Smooth Muscle Tumors of the Uterus
A Practical Approach
Gemma Toledo, MD, PhD; Esther Oliva, MD
● Smooth muscle tumors (SMTs) are the most frequent
mesenchymal tumors of the uterus. The majority of the
uterine SMTs are readily classificable as benign or malig-
nant based on their gross and microscopic appearances.
However, when unusual features are seen in some leio-
myoma variants, the differential diagnosis with a leiomyo-
sarcoma may become challenging. Moreover, diagnostic
criteria for the different subtypes of leiomyosarcoma are
not uniform. Finally, non–smooth muscle tumors that orig-
inate in the uterus may show overlapping histologic and
even immunohistochemical features with uterine SMTs,
more commonly with the spindle and epithelioid variants,
complicating their correct classification. The diagnosis of
malignant uterine SMTs has important prognostic and ther-
apeutic implications. This review provides a practical ap-
proach to the diagnosis of uterine leiomyosarcoma based
on a systematic assessment of histologic parameters as well
as a systematic approach to its differential diagnosis based
on histologic and immunohistochemical features.
(Arch Pathol Lab Med. 2008;132:595–605)
L eiomyosarcoma (LMS), the most frequent uterine sar-
coma, typically affects women older than 40 years.1
Patients frequently present with abnormal vaginal bleed-
ing, pain, or both. Rarely, hemoperitoneum due to tumor
rupture, extrauterine extension, or metastases may be the
presenting manifestation.2 An accurate diagnosis of LMS
is relevant, since patients diagnosed with LMS should un-
dergo radical hysterectomy, as surgery is the mainstay of
treatment.3,4 Furthermore, at the present time there are no
consensual histologic or molecular parameters that predict
behavior of LMS, even in stage I tumors.5–8 Finally, pa-
tients with LMS have a relatively poor 5-year survival rate
(25%–75%) and a high recurrence rate (45%–75%), includ-
ing LMSs confined to the uterus,3,4,6,9 which contrast with
the better prognosis of the majority of the tumors in the
differential diagnosis.10,11
Accepted for publication September 12, 2007.
From the Department of Pathology, Massachusetts General Hospital,
Boston.
The authors have no relevant financial interest in the products or
companies described in this article.
Presented in part at the 28th Annual Course, Current Concepts in
Surgical Pathology, Massachusetts General Hospital and Harvard Med-
ical School, Boston, November 2006.
Reprints: Esther Oliva, MD, Department of Pathology, Massachusetts
General Hospital, 55 Fruit St, Warren 2, Boston, MA 02114 (e-mail:
eoliva@partners.org).
Arch Pathol Lab Med—Vol 132, April 2008
Grossly, most LMSs are large, solitary, poorly circum-
scribed masses (average 10 cm) or the largest mass in a
fibroid uterus that typically display a fleshy variegated cut
surface with areas of hemorrhage or necrosis. However,
some of these features may be seen in leiomyoma variants
and also in non–smooth muscle tumors of the uterus.2,10,11
In these cases, extensive sampling, especially of these un-
usual areas, is mandatory to elucidate the nature of the
tumor. The final diagnosis of LMS is based on the assess-
ment of 3 major histologic features: (1) mitotic activity, (2)
nuclear atypia, and (3) tumor cell necrosis.
MITOTIC ACTIVITY
In the past, the presence of 10 or more mitoses per 10
high-power fields (HPFs) was considered key to establish-
ing the diagnosis of leiomyosarcoma.1,8,12–14 Even though
mitotic index is an important feature in the assessment of
malignancy, several studies based on large series of uter-
ine smooth muscle tumors (U-SMTs) have shown that mi-
totic activity alone is not predictive of poor outcome in
these tumors.8,11,12,15,16 The classification of U-SMTs pro-
posed by Bell and colleagues16 has the advantage of down-
playing the importance of mitotic rate as a determinant
diagnostic feature in malignant U-SMTs, reducing the
number of cases diagnosed as leiomyosarcoma that follow
a benign course.16,17 Assessing mitotic activity in smooth
muscle tumors (SMTs) also has been a subject of debate.
Apoptotic cells, pyknotic nuclei, lymphocytes, mast cells,
precipitated hematoxylin or cellular debris can be misin-
terpreted as mitotic figures.12 Some authors recommend
the use of strict criteria to identify mitotic figures and have
proposed different methods to standardize and thus to
increase reproducibility to measure mitotic activity in-
cluding the use of immunohistochemistry.18–20 Criteria for
strict mitotic count in hematoxylin-eosin–stained tissue in-
clude the absence of nuclear membrane with discernible
cytoplasm and the presence of hairy extensions of chro-
matin extending from a central clotlike dense mass of
chromosomes (single clot in metaphase or separate in telo-
phase) (Figure 1).12 The presence of atypical ‘‘mitosis-like’’
figures in the absence of typical mitoses should alert to
the possibility of being confronted with apoptotic cells.
Finally, it also is important to keep in mind that mitotic
activity in U-SMTs, in contrast to mitotic activity in soft
tissues in general, does not possess the same prognostic
implications. A high mitotic index is acceptable in benign
U-SMTs, in contrast to other soft tissues and organ-based
SMTs, where any mitotic activity raises high suspicion for
malignancy.21,22
Smooth Muscle Tumors of the Uterus—Toledo & Oliva 595
Figure 1. Mitotic figure. A cell shows clear cytoplasm and linear extensions of chromatin extending from a central clotlike dense mass of
chromosomes (hematoxylin-eosin, original magnification ⫻400).
