Mesenchymal Neoplasms of the Female Genital Tract
Case 4 -
Low-Grade Endometrial Stromal Sarcoma With Extensive Glandular Differentiation
Teri Longacre, Esther Oliva and Robert Soslow
Endometrial stromal tumors are the second most common category of mesenchymal tumors of the uterus.
They are typically composed of neoplastic cells that resemble the endometrial stromal cells of the
proliferative endometrium. In the uterus they are divided into two main categories, endometrial stromal
nodule (ESN) and low-grade endometrial stromal sarcoma (ESS), the latter being by far more common
(constituting 10-15% of uterine malignancies with a mesenchymal component).
These tumors are more commonly seen in late reproductive age or peri-menopausal women and some of them
have been reported in association with a hyperestrogenic state. Patients commonly present with abnormal
uterine bleeding or pelvic pain, but patients are not infrequently asymptomatic. Of note, extrauterine
pelvic extension at presentation is found in up to 1/3 of patients and rarely, the patient presents with
tumor at a metastatic site such as the ovary. In such cases it is always important to ask the surgeon if
he/she has examined the uterus and about any relevant previous clinical history.
Most tumors show a nodular or diffuse permeation of the myometrium, including worm-like plugs of tumor
in myometrial or parametrial veins, although some tumors are deceptively well circumscribed from the
surrounding tissues on gross examination. They typically have a soft, fleshy, bulging, and tan to yellow
cut surface. They may show areas of cyst formation, hemorrhage, and necrosis. On low-power examination,
the tumor characteristically permeates the myometrium as irregular tongues. Extrauterine veins and
lymphatics are frequently invaded. The tumors are cellular ("blue"), the cells grow in sheets, they have
scant cytoplasm and uniform, oval to spindle-shaped nuclei with a tiny nucleolus as seen in endometrial
stromal-type cells. The cells focally may whorl around small vessels reminiscent of the arterioles seen
in the proliferative phase of the endometrium. This is a very characteristic feature of all endometrial
stromal tumors, (ESN and ESS), but it is often not very striking. Significant degrees of nuclear atypia
are absent and mitotic rates are usually <3/10HPFs; higher rates do not exclude this diagnosis. It is
important to keep in mind that mitoses are no longer used to differentiate between low-grade and
high-grade endometrial stromal sarcoma. Tumors with the
typical morphology of endometrial stromal tumors and characteristic tongue-like growth should be
classified as low-grade ESSs regardless of their mitotic counts because the prognosis of these tumors is
similar. In contrast, pleomorphic tumors with an endometrial origin but lacking
endometrial stromal differentiation should be classified as poorly differentiated endometrial sarcomas as
they are associated with a very poor prognosis.
Other microscopic features that may be seen include collagen bands, focal thickening of the vessels
wall secondary to hyalinization, foamy histiocytes (isolated in between neoplastic stromal cells or in
compact groups) and cholesterol clefts. Both ESS and ESN may show: a) smooth muscle metaplasia; b)
myxoid and fibrous background; c) sex cord-like differentiation; d) endometrioid glandular
differentiation; e) clear or eosinophilic, granular cell change; f) rhabdoid appearance; g)
rhabdomyoblastic differentiation; h) fatty differentiation; and i) bizarre nuclei.
a) Smooth muscle differentiation: In general it is required that
the smooth muscle component occupy at least 30% of the neoplasm to merit this categorization. On gross
examination, some of these tumors contain one or more tan to yellow, soft nodules alternating with firm,
white whorled nodules or they are embedded in or at the periphery of paler, firmer tissue. On
microscopic examination, the endometrial stromal component shows the characteristic cells and associated
arterioles. The smooth muscle component may show nodules with central hyalinization ("starburst"
pattern) that merge with disorganized short fascicles of smooth muscle or long fascicles of
mature-appearing smooth muscle. If smooth muscle differentiation is present in an ESN, a not uncommon
pitfall in the evaluation of the margin is posed by the irregular interdigitation of both components,
particularly when the smooth muscle is mature and relatively well organized. If the latter is
misconstrued as myometrial muscle, an ESN with a well circumscribed margin may be misinterpreted as an
invasive endometrial stromal tumor--an ESS. It is crucial to appreciate that in such cases one is
examining regions with divergent differentiation within the mass itself rather than invasion.
