JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
APRIL 2022
M-N08

SIGNALMENT (NIEHS#15-0076):  11.5-month-old male B6.129-Trp53^tm1Brd mouse

 

HISTORY:  This mouse was exposed to a chemical via inhalation for 5 days a week for up to 8 weeks.  At the end of the exposure period the mouse was held without further exposure until death.  The mouse died prior to the time of scheduled sacrifice.

 

GROSS PATHOLOGY: Subcutaneous mass located above and around the right front shoulder.

 

HISTOPATHOLOGIC DESCRIPTION:  Striated muscle and fibrovascular tissue, right shoulder (per contributor):  Infiltrating and effacing normal skeletal muscle and subcutaneous adipose tissue is an unencapsulated, well circumscribed, 2x2cm, densely cellular neoplasm composed of tightly packed moderately to highly pleomorphic spindle cells  arranged in disorganized interlacing streams, bundles, and solidly cellular sheets on a scant collagenous matrix surrounded by multifocal areas of coagulative and lytic necrosis and hemorrhage, fibrin, and edema.  Neoplastic cells have indistinct borders, a moderate to abundant amount of eosinophilic fibrillar to vacuolated cytoplasm, and a large, eccentrically located pleomorphic nucleus with finely stippled chromatin and 1-4 nucleoli. Mitoses average 1-4 per 2.37mm² and are occasionally bizarre.  Anisokaryosis and anisocytosis are marked. Multinucleated and karyomegalic cells are numerous and occasionally these cells contain nuclei that line up within elongated cytoplasm (strap cells), or rarely, are globoid with one end tapering into an elongate or wispy tail (racquet cell).  These cells contain large, round eosinophilic glycogen inclusions and rarely very faint cytoplasmic cross striations.  Multifocally scattered throughout are small numbers of neutrophils.  Adjacent pre-existing muscle fibers are surrounded, separated, and shrunken (atrophy) or are swollen with loss of cross striations (degeneration).

 

MORPHOLOGIC DIAGNOSIS:  Striated muscle and fibrovascular tissue, right shoulder (per contributor): Rhabdomyosarcoma, B6.129-Trp53^tm1Brd mouse, murine.

 

GENERAL DISCUSSION:

• Rhabdomyosarcoma (RMS) is a rare type of sarcoma arising from pluripotent progenitor cells that differentiate towards skeletal muscle
• They can arise in skeletal muscle, but more commonly occur in locations that normally lack skeletal muscle
• Typically aggressive with rapid growth, local invasion, and metastasis to unusual locations (i.e. other muscles, heart, spinal cord, as well as lung, liver, and spleen)
• Embryonal RMS and its botryoid variant are the most common form in animals
• Embryonal RMS
  • Round/myoblast-like (most common) or elongated/myotube-like (strap cells)
  • Mononuclear to multinucleated
  • Most common in young animals involving the head or neck; an important differential for non-histiocytic, non-lymphoid round cell neoplasms of the head and neck
• Botryoid variant of embryonal RMS (U-N03)
  • Most often in the trigone area of urinary bladder in young large breed dogs; occurs in females more than males
  • Spindle and stellate cells within myxoid stroma
• Alveolar RMS
  • Sheets of undifferentiated small round cells, forming alveolar-like structure
• Pleomorphic RMS
  • Least common; must completely lack features of embryonal and alveolar rhabodomyosarcomas
• Cardiac rhabdomyosarcoma
  • Rare, only reported in dogs; poorly differentiated and invasive

 

PATHOGENESIS:

• Animal models indicate that suppression of p53 is required for tumor development
• Cytogenetic abnormalities play a role in human RMS, unknown in animals
• Possible genetic component as related litters of pigs developed RMS

 

TYPICAL CLINICAL FINDINGS:

• Fleshy growth in a variety of locations
• Botryoid RMS can cause urinary obstruction (dysuria, stranguria, and hematuria) and be associated with hypertrophic osteopathy

 

TYPICAL GROSS FINDINGS:

• Pink, fleshy mass most often affecting the head, neck, urinary bladder, tongue, larynx, heart, or orbit, but can occur anywhere
• Botryoid RMS most often occur in the trigone of bladder as polypoid, grape-like (i.e. botryoid) masses protruding into the lumen

