Oncology (Research)

Veterinary Pathology
55(5) 806-826
The Author(s) 2013
A Comparative Review of Canine and Reprints and permission:
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Human Rhabdomyosarcoma With Emphasis DOI: 10.1177/0300985813476069
vet.sagepub.com
on Classification and Pathogenesis

B. G. Caserto, DVM, Dipl ACVP1

Abstract
Rhabdomyosarcomas are a diverse group of malignant mesenchymal neoplasms exhibiting variable levels of differentiation toward
skeletal myocytes. Neoplastic cells may resemble relatively undifferentiated myoblasts, satellite cells, or more differentiated
elongated spindle cells and multicellular myotubes. In veterinary medicine, classification into subtypes and variants is based on an
outdated system derived from human pathology and is solely based on histologic characteristics. In contrast, classification of
human rhabdomyosarcoma is based on histologic, immunohistochemical, and molecular diagnostic techniques, and sub-
classification has clinical and prognostic relevance. Relevance of tumor subtyping has not been established in veterinary medicine.
Recent discoveries of components of the molecular pathogenesis and genomes of human rhabdomyosarcomas have led to new
diagnostic techniques and revisions of the human classification system. The current classification system in veterinary medicine is
reviewed in light of these changes. Diagnosis of rhabdomyosarcoma using histopathology, electron microscopy, and the clinical
aspects of human and canine rhabdomyosarcomas is compared. The clinical features and biologic behavior of canine rhabdo-
myosarcomas are compared with canine soft tissue sarcomas.

Keywords
dog, musculoskeletal, oncology, ultrastructure, immunohistochemistry

Rhabdomyosarcomas (RMS) are relatively rare neoplasms of
domestic animals that have a variety of gross morphologies, his-
tologic variations, and cellular phenotypic variations. Common
histologic subclasses include embryonal RMS, alveolar RMS,
and botryoid RMS (also called botryoid embryonal RMS). Less
common subclasses include pleomorphic RMS. The relative rar-
ity of these tumors makes diagnosis, clinical prognosis, and
treatment difficult. In some cases, these neoplasms are lumped
into the category of high-grade soft tissue sarcomas89,158 but are
explicitly excluded from the common grading system of canine
soft tissue sarcomas.72 The low prevalence of these neoplasms
in the literature may be due to a failure to diagnose them, since
their extreme variation in phenotype, age of onset, and cellular
morphology makes diagnosis and classification difficult. The
most aggressive of these neoplasms arise in juvenile dogs
younger than 2 years and include alveolar RMS and embryonal
RMS. Histopathological findings of these primitive neoplasms
typically consist of sheets or packets of small round cells with
a lymphoid appearance, or sheets of round cells with abundant
cytoplasm, and may be misdiagnosed as lymphomas or other
primitive neoplasms. Other phenotypes arising in adult animals
consist of anaplastic cells with large nuclei, abundant cyto-
plasm, and bizarre mitotic figures. These neoplasms may be
misdiagnosed as undifferentiated sarcoma, anaplastic sar-
coma, or even a poorly differentiated sarcoma depending
on the phenotype of the variant.33,48,146,158 Diagnostic features
of skeletal muscle differentiation may not be evident at the light
microscopic level and may only be recognized by immunohis-
tochemistry or electron microscopy. This article reviews the
diagnostic features, pathogenesis, and classification of rhabdo-
myosarcomas in dogs and compares them with their human
counterparts to facilitate the recognition of these tumors by
veterinary diagnostic pathologists.
Developmental Biology
In the developing embryo, uncommitted mesodermal cells dif-
ferentiate into myogenic progenitor cells under the control of
transcription factors such as PAX3, PAX7, and the Fox family
of transcription factors.2,136 Myogenic precursors then proliferate
by asymmetric replication, forming immature myoblasts under
the direction of myoblast determination protein 1 (MyoD1) and
1
Cornell University College of Veterinary Medicine, Department of Biomedical
Sciences, Ithaca, NY, USA
Corresponding Author:
B. G. Caserto, Cornell University College of Veterinary Medicine, Department
of Biomedical Sciences, Ithaca, NY, USA.
Email: bgc7@cornell.edu
Caserto
Figure 1. Skeletal muscle development and myoblast fusion. Under
the direction of myogenin as well as PAX, myoblasts leave the cell
cycle and begin to fuse with each other or with preexisting myotubes.
Myotube fusion begins with 2 cells lining up, with their plasma mem-
branes contacting each other (a). Next, paired vesicular structures
form along the apposed membrane surfaces (prefusion complexes)
(b). These prefusion complexes resolve into fusion plaques (c) that
appear similar to adherens junctions and contain M-cadherin. The
fusion process requires calcium, which is further evidence that these
fusion plaques are members of the adherens junction family of cell-
cell attachments. Once fusion plaques form, the plasma membrane
adjacent to them dissolves and the cytosols of the 2 cells are in direct
contact with each other (d). By some yet unexplained mechanism, the
fusion plaques then disappear, and the walls of each adjoining cell are
removed, fusing the 2 cells (e). The fused cells then elongate, the nuclei
line up in rows to form myotubes, and the cells begin producing con-
tractile filaments and myoglobin (f). Additional myoblasts may fuse
with myotubes in a similar fashion. Adapted from Doberstein et al40
and Paululat et al.112
other transcription factors of the Myf family that includes myo-
genin (myf4).165 During development and after injury, these
cells proliferate, elongate, and fuse together, forming myotubes.
Under the direction of myogenin, the myotubes begin forming
actin and myosin filaments organized into sarcomeres character-
istic of striated muscle.58 In both neoplastic and nonneoplastic
myogenic cells, MyoD1 is associated with cellular differentiation
into myoblast cells with a high proliferative capacity, whereas
myogenin is associated with cell cycle arrest, cell fusion into mul-
tinucleated myotubular cells, and formation of muscle fibers.58
Mature skeletal muscle expresses very little of these transcription
factors,19,60,67,121 and as normal skeletal muscle matures, it loses
its replicative capacity but retains undifferentiated satellite cells at
the periphery of the myotube as stem cells, which are activated
when the muscle is damaged. Figure 1 illustrates the major events
in skeletal muscle myoblast fusion. More extensive reviews of the
subject have been published.2224,32,111
Diagnosis and Classification
Histologic Patterns
RMS in humans and dogs can resemble undifferentiated myo-
blasts or early embryonic myotubes. The term embryonal is a
descriptive term for neoplasms exhibiting a range of cellular
807
morphologies that resemble various developmental intermediates
and often have a myxomatous stroma as seen in developing mus-
cle.31,109,127 In the case of RMS, these cells range in morphology
from round, immature myoblast cells with variable amounts of
eosinophilic cytoplasm to multinucleated myotubular cells that
resemble the cellular phenotypes of developing skeletal muscle.
Embryonal muscle tumors consist of embryonal RMS, alveolar
RMS, and botryoid RMS; however, alveolar RMS is given its
own category due to its less favorable prognosis in humans.19,127
In humans, alveolar RMS and embryonal RMS occur predomi-
nantly in children younger than 15 years and is dubbed juvenile
or pediatric RMS.127 In dogs, this same association between age
of onset and histologic type has been recognized by several
authors61,65 but has not been universally accepted, as many cases
of embryonal RMS occur in dogs older than 2 years.31 Pleo-
morphic RMS occurs mostly in adult people,19,109 and the 2 cases
in dogs have been in a 3-year-old and a 14-year-old dog.8,31
Attempts have been made to segregate neoplasms into
different categories for the purpose of making predictions of
biologic behavior based on histomorphologic, ultrastructural,
or immunohistochemical features. The most recent, and widely
used, human classification system is the international classifica-
tion system developed by Newton et al;104 however, similar yet
differing systems exist and may be encountered periodically in
literature searches.109 According to the international classifica-
tion system, human RMS is subdivided into embryonal,
botryoid, alveolar, and pleomorphic (anaplastic) subcate-
gories.31,65,109 With regard to human childhood RMS, there are
3 main categories: embryonal, alveolar, and undifferentiated,
and these are distinguished from each other by histologic pattern
and cytogenetic studies.109,145 The undifferentiated juvenile
RMS has not been recognized in veterinary medicine. Classifi-
cation of canine RMS closely parallels classification schemes in
human medicine (Table 1). Furthermore, embryonal and alveo-
lar RMS can be further subdivided into variants based on the
predominant cell morphology. Variants of embryonal RMS
include the rhabdomyoblastic, myotubular, and spindyloid var-
iants. Variants of alveolar RMS include the classic alveolar pat-
tern and the solid alveolar pattern, which lacks fibrous septa.31
Such a precise classification system would potentially allow for
subsequent study of clinical course of disease and response to
treatment. Detailed descriptions of histologic characteristics of
each category are below.
Embryonal Rhabdomyosarcoma
Embryonal RMS includes 3 variants that are named because of their
predominant cellular morphology.31,35,36,109 The myotubular var-
iant of embryonal RMS is dominated by multinucleated strap
cells forming myotubes with frequent cross-striations (often only
identified by histochemical staining with phosphotungstic acid
hematoxylin [PTAH] stain, which highlights striations as dark
blue/purple lines among paler blue/purple myofibers), whereas the
rhabdomyoblastic variant is dominated by round to polygonal cells
with abundant eosinophilic cytoplasm (Fig. 2), with only rare
PTAH positive cross-striations.36,109 The rhabdomyoblastic variant
808 Veterinary Pathology 55(5)