For prognostic purposes these tumors should be reported as ESNs or
ESSs with smooth muscle differentiation (depending on the margins). The designation mixed endometrial
stromal-smooth muscle tumor may be given in parentheses. Any other unusual features of either component
can be recorded in a notation. It is important to keep in mind that the recurrences may
show endometrial stroma, smooth muscle or both components. We do not use the term "stromomyoma" because
this term implies a benign tumor.
b) Myxoid and/or fibrous background. As a consequence of the
presence of myxoid or collagenous background these tumors tend to be hypocellular in contrast to most
endometrial stromal tumors. In case of an ESS, the tumor still shows the typical permeative growth, the
arterioles, and in most cases areas of conventional endometrial stromal neoplasia. As with endometrial
stromal tumors with smooth muscle differentiation, these tumors may also cause diagnostic problems when
they metastasize, particularly to the lung, where a myxoid/fibrous appearance can predominate. It is
important to note that in some instances this appearance will be encountered in metastatic sites, but not
in the primary tumor.
c) Sex cord-like differentiation. It is characterized by variety
of epithelial and stromal patterns that create a resemblance to those of ovarian sex-cord tumors,
especially granulosa cell and Sertoli cell tumors, alone or in combination. Anastomosing cords one to
two cells in width, broad trabeculae, small nests, sertoliform or retiform tubular structures,
Call-Exner-like bodies, and diffuse sheets of uniform cells reminiscent of a diffuse adult granulosa cell
tumor may be seen. The epithelial-like cells vary from small, round, and regular with scanty cytoplasm
to large with abundant eosinophilic, clear, or foamy cytoplasm that is often lipid-rich. The nuclei are
generally small and regular with little pleomorphism and indistinct nucleoli. This morphology overlaps
with that seen in a uterine tumor resembling an ovarian sex cord stromal tumor, but differs from the
latter because conventional areas of endometrial stromal neoplasia are typically found. This finding
does not have any prognostic significance.
d) Endometrioid glandular differentiation.
The endometrioid-like glands can be either benign or malignant. The origin of the glands has been
attributed to entrapment of non-neoplastic endometrial or adenomyotic glands or epithelial
differentiation in these neoplasms.
Low-grade endometrial stromal sarcoma vs endometrial stromal nodule
First of all, it is important to keep in mind that ESN and ESS have identical histologic appearance,
thus, the differential diagnosis between ESN and ESS is not possible in a curettage specimen except in
the rare case in which the former is completely curetted during the procedure such that the pathologist
can appreciate the margins of the lesion. Distinction between
an ESN and an ESS is primarily based on the presence of infiltrative margins or vascular permeation in
ESS, which in most cases can only be established in a hysterectomy specimen. Only small
ESNs are likely to be diagnosable with confidence on a curettage, an important issue when the patient is
in her reproductive age and desires to preserve her uterus. In these women a combination of diagnostic
imaging and hysteroscopy may be useful in monitoring the growth of the lesion and in occasional cases
local excision has been successful. The same rules apply when fragments of tumor seen in the curettage
specimen are predominantly composed of sex cord-like elements. In those cases the differential diagnosis
includes a uterine tumor resembling an ovarian sex cord tumor and a conventional EST with sex cord-like
differentiation. Although the former in most cases is well circumscribed, the pathologist needs to
evaluate margins in order to properly sub-classify the tumor and for this reason a hysterectomy is
usually the treatment of choice.
Secondly, as mentioned earlier, some ESSs may be grossly well circumscribed and may be thought to
represent an ESN. In such cases it is extremely important to generously sample the tumor-myometrium
interface to detect areas of clear-cut invasion. Finally, recently, we have reported a series of 50 ESNs
including 3 tumors that did not fulfill the criteria for ESN but still did not have the overt permeative
growth seen in ESS. As these tumors are associated with a much more limited infiltration of the
myometrium, it may be hypothesized that they would have a much better prognosis. However, follow-up in
these 3 cases was limited, thus limiting our ability to establish firm conclusions regarding their
prognosis. For the moment these tumors have been descriptively referred to as "endometrial stromal
tumors with limited infiltration" until more information is obtained regarding their prognosis.
Low-grade endometrial stromal tumor vs cellular endometrial polyp
Endometrial polyps may be fragmented in curettage specimens and some of the fragments may consist of
cellular stroma only. Although endometrial stromal tumors may arise in endometrial polyps, in such cases
one sees an expansile growth of endometrial stroma with the typical vascular network, which contrasts
with the more compact, atrophic appearance of the endometrial stroma of a benign polyp in which vessels,
if prominent, tend to be larger, thick-walled, and irregularly distributed.
