JPC SYSTEMIC PATHOLOGY
INTEGUMENT SYSTEM
November 2022
I-V13
Signalment (JPC# 2061960): Broiler chicken, age and breed unspecified
HISTORY: Tissue taken at slaughter
MICROSCOPIC DESCRIPTION: Feathered skin, scalded and plucked: Multifocally expanding the dermis and subcutis, primarily surrounding follicles and to a lesser extent vessels, extending into and replacing adjacent fibroadipose tissue, and surrounding, separating, and replacing variably degenerate and necrotic erector feather muscles (mm. pennati) myocytes are low to moderate numbers of variably sized lymphocytes and few scattered macrophages. The variably sized lymphocytes range from small mature lymphocytes with scant cytoplasm, small round nuclei, and ropey chromatin to large lymphocytes with large, irregularly round nuclei and dense chromatin. Dermal and subcuticular vessels are occasionally lined by hypertrophic endothelium. Multifocally, dermal collagen is separated by a small to moderate amount of clear space (edema). Diffusely, feather follicles are devoid of feathers, and follicular epithelium is multifocally disrupted or absent (scalding artifact).
MORPHOLOGIC DIAGNOSIS: Feathered skin: Lymphoid proliferation, perifollicular, multifocal, moderate, chicken, avian.
ETIOLOGY: Gallid herpesvirus-2 [Marek's disease virus (MDV), serotype 1]
ETIOLOGIC DIAGNOSIS: Herpesviral perifolliculitis
CONDITION: Marek's disease, skin leukosis
GENERAL:
- Highly contagious disease caused by Gallid alphaherpesvirus 2 of the Mardivirus genus
- Lymphoproliferative disease characterized by infiltration of nerves and other organs with pleomorphic lymphocytes
- The most common lymphoproliferative disease of chickens worldwide; in a recent report of mortality in backyard poultry in the US, Marek’s disease was the most common cause of death in all states studied (Cadmus, Jour Vet Diagn Invest. 2019)
- Three serotypes: serotype 1 is the only oncogenic type and it is ubiquitous in chickens; serotype 2 is common in chickens; serotype 3 is ubiquitous turkeys; all have antigenic cross-reactivity and serotypes 2 and 3 used as vaccines
- Serotype 1 pathotypes: mild (mMDV), virulent (vMDV), very virulent (vvMDV), or very virulent plus (vv+MDV)
- Vaccination (developed in 1970) has reduced the incidence of clinical disease but not infection, creating concern that there is selection for increasingly virulent strains
PATHOGENESIS:
- Enveloped virus (cell-free) shed primarily in feather follicle dander, also present in excretions/secretions but of lesser importance; infection through inhalation
- Subclinically infected birds can carry and shed virus throughout their lifetime
- Vertical transmission does not occur
- Four phases of infection (Crespo, Pathology of Wildlife and Zoo Animals. 2018)
- Inhalation of virus à infection of respiratory epithelial cells and local macrophages à viremia à cytolytic viral replication in lymphocytes
- Latency in CD4+ T cells à systemic viral spread, including cutaneous viral infection, replication, and shedding
- Reactivation of CD4+ T cells à late cytolytic stage and immunosuppression
- Viral reactivation and neoplastic transformation of CD4+ T cells
- Important MD-specific genes:
- Meq (MDV-EcoRI-Q): oncogene; one of the most important determinants of oncogenicity (Kurokawa, J Vet Diagn. Invest. 2022)
- vTR: viral homologue of telomerase (Wilson, J Vet Diagn. Invest. 2022)
- pp38: virus replication (Crespo, Pathology of Wildlife and Zoo Animals. 2018)
TYPICAL CLINICAL FINDINGS:
- Clinical signs peak between 2 and 5 months of age; do not appear before 3 weeks
- Asymmetric partial paralysis due to peripheral nerve involvement
- Dilation of the crop due to vagal nerve paralysis
- Blindness if iris involved
- Depression, cachexia if visceral tumors present