Figure 2. Main types of necrosis in smooth muscle tumors. a, Tumor cell necrosis. There is an abrupt transition from viable to nonviable tumor
with preserved tumor cells showing perivascular growth. b, Infarct-type necrosis. A zone of fibrosis associated with recent hemorrhage is seen
between viable (bottom right) and ghost tumor (upper left) cells. c, Early infarct-type necrosis. Apoptotic smooth cells are intercalated with viable
cells and may cause concern for tumor cell necrosis (hematoxylin-eosin, original magnifications ⫻100 [a, b] and ⫻200 [c]).
Figure 3. Spindle cell leiomyosarcoma. Cohesive spindle cells form large intersecting fascicles. The tumor is hypercellular, and the cells show
marked cytologic atypia (hematoxylin-eosin, original magnification ⫻100).
Figure 4. Apoplectic leiomyoma. A central area of hemorrhage is surrounded by a more cellular rim of neoplastic smooth muscle cells (arrows).
Further away, the tumor becomes less cellular (typical leiomyoma; ‘‘zonation phenomenon’’; hematoxylin-eosin, original magnification ⫻2.5).

596 Arch Pathol Lab Med—Vol 132, April 2008 Smooth Muscle Tumors of the Uterus—Toledo & Oliva
 NUCLEAR ATYPIA
A constellation of cytologic features, including nuclear
pleomorphism, hyperchromatism, irregularity in nuclear
membranes, high nuclear size, and prominent nucleoli,
when present, are indicative of significant atypia.12,15 How-
ever, cytologic atypia may be overestimated when study-
ing SMTs, and in general any tumor, at high-power mag-
nification. Nuclear atypia must be recognized and taken
into account at low-power magnification (⫻10), comparing
it with the nuclear features of the adjacent myometrium
when possible.12,15
TUMOR CELL NECROSIS
Tumor cell necrosis is only seen in LMSs.16 This type of
necrosis is defined by finding an abrupt transition from
necrotic to nonnecrotic tumor, without interposed granu-
lation or fibrous tissue. Preserved nuclei with marked
pleomorphism and hyperchromasia and nuclear debris
that are usually lacking inflammation are frequently seen
within the necrotic areas. Viable tumor often shows a peri-
vascular growth (Figure 2, a).10,15 In our experience, it is
extremely rare to find tumor cell necrosis in an LMS in
the absence of both cytologic atypia and brisk mitotic ac-
tivity.5 In a recent series, we found that of 77 LMSs, in-
cluding 44 spindle, 22 epithelioid, 6 myxoid, and 5 mixed
spindle and epithelioid LMSs, all but 1 tumor showed
marked nuclear pleomorphism and more than 10 mitoses
per 10 HPFs when tumor cell necrosis was present in the
neoplasm.5
In contrast to tumor cell necrosis, infarct type necrosis,
secondary to ischemia, can occur either in benign or ma-
lignant U-SMTs. It is characterized by finding either gran-
ulation tissue or hyalinization between the necrotic and
nonnecrotic areas, frequently associated with recent hem-
orrhage.10,12,15 The necrotic areas have a mummified ap-
pearance showing ghost outlines of the tumor cells, and
both tumor and vessels appear dead (Figure 2, b). The end
result is the replacement of the infarcted area by dense
hyalined tissue.10,12 It is important to keep in mind that
when necrosis is seen at an early stage, the microscopic
features just described are typically absent, and in those
instances it may be very difficult to distinguish infarct
from tumor cell necrosis. Furthermore, very early infarct
type necrosis, characterized by single apoptotic cells ad-
mixed with viable cells, may also be confused with tumor
cell necrosis (Figure 2, c). Thus, it is always very impor-
tant to evaluate cytologic atypia and mitotic activity. If
tumor cell necrosis is present in a tumor, it is almost al-
ways accompanied by cytologic atypia and brisk mitotic
activity.5 Ulcerative necrosis often seen on the surface of
a U-SMT is associated with inflammatory cells, and it is
easy to distinguish from the other types of necrosis.
Potential Pitfalls
● Apoptotic cells can be confused with atypical mitoses.
● High-power scrutiny may mislead to identification of
inexistent nuclear atypia.
● Early necrosis may be difficult to classify as either tu-
mor or infarct-type.
Recommendations
● Cytologic features should be evaluated at ⫻10 magni-
fication.
● Cytology of tumor cells should be compared with non–
tumoral smooth muscle.
Arch Pathol Lab Med—Vol 132, April 2008
● Caution is required in interpreting ‘‘atypical mitoses’’
as such in the absence of conventional mitotic figures.
● Evaluation of ‘‘early’’ non–well-characterized necrosis
should be made in conjunction with nuclear atypia and
mitotic activity.
● Perform extensive sampling when unusual features are
present in a U-SMT.
