Three-week-old, male, Mox-2 Cre transgenic mouse (Mus musculus).A mass was noted on left front leg.

Gross Description:  

A firm mass encompassed the left front leg from the shoulder to the paw (~2 cm in diameter).

Histopathologic Description:

A cross-section of the left forelimb has an unencapsulated, expansile, and infiltrative mass expanding the dermis, extending into the subcutis, and replacing skeletal muscle. The mass is composed of densely-packed neoplastic cells haphazardly arranged as long and short interweaving streams and bundles within a minimal fibrovascular matrix. Neoplastic cells are predominantly spindle-shaped with some ovoid profiles; have abundant granular to fibrillar amphophilic cytoplasm; and prominent round to oval nuclei with marginalized chromatin and multiple magenta nucleoli. Many of these cells are quite long with a fairly consistent width, and fusiform nuclei (presumed strap cells). Neoplastic cells exhibit marked anisocytosis, anisokaryosis, and pleomorphism. Mitoses are numerous, varying between ~2 to ~10 per high-power field (40x). Multinucleated giant cells with abundant eosinophilic cytoplasm and 2 to 5 nuclei clustered at the periphery are frequently present (racket cells). Multifocal areas of the neoplasm are necrotic with hemorrhage and copious cytoplasmic and karyorrhectic debris. Small bundles of skeletal muscle entrapped by neoplastic cells are present at the periphery of the mass adjacent to sections of cortical bone. Mild edema (clear spaces) and moderate aggregates of lymphocytes and plasma cells multifocally expand the superficial dermis. The overlying epidermis has multiple variably sized ulcers with replacement by moderate amounts of degenerate neutrophils and eosinophilic debris. Small pockets of degenerate neutrophils are occasionally apparent within the stratum corneum.

Morphologic Diagnosis:  

Left forelimb, skeletal muscle: Rhabdomyosarcoma.



Contributor Comment:  

Spontaneous rhabdomyosarcomas in mice are rare with those of skeletal muscle occurring more often than those of the heart.(6) Rhabdomyosarcomas are typically induced experimentally via exposure to a variety of viruses, metals, and/or chemical carcinogens.(6) An investigation at the Jackson Laboratory identified 14 spontaneous welldifferentiated rhabdomyosarcomas out of 10,000 mice, approximately 4 months old.(7) Landau et al(3) found a higher incidence of rhabdomyosarcomas (34% of controls); however, these mice were approximately 14 months old.

The mouse currently described was transgenic for the Mox-2 gene, which is an important regulator of vertebrate limb myogenesis.(4,8) Mox-2 is part of a cohort of genes important to normal myogenic differentiation. Historically, mice homozygous for a null mutation of Mox-2 have a developmental defect of the limb musculature, characterized by an overall reduction in muscle mass and elimination of specific muscles (

Identification of strap cells may be difficult by light microscopy; however, phosphotungstic acidhematoxylin (PTAH) stain is useful for identification of cross-striations.(6,5) Malignant fibrous histiocytoma and leiomyosarcoma are differential diagnoses for rhabdomyosarcoma.(6) Immunolabels useful for differentiating these neoplasms include pan myosin, sarcomeric actin, desmin, actin, myosin, and smooth muscle actin.(7) The most useful antibodies are those that react with sarcomeric or smooth muscle actin.

JPC Diagnosis:  

Skeletal muscle, left forelimb: Rhabdomyosarcoma.

Conference Comment:  

Rhabdomyosarcomas (RMS) occur infrequently in domestic animals, as they do in mice. A recent publication reviewed the classification and pathogenesis of this diverse group of rare tumors, comparing canine rhabdomyosarcomas with those that occur in humans and with other canine soft tissue sarcomas.(1) Although in veterinary medicine rhabdomyosarcomas are often categorized as high grade soft tissue sarcomas, they are excluded from the soft tissue sarcoma grading scheme as recently proposed by Dennis et al.(2)

Diagnosis and classification is difficult due to their variation in phenotype, cellular morphology and age of onset. It is likely that some RMS are diagnosed as undifferentiated sarcomas, anaplastic sarcomas or poorly differentiated sarcomas, since skeletal muscle differentiation is not always evident by light microscopy. Therefore, immunohistochemistry can aid in the diagnosis. In addition to the immunolabels discussed by the contributor, MyoD1 and myogenin (early embryological transcription factors involved in mesoderm cell differentiation into myoblasts, myoblast proliferation and myoblast differentiation into myotubules) are associated with RMS of more undifferentiated cells.

Transmission electron microscopy can also aid in the diagnosis; however, EM is not helpful in classification, as several subtypes exhibit similar subcellular structures, including Z-lines, numerous mitochondria, myofilament tangles, and myosin-ribosome complexes.(1) Canine classification of RMS is similar to the human classification of RMS, with the following subclasses:
More studies are needed to determine if these classifications have prognostic significance in veterinary medicine.1


1. Caserto BG. A comparative review of canine and human rhabdomyosarcoma with emphasis on classification and pathogenesis. Vet Pathol Online First. Published online 25 February 2013. Accessed online 2 March 2013. 2. Dennis MM, McSporran KD, Bacon NJ, Schulman FY, Foster RA, Powers BE. Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in Dogs. Vet Pathol. 2011;48(1):73-84. 3. Landau JM, Wang ZY, Yang GY, Ding W, Yang CS. Inhibition of spontaneous formation of lung tumors and rhabdomyosarcomas in A/J mice by black and green tea. Carcinogenesis. 1998;19:501-507. 4. Mankoo BS, Collins NS, Ashby P, Grigorieva E, Pevny LH, Candia A, et al. Mox2 is a component of the genetic hierarchy controlling limb muscle development. Nature. 1990;400:69- 73. 5. Leininger JR. Skeletal muscle. In: Maronpot RR, ed. Pathology of the Mouse. St. Louis, MO; Cache River Press. 1999;640-642. 6. Mohr U, ed. International Classification of Rodent Tumors, The Mouse. Berlin, Heidelberg: Springer-Verlag. 2001;385, 386. 7. Sundberg JP, Adkison DL, Bedigian HG. Skeletal muscle rhabdomyosarcomas in inbred laboratory mice. Veterinary Pathology. 1991;28:200-206. 8. Tiffin N, Williams, RD, Robertson D, Hill S, Shipley J, Pritchard-Jones K. WT1 expression does not disrupt myogenic differentiation in C2C12 murine myoblasts or in human rhabdomyosarcoma. Experimental Cell Research. 2003;287:155165.

Click the slide to view.

3-1. Left forelimb

3-2. Left forelimb

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