JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

November 2022

I-V10

 

Signalment (JPC# 1902404):  Adult female European wild rabbit

 

HISTORY:  This rabbit was in poor nutritional condition and had severe bilateral swelling and erythema of the eyelids and a white ocular discharge.

 

MICROSCOPIC DESCRIPTION: Mucocutaneous junction, palpebra: Markedly and diffusely expanding the dermis and elevating the overlying ulcerated and mildly hyperplastic epidermis is an unencapsulated, poorly demarcated, infiltrative, moderately cellular proliferation of large spindle to stellate cells (myxoma cells) arranged in streams and rarely whorl around adnexa and vasculature. Spindle cells are widely separated by abundant, loose, myxomatous matrix. Spindle cells have distinct borders, a moderate amount of eosinophilic cytoplasm, and a large round to oval nucleus measuring up to 20µm in diameter with dense chromatin and indistinct nucleoli. Mitotic figures average <1 per 2.37mm². Multifocal epithelial cells within the epidermis and follicular epithelium are characterized by intracellular edema (ballooning degeneration); occasionally contain a round, 10µm, eosinophilic, intracytoplasmic viral inclusion bodies that peripheralize the nucleus; and rarely have shrunken borders with hypereosinophilic cytoplasm and karyorrhexis (necrosis). The myxomatous matrix and epithelium are infiltrated by moderate numbers of heterophils.  Multifocal blood vessel walls are infiltrated by inflammatory cells, fibrin and, rarely, necrotic debris (vasculitis). The dermis is multifocally expanded by hemorrhage, fibrin, and few small blood vessels containing fibrin thrombi. There epithelium is focally replaced by a serocellular crust subtended by a dense band of viable and degenerate heterophils (ulceration). Multifocal skeletal muscle fibers are either hypereosinophilic and homogenized with loss of striations and nuclear pyknosis (necrosis), lost and replaced by previously described spindle cells or inflammation, swollen with vacuolated sarcoplasm (degeneration), or shrunken and angular (atrophy).  

 

MORPHOLOGIC DIAGNOSIS:  Mucocutaneous junction, palpebra: Atypical mesenchymal proliferation, dermal, myxomatous, focally extensive, with ulceration, moderate heterophilic dermatitis, and epidermal and follicular epithelial ballooning degeneration with intracytoplasmic viral inclusion bodies, European rabbit (Oryctolagus cunniculus), lagomorph.

 

ETIOLOGIC DIAGNOSIS:  Cutaneous myxomatosis

 

ETIOLOGY:  Leporipoxvirus (myxoma virus)

 

CONDITION:  Myxomatosis

 

SYNONYMS:  Bighead; mosquito disease

 

GENERAL DISCUSSION: 

• Family Poxviridae, subfamily Chordopoxvirinae, genus Leporipoxvirus; double stranded DNA virus, replicates and matures within host cell cytoplasm 
• In the Americas, wild rabbits in the Americas (Sylvilagus sp.), myxoma virus causes only localized benign skin tumors; in contrast, in the European rabbit (Oryctolagus cuniculus) it causes a severe generalized disease with a very high mortality rate
• Enzootic in Sylvilagus spp. in the Americas and Oryctolagus spp. in Europe, Australia, and New Zealand
• OIE reportable disease

 

PATHOGENESIS: 

• Transmission is mainly by arthropod vectors (primarily mosquitoes in North and South America and Australia, fleas in Europe), but it can be transmitted via respiratory droplets
• Virus infects several cell types, including mucosal cells, lymphocytes, and fibroblasts
• Virus replication and tumor-like lesions occur initially at the site of intradermal inoculation, followed by spread to regional lymph nodes with systemic spread through leukocytes and generalized cell-associated viremia; virus is not found free in the serum

 

TYPICAL CLINICAL FINDINGS: 

• Clinical disease varies with virus strain and host species
  • Sylvilagus sp. infection usually results only in the development of skin tumors at the site of inoculation which appear 4-8 days after exposure; skin tumors persist for up to 40 days; very young rabbits may succumb to generalized disease
  • Oryctolagus cuniculus infection with virulent virus results in severe generalized disease with a high mortality rate
    • Within 3-4 days, development of a primary subcutaneous myxoid mass
    • Within 6-8 days, mucopurulent conjunctivitis, subcutaneous edema, and multiple subcutaneous mucoid, gelatinous masses
    • May be found dead with only conjunctival redness, if peracute form
  • Lepus species (hares) are highly resistant and only rarely develop mild to severe generalized myxomatosis
• Atypical (amyxomatous) form that results in respiratory distress without cutaneous lesions