Low-grade endometrial stromal sarcoma vs adenomyosis with sparse glands and intravascular adenomyosis
Adenomyosis with a scant glandular component or in which adenomyotic foci are present in vascular
spaces or associated with intravascular endometrial tissue may cause concern for a low-grade ESS. On
gross examination adenomyosis occurs as an incidental finding, produces an ill-defined nodularity or
asymmetric thickening of the uterine wall. There is a zonation phenomenon within the adenomyotic foci
with a less cellular central area surrounded by a more cellular periphery composed of a rim of
endometrial stroma, smooth muscle or both, and the atrophic appearance of the stromal nests and cells
that lack nuclear atypia and mitotic activity are in contrast with the expansile growth of the stromal
nests and proliferative appearance of the cells in ESS. Other helpful features to establish the
diagnosis of adenomyosis with sparse glands or intravascular adenomyosis include: a) the absence of
other typical morphologic features of ESS; b) the presence of typical areas of adenomyosis elsewhere, c)
the absence of a mass; and d) the postmenopausal age of the patients.
Low-grade endometrial stromal sarcoma vs intravascular endometrial tissue, and menses-associated cellular stroma
Intravascular menstrual endometrium if only composed of stromal cells may cause problems in the
differential diagnosis with an ESS. However, the stromal cells form tight clusters of small spindle
cells with hyperchromatic nuclei showing high nuclear/cytoplasmic ratio. Some of the nests may have a
necrotic appearance and/or may be surrounded by a cuff of larger cuboidal to low columnar epithelial
cells with more abundant eosinophilic cytoplasm. These clusters of cells are frequently associated with
neutrophils and lymphocytes.
Low-grade endometrial stromal tumor vs highly cellular leiomyoma (HCL)
Many highly cellular leiomyomas have a somewhat different consistency and color from that of
conventional leiomyomas, on average being softer and having a tendency to be yellow or yellow-tan,
closely resembling the gross appearance of endometrial stromal tumors. On microscopic examination, as
their definition implies, they are as cellular as endometrial stromal tumors and they may have prominent
vascularity as well as irregular margins with the surrounding stroma that would cause concern for an
ESS. Histologic findings that favor a highly cellular leiomyoma include: a) focal merging of the highly
cellular areas with typical fascicular areas of smooth muscle neoplasia in most of the cases, b) large
thick muscular blood vessels in contrast to the arterioles seen in an endometrial stromal neoplasm, c)
cleft-like spaces, some apparently representing compressed vessels, others apparently the result of
edema, and d) strong and multifocal or diffuse immunoreactivity for smooth muscle markers including
desmin and h-caldesmon.
Low-grade endometrial stromal sarcoma vs intravenous leiomyomatosis (IVL)
This entity may cause confusion with an ESS mainly because of its prominent intravascular growth
especially and when the tumor is highly cellular, resembling HCL. Helpful features to establish the
diagnosis of IVL include: a) clefted or lobulated contour of the intravascular masses, b) focal
fascicular architecture, c) cells with blunt-ended nuclei, d) prominent thick-walled vessels, and e)
hydropic change. Finally, if a tumor shows vascular permeation, a useful diagnostic feature of some
cases of IVL is that the tumor cells may be seen not only in vascular lumina but also beneath the
vascular endothelium and "colonizing" the walls of veins. Cardiac involvement is seen in up to 40% of
cases of IVL, but low-grade ESSs may also demonstrate this finding infrequently.
Low-grade endometrial stromal sarcoma vs high-grade endometrial sarcoma
The lack of specific evidence of endometrial stromal cell origin in most cases of high-grade
endometrial sarcoma precludes their placement in the endometrial stromal group of uterine tumors.
Myometrial invasion is common but the intravascular worm-like plugs characteristic of low-grade ESS are
usually absent. They have marked cellular pleomorphism, brisk mitotic activity and carry a very bad
prognosis. These tumors should be diagnosed only after extensive sampling has excluded smooth or
skeletal muscle differentiation or even small foci of carcinoma that would result in a diagnosis of
MMMT. Occasional tumors have a component of low-grade ESS indicating that in those cases at least the
high-grade component presumably is truly of endometrial stromal derivation.
