injury.⁷ In cats, the pancreatic and bile ducts join into the common bile duct prior to entry into the duodenum. Thus, ascending infections may extend to the pancreas with pancreatitis as potential sequela,^3,8 as was suspected for the cat of the present report. The cat may have been at even higher risk of ascending bacterial choledococystitis because of IBD. It has been postulated that IBD can lead to an immune-mediated shift in the enteric microbiome⁹; Enterococcus spp are present in higher concentrations in duodenal biopsy specimens from cats with IBD, compared with findings for duodenal biopsy specimens from healthy cats.¹⁰ Opportunistic pathogens, which commonly include E coli and Enterococcus spp (as detected in the cat of the present report), cause choledococystitis with thickening of the gallbladder wall and exacerbate the reduction of bile flow.⁶

In cats, the combination of biliary, pancreatic, and intestinal inflammation is often referred to as triaditis.^4,8 Cats with triaditis tend to have various nonspecific clinical signs associated with inflammatory lesions in several organs.⁹ Hematologic and serum biochemical alterations are often consistent among cats with triaditis, and their severity generally depends on the severity of the inflammatory lesions. Inflammatory bowel disease is commonly associated with low PCV, lymphopenia, and hypoalbuminemia. Cholangiohepatitis is associated with high circulating alanine aminotransferase activity, neutrophil count, and feline pancreatic lipase immunoreactivity. Similarly, pancreatitis is associated with increased coagulation times, serum alanine aminotransferase activity, and feline pancreatic lipase immunoreactivity and decreased PCV.^8,9 Interestingly, EHBO can also lead to increased clotting times secondary to a decreased concentration of bile salts in the small intestine.¹¹

Severe IBD, characterized by lymphoplasmacytic and neutrophilic infiltrates, has been strongly associated with concurrent cholangiohepatitis; in 1 study,⁹ 22 of 30 (73%) cats with cholangiohepatitis had concurrent IBD, and the histopathologic lesions of IBD in cats with triaditis are substantially more severe than those in cats with IBD alone. Ascending bacterial infections of the biliary system from the IBD-affected portion of the intestines are thought to contribute to development of cholangiohepatitis.

Diagnosis of primary hepatic neoplasms in cats can be challenging. Clinicopathologic findings are often vague and include lethargy, anorexia, jaundice, high circulating liver enzyme activities, and hyperbilirubinemia. Concurrent disease often masks underlying neoplasia, and differential diagnoses such as cholangiohepatitis, pancreatitis, parasitic infection, and foreign body obstruction have clinically similar features.^1,9,12 Ultrasonography fails to identify as many as 21% of primary liver neoplasms, and findings of examinations of fine-needle aspirate and surgical biopsy specimens are often nondiagnostic.¹ It is therefore important to consider cholangiocarcinoma as a differential diagnosis in cats with EHBO even when other disease processes are present.

In humans, a strong association of IBD with idiopathic primary sclerosing cholangitis exists. In cases of primary sclerosing cholangitis, intra- and extrahepatic bile ducts contain lymphocytic infiltrates, and atrophy of the epithelium and biliary proliferation are present. The progressive inflammation of the biliary tree leads to pericholangiolar (so-called onion-skin) fibrosis, which results in stricture and ultimately loss of biliary ductiles,¹³ and cholangiocarcinoma is a common sequela of primary sclerosing cholangitis associated with IBD.¹³ Fibrotic bile duct masses in cats with EHBO secondary to chronic inflammatory diseases such as triaditis have been reported,¹⁴ and cholangiocarcinoma has been linked to cholangitis caused by infection with the digenetic trematode Platynosomum fastosum.¹⁵ It is possible, albeit not probable, that chronic inflammation may have contributed to the development of cholangiocarcinoma in the cat of the present report.