The finding of any 1 of these 3 key features (mitotic
activity, nuclear atypia, and tumor cell necrosis) in a
U-SMT should be taken seriously, but a single feature is
neither necessary nor sufficient to establish a diagnosis of
malignancy.16,23
LEIOMYOSARCOMA: DIAGNOSTIC CRITERIA
The criteria to establish a diagnosis of malignancy in a
U-SMT differ for each subtype, increasing the difficulty in
diagnosis and reproducibility among pathologists. These
can be summarized as follows:
1. Conventional (Spindle Cell) LMS
On microscopic examination, spindle cell LMS is typi-
cally composed of elongated cells with eosinophilic fibril-
lary cytoplasm and elongated blunt-ended nuclei. The
cells form long intersecting fascicles and frequently dis-
play an infiltrative growth into the surrounding myome-
trium (Figure 3).10,11,24 Variable degrees of atypia (often
moderate to marked) and variable mitotic activity (typi-
cally brisk) with or without tumor cell necrosis are iden-
tified.14 The tumors are frequently hypercellular, but they
can be normocellular or hypocellular. Rarely conventional
LMSs can have osteoclast-like giant cells or xanthomatous
cells disposed in sheets or admixed with the spindle
smooth muscle cells.10,24 In this LMS subtype, the diag-
nosis of malignancy is established when any 2 of the fol-
lowing 3 criteria are present:
● Diffuse moderate to marked cytologic atypia.
● Mitotic rate 10 or more mitoses per 10 HPFs.
● Tumor cell necrosis.
Additional findings, such as hypercellularity, atypical
mitoses, vascular invasion, or infiltrative borders, are seen
in most conventional LMSs, but they are not considered
diagnostic criteria of malignancy.10,14
Differential Diagnosis
The distinction between spindled cell LMS and some
leiomyoma (LM) variants may be quite difficult but cru-
cial, as it carries important therapeutic and prognostic im-
plications. Leiomyoma variants, although uncommon,
have an overall higher frequency compared with LMS,
simply because LM is the most common neoplasm of the
female genital tract, present in about 40% of women older
than 50 years and in up to 75% of hysterectomy speci-
mens.13 Clinically, LMs may cause pelvic pain, abnormal
vaginal bleeding, and rapid uterine enlargement, symp-
toms that overlap with those seen in LMS. Typical LM is
readily distinguished from LMS on gross and microscopic
examination in most instances. However, there are some
LM variants that may display worrisome gross or micro-
scopic features, raising the possibility of malignancy.
Those include (1) mitotically active LM; (2) LMs with hor-
mone-related changes, including apoplectic LM; (3) LM
with bizarre nuclei; and (4) cellular and highly cellular
LM.
Smooth Muscle Tumors of the Uterus—Toledo & Oliva 597
 Mitotically Active LM Versus Conventional LMS.
This LM variant is defined by the finding of brisk mitotic
activity in an otherwise typical LM that occurs in women
in their reproductive age, associated with the secretory
phase of the menstrual cycle, pregnancy, or the use of ex-
ogenous hormones.11–13,15 Grossly, the majority of mitoti-
cally active LMs are submucosal with a typical gross cut
surface in contrast to LMS, which is intramyometrial in
two thirds of cases and frequently has a heterogeneous
cut surface. The most important criterion to establish the
diagnosis of mitotically active LM (or LM with increased
mitotic index) is the absence of cytologic atypia or, at
most, the presence of mild nuclear atypia when scanning
the tumor at ⫻10 magnification. These tumors often have
more than 10 mitoses per 10 HPFs (between 5 and 15, or
even 19 in one series).25–27 Moreover, mitoses are usually
‘‘typical,’’ but exceptional abnormal mitotic figures are al-
lowed.11,12,15 Ulcerative necrosis and inflammation with re-
active changes but no tumor cell necrosis can be observed
in a submucosal, mitotically active LM. In the absence of
cytologic atypia and tumor cell necrosis, an increased mi-
totic index up to 20 mitoses per 10 HPFs has no prognostic
significance. As mitotically active LMs with more than 20
mitoses per 10 HPFs are extremely rare, tumors in that
category may be classified as ‘‘leiomyoma with increased
mitotic activity, but experience limited.’’ 11,12,16 However,
other authors prefer to include these tumors in the group
of U-SMT of uncertain malignant potential.21
Potential Pitfalls
● Mitotic activity more than 10 per 10 HPFs.
● Cytologic atypia associated with superficial ulceration.
Helpful Clues
● Minimal to absent cytologic atypia with a ⫻10 objective.
● Homogeneous bland appearance.
