bb5_11.qxd 13.9.2006 10:52 Page 141
CHAPTER 6
Skeletal Muscle Tumours
Extracardiac rhabdomyomas take several forms, may affect
adults or children and are very rare. They are clinically benign
and usually have no great biologic significance once they have
been accurately diagnosed.
Malignant tumours showing skeletal muscle differentiation are
very uncommon, but retain importance as they represent the
largest subset of soft tissue sarcomas in infants and children.
Because of the important prognostic differences, much empha-
sis has been placed in recent years on the more accurate and
reproducible distinction between the embryonal and alveolar
variants of rhabdomyosarcoma. Validation of this distinction
(and important support for the existence of a solid variant of
alveolar rhabdomyosarcoma) has come particularly from cyto-
genetic and molecular genetic analysis. With increasing and
more reliable use of immunostains, rhabdomyosarcoma in
adults is no longer regarded as exceptionally rare. In this age
group it is most often represented by the pleomorphic subtype.
bb5_11.qxd 13.9.2006 10:52 Page 142
S.B. Kapadia
Rhabdomyoma
F.G. Barr
Rhabdomyoma (RM) is a benign mes- aerodigestive mucosa (pharynx, oral nucleoli. Haphazardly arranged rod-like
enchymal tumour with skeletal muscle cavity, and larynx) and soft tissue of neck cytoplasmic inclusions and cross stria-
differentiation that is classified into car- {1065}. tions are seen focally. The glycogen-rich
diac and extracardiac types based on cytoplasm is periodic acid-Schiff (PAS)-
location {1978}. Cardiac RM will be dealt Clinical features positive, diastase sensitive. Phospho-
with in the WHO classification of heart The median age is 60 years (range 33 to tungstic acid-hematoxylin, Masson
tumours. Extracardiac RM is further clas- 80 years) with a 3:1 male predominance trichrome or immunohistochemical stains
sified into adult and fetal types, depend- {1065}. Symptoms include upper airway highlight the cytoplasmic cross striations
ing on the degree of differentiation, and obstruction and mucosal or soft tissue as well as the crystalline or rod-like
has a predilection for the head and neck mass (median duration 2 years, range 2 inclusions {1065}.
{515,1063,1065,1155,2274}. Rarely, RM weeks to 3 years); in 10% the mass is
may occur in the genital tract (genital asymptomatic {1065}. A-RM is often soli- Immunophenotype
RM). Unlike cardiac RM, there is no tary (70%), but may be multinodular The skeletal muscle differentiation is eas-
association with tuberous sclerosis (26%) with discrete nodules in the same ily demonstrated on immunohistochemi-
{1065,1978,2274}. anatomic area or, rarely, multicentric cal stains with cytoplasmic positivity for
(4%) {1065}. MSA, desmin and myoglobin in all cases
ICD-O code 8900/0 {368,616,880,933,1063,1065,2274}.
Macroscopy Focal or rare positivity may be seen for
The mass (median size 3 cm, range 1.5 vimentin, SMA and S100 protein. GFAP,
to 7.5 cm) is circumscribed deep tan to cytokeratin, EMA, and CD68 stains are
Adult rhabdomyoma
red-brown, soft, and nodular or lobulated negative {1065}.
{1065}.
Definition Ultrastructure
Adult rhabdomyoma (A-RM) is a rare Histopathology Electron microscopy demonstrates cyto-
benign mesenchymal tumour with mature A-RM is well circumscribed but unen- plasmic myofilaments, Z-bands and
skeletal muscle differentiation and a capsulated and composed of lobules of glycogen granules {142,368,933,1155}.
predilection for the head and neck region. closely packed uniform large polygonal
cells in a scant stroma {1065}. The cells Prognostic factors
ICD-O code 8904/0 have abundant, eosinophilic, granular or Complete excision is the recommended
vacuolated cytoplasm ("spider" cells) treatment. In one study, follow-up
Sites of involvement with well defined borders, and vesicular, showed local recurrence (42%) in the
The head and neck region (90%) is the small, round, centrally or peripherally same anatomic site, from 2-11 years
most common site, mainly the upper located nuclei, at times with prominent after diagnosis, often after incomplete
A B
Fig. 6.01 Adult rhabdomyoma. A Well circumscribed mass composed of large polygonal cells with eosinophilic vacuolated cytoplasm and surrounded by normal skeletal
muscle. B Higher magnification shows large, polygonal cells with abundant granular and vacuolated cytoplasm.
142 Skeletal muscle tumours
bb5_11.qxd 13.9.2006 10:52 Page 143
haphazardly arranged in abundant myx-
oid stroma. "Intermediate" F-RM (also
referred to as "juvenile" or "cellular") dis-
plays a wider spectrum of differentiation
or more advanced maturation between
that of the "classic" F-RM and A-RM {485,
515, 1064, 1155, 1620}. Interlacing large
strap-like striated muscle cells, broad
fascicles of delicate spindled rhabdomy-
oblasts simulating a smooth muscle
A B
tumour, or ganglion-like rhabdomyoblasts
Fig. 6.02 Adult rhabdomyoma. A Vesicular nuclei and prominent round nucleoli are the hallmark of "spider" cells.
may be seen {1064}. Nuclear atypia and
B Cytoplasmic immunopositivity for myoglobin.
necrosis are absent in F-RM. Mitoses are
usually absent, but in one study 5/24 F-
RM had had 1-14 mitoses/50HPF {1064}.
excision {1065}. A-RM may recur after Macroscopy The relationship of the latter cases to well
many years or on more than one occa- F-RM presents as a solitary, circum- differentiated embryonal rhabdomyosar-
sion, but lacks aggressive behaviour or scribed, soft, gray-white to tan-pink mass coma is unclear. Lack of prominent
malignant potential. with a glistening cut surface. In mucosal nuclear atypia is the most important crite-
sites F-RM is polypoid. rion separating F-RM from rhab-
domyosarcoma {1064}.