Table 1. Classification of Rhabdomyosarcomas, With Variants and Relevant Clinical Aspects.

Subclass Variant Distinguishing Histologic Features Age Locations

Embryonal Cells exhibit different stages of development from Juvenile/adult Face, skull, masticatory muscle,
myoblast to myotubular, in a mucinous stroma oropharynx, trachea, axilla,
scapula, perirenal, tongue, flank,
leg, mammary gland, hard palate
Myotubular Myotube forms predominate
Rhabdomyoblastic Large myoblast cells with abundant cytoplasm
Spindle cell Streams of plump spindle cells Skull
Botryoid Characteristic submucosal location and gross Juvenile Urinary bladder, uterus
appearance; mixed round and myotubular cells
in mucinous stroma
Alveolar Juvenile Hip, maxilla, greater omentum,
uterus
Classic Fibrous bands divide small round cells into
clusters, loose aggregates
Solid Closely packed cells, thin fibrous septa
Pleomorphic Haphazardly arranged plump spindle cells with Adult Skeletal muscle
marked anisocytosis and anisokaryosis and
bizarre mitotic figures
The 3 major subclasses of rhabdomyosarcoma (RMS) are embryonal, alveolar, and pleomorphic. Botryoid RMS is often considered a separate subclass but is
technically a subset of embryonal RMS. In addition, embryonal RMS has 3 variants that are differentiated by the predominant cell morphology. Myotubular
embryonal RMS is dominated by multinucleated and elongated tubular cells. Rhabdomyoblastic embryonal RMS is dominated by large round cells with
abundant cytoplasm. Spindle cell embryonal RMS is dominated by fusiform, elongated cells arranged in streams. Alveolar RMS is divided into the classic
alveolar pattern with distinct fibrous septa lined by neoplastic round cells with a central open space. The solid variant of alveolar RMS lacks the clear space
and often lacks obvious fibrous septa. The pleomorphic RMS most often occurs in adult animals and is composed of haphazard spindle cells with large
myoblast cells often containing large pleomorphic nuclei and bizarre mitotic figures. Adapted from Parham.109

is included along with alveolar RMS and undifferentiated RMS in
the general category of small round cell neoplasms of childhood
sarcomas.5,149 These 3 categories are more commonly diagnosed
with the aid of molecular diagnostic techniques that are unavailable
in veterinary medicine.145 There is no evidence that classification
into the myotubular or rhabdomyoblastic variants has any bearing
on prognosis or clinical course in human or canine medicine.36,109
month-old Boxer dog. This mass was composed of interlacing
fascicles of plump spindle cells.35 The spindyloid embryonal
RMS, as the name implies, is composed of thin spindyloid myo-
blast cells forming bundles within a myxoid stroma. Although
limited case reports exist, these neoplasms in humans typically
have a better prognosis than any other variant of RMS.94

Botryoid Embryonal RMS Alveolar RMS

Botryoid rhabdomyosarcomas are tumors that have a character-
istic gross appearance and anatomic location. The term botryoid
refers to the grape-like masses protruding from the mucosa of
the urinary bladder, which is the most common location. Like
embryonal RMS, these tumors also recapitulate skeletal muscle
embryogenesis and therefore contain undifferentiated myoblast
cells as well as multinucleated myotube cells within a myxoma-
tous stroma (Fig. 3).31,127 Histologically, botryoid RMS of the
urinary bladder is located in the submucosa, and neoplastic cells
are separated from the mucosal epithelium by a cambium
(ie, transitional) layer of connective tissue. Because of their
distinct anatomic location and histologic characteristics, these
neoplasms have been placed into a distinct subcategory of
embryonal RMS in human and veterinary medicine.109
Spindyloid Embryonal RMS
The spindyloid variant of embryonal RMS is a relatively new
category. This type of tumor has been reported only once in
veterinary medicine as a mass arising from the skull of an 11-
Alveolar RMS is the second RMS in the small round cell cate-
gory of childhood RMS. It is characterized by small, poorly dif-
ferentiated, round cells with scant cytoplasm, arranged into
packets of cells separated from each other by fibrous connec-
tive tissue, forming alveolar-like patterns (Figs. 4, 5).149
Alveolar RMS is further subdivided into the classic alveolar
pattern, which is characterized by extensive sloughing of neo-
plastic cells into a central open space with additional neoplas-
tic cells lining the fibrous septa. The second subtype of
alveolar RMS is the solid variant, which is characterized by
sheets of small round cells closely packed together (Fig. 6).5,149
This variant in dogs may have thin fibrous septa dividing nests
of round cells similar to the classic neuroendocrine pattern31
but is most often lacking this histologic distinction, making
differentiation between solid alveolar RMS and rhabdomyo-
blastic embryonal RMS very difficult.36,109 Differentiation
between alveolar RMS and embryonal RMS is important in
human medicine because alveolar RMS of any variant is more
locally aggressive and has a higher metastatic rate, carrying a
poorer prognosis than embryonal RMS.36,60,116,127 Currently,
Caserto 809

Figure 2. Dog, embryonal rhabdomyosarcoma (RMS), rhabdomyoblastic variant: neoplastic cells are uniform in size with abundant eosino-
philic cytoplasm with variable amounts of cytoplasmic glycogen or lipid vacuoles. Hematoxylin and eosin (HE). Figure 3. Dog, botryoid RMS:
this is the prototypical embryonal tumor, characterized by both uninucleate myoblastic cells similar to the rhabdomyoblastic embryonal
RMS, but also has a large proportion of myotubular cells or strap cells, which have single or multiple nucleoli. This is the typical histologic
appearance of RMS of the urinary bladder or urogenital tracts. HE. Figure 4. Dog, classic alveolar RMS: neoplastic cells are subdivided into
packets separated by fibrous septa in an alveolar pattern. Neoplastic cells vary in size and amount of cytoplasm, occasionally slough into the
lumen, and occasionally have multiple nuclei. HE. Figure 5. Dog, classic alveolar RMS: an additional variant of the classic alveolar pattern with
810 Veterinary Pathology 55(5)

there are insufficient data to draw the same prognostic conclu-

sion in veterinary medicine.

Pleomorphic Rhabdomyosarcoma
Pleomorphic RMS occurs less frequently than alveolar and
embryonal RMS in humans. It is found more often in adult
humans and animals and arises almost exclusively within skeletal
muscle. Histologically, it is composed exclusively of haphazardly
arranged spindle cells with rare multinucleated cells present and
is recognized by the appearance of bizarre or multipolar mitotic
figures and a high degree of cellular and nuclear pleomorphism
(Fig. 7).35,109 This diagnosis should be used only when there are
no areas of embryonal or alveolar morphology within the
tumor.31 This tumor undoubtedly causes confusion for patholo-
gists, as histologic evidence of skeletal muscle differentiation can
be rare. Without the aid of immunohistochemistry, some of these
neoplasms may be diagnosed as anaplastic sarcomas.

