Signalment:  

Adult male rhesus macaque, (Macaca mulatta).This SIV infected adult male Rhesus macaque had a several month history of severe icterus and subsequent terminal malaise, the pathogenesis of which was undetermined. It was sacrificed at its study endpoint and submitted for necropsy evaluation.

Gross Description:  

The pancreas was described as markedly enlarged and firm, with mottled areas of hemorrhage and an accentuated lobular pattern. Some patchy regions of normal appearing parenchyma remained.

Histopathologic Description:

H&E sections of grossly abnormal pancreas are examined. There is massive, near diffuse necrosis of most lobules, with many demonstrating extensive hemorrhage, severe infiltrates of degenerative neutrophils and prominent acinar cell necrosis, with pyknosis, karyorrhexis and karyolysis. Some sections contain small adjacent and adhered portions of splenic parenchyma, in which there is moderate eosinophilic hyaline amyloid type material centrally within white pulp areas. In many necrotic lobules, remaining identifiable acinar cells contain extremely large basophilic or amphophilic intranuclear inclusion bodies, generally filling and expanding the entire nucleus and sometimes appearing to fuse with cytoplasmic contents, creating nucleocytoplasmic blurring (smudge cells). On highest light microscopy magnification, some of these inclusion structures have a fine interlaced or lattice type pattern visible. Inclusions are noted less frequently in remaining pancreatic ductal epithelium as well.

In addition, some lobules not completely necrotic demonstrate prominent regenerative hyperplasia with some atypia. Islet cell structures were infrequently observed and when visible, did not have evidence of primary viral cytopathic effect.

Although the organ was extensively effaced by this necrotizing process, there were small, patchy remaining areas of relatively normal appearing parenchyma (not generally seen in sections distributed). In some sections, overlying pancreatic capsule was markedly thickened and fibrotic, with infrequent fibrous adhesive tags.

Morphologic Diagnosis:  

Pancreatitis, necrotizing and hemorrhagic, focally extensive to near diffuse, severe, with large basophilic and amphophilic intranuclear inclusion bodies and regions of marked regenerative hyperplasia (some sections).

Condition:  

Simian adenovirus 23

Contributor Comment:  

The microscopic findings are consistent morphologically with the entity of Adenoviral pancreatitis. This spontaneously occurring condition was originally described from a single case in the early 1970s(5) and further reported in the literature as additional individual entities or small clusters on subsequent occasions.(2,3,9,11,12) The paucity of both total cases described as well as absence from retrospective surveys suggests that although this is clearly a defined and consistent entity, it is not a commonly occurring one. An association between retroviral infection and adenoviral pancreatitis has been noted,(6,11) although SIV or other immunosuppressive agents do not appear to be a necessary condition for infection. Most cases are diagnosed based on visualization of characteristic inclusion bodies and the presence of typical adenoviral ultrastructural morphology. In two cases where viral culture has been performed, Adenovirus types 23 and 31 have been isolated.(11,12) Disease has been reported in both juvenile and adult animals, although, unlike this case, the clinical course is typically short, with a rapid (1-2 week) demise, often accompanied by severe bloody diarrhea.(3) Classical signs of acute pancreatitis as described in humans and domestic animal species such as abdominal pain and vomiting are not described. As in previously reported cases of this distinct clinical entity, viral inclusion bodies were not noted outside of the pancreas.(3,5,9,11) However, in several cases of fatal adenoviral pneumonia in non-human primates, intranuclear inclusion bodies were also occasionally observed in bile duct and pancreatic duct epithelium.(10) The presenting jaundiced condition seen in this animal was thought to be due to compression and obstruction of the common bile duct due to pancreatic parenchymal swelling and necrosis. Concurrent hepatic histological findings included prominent canalicular and ductal bile stasis, biliary ductal hyperplasia and mild cholecystitis. Inclusion bodies or other viral cytopathic effects were not noted in hepatocytes or biliary epithelium in this case. 

Adenovirus has been isolated from a wide variety of tissues from healthy monkeys(6) and consensus suggests that these viruses usually exist in a latent state, only rarely causing disease,(3) although fatal adenoviral pneumonia has been encountered in a wide range of simian primates.(10) The immunofluorescent-demonstrated presence of duodenal adenovirus antigen was documented in two cases of monkeys with adenoviral pancreatitis and this, along with the common concurrent presence of clinical enteric disease suggests that pancreatic infection may occur from GI ascension through pancreatic ducts.(3) Adenovirus enteritis has been documented in SIV infected Rhesus monkeys.(6)

Necrotizing pancreatitis in animals is not typically associated with an infectious pathogenesis. Foals have been reported to have naturally occurring adenoviral pancreatitis, although this appears as part of a widespread infection with primary lung and other tissue involvement.(13) Experimental pancreatitis has been induced in mice with a wide variety of viruses including Encephalomyocarditis virus (EMC), Reovirus, Coxsackie B virus, Foot and Mouth Disease virus, Venezuelan Equine Encephalomyelitis virus and others.(5,7) Economou & Zissis and others have enumerated infectious causes of acute pancreatitis in humans,(1,4) including multiple viruses such as Mumps, Coxsackie B virus and Hepatitis B virus, although it appears that many of these associations are based on antibody titer presence, clinical presentation and the exclusion of other known causes. 