Histopathology
F-RM is circumscribed but unencapsulat- Immunophenotype
Fetal rhabdomyoma
ed. "Classic" immature F-RM is com- A skeletal muscle immunophenotype is
posed of bland primitive spindled cells demonstrated in all cases, with strong
Definition associated with delicate fetal myotubules positivity for MSA, myoglobin and
Fetal rhabdomyoma (F-RM) is a rare
benign mesenchymal tumour that
exhibits immature skeletal muscle differ-
entiation and a predilection for the head
and neck.
ICD-O code 8903/0
Sites of involvement
More than 90% of F-RM occur in the soft
tissue or mucosal sites of the head and
neck although, rarely, other sites may be
involved {409,485,1064,1620}. "Classic"
F-RM has a predilection for the postau-
ricular soft tissue {485,1064}, and those
with "intermediate" differentiation tend to
occur in soft tissue of face or in mucosal
sites, but both subtypes may occur at
any site in head and neck {1064}.
Clinical features
A
The median age is 4 years (range, 3
days-58 years) with a 2.4:1 male pre-
dominance {1064}. In one study, 10/24
cases (42%) were <1 year old, 6 (25%)
were congenital, and 11 (46%) occurred
in patients >15 years of age.
The median size is 3.0 cm (range 1-12.5
cm). F-RM presents as a well defined
solitary mass involving soft tissue or
mucosa (median duration 8 months,
B C
range 3 days to 19 years) {1064}. Some
Fig. 6.03 Classic fetal rhabdomyoma. A Tumour is composed of cytologically bland, delicate fetal myotubules.
cases are associated with naevoid basal
B Primitive spindle cells in a myxoid stroma. C Occasional delicate rhabdomyoblasts display cross striations.
cell syndrome.
Rhabdomyoma 143
bb5_11.qxd 13.9.2006 10:52 Page 144
desmin {1064}. Focal reactivity may also duration 49 months, range 2 months-52
be noted for SMA, S100 protein, GFAP, years) showed local recurrence in only 1
and vimentin {1064}. Vimentin staining is case, at 3 months after excision, proba-
variable and often weak. Cytokeratin, bly due to incomplete excision {1064}.
CD68, and EMA are negative {1064}. None of the tumours metastasized.
Ultrastructure
Electron microscopy demonstrates thick
and thin myofilaments with Z-bands and
Genital rhabdomyoma
glycogen within cytoplasm of immature
rhabdomyoblasts {485}.
Definition
Genetic susceptibility Genital rhabdomyoma (G-RM) is a rare
Multiple cases of fetal rhabdomyoma benign mesenchymal tumour with an
have been reported in patients with advanced degree of skeletal muscle dif-
nevoid basal cell carcinoma syndrome ferentiation and a predilection for the
{818}. This syndrome is caused by muta- vagina, almost exclusively in middle-
tions in the tumour suppressor gene aged women.
PTCH {524,866,1043}. PTCH encodes an
inhibitory receptor in the sonic hedgehog ICD-O code 8905/0
signaling pathway, and germline muta-
tions often lead to protein truncation and Sites of involvement
functional inactivation {2264}. Though Most cases present as polyps in the
rhabdomyomas have not been specifi- vagina, vulva or cervix {322,750,803,
Fig. 6.05 Intermediate fetal rhabdomyoma.
cally examined, the wild-type allele is 1066,1240,1283,2049}. Rare G-RM have Submucosal mass shows broad strap-like rhab-
domyoblasts with abundant eosinophilic cyto-
often eliminated by an allelic loss mech- been described in males in the parates-
plasm.
anism in other tumours found in this syn- ticular region or epididymis {2085, 2225}.
drome {755}.
Clinical features
Prognostic factors The mean age is 42 years (range 30-48 defined, solitary mass with the clinical
Complete excision of the mass is the rec- years) {1066}. The mass may be asymp- appearance of a benign vaginal polyp.
ommended treatment. In one study, fol- tomatic or known to be present for 4-5
low-up available in 15 cases (median years {1066}. Vaginal RM is a well Macroscopy
The polypoid vaginal mass (median size
2 cm, range 1-3 cm) is covered by
smooth mucosa. A pedicle (0.6-1.5 cm
long) is seen in some cases.
Histopathology
The polypoid unencapsulated mass is
composed of a haphazard arrangement
of bland, interlacing, broad strap-like or
round striated muscle cells embedded
in a fibrous stroma containing dilated
vascular channels {1066}. The cells
A B
have abundant eosinophilic glycogen-
rich cytoplasm that displays uniform
advanced maturation with cross stria-
tions and longitudinal myofibrils seen in
many cells. One (or more) uniform, cen-
trally located round vesicular nucleus
contains prominent round nucleoli.