Ultrastructural Diagnosis of
Rhabdomyosarcoma
Transmission electron microscopy is the gold-standard diagnos-
tic test for rhabdomyosarcomas in humans and dogs, but
attempts to use ultrastructural characteristics to aid in classifica-
tion have been relatively unrewarding in human medicine, with
both alveolar and embryonal RMS exhibiting a variety of sub-
cellular structures.133 Common to all human RMS are Z-lines,
large numbers of mitochondria, myofilament tangles, and
myosin-ribosome complexes (Fig. 8). Several studies have indi-
cated the presence of basement membranes in both alveolar and
embryonal tumors in human RMS.95,142 Desmosome-like struc-
tures may be a unique feature of alveolar RMS,27 but since pub-
lication of this study, there has not been further investigation
into these unique structures.
Cytoskeletal Proteins
In the absence of myotubes, strap cells, and cross-striations,
small round cell neoplasms must be differentiated from lympho-
mas and primitive neuroectodermal tumors or other embryonal
neoplasms. Early studies of human RMS identified many ultra-
structural features unique to skeletal muscle that can aid diagno-
sis of rhabdomyosarcomas. Identification of sarcomeric
structures such as unambiguous Z-lines within I-bands,
A-bands with H- and M-bands, and other structures such as free
ribosomes closely associated with myofilaments, abundant gly-
cogen granules, external lamina, prominent nucleoli, and pleo-
morphic mitochondria can all be used to support a diagnosis
of rhabdomyosarcoma.17 Electron microscopy studies of both
alveolar and embryonal RMS in humans have consistently
Figure 8. Dog, skeletal muscle, rhabdomyosarcoma (RMS). Transmis-
sion electron micrograph showing a small crescent of the nucleus on
the right, a mitochondrion (arrowhead), and a developing muscle fiber
consisting of numerous polyribosomes with myosin thick filaments
(short arrows) and an M-line (block arrow). Z-lines were poorly
formed and scattered haphazardly (30 k; scale bar = 500 nm). Inset
(upper left corner) shows a closeup of the polyribosomes and myosin
filaments (40 k).
identified actin and myosin filaments, Z-lines, and A- and
I-bands in both alveolar and embryonal tumors.129,133,139 In
some cases of embryonal RMS, myofilament tangles are
observed, indicating poor formation and disorganization.133
Adhesion Structures in Human RMS
Some alveolar RMS contains desmosome-like structures
between adjacent neoplastic cells lining the fibrous septa.27
Churg and Ringus27 described these structures and hypothe-
sized that they are remnants from the embryological ectoderm
before the epithelial to mesenchymal transition. To complicate
matters, these structures resemble skeletal muscle fusion pla-
ques found in Drosophila and mouse myoblast cultures.22,23,40
Fusion plaques appear similar to desmosomes and adherens
junctions by electron microscopy. They are transient structures,
like adherens junctions, and contain M-cadherin rather than

Figure 5. (continued) larger cells but clearly defined fibrous septa between groups of cells. HE. Figure 6. Dog, solid alveolar RMS:
this variant consists of dense sheets of small round cells with small amounts of cytoplasm and hyperchromatic nuclei. Fibrous septa are
not present. HE. Figure 7. Dog, pleomorphic RMS: neoplastic cells vary in size and shape, as well as nuclear size and shape, with frequent
karyomegalic cells and bizarre mitotic figures. HE.
Caserto
desmosomal cadherins or desmoglein.10,22,46,53 Myoblasts of
Drosophila spp that lack the gene Rolling stone (Rost) fail to
complete myoblast fusion and accumulate fusion plaques
resembling the junctional complexes described in human alveo-
lar RMS.27,32,40 It is unknown whether these junctional com-
plexes in human RMS are arrested fusion plaques since they
have not been studied extensively. It is unknown whether
human embryonal RMS has similar desmosome-like struc-
tures, and it is unclear whether these junctional complexes are
related to the pathogenesis of RMS in humans. RMS cells of
C2C12 mouse myoblast cultures have reduced M-cadherin
expression and elevated R-cadherin expression, both of which
can activate Rac1 GTPase,22,70 which has been implicated in
promoting myoblast proliferation and myoblast fusion, and yet
later acts as an inhibitor of myogenesis induction.22 Although
not proven, it is possible that adhesion structures are involved
in the failure of many RMS types to fuse into myotubes and
therefore fail to histologically resemble skeletal muscle.
Canine RMS
There are few electron microscopic studies of canine RMS and no
descriptions of differences between histologic variants. Actin and
myosin filaments, polyribosomes, Z-bands, and mitochondria
(Fig. 8) are prominent in botryoid RMS, laryngeal muscle tumors
(both rhabdomyomas and RMS), and RMS that is not further
classified (RMS not otherwise specified [NOS]).3,76,93,113
Immunohistochemical Diagnosis of RMS
Immunohistochemistry (IHC) is useful in differentiating rhab-
domyosarcomas from other mesenchymal tumors or embryonal
tumors. A potential diagnostic pitfall is the fact that all
myogenic markers used to diagnose RMS will also be present
in developing and regenerating skeletal muscle,19,168 so it is the
job of the diagnostic pathologist to first differentiate satellite cell
proliferation and differentiation from a neoplastic proliferation.
Diagnosis of RMS in humans and dogs is based on detection of
1 or more muscle-specific markers and absence of smooth mus-
cle markers. The presence of these markers depends to some
extent on the degree of differentiation of the neoplastic cells but
is also subject to variation due to altered expression of myogenic
regulating factors.26,34,97,133
Vimentin and Desmin
Identification of skeletal muscle fibers is largely based on
specific expression of cytoskeletal proteins such as intermediate
filaments or contractile proteins. Skeletal muscle cells are char-
acterized by expression of different cytoskeletal proteins at pro-
gressive stages of development.31 Like all mesenchymal cells,
myoblast cells first express the intermediate filament vimentin.
Later, during differentiation, they express another intermediate
filamentdesmin, which is common to skeletal muscle, cardiac
muscle, smooth muscle, and myofibroblasts.9,97 Desmin has
been proven a useful marker even in relatively undifferentiated
811
RMS in both humans and dogs95,129,166,167 (Figs. 9, 10), but
staining can be patchy and sparse, and other neoplastic and nor-
mal tissue can express desmin.71,121 Despite the variability in
staining pattern and intensity, it is a useful marker of myogenic
differentiation in poorly differentiated RMS such as alveolar
and embryonal RMS. Because of desmins low specificity and
high degree of variability of staining, newer methods of identi-
fying undifferentiated myoblast cells have been developed,
including using MyoD1 and myogenin, 2 nuclear transcription
factors.
Actin, Myosin, Sarcomeric Actin, and Myoglobin
Muscle actin (ms actin or HHF35) is an antibody that can iden-
tify -actin isoforms in both human and canine skeletal, cardiac
and smooth muscle, and myofibroblasts, myointimal cells, and
reactive mesothelial cells49,150 with an equivalent specificity
to desmin.126 Identification of desmin or ms actin in myogenic
sarcomas cannot confirm a diagnosis of RMS by themselves,
but neoplasms with negative immunostaining for smooth mus-
cle actin can help rule out leiomyosarcomas and malignant myo-
fibroblastic tumors and make a reasonably certain diagnosis of
RMS.51,133
More specific to skeletal muscle is expression of proteins
involved in sarcomere construction such as the -actin isoform
found in sarcomeres, identified by the antibody sarcomeric actin
(src actin).31 As skeletal myocytes differentiate further, they begin
to accumulate sarcomeric actin, followed by myosin or fast
myosin, and finally myoglobin, which is first seen in large
amounts following myoblast fusion to form myotubes or strap
cells.9,31,36,60,83,101,121,166,167 Mature skeletal muscle typically has
little vimentin expression, whereas immature skeletal muscle and
undifferentiated rhabdomyosarcomas typically have rare expres-
sion of myoglobin and myosin.36 See Table 2 for a brief summary
of common IHC markers used in canine rhabdomyosarcomas.
In humans and dogs, rhabdomyosarcomas are consistently
immunohistochemically positive using antibodies for vimentin,
desmin (Fig. 10), muscle actin, and src actin (Fig. 11),133 but
because of their lack of cellular differentiation, myoglobin stain-
ing is variable.3,31,61,65,109,167 In dogs, embryonal and botryoid
RMS are frequently positive for myoglobin compared with
alveolar RMS (Table 2).67
Myo D1 and Myogenin
MyoD1 and myogenin are early embryological transcription fac-
tors involved in the differentiation of mesoderm cells into myo-
blast cells, myoblast cell proliferation, and myoblast
differentiation into multinucleated myotubes. MyoD1 expression
is associated with immature rhabdomyoblasts that have a higher
proliferative capacity, whereas myogenin is expressed during
myoblast fusion and is associated with exit from the cell cycle.
Rhabdomyosarcomas that are composed of relatively undifferen-
tiated cells should be expected to express less desmin, actin, myo-
sin, and myoglobin and more MyoD1 and myogenin. Several
studies have confirmed the specificity of myogenin and MyoD1
812 Veterinary Pathology 55(5)

