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REVIEW ARTICLE

Uterine Smooth Muscle Tumors Other Than the Ordinary


Leiomyomas and Leiomyosarcomas: A Review of Selected
Variants With Emphasis on Recent Advances and Unusual
Morphology That May Cause Concern for Malignancy
Philip P. C. Ip, MBChB, FRCPath,* Ka Yu Tse, MBBS, MRCOG,w
and Kar Fai Tam, MBBS, MRCOGw

Abstract: Uterine smooth muscle tumors are classied according to


their morphologic features that include architecture, growth pattern,
cellular characteristics and constituents of the intercellular stroma.
While terminologies used for the pathologic diagnosis of various
subtypes may be eloquent and histologically accurate, some of these
are confusing for the clinician and may also be open to interpretation
by dierent pathologists: the labeling of atypical leiomyomas epitomizes this intricate system. Clinically, it is probably more useful to
classify them as either tumors with or tumors without recurrent
and/or metastatic potential. The term atypical leiomyoma has been
used to label tumors that have a low risk of recurrence and is
synonymous with benign tumors. The latter are known variously as
leiomyoma with bizarre nuclei, symplastic leiomyoma, or pleomorphic leiomyoma. Variants of benign uterine smooth muscle tumors,
such as mitotically active leiomyoma, cellular and highly cellular
leiomyoma, epithelioid leiomyoma, and myxoid leiomyoma each
have distinctive hallmarks that enable subclassication. Nevertheless,
they may occasionally possess one or more unusual features that are
cause for alarm. Tumors that have a dissecting growth pattern, with
or without extrauterine extension, may mimic malignancy both
grossly and microscopically. The current review discusses the pathologic diagnosis of and terminology applied to selected variants of
uterine smooth muscle tumors other than the ordinary leiomyomas
and leiomyosarcomas with emphasis on unusual reported features
that may indicate malignancy. This includes an update on uterine
smooth muscle tumor of uncertain malignant potential (STUMP),
intravenous leiomyomatosis, benign metastasizing leiomyoma, and
diuse leiomyomatosis. Their clinicopathologic features, dierential diagnoses, and management options based on ndings in the
previously reported cases will also be reviewed.
Key Words: leiomyoma, uterine smooth muscle tumor of uncertain
malignant potential, STUMP, atypical leiomyoma, epithelioid
leiomyoma, myxoid leiomyoma, mitotically active leiomyoma, cellular
leiomyoma, dissecting leiomyoma, cotelydonoid dissecting leiomyoma, intravenous leiomyomatosis, benign metastasizing leiomyoma, diuse leiomyomatosis

(Adv Anat Pathol 2010;17:91112)

terine smooth muscle tumors are classied according to


their pathologic features.1,2 Most diagnostic terminologies accurately reect the morphology of the lesions, but they
From the Departments of *Pathology; and wObstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong
Kong SAR.
Reprints: Philip P. C. Ip, MBChB, FRCPath, Department of Pathology,
The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam
Road, Hong Kong (e-mail: philipip@pathology.hku.hk).
All gures can be viewed online in color at http://www.anatomicpathology.com.
Copyright r 2010 by Lippincott Williams & Wilkins

Adv Anat Pathol

Volume 17, Number 2, March 2010

provide little relevant clinical details or prognostic information to guide postoperative management. An example of
this includes the mitotically active leiomyoma in which the
high proliferative rate alone has little impact on the recurrence potential.35 The term atypical leiomyoma is even
more confusing; it is used by some to label smooth muscle
tumors with a low risk of recurrence,2 but for others, it is
used interchangeable with a benign tumor containing microscopically atypical cells that are clinically inconsequential.6
Clinically, it is probably more useful to classify them as
tumors with or without (or little) recurrent and/or
metastatic potential. A summary is listed in Table 1.