Vaginal RM lacks the vacuolated "spider"
cells seen in A-RM, and the prominent
myxoid stroma and primitive spindle
cells or delicate fetal-type rhabdomy-
C D
oblasts seen in "classic" F-RM. They
Fig. 6.04 Intermediate fetal rhabdomyoma. A Mucosal lesion showing more advanced rhabdomyoblastic
show more rhabdomyoblastic maturation
maturation than the "classic" type. B Fascicles of spindled rhabdomyoblasts simulating smooth muscle cells. C
than the "classic" F-RM and are analo-
Note round ganglion cell-like rhabdomyoblasts. D Cytoplasmic cross striations are highlighted by Masson
trichrome stain. gous to some "intermediate" mucosal F-
144 Skeletal muscle tumours
bb5_11.qxd 22.9.2006 10:18 Page 145
A B C
Fig. 6.06 Vaginal rhabdomyoma. A Whole mount shows a polypoid configuration and a fibrous stroma. B Medium magnification displays fibrous stroma with dila-
ted vessels and round or strap-like rhabdomyoblasts with abundant eosinophilic cytoplasm. C Cellular details of rhabdomyoblasts.
RM of the head and neck. However, they MSA, myoglobin and desmin {1066, Prognostic factors
lack the more variable cellular morpho- 1283, 2049, 2085, 2225}. The SMA, Local excision is adequate treat-
logy and architecture of head and neck vimentin, cytokeratin, S-100, GFAP, ment. Follow-up available in four
"intermediate" F-RM {1066}. Leu 7, EMA and CD 68 stains are nega- vaginal RM in one study (median
tive {1066}. duration 11 years, range 2 to 20
Immunophenotype years) revealed no recurrence after
The skeletal muscle differentiation of Ultrastructure excision and no evidence of tumour
G-RM is confirmed in all cases on Electron microscopy confirms the stria- at other sites {1066}. G-RM lacks
immunohistochemical stains which ted muscle origin of the striated rhab- aggressive behaviour or any malignant
show diffuse cytoplasmic positivity for domyoblasts in G-RM {803,1240, 2085}. potential.
Rhabdomyoma 145
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D.M. Parham
Embryonal rhabdomyosarcoma
F.G. Barr
Definition in children less than 5 years of age. Five and middle ear, pterygoid fossa,
A primitive, malignant soft tissue sarco- per cent of rhabdomyosarcomas affect nasopharynx, nasal passages and
ma that recapitulates the phenotypic infants {1746}, and a few are congenital paranasal sinuses, tongue, and cheek.
and biological features of embryonic {1011}. Embryonal rhabdomyosarcoma Besides these two general regions,
skeletal muscle. The term embryonal also constitutes important histological embryonal rhabdomyosarcomas occur
rhabdomyosarcoma encompasses the variant in adults {610, 910}, albeit such in the biliary tract, retroperitoneum,
spindle cell, botryoid, and anaplastic cases are rare. pelvis, perineum, and abdomen and
variants. In the U.S., embryonal rhabdomyosar- have been reported in various visceral
comas show a slight male:female pre- organs, such as the liver, kidney, heart,
ICD-O codes dominance (1.2:1) {860}. Seventy per and lungs. Embryonal rhabdomyosarco-
Embryonal rhabdomyosarcoma 8910/3 cent of U.S. rhabdomyosarcomas occur mas may involve the soft tissues of the
Spindle cell rhabdomyosarcoma 8912/3 in non-Hispanic whites, compared to trunk and appendicular skeleton but
Botryoid rhabdomyosarcoma 8910/3 14% in African-Americans, 10% in much less frequently than alveolar rhab-
Anaplastic rhabdomyosarcoma 8910/3 Hispanics, and 4.5% in Asians {846}, domyosarcomas (see below). Primary
and incidence rates are higher in whites origin in the skin also rarely occurs.
Synonyms {1664}. Incidence figures in Europe Spindle cell and botryoid variants of
Myosarcoma, malignant rhabdomyoma, resemble those in the U.S., with a simi- rhabdomyosarcoma involve a relatively
rhabdomyosarcoma, rhabdopoietic lar male excess, whereas incidence limited repertoire of organs. Spindle cell
sarcoma, rhabdosarcoma, embryonal rates appear somewhat lower in eastern rhabdomyosarcomas most commonly
sarcoma. and southern Asia {1664}. arise in the scrotal soft tissues, with the
remainder mostly involving head and
Epidemiology Sites of involvement neck regions {316}. Spindle cell rhab-
Rhabdomyosarcomas comprise the sin- Although embryonal rhabdomyosarco- domyosarcoma also occurs in adults,
gle largest category of soft tissue sarco- mas contain cells that are histologically usually in non-paratesticular locations
mas in children and adolescents, occur- identical to developing striated muscle, {1818}. By definition, botryoid rhab-
ring in 4.6/million U.S. children <15 less than 9% arise within the skeletal domyosarcomas must arise beneath a
years of age {860}. Embryonal rhab- musculature of the extremities. The mucosal epithelial surface, limiting it to
domyosarcomas constitute the most greatest proportion occur within head organs such as the urinary bladder, bil-
common subtype of rhabdomyosarco- and neck (about 47%), followed by the iary tract, pharynx, conjunctiva, or audi-
ma, occurring in 3.0/million U.S. chil- genitourinary system (about 28%) tory canal.
dren <15 years of age {860}. Children {1550}. Common locations in the geni-
less than ten years of ages are typically tourinary tract include the urinary blad- Clinical features
affected; among patients <15 years of der, prostate, and paratesticular soft tis- Coincident with the diversity of their
age, only 17% of embryonal rhab- sues. Typical sites of origin in the head anatomic origins, embryonal rhab-
domyosarcoma arise in adolescents and neck include the soft tissues intrin- domyosarcomas produce a variety of
{860}. The greatest proportion (46%) of sic to or surrounding the orbit and eye- clinical symptoms, generally related to
embryonal rhabdomyosarcomas occur lid, oropharynx, parotid, auditory canal mass effects and obstruction {1829}.