Figure 9. Dog, embryonal rhabdomyosarcoma (RMS). This is a biphasic embryonal RMS with round myoblast cells in the upper left corner and a
more spindyloid population in the lower right with a very myxomatous stroma. Hematoxylin and eosin (HE). Figure 10. Dog, embryonal RMS,
desmin immunohistochemistry. Neoplastic rhabdomyoblasts (a) and spindle cells (b) have diffuse positive cytoplasmic immunoreactivity for anti-
desmin antibodies (3,3-diaminobenzidine [DAB]/hematoxylin). Figure 11. Dog, embryonal RMS. Sarcomeric actin immunohistochemistry.
Scattered neoplastic cells have positive cytoplasmic immunoreactivity to antisarcomeric actin antibodies (DAB/hematoxylin) Figure 12. Dog,
embryonal RMS. Myogenin immunohistochemistry. Neoplastic cells have frequent positive nuclear immunoreactivity for antimyogenin antibo-
dies (DAB/hematoxylin). Figure 13. Dog, alveolar RMS. MyoD1 immunohistochemistry. Neoplastic cells have moderate multifocal nuclear
immunoreactivity (DAB/hematoxylin).

as specific and sensitive markers of undifferentiated RMS in
humans.19,60,101,121,127,165 Furthermore, several studies have con-
cluded that differential expression of myogenin can be used to
subclassify human RMS into alveolar or embryonal RMS (Table
3).19,60,109,165 Human alveolar RMS has been found by several
investigators to diffusely express myogenin in the majority of
nuclei of neoplastic cells by immunohistochemistry, whereas
nuclear MyoD1 expression, although consistently present, is pat-
chy and less intense. Conversely, human embryonal RMS has
few cells expressing either myogenin or MyoD1.19,39,60,109 The
different IHC staining patterns between myogenin and MyoD1
were used to differentiate human alveolar RMS from embryonal
RMS.127,146 Although immunohistochemical identification of
myogenin and MyoD1 is a useful tool in human medicine, more
specific tools have been developed that are in the process of sup-
planting these methods.
Precise correlations cannot yet be made between human and
canine RMS using myogenin or MyoD1 staining. One study of
canine botryoid RMS found myogenin IHC stained elongated
strap cells preferentially, whereas immunohistochemical detec-
tion of MyoD1 was limited to the nuclei of small, round myo-
blast cells.67 In published case reports, both myogenin and
MyoD1 have been used to diagnose canine RMS, but there have
been no differences in the staining pattern or intensity
Caserto 813

Table 2. Common Immunohistochemistry Antibodies in Veterinary Medicine.

Canine, All Ages Vimentin Desmin Ms Actin Src Actin Myoglobin Myogenin MyoD1 Smooth Muscle Actin

Alveolar 5/5 6/6 1/1 2/2 1/2 1/1 1/1 0/3

Embryonal 10/10 15/15 5/5 7/7 9/10 1/1 2/2 1/5
Botryoid 9/9 13/13 3/3 5/5 5/8 2/2 2/2 0/4
Pleomorphic 2/2 2/2 1/1 1/1 1/1 NA NA 0/2
RMS NOS 5/5 4/5 2/2 NA 2/2 NA 1/1 0/2

Numbers indicate the number of cases with positive staining (numerator) over the number of cases stained (denominator). Vimentin, desmin, muscle actin (ms
actin), and sarcomeric actin (src actin) are consistently positive in canine rhabdomyosarcoma (RMS). Myoglobin staining is inconsistent but positive in many cases
of embryonal and botryoid RMS and is rarely used in alveolar RMS. Positive staining with desmin, ms actin, src actin, or myoglobin plus negative smooth muscle
actin staining is diagnostic for rhabdomyosarcoma. Rarely is canine RMS positive for smooth muscle actin, making myogenin and MyoD1 necessary for diagnosis.
NA, not applicable; NOS, not otherwise specified.31,109

Table 3. Comparison of Myogenin and MyoD1 Staining in Different Categories of RMS Between Human and Canine Neoplasms.

Human Canine

Myogenin MyoD1 Myogenin MyoD1

Alveolar + Uniform + Sparse + +

Embryonal + Multifocal + Sparse + +
Botryoid NA NA Myotube cells Round cells
Alveolar rhabdomyosarcoma (RMS) tends to have uniform and more abundant myogenin staining compared with embryonal RMS. MyoD1 staining is present is both
but sparse. In dogs, both alveolar and embryonal RMS stains with myogenin and MyoD1, but staining can be sparse, and there is no proven difference between the two.
In canine botryoid RMS, myogenin stained the myotube cells preferentially, and MyoD1 stained the round cells preferentially.60,68,121,127 NA, not applicable.