Miscellaneous other problems in the differential of pure endometrial stromal tumors
If tissue sample is small and shows crush artifact, metastatic breast cancer or lymphoma may be in the
differential. The history as well as immunohistochemistry will facilitate the diagnosis.
- It is important to keep in mind that common tumors outside the uterus may rarely occur in the
uterus (primitive neuroectodermal tumors, lymphoma, others). Thus, if a tumor composed of small blue
cells does not stain for the typical panel (CD10, desmin and h-caldesmon) used to differentiate
endometrial stromal tumors from smooth muscle tumors (the two more common pure mesenchymal tumors) it is
important to explore other diagnostic possibilities and perform appropriate studies
(immunohistochemistry, cytogenetics, flow cytometry, others).
Endometrial stromal tumor with gland and/or smooth muscle vs endometrioid adenomyoma
Even though endometrioid adenomyoma contains endometrioid-type glands, endometrial-type stroma and
smooth muscle as may be seen in endometrial stromal tumors, they typically show an orderly distribution
of the three elements, where the glands are surrounded by variable amounts of endometrial stroma which in
turn is surrounded by mature muscle with an appearance that differs from the metaplastic muscle seen in
endometrial stromal tumors. Furthermore they are well-circumscribed tumors that in most cases have the
gross appearance of a leiomyoma.
Fibrous-myxoid endometrial stromal tumor vs other mesenchymal tumors
The most frequent and problematic differential diagnosis pertains to smooth muscle tumors including
myxoid leiomyomas, the rare myxoid variant of IVL and myxoid leiomyosarcomas. Helpful features in
establishing the diagnosis of myxoid/fibroblastic endometrial stromal tumor include: a) frequent
presentation as an endometrial polypoid mass, b) prominent multinodular or tongue-like pattern of
myometrial infiltration, c) focal presence of typical endometrial stromal neoplasia with characteristic
arterioles, and d) the absence or minimal staining for muscle markers in most cases (desmin and
Low-grade endometrial stromal sarcoma with extensive sex cord-like differentiation vs uterine tumor resembling a sex cord ovarian tumor (UTROSCT)
The diagnosis of UTROSCT should only be established when no clear-cut areas of endometrial stromal
neoplasia are identified. Thus, extensive sampling is mandatory to identify any area with the pattern of
typical endometrial stromal neoplasia. The distinction is important as patients with a UTROSCT have an
excellent prognosis. Immunohistochemical stains are not helpful in this differential diagnosis.
Low-grade endometrial stromal sarcoma with extensive sex cord-like differentiation vs epithelioid leiomyosarcoma
Epithelioid smooth muscle tumors may exhibit a sex cord-like pattern, although generally not as
strikingly as in tumors of probable endometrial stromal cell derivation. Smooth muscle markers,
epithelial markers as well as some sex cord markers may be present or lacking in both tumor types. Thus,
the immunohistochemical findings must be evaluated in the light of conventional microscopy, as most
epithelioid smooth muscle tumors will show at least focally a spindle cell component.
Low-grade endometrial stromal sarcoma with gland differentiation vs adenomyosis
Adenomyosis is typically an incidental finding that never presents as a mas,s as discussed earlier.
Even though both entities show endometrial-type glands surrounded by endometrial-type stroma, the stroma
in adenomyosis has an inactive appearance while in low-grade ESS show an expansile growth and a
proliferative appearance of the stromal cells. Furthermore, low-grade ESS typically form a mass, and in
some areas the tumor may show the more typical appearance without the glandular component.
Low-grade endometrial stromal sarcoma with gland differentiation vs low-grade mullerian adenosarcoma
Both tumors show endometrioid-type glands, endometrial-type stroma and both components infiltrate the
myometrium. However, mullerian adenosarcoma shows a more uniform distribution of the glands within the
stromal component as well as intraglandular polypoid stromal projections and periglandular stromal
condensation. In addition adenosarcomas are more circumscribed, if they infiltrate do not show the
typical tongue-like growth and less often have vascular invasion.
Metastatic low-grade endometrial stromal sarcoma to the ovary vs stromal or sex-cord stromal tumor
The findings of tumor outside the ovary as well as endometriosis favor the diagnosis of low-grade
ESS. Immunohistochemical stains are of limited help. Sex cord but not pure stromal tumors may be
positive for CD10, although the degree and extent of positivity is much less than that observed in
endometrial stromal tumors. Furthermore, sex cord-like areas in endometrial stromal tumors stain
similarly to sex cord stromal tumors. In these cases extensive sampling is required to show areas of
conventional endometrial stromal neoplasia.