Apoplectic LM Versus Conventional LMS. This is a
distinctive U-SMT characterized by multifocal areas of re-
cent hemorrhage that occurs in women in reproductive
age either taking oral contraceptives or who are pregnant
or recently postpartum.28–30 This clinical scenario contrasts
with that seen in LMS, which occurs more commonly in
postmenopausal women. However, the presenting symp-
toms may be similar to those encountered in LMS.28,29 On
gross examination, there are small and frequently multiple
hemorrhagic areas that may be accompanied by cystic
change. Microscopically, this LM variant is characterized
by patchy zones of recent hemorrhage juxtaposed to areas
of hypercellular smooth muscle (Figure 4). Secondary to
ischemia, the smooth muscle cells in these areas may show
dense eosinophilic cytoplasm, enlarged nuclei, plump nu-
cleoli, and brisk mitotic activity (as high as 8 mitoses per
10 HPFs), and they may be focally associated with a myx-
oid background,28–30 features that may raise concern for
malignancy. However, the average mitotic count is typi-
cally low (⬍2 mitoses per 10 HPFs)11,28–30 and, most im-
portantly, there is a ‘‘zonation’’ phenomenon, whereby fur-
ther away from these areas the cellularity decreases and
the overall cytologic appearance is that of a conventional
LM (Figure 4).16,29,31
Finally, some LMs treated with gonadotrophin-releasing
hormone analogs (GnRHa) given to reduce the size of the
LMs prior to their removal may show infarct necrosis in
the absence of increased mitotic index or atypia.31–33 How-
ever, it is important to keep in mind that the same LM
598 Arch Pathol Lab Med—Vol 132, April 2008
removed several weeks after withdrawal of the GnRHa
treatment can show increase mitotic activity. Clinical in-
formation is essential to avoid the misdiagnosis of LMS.
Potential Pitfalls
● Hemorrhagic areas with cystic change.
● Increased cellularity with cytologic atypia and in-
creased mitotic activity.
● Focal myxoid background.
Helpful Clues
● ‘‘Zonation’’ phenomenon from cellular areas next to
hemorrhage to distant areas, with appearance of con-
ventional LM at low-power examination.
● Evaluate mitotic rate and cytologic atypia in areas far
away from hemorrhage.
LM With Bizarre Nuclei Versus Conventional LMS.
Worrisome features that can be seen in LM with bizarre
nuclei include large atypical mononucleated or multinu-
cleated cells, karyorrhectic nuclei, prominent nucleoli, nu-
clear pseudoinclusions, coarse chromatin, or even in-
creased mitotic activity by the highest count (up to 7 mi-
toses per 10 HPFs).34,35 On microscopic examination, an
important clue to this diagnosis is the patchy or multifocal
distribution of the bizarre cells in the tumor (Figure 5, a).
However, in rare cases, cells with bizarre nuclei may have
a diffuse distribution, and karyorrhectic nuclei may mimic
atypical mitoses, raising even more concern for LMS (Fig-
ure 5, b).34,35 Other helpful features to distinguish LM with
bizarre nuclei from LMS include bland cytologic appear-
ance of the smooth muscle cells in areas without bizarre
nuclei, low average mitotic account (⬍2 mitoses per 10
HPFs), and absence of tumor cell necrosis.11,15,34 Ancillary
techniques, such as ploidy, MIB-1 activity, and p53 ex-
pression, also may be used.11,17,34,35 Distinction between the
two entities is of paramount importance, as LM with bi-
zarre nuclei has an excellent prognosis, including tumors
that are only treated with myomectomy.11,34
Potential Pitfalls
● Mononucleated or multinucleated cells with bizarre nu-
clei.
● Diffuse distribution of atypical cells within the tumor.
● Karyorrhectic nuclei mimicking atypical mitoses.
● Mitotic rate up to 7 mitoses per 10 HPFs by highest
count.
Helpful Clues
● Minimal or no cytologic atypia in background non–bi-
zarre smooth muscle cells.
● Dense eosinophilic cytoplasm and clumpy-coarse chro-
matin indicative of apoptosis.
● Average mitotic rate of 1 to 2 mitoses per 10 HPFs.
● Absence of tumor cell necrosis.
Highly Cellular LM Versus Conventional LMS.
Highly cellular LM may be confused with LMS because
of its marked cellularity and, furthermore, it may show an
increased mitotic activity or even bizarre nuclei. However,
it typically lacks cytologic atypia and tumor cell necrosis,
and in most cases the mitotic activity is very low.36
Others. Rarely undifferentiated endometrial sarcoma
and spindle cell rhabdomyosarcoma should be considered
in the differential diagnosis of spindle LMS. The former
is a diagnosis of exclusion,11 whereas the latter shows cells
with bright eosinophilic cytoplasm, which at least should
Smooth Muscle Tumors of the Uterus—Toledo & Oliva

Figure 5. Leiomyoma with bizarre nuclei. a, Bizarre mononucleated
and multinucleated cells with a patchy distribution are present in a
background of smooth muscle cells with bland cytologic features. b,
Bizarre cells have a diffuse distribution and show hyperchromatic ir-
regular nuclei resembling atypical mitoses (arrows) mimicking a leio-
myosarcoma (hematoxylin-eosin, original magnifications ⫻125 [a] and
⫻200 [b]).
alert to search for cross-striations and perform immuno-
histochemical stains for skeletal markers.37,38
2. Myxoid LMS
This unusual variant of LMS frequently displays a jel-
lylike cut surface with infiltrative borders (Figure 6, a),
but it may have deceptive well-delineated margins. On
microscopic examination, these tumors are hypocellular,
in contrast to most spindle LMS, the cells being embedded
in an abundant weakly basophilic myxoid matrix (Figure
6, b) strongly positive with Alcian blue and colloidal iron
stains.39 The neoplastic cells may be uniformly distributed
throughout the myxoid matrix or arranged in loose fas-
cicles. They have scant cytoplasm, oval, spindle, or stellate
nuclei with small nucleoli,10,40 and not infrequently only
exhibit focal mild to moderate atypia (Figure 6, b) and low
mitotic rate (0–2 per 10 HPFs).39,41 Helpful features to es-
tablish the diagnosis of malignancy include the finding of
high-grade areas, conventional areas of LMS, irregular in-
filtration of the myometrium (Figure 6, a), and venous in-
vasion.40–45 Because identification of marked nuclear atyp-
ia, tumor cell necrosis, and high mitotic rate is not as fre-
Arch Pathol Lab Med—Vol 132, April 2008
quently encountered in myxoid LMS compared with spin-
dle LMS, despite its malignant course, the consensus
diagnostic criteria for this specific variant include40,41,45
1. Severe cytologic atypia and/or tumor cell necrosis,
with any mitotic index.