A B
Fig. 6.07 A Large embryonal rhabdomyosarcoma involving the paratesticular soft tissues. The tumour forms a Fig. 6.08 Rhabdomyosarcoma. In the centre, a typical
fleshy, pale tan mass with compression of the adjacent testis (arrows). B Botryoid rhabdomyosarcoma pre- rhabdomyoblast, with an eccentric oval nucleus,
senting as polypoid mucosal excrescences, obliterating the lumen of the gall bladder. central nucleolus, and eosinophilic cytoplasm.
146 Skeletal muscle tumours
bb5_11.qxd 13.9.2006 10:52 Page 147
A B
Fig. 6.09 Embryonal rhabdomyosarcoma. A Numerous rhabdomyoblasts with brightly eosinophilic cytoplasm and occasional multinucleated strap cells. B A compact area
with rhabdomyoblastic differentiation adjacent to an area with loose, mucoid stroma.
Hence, head and neck lesions can oid stroma, and necrosis. Of particular been identified but have been found in
cause proptosis, diplopia, sinusitis, or note is the striking appearance of botry- studies of mice {2124} and zebrafish
unilateral deafness, depending on their oid lesions, which create a cluster of {2012}.
location. Similarly, genitourinary lesions tumour nodules of variable size, typical-
may produce a scrotal mass or urinary ly within hollow viscera such as the uri- Macroscopy
retention, and biliary tumours may nary bladder or gall bladder. Like most primitive pediatric neoplasms,
cause jaundice. Otherwise, the symp- embryonal rhabdomyosarcomas form
toms are generally those of a rapidly Aetiology poorly circumscribed, fleshy, pale tan
growing soft tissue mass. Embryonal rhabdomyosarcomas may masses that directly impinge upon
Imaging studies are primarily used in result from sporadic or inherited muta- neighbouring structures. Spindle cell
delineating the extent of lesions for tions, as discussed below. Generally and botryoid variants display additional
staging and prior to definitive surgery. this occurs as a variation of the distinctive features. Spindle cell rhab-
Computed tomography and magnetic Knudson-Strong two-hit hypothesis, domyosarcomas, like other spindle cell
resonance imaging are most useful for which theoretically may involve loss of lesions, form firm, fibrous tumours with
these purposes, although ultrasonogra- heterozygosity or aberrant gene methy- tan-yellow, whorled cut surfaces.
phy can be used as a screening modal- lation as well as DNA mutations. Botryoid tumours, as the name implies,
ity. Images generally recapitulate those Malignant transformation of rhabdomy- have a characteristic polypoid appear-
of an expansile soft tissue mass in vari- omas very rarely causes rhabdomyosar- ance with clusters of small, sessile or
ous organs, with heterogenous signals coma. Carcinogens causing rhab- pendunculated nodules that abut an
reflecting the variable vascularity, myx- domyosarcomas in humans have not epithelial surface.
A B
Fig. 6.10 Botryoid rhabdomyosarcoma. A A dense layer of tumour cells abuts an epithelial surface and forms a cambium layer. B Squamous epithelium outlines polypoid
masses of tumour cells.
Embryonal rhabdomyosarcoma
147
bb5_11.qxd 13.9.2006 10:52 Page 148
epithelial surface. This feature, known
as a "cambium layer", typifies these
tumours. Botryoid rhabdomyosarcomas
also contain variable numbers of poly-
poid nodules, often with an abundant,
loose, myxoid stroma that can appear
deceptively benign.
Densely arrayed whorls or fascicles of
spindle cells constitute the spindle cell
variant of embryonal rhabdomyosarco-
ma. These spindle cells often resemble
smooth muscle cells, with blunted cen-
tral nuclei and tapered ends, but cyto-
plasmic cross striations, if present,
A B
and/or bright eosinophilia indicate stri-
Fig. 6.11 Spindle cell rhabdomyosarcoma. A The fascicular architecture of this paratesticular tumour may
ated muscle differentiation, which
readily be mistaken for other forms of spindle cell sarcoma. B Some tumour cells show nuclear immunopo-
should be confirmed by immunohisto-
sitivity for myf-4 (myogenin).
chemistry. Spindle cell rhabdomyosar-
comas may have a storiform architec-
Histopathology population, separated by therapy- ture similar to fibrous histiocytoma or a
Analogous to embryonic skeletal mus- induced necrosis and fibrosis {379}. wavy character like neurofibroma.