- Outbreaks in vaccinated layers can occur after onset of egg production (> 5 months) associated with vv+ MDV, called “late Marek’s”
TYPICAL GROSS FINDINGS:
- Feather follicle enlargement with reddening (skin leukosis, Alabama redleg)
- Visceral tumors (most common): liver (big liver disease), heart, spleen, gonad, kidney, proventriculus, others; may occur as focal nodular growths of varying sizes or diffuse enlargement
- Asymmetrical enlargement of peripheral nerves and/or yellowing, loss of cross striations (fowl or range paralysis, classical Marek’s, neurolymphomatosis)
- Discoloration of iris, irregular pupil
- Bursal and thymic atrophy, or rarely diffuse enlargement (Crespo, Pathology of Wildlife and Zoo Animals. 2018)
TYPICAL MICROSCOPIC FINDINGS:
- Generally a mixture of pleomorphic lymphocytes that likely represent neoplastic CD-4+ T-cells and reactive/inflammatory populations (reactive B/T cells, macrophages)
- Transformed MD-infected T-cells often overexpress an activated T-cell surface marker, MD tumor-associated surface antigen (MATSA) and only few are positive for IgM
- Skin: Lymphocytes localized around feather follicles; eosinophilic intranuclear inclusion bodies may occur within transitional zone and stratum corneum of feather follicle epithelium (Crespo, Pathology of Wildlife and Zoo Animals. 2018)
- Peripheral nerves: May have edema, demyelination (Crespo, Pathology of Wildlife and Zoo Animals. 2018)
- CNS: Cerebral perivascular cuffing, vasculitis, edema, gliosis, lymphocytic meningitis (Crespo, Pathology of Wildlife and Zoo Animals. 2018)
- Visceral organs: Most common site for lymphoid tumors
- Eye: Present in anterior and posterior uvea (Crespo, Pathology of Wildlife and Zoo Animals. 2018)
ULTRASTRUCTURE:
- Enveloped 150-160 nm diameter, dsDNA virus with 85-100 nm icosahedral nucleocapsid
- Virions are common in the nucleus but rare in cytoplasm and extracellular spaces
- Within feather follicle epithelium, the enveloped viral particles are 273-400 nm
ADDITIONAL DIAGNOSTIC TESTS:
- Histologic examination (with IHC to determine lymphocyte type) and real-time PCR to quantify MDV copies are reliable methods for diagnosis (Kurokawa 2022)
- IHC recently developed for MeQ (Kurokawa 2022)
- Virus isolation, conventional PCR, or antibody serology alone are not confirmatory as the virus is ubiquitous and most chicken flocks are persistently infected
DIFFERENTIAL DIAGNOSIS:
Other causes of lymphoproliferative disease in chickens:
- Lymphoid leukosis (avian leukosis, retrovirus): see chart below
- Reticuloendotheliosis virus (retrovirus): Causes non-neoplastic runting syndrome (bursal and thymic atrophy), acute neoplastic disease resulting in T-cell lymphomas (resembles Marek’s disease), and chronic neoplastic disease resulting in B-cell lymphomas (resembles lymphoid leukosis); in chickens, turkeys, ducks, quail, and geese after either experimental or accidental infection from contaminated vaccines
- Recent report in three flocks in China of coinfection with ALV subgroup J, MDV, and REV; fluorescent multiplex immunohistochemistry revealed individual cells coinfected with all three viruses (Liu 2019)
|
FEATURES |
LYMPHOID LEUKOSIS |
MAREK'S DISEASE |
|
Etiology |
Type C Retrovirus |
Alphaherpesvirus |
|
Age |
> 16 weeks |
> 4 weeks (usually 2-5 months) |
|
Paralysis |
Absent |
Present |
|
Bursa of Fabricius |
Nodular tumor |
Diffuse enlargement, or atrophy (or no lesions) |
|
Skin or Muscle Involvement |
Absent |
May be present |
|
Peripheral Nerve Infiltration |
Absent |
Present |
|
Bursal Proliferation |
Intrafollicular |
Interfollicular |
|
Lymphoid Cells |
Uniform blasts |
Pleomorphic |
|
Tumor Cell Type |
Predominantly B-cells |
Predominantly T-cells |
|
Tumor Cell |