JPC Diagnosis:  

Pancreas: Pancreatitis, necrotizing, diffuse, severe, with marked acinar atrophy and loss, and numerous intranuclear viral inclusions. 

Conference Comment:  

In the most common adenoviral diseases of veterinary importance, including the equine adenovirus-1 (intestinal epithelial cells of SCID foals), canine adenovirus-2 (alveolar macrophages of dogs with kennel cough), canine adenovirus-1 (hepatocytes and endothelial cells of unvaccinated puppies), and adenoviral infection of macaques (pancreatic acinar cells of nonhuman primates), the characteristic intranuclear amphophilic inclusions are readily recognized and often associated with prior immune suppression. Adenoviruses occur worldwide and are generally species specific, although transmission between closely-related species can occur, including zoonotic transmission between monkeys and people.(14) Approximately 50 adenoviral serotypes have been identified in nonhuman primates. 

Adenoviruses eject DNA from the viral capsid and into the nucleus, where subsequent DNA and protein synthesis create the distinctive inclusions and ultimately result in death of the cell. Ultrastructurally, the inclusions are composed of prominent paracrystalline arrays of virions and unassembled capsid proteins. Respiratory and gastrointestinal epithelial cells are the most common targets of viral replication; however, the epithelial cells of the conjunctiva, cornea, urinary bladder, and kidney, in addition to hepatocytes and pancreatic acinar cells, can also be infected. Although adenoviral inclusions are generally quite distinctive, they can resemble those of cytomegalovirus (herpesvirus) and SV40 (polyomavirus), which also cause significant cytomegaly and nucleomegaly.(14)

References:

1. Adler JB, Mazzotta SA, Barkin JS. Pancreatitis caused by measles, mumps and rubella vaccine (Case report). Pancreas. 1991;6:489-490. 

2. Baskin GB, Murphey-Corb, M, Watson A, Martin LN. Necropsy findings in Rhesus monkeys experimentally infected with cultured Simian Immunodeficiency Virus (SIV)/Delta. Vet Pathol. 1988;25:456-467. 

3. Baskin GB, Soike KF. Adenovirus Enteritis in SIV-infected Rhesus monkeys. Journal of Infectious Diseases. 1989;160(5):905-906.

4. Boyce JT, Giddens WE, Valerio M. Simian adenoviral pneumonia. Am J of Path. 1978;91(2):259-276.

5. Chandler FW, Callaway CS, Adams SR. Pancreatitis associated Adenovirus in a Rhesus monkey. Vet Pathol. 1974;11:165-171.

6. Chandler FW, McClure HM. Adenoviral Pancreatitis in Rhesus monkeys: current knowledge. Vet Pathol. 1982;19(Supp. 7):171-180.

7. Craighead JE, Kanich RE, Kessler JB. Lesions of the Islets of Langerhans in Encephalomyocarditis virus infected mice with diabetes mellitus-like disease. Am J of Path. 1974;74(2):287-294.

8. Daniel MD, Desrosiers RC, Letvin NL, King NW, Schmidt DK, Sehgal P, Hunt RD. Simian models for AIDS. Cancer Detection and Prevention Supplement. 1987;1:501-507.

9. Daniel MD, Letvin NL, Sehgal PK, Desrosiers RC, Hunt RD, Waldron LM. Induction of AIDS-like disease in macaque monkeys with T-Cell tropic retrovirus STLV-III. Science. 1985;230:71.

10. Economou M, Zissis M. Infectious cases of acute pancreatitis. Annals of Gastroenterology. 2000;13(2):98-101.

11. Martin BJ, Dysko RC, Chrisp CE. Pancreatitis associated with Simian Adenovirus 23 in a Rhesus monkey. Laboratory Animal Science. 1991;41(4):382-384.

12. McClure HM, Chandler FW, Hierholzer JC. Necrotizing pancreatitis due to Simian Adenovirus Type 31 in a Rhesus monkey. Arch Pathol Lab Med. 1978;102:150-153.

13. McChesney AE, England JJ, Adcock JL, Stackhouse LL, Chow TL. Adenoviral infection in suckling Arabian foals. Vet Pathol. 1970;7:547-565. 

14. Wachtman L, Mansfield K. Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol. 2. 2nd ed. San Diego, CA: Academic Press; 2012:28-30.

Click the slide to view.

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3-1. Pancreas

3-2. Pancreas

3-3. Pancreas

3-4. Pancreas

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