cle, embryonal rhabdomyosarcomas The histological architecture of embry- The presence of enlarged, atypical
are composed of primitive mesenchy- onal rhabdomyosarcoma also resem- cells with hyperchromatic nuclei
mal cells in various stages of myogene- bles embryonic muscle, which forms defines the anaplastic variant of rhab-
sis, i.e. rhabdomyoblasts. Stellate cells aggregates of myoblasts amid loose, domyosarcoma {1149}. This feature
with lightly amphophilic cytoplasm and myxoid mesodermal tissues {1549}. may be seen in both embryonal and
central, oval nuclei represent the most Similarly, alternating areas of dense, alveolar tumours but is more prevalent
primitive end of this spectrum. As these compact cellularity and loose, myxoid in the former. Bizarre, multipolar
cells differentiate, they progressively tissues constitute embryonal rhab- mitoses are also often present.
acquire more cytoplasmic eosinophilia domyosarcomas. The amount of loose Anaplastic features can be focal or dif-
and elongate shapes, manifested in and dense cellularity varies from case fuse. Focal anaplasia indicates the
descriptive terms such as "tadpole", to case: an abundant, mucoid stroma presence of only single, dispersed
"strap", and "spider" cell. Bright containing scattered rhabdomyoblasts anaplastic cells, whereas diffuse
eosinophilia, cytoplasmic cross stria- and resembling myxomas predomi- anaplasia indicates the presence of
tions, and multinucleation indicate ter- nates in some examples, and compact clone-like clusters of anaplastic cells.
minal differentiation, and myotube aggregates of densely arrayed spindle
forms may be evident. Differentiation cells form other tumours. Immunophenotype
tends to be more evident following The botryoid variant of embryonal rhab- Markers of skeletal muscle differentia-
chemotherapy, as differentiated ele- domyosarcoma contains linear aggre- tion typify embryonal rhabdomyosarco-
ments become the predominant cell gates of tumour cells that tightly abut an mas {1653}. The presence of these
markers correlates with the degree of
tumour cell differentiation, as it does in
embryogenesis. Thus, only vimentin is
present in the cytoplasm of the most
primitive cells, and desmin and actin
are acquired by developing rhabdo-
myoblasts. Differentiated cells exhibit
myoglobin, myosin, and creatine kinase
M, markers that correspond to terminal
differentiation. A variety of less com-
monly used muscle markers, such as
titin, dystrophin, and acetylcholine
receptor antigens alsocharacterize
rhabdomyosarcomas. Muscle markers
such as desmin and muscle-specific
actin (HHF-35) are shared by cells with
A B a myogenic phenotype, including
smooth muscle, cardiac muscle, myofi-
Fig. 6.12 A Anaplastic embryonal rhabdomyosarcoma. Some cells contain enlarged, hyperchromatic nuclei.
B Desmin stain of rhabdomyosarcoma. Scattered tumour cells contain strongly positive cytoplasmic tails. broblasts, myoepithelial cells, peri-
cytes, and some mesothelial cells.
148 Skeletal muscle tumours
bb5_11.qxd 13.9.2006 10:52 Page 149
microfilaments. Leptomeric fibrils may
be seen on occasion.
Genetics
Molecular analyses of polymorphic loci
revealed allelic loss in chromosomal
region 11p15 in most embryonal rhab-
domyosarcomas {1160,1915}. The find-
ing of growth suppression when chro-
mosomal fragments containing the
11p15 region were introduced into
embryonal rhabdomyosarcoma cells
further supports the premise that there
is a tumour suppressor gene within this
region {1152,1278}. Furthermore, inhe-
rited alterations of the 11p15 region
Fig. 6.13 Electron micrograph of an uncommitted Fig. 6.14 Electron microscopic appearance of embry-
mesenchymal cell in rhabdomyosarcoma. There are occur in Beckwith-Wiedemann syn- onal rhabdomyosarcoma showing well-formed Z-
no features of myoblastic differentiation. Note the
drome {1251}, a heterogeneous over- bands.
subplasmalemmal microfilaments (arrows).
growth syndrome with an increased risk
for development of several cancers,
including embryonal rhabdomyosarco- variable collaborating events that occur
Antibodies against MyoD1 and myo- ma. Expression studies have indicated during embryonal rhabdomyosarcoma
genin are highly specific and sensitive that several 11p15 genes, such as tumourigenesis.
for rhabdomyosarcoma and are current- IGF2, H19, and CDKN1C, are ex-
ly used as standard antibodies for diag- pressed from one of the two alleles in Prognostic factors
nosis {321}. However, one must note a parent-of-origin specific process Prognosis can be determined by stage,
that only nuclear staining is specific termed imprinting. These combined histological classification, age, and site
and that non-specific cytoplasmic findings suggest a model in which an of origin. Staging is accomplished by
MyoD positivity is common in heat- imprinted tumour suppressor gene is clinical evaluation (IRSG Stage) or
retrieved, paraffin-embedded tissues inactivated during embryonal rhab- surgicopathological evaluation (IRSG
{2214}. domyosarcoma tumourigenesis by Group) {1755}. Younger patients tend
Occasional aberrant staining with a allelic loss of the active allele and to have a more favourable prognosis.
