Mesenchymal Neoplasms of the Female Genital Tract
Case 1 -
Teri Longacre, Esther Oliva and Robert Soslow
Rhabdomyosarcoma (RMS) is a malignant neoplasm originating from myogenic progenitors cells that show
variable stages of skeletal muscle differentiation. RMS is the most common soft tissue tumor found in
children, accounting for less than 10% of all pediatric solid tumors. Approximately 20% of pediatric
RMSs originate in the genital tract, making this the second most common site. Soft tissue sarcomas in
the adult population account for 1% of adult malignancies, and RMS accounts for only a small fraction of
these tumors. Although childhood RMS has a predilection for the genitourinary system, this is not the
case for adults, making RMS of the adult female genital tract an extremely rare tumor
RMS may be categorized into three major variants with significant differences in clinical behavior and
prognosis. The most common and generally most favorable variant is embryonal RMS, which encompasses
botryoid, spindle cell, and anaplastic histologic subtypes. The recently described sclerosing RMS
subtype  may also be related to the embryonal tumors. The other less common histologic variants
include alveolar and pleomorphic RMS, which are usually associated with a significantly poorer clinical
outcome. Identification of the clonal chromosomal translocations t(2;13)(q35;q14), involving the PAX3-FKHR fusion, and t(1;13) (p36;q14), involving the PAX7-FKHR fusion, plays an important role in the etiology, diagnosis and prognosis
of alveolar rhabdomyosarcoma.
Botryoid embryonal rhabdomyosarcoma is the most common RMS subtype in the female genital tract. Rare
examples of vulvar alveolar rhabdomyosarcoma 
and spindle cell rhabdomyosarcoma  have been
reported. Most of the clinical and pathologic data that have been collected on RMS have been through
cooperative group trials looking at multimodality treatment for pediatric RMS at multiple anatomic
locations, including the female genital tract
The case selected for discussion is very unusual
in that the patient is an adult.
Our group studied the clinical features of adults with rhabdomyosarcomas of the female genital tract
The median age at diagnosis was 48 years (range, 16–69) and the most common presenting symptom was
abnormal vaginal bleeding, which included post menopausal bleeding and menometrorrhagia in premenopausal
women. The majority of women presented with locoregional disease. Ten women (71%) presented with FIGO
stage I/II disease, and 12 (86%) presented with IRSG classification I–III disease. The average size of
the tumors at presentation was 34 mm (range, 8–60 mm).
The primary site of disease was the cervix in 8 women (53%), making it the most common. The other
sites included uterine corpus, 3 (20%); vulva, 2 (13%); fallopian tube, 1 (7%); and ovary, 1 (7%). In
this adult population, none of the tumors originated in the vagina. There were 11 (73%) embryonal RMSs,
and 8 (73%) of these had classic botryoid features. The other histologic subtypes included 2 (13%)
pleomorphic and 2 (13%) alveolar. All cervical lesions were embryonal, and both vulvar lesions were of
alveolar histology. There was no distinct pattern of distribution of histologic subtypes at the other
gynecologic sites. The majority (80%) of women with embryonal RMS presented with early-stage disease
(Intergroup Rhabdomyosarcoma Studies [IRSG] group I); in comparison, 75% of women with non-embryonal RMS
presented with advanced-stage disease (IRSG group III/IV).
For the entire cohort, the median time to progression was only 9 months and the median disease
specific survival was 21 months. The 2-year progression free survival was 15% and the 5-year disease
specific survival was 29%. Neither age nor stage correlated with survival. Women with a cervical
primary RMS had a significantly increased time to progression compared to women with disease at other
gynecologic sites. In addition, women with an embryonal histologic variant had significantly improved
progression free survival compared to non-embryonal variants. These survival statistics contrasted
sharply with the historically rather positive survival rates in pediatric RMS: 5-year overall survival
of 82% compared with 66% for non-embryonal variants and 5-year survival rates of 94% for the botryoid
histologic subtype specifically
Most adult patients have been treated surgically, with or
without chemotherapy and radiation therapy. They have not, for the most part, been treated with regimens
used in children, where primary surgical management is very uncommon. This may contribute to some of the
survival differences noted.
