JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2023

N-V08

 

Signalment (JPC #1690060): Chicken

 

HISTORY: This chicken developed flaccid paralysis of the legs and wings.

 

HISTOPATHOLOGIC DESCRIPTION: Peripheral nerves: Multifocally infiltrating the endoneurium and separating and surrounding individual nerve fibers and small caliber vessels are low numbers of lymphocytes with fewer plasma cells and macrophages. There are scattered aggregates of lymphocytes within the surrounding adipose tissue.

 

MORPHOLOGIC DIAGNOSIS: Peripheral nerves: Neuritis, lymphocytic, multifocal, mild, chicken, breed not specified, avian

 

ETIOLOGIC DIAGNOSIS: Alphaherpesviral neuritis

 

CAUSE: Gallid alphaherpesvirus-2 

 

CONDITION: Marek's disease 

 

CONDITION SYNONYMS: Fowl or range paralysis; polyneuritis; neurolymphomatosis; transient paralysis

 

GENERAL DISCUSSION:   

• Marek's disease (MD) is a herpesvirus-induced lymphoproliferative disease characterized by infiltration of nerves and other organs with pleomorphic T-lymphocytes
• Alphaherpesvirus of subgroup a3, Gallid-alphaherpesvirus-2 with three serotypes (Genus Mardivirus)

• Serotype 1: Cause of Marek’s disease; ubiquitous in chickens; range from nearly avirulent (mild), virulent (vMDV), very virulent (vvMDV), and very virulent plus (vv+MDV)
• Serotype 2 (“Gallid-alphaherpesvirus-3”): Common in chickens; nononcogenic
• Serotype 3 (“turkey herpesvirus” or “Meleagrid-alphaherpesvirus-1”): Ubiquitous in turkeys; nononcogenic; used as a vaccine in chickens

 

PATHOGENESIS:

• Infected feather follicle dander (most important), other excretions or secretions à inhalation à dissemination via macrophages to regional lymph nodes à cytolytic replication in lymphocytes (suppressing host ability to eliminate infected cells) à latency in CD4+ T-cells with systemic dissemination, cutaneous viral infection and shedding à reactivation of cytolytic replication and immunosuppression à proliferative/neoplastic transformation of T-cells 
• Viral transformation of T-cells promoted by various oncogenes including Meq, pp38, and viral telomerase 
• Carriers may or may not be clinically ill and can sporadically shed virus throughout their lifetime 
• No transmission through the egg or via shell contamination 

 

TYPICAL CLINICAL AND GROSS FINDINGS:  

• Most common in young, sexually immature chickens 2-7 months old, but can occur as young as 3 weeks old and in older birds (“late Marek’s” in older vaccinated birds is usually associated with more highly virulent vv+ pathotypes)
• Clinical signs dependent on organ(s) affected – common signs include asymmetrical paralysis and/or crop dilation (from nerve infiltration), depression and cachexia (from visceral tumors), and blindness (from eye infiltration) 
• Four different lesion patterns are recognized, but combinations of these are common:
  • Gross enlargement and/or yellowing of peripheral nerves; unilateral or bilateral; most common in sciatic, brachial, and vagus nerves and spinal root ganglia 
  • Discoloration of the iris and irregularly shaped pupil 
  • Nodular enlargement of feather follicles with reddening (skin leukosis)
  • Pale visceral tumors (most common) involving the liver, heart, spleen, gonad, kidney, proventriculus and other organs/tissues 
• Bursa of Fabricius: No lesions, atrophied, or rarely diffusely thickened 
• Thymic atrophy and immunosuppression 

 

TYPICAL MICROSCOPIC FINDINGS:  

• Lymphoma consisting of pleomorphic lymphocytes (positive for T-cell antigens and MD tumor associated antigen [MATSA]; minimal IgM positivity) admixed with reactive T- and B-cells in various tissues; detection of lymphoma in peripheral nerves, brain, and eye support diagnosis of Marek’s disease 
• Peripheral nerves: Lesions are termed Type A (proliferative/neoplastic with pleomorphic lymphoblastic cells) or Type B (inflammatory, small lymphocytes and plasma cells with edema)
• Brain: Lymphocytic perivascular cuffing, vasculitis, edema, gliosis, lymphocytic meningitis 
• Visceral organs: Infiltrated by pleomorphic and neoplastic T-cells 
• Eye: Anterior and posterior uvea infiltrated by neoplastic T-cells 
• Skin: May be inflammatory of neoplastic lymphocytes, usually surrounding feather follicles; there may be eosinophilic intranuclear inclusions within follicular epithelial cells (stratum corneum, transitional zone) 

