21 years, 9 months old, intact female Japanese macaque (Macaca fuscata fuscata).This macaque was born and raised at the Milwaukee County Zoo (Milwaukee, WI, USA). The zoos Japanese macaque troop was formed in 1981 when 12 animals were brought in to live on Monkey Island at the zoo. Over the next 13 years, the troop had about 50 offspring. Members of the troop were relocated to other zoos in the late 1980's and again in the early 1990's. At its most populated, Monkey Island housed approximately 30-40 individuals. All males were vasectomized in the mid 1990's, with the last natural addition to the troop being born in 1995. This species, and this troop, are carriers of Cercopithecine herpersvirus 1 (B virus), so the decision was made to prevent additional births but maintain the colony throughout the lives of the remaining animals. There were 16 macaques remaining on the island at the time of this macaques death.

In early February, 2009 the keeper noted that this animals urine was dark yellow. In March, 2009 the animal became icteric. Ultrasound indicated that there was a 4 x 3 cm mass located at the head of the pancreas. The liver had an increased echogenicity and the extrahepatic and intrahepatic bile ducts were dilated and variably tortuous. Obstructive jaundice was diagnosed and euthanasia was elected due to poor prognosis and lack of response to medical management, which included antibiotics and ursodeoxycholic acid administration. The animal maintained her preclinical disease body weight of 8 kg -¦ 0.2 throughout the final months of her life. Prior to late January 2009, this animal was considered to be in good health with no significant disease(s) reported in the medical history.

Gross Description:  

Conjunctival and oral mucous membranes, skin, subcutis, and internal soft tissues including adipose tissue, nerves, and serosal surfaces are discolored yellow (icterus). The abdominal cavity contains 150 mL of yellow-orange, minimally viscous, and moderately cloudy fluid. Approximately 2.5 cm aboral from the pyloric sphincter, a 4.5 x 3 x 2.5 cm, diffusely tan, firm, lobulated mass focally effaces and expands the medial side of the duodenal wall, elevating the ulcerated mucosa and effacing the duodenal papilla. The mass extends into the adjacent head of the pancreas, encompasses and effaces the wall of the common bile duct, and extends into and around distended, bile-filled extrahepatic and intrahepatic bile ducts with mass extension and metastases scattered deep into the hepatic parenchyma. The gallbladder could not be manually expressed. The liver is enlarged based on percent body weight (4% body weight) and has slight rounding of the margins. The capsular surface of the liver is undulated and roughened by pitting. Numerous firm tan, often coalescent, masses are scattered throughout the omentum. The mesentery of the small intestine at the serosal junction is thickened (up to approximately 1 cm), firm, and tan; linear projections of this tan proliferative tissue extend into the mesentery and onto the adjacent serosal surfaces of the small intestine. Few firm tan plaque like masses are scattered along the parietal peritoneum along the ventral midline of the body wall with varying extension into the adjacent skeletal muscle and focal adherence of the omentum to the mid-ventral body wall at the level of the umbilicus.

Histopathologic Description:

The submitted slide contains duodenum, large and ectatic bile and pancreatic ducts (hepatopancreatic duct or ampulla of Vater) and includes adjacent pancreas. The section is taken from the focally expanded region of the duodenum at the major duodenal papilla. Extending from and filling the major pancreatic and common bile ducts at the opening into the major papilla (ampulla of Vater or hepatopancreatic ampulla), regionally and transmurally expanding and/or effacing the duodenum and regionally invading the adjacent pancreas is an epithelial neoplasm. The neoplastic cells form tubules and acini and small islands that are supported by and embedded within both pre-existing stroma and small to massive amounts of newly formed fibrous connective tissue of low to moderate vascularity and cellularity (desmoplasia). Neoplastic epithelial cells are polygonal to cuboidal to columnar with variably distinct cell margins and contain small to moderate amount of amorphous, eosinophilic to amphophilic cytoplasm and 1 to occasionally 2 plump oval nuclei. Nuclei contain finely to coarsely stippled chromatin and 1 to 5 variably distinct and irregular-shaped nucleoli. Mitoses vary from region to region from being rare (0-2/10HPF) to occasionally 3-4 per HPF. There is individual cell necrosis and tubular structures often contain necrotic cellular debris. Multifocally within the neoplasm are few to moderate aggregated to loosely scattered lymphocytes and plasma cells and fewer neutrophils and histiocytes/macrophages.

Not present in the submitted slide: The described epithelial neoplasm extends into the liver multifocally along portal tracts. The neoplasm is also seen within the mesentery and the visceral and parietal peritoneum of the intestine and body wall where it multifocally invades subtending smooth and skeletal muscle, respectively. Throughout examined sections of liver there is severe portal to portal bridging fibrosis with markedly accentuated lobulation of the liver. Fibrosis occasionally extends tendrils into the periportal to midzonal regions of the lobules. There are moderate numbers of lymphocytes and plasma cells scattered within the portal tracts and bile duct proliferation is marked. Moderate to marked widespread bile stasis and bile duct ectasia is present.

Morphologic Diagnosis:  

1. Ampulla of Vater (hepatopancreatic ampulla), duodenal papilla, duodenum, pancreas: Ampullary adenocarcinoma with pancreatic metastasis (local invasion).
2. Liver (not provided on submitted slide): Metastatic adenocarcinoma, portal associated and common bile duct obstruction with severe biliary ectasia and bile stasis, widespread bridging portal to portal and periportal fibrosis, bile duct hyperplasia, and portal lymphoplasmacytic hepatitis.