Botryoid rhabdomyosarcomas are polypoid tumors with a densely cellular zone of primitive cells in a
subepithelial distribution (cambium layer)
. The substance of the polyps is generally myxoid or
edematous, with varying cellularity. The lesional cells are rhabdomyoblasts, which have assorted
appearances, ranging from small, round, blue and undifferentiated, to strap-shaped, with eosinophilic
cytoplasm and easily appreciated cross striations. Interestingly, cartilaginous differentiation is found
in a significant minority of cases.
The non-polypoid and infiltrative portions of botryoid rhabdomyosarcomas are histologically
indistinguishable from embryonal rhabdomyosarcomas of the usual (non-botryoid) sort. There are commonly
cellular zones that contrast with paucicellular zones containing myxoid or edematous matrix. Rarely,
cambium layers are found cuffing non-neoplastic endocervical glandular clefts. Like botryoid tumors,
these sarcomas contain mixtures of rhabdomyoblasts in different stages of differentiation. Round and
spindled cells with brightly eosinophilic cytoplasm are present in nearly every case and are important
clues to the diagnosis.
The typical immunophenotype includes expression of desmin, muscle-specific actin, myogenin and
Myo-D1. These markers are found in 90-100% of RMSs (they are sensitive markers
), but desmin and
muscle-specific actin are certainly not specific, as they are commonly found in tissues demonstrating
smooth muscle and myofibroblastic differentiation. Myogenin and Myo-D1 are regulatory proteins expressed
early in skeletal muscle differentiation and show nuclear localization. In general, the expression of
these markers is negatively correlated with differentiation, such that only scattered myogenin positive
cells are found in embryonal rhabdomyosarcomas lacking strap cells. According to the recent publication
of Morotti and colleagues , only 2-3% of rhabdomyosarcomas lacked Myo-D1 or myogenin expression—but
all of these samples had been subjected to fixation in B5. Expression of myogenin and Myo-D1 is common
to all tumors demonstrating skeletal muscle differentiation, which means that tumors other than
rhabdomyosarcoma (e.g. carcinosarcoma containing rhabdomyoblasts) should be excluded before using
myogenin immunoreactivity alone to make a confident diagnosis of rhabdomyosarcoma. Morotti's study 
highlighted the specificity of these markers, reporting expression limited to tumors containing
rhabdomyoblasts (RMBs). These included not only rhabdomyosarcomas, but also Wilms tumor containing RMBs,
germ cell tumors with RMBs and pleuropulmonary blastoma. Tumors frequently confused with the spindle
cell variant of rhabdomyosarcoma, congenital infantile fibrosarcoma, desmoid tumors and myofibromatosis,
were negative for these markers. It should be also be pointed out that small numbers of RMSs have been
described to express markers such as CD99 (O13), cytokeratin, S100 and WT1, markers more commonly
expressed in histologic mimics of RMS.
The histologic differential diagnosis of embryonal rhabdomyosarcoma in the gynecologic tract in
adults includes mesodermal stromal polyp, genital rhabdomyoma, leiomyosarcoma, and vaginal, cervical and
uterine neoplasms that may contain rhabdomyoblasts; these include adenosarcoma
and, unusually, endometrial stromal sarcoma . The extent of skeletal muscle differentiation in these
tumors may be such that isolated microscopic fields are indistinguishable from rhabdomyosarcoma. Very
rarely encountered sarcomas in this region include alveolar soft part sarcoma, Ewing sarcoma/peripheral
primitive neuroectodermal tumor (PNET)
and malignant peripheral nerve sheath tumor .
Mesodermal stromal polyp vs embryonal rhabdomyosarcoma
Mesodermal stromal polyps, also referred to as fibroepithelial stromal polyps or vaginal polyps, are
benign polyps that usually occur in the vagina and are commonly diagnosed during pregnancy. Unusual
sites of occurrence include cervix, vulva ,
and even endometrium . Most polyps contain an
edematous or myxoid ground substance with the type of thick-walled vessels commonly found in usual
endocervical or endometrial polyps. The predominant lesional cell is spindle shaped, although there is
typically an admixture of cells with a single ovoid nucleus or multiple rounded, hyperchromatic and
smudged nuclei arranged in wreaths. Although there is no well-defined Grenz zone between the polyp's
stroma and the overlying epithelium, a cambium layer of the sort seen in embryonal rhabdomyosarcoma is
not observed. It should not be difficult to find desmin, ER, PR  and smooth muscle actin
immunoreactivity in these lesions, but myogenin and myo-D1 expression should not be encountered.