> 90% IgM+ |
< 5% IgM+ |
Other chicken skin tumors:
- Keratoacanthoma (dermal squamous cell carcinoma, I-N05): Nodular to ulcerative neoplasm often with central crater and with central keratin-filled core
- Feather folliculoma: Cystic, multilobulated neoplasm lined by basaloid cells that undergo abrupt keratinization and exhibit feather formation
- Cutaneous hemangioma, fibroma/sarcoma, myxoma/sarcoma: Usually induced by retroviruses
- Xanthoma (I-M03): Non-neoplastic yellow to orange nodules composed of foamy macrophages, Touton multinucleated giant cells, and acicular cholesterol clefts
COMPARATIVE PATHOLOGY:
Marek’s disease in other avian species:
- Less common in quail, turkeys, pheasants, jungle fowl
- Recent case report in single Indian peafowl with unilateral ocular swelling, paraparesis (Wilson 2022)
Other Oncogenic Viruses:
|
FAMILY |
VIRUS |
SPECIES |
NEOPLASM |
|
Adenoviridae |
Various Strains |
Hamster |
Experimental Sarcomas |
|
Hepadnaviridae |
Hepatitis B Virus (Orthohepadnavirus) |
Human |
Hepatocellular Carcinoma |
|
Woodchuck Hepatitis Virus (Orthohepadnavirus) |
Wood-chuck |
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 |
|
|
Herpes saimiri & H. ateles (Gammaherpesvirus) |
NHPs |
Lymphoma |
|
|
Herpes sylvilagus (Gammaherpesvirus) |
Rabbit |
Lymphoma |
|
|
Ranid Herpesvirus (Unclassified) |
Leopard Frog |
Renal Adenocarcinoma |
|
|
Papovaviridae |
Polyomaviruses |
Mouse & Hamster |
Experimental carcinomas, sarcomas; trichoepithelioma (hamster) |
|
Simian Virus 40 (SV40) |
Rodents |
Experimental Sarcomas |
|
|
Papillomaviruses |
Many |
Papillomas, Carcinomas |
|
|
Poxviridae |
Yaba Virus (Yatapoxvirus) |
Rhesus Macaque |
Histiocytoma |
|
Shope Fibroma Virus (Leporipoxvirus) |
Rabbit |
Fibroma, Myxoma |
|
|
Flaviviridae |
Hepatitis C Virus |
Human |
Hepatocellular Carcinoma |
|
Retriviridae |
Mammary Tumor Virus |
Mouse |
Mammary Adenocarcinoma |
|
Murine Leukemia & Sarcoma Viruses |
Mouse |
Leukemia, Lymphoma, & Sarcoma |
|
|
Feline Leukemia & Sarcoma Viruses |
Cat |
Leukemia, Lymphoma, & Sarcoma |
|
|
Avian Leukosis Virus |
Chicken |
Lymphoma |
|
|
Reticuloendotheliosis Virus |
Chicken |
Lymphoma |
|
|
Lymphoproliferative Disease Virus (LPDV) |
Turkey |
Lymphoma |
|
|
Jaagsiekte Retrovirus (JSRV) |
Sheep |
Pulmonary Carcinoma |
|
|
Ovine and Caprine Nasal Adenocarcinoma Retrovirus |
Sheep and Goats |
Nasal Adenocarcinoma |
|
|
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 |
REFERENCES:
- Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: John Wiley and Sons Inc.; 2016:39-44, 176-178, 262-264.
- Boulianne M, et al. Avian Disease Manual. 8th ed. Jacksonville, FL: AAAP;2019: 34-40.
- Cadmus K, 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.
- Crespo R, Franca MS, Fenton H, Shivaprasad HL. Galliforms and Columbiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 747-748.
- Kurokawa A, Yamamoto Y. Development of monoclonal antibodies specific to Marek disease virus-EcoRI-Q (Meq) for the immunohistochemical diagnosis of Marek disease using formalin-fixed, paraffin-embedded samples. J Vet Diagn Invest. 2022; 34(3): 458-464.
- Liu H, Ma K, Liu M, et al. Histologic findings and viral antigen distribution in 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.
- Nair V, Gimeno I, Dunn J. Marek’s disease. In: Swayne DE, et al, eds. Diseases of Poultry. 14th ed. Ames, IA: Iowa State University Press; 2020: 550-585.
- Watchman L, Mansfield, K. Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, et al., eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2nd ed. San Diego, CA: Academic Press; 2012:6-26.
- Wilson LA, Lewis M, Baigent SJ. Marek’s Disease in an Indian Peafowl (Pavo cristatus) with Clinical Ocular Disease and Paraparesis. J Comp Pathol. 2022; 195: 7-11.