Metastatic low-grade endometrial stromal sarcoma vs solitary fibrous tumor
When low-grade ESS has a fibrous background and it is present in the lung or even in the peritoneum,
one should consider a solitary fibrous tumor in the differential diagnosis. However, the latter is
frequently associated with a more haphazard orientation of the tumor cells and a vascular component not
only showing arterioles. These tumors may be positive for CD10 and estrogen and progesterone receptors,
thus, these markers are not helpful in this differential diagnosis. CD34 may be of help in
distinguishing these two tumors.
Metastatic low-grade endometrial stromal sarcoma vs gastrointestinal stromal tumor
Even though these two entities have different histologic appearance, one may not think about the
possibility of an endometrial stromal tumor when outside the uterus, especially as the histologic
appearance may differ to some extent from that seen in typical tumors.
Although in most instances the diagnosis of endometrial stromal tumors (EST) is based on morphologic
grounds alone, immunohistochemical stains may be helpful in the diagnosis of problematic cases. The
neoplastic endometrial stromal cells are typically immunoreactive for vimentin, muscle-specific and
smooth muscle actin, and keratin. This panel of antibodies, however, is not very sensitive in
distinguishing ESTs from smooth muscle tumors, the commonest and most problematic group of tumors in the
differential diagnosis. Desmin staining has been of help in our experience, but the frequency of desmin
staining in ESTs and percentage of desmin positive tumor cells varies among studies. In the study by
Franquemont et al., two of two ESNs were strongly and diffusely positive and 7 of 12 ESSs were
immunoreactive for desmin, although the staining was diffuse in only four of them, and limited to
scattered cells in the other three. Similarly, normal endometrial stromal cells were desmin positive in
9 of 10 cases. The staining was confined to scattered cells in 8 cases, but it was diffuse in the
ninth. In some studies the sex cord-like elements in ESSs and UTROSCTs have been desmin-positive
suggesting smooth muscle differentiation. More recent studies, however, have suggested that these
elements represent sex cord differentiation as discussed below. Other studies have shown a frequency of
desmin positivity ranging from 0 to 30% in typical ESS. In our laboratory, desmin has been focally
positive in only 3 out of 29 ESTs studied, a finding we consider consistent with smooth muscle
differentiation in ESTs as discussed earlier. In recent years, a few other antibodies have been tested
CD10, initially described as tumor-specific antigen in acute lymphoblastic
leukemia, was strongly and diffusely positive in 5/5 ESSs in a recent study. The normal endometrial
stromal cells were also positive. In the study just cited only one of 16 malignant smooth muscle tumors
including one from the uterus was positive for CD10. However, more recent studies have shown that smooth
muscle tumors as well as mixed mullerian tumors (including adenosarcoma and malignant mixed mullerian
tumor) or even rhabdomyosarcomas may be positive for CD10. For this reason this antibody should not be
used in isolation when evaluating the origin of a mesenchymal tumor of the uterus. In the ovary, CD10 is
positive in sex-cord stromal tumors, the latter usually showing weak and focal staining. For that
reason, although CD10 is not widely used in the diagnosis of sex-cord stromal tumors, it is important to
be aware of this finding.
h-caldesmon is also helpful in the differential diagnosis of ESTs versus
smooth muscle tumors. h-caldesmon is a calcium, calmodulin, and actin-binding protein widely distributed
in smooth and non-smooth muscle cells and is thought to regulate cellular contraction. Its isoform,
high-molecular-weight caldesmon, is specific for smooth muscle cells and smooth muscle tumors and is
never expressed in myofibroblasts. In a study of 9 ESTs and 15 benign and malignant smooth muscle
ors, Hey! Our study was first J why did everyone like Nucci's better?? Nucci et al found that all
ESTs were negative for this antibody. In contrast all leiomyomas and leiomyosarcomas were positive,
although staining was focal or confined to isolated cells in three leiomyosarcomas. Others have
confirmed these findings.