Unusually and particularly during pregnancy, mesodermal stromal polyps can show hypercellularity, marked
pleomorphism and significant mitotic activity (more than 10 mitotic figures per 10 high power fields)
. The absence of a cambium layer and rhabdomyoblasts that express myogenin in a pregnant patient
with a vaginal polyp would be against rhabdomyosarcoma, although other sarcomas and pseudosarcomatous
tumors should be considered.
Genital rhabdomyoma vs embryonal rhabdomyosarcoma
Genital rhabdomyomas are extremely rare proliferations that have been reported to present as polypoid
masses or cysts in the vagina or vulva of young to middle-aged women
In contrast to embryonal
rhabdomyosarcoma, these tumors are slow growing, devoid of pleomorphic cells and composed almost entirely
of well-differentiated strap cells arranged in a myxomatous or collagenous background. A cambium layer
is not identified and mitotic activity is scant.
Leiomyosarcoma vs embryonal rhabdomyosarcoma
Rare primary vaginal
and cervical  leiomyosarcomas have been reported. Myxoid variants
of leiomyosarcoma may resemble embryonal rhabdomyosarcoma, and pleomorphic leiomyosarcoma can appear
similar to pleomorphic rhabdomyosarcoma. Cervical leiomyosarcoma and rhabdomyosarcoma are both very
uncommon tumors, but their histologic appearance frequently overlaps when they are composed predominantly
of spindle cells. Embryonal rhabdomyosarcoma, when spindled and growing in fascicles, frequently has a
subtle moth-eaten appearance that result from a heterogeneous admixture of cells, some containing densely
eosinophilic cytoplasm and others clear or amphophilic cytoplasm; round rhabdomyoblasts with bright red
cytoplasm are often haphazardly intermixed. The low power appearance of leiomyosarcoma, in contrast, is
generally more uniform. Most embryonal rhabdomyosarcomas with an infiltrative, spindle cell appearance
underlie a botryoid tumor and/or are clearly epitheliotropic. Leiomyosarcomas, in contrast, are usually
more deeply seated lesions. Skeletal muscle-specific immunostains are useful for distinguishing the two
entities, but be aware that diffuse desmin expression is expected in both.
Mullerian adenosarcoma vs embryonal rhabdomyosarcoma
Adenosarcoma and embryonal RMS both share polypoid growth and stromal condensation underneath
epithelium, but only botryoid RMS typically contains conspicuous myxoid stroma and the sprinkling of
small cellular aggregates of dark blue cells set in a paucicellular background. In contrast to
adenosarcoma, RMS does not exhibit phyllodes-like growth or intraglandular stromal papillae.
Carcinosarcoma vs embryonal rhabdomyosarcoma
It is necessary to exclude stromal-predominant carcinosarcomas by searching carefully for lesional
epithelium with a malignant appearance. However, it is generally assumed that some genital pleomorphic
rhabdomyosarcomas might represent carcinosarcomas in which the epithelial component is overgrown by
stroma or is not sampled.
Alveolar soft part sarcoma is covered in the discussion of epithelioid smooth muscle tumors, case 4.
A Managerial Approach
A) Polypoid tumors:
Two of the most common entities confused with botryoid embryonal RMS, a highly aggressive tumor in
adults, are benign polyps (endocervical and mesodermal stromal polyps) and cervical adenosarcoma. None
of these entities typically contains the conspicuous myxoid stroma that is characteristic of botryoid RMS
or the sprinkling of small cellular aggregates of dark blue cells set in a paucicellular background.
These features can sometimes be appreciated macroscopically, such that gross inspection of a glass slide
can suggest the correct diagnosis. Once these features are recognized, it is usually considered
mandatory to establish the presence of rhabdomyoblasts, although in some cases, the findings on
examination of a picture-perfect H&E slide are sufficient to at least strongly suggest the
diagnosis. Either a skeletal muscle-specific immunostain such as myogenin or myo D1 or diagnostic cross
striations are considered acceptable for establishing skeletal muscle differentiation. The presence of
rhabdomyoblasts excludes a diagnosis of benign endocervical polyp, mesodermal stromal polyp and
adenosarcoma lacking heterologous elements.
