JPC SYSTEMIC PATHOLOGY

HEMOLYMPHATIC SYSTEM

April 2024

H-V02

 

Signalment (JPC #1350931): Unknown age and gender owl monkey 

 

HISTORY: This owl monkey was housed in a cage next to a squirrel monkey

 

HISTOPATHOLOGIC DESCRIPTION: Liver: Diffusely infiltrating portal areas and sinusoids; separating, surrounding, and replacing adjacent hepatocytes; and surrounding central veins is an unencapsulated, poorly demarcated, infiltrative, moderately cellular neoplasm composed of round cells arranged in sheets on a preexisting fibrovascular stroma. Neoplastic cells have variably distinct borders, scant amounts of eosinophilic granular cytoplasm, with a round to oval, vesiculate nucleus that is approximately 1.5 times the diameter of a red blood cell and contains 1 - 3 magenta nucleoli. The mitotic count averages 1-2 per 40x fields. Neoplastic cells are frequently within the lumen of blood vessels and sinusoids. Multifocally there is a moderate amount of single cell necrosis and low numbers of neutrophils. Diffusely, remaining hepatocytes are distended with one or more round clear vacuoles up to 20 µm in diameter (lipid) that often contain small amounts of pale green-brown granular intracytoplasmic pigment (hemosiderin or bile). 

 

MORPHOLOGIC DIAGNOSIS: Liver: Lymphoma, owl monkey (Aotus trivirgatus), nonhuman primate

 

ETIOLOGIC DIAGNOSIS: Herpesviral lymphoma

 

CAUSE: Herpesvirus saimiri (Saimiriine herpesvirus 2)

 

GENERAL DISCUSSION: 

• Family Herpesviridae (dsDNA), subfamily Gammaherpesvirinae, genus Rhadinovirus
• Herpesvirus saimiri (HSV) causes enzootic asymptomatic infections in the natural host [squirrel monkey (Saimiri sciureus)] and fatal lymphoproliferative diseases (lymphoma, lymphocytic leukemia) in susceptible species
• Susceptible species include rabbits and New World primates [marmosets (Callithrix sp), tamarins (Saguinus sp), cebus monkeys (Cebus sp), owl monkeys (Aotus sp), spider monkeys (Ateles sp), howler monkeys (Alouatta sp)]
• Serologic studies indicate more than 95% of adult squirrel monkeys are infected 
• HSV is used in research on the mechanisms of viral oncogenesis

 

PATHOGENESIS:

• In squirrel monkeys, the virus persists as latent infection in T lymphocytes
• Neoplastic cells are CD3+/CD8+ T lymphocytes 
• A majority of squirrel monkeys have HSV antibodies; transmission is horizontal through oropharyngeal secretions
• HSV produces cell protein homologues important in the pathogenic persistence in the natural host to include: D-type cyclins, interleukin-17, and complement cascade and apoptosis pathway inhibitors
• Viral encoded cyclins phosphorylate RB, promoting cell cycle progression and allowing lymphoproliferation 
• In susceptible species, HSV causes neoplastic transformation of T lymphocytes 
• Based on pathogenic phenotypes and different alleles, three subgroups are assigned: A, B, and C
• Produces two oncoproteins: Saimiri transformation-associated protein (StpC) and tyrosine kinase interacting protein (Tip) - thought to be essential for neoplastic transformation

 

TYPICAL CLINICAL FINDINGS:

• Acute form: Conjunctivitis, anorexia, depression, large oral ulcers (death can occur within 48 hours)
• Lymphocytic leukemia may or may not be present
• Clinical course varies between and within susceptible species

• Can develop lymphoma as soon as three weeks after infection

• Generalized lymphadenopathy and/or hepatosplenomegaly are typical
• Three lymphoma patterns / outcomes

• Survival less than 40 days with development of disseminated lymphoma; necrosis and severe organ invasion/replacement
• Survival between 50 -150 days with a less aggressive form involving multiple organs and associated lymphocytic leukemia
• Survival over 150 days with a well-differentiated lymphocytic lymphoma

 

TYPICAL GROSS FINDINGS:

• Multifocal nodules in the liver, spleen; occasionally solitary nodules in the kidney, orbit, and abdominal cavity
• Enlargement of lymph nodes, spleen, thymus, kidney, adrenal gland with gray-white homogenous tissue that displaces and effaces normal parenchyma
• Necro-ulcerative and vesicular glossitis of large areas of oral mucosa

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Sheets of neoplastic T lymphocytes with scant eosinophilic cytoplasm, large pleomorphic occasionally indented nuclei, distinct nucleoli, and frequent mitoses
• More aggressive form: Large pleomorphic neoplastic cells that resemble histiocytes with a high mitotic rate; often large areas of necrosis
• Less aggressive form: Neoplastic cells more closely resemble normal lymphocytes; most likely associated with leukemia
• In liver, there are frequently portal infiltrates that extend into hepatic lobules
• In kidney, neoplastic cells generally are confined to the cortex
• In lymph nodes, spleen, and thymus, neoplastic infiltrates are generally diffuse
• CNS: Usually restricted to the medulla, perivascular cuffing, neuronal/glial INIBs

 

DIFFERENTIAL DIAGNOSIS: 

 

COMPARATIVE PATHOLOGY: 

• Other Rhadinoviruses of importance:

• Retroperitoneal fibromatosis herpesvirus (RFHV): Related to HHV-8; causes peritoneal or subcutaneous masses in association with simian retrovirus-2 (SRV)
• Human herpesvirus-8: “Kaposi’s sarcoma-associated virus”; endothelial sarcomas
• Bovine herpesvirus-4 (BHV-4): Mammary pustular dermatitis; milder disease than localized form of bovine herpesvirus-2 (bovine herpes mammillitis virus)

• Other Gammaherpesviruses of importance:

• Macacine herpesvirus-4 (Cercopithecine herpesvirus-15 / “Rhesus lymphocryptovirus”): EBV-like virus; in rhesus monkeys, SIV-associated lymphoma (B-cell origin) with concurrent rhesus lymphocryptovirus infection
• Callitrichine herpesvirus-3 (Marmoset lymphocryptovirus): Induces a rapidly fatal lymphoma (principally B cell) or chronic mononucleosis-type disease in Marmosets
• Human herpesvirus-4: “Epstein-Barr virus”; Burkitt's lymphoma, infectious mononucleosis, nasopharyngeal carcinoma, hairy leukoplakia
• Ovine herpesvirus type 2 (OvHV-2): Natural host is the sheep; infected aberrant host ungulates (e.g. cattle, bison) develop malignant catarrhal fever, sheep may also develop MCF-like vasculitis (Pesavento, Vet Pathol. 2019) (genus Macavirus)
• Alcelaphine herpesvirus type 1: Natural host is the wildebeest; infected ungulates (e.g. cattle and buffalo) develop malignant catarrhal fever (genus Macavirus) (D-V15, S-V01, U-V02)
• Equid herpesvirus-5 (EHV-5): Associated with equine multinodular pulmonary fibrosis (genus Percavirus) (P-V27)

• Other oncogenic herpesviruses of importance:

• Marek's disease virus (Gallid herpesvirus 2): Atypical lymphoid proliferations in several tissues (T cell lymphoma), liver, kidney, eyes, peripheral nerves (H-V01, I-V13, N-V08)
• Ranid herpesvirus-1: “Frog herpesvirus” (genus batrachovirus) causes renal adenocarcinoma in leopard frogs (Lithobates pipiens) and other frogs

 

REFERENCES:

1. Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2^nd ed. San Diego, CA: Elsevier; 2012:8, 25, 331-332, 344, 592, 737.
2. Brannick EM, Newkirk KM, Schaefer MW. Neoplasia and Tumor Biology. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:376, 376.e1.
3. MacLachlan NJ, Dubovi EJ, eds. Herpesvirales. In: Fenner's Veterinary Virology, 5^th Ed. San Diego, CA: Elsevier. 2017:189-212.
4. Pesavento P, Dange RB, Ferreras MC. Systemic necrotizing vasculitis in sheep is associated with Ovine Herpesvirus 2. Vet Pathol. 2019;56(1):87-92.

 

 

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