2. In the absence of atypia or tumor cell necrosis, the
finding of 2 or more mitoses per 10 HPFs.
Differential Diagnosis
Myxoid LM Versus Myxoid LMS. Myxoid change oc-
curs in about 2% of LMs, but this change is rarely exten-
sive and is frequently seen near the zone of repair of an
organizing infarct.11,15 Grossly, both myxoid LM and LMS
show a soft, gray, gelatinous cut surface, and often a well-
circumscribed border.39,41 On microscopic examination,
myxoid LM is well demarcated, but the presence of alter-
nating myxoid and nonmyxoid areas in an LM may be
misinterpreted as an infiltrative margin into the myome-
trium. It is very important to rely on the low-power scru-
tiny to identify the real margin of the tumor. It is even
more important to sample the tumor very extensively in
order to find areas with more pronounced atypia or mi-
totic activity.39 Finally, when facing a U-SMT with myxoid
and nonmyxoid areas, the latter usually exhibit higher nu-
clear atypia and mitotic activity in an LMS.10,11,41 As most
myxoid LMSs have been large tumors (average ⬎10 cm),
any myxoid tumor more than a few centimeters in size,
with any mitotic activity, or with an infiltrative margin is
best regarded as potentially aggressive.2 Distinction be-
tween myxoid LM and myxoid LMS may be difficult in
curettage specimens or when performing a frozen section
due to limited sampling,39 and in these cases the final di-
agnosis should be deferred.
Potential Pitfalls
● Well-demarcated margin on gross examination.
● Hypocellularity, minimal atypia, and low mitotic activ-
ity.
● Alternating myxoid and nonmyxoid areas in an LM
misinterpreted as invasion.
Helpful Clues
● Extensive sampling.
● Low-power examination allows recognition of the well-
circumscribed interphase.
● In absence of tumor cell necrosis or severe cytologic
atypia, a mitotic index of 2 or more per 10 HPFs is key
to the diagnosis of myxoid LMS.
Hydropic LM Versus Myxoid LMS. Generally, hy-
dropic degeneration in LMs is focal and associated with
hyalinization.2,46 However, sometimes hydropic change
may be extensive and present beyond the confines of the
LM, simulating the infiltrative border of a myxoid
LMS.11,46 Whereas hydropic degeneration appears as wa-
tery, pale, eosinophilic fluid (Figure 7, a), myxoid matrix
is basophilic and could be identified by staining for acidic
mucins (colloidal iron and Alcian blue).11,15 It is important
to keep in mind that a rapidly growing mass in the uterus
is frequently interpreted by the clinician as a malignant
tumor. Thus, not infrequently, a clinician may ask for an
intraoperative consultation. In some cases, these tumors
may have a gross appearance that may overlap with that
seen in myxoid smooth muscle tumors (Figure 7, b). How-
ever, in most cases, the uniform white-gray gross appear-
Smooth Muscle Tumors of the Uterus—Toledo & Oliva 599
Figure 6. Myxoid leiomyosarcoma. a, The tumor has an infiltrative growth pattern into the myometrium. b, The tumor is hypocellular, the cells
show minimal atypia, and there is abundant myxoid matrix (hematoxylin-eosin, original magnifications ⫻20 [a] and ⫻100 [b]).
Figure 7. Hydropic leiomyoma. a, Benign smooth muscle tumor cells are separated by abundant edematous fluid (hematoxylin-eosin, original
magnification ⫻100). b, The tumor shows a pale ‘‘jellylike’’ cut section resembling a myxoid smooth muscle tumor (gross picture).
Figure 8. Epithelioid leiomyosarcoma. a, A solid/nested growth of epithelioid cells with eosinophilic or clear cytoplasm is seen. b, The tumor
cells form anastomosing cords and trabeculae in a hyalinized and edematous stroma (hematoxylin-eosin, original magnification ⫻100).

600 Arch Pathol Lab Med—Vol 132, April 2008 Smooth Muscle Tumors of the Uterus—Toledo & Oliva
ance of the tumor oozing watery fluid even more when it
is squeezed is helpful to establish the diagnosis of hy-
dropic LM. If the tumor is myxoid and the representative
frozen section does not show obvious features of malig-
nancy, it is best to indicate the myxoid nature of the tumor
to the surgeon and defer the final interpretation after ex-
tensive sampling has been performed.
Potential Pitfalls
● Hydropic change extending outside the LM may be in-
terpreted as invasion.
Helpful Clues
● Gross appearance includes oozing watery fluid.