described.21,25,35,62,67,100,140 Myogenin staining can also be
seen in large round rhabdomyoblastic cells of embryonal RMS
in dogs (Fig. 12). These cells often contain large amounts of
eosinophilic cytoplasm but may be mixed with smaller cells that
resemble undifferentiated myoblast cells. In dogs, MyoD1
immunostaining of embryonal RMS is rare and sometimes non-
existent (B. G. Caserto, unpublished data), but MyoD1 staining
can be observed in alveolar RMS more frequently (Fig. 13). At
present, there is insufficient information to conclude whether
myogenin or MyoD1 is useful in subclassifying RMS into
alveolar or embryonal categories.
Histogenesis and Cytogenetics
Many different hypotheses have been proposed regarding the
histogenesis of RMS in all species. RMS of any species may
develop from pluripotent stem cells from the primitive urogen-
ital ridge remnants (in the case of botryoid RMS) or from
mesenchymal progenitor cells invading the Mllerian and Wolf-
fian ducts, either locally or through the circulation originating
from the bone marrow stroma.58,91 The presence of mesenchy-
mal stem cells capable of myogenic differentiation in the bone
marrow and elsewhere in the body may explain why RMS can
be found in tissue with no skeletal muscle.58 Alternatively, RMS
can develop from early myogenic progenitor cells remaining
from embryonic development or from myoblast cells within the
pool of satellite cells. Using a mouse model, Nitzki et al105 sug-
gest that early mesenchymal stem cells (embryonic cells uncom-
mitted to myogenesis) are the major source of embryonal RMS.
This view is contradicted by others who have suggested that
embryonal RMS develops from muscle progenitor cells, or ske-
letal muscle stem cells present within the pool of satellite cells,
because embryonal RMS in mice contains a high number of
muscle stem cells.58 It has been suggested that the pleomorphic
RMS subclass is derived from adult skeletal muscle, but
whether they are derived from satellite cells or other cell popu-
lations in the adult muscle was not mentioned.125
Cytogenetics of RMS in Domestic Animals
Very little is known about the cytogenetics of RMS in dogs and
other domestic animals when compared with knowledge of
human RMS. Although a tumor cell line was established from
a pleomorphic RMS from a 14-year-old mixed breed dog, no
cytogenetic abnormalities were reported.8 One report described
single or multiple RMS developing in 25 of 100 piglets from
multiple litters over a 6-month period in the Netherlands,
suggesting an inherited component.157 van der Loop and
colleagues established a cell culture from a pleomorphic RMS
in a 3.5-week-old female piglet and described a deletion of the
long arm of the X chromosome (Xq24-qter) in these cells.154
Cytogenetics of Human RMS
Human embryonal RMS has been associated with abnormalities
of chromosome 11p15, leading to loss of maternal information
and duplication of paternal genetic information (loss of hetero-
zygosity or LOH). The IGF-II gene is normally expressed by
the paternal allele only, so the loss of the maternal allele in
these tumors with a duplication of the paternal allele leads to
814
a 2-fold increase of IGF-II, leading to uncontrolled cell cycle
progression and cell proliferation.36 Embryonal RMS can also
have DNA contents ranging between diploid and hyperdiploid,
with diploid tumors having a worse prognosis than hyperdiploid
tumors.36
Human alveolar RMS has a characteristic translocation
between the long arm of chromosome 2 and the long arm of
chromosome 13: [t(2;13)(q35;q14)]. This mutation fuses the
PAX3 gene (Paired box family) with the FKHR gene (Forkhead
box family). A variant of the mutation, t(1;13)(p36;q14), fuses
the PAX7 gene from chromosome 1 with the FKHR gene and
leads to more aggressive neoplasms in younger children. These
mutations are detectable in 70% to 90% of histologically
diagnosed alveolar RMS.2,36,60,127,136
Polymerase chain reaction (PCR) identification of mRNA
transcripts of fused genes (PAX3 or PAX7-FKHR) can identify
and distinguish human alveolar RMS from embryonal
RMS.136,160 This is a rapid diagnostic test that can detect the
mutation in cases identified by histology as alveolar RMS. In
addition, studies of alveolar RMS lacking this mutation
(fusion-negative alveolar RMS) found that the biologic beha-
vior was similar to embryonal RMS and, like embryonal RMS,
showed high levels of expression of genes from chromosome 8.
The biological behavior of fusion-negative alveolar RMS is dis-
tinct from fusion-positive alveolar RMS, indicating that histolo-
gic pattern is not as specific a predictor of biologic behavior as
cytogenetic studies.160 It was concluded that the presence of the
PAX-FKHR mutation is a significant factor in the aggressive
phenotype of human alveolar RMS. Using this method to help
classify human RMS is especially helpful in cases where there
is lack of distinct histologic features.160 It is becoming more
common in human medicine to test for these mutations using
reverse transcription PCR (RT-PCR) and making the diagnosis
in conjunction with a biopsy.145,160
Proposed Molecular Pathogenesis of RMS
Human alveolar RMS and embryonal RMS are thought to arise
by a multistep process leading to loss of tumor suppressor genes
and genes affecting the regulation of apoptosis and cellular
senescence.79 Recent molecular studies have suggested that
alveolar RMS represents an arrested stage of development in
undifferentiated myoblast cells.165 The cause of the arrested
stage of development could be related to the PAX-FKHR muta-
tion; under certain circumstances, increased expression of PAX
inhibits myogenic differentiation in mesoderm cells.43 The
fusion of the PAX and FKHR genes leads to uncontrolled cell
growth signals, cell cycle progression, failure of tumor suppres-
sor gene function, and myogenic differentiation. Fusion of PAX-
FKHR causes increased levels of MyoD1, resulting in cell pro-
liferation and also increased levels of myogenin, leading to
myogenic differentiation. Increased levels of IGF-II also result
in cell proliferation.163 Human alveolar RMS has been associ-
ated with increased expression of c-Met receptor and CXCR4,
both of which enhance cell growth and cell cycle progression.87
Veterinary Pathology 55(5)
Studies of the mRNA transcripts and in vitro studies of trans-
fected cultured myoblasts have discovered increased activity of
MDM2, CDK4, and cyclin D.163,169 A recent study of in vitro
mouse mesenchymal stem cells demonstrated the ability of the
PAX-FKHR translocation to produce alveolar RMS when
coupled with loss of RB and p53 tumor suppressor gene func-
tion and constitutive H-RAS activation.120 In normal cells,
CDK4 and cyclin D form a complex that begins a cells pro-
gression through the G1 phase of the cell cycle. Uncontrolled
accumulation of CDK4 and cyclin D lead to uncontrolled cell
cycle progression through phosphorylation of RB. RB is a
tumor suppressor protein normally present in the nucleus
bound to E2F, thereby preventing transcription of mRNA
needed for cyclin production and cell cycle advancement
beyond the G1 phase. When RB is phosphorylated, E2F is
freed, leading to transcription of cyclins needed for cell cycle
progression. If H-RAS is constitutively active as in this mouse
model,120 RAS continually sends positive signals for cell cycle
progression. These continuous growth signals, coupled with
the inability to halt the cell cycle or undergo apoptosis, leads
to neoplastic growth.169,170
P53 is an important regulator of cell senescence and apopto-
sis. It senses DNA damage and can halt cell cycle progression,
leading to either senescence or apoptosis. MDM2 is responsible
for inactivating p53, thereby possibly preventing apoptosis in
these cells.163,170 Inactivation of P53 coupled with uncontrolled
cell cycle advancement results in neoplastic growth. There are
more alterations in cell senescence and growth found in human
and mouse models of RMS. Mirk expression is elevated in
human RMS. Normal functions of Mirk range from cell senes-
cence in the G0 phase to responses to cellular injury and reduc-
tion in apoptosis. Increased expression of Mirk in RMS is
thought to result in reduced apoptosis and increased survival
of all RMS variants.90 Alterations in other tumor suppressors
have also been found. Micro-RNAs act as tumor suppressors
and are downregulated in human RMS.124
Furthermore, other studies of transfected cultured pediatric
RMS and mouse mesenchymal stem cells have demonstrated
that the PAX-FKHR mutation is necessary for myogenic differ-
entiation in alveolar RMS but in itself is not sufficient to pro-
duce a neoplasm without additional mutations. Consequently,
multiple mutations over several generations are needed to
produce a sarcoma with the phenotype of alveolar RMS.58,165
Further study is needed to better clarify the origin of RMS in
human and veterinary medicine.
Currently, there are so few cases of canine RMS that there is
no information available regarding molecular pathogenesis of
this neoplasm. Although genetic mutations may prove useful
in future diagnosis of canine RMS, the relative rarity of this neo-
plasm and the difficulty in making a diagnosis make genomic
analysis less useful as a diagnostic tool. At present, immunohis-
tochemistry is the most feasible adjunct to standard histopathol-
ogy for diagnostic purposes. The diagnostic utility of myogenin
and MyoD1 immunohistochemistry can be investigated from
archived cases and be readily applied to diagnostic laboratories
throughout the country.
Caserto
Pathogenesis of Metastatic Disease in
Human RMS
Mutations in the oncogene FGFR4 have been found in 7.5% of
human alveolar and embryonal RMS.80 This mutation is
associated with advanced stage of disease in alveolar RMS in partic-
ular, whose uncontrolled expression leads to cell cycle progression
and has a role in metastasis that is not well defined.143 Interleukin-4
(IL-4) helps recruit myoblasts to form myotubes in normal mamma-
lian myogenesis and has been associated with childhood and mouse
RMS differentiation, mitogenesis, and metastasis.59
Immunohistochemical identification of receptors down-
stream of Hedgehog signaling such as Smoothened (SMO) and
glioblastoma transcription factor 2 (GLI2) are common in
human RMS and are the result of increased Hedgehog signaling
in these tumors. In fact, inhibition of SMO by cyclopamine
slows the growth of RMS cell lines in vitro. Inhibition of GLI1
by GANT61 (inhibitor of Hedgehog signaling by interfering in
DNA binding with GLI1) also slowed growth of in vitro RMS
cell lines.63,148 Inhibitors of Hedgehog signaling have been sug-
gested as a therapeutic method for human gliomas and may be
useful in the treatment of RMS as well.29
In patients with distant metastasis, there is high expression of
FOXF1 (Forkhead family of transcription factors) and LMO4
(LIM domain transcription factor), which are thought to aid in
tumor cell migration.4 Overexpression of MET by some tumors
may provide RMS cells with the same property as embryonal
myoblasts to migrate into surrounding connective tissues.36
Snail1 is highly expressed in alveolar RMS, E-cadherin is
downregulated, and expression of MMP2 and MMP9 is upregu-
lated in alveolar RMS.117 Because of Snail1s known roles in
the metastasis of other tumors, it is presumed, yet unproven,
to aid in metastasis of RMS. The role of E-cadherin and MMP2
in the pathogenesis of RMS and metastasis is less well known.
Loss of E-cadherin is thought to reduce sensitivity of cell
growth to external factors such as contact with other cells or the
extracellular matrix. Increased amounts of matrix metallopro-
teases presumably aid in cell migration, local invasion, and
metastasis.59,117
Case Reports in Veterinary Literature
Frequency of Published Cases
The frequency of (nonlaryngeal/noncardiac) canine rhabdomyo-
sarcoma in veterinary medicine is low, with 65 total case reports
published (Table 4) and available by a PubMed search and in the
textbook Tumors of Domestic Animals.31 Pleomorphic RMS is the
least common (n = 2; 3%),8,31 and botryoid RMS is the most com-
mon (n = 28; 43%),3,11,31,47,54,64,65,68,73,83,108,115,131,138,140,141,144,155
followed by embryonal RMS (n = 15; 23%).7,31,35,61,62,65,153,166,167
Unclassified RMS (RMS NOS) is prevalent in the literature (n =
13; 20%),14,16,21,49,74,75,99,102,103,113,162 and probably reflects the
lack of knowledge of RMS classification in veterinary medicine.
Alveolar RMS (n = 7; 11%) is less frequently diagnosed in canines
second only to pleomorphic RMS.11,31,65,100,125,128,134 In human
815
medicine, embryonal RMS and alveolar RMS are by far the most
common tumors in children.78
Twelve laryngeal rhabdomyomas/rhabdomyosarcomas have
been reported in dogs, all but one in dogs older than 2 years. It
is generally believed that laryngeal rhabdomyomas/rhabdomyo-
sarcomas are a distinct clinical entity of dogs, being locally inva-
sive yet rarely metastatic.13,15,30,31,56,77,84,92,107,164,166 Complete
excision is often difficult due to local invasion, and recurrence
of these tumors often leads to euthanasia. Histologically, these
neoplasms contain large cells with granular eosinophilic cyto-
plasm containing large amounts of periodic acid-Schiff (PAS)
positive glycogen and mitochondria. Although some have been
diagnosed as oncocytomas based on ultrastructural findings of
large numbers of mitochondria, laryngeal rhabdomyomas can
be distinguished from oncocytomas by positive staining for myo-
globin and desmin or by the ultrastructural presence of myofibers
in addition to glycogen and mitochondria.76,92,161
Cutaneous rhabdomyomas are rarely reported. Two cases of
cutaneous rhabdomyoma were reported by Copper and Valen-
tine,31 one occurring in the skin and subcutis of a leg and the
other in the skin of a foot in 11-year-old and 14-year-old dogs,
respectively. Cutaneous RMS can occur in the dermis or subcu-
tis of humans.86 These occur mostly in adults and are diagnosed
as pleomorphic RMS. Those that occur in children are usually
embryonal and alveolar RMS. In 1 report, 6 of 12 cases metas-
tasized.86 Primary cutaneous RMS can occur in dogs, and some
cutaneous RMS that occurs in the dermis is likely misdiagnosed
as anaplastic or poorly differentiated soft tissue sarcoma if
immunohistochemical studies are not pursued. Despite being
excluded from the category of soft tissue sarcomas by some
investigators,37,72,130 others have included them in their soft tis-
sue sarcoma category on the basis of similar behavior.156 Some
subcutaneous masses undoubtedly arise from muscles of the
appendicular skeleton but invade superficially, making determi-
nation of origin difficult from a biopsy.
Cardiac muscle tumors are rare in dogs, but the majority of those
reported and available through PubMed are RMS (6/12),1,6,52,69,114
3 of which had metastasized. Four (4/12) cardiac rhabdomyomas
are reported,50,66,85,119 as well as 1 myocardial hamartoma of the
right atrium.81 One malignant mixed mesenchymal tumor
(mesenchymoma) with rhabdomyosarcomatous differentiation
was reported in the heart of an 8-year-old female Pug.82
One rhabdomyoma of the tongue was reported in a 9-year-
old, castrated male, mixed breed dog.122 One mesenchymoma
with rhabdomyosarcomatous differentiation was reported in the
spleen of a dog.159 There are 15 reports of cats with
RMS,20,31,57,88,96,98,110,132,137 8 in sheep,41,106,142 and 15 in the
horse.18,28,44,45,55,147,151 Feldman recounts 1 rhabdomyoma in
the shoulder of a 13-year-old horse.44
In addition to the skeletal muscle RMS mentioned in pigs,
cardiac rhabdomyomas are found in pigs more often than in
other species. A peculiar tumor of cattle appears histologically
as cuboidal epithelioid cells arranged in glandular acini in a col-
lagenous stroma. These have been termed myocardial epithelial
inclusions or myocardial adenomatoid tumors.12,135,152 They
are hamartomas composed of pericardial mesothelial inclusions.
 Table 4. Veterinary Case Reports and Literature Review of Canine Rhabdomyosarcomas (Noncardiac).