Inhibin is a gonadal hormone that acts as a suppressor in the synthesis and
secretion of pituitary follicle stimulating hormone. It is a very useful marker for sex cord stromal
tumors of the ovary although not pathognomonic Inhibin has been negative in 20 ESSs of the ovary
reported in different series from the literature. In the uterus, Baker and colleagues studied the
expression of inhibin in 10 ESTs with sex cord-like differentiation. It was positive in 3/10 of these
tumors usually being focal and weak and confined to sex cord-like areas. Additionally, 5 of 5 UTROSCTs
were positive for inhibin, although the staining varied from weak and punctate to diffuse and strong and
was generally much stronger and more extensive in areas with prominent foam cells. Krishnamurthy and
colleagues found that 3 of 7 UTROSCTs were inhibin positive, ranging from focal (1) to extensive (2).
The authors concluded that the inhibin staining in certain areas of these tumors was indicative of true
sex cord-like differentiation rather than smooth muscle differentiation. In the same study, 4 of seven
UTROSCTs stained for Mart-1, an antigen expressed by normal melanocytes and melanocytic neoplasms, and
steroid producing cells and tumors composed of such cells located in the adrenal cortex, ovary, and
testis. The positive staining for Mart-1 in UTROSCTs isconsistent with the
presence of steroid-producing cells and is supportive of their specialized gonadal stromal nature . Inhibin is the paramount marker for sex cord-stromal tumors of the ovary (I think
Mike Deavers would disagree with you—what about calretinin?), however, remember that inhibin is not
totally specific for sex cord-stromal tumors and that mesonephric tumors frequently show focal and weak
positivity and that a minority of ovarian carcinomas have been reported to be also positive for
Calretinin has been shown to be highly sensitive but not as specific marker
as inhibin for sex cord -stromal tumors. Some sex cord-stromal tumors that are negative for inhibin may
be calretinin positive. Calretinin is also positive in fibromas of the ovary. This antibody is
expressed in non-neoplastic ovarian sex cord-stromal cells, but also in secretory endometrial stromal
cells. There is limited experience with ESTs at the moment, although some ESTs have reported to be
calretinin positive. Moreover, other tumors may stain for calretinin including leiomyosarcomas,
mesonephric tumors as well as endometrioid carcinomas of the ovary and endometrium and for that reason
positive calretinin immunoreactivity should be used in the appropriate context.
CD99 was initially described as a marker for Ewing's sarcoma as well as
primitive neuroectodermal tumors, but it also stains normal sex-cord elements as well as tumors derived
from them. Loo and colleagues studied 5 ESSs, one of which had sex cord-like differentiation; positive
staining for CD99 was confined to the sex-cord-like areas. In the series reported by Baker and
colleagues, only three of ten ESTs with a sex cord-like component were positive for CD99, with weak and
focal positivity confined to the sex-cord areas. CD99 was positive in all 5 UTROSCTs in that series,
ranging from weak and slightly punctate to intense and diffuse. In the series by Krishnamurthy and
colleagues, all 7 UTROSCTs were positive for CD99, ranging from one to three in intensity. In contrast,
smooth muscle tumors have been negative for inhibin as well as for CD99 with the exception of one
epithelioid smooth muscle tumor that showed weak positivity for this antigen. The combination of
positive staining for keratin, desmin, and CD99 has been documented in granulosa cell tumors of the ovary
and the same findings in ESSs with sex-cord-like differentiation and UTROSCTs support true sex-cord
rather than smooth muscle differentiation.CD99 reacts with normal sertoli and
granulosa cells and it is marker for sex-cord stromal tumors. The degree of expression may be related to
the degree of tumor differentiation and the staining may be membranous or cytoplasmic. It has been shown
that CD99 is much less sensitive and less specific than inhibin in the diagnosis of sex cord-stromal
Mart-1 (Melan A, A103) is typically positive in steroid cell tumors but
also in other sex cord -stromal tumors, including Sertoli-Leydig cell tumors, adult and juvenile
granulosa cell tumors, and even in the fibroma-thecoma category of ovarian tumors, although experience is
very limited. Endometrial/ioid stromal tumors have been shown to be negative for Mart-1, with the
exception of sex-cord areas that may be positive.
WT-1 Nonneoplastic endometrial stroma as well as endometrial stromal tumors
are WT-1 positive . However, smooth muscle tumors, the most problematic
tumors in the differential diagnosis of endometrial stromal tumors are also positive for this antibody.
