JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
D-N09 (NP)

 

Signalment (JPC# 2547361):  6-year-old male military macaw (Ara militaris)

 

HISTORY:  Behavior and appetite were normal at time of death.  The macaw was exposed to a conure that died with nonspecific signs.

 

HISTOPATHOLOGIC DESCRIPTION:  Liver:  Effacing approximately 85% of the hepatic parenchyma and separating, surrounding, and infiltrating remaining islands of normal hepatocytes is an unencapsulated, infiltrative, moderately cellular neoplasm composed of polygonal cells arranged in irregular, branching, and anastomosing tubules and acini on a moderate fibrovascular and desmoplastic stroma. Neoplastic cells have variably distinct cell borders, a moderate amount of pale eosinophilic and vacuolated cytoplasm, and a round to oval nucleus with finely-stippled chromatin and 1-2 distinct nucleoli. The mitotic count is 1 per 10 HPF (2.37mm²), and there is occasional single cell necrosis within the neoplastic cells. Multifocally, remaining hepatocytes are occasionally swollen with lacy, microvacuolated cytoplasm (glycogen degeneration) or shrunken with brightly eosinophilic cytoplasm and a pyknotic nucleus (necrosis).  There are low numbers of lymphocytes and plasma cells scattered through the hepatic parenchyma.

 

Mucosa, oropharynx (per contributor):  Extending from a thin fibrovascular stalk is an exophytic neoplasm composed of polygonal cells undergoing squamous differentiation arranged in anastomosing trabeculae that form papillary frond-like projections supported by a highly vascular fibrous stalk.  Neoplastic cells have variably distinct cell borders, a moderate amount of eosinophilic cytoplasm, and a round to oval nucleus with finely stippled chromatin and a single prominent nucleolus.  The mitotic count is 1 per 10 HPF (2.37mm²).  Multifocally, there is parakeratotic hyperkeratosis and epidermal erosions.  Multifocally, there are moderate numbers of heterophils that transmigrate the epidermis and moderate numbers of lymphocytes and plasma cells within the dermis.

 

MORPHOLOGIC DIAGNOSIS:  

1. Liver: Cholangiocarcinoma, military macaw (Ara militaris), avian.
2. Mucosa, oropharynx (per contributor): Papilloma.

 

GENERAL DISCUSSION:

• Cholangiocarcinoma
  • Reported in dogs, cats, sheep, cattle, horses, and goats; most common avian hepatic neoplasm
  • Adenocarcinoma arising from a bile duct
  • Can be intrahepatic, hilar, or extrahepatic
  • Desmoplasia imparts a white fibrous appearance and firm texture
  • Spreads along the biliary tract to the capsule
  • Metastasizes to abdominal lymph nodes, mesentery, viscera, and lungs
  • High levels of IL-6 produced by the cholangiocytes upregulates antiapoptotic Bcl-2 and Mcl-1 making the neoplastic cells resistant to cytotoxic therapy
• Internal papillomatosis of parrots (IPP) is a disease of New World parrots
  • Papillomas are the most common neoplasm of the oral cavity and cloaca in New World psittacines
  • Psittacid herpesvirus (PsHV) genotypes 1, 2, and 3 have been linked to mucosal papillomas in New World parrots
  • Hyperplastic and neoplastic changes of bile and/or pancreatic ducts occur within increased frequency in birds with mucosal papillomas
  • Oral papillomas tend to occur at the base of tongue, margins of the choana, and glottis
  • Oral and cloacal papillomas are more common than those in the esophagus, proventriculus, and ventriculus

 

PATHOGENESIS:

• PsHV 1, 2, and 3 has been associated with internal papillomatosis and hyperplastic and neoplastic bile duct and pancreatic duct lesions in New World psitticines (particularly macaws and Amazon parrots) which can occur concurrently
• Papilloma viruses have been associated with squamous papillomas in Amazon parrots, but are not associated with mucosal papillomas in Amazon parrots and macaws
• See systemic I-V01 for further discussion of viral papillomas

 

TYPICAL CLINICAL FINDINGS:

• Cholangiocarcinoma: Emaciation, weakness, hepatomegaly, ataxia, trembling, seizures (due to hepatic encephalopathy), sudden death
• Mucosal/alimentary papillomas: Mucosal discoloration, blunting, dyschezia, vent staining, infertility (mechanical obstruction and interference with breeding), hematochezia
• Cutaneous papilloma: Slow growing, wart-like proliferations on non-feathered skin (feet, legs, face, eyelids, wing, and beak commissure)
• Cloacal papilloma: Cloacal prolapse, dyschezia, tenesmus, hematochezia, flatulence, cloacoliths, infertility

 

TYPICAL GROSS FINDINGS:

• Cholangiocarcinoma:
  • Can usually be distinguished from hepatocellular neoplasia by multiplicity, firmness, pale beige color (increased stroma), and umbilicate appearance of those involving the capsule
• Papilloma:
  • Pink to white, fleshy or cobblestone-like growths
  • May be smooth and pale in the oral cavity and esophagus
  • Single large masses or many small masses
  • Friable; bleed or bruise easily; may be ulcerated

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Cholangiocarcinoma
  • Ductules, acini, and occasionally papillary projections of columnar to cuboidal cells
  • Abundant mitotic figures
  • May induce a marked scirrhous reaction (desmosplasia)
  • Highly invasive growth pattern
  • Difficult to distinguish from metastatic adenocarcinomas
• Papilloma
  • Papillary mass with pedunculated fibrovascular connective tissue stalk
  • Heavily keratinized stratified squamous epithelium
  • May see intranuclear herpesviral inclusion bodies at junction of keratinized and non-keratinized epithelium
  • In gastrointestinal tract, may contain mucous glands
  • Inflammatory cells in the stroma

 

 

DIFFERENTIAL DIAGNOSIS:

• Cholangiocarcinoma
  • Cholangiocellular tumors are immunoreactive for: cytokeratin 7, epithelial membrane antigen/mucus 1, carcinoembryonic antigen
  • Cholangioma is a benign, commonly solitary neoplasm
  • Bile duct hyperplasia associated with hepatic lipidosis or portal fibrosis
  • Bile duct proliferation induced by chronic hepatotoxins (e.g., aflatoxicosis)
  • Hepatocellullar carcinomas are immunoreactive for: alpha-fetoprotein; HepPar-1
  • Mixed hepatocellular and cholangiocellular carcinoma: rare; IHCs as described above can confirm hepatocytic nature
• Papilloma
  • Nodular forms of avian pox, characterized by epithelial ballooning degeneration and presence of Bollinger bodies (large, lipophilic intracytoplasmic viral inclusion bodies)
  • Cutaneous/squamous papillomas in multiple avian species are linked to avian papilloma viruses

 

COMPARATIVE PATHOLOGY:

• Cholangiocarcinoma:
  • Cholangiocarcinoma occurs in all species
  • There are case reports of chemically induced cholangiocarcinomas (e.g. diethylnitrosamine)
  • Case report of cholangiocarcinoma in an aye-aye (Rodriguez-Barbon, et. al. J Comp Pathol. 2018) and vervet monkey with unique immunohistochemical staining (Suárez-Bonnet, et. al. J Comp Pathol. 2020)
• Alimentary papilloma:
  • Reported in most domestic species
  • Bovine alimentary papillomatosis is caused by bovine papillomavirus 4 (BPV-4)

 

REFERENCES:

1. Cullen JM, Stalker MJ. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:348-349.
2. Gelberg HB. Alimentary system and the peritoneum, omentum, mesentery, and peritoneal cavity. In: Zachary JF ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Elsevier Mosby; 2017:350, 454.
3. Munday JS. Bovine and human papillomaviruses: A comparative review. Vet Pathol. 2014;51(6)1063-1075.
4. Reavill DR, Dorrestein G. Psittacines, coliiformes, musophagiformes, cuculiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier Inc. 2018:783-784.
5. Rodriguez-Barbon A, Cowen R, Knott C, Hughes K, Allinson K, Williams CV, Routh A. Neoplasia in three aye-ayes (Daubentonia madagascariensis). J Comp Pathol. 2018;159:16-20.
6. Suárez-Bonnet A, Priestnall SL, Ramírez GA, Molín J, Jaber JR. Aberrant Expression of Cell Cycle Regulator 14-3-3-σ and E-Cadherin in a Metastatic Cholangiocarcinoma in a Vervet Monkey (Chlorocebus pygerythrus). J Comp Pathol. 2020;179:25-30.

 

 

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