816
Reference Species/Breed Sex Age Clinical Signs Location Metastasis

Alveolar RMS
Seibold, 1974128 Mixed breed FS 2y Subcutaneous mass in the left maxillary Maxilla Pancreas, adrenals, left
area popliteal, and right
sublumbar lymph node;
local infiltration into bone
Sarnelli et al, 1994125 Dog FS 2y Palpable abdominal mass Greater omentum None
Kim et al, 199665 Rottweiler F 11 mo Maxillary swelling Gingiva/ maxilla None
Cooper and Valentine, 200231 Dog M 7y Hip Not reported
Bae et al, 200711 Golden F 2y Uterus Lung, liver, kidney LN
Murakami et al, 2010100 Mixed breed MC 15 mo Epistaxis and sneezing Cauliflower-shaped gingival mass Lung, brain
Snyder and Michael, 2011134 Golden MC 7 mo Maxillary Gingiva None
Embryonal RMS
Kim et al, 199665 Basset M 1.5 y Unilateral periorbital swelling, Oropharynx and the temporal Regional lymph node and
exophthalmia, and pain upon opening muscles maxillary gingiva lungs
the mouth
Yanoff et al, 1996166 Akita M 4 mo Noisy respiration, excessive panting, Trachea/neck/recurrent None
and exercise intolerance; veterinarian laryngeal nerve
showed a lateral deviation in the
cervical trachea
Cooper and Valentine, 200231 Dog F 14 y NA Axilla Not reported
Dog M 6y NA Perirenal Not reported
Dog F 12 y NA Tongue Not reported
Dog M 4y NA Muscle of flank Not reported
Dog F 11 y NA Tongue Not reported
Dog F Adult NA Mammary Not reported
Dog M 1.5 y NA Hard palate Not reported
Illanes, 200261 Labrador Retriever M 23 mo Unilateral atrophy of masticatory Right side masticatory muscle Liver
muscles invasive and trigemical nerve
Ueno et al, 2002153 Labrador Retriever MC 11 y Mass on perineum Perineum None confirmed
Yhee et al, 2008167 Golden M 8 mo Left forelimb lameness Mass in the left axillary region; Lung
osteolytic lesion in the scapula
Avallone et al, 20107 English Pointer FI 11 y Subcutaneous mass Left forearm None
da Roza et al, 201135 Boxer M 11 mo Incoordination and presence of a little Skull None
mass in the frontal region of the skull
Kato et al, 201262 Welsh Corgi M 2y Left upper eyelid enlargement Lacrimal gland, orbit Subcutis, multifocally, body
Botryoid
Osborne et al, 1968108 St Bernard M 5y Bladder None
Stamps and Harris, 1968138 Basset Hound F 1y dysuria Bladder, ureters Retroperitoneal lymph node,
great and lesser omentum,
small intestine, mesentery,
peritoneal surface, kidneys,
adrenal glands, liver, spleen,
lungs
Teunissen and Misdorp, 1968144 Great Dane FI 1.5 y Dysuria Bladder None
(continued)
 Table 4. (continued)