● Edematous areas alternating with areas of hyalinization.
● Negative Alcian blue and colloidal iron.
Myxoid Endometrial Stromal Tumors Versus Myxoid
LMS. Myxoid LMS must be differentiated from endo-
metrial stromal sarcoma with myxoid change, as both
share prominent myometrial infiltration and intravascular
growth.10,47,48 In these cases, the multinodular or tongue-
like pattern of infiltration of the myometrium, focal areas
of typical endometrial stromal tumor with characteristic
arterioles and frequent negativity for smooth muscle
markers, are useful criteria for the diagnosis of endome-
trial stromal sarcoma.10,11,15,47–49 However, it is important to
keep in mind that myxoid LMSs may show lesser degrees
of positivity for smooth muscle markers than conventional
LMS and that U-SMT in general and LMS in particular
frequently express CD10.50
Intravenous Leiomyomatosis Versus Myxoid LMS.
Although LMS can show prominent intravascular growth
similar to that encountered in intravenous leiomyomatosis
with myxoid change,51 the presence of a fleshy myometrial
mass, any degree of cytologic atypia, and mitotic index is
indicative of LMS.2,10,12,24,51,52
3. Epithelioid LMS
This LMS subtype is defined by the finding of rounded
to polygonal cells in more than 50% of the tumor.53–55
Grossly, epithelioid U-SMTs may lack a whorled cut sur-
face and may have a softer and tan cut surface compared
with conventional SMTs. On microscopic examination, the
epithelioid cells have round nuclei and eosinophilic (in ap-
proximately 75% of cases) and less frequently vacuolated
or clear cytoplasm.53,55–57 Tumoral cells often show a dif-
fuse growth pattern (Figure 8, a) but can also be disposed
in clusters or anastomosing cords and trabeculae, with a
varying degree of hyalinization or edema in the back-
ground stroma (Figure 8, b).53,55,57,58 Even though in the
past these tumors were designated based on their micro-
scopic appearance as leiomyoblastoma,53,59 clear cell, and
plexiform epithelioid SMTs,53 we prefer to use epithelioid
U-SMT as a unifying term to avoid possible confusion.
The term plexiform tumorlet is only used for tumors with a
plexiform architecture that measure more than 1 cm.53,60,61
As epithelioid U-SMTs are infrequent, criteria predictive
of malignant behavior are less well established than for
conventional LMS. In the four largest reported se-
ries,53,55,57,62 criteria applied to define an epithelioid SMT
as malignant are
1. Any degree of cytologic atypia and 5 or more mitoses
per 10 HPFs in the absence of tumor cell necrosis.
2. Five or more mitoses per 10 HPFs and tumor cell
necrosis with any degree of cytologic atypia.
Arch Pathol Lab Med—Vol 132, April 2008
In addition, some authors considered that an epithelioid
U-SMT more than 5 cm in diameter with at least moderate
pleomorphism and a mitotic index of 1 or more mitoses
per 10 HPFs or tumor cell necrosis should be classified as
epithelioid SMT of low-malignant potential.1,23 Thus, as a
general rule, extensive sampling in any unusual SMT is
very important to be able to unmask these features.24
Differential Diagnosis
Primary poorly differentiated endometrial or metastatic
carcinoma, PEComa, uterine tumor resembling an ovarian
sex cord–like tumor, tumors derived from intermediate
trophoblast (placental site trophoblastic tumor and epithe-
lioid trophoblastic tumor), and melanoma are the main
entities to be considered in the differential diagnosis of
epithelioid U-SMTs. Rarely, epithelioid endometrial stro-
mal sarcoma, alveolar soft part sarcoma, epithelioid an-
giosarcoma, pleomorphic rhabdomyosarcoma, or rhab-
doid tumor may enter in this differential diagnosis.10,11,24
Poorly Differentiated Carcinoma (Primary or Meta-
static) Versus Epithelioid LMS. Cells in epithelioid LMS
show a cohesive growth, abundant cytoplasm, and round
nuclei and may display a signet-ring cell appearance, fea-
tures that overlap with those seen in poorly differentiated
carcinomas.10,63 Most carcinomas, however, exhibit, at least
focally, glandular or squamous differentiation, the differ-
ential diagnosis being more problematic in a biopsy or
curettage specimen, as foci of typical carcinoma may not
have been sampled. Finally, when an epithelioid U-SMT
shows striking plexiform architecture, the appearance
may closely imitate the ‘‘indian-file’’ growth characteristic
of metastatic breast carcinoma, more often lobular type.24,64
Immunohistochemical studies may be helpful, especially
using a panel of antibodies rather than a single antibody,
as epithelioid U-SMTs are frequently positive for cytoker-
atins and epithelial membrane antigen (EMA)65 and ex-
press less frequently muscle markers compared with con-
ventional LMS.10,11,5064
Potential Pitfalls
● Diffuse cohesive architecture with scant intervening
stroma.
● ‘‘Cordlike’’ pattern simulating metastatic breast carci-
noma.
● Frequent positivity for keratin and EMA.
● Negative staining for smooth muscle markers.
Helpful Clues
● Extensive sampling allows identification of foci of well-
differentiated carcinoma.
● Exclusive positivity for epithelial markers.