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Virology and serology of little value (virus is ubiquitous) 
• IHC for antigens pp38, Meq, MATSA
• PCR of tumor from feather tips, blood, or tissues 

 

DIFFERENTIAL DIAGNOSIS:  

• Lymphoid leukosis (avian leukosis; AL or LL): Avian leukosis virus is an alpha retrovirus with10 subgroups (A-J) with lymphoid leukosis most commonly associated with subgroup A in chickens and myelocytomatosis most commonly associated with subgroup J; LL is a B-cell neoplasia of the bursa of Fabricius with metastasis to other organs, including liver, spleen, and kidney; with myelocytomatosis can see osteopetrosis of long bones, skeletal masses, hemangiomas
• Reticuloendotheliosis virus (REV-retrovirus): Non-defective REV is a gamma retrovirus that causes non-neoplastic runting syndrome (bursal and thymic atrophy, stunted growth, feather abnormalities) or chronic neoplastic disease resulting in T-cell lymphomas (resembles Marek’s disease) or B-cell lymphomas (resembles lymphoid leukosis); in chickens, turkeys, ducks, quail, and geese 

 

FEATURES	LYMPHOID LEUKOSIS	RETICULO-  ENDOTHELIOSIS (RE)	MAREK'S DISEASE
Etiology	Alpha Retrovirus (avian leukosis virus)	Gamma retrovirus (Nondefective RE-virus)	Alphaherpesvirus (Gallid alphaherpesvirus 2)
Age	>3 months (usually 4-10 months)	>1 month (usually 2-6 months)	> 3 weeks (usually 2-7 months)
Transmission	Vertical (eggs infected)	Horizontal, mosquito vectors	Horizontal (feather dander)
Paralysis	Absent	+/-	Present
Bursa of Fabricius	Nodular tumor	Atrophy	No lesions, atrophy or rarely diffuse enlargement
Skin, Muscle, or Eye Involvement	Absent	+/-	May be present
Peripheral Nerve Infiltration	Absent	+/-	Present
Osteopetrosis	Present	Absent	Absent
Bursal Proliferation	Intrafollicular	+/-	Interfollicular
Lymphoid Cells	Uniform blasts	Uniform or pleomorphic	Pleomorphic
Tumor Cell Type	Predominantly B-cells	T-cell or B-cell	Predominantly T-cells
Tumor Cell	> 90% IgM+	+/-	< 5% IgM+
MATSA (on tumor cells)	Absent	Absent	Present (5-40%)

 

 

COMPARATIVE PATHOLOGY: 

• Marek’s disease has been reported in quail and rarely in turkeys, pheasants, jungle fowl, and peafowl; ducks and geese may act as a reservoir; nerve lesions rare in these species; recent report (Dolega et al, JCP 2022) in a peafowl with hindlimb paraparesis, intraocular swelling of the right eye, and coelomic masses 
• In pet and aviary birds, there is no link between lymphoma and oncoviruses
• Other oncogenic viruses:

 