Reference Species/Breed Sex Age Clinical Signs Location Metastasis

Kelly, 197364 St Bernard F 1y Dysuria, hematuria Urinary bladder neck None

Miniature Poodle F 1.5 y Dysuria, hematuria Urinary bladder neck None
St Bernard F 1.5 y Dysuria, hematuria Urinary bladder neck None
St Bernard F 14 mo Dysuria, hematuria Urinary bladder neck None
Great Dane F 1.5 y Dysuria, hematuria Urinary bladder neck None
St Bernard M 5y Dysuria, hematuria Urinary bladder neck None
Basset Hound F 1y Dysuria, hematuria Urinary bladder neck Local lymph nodes,
mesentery, kidney, adrenal,
liver, spleen, and lungs
Halliwell and Ackerman, 197454 Doberman Pinscher M 1.5 y Cystitis, enlarged tarsal and carpal joints Bladder None
Pletcher and Dalton, 1981115 Irish Setter M 20 mo Dysuria and hematuria Bladder Not reported
Andreasen et al, 19883 Doberman Pinscher M 2y Dysuria, hematuria Bladder Not reported
Labrador FS 18 mo Hematuria, pollakiuria Bladder Not reported
Great Dane MC 1y Stranguria, dysuria Bladder Not reported
van Vechten et al, 1990155 Doberman Pinscher MC 13 mo Urinary incontinence Bladder Colonic lymph node
Senior et al, 1993131 Labrador Retriever M 10 mo Stranguria, pollakiuria, hematuria Bladder None
Kim et al, 199665 Rottweiler F 11 mo Cystitis Urinary bladder None
Kuwamura et al, 199873 Newfoundland F 13 mo Hematuria and stranguria Urinary bladder None
Cooper and Valentine, 200231 Dog F 6 mo Bladder Not reported
Dog F 1y Bladder Not reported
Takiguchi et al, 2002141 Maltese F 2y Hematuria, pollakiuria Urinary bladder Liver
Madarame et al, 200383 Labrador Retriever F 9 mo Pollakiuria, anorexia Urinary bladder None
Kobayashi et al, 200467 Dog F 18 mo Hematuria Urinary bladder None
Dog F 12 mo hematuria Urinary bladder Liver, lung, heart, kidney,
ovary, and skin
Suzuki et al, 2006140 Dog 10 y Vagina None
Bae et al, 200711 Golden Retriever F 2y Pain, vaginal bleeding, dysuria Urinary bladder None
Gerber and Rees, 200947 Labrador Retriever MI 8 mo Lower urinary tract obstruction, Urinary bladder Lymph nodes and the liver,
hydronephrosis, hyrodureter lungs, mesenteric lymph
nodes, mediastinum, heart,
subcutaneous tissue, and
several muscle groups
Pleomorphic RMS
Cooper and Valentine, 200231 Dog M 3y Neck Not reported
Azakami et al, 20118 Mixed MI 14 y Prostate Not reported
Rhabdomoysarcoma NOS
Mulligan, 194999 Dog Unknown Tongue Not reported
Worley and Gorham, 1954162 English Setter M 8y Weight loss, lameness left rear leg Thigh Lung, liver, spleen, kidney,
lymph node, adrenal glands
Peter and Kluge, 1970113 German Shepherd M 2y Dysphagia Mandible Parotid, mandibular,
retropharyngeal,
mediastinal, and bronchial
lymph nodes; lungs; heart
(continued)

817
818
Table 4. (continued)

Reference Species/Breed Sex Age Clinical Signs Location Metastasis

Ladds and Webster, 197174 Welsh Corgi FI 6y Dysphagia Pharynx, soft palate Locally invasive to lymph
node
Bastianello, 198314 Dog Ocular muscle Not reported
Lascelles et al, 199875 Staffordshire Bull Terrier 6y Dysphagia Tongue None
Ginel et al, 200249 Boxer FI 7y Left forelimb lameness Fifth metacarpal Another limb
Necas et al, 2003103 Hovawart F 3y Right eye hyperemia, epiphora, Retrobulbar None
exophthalmos
Brockus and Myers, 200416 Dog 10 y Tongue Multicentric
Chapman et al, 200821 Rat Terrier FS 3.5 y Dysphagia, gagging Tongue None
Nakaichi et al, 2007102 Dog 10 y Left maxillofacial area Lung
Dog 10 y Left maxillofacial area Lymph node
Dog 12 y Right upper molar Lung
Laryngeal rhabdomoyoma or RMS
Liggett et al, 198577 Schnauzer cross F 4y Dyspnea Larynx None
Meuten et al, 198592 Scottish Terrier F 2y Dyspnea Larynx None
Doberman Pinscher MC 7y Dyspnea larynx None
Henderson, et al, 199156 Spitz FS 6y Exercise intolerance, stridor Larynx Liver
Block et al, 199515 Mixed breed dog FS 9y Larynx None
Clercx et al, 199830 Golden Retriever M 3y Dyspnea, exercise intolerance, stridor larynx None
Madewell et al, 198884 Doberman Pinscher F 11 y Larynx None
Barnhart and Lewis, 200013 Dachshund FS 3y Dyspnea Larynx None
OHara et al, 2001107 Golden FS 4y Dyspnea Larynx None
Cooper and Valentine, 200231 Dog FS 10 y Larynx None
Dog M 8y Larynx None
Yamate et al, 2011164 Mixed breed dog FS 6y Dyspnea, stridor Larynx, epiglottis None

F, female; FS, FI, female intact; female spayed; LN, lymph node; M, male; MC, male castrated; MI, male intact; NA, ; NOS, not otherwise specified; RMS, rhabdomyosarcoma.
Caserto
Table 5. Comparison of Signalment and Biologic Behavior of Canine Rhabdomyosarcoma (RMS) and Canine Soft Tissue Sarcomas.
Soft Tissue Sarcoma
Metastasis 17% overall/grade 3 up to 50%
Survival 60%
Growth rate Slow
Degree of differentiation Grade 1 = well differentiated/grade 3 = poor
Cell morphology Spindyloid-polygonal
Age 10+ y
Canine soft tissue sarcoma (STS) has a range of metastatic rates. Grade 3 STS compares with the metastasis of alveolar and embryonal RMS, and grade 2 STS
compares with metastatic rates of botryoid RMS. Survival is generally poor in canine RMS, but survival depends on grade of STS. Growth rate of RMS tends to be more
rapid than the average growth rate of STS. STS has a range of cellular morphologies, and RMS tends to have poor differentiation. Age of onset of STS differs greatly
with RMS, being about 10 years on average for STS and most RMS occurring <10 years old, with 53% (n = 39/73) occurring in dogs <2 years old.38,42,47,72,130
Poorly differentiated sarcomas are occasionally reported in
the literature. These microscopically resemble embryonal
tumors, with small cells and scanty cytoplasm, and have
hyperchromatic nuclei. Immunohistochemical studies often
do not include myogenin or MyoD1 but are negative for des-
min.33 Young age, or genitourinary location, should indicate
a possible RMS despite negative desmin staining. Increased
availability of myogenin, MyoD1, or other primitive myogenic
markers may help diagnose alveolar and embryonal RMS in
these circumstances.
In a single case report,16 a dog developed multiple rhabdo-
myosarcomas in multiple locations that were categorized as
embryonal RMS at one location and alveolar RMS at another.
It is unclear whether these neoplasms arose separately or are the
product of a metastatic process and subsequent divergence in
phenotype. Kim et al65 diagnosed an alveolar RMS in the gin-
giva of an 11-month-old Rottweiler, and upon necropsy,
although no metastasis was reported, a botryoid RMS was diag-
nosed in the urinary bladder. These tumors were considered to
arise independent of each other. A report of orbital embryonal
RMS in a dog described metastasis to the cervical region with
a histologic pattern of alveolar RMS.62 Clearly, these incidences
warrant further investigation into the diagnosis, pathogenesis,
and the identification of prognostic markers of RMS in dogs.
In the meantime, comparison to human RMS pathogenesis and
prognosis should be made with caution.
Clinical Features of Rhabdomyosarcomas
Human Rhabdomyosarcoma
Childhood rhabdomyosarcoma primarily affects children
younger than 15 years19,36,47,58,60,101,109,116 and comprises
about two-thirds of soft tissue sarcomas in children.146 Because
of the significant difference in survival times in humans
between alveolar and embryonal rhabdomyosarcomas, it is nec-
essary for human pathologists to reliably differentiate the two,
even when both appear as small round cell neoplasms. With cur-
rent chemotherapy treatments, the 5-year survival of embryonal
RMS in children is about 67% to 70%, whereas for alveolar
RMS, it is about 40% to 49%.116,158 Age and location also have
819
Rhabdomyosarcoma
Alveolar and Embryonal Botryoid
50% 27%
Poor Poor
Rapid Rapid
Poor Moderate
Round/mixed Mixed round/spindle
<2 y (57%); <10 y (86%)
prognostic implications. Children 1 to 4 years old have a 5-year
survival of 77%, and for those with localized disease, it is even
higher at 83%.116 Orbital and genitourinary locations have a 5-
year survival of 86% and 80%, respectively.116 Poor prognosis
is associated with RMS diagnosed at infancy or adolescence
(47%-48%, respectively) and locations including the limbs
(50%), trunk (52%) and retroperitoneum (52%).116
In humans, there is slightly better survival with embryonal
histology (67%) compared with alveolar histology (49%). Low-
est 5-year survival is correlated to metastasis at the time of pre-
sentation (31%) and alveolar histology (49%).116 Prognosis of
patients with regional lymph node metastasis is similar to distant
metastasis in alveolar RMS but not embryonal RMS.123
Botryoid rhabdomyosarcomas in humans are locally infiltrative
and are second only to the less common spindyloid variant
embryonal RMS in favorable prognosis.94 Most human embry-
onal rhabdomyosarcomas fall into the intermediate risk category
(55%), with a 3-year survival of 59% to 85%94 and a 5-year sur-
vival of 67%.116 In contrast, even though spindyloid RMS com-
prises 3% of all RMS, it has a 95% survival at 5 years. Survival
of people with alveolar RMS ranges from 49% to 66% at 5
years.94,116 Embryonal and botryoid RMS are frequently
reported to have lower metastatic rates than alveolar RMS, but
precise figures are not often reported.118 Only about 15% to
20% of patients have clinically detectable distant metastasis at
the time of diagnosis, but all are considered to have micrometa-
static disease.94
Canine Rhabdomyosarcoma and Soft Tissue Sarcomas. Rhabdo-
myosarcomas are occasionally grouped together within the broad
category of canine soft tissue sarcomas,89 yet they often have a
different clinical signalment and location. Soft tissue sarcomas
graded by the Kuntz et al72 system are restricted to subcutaneous
neoplasms and exclude hemangiosarcomas and rhabdomyosarco-
mas. Table 5 compares the biological behavior of canine RMS
and soft tissue sarcomas. The most significant difference between
the two is the age of onset, location, and survival.
RMS is often reported as appearing most often in younger
dogs, 2 years old or younger. A survey of the reported cases
of nonlaryngeal RMS indicates that 63% (n = 39/62) occurs
in young dogs (2 years old) (Fig. 14). In dogs, 89% (n = 25/
820 Veterinary Pathology 55(5)