PEComa Versus Epithelioid LMS. The perivascular
epithelioid cell tumor (PEComa) is a relatively newly de-
scribed low-grade mesenchymal tumor first described in
the uterus by Pea and colleagues66 in 1996. It belongs to
the family of lesions that originate from the perivascular
epithelioid cell (PEC). The PEC has abundant clear to eo-
sinophilic granular cytoplasm and shows positive staining
for melanocytic markers with variable expression of
smooth muscle markers.66,67 The tumor shows a particular
association with lymphangiomyomatosis and tuberous
sclerosis.67–70 PEComa usually presents as a solitary mass
that may either be well circumscribed or show infiltrative
growth, as it may occur in epithelioid LMS.67,69–71 On mi-
croscopic examination, PEComas show overlapping fea-
Smooth Muscle Tumors of the Uterus—Toledo & Oliva 601
tures with epithelioid U-SMTs, as they have cells with
abundant clear or eosinophilic cytoplasm and round to
oval nuclei arranged in sheets, small solid nests, or cords
separated by scant hyalinized stroma (Figure 9, a).67,69,72,73
Spindled areas can also be seen with the cells having elon-
gated nuclei.67,69 Furthermore, recent studies have shown
expression of HMB-45 in uterine tumors, including LMs,
epithelioid LMSs, and even in normal myometrium.54,58,72,74
Because of these overlapping histologic and immunohis-
tochemical features, there has been some debate in the lit-
erature about the origin of PEComa. While some authors
agree that PEComa is a true entity,67,69,70,72 other investi-
gators argue that it belongs in the category of SMTs.54,58,73–75
Features that will favor the diagnosis of PEComa over an
epithelioid U-SMT include the association with tuberous
sclerosis and lymphangiomyomatosis,67–69 the presence of
multinucleated giant cells and ‘‘spiderlike’’ cells in PE-
Coma,67 and the expression of HMB-45 (Figure 9, b), Me-
lan A, and MiTF.67,72
Potential Pitfalls
● Epithelioid cells and diffuse growth.
● Focal spindle cell component.
● Thick blood vessels.
● Positivity for smooth muscle markers.
Helpful Clues
● Delicate capillary network absent in epithelioid SMT.
● Presence of multinucleated giant cells and spiderlike
cells laking in epithelioid U-SMTs.
● HMB-45 but not Melan A expressed in epithelioid
U-SMTs.
● Frequent keratin and EMA expression in epithelioid
U-SMTs but none in PEComa.
Uterine Tumor Resembling an Ovarian Sex Cord Tu-
mor Versus Epithelioid LMS. Uterine tumors resem-
bling ovarian sex cord tumors (UTROSCT) are rare stro-
mal tumors showing massive sex cord–like differentia-
tion.76 On gross examination they may resemble an epi-
thelioid U-SMT due to their yellow cut surface and soft
consistency. On microscopic examination, the neoplastic
cells show an epithelioid appearance with indistinct eo-
sinophilic (sometimes vacuolated) cytoplasm and oval to
round nuclei and grow in tight nests, cords, and sheets76
(Figure 9, c). Sometimes, spindle-shaped cells are present,
and the stroma is generally sparse with some hyaline
strands, features closely mimicking the appearance of ep-
ithelioid U-SMT.76–78 Furthermore, up to one third of
UTROSCTs express smooth muscle markers, and they also
express epithelial markers, including keratin in up to 50%
and EMA in 10% of cases,78,79 a coexpression pattern also
observed in epithelioid U-SMTs. However, the overall de-
gree of epithelial differentiation in most UTROSCTs is
more pronounced than in epithelioid U-SMTs, with tu-
bular formation, retiform differentiation, or prominent
vacuolated cytoplasm, as seen in the luteinized cells of sex
cord stromal tumors of the ovary. The absence of sex cord
stromal markers (inhibin and calretinin; Figure 9, d) in
epithelioid LMS is helpful in this differential diagno-
sis.50,76–80
Potential Pitfalls
● Nests, cords, and trabeculae with minimal intervening
stroma.
● Positivity for epithelial and smooth muscle markers.
602 Arch Pathol Lab Med—Vol 132, April 2008
Helpful Clues
● Architectural patterns resembling sex cord stromal tu-
mors of the ovary.
● No clearcut spindle component.
● In approximately half of cases, positivity for inhibin,
calretinin, or Mart-1.
Placental Site Trophoblastic Tumor and Epithelioid
Trophoblastic Tumor Versus Epithelioid LMS. Malig-
nant trophoblastic neoplasms of the intermediate tropho-
blast are typically seen in reproductive-age women with
history of a recent pregnancy.81 Microscopically, placental
site trophoblastic tumors (PSTTs) and epithelioid tropho-
blastic tumors (ETTs) are composed of mononucleated
round or polyhedral intermediate trophoblastic cells with
abundant eosinophilic to clear cytoplasm frequently as-
sociated with a diffuse or nested growth (Figure 9, e).81,82
Features favoring a diagnosis of trophoblastic tumor in-
clude history of recent pregnancy or abortion and an el-
evated serum human chorionic gonadotropin level,83 an
infiltrative growth of single cells or small aggregates of
cells dissecting individual muscle fibers (PSTT; Figure 9,
e), prominent vascular involvement with associated fibri-
noid change (PSTT),82 islands or nests of cells surrounded
by extensive necrosis or a hyaline-like matrix (ETT),84 as
well as immunoreactivity for inhibin (Figure 9, f), human
placental lactogen, and p63 (ETT), with negativity for
smooth muscle markers.11,85–89
Potential Pitfalls
● Infiltrative growth (PSTT).