UTERINE SMOOTH MUSCLE TUMORS WITH


RECURRENT AND/OR METASTATIC POTENTIAL
Uterine Smooth Muscle Tumor of Uncertain
Malignant Potential (STUMP): Standard
(Spindle Cell) Smooth Muscle Differentiation
Description and Terminology
The World Health Organization classication indicates that a uterine smooth muscle tumor that cannot be
diagnosed unequivocally as benign or malignant should be
termed smooth muscle tumor of uncertain malignant potential
(STUMP).1 The current approach to diagnosis was derived
by the Stanford investigators after studying 213 cases of
problematic uterine smooth muscle tumors.2 In that study,
although they did not use the term STUMP, they delineated 4 histologic subgroups of uterine smooth muscle
tumors that had a low or uncertain malignant potential: (1)
atypical leiomyoma with limited experience, if the tumor
showed focal or multifocal moderate-to-severe atypia,
r10 mitotic gures (MFs)/10 high power elds (HPFs) and
no tumor cell necrosis; (2) smooth muscle tumor with low
malignant potential, if the tumor showed tumor cell
necrosis, but absent-to-mild atypia and <10 MFs/10 HPFs;
(3) atypical leiomyoma with low risk of recurrence, if
there was diuse moderate-to-severe atypia, <10 MFs/
10 HPFs, and no tumor cell necrosis; and (4) mitotically
active leiomyoma with limited experience, if the only
worrisome feature is a mitotic count of Z20/10 HPFs.2,7,8

Clinical Features
Patients with STUMPs present with the same clinical
picture as those with ordinary leiomyomas which include
abnormal vaginal bleeding, anemic symptoms, pelvic mass,
pressure symptoms, or combinations thereof. Although the
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TABLE 1. Classification of Uterine Smooth Muscle Tumors Other


Than Ordinary Leiomyomas and Leiomyosarcomas According to
Their Behavior
Recurrent and/or metastatic potential
 Uterine smooth muscle tumor of uncertain malignant
potential (STUMP)
Standard (spindle cell) smooth muscle dierentiation
Epithelioid or myxoid dierentiations
 Intravenous leiomyomatosis
 Benign metastasizing leiomyoma
Little or no recurrent and/or metastatic potential
 Leiomyoma with bizarre nuclei (bizarre/symplastic/atypical
leiomyoma)
 Mitotically active leiomyoma
 Cellular and highly cellular leiomyoma
 Dissecting leiomyoma, cotelydonoid dissecting leiomyoma,
and cotelydonoid leiomyoma
 Myxoid leiomyoma
 Epithelioid leiomyoma
 Diuse leiomyomatosis

age at presentation is similar to those with leiomyosarcomas and benign leiomyomas,9 patients diagnosed with
STUMP and a subsequent recurrence appear to be younger
than those with an uneventful follow-up. In two studies, the
mean age of patients with recurrent disease was 44.5 and
33.7 years, respectively, compared with 47.5 and 43.9 years
in those without.7,10

Pathologic Diagnosis of STUMP


The histologic diagnosis of malignant uterine smooth
muscle tumors is usually based on the Stanford criteria,
as noted above. This involves an assessment of a combination of three histologic features, including atypia, mitotic
rate, and type of necrosis.1,2 A leiomyosarcoma usually
exhibits diuse moderate-to-severe atypia, a mitotic count
of Z10 MFs/10 HPFs, and tumor cell necrosis. A tumor
with any 2 of these features is clinically malignant often
enough to warrant a diagnosis of leiomyosarcoma. As the
Stanford study2 was the rst to appreciate that the type of
necrosis in a uterine SMT was of crucial importance;
studies that preceded it did not evaluate the presence or
absence of tumor cell necrosis.
If a tumor shows any unusual combinations of the 3
features that do not satisfy the Stanford criteria for leio-

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myosarcoma,2 a diagnosis of uterine smooth muscle tumor


of uncertain malignant potential (STUMP) is appropriate.1
Examples of such ambiguity include presence of borderline
mitotic count (around 8 or 9 per 10 HPFs) in a tumor
with moderate-to-severe atypia and absence of tumor cell
necrosis7; uncertainty of the type of necrosis, that is, whether
it is the bad type (tumor cell necrosis) or the good type
(hyaline or infarct type) found in a tumor lacking atypia or
mitotic activity.7,11 Cases with dierent combinations that
have been classied as STUMPs are listed in Table 2,
although it is not exhaustive. Other investigators have
included tumors with any other unusual histologic features,
although the number of such cases reported is too small, and
their true recurrence rate is unknown.