Benign polyps are treated with polypectomy whereas cervical rhabdomyosarcomas in adults are treated
with hysterectomy followed by combination chemotherapy and radiation. In children, whose RMS survivals
are superior to those reported for adults, biopsy (not hysterectomy) followed by radiation and, usually,
chemotherapy is the standard of care. Adenosarcoma patients whose tumors are organ-confined and lack
stromal overgrowth or heterologous elements are generally treated with hysterectomy, but not adjuvant
The differential diagnosis of a polypoid cervical tumor containing rhabdomyoblasts still includes
adenosarcoma and carcinosarcoma (MMMT) with heterologous elements. Of course, every effort should be
made to distinguish between these tumors, but the mere presence of malignant rhabdomyoblasts seems to
place the patient in a very unfavorable risk category. Patients with stage I uterine carcinosarcomas
containing rhabdomyoblasts have survivals that are indistinguishable from patients with pure RMS (see
case 3) and there is a recent abstract suggesting that adenosarcomas containing rhabdomyoblasts are
similarly aggressive, although this may not apply for small cervical lesions. The distinction between
these entities rests predominantly on the examination of multiple sections from a well sampled tumor. In
contrast to botryoid RMSs, adenosarcomas contain, at least focally, a phyllodes like appearance, and
carcinosarcoma, of course, typically shows foci of high grade carcinoma.
Despite the fact that overall survivals are likely to be similar across these tumor types,
therapeutic strategies usually differ. First, radical hysterectomy is sometimes favored if adenosarcoma
or carcinosarcoma is recognized to be deeply invasive preoperatively. Carcinosarcoma patients are
typically treated with both chemotherapy and radiation therapy, although the chemotherapeutic agents
generally differ from those used for RMS. Treatment recommendations for adenosarcomas containing
rhabdomyoblasts, however, are poorly defined.
In summary, check for the presence of a polyp with extensive myxoid stroma and small aggregates of
immature-appearing stromal cells. If present, confirm rhabdomyoblastic differentiation and search for
foci of carcinoma or phyllodes like growth. Liberally section large tumors and hesitate to establish a
final diagnosis given small samples. It is not always possible to differentiate RMS versus
carcinosarcoma and adenosarcoma containing rhabdomyoblasts when samples are small, distorted and not
B) Invasive spindle cell tumors:
Cervical leiomyosarcoma and RMS are both very uncommon tumors, but their histologic appearance
frequently overlaps when they are composed predominantly of spindle cells with obvious nuclear features
of malginancy. Embryonal RMS, when spindled and growing in fascicles, frequently has a subtle moth-eaten
appearance that results from a heterogeneous admixture of cells, some containing densely eosinophilic
cytoplasm and others clear or amphophilic cytoplasm; round rhabdomyoblasts with bright red cytoplasm are
often haphazardly intermixed. The low power appearance of leiomyosarcoma, in contrast, is generally more
uniform. Most embryonal RMSs with an infiltrative, spindle cell appearance underlie a botryoid tumor
and/or are clearly epitheliotropic. Leiomyosarcomas, in contrast, are usually more deeply seated
lesions. Skeletal muscle-specific immunostains are useful for distinguishing the two entities.
Leiomyosarcoma patients are generally treated with hysterectomy. Radiation and chemotherapy are
usually reserved for patients with tumors with extrauterine spread. Chemotherapy is sometimes also used
in an experimental setting for patients with organ-confined leiomyosarcoma.
Very rare examples of spindle cell RMS involving the vulva have been reported. While considered part
of the spectrum of embryonal RMS, these tumors do not show the obvious cytologic atypia and immaturity
described above in the infiltrative tumors that underlie botryoid RMS. In contrast, these tumors
histologically resemble leiomyoma, fibromatosis, myofibromatosis or, perhaps, grade I fibrosarcoma; they
do not resemble typical uterine leiomyosarcoma. I therefore recommended myo D1 or myogenin immunostains
for all paracervical and vulvar tumors that resemble leiomyoma, fibromatosis, myofibromatosis and grade I
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