variety of immunohistochemical mark- retention of the inactive allele. Histological classification in paedia-
ers has been noted. Aberrantly Cytogenetic studies of embryonal rhab- tric patients predicts outcome inde-
expressed markers include cytokeratin, domyosarcoma have found complex pendent of age, stage, and location,
S100 protein, neurofilaments, and structural and numerical chromosomal with embryonal tumours having a
B cell proteins such as CD20 and changes, often including extra copies better prognosis than alveolar tumours
immunoglobulins {384, 1450, 1709}. of chromosomes 2, 8, and 13 {816, {1755}. Spindle cell and botryoid
Smooth muscle actin and neuron-spe- 2210}. Rearrangements of the 1p11- variants have a superior outcome as a
cific enolase staining occurs more fre- q11 and 12q13 regions have also group. However, the rare spindle cell
quently (in 10% and 30% of rhab- been noted in a fraction of cases. lesions in adults are more aggressive
domyosarcomas, respectively) {1652, Subsequent comparative genomic {1818} and, in fact, histological sub-
1653}. hybridization analyses of genome- type in adults with rhabdomyosarcoma
wide copy number changes confirmed appears to have no prognostic rele-
Ultrastructure chromosomal gains and identified vance. Embryonal rhabdomyosarcomas
Rhabdomyosarcomas exhibit a range of several regions of loss, such as chro- with diffuse anaplasia may have a
ultrastructural characteristics corre- mosome 16, in embryonal rhab- worse outcome than the other subsets
sponding to those of developing striat- domyosarcoma subsets {260, 2223}. of embryonal rhabdomyosarcoma
ed muscle, primarily bundles of 5 and These analyses also indicated that {1149}. Parameningeal and extremity
15 nm thick and thin filaments punctu- genomic amplification was generally tumours tend to have a bad outcome
ated by abortive Z-bands. Parallel rare in embryonal rhabdomyosarcoma, compared to other locations, whereas
arrays of 15 nm filaments and ribo- except for its subset with anaplastic orbital and paratesticular tumours tend
somes (myosin-ribosome complexes) features {259}. Finally, directed analy- to have a better one.
comprise the earliest diagnostic stage ses of known oncogenes and sup- Tumour cell ploidy predicts outcome in
{609}. Earlier cells show non-specific pressor genes identified inactivating some reports, with hyperdiploid em-
features of primitive mesenchyme, such mutations of TP53 {648} and CDKN2A bryonal rhabdomyosarcomas having a
as discontinuous basal lamina, phago- {1009} and activating mutations of RAS better outcome. However, this phenom-
cytosed collagen, and ergastoplasm family genes in subsets of embryonal enon has not been universally con-
{520}. These uncommitted cells may rhabdomyosarcoma {2041}. These va- firmed and does not appear to be an
contain lipid or subplasmalemmal rious genetic alterations may indicate independent variable {478,1107,1928}.
Embryonal rhabdomyosarcoma 149
bb5_11.qxd 13.9.2006 10:52 Page 150
D.M. Parham
Alveolar rhabdomyosarcoma
F.G. Barr
Definition masses. Paranasal lesions may present Macroscopy
Alveolar rhabdomyosarcoma is a primi- with proptosis or cranial nerve deficits. Alveolar rhabdomyosarcomas form
tive, malignant, round cell neoplasm that Perirectal tumours can cause constipa- expansile, rapidly growing soft tissue
cytologically resembles lymphoma and tion. Paraspinal lesions can cause nerve tumours with a fleshy, grey tan quality.
which shows partial skeletal muscle dif- root abnormalities, such as paresthesia, They contain variable amounts of fibrous
ferentiation. hypesthesia, or paresis. Imaging is best tissue.
accomplished by nuclear magnetic reso-
ICD-O code 8920/3 nance, which reveals an infiltrative, Histopathology
expansile, soft tissue mass. Rare Three major histological subtypes com-
Synonyms tumours present as disseminated lesions prise alveolar rhabdomyosarcoma: those
Rhabdomyoblastoma, rhabdomyopoietic with no obvious primary and resemble with typical features, those with a solid
sarcoma, monomorphous round cell leukaemia {613}. pattern, and those with mixed embryonal
rhabdomyosarcoma. Alveolar rhabdomyosarcomas tend to be and alveolar features {1549}. All alveolar
high stage lesions at presentation {1158, rhabdomyosarcomas exhibit round cell
Epidemiology 1756}. cytological features reminiscent of lym-
Alveolar rhabdomyosarcomas occur at phomas but with primitive myoblastic dif-
all ages, but they do not show a predilec- ferentiation. Morphologic features vary,
tion for younger children and more often depending on the presence or absence
occur in adolescents and young adults; of fibrous stroma and embryonal histol-
very rare cases may be congenital. The ogy. Typical alveolar rhabdomyosarco-
median ages of affected patients was 6.8 mas produce fibrovascular septa that
and 9.0 years in reports from the separate the tumour cells into discrete
International Society of Pediatric nests. These nests contain central clus-
Oncology (SIOP) {291}, and the ters of cells with loss of cohesion around
Intergroup Rhabdomyosarcoma Study the periphery. Tumour cells align the
(IRS) {1550}. They occur less frequently septa in a picket fence pattern. Giant
than embryonal rhabdomyosarcomas cells with rhabdomyoblastic differentia-
(21% of rhabdomyosarcomas in the IRS tion are common. Occasional cases
report; 19% in the SIOP report). The show clear cell morphology and may
male:female ratio is approximately even. mimic clear cell carcinoma or liposarco-
No geographic or racial predilection is ma.
reported. Solid variant alveolar rhabdomyosarco-
Fig. 6.15 Nuclear magnetic image of a cranial alve- mas lack the fibrovascular stroma and
olar rhabdomyosarcoma. The expansile lesion
Sites of involvement form sheets of round cells with variable
destroys the nasal and paranasal bone and
Alveolar rhabdomyosarcomas commonly rhabdomyoblastic differentiation (often
extends into the orbit and parameningeal tissues
arise in the extremities, where 39% were little). Occasional small nests may be
(arrows).
reported in the the Kiel Paediatric seen, particularly with larger samples.