Figure 14. Age of diagnosis of canine rhabdomyosarcoma (RMS). A literature search shows 63% (n = 39/62; in 2 cases, the age was not
reported) of canine RMS (excluding laryngeal rhabdomyomas/rhabdomyosarcoma) occurs in dogs younger than 2 years. The remaining 37%
is divided between animals 3 to 6 years old (n = 9/62; 15%), 7 to 10 years old (n = 7/62; 11%), and >10 years old (n = 7/62; 11%). Eighty-
nine percent (n = 55/62) of cases occur in dogs younger than 10 years. Figure 15. Subclasses of canine RMS. (a) Botryoid RMS was the most
frequent canine RMS (n = 28/65; 43% of cases excluding laryngeal tumors). Embryonal RMS was diagnosed in 23% of cases of nonlaryngeal ske-
letal muscle tumors (n = 15/65). RMS not otherwise specified (NOS) was diagnosed in 20% of cases (n = 13/65), and alveolar RMS was diagnosed
in 11% (n = 7/65) of cases. Pleomorphic RMS was diagnosed least frequently (n = 2/65; 3%). Most of the alveolar (86%; n = 6/7) and botryoid RMS
Caserto 821

28) of botryoid RMS occurs in dogs 2 years old or younger.
Similarly, in alveolar RMS, 86% (n = 6/7) occurs in young dogs.
By contrast, only 47% of embryonal RMS occurs in dogs 2
years old or younger. Only 8% (n = 1/13) of RMS NOS occurs
in young dogs, and no reported cases of pleomorphic RMS have
occurred in young dogs. Although this seems to correspond to
the high prevalence of this subclass in human adults, the fre-
quency of this diagnosis is very low (n = 2) (Fig. 15).
Soft tissue sarcomas arise mostly in middle-aged to older
dogs and occur in the skin and subcutis of the trunk and extre-
mities and oral cavity.38,42 RMS occurs often in the urogenital
tract (n = 32/65; 49%), and these are most frequently botryoid
RMS of the urinary bladder. The second most common location
is the head, neck, and face (n = 24/65; 37%), and a small per-
centage occurs in the hip/pelvis/spinal column (n = 2/65; 3%),
appendicular skeleton (n = 5/65; 8%), and skin (including mam-
mary gland) (n = 2/65; 3%) (Fig. 16).
It is difficult to compare metastatic rates between canine
RMS subgroups because in some cases, these data were not
reported or euthanasia was elected at the time of diagnosis. In
veterinary medicine, the prognosis depends on the severity and
extent of invasiveness, as well as the presence of metastatic dis-
ease at the time of diagnosis. In cases of extensive local infiltra-
tion or radiographic evidence of metastatic disease, euthanasia
may be sought instead of radical surgery or adjunct therapy.31,65
Metastasis reported at the time of RMS diagnosis or at necropsy
shows that metastatic rates of RMS in dogs is highest in RMS
NOS (n = 6/11; 55%), followed closely by embryonal RMS
(n = 4/8; 50%) and alveolar RMS (n = 3/6; 50%). Botryoid
RMS has the lowest metastatic rate (n = 6/22; 27%) (Fig. 17).
In reported literature, botryoid RMS is reported to rarely metas-
tasize.65,149 There are no data on metastasis of pleomorphic
RMS (n = 2). It is interesting that of the metastatic cases of
canine botryoid, embryonal, and alveolar RMS, all are 2 years
old, whereas the metastatic cases of RMS NOS are mostly older
than 2 years (Fig. 17).
High-grade soft tissue sarcomas have similar rates of metas-
tasis and recurrence to reported incidence of canine RMS and
therefore may carry the same prognosis. Kuntz et al72 reported
the metastatic rate of grade 3 soft tissue sarcomas without adju-
vant therapy as 46% (ranging from 41%50%), which is
roughly equivalent to embryonal RMS, alveolar RMS, and
RMS NOS but is greater than botryoid RMS.130 Grade 1 and
2 soft tissue sarcomas fare better at 11% and 19%, respectively.
In addition, high-grade soft tissue sarcomas may be poorly dif-
ferentiated, resembling alveolar and embryonal RMS, and yet
may also resemble pleomorphic RMS with numerous cells hav-
ing bizarre mitotic figures and having cells with a high degree of
anisocytosis and anisokaryosis.42,72 Drawing conclusions from
these data is difficult because of the paucity of clinical cases,
lack of follow-up and survival data, and in many cases unknown
frequency of metastasis. Improved diagnostic techniques for
RMS may lead to more diagnosed cases and better data on sur-
vival and prognosis.
Summary
Rhabdomyosarcomas are a diverse and histologically variable
set of highly malignant neoplasms occurring predominately in
younger individuals. Subclassification has been attempted
based on histologic morphology, but these classification
schemes in human and veterinary medicine fall short when deal-
ing with very homogeneous cell populations with no particu-
larly identifying characteristics. Identification of particular
gene mutations is useful in human medicine and may become
the standard for distinguishing between alveolar and embryonal
tumors. The use of IHC to identify desmin, -actins, myogenin,
and MyoD1 and electron microscopic identification of sarco-
meric structures can be used to identify RMS in relatively undif-
ferentiated neoplasms. In veterinary medicine, much work
needs to be done to evaluate the prognostic significance of sub-
classifications and to identify new methods to characterize these
neoplasms to make classification effective and useful for veter-
inary oncologists and pathologists. Further investigation is
needed to better understand the biology of these neoplasms that
may aid in diagnosis and prognosis. Unless veterinary medicine
can identify prognostically significant markers or mutations in
dogs, the classification system currently used may continue to
yield poorly prognostic diagnoses.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship,
and/or publication of this article.
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