JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
March 2022
M-M12

Slide A: Signalment (JPC# 75-36):  3-year-old German shepherd dog     

 

HISTORY:  This dog had a two week history of hematuria, bilateral exophthalmos, conjunctivitis, and protrusion of the nictitating membranes.

 

HISTOPATHOLOGIC DESCRIPTION:  Skeletal muscle:  Multifocally affecting 80% of the section, expanding the epimysium, perimysium, and endomysium and separating, surrounding, and replacing myocytes, often perivascularly, there are numerous eosinophils and plasma cells with fewer lymphocytes and macrophages admixed with bands of fibrous connective tissue. Myocytes exhibit polyphasic degenerative and necrotic changes characterized by: pale, swollen, and vacuolated sarcoplasm with disrupted myofibrils (degeneration); hypereosinophilic, shrunken, and fragmented or hyalinized sarcoplasm with loss of cross striations and a pyknotic or karyorrhectic nucleus (necrosis); or lightly basophilic sarcoplasm with multiple internalized, linearly arranged, vesiculate nuclei with prominent nucleoli (regeneration). There is multifocal hemorrhage, fibrin, edema, and few hemosiderin-laden macrophages, and vessels are lined by hypertrophic (reactive) endothelial cells.

 

MORPHOLOGIC DIAGNOSIS:  Skeletal muscle:  Myositis, eosinophilic, lymphoplasmacytic, and histiocytic, chronic, polyphasic, multifocal, marked, with myofiber degeneration, necrosis, loss, and regeneration, German shepherd dog, canine.

 

ETIOLOGIC DIAGNOSIS:  Immune-mediated myositis

 

CONDITION:  Masticatory myositis

 

SYNONYMS:  Previously considered two separate disorders - eosinophilic myositis and atrophic myositis

 

Slide B: Signalment (JPC# 75-37):  18-month-old heifer 

 

HISTORY:  None

 

HISTOPATHOLOGIC DESCRIPTION:  Skeletal muscle:  Diffusely infiltrating and variably (minimally to markedly) expanding the epimysium, perimysium, and endomysium, and separating, surrounding, replacing, and fragmentating myofibers are large numbers of eosinophils, fewer macrophages, and rare lymphocytes, which are often perivascular, admixed with bands of fibrous connective tissue. There is diffuse atrophy of myofibers, and rarely myocytes exhibit polyphasic degeneration and necrosis characterized by: pale, swollen, and vacuolated sarcoplasm (degeneration) or hypereosinophilic, shrunken, hyalinized and fragmented sarcoplasm with loss of cross striations and a pyknotic or karyorrhectic nucleus (necrosis). Multifocally macrophages infiltrate individual necrotic myofibers. Multifocal myocytes are expanded by intrasarcoplasmic, up to 30-50 um, protozoal cysts that contain many basophilic, oval to crescent-shaped, 1 X 3 um zoites. Vessels are lined by hypertrophic (reactive) endothelial cells, and multifocally within areas of inflammation, edema expands the tunica media, tunica adventitia, and perivascular areas of vessels. Within one focal area, myofibers are replaced by mature adipocytes.

 

MORPHOLOGIC DIAGNOSIS:  Skeletal muscle:  Myositis, eosinophilic and lymphocytic, chronic-active, diffuse, marked, with myofiber atrophy and multiple intracellular sarcocysts, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS:  Sarcocystic myositis

 

CAUSE:  Sarcocystis sp.

 

CONDITION:  Eosinophilic myositis

 

GENERAL DISCUSSION:

• Eosinophilic myositis and immune mediated myositis are two separate conditions with different etiologies and species affected, but have in common eosinophil infiltration and myofiber degeneration/necrosis in skeletal and/or cardiac muscle; immune mediated conditions will also have a lymphoplasmacytic component
• Immune-mediated myositis:
• Diagnosis dependent on determining if cellular infiltrate is causing the myofiber necrosis or if inflammation is secondary to muscle damage
  • Characterized by interstitial and perivascular infiltration of lymphocytes and/or plasma cells admixed with variable numbers of eosinophils, macrophages, and neutrophils
  • Hallmark of primary myositis = mononuclear leukocytic cells surrounding or invading intact muscle fibers, leaving a “cored out” appearance
• Myofiber necrosis occurs due to:
  • Circulating antibodies against muscle cell components
  • Cytotoxic T-cells attacking muscle
  • Immune-complex deposition leading to inflammation and ischemia
• Includes masticatory myositis of dogs, extraocular myositis of dogs, polymyositis of dogs and cats, immune-mediated myositis of horses, and other myositides
• Canine Masticatory Myositis
  • Localized to the mastricatory muscles (masseter, temporal, and pterygoid muscles), leading to fixation of the jaw
  • Previously designated as two separate disorders (eosinophilic myositis and atrophic myositis) that are now recognized to be along the spectrum of a single disease process (masticatory myositis)
  • German shepherd dogs are predisposed, but can occur in any breed
• Eosinophilic Myositis (Large Animal)
  • Relatively rare condition in cattle, horses, camelids of all ages, and sheep <2 years old; only experimentally induced in pigs
  • May be caused by a hypersensitivity reaction to the degeneration of Sarcocystis spp, a protozoal parasite of muscle; see M-P04 for more detailed information on Sarcocystis