 

TYPICAL GROSS FINDINGS: 

• Multiple subcutaneous mucinous, gelatinous masses particularly on the face and perineum 
• Nasal and conjunctival discharge; eyelid edema
• Hemorrhages in skin, heart, gastrointestinal tract, kidney, lymph nodes, and testes 
• Splenomegaly
• Lymph node edema

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Dermal proliferation of undifferentiated mesenchymal spindloid to large stellate cells (myxoma cells) separated by abundant, loose myxomatous matrix
  • Myxoma cells may also be present in lymph nodes, bone marrow, uterus, ovaries, testes, and lungs
• Epithelial hyperplasia, ballooning degeneration, and large eosinophilic intracytoplasmic viral inclusions in affected epidermis and conjunctival epithelial cells (not typically within myxoma cells)
• Combination of viral inclusions within epithelial cells and histomorphology of myxoma cells within myxomatous matrix is diagnostic
• Lymphoid depletion within spleen and lymph nodes
• Focal areas of necrosis in lymph nodes, pneumocytes, spleen, and centrilobular hepatocytes

 

ADDITIONAL DIAGNOSTIC TESTS:

• Virus isolation, IHC
• PCR (conjunctival swabs are useful ante mortem test) – virus may be shed for up to 30 days

 

ULTRASTRUCTURE:

 

DIFFERENTIAL DIAGNOSIS: 

• Shope fibroma virus (Rabbit fibromavirus - leporipoxvirus)(I-V09A):  Wild and domestic rabbits; localized fibroblast proliferation, distinguished from myxomatosis by presence of fibromas on both limbs and face; may vary from myxoid to typical fibromas; eosinophilic intracytoplasmic inclusions in epidermal cells overlying tumors and proliferating fibroblasts
• Shope papilloma virus (Cottontail rabbit papilloma virus – Kappapapillomavius-2):  Wild rabbits, hares, and jackrabbits; firm white warts and horn-like projections on head, neck, ears, and eyelids; histologic lesions include epidermal hyperplasia with parakeratotic hyperkeratosis; intracytoplasmic and intranuclear viral inclusions within epithelial cells of stratum spinosum
• Myxoma/myxosarcoma
• Rabbit pox (Poxviridae family and Orthopoxvirus genus): Rare; readily transmitted via aerosol; respiratory tract is primary replication site; papular lesions in oropharynx, respiratory tract, spleen, and liver; lesions contain multifocal necrosis with mixed inflammatory infiltrates; rabbits are used as model of variola virus infection due to similarities between smallpox and rabbitpox
• Treponema paraluis-cuniculi (I-B07):  Periorbital and genital lesions including edema, papules, and erythema; lesions progress to ulcerations and crusting; Gram-negative, filamentous spirochetes visible with Warthin-Starry and Steiner’s silver stain; asymptomatic bucks often serve as carriers; no impact on fertility; not zoonotic

 

COMPARATIVE PATHOLOGY:

• Other leporipoxviruses: 
  • Shope fibroma virus (see Differential Diagnosis above, I-V09A)
  • Squirrel fibroma virus (SFV) (I-V09B):  Firm subcutaneous/cutaneous nodules on all body areas and/or marked periorbital and periaural epidermal thickening; systemic infection in immunocompromised or juvenile squirrels; prominent eosinophilic intracytoplasmic viral inclusion bodies
  • Hare fibroma virus:  Close relative of rabbit fibroma and myxoma virus; documented infections in captive European hares; 1-3cm fibromatous lesions that most commonly arise on the legs and ears which undergo spontaneous regression in adults; large spindle and stellate cells with intracytoplasmic viral inclusions; transmitted by insect vectors and direct contact 
  • Malignant rabbit fibroma virus (MRV):  A recombinant virus of Shope fibroma virus and myxoma virus; causes generalized infection, tumors, and immunosuppression; typically fatal

 

REFERENCES: 

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:261-263.
2. Baum B. Not Just Uterine Adenocarcinoma-Neoplastic and Non-Neoplastic Masses in Domestic Pet Rabbits (Oryctolagus cuniculus): A Review. Vet Pathol. 2021;58(5):890-900.
3. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:487-489, 494.
4. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier Inc; 2016:670, 672.

 

 

 

 

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