Tumour registry {887}. The Armed Forces The cytologic features do not differ from
Institute of Pathology series indicates typical lesions {2138}.
that there is no favoured site of origin Mixed embryonal / alveolar rhadomyo-
{596}. Additional sites of involvement sarcomas contain foci with embryonal
include the paraspinal and the perineal histology, i.e., myxoid stroma and spindle
regions and the paranasal sinuses. cell myoblasts as well as areas with alve-
Mixed embryonal/alveolar tumours may olar histology. The alveolar foci usually
arise in areas favoured by embryonal contain nests with fibrous stroma,
rhabdomyosarcomas, such as the uro- although highly cellular solid foci resem-
genital tract and orbit, but generally bling lymphoma may occur.
these are unusual sites of origin {887}.
Immunophenotype
Fig. 6.16 Sagittal section of foot containing alveolar
Clinical features Alveolar rhabdomyosarcomas stain with
rhabdomyoasarcoma. An infiltrative, haemorrhagic
Alveolar rhabdomyosarcomas typically antibodies against muscle proteins, as
mass arises in the soft tissue of the plantar and
present as rapidly growing extremity metatarsal soft tissues (arrows). described under "Embryonal rhab-
150 Skeletal muscle tumours
bb5_11.qxd 13.9.2006 10:52 Page 151
A B
Fig. 6.17 A Typical alveolar rhabdomyosarcoma. Collagenous fibrovascular septa divide mixtures of undifferentiated tumour cells and rhabdomyoblasts into discrete
nests. B Myogenin stain of alveolar rhabdomyosarcoma. Many tumour cell nuclei show strong immunopositivity.
domyosarcoma" (see above), although 759}. PAX3 and PAX7 are related mem- entiation {170,605,1097,1211}
primitive tumours may have focal or lack bers of the paired box family of tran- As part of an effort to find other genetic
positivity. MyoD-related stains, especially scription factors whereas FKHR is a alterations that collaborate with the gene
myogenin, typically show a diffuse, member of the forkhead transcription fusion events in alveolar rhabdomyosar-
strong nuclear staining pattern {516}. factor family. The PAX3/FKHR and coma tumourigenesis, comparative
PAX7/FKHR fusion products contain the genomic hybridization studies of ARMS
Genetics PAX3/PAX7 DNA binding domain and the cases identified a variety of amplification
Cytogenetic analyses demonstrated FKHR transcriptional activation domain, events {814}. The most frequent amplifi-
recurrent translocations that are consis- and function as potent transcriptional cation events in alveolar rhabdomyosar-
tently and specifically associated with activators {162, 163}. In addition to this coma, each occurring in roughly one-
alveolar rhabdomyosarcoma. A functional change, the translocations third of cases, involve chromosomal
t(2;13)(q35;q14) was found in the majori- also alter the expression and subcellular regions 12q13-15 and 2p24. The 12q13-
ty of alveolar rhabdomyosarcoma cases localization of regulatory pathways to 15 region contains many growth-related
and a t(1;13)(p36;q14) was noted in a generate high levels of these chimeric genes such as the GLI, CDK4, and
smaller subset of cases {125}. These proteins that are constitutively present in MDM2, whereas the 2p24 region har-
translocations juxtapose the PAX3 or the nucleus {455, 495}. These changes bours the MYCN oncogene, which is
PAX7 genes on chromosomes 2 and 1, maximize the ability of these chimeric amplified in several tumour categories,
respectively, with the FKHR gene on proteins to activate downstream tran- such as neuroblastoma. Other less fre-
chromosome 13, to generate chimeric scriptional targets, and are postulated to quent amplicons occur at chromosomal
genes which encode PAX3/FKHR and exert oncogenic effects by altering con- regions 13q31, 2q34-qter, 15q24-26, and
PAX7/FKHR fusion proteins {127,456, trol of proliferation, apoptosis, and differ- 1p36. The PAX7/FKHR fusion gene is
A B
Fig. 6.18 A Solid variant alveolar rhabdomyosarcoma. Sheets of undifferentiated rhabdomyosarcoma cells without fibrovascular septa. Cytogenetic analysis revealed a
t(2;13) translocation, characteristic of alveolar rhabdomyosarcoma. B Mixed alveolar-embryonal rhabdomyosarcoma. A discrete, highly cellular focus of alveolar rhab-
domyosarcoma contrasts with the adjacent loose embryonal histology.
Alveolar rhabdomyosarcoma 151
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Fig. 6.19 1460 Alveolar rhabdomyosarcoma.
Interphase fluorescence in situ hybridization (FISH)
analysis showing amplification of the PAX7/FKHR
fusion gene (juxtaposed red and green signals) by
1;13 translocation breakpoint-flanking probes.
amplified in the majority of ARMS cases
with the 1;13 translocation in contrast to
the less frequent amplification of the
Fig. 6.20 Wild-type and fusion products associated with the 2;13 and 1;13 translocations. The paired box,
PAX3/FKHR fusion in alveolar rhab- octapeptide, homeobox and fork head domain are shown as grey boxes. Transcriptional domains (DNA
domyosarcoma with the 2;13 transloca- binding domain - DBD, transcriptional activiation domain - TAD) are indicated as solid horizontal bars. The
translocation fusion point is shown as a vertical dashed line.
tion {128}.