 

PATHOGENESIS:

• Canine Masticatory myositis:
  • Canine masticatory muscles have a unique myosin isoform (type 2M myosin) and a muscle protein in the myosin binding protein C family (myositigen)
  • Various bacterial infections may lead to antibodies directed against type 2M myosin and myositigen > inflammation of the masticatory muscles > bilaterally symmetric muscle swelling > ischemia > necrosis and atrophy
  • If present, eosinophils will always be admixed with lymphocytes; lymphocytes are the primary inflammatory cell causing destruction of myofibers; there is a mixture of B and T lymphocytes with more CD4+ than CD8+ T cells
  • MHC expression may play a role in this condition
• Eosinophilic myositis (large animal):
  • Affected cattle and horses are suspected to be genetically predisposed to produce IgE in response to Sarcocystis bradyzoite antigens, leading to an abnormal response to degeneration of the cyst via a type-I hypersensitivity reaction
  • Suspected pathogenesis: sarcocyst ruptures > IgE production triggers eosinophilic inflammation > excessive numbers of eosinophils cause muscle discoloration and atrophy +/- necrosis (if granulomas occur)

 

TYPICAL CLINICAL FINDINGS:

• Canine Masticatory myositis:
  • Acute: Bilaterally symmetrical swelling of, and pain in the temporalis and masseter muscles; inability to fully open jaws (trismus); possible difficulty prehending food
    • May last up to 2-3 weeks and recur between two weeks and three years
    • Clinical pathology: serum CK and AST are normal to moderately increased +/- peripheral eosinophilia
  • Chronic or insidious cases: bilaterally symmetric atrophy of the temporal and masseter muscles and decreased jaw mobility; progressive condition if not treated and can lead to permanent inability to fully open the jaw
• Eosinophilic myositis (large animal):
  • Typically asymptomatic (lesions in skeletal muscle and heart incidentally found at slaughter); can cause sudden death due to myocarditis
  • Recent case report of a horse that presented with swelling of the right forelimb (Veronesi, J Vet Diagn Invest. 2020)

 

TYPICAL GROSS FINDINGS:

• Canine masticatory myositis:
  • Acute: Swollen, dark red, and doughy or hard masticatory muscles; cut surface reveals hemorrhagic streaks and irregular, yellow-white patches
  • Chronic: Muscular atrophy and fibrosis
• Eosinophilic myositis (large animals):
  • Well-demarcated, 0.2-6 cm, green, focal stripes or patches, which fade to off-white when exposed to air; may involve any muscle (including cardiac muscle)
  • If granulomatous, may have palpable nodules

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Masticatory myositis:
  • Multifocal polyphasic necrosis with interstitial and perivascular lymphocytic and eosinophilic inflammation; eosinophilic component varies; may also have variable numbers of plasma cells and macrophages; may be patchy
  • Lymphocytes are a mix of T and B cells with more CD4+ T cells than CD8+ T cells (distinguishes from polymyositis which is more CD8+ cells)
  • Myofiber degeneration +/- regeneration, even without obvious inflammation, in light of consistent clinical history is suspicious for myositis
  • Fibrosis of the endomysium and perimysium
• Eosinophilic myositis of cattle, sheep, and camelids:
  • Acute: numerous eosinophils separating endomysial sheaths and perimysial trabeculae +/- sarcocystic remants in the center of lesions and minimal or absent myocyte degeneration
• Chronic: dense collagenous tissue predominates with few lymphocytes, plasma cells, and histiocytes
• In some cases, may look like a granuloma with a central necrotic mass of eosinophils and muscle fibers rimmed by epithelioid macrophages, multinucleated giant cells, and fibrosis

 

ADDTIONAL DIAGNOSTIC TESTS:

• Serology for anti-type 2M myosin antibodies
• Electromyography (EMG)
• IHC: Unlike most other tissues, myocytes do NOT normally express MHC I or II; these are induced in several inflammatory/immune-mediated myopathies (Durward-Akhurst, Vet Pathol. 2018; Pagano, Vet Pathol. 2020)

 

DIFFERENTIAL DIAGNOSIS:

For atrophy of the muscles of mastication:

• Polymyositis:
  • Occurs most commonly in adult dogs of various breeds; large breeds overrepresented, especially Newfoundlands (breed associated, as young as 6 months) and German shepherd dogs
  • Do NOT have serum antibodies to 2M myosin - muscle fiber damaged mediated by CD8+ cytotoxic or suppressor T lymphocytes
  • Associated with:
    • Systemic lupus erythematosus (positive antinuclear antibody [ANA] titer)
    • Paraneoplastic disease, especially thymoma
    • Neoplastic disease, especially round cell (lymphoma, plasmacytoma, and anaplastic round cell tumors)
    • Myocarditis, inflammatory bowel disease, and thyroiditis
  • Clinical signs and gross findings variable – often present with masticatory muscle atrophy, but may also see exercise intolerance, mild to severe generalized muscle atrophy and weakness, stiff gait, pain with deep palpation, fever, regurgitation (esophageal fibrosis and megaesophagus), and respiratory distress (diaphragm dysfunction)
  • Microscopic findings:
    • Multifocal and polyphasic with interstitial and perivascular lymphocytic infiltrates (predominantly cytotoxic CD8+ T cells) and invasion of otherwise intact skeletal muscle +/- eosinophils and neutrophils; no B-cells
    • Regenerating and degenerating fibers common
    • Chronically, endomysial/perimysial fibrosis and esophageal fibrosis
  • X-linked muscular dystrophy (M-M06): prominent temporal muscle atrophy and inability to fully open mouth; non-painful; best characterized in the golden retriever
  • Idiopathic temporalis atrophy: dogs with generalized illness may develop rapid temporal muscle atrophy that resolves with treatment of the primary problem; non-painful; normal jaw mobility
  • Denervation atrophy: typically unilateral; non-painful
  • Hyperadrenocorticism (E-N08, E-N09): May cause profound temporalis muscle atrophy as well as atrophy of the muscles of the limbs and abdomen

For eosinophilic myositis: 

• Protozoa: Trichinella spiralis, Neospora caninum, Toxoplasma gondii, Hepatozoon canis, H. americanum, and Leishmania infantum
• Larval Cestodes: Cysticercosis, hydatid disease, and coenuriasis 

For lymphocytic myositis:

• Infiltration by malignant lymphoma

 

 

COMPARATIVE PATHOLOGY:

• Other immune-mediated myositis not discussed above:
  • Pembroke Welsh Corgis in Japan: immune-mediated attack directed at the tongue and facial muscles leading to muscle atrophy, fibrosis, and fat infiltration; predominately B lymphocytes and macrophages; autoantibody towards a 42-kDa molecule in skeletal muscle has been detected (NOT 2M fibers)
  • Canine extraocular muscle myositis: immune-mediated attack directed specifically at the extraocular muscles (rectus and oblique muscles); Golden Retriever dogs appear predisposed; onset at 6-18 months
    • Present with acute bilateral nonpainful exophthalmos
    • Multifocal and polyphasic; interstitial lymphocytic inflammatory infiltrates causing myofiber necrosis and regeneration
  • Feline lymphocytic polymyositis: in cats experimentally infected with FIV and in one Bengal tiger; no clinical symptoms of muscular dysfunction, but have moderately increased serum CK and interstitial/perivascular infiltration of CD8+ T-cells leading to myofiber necrosis; most commonly affects the thoracic limb muscles
    • Most reported cases of polymyositis in cats are actually degenerative polymyopathy due to hypokalemia
  • Non-human primate polymyositis: associated with SIV infection; similar to that reported in cats
  • Immuned-mediated myositis of horses (Durward-Akhurst, Vet Pathol. 2018)
    • Note – exertional and postanesthetic myopathies in horses are degenerative; not inflammatory, despite often being called “myositis”
    • Interstitial lymphocytic myositis; predominantly T-cells; uncommon
    • Necrohemorrhagic myositis due to immune complex disease from Streptococcus equi-associated purpura hemorrhagica; markedly increased serum CK and AST; muscle weakness, pain +/- dependent edema; hemorrhagic infarcts in affected muscles with vasculitis and fibrinoid necrosis of vessel walls; inflammatory infiltrates only a the periphery of necrosis; infarcts in other organs; equi often cultured from lymph nodes or guttural pouches; immune complexes composed of IgA and S. equi M protein
  • Sarcocytis affect many animals (see M-P04), but is not known to cause eosinophilic myositis

 

REFERENCES:

1. Araoz V, da Silva Silveira C, More Gaston, et al. Fatal Sarcocystis cruzi-induced eosinophilic myocarditits in a heifer in Uruguay. J Vet Diagn Invest. 2019;31(4):656-660.
2. Cooper BJ, Valentine BA. Muscle and tendon. In: Maxie MG, ed. Jubb Kennedy Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 225-229, 236-237.
3. Durward-Akhurst SA, Valberg SJ. Immune-Mediated Muscle Diseases of the Horse. Vet Pathol. 2018;55(1):68-75.
4. Pagano TB, Prisco F, De Biase D, et al. Muscular sarcocystosis in sheep associated with lymphoplasmacytic myositis and expression of major histocompatibility complex class I and II. Vet Pathol. 2020;57(2):272-280.
5. Rosol TJ, Gröne, A. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed, St. Louis, MO: Elsevier; 2016: 282.
6. Valentine BA. Skeletal muscle. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:927, 935, 942, 944-945, 949-953.
7. Veronesi F, Di Palma S, Gabrielli S, et al. Sarcocystis gigantea infection associated with granulomatous eosinophilic myositis in a horse. J Vet Diagn Invest. 2020;32(4):611-615.

 

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