The Controversy of Atypical Leiomyoma


The use of the term atypical leiomyoma is not
universal among pathologists, and the natural history of
such tumors remains controversial. Histologically, tumors
that fall into this category are those with diuse or multifocal moderate-to-severe atypia and no tumor cell necrosis.
Tumors with these features, and <10 MFs/10 HPFs are
regarded by the Stanford investigators as atypical
leiomyomas with low risk of recurrence2,8; 2 of 50 such
tumors have been reported to recur after 2 and 9 years of
follow-up, respectively.2,15 Other investigators consider tumors
with similar cytologic features, but mitotic counts at the lower
end of this spectrum, on average <2 MFs/10 HPFs, a benign
variant of leiomyoma known as bizarre leiomyomas. We
prefer the term leiomyomas with bizarre nuclei (LBNs) (see
subsequent section on leiomyoma with bizarre nuclei). Of
the 24 reported cases of bizarre leiomyomas, none recurred
after a mean follow-up of 11.2 years.6
In a more recent study, the Stanford investigators
reported 46 additional cases of atypical leiomyomas, 4 of
which recurred. None of these tumors, including those that
recurred, had a mitotic count more than 3 per 10 HPFs.13
This nding raises the possibility that the upper limit of
the number of mitotic gures in LBNs is dicult to dene.
It may justify the inclusion of LBNs with any mitotic
activity in the category of atypical leiomyomas, as
dened in the current World Health Organization (WHO)
classication.1
The varying outcomes for patients, who have almost
pathologically identical atypical leiomyomas, may be
partly explained by the subjective assessment of cytologic

TABLE 2. Histologic Subclassification of Uterine STUMP

Atypia

MF

Tumor Cell
Necrosis

Focal/multifocal,
moderate to severe
Diuse,
moderate to severe
None-to-mild
None
None
Diuse/multifocal,
moderate to severe

r10

None

4 of 23 (17.4)7,9,12

<10

None

2 of 50 (4)2,15

<10
Z15*
Z10
Borderline,
or Uncertain

Present
None
Uncertain
None

Histologic Subtype
AL-LE2,7
AL-LRR2,7
SMT-LMP2,7
MAL-LE2,7
Unnamed STUMP
Unnamed STUMP

Cases Recurred
in Literature (%)

4 of 15 (26.7)2,9,14
0 of 3 (0)2,7
No report
No report

*indicates Z20 used originally in Bells study,2 see also Ip.7


AL-LE indicates atypical leiomyoma with limited experience; AL-LRR, atypical leiomyoma with low risk of recurrence; borderline, 8 or 9 per 10 high
power elds; MAL-LE, mitotically active leiomyoma, limited experience; MF, mitotic count per 10 high power elds; SMT-LMP, smooth muscle of low
malignant potential; STUMP, smooth muscle tumor of uncertain malignant potential.

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FIGURE 1. Leiomyoma with bizarre nuclei. The tumor cells have


eosinophilic cytoplasm and bizarrely shaped, multilobated or
multinucleated nuclei. The chromatin is often smudged and
often has cytoplasmic pseudoinclusions.

atypia and mitotic count. The microscopic description of


bizarre tumor cells by the Stanford investigators2 and
Downes and Hart6 in their respective papers, are almost
identical. The former consider these as malignant, whereas
the latter consider these as degenerative. It would be
extremely dicult to condently distinguish malignant
from degenerative by light microscopic examination of
these cells alone, when in fact, the cellular morphology is
equally ominous in atypical leiomyomas with low risk of
recurrence and LBNs (Figs. 1, 2). For LBNs, although the
bizarre cells are said to array against a background of more
uniform, bland myoma cells, atypical leiomyomas that were
followed by a recurrence have often been noted to have
these cells scattered multifocally in a background of tumor
cells lacking atypia.7 Bizarre cells have been shown to have
increased global methylation of DNA suggesting that the
bizarre nuclear atypia may represent abundant heterochromatin with associated inactivated DNA.16 This observation was nonetheless made in LBNs with benign outcome; it
would be useful to carry out DNA methylation studies in
atypical leiomyomas that were followed by a recurrence.
The most important feature that distinguishes an atypical
leiomyoma with low risk of recurrence (or STUMP) from a
LBN is the mitotic count. Reliable mitosis counting in such
tumors is nonetheless dicult and subjective. As both the
nuclear pyknosis and the karyorhexis are common ndings
in LBNs,6 the degenerating nuclei undergoing apoptosis
may have an appearance that mimics a mitotic gure, so-called
pseudoatypical mitosis (Fig. 3).7,17 The use of immunohistochemical markers to conrm a true mitotic gure is
thus helpful. Phosphohistone H3 is a recently described
r

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Uterine Smooth Muscle Tumors

FIGURE 2. Atypical leiomyoma with low risk of recurrence (smooth


muscle tumor of uncertain malignant potential). The tumor cells are
equally bizarre as those in leiomyoma with bizarre nuclei; additionally, there are more than 2 to 9 mitotic figures per 10 high power
fields, and sometimes including atypical mitoses (centre).

FIGURE 3. Leiomyoma with bizarre nuclei. Degenerating nuclei


may have an appearance that mimics a mitotic figure, so-called
pseudoatypical mitosis.

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?, Liver
?, Liver
LMS, 4 years, pelvis
STUMP, 60 months, within uterus and at
84 months, omentum
Yes
Yes
Yes
Yes
1
4
3
3
1
1
None
1
NA
NA
Increased
Increased
SMT-LMP NA
SMT-LMP NA
SMT-LMP 48
SMT-LMP 31
Atkins, no. 29
Atkins, no. 39
Amant14
Bell, no. 212

NA
NA
7
NA

AL-LE
AL-LE
AL-LE
AL-LE
AL-LRR
AL-LRR
Ip, no. 17
Ip, no. 37
*Atkins, no. 19
Shapiro12
Berretta, no. 315
Bell, no. 132
r

*Additional unusual feature, including inltrative border.


wAtypical mitoses.
Atypia: 0 indicates none; 1, mild; 2, moderate; 3, severe; AL-LE, atypical leiomyoma with limited experience; AL-LRR, atypical leiomyoma with low risk of recurrence; ANED, alive with no evidence of disease;
AWD, alive with disease; GnRH-a, gonadotropin-releasing hormone analogue; LMS, leiomyosarcoma; MF, mitotic count per 10 high power elds; NA, Not available; SMT-LMP, smooth muscle of low malignant
potential; STUMP, smooth muscle tumor of uncertain malignant potential.

AWD (?)
?
ANED (48)
AWD (84)

ANED
ANED
ANED
AWD
AWD
AWD

Radiotherapy
Chemotherapy
Progesterone
None
GnRH-a
Chemotherapy and
radiotherapy
?
?
Medroxyprogesterone
None
LMS, 51 months, pelvis
LMS, 15 months, pelvis and lymph nodes
Unknown, pelvis and lymph nodes
LMS, 51 months, bone and at 68 months, lung
STUMP, 9 years, lung
Unknown, 24 months, abdomen and pelvis
None
None
None
None
None
None
Multifocal, 2-3
4
Multifocal, 2-3
5
1-2
3
Multifocal, 2-3 15
2-3
<10
Diuse, 3
2w
Increased
Increased
Increased
Increased
NA
Increased

Recurrence Type, Interval


to Recurrence, Site(s)
Tumor Cell
Necrosis
MF
Atypia
Stanford
Scheme2

Size
Age (cm) Cellularity

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Source,
Case No. (ref)

Comparison of dierent studies of STUMPs is dicult because of diering and evolving diagnostic criteria
(as noted above); classication schemes of studies predating that of Bell et al in 1994 did not evaluate tumor cell
necrosis,2325 whereas other studies have scant information
about detailed pathologic features of individual cases and/
or follow-up information.26,27
Studies of STUMPs followed by recurrence are rare.
An evaluation of all published studies that used the same
diagnostic criteria for STUMPs as dened by the Stanford
investigators,2 and in which there were sucient clinical
follow-up information and pathologic details for comparison, reveals a recurrence rate of approximately 11% (10 of
91 cases) (Table 2).2,7,9,12,14,15 A more recent study by
the same investigators revealed a recurrence rate of 8.7%
(4 of 46) in patients with atypical leiomyomas after a mean
follow-up of 42 months.13 The incidence of recurrence in 2
other studies that used dierent diagnostic criteria was
7.3% (3 of 41 cases) and 26.7% (4 of 15 cases).10,25 Nonetheless, it may be dicult to interpret the recurrence rate
from a large group of patients in a single study, when the
denition of STUMP is so variable.
It is conceivable that some tumors regarded as
STUMPs are underdiagnosed leiomyosarcomas. Alternatively, others may be variants of leiomyomas with unusual
pathologic features. Emerging evidence has shown that
STUMPs that recur likely represent a form of borderline
tumor or a low-grade leiomyosarcoma.7 Despite applying
the Stanford 3-feature criteria, it is not always possible to
predict whether a STUMP will recur until a recurrence has
developed. Recent studies have suggested the use of immunohistochemical stains, including p16, p53, MIB-1, Twist, bcl-2,
estrogen and progesterone receptors to identify uterine
smooth muscle tumors with a higher risk of recurrence.7,9,2731
Although tumors regarded as STUMPs with recurrence are
associated with diuse immunoreactivity for p16 and p53,7,9,30
the number of cases in these studies are small, and further
study is required to conrm the reliability of employing such
markers.
In patients with a high-grade leiomyosarcoma, the
clinical course is often aggressive with early recurrence
and metastases. In contrast, in those with STUMPs, tumor
growth is slower and recurrence is often delayed, on
average, 51 months (range 15 to 108 mo) after the initial
diagnosis.2,7,9,12,14,15 The clinical course is often prolonged
with a median survival of 61.5 months (range 40 to 108 mo)
(Table 3).

TABLE 3. Clinicopathologic Features, Treatment, and Follow-up Data of Uterine STUMPs With Recurrence

Behavior and Frequency of Recurrence

4
5.8
NA
4
10
NA

Additional Treatment for


STUMP Recurrence

Outcome
(mo)

immunohistochemical marker that specically identies


cells undergoing mitoses. Rapid identication of mitoses
has been reported in breast carcinomas,18 ovarian serous
adenocarcinomas,19 meningiomas,20 and astrocytomas21 in
which an accurate mitotic count is crucial. Phosphohistone
H3 has recently been shown to be a more sensitive and
reliable marker for highlighting true mitotic gures in uterine
smooth muscle tumors.22
Irrespective of the ongoing debate that surrounds
labeling of these atypical leiomyomas, on a practical level,
it is more important for the clinician to clarify with the
pathologist whether the atypical uterine smooth muscle tumor
represents a benign tumor (LBN) or a STUMP, as these are
managed quite dierently.

(74)
(40)
(36)
(68)
(>108)
(60)

Adv Anat Pathol

50
39
NA
46
33
47

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Volume 17, Number 2, March 2010

Proposed Follow-up Plan


A paucity of cases means there is limited experience on
which to base standard guidelines for follow-up. On the
basis of the ndings discussed here, the follow-up interval
for patients who have STUMP diagnosed in hysterectomy
specimens should probably be a minimum of every 6 months
until the 5th year and, thereafter, annual surveillance for a
further 5 years. Each visit should include symptom checking and a general and pelvic examination. Imaging studies
should be conducted at least once a year; chest X-ray
should be done to exclude metastasis; pelvic ultrasound
scan, computed tomography or magnetic resonance imaging may be used to detect any new lesions. For STUMPs
diagnosed in myomectomy specimens, hysterectomy should
be the treatment of choice for those who have completed
their family, as recurrent uterine tumors have been reported.13 These patients should be followed-up postoperatively
as suggested earlier. For those who wish to preserve fertility,
successful pregnancy after myomectomy have been described,13 but these patients should be informed of the
likelihood of recurrence and be followed-up vigilantly with
imaging studies.

Treatment for Recurrent STUMP


STUMPs may recur as STUMPs2,10,15 or as leiomyosarcomas.7,10,12,14 The treatment of choice for recurrence is
surgical excision with the majority of patients prescribed
some form of single or combined additional therapy, such
as pelvic irradiation,2,7 chemotherapy (such as doxorubicin
and cisplatin),2,7,10 medroxyprogesterone,9,10,14 and gonadotropin-releasing hormone analogue (Table 3).15 Additional
therapy seems to be eective, although in its absence,
patients have also been reported to have an uneventful
clinical course.2,12

Smooth Muscle Tumor of Uncertain Malignant


Potential: Epithelioid and Myxoid
Differentiations
Malignant smooth muscle tumors with epithelioid or
myxoid dierentiation are less common than their spindle
cell counterpart, and the diagnostic criteria predictive of
malignancy are less well established. Malignant tumors
of these dierentiations usually show a lesser degree of
cytologic atypia and lower mitotic counts required for a
diagnosis of leiomyosarcoma compared with the spindle
cell type. For example, in epithelioid smooth muscle tumors
with moderate-to-severe atypia, a mitotic count of more
than 5 per 10 HPFs is sucient for the diagnosis of epithelioid
leiomyosarcoma32; similarly, for myxoid leiomyosarcoma,
the presence of as few as more than 2 MFs/10 HPFs in
tumors devoid of atypia or tumor cell necrosis is often
sucient to justify a diagnosis of malignancy.33
Owing to their rarity, STUMPs of either epithelioid or
myxoid dierentiation have not been specically studied,
and the behavior of these lesions is virtually unknown.
Currently, as for their spindle cell counterpart, there are
no universally accepted criteria for the diagnosis of epithelioid STUMP, and none so-far have been described for the
myxoid variant. The proposed criteria for epithelioid STUMP
are tumors with 2 or more of the subsequent features: size
more than 6 cm, 2 to 4 MFs/10 HPFs, moderate-to-severe
atypia, and tumor cell necrosis.1 For myxoid STUMP, the
possible criteria for making such a diagnosis include nding
of necrosis of an uncertain type and/or inltrative border in
r

2010 Lippincott Williams & Wilkins

Uterine Smooth Muscle Tumors

a myxoid smooth muscle tumor without mitotic activity or


nuclear atypia.