	SPECIES	NEOPLASM
DNA VIRUSES
Adenoviridae
Various strains	Hamster	Experimental sarcomas
Hepadnaviridae
Hepatitis B Virus (Orthohepadnavirus)	Human	Hepatocellular carcinoma
Woodchuck Hepatitis Virus (Orthohepadnavirus)	Woodchuck	Hepatocellular carcinoma
Duck Hepatitis Virus (Avihepadnavirus)	Duck	Hepatocellular carcinoma
Herpesviridae
Marek's Disease Virus (Alphaherpesvirus)	Chicken	Lymphoma
Epstein-Barr Virus (EBV) (Gammaherpesvirus)	Human	Burkitt's lymphoma, nasopharyngeal carcinoma
Macacine herpesvirus 4; Ateline herpesvirus 2,3; Saimirine herpesvirus 2 (H-V02) Callitrichine herpesvirus 3 (Gammaherpesviruses)	Nonhuman primates	Lymphoma
Herpes sylvilagus (Gammaherpesvirus)	Rabbit	Lymphoma
Ranid Herpesvirus-1 (Alloherpesvirus, U-V01)	Leopard frog	Renal adenocarcinoma
Papovaviridae
Polyomaviruses	Mouse & hamster	Experimental carcinomas and sarcomas; trichoepithelioma (hamster)
Simian Virus 40 (SV40)	Rodents	Experimental sarcomas
Papillomaviruses	Many species,  including humans	Papillomas, carcinomas
Poxviridae
Yaba Virus (Yatapoxvirus, I-V08)	Rhesus macaque	Histiocytoma
Shope Fibroma Virus (I-V09) Squirrel fibroma virus (I-V09)  Rabbit myxomatosis virus (I-V10) (Leporipoxvirus)	Rabbit, Squirrel	Fibroma, myxoma
RNA Viruses
Flaviviridae
Hepatitis C Virus	Human	Hepatocellular carcinoma
Retroviridae
Alpharetrovirus (Avian Type C retrovirus)
Avian Leukosis Virus	Chicken	Lymphoma
Lymphoproliferative Disease Virus (LPDV)	Turkey	Lymphoma
Mammary Tumor Virus	Mouse	Mammary adenocarcinoma
Betaretrovirus (Type B)
Mammary Tumor Virus	Mouse	Mammary adenocarcinoma
Betaretrovirus (Type D)
Jaagsiekte Retrovirus (JSRV, P-V16)	Sheep	Pulmonary carcinoma
Ovine and Caprine Nasal Adenocarcinoma Retrovirus (P-N04)	Sheep and goats	Nasal adenocarcinoma
Deltaretrovirus
Bovine Leukemia Virus (BLV)	Cattle	Lymphoma and leukemia
Human T-Lymphotropic Virus Type 1 (HTLV-1)	Human	T-Cell leukemia and lymphoma
Simian T-Lymphotropic Virus (STLV)	Nonhuman primates	T-Cell leukemia and lymphoma
Epsilonretrovirus (Type C retrovirus)
Walleye dermal sarcoma virus	Walleye	Dermal sarcoma
Gammaretrovirus (Mammalian Type C retrovirus)
Reticuloendotheliosis Virus	Chicken	Lymphoma
Murine Leukemia & Sarcoma Viruses	Mouse	Leukemia, lymphoma, & sarcoma
Feline Leukemia & Sarcoma Viruses	Cat	Leukemia, lymphoma, & sarcoma

 

References: 

1. Boulianne M, et al.   Avian Disease Manual.  7^th ed.  Jacksonville, FL: AAAP; 2013: 30-38.
2. Brannick EM, Newkirk KM, Schaefer DMW. Neoplasia and tumor biology. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th Ed. St. Louis, MO: Elsevier. 2022;376. 
3. Brochu NM, Guerin MT, Varga C, et al. A two-year prospective study on small poultry flocks in Ontario, Canada, part 2: causes of morbidity and mortality. J Vet Diagn Invest. 2019;31(3):336-342. 
4. Cadmus KJ, Mete A, Harris M, et al. Causes of mortality in backyard poultry in eight states in the United States. J Vet Diagn Invest. 2019;31(3):318-326. 
5. Crespo R, Franca MS, Fenton H, et al. Galliformes and Columbiformes. In: Terio KA, McAloose D, St. Leger J eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018: 753-754.
6. Liu H, et al. Histologic findings and viral antigen distribution in a natural coinfection of layer hens with subgroup J avian leucosis virus, Marek’s disease virus, and reticuloendotheliosis virus. J Vet Diagn Invest. 2019; 31(5): 761-765.
7. Schmidt RE, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2^nd Ed. Ames, IA: John Wiley and Sons, Inc. 2015;12, 29, 143, 181, 190, 205, 232-233, 234, 258-259, 275-276. 
8. Wilson LA, Lewis M, Baigent SJ, et al. Marek’s disease in an Indian peafowl (Pavo cristatus) with clinical ocular disease and paraparesis. J Comp Pathol. 2022;195:7-11. 

 

 

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