● Positivity for epithelial markers.
Helpful Clues
● Relevant clinical history.
● Prominent vascular replacement (PSTT).
● Prominent hyaline-like matrix (ETT).
● Positivity for inhibin and human placental lactogen.
Endometrial Stromal Sarcoma Versus Epithelioid
LMS. Cells with abundant dense eosinophilic cytoplasm
have been rarely described in endometrial stromal tumors,
and this finding may lead to favor strongly the diagnosis
of an epithelioid U-SMT, especially in small samples.90 In
these cases, the morphologic and immunohistochemical
features described above in the differential diagnosis be-
tween myxoid stromal sarcoma and LMS can be ap-
plied.50,90 Another potentially helpful feature is that epi-
thelioid LMS exhibit more cytologic atypia than that typ-
ically present in endometrial stromal sarcomas.
Metastatic Melanoma Versus Epithelioid LMS. Al-
though unusual, metastatic melanoma from other genital
or extragenital sites could involve the uterus91,92 and
should always be in the differential diagnosis of an epi-
thelioid neoplasm. Positivity for S100, HMB-45, and Mart-
1, and negative expression of smooth muscle markers will
favor the diagnosis of melanoma.11
Alveolar Soft Part Sarcoma Versus Epithelioid LMS.
Although alveolar soft part sarcoma of the female genital
tract is uncommon, the presence of cells with abundant
pale cytoplasm with a solid or nested growth may resem-
ble an epithelioid U-SMT.93 However, a typical alveolar
growth and PAS-positive diastase-resistant granules and
crystals are not seen in epithelioid U-SMTs, whereas al-
veolar soft part sarcoma rarely shows a spindle cell com-
ponent.94 Immunohistochemical stains for smooth muscle
markers are of no help, as both tumors are positive, the
Smooth Muscle Tumors of the Uterus—Toledo & Oliva
Figure 9. a, PEComa. Nests of epithelioid clear cells are separated by delicate collagenous septa. b, The tumor cells show diffuse and strong
HMB-45 expression. c, Uterine tumor resembling an ovarian sex cord tumor. A predominant solid growth pattern mimics an epithelioid smooth
muscle tumor. d, The tumor cells are positive for inhibin. e, Placental site trophoblastic tumor. Sheets of round cells with eosinophilic cytoplasm
diffusely infiltrate the myometrium. f, The tumor cells show intense immunoreactivity with inhibin (hematoxylin-eosin, original magnifications
⫻200 [a and c] and ⫻100 [e]; immunostain, original magnifications ⫻100 [b, d, and f]).

Arch Pathol Lab Med—Vol 132, April 2008 Smooth Muscle Tumors of the Uterus—Toledo & Oliva 603
most helpful marker being TFE3, which is only expressed
in alveolar soft part sarcoma.80,95
Rhabdoid Tumors and Epithelioid LMS. Some epi-
thelioid LMSs exhibit a rhabdoid phenotype,24 which
should be distinguished from pure rhabdoid tumors, pleo-
morphic rhabdomyosarcomas, or even angiosarcomas of
the uterus with an epithelioid morphology.37,38,96 Immu-
nohistochemistry may be needed in this differential di-
agnosis.38,57,97
GENERAL RECOMMENDATIONS
● Extensive sampling is recommended for any U-SMT
with unusual gross appearance (at least one section per
centimeter).
● The diagnostic criteria for malignancy vary for the dif-
ferent subsets of LMS, but they always include mitotic
index, cellular atypia, and presence of tumor cell necro-
sis.
● Diagnostic criteria to establish the diagnosis of LMS
should be strictly applied.
● Diagnosis of conventional (spindle) LMS is established
when any 2 of the following 3 criteria are present: (1)
diffuse moderate to marked cytologic atypia, (2) mitotic
rate of 10 or more mitoses per 10 HPFs, and (3) tumor
cell necrosis.
● Diagnosis of myxoid LMS is established when there is
(1) severe cytologic atypia and/or tumor cell necrosis
with any mitotic index or (2) 2 or more mitoses per 10
HPFs in the absence of atypia or tumor cell necrosis.
● Diagnosis of epithelioid LMS is established when there
is (1) any degree of cytologic atypia and 5 or more mi-
toses per 10 HPFs in the absence of tumor cell necrosis
or (2) 5 or more mitoses per 10 HPFs and tumor cell
necrosis with any degree of cytologic atypia.
● Always exercise caution in reaching a definitive diag-
nosis of malignancy in a curettage specimen or intra-
operative consultation.
● Clinical information plays an important role (pregnancy
or menstrual status, exogenous intake of hormones, oth-
ers) in the final pathologic interpretation.
● A panel of antibodies rather than a single antibody
should be used when the differential diagnosis is be-
tween U-SMTs and their mimics.
Gemma Toledo was supported by a grant from the Spanish
Ministry of Health (FIS: BAE 06/90009).
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