CD34, a myeloid progenitor cell antigen present in endothelial cells and
some other mesenchymal cells, including perivascular and periadnexal dermal fibroblasts, has been found
to be present in the stromal cells of the basal endometrium but was negative in 6 ESSs tested.
Additionally we found that CD34-staining was absent in 10 fibrous and myxoid ESTs. In contrast, Rizeq
and colleagues found CD34 positivity in 36% of 22 conventional smooth muscle tumors with a spindle cell
morphology and 6% of 36 epithelioid smooth muscle neoplasms, although normal myometrium in most cases did
not stain for CD34. Furthermore, as previously noted in the rare cases in which the differential
diagnosis includes a gastrointestinal stromal tumor, the latter frequently is positive for CD34 in
contrast to EST. CD34 may be helpful in cases of metastatic ESS to lungs where the differential
diagnosis is mainly with solitary fibrous tumors, the latter typically positive for this marker.
C-KIT, a well known marker for gastrointestinal stromal tumors and it has
been to be the most useful immunohistochemical marker for gastrointestinal stromal tumors and it is
typically positive in 72-100% of these tumors. It has been recently tested in endometrial stromal and
smooth muscle neoplasms. In our study all endometrial stromal tumors where negative for c-kit and Klein
and Kurman found that only 1/10 endometrial stromal sarcomas and 3/6 endometrial stromal nodules were
positive for c-kit but no more than 5% of the cells stained with the antibody. In contrast to the
homogenous results obtained in endometrial stromal tumors, the literature on smooth muscle tumors and
c-kit is confusing. Some studies have shown that leiomyosarcomas are c-kit negative while others have
reported variable degrees of positivity in malignant smooth muscle tumors and have even found correlation
Oxytocin, a neurohypophyseal peptide associated with muscle contraction
during labor, is expressed in smooth muscle tumors but not in endometrial stromal tumors. In the study
conducted by Loddenkemper and colleagues they found that oxytocin was present in all conventional and
highly cellular leiomyomas as well as in all leiomyosarcomas while all nine ESS (9) were oxytocin
negative. These authors postulate that this antibody may be used as part of the panel to distinguish
ESTs from smooth muscle tumors.
Aromatase, participates in the extraovarian estrogen production via
conversion of androgen to estrogen through the aromatase enzyme complex. Aromatase has been described in
stromal cells of endometriosis, adenomyosis, endometrial carcinomas as well as ESSs. Reich and Regauer
found that most low-grade ESSs expressed aromatase and little or no expression of aromatase tended to
correlate with stage I disease.
Finally, numerous studies have shown that ESTs frequently contain estrogen, progesterone and androgen
receptors, findings that may have therapeutic and prognostic implications, although the presence of these
receptors has limited utility in differential diagnosis inasmuch as these receptors may be found in many
other epithelial and mesenchymal tumors of the uterus.
- It is important to remember that one should not rely in one antibody but on a panel when
trying to interpret mesenchymal tumors of the uterus.
At least 60 to 70% of typical low-grade EESs show the t(11;17), involving JAZF1
and JJAZ1 translocation, including tumors with smooth muscle
metaplasia, fibrous and/or myxoid background or sex cord-like differentiation. The prevalence of this
translocation is much lower in so-called high-grade endometrial stromal sarcoma.
Prognosis and Treatment
As in most cases it is impossible to separate between an endometrial stromal nodule and a low-grade
endometrial stromal sarcoma in a curettage specimen, the optimal treatment is always hysterectomy
accompanied by bilateral salpingo-oophorectomy because these tumors are often hormone sensitive and it
has been shown that patients retaining their ovaries have a much higher risk of recurrence (up to 100%).
The 5-year survival rate is approximately 80-90% and the 10-year survival is a bit lower (about 70%).
Patients who present with Stage I (organ confined) disease have better prognosis, with a 5-year survival
close to 100% and a 10-year survival around 90%. In contrast, patients who present with high-stage ESSs
have only a 40% survival that remains constant at 10 years. Therefore, patients who present with
low-stage tumors probably continue to experience recurrence decades after diagnosis whereas patients
diagnosed with high stage tumors experience recurrence and frequently die of disease within 5 years of
- Stage is therefore the most powerful prognostic factor in endometrial stromal sarcomas.
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Problems in differential diagnosis of endometrial stromal tumors:
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Mixed endometrial stromal and smooth muscle tumors:
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Myxoid and fibrous endometrial stromal tumors:
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