The subset of alveolar rhabdomyosarco-
mas not displaying a typical PAX/FKHR
gene fusion is genetically heteroge- more aggressive than embryonal rhab- outcome of rhabdomyosarcomas in gen-
neous, with some cases showing alterna- domyosarcomas {1755}. Surgicopatholo- eral {1200}. Preliminary data indicate that
tive fusions with other genes or unusual gical staging (IRS grouping) is predictive genetic fusions predict outcome, with
fusion products and some possibly of outcome. With mixed embryonal / PAX7/FKHR positive tumours behaving in
being true fusion-negative cases {129}. alveolar tumours, site may also be pre- a more benign fashion than PAX3/FKHR
dictive, as described under "Embryonal positive ones {1085}.
Prognostic factors rhabdomyosarcoma", although, in gener-
Alveolar rhabdomyosarcomas are high al these mixed lesions behave the same
grade neoplasms that are inherently as the alveolar subtype. Age predicts
152 Skeletal muscle tumours
bb5_11.qxd 13.9.2006 10:52 Page 153
E. Montgomery
Pleomorphic rhabdomyosarcoma
F.G. Barr
Definition heterogeneous on T2 images. Necrotic myoglobin, MyoD1, skeletal muscle myo-
Pleomorphic rhabdomyosarcoma is a foci are readily identifiable in many cases. genin, fast (skeletal muscle) myosin, and
high grade sarcoma occurring almost desmin. They variably express muscle
exclusively in adults and consisting of Macroscopy specific actin, smooth muscle actin, and
bizarre polygonal, round, and spindle Tumours are well circumscribed, usually myogenin {517, 675, 746, 748, 753, 1149,
cells which display evidence of skeletal large (5-15 cm), and often surrounded by 1897, 2251}. Interestingly, myoD1 and
muscle differentiation. No embryonal or a pseudocapsule. The cut surface is myogenin seem to show more limited pos-
alveolar component should be identified. whitish and firm with variable haemor- itivity than in paediatric rhabdomyosarco-
rhage and necrosis. mas. They lack epithelial markers and
ICD-O code 8901/3 S100 protein.
Histopathology
Epidemiology These are pleomorphic sarcomas com- Ultrastructure
These lesions occur almost exclusively in posed of undifferentiated round to spin- By ultrastructure, rudimentary sarcomere
adults, are more common in men and dle cells and an admixture of polygonal formation is the key criterion. Such sar-
present at a median age in the 6th decade cells with densely eosinophilic cytoplasm comeres consist of Z-bands or irregular
{675,746,748,753,1897}. in spindle, tadpole, and racquet-like con- masses of Z-band material with converg-
Exceptional cases may be seen in chil- tours. Some observers have classified ing thick (16nm) and thin (8nm) filaments
dren but their existence has been dispu- adult lesions into "classic" (pleomorphic {748, 1897}.
ted {1550}. rhabdomyoblasts in sheets), "round cell",
and "spindle cell" patterns {748}. Cross Genetics
Sites of involvement striations are vanishingly rare. The pres- Only six pleomorphic rhabdomyosarcomas
These tumours usually occur in the deep ence of pleomorphic polygonal rhab- with chromosome aberrations have been
soft tissues of the lower extremities but domyoblasts on routine hematoxylin and reported. All had highly complex kary-
have been reported in a wide variety of eosin stains coupled with immunohisto- otypes, and in none of them could a t(1;13)
other locations {37,389,675,746,748, chemical evidence of at least one skele- or t(2;13) translocation be detected {1477}.
753,1149,1897}. tal muscle-specific marker by immunohis-
tochemistry is required for diagnosis Prognostic factors
Clinical features {675,748,753}. The prognosis for these tumours is poor
Most patients present with a rapidly- and reliable prognostic factors have yet to
growing painful swelling {748}. On Immunophenotype be developed. In two series with follow-
imaging, lesions are isointense to skeletal Pleomorphic rhabdomyosarcomas, like up, 28/38 patients (74%) died of disease
muscle on T1 weighted images and other rhabdomyosarcoma types, express {748, 753}.
A B
Fig. 6.21 A CT without contrast enhancement of a recurrent pleomorphic rhabdomyosarcoma. The tumour is similar in consistency to the adjacent skeletal muscles.
B This mass, which displays zones of necrosis, was excised from the thigh of a 56-year-old man. The lesion extended into the pelvis and recurred quickly following the
initial resection.
Pleomorphic rhabdomyosarcoma 153
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A B
Fig. 6.22 A Pleomorphic rhabdomyosarcoma composed of intensely eosinophilic polygonal cells. B Note the wide range of cell shapes from round to tadpole-like.
A B
Fig. 6.23 A Pleomorphic rhabdomyosarcoma composed of spindled and polygonal cells. B Bizarre nuclei and abundant cytoplasm are seen in this example of pleo-
morphic rhabdomyosarcoma.
A B
Fig. 6.24 A Strong diffuse desmin expression in pleomorphic rhabdomyosarcoma. B On electron microscopy, rudimentary sarcomere formation is the key criterion.
Such sarcomeres consist of Z-bands or irregular masses of Z-band material with converging thick (16 nm) and thin (8 nm) filaments.
154 Skeletal muscle tumours