Lab Results:  

Urine collected from the floor early in February was positive for bilirubin. Pertinent blood chemistry results from blood collected in early March included elevated blood urea nitrogen (31 mg/dl; International Species Inventory System [ISIS]: 21 -¦ 6); decreased total calcium (8.0 mg/dl; ISIS: 9.7 -¦ 6); decreased total protein (6.1 g/dl; ISIS: 7.6 -¦ 0.8); decreased albumin (2.3 g/dl; ISIS: 4.3 -¦ 0.4); increased cholesterol (484 g/dl; ISIS: 168 -¦ 40); increased total bilirubin (6.6 mg/dl; ISIS 0.2 -¦ 0.1); increased gamma glutamyl transferase (GGT: 443 IU/L; ISIS: 61 -¦ 25); increased aspartate aminotransferase (AST: 241 IU/L; ISIS: 55 -¦ 27); increased alanine aminotransferase (ALT: 280 IU/L; ISIS: 46 -¦ 21); and increased alkaline phosphatase (ALP: 9070 IU/L; ISIS: 348 -¦ 266).


Ampullary adenocarcinoma

Contributor Comment:  

The ampulla of Vater, also referred to as the hepatopancreatic ampulla, is the site of convergence of the common bile duct and pancreatic duct within the major duodenal papilla. Ampullary adenocarcinoma is a recognized entity that is well described in humans and has been reported in a group of aged rhesus macaques (Macaca mulatta).(4,5) Adenocarcinoma of the hepatopancreatic ampulla has also been reported in a domestic cat.(3) In humans, adenocarcinoma arising from the ampulla of Vater has been reported in association with familial adenomatous polyposis.(2) The etiology in non-human primates is uncertain.

The Japanese macaque in this report was clinically diagnosed with obstructive jaundice. One month prior to any clinical evidence of jaundice, the animal was diagnosed with bilirubinuria. Bilirubinuria indicates obstruction to bile flow with conjugated bilirubin spilling into the blood. Due to the low renal threshold for conjugated bilirubin, bilirubin can be detected prior to detection of bilirubinemia and prior to clinically recognized jaundice. Increased liver enzymes supported the diagnosis of cholestasis (GGT and ALP) and indicated hepatocellular injury (AST, ALT), which can occur secondary to the damaging effects of bile acids on hepatocytes. The decrease in total protein in this patient was due to decreased albumin which was likely secondary to decreased hepatic production. Since approximately 40% of the bodys total calcium is bound to albumin, hypoalbuminemia can result in hypocalcemia as seen in this case.

JPC Diagnosis:  

Small intestine; hepatopancreatic ampulla; and pancreas: Ampullary adenocarcinoma, favor pancreatobiliary origin.

Conference Comment:  

Conference participants discussed the possible origin of this neoplasm, which includes intestinal, pancreatic, biliary, and pancreatobiliary. Based on the histomorphologic features of the neoplasm, most participants preferred pancreatobiliary origin. A recent human pathology immunohistochemical reference reports that epithelial tumors of intestinal origin are typically immunopositive for CK20 and CDX2, while pancreatobiliary types are immunopositive for CK7, MUC1 and MUC5a.(1) In this case, immunohistochemical stains performed at the AFIP demonstrated positive immunoreactivity for CK7. In humans, distinguishing between intestinal type and pancreatobiliary type ampullary adenocarcinomas is clinically important, as the latter are more aggressive and are associated with a less favorable prognosis.(1)

This case was also studied in consultation with the Department of Gastrointestinal Pathology; the pathologists from that department also favored the diagnosis of ampullary adenocarcinoma of pancreatobiliary origin based on the mixture of well-formed ductal structures and small infiltrative nests. The gastrointestinal specialty pathologists interpreted the involvement of the duodenal mucosa as local invasion of malignant epithelial cells, although they could not completely exclude the possibility of a primary neoplasm arising in the duodenum.

The comprehensive clinical pathology data and corresponding interpretation from the contributor provide an informative synopsis of the effects of hepatic disease on various clinical chemistry parameters.

We would like to thank the Department of Gastrointestinal Pathology for their review of this case and Dr. Nancy Dow of that department for her comments.


1. Basturk O, Farris AB III, Adsay NV. Immunohistology of the pancreas, biliary tract, and liver. In: Dabbs DJ, ed. Diagnostic Immuhistochemistry: Theranostic and Genomic Applications. Philadelphia, PA: Saunders Elsevier; 2010:563-564.

2. Bjork J, Akerbrant H, Iselius L, et al. Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: cumulative risks and APC gene mutations. Gastroenterol. 2001;121:1127-1135.

3. Haines VL, Brown PR, Hruban RH, et al. Adenocarcinoma of the hepatopancreatic ampulla in a domestic cat. Vet Pathol. 1996;33:439-441.

4. Schirmacher P, Buchler MW. Ampullary adenocarcinoma-differentiation matters. BMC Cancer. 2008;8:251.

5. Usborne AL, Bolton ID. Ampullary carcinoma in a group of aged Rhesus Macaques (Macaca mulatta). Comp Med. 2004;54(4):438-442.

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