Value of Immunohistochemistry in Gynecological Pathology
Moderator: Dr. W. Glenn McCluggage
Case 11 -
Cervical Embryonal Rhabdomyosarcoma
Dr. Robert Soslow
New York, NY
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 based on histomorphology. Identification of the
clonal chromosomal translocations t(2;13) and t(1;13) plays an important role in the diagnosis of
alveolar rhabdomyosarcoma. It is critical to accurately differentiate the histologic subtypes of RMS
since there are 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 other less common histologic variants include alveolar and
pleomorphic RMS, which are usually associated with a significantly poorer clinical outcome.
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).
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 .
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.
Case 11 - Figure 1
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 with few strap cells. As will be discussed subsequently,
expression of myogenin and Myo-D1 are 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. 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.
Diagnosis: Cervical embryonal rhabdomyosarcoma
The histologic differential diagnosis of embryonal rhabdomyosarcoma in the gynecologic tract in
adults  includes adenosarcoma, carcinosarcoma, endometrial stromal sarcoma, and leiomyosarcoma. To
further complicate matters, adenosarcoma
carcinosarcoma and even endometrial stromal sarcoma
 can demonstrate skeletal muscle differentiation such that isolated microscopic fields are
indistinguishable from rhabdomyosarcoma. Myxoid variants of endometrial stromal sarcoma and
leiomyosarcoma may resemble embryonal rhabdomyosarcoma, and pleomorphic leiomyosarcoma can appear similar
to pleomorphic rhabdomyosarcoma. To diagnose rhabdomyosarcoma and exclude adenosarcoma, one should not
find phyllodes-like growth and intraglandular stromal papillae. We make an attempt 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.
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