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Highly variable presentation- round cells, spindle cells, or mixed morphologies
  • Primitive embryonal round cells with either prominent eosinophilic cytoplasm (rhabdomyoblasts), or indistinct cytoplasm (lymphoid-like appearance), and rare cross striations
  • More differentiated spindle cells with myotube formation, multinucleation, frequent cross striations, and strap/racquet cells
• Often considerable pleomorphism with multinucleated cells
• Cross striations when present aide the diagnosis, but are often not seen; polarized light microscopy may assist in visualization
• Elongated ‘strap’ cells or ovoid ‘racquet’ cells may be present

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Electron microscopy –primitive myofilaments and Z-band structures
• Phosphotungstic acid hematoxylin (PTAH): highlights cross striations, which are variably present depending on differentiation
• Immunohistochemistry:
  • Positive for: vimentin, desmin, muscle specific actin, sarcomeric actin, myoglobin, myogenin, and MyoD1
    • Sarcomeric actin, myoglobin, myogenin and MyoD1 are specific for skeletal muscle
    • Myogenin and MyoD1 are skeletal muscle specific nuclear transcription factors expressed early in skeletal muscle development (Tuohy, Vet Pathol. 2021)
      • MyoD1 expression is associated with immature rhabdomyoblasts that have a higher proliferative capacity
      • Myogenin is expressed during myoblast fusion and is associated with exit from the cell cycle
      • RMSs that are composed of relatively undifferentiated cells are expected to express less desmin, actin, myosin, and myoglobin and more MyoD1 and myogenin
    • Negative for: cytokeratin, smooth muscle actin

 

DIFFERENTIAL DIAGNOSIS:

• Poorly differentiated and multinucleated sarcomas (that do not express muscle markers) are often misdiagnosed as rhabdomyosarcoma
• Rhabdomyoma – most often occurs as a round cell tumor in the larynx of adult dogs
• Leiomyosarcoma - smooth muscle actin positive
• Tumors metastatic to muscle
• Soft tissue sarcoma
• Lymphoma
• Oncocytoma
• Chondroma/sarcoma
• Osteochondroma (larynx)
• Liposarcoma, hibernoma, and rhabdomyosarcoma share some overlapping histologic and IHC features (desmin and myogenin) (LaDouceur, Vet Pathol. 2017)

 

COMPARATIVE PATHOLOGY:

• Reported in numerous species, including horses, cats, pigs, goats, sheep, rhesus macaques, rodents, camelids, turtles, fish, among others
• Mice: A strain and BALBc overrepresented as well as GEMs and SCID
• Dog:
• Laryngeal rhabdomyomas (non-invasive, low mitoses, no metastasis)
• Case report of esophageal embryonal rhabdomyosarcoma (Devriendt, J Comp Pathol. 2017)
• Case report of primary meningeal rhabdomyosarcoma of spinal cord (Hoon-Hanks, J Comp Pathol. 2018)
• Pig: Cardiac rhabdomyoma (some consider it a hamartoma); possible Purkinje cell orgin (PGP 9.5 expression)
• Guinea pig: Cardiac rhabdomyomatosis (C-M02)

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. West Sussex, UK. John Wiley & Sons, Inc.; 2016: 115-116, 241-242.
2. Caserto BG. Comparative review of canine and human rhabdomyosarcoma with emphasis on classification and pathogenesis. Vet Pathol. 2013; 50:806-826.
3. Cooper BJ, Valentine BA. Muscle and Tendon. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St Louis, MO: Elsevier; 2016: 241-243.
4. Devriendt N, Van Brantegem L, Willems A, et al. Embryonal Rhabdomyosarcoma of the Oesophagus in a Young Dog. J Comp Pathol. 2017;156(1):21-24.
5. Hoon-Hanks LL, Frank CB, Edmondson EF. Primary Meningeal Rhabdomyosarcoma of the Spinal Cord of a Young Dog with Neuromelanocytosis and Multiple Cutaneous Neurofibromas. J Comp Pathol. 2018;165:57-61.
6. LaDouceur EEB, Stevens SE, Wood J, Reilly CM. Immunoreactivity of canine liposarcoma to muscle and brown adipose antigens. Vet Pathol. 2017; 54(6); 885-891.
7. Schwarz S, Mathes K, Wohlsein P. Rhabdomyosarcoma on the Forelimb of a Common Musk Turtle (Sternotherus odoratus). J Comp Pathol. 2021;186:73-76.
8. Tuohy JL, Byer BJ, Royer S, et. al. Evaluation of Myogenin and MyoD1 as Immunohistochemical Markers of Canine Rhabdomyosarcoma. Vet Pathol. 2021;58(3):516-526.

Valentine BA. Skeletal Muscle. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 1015-1016.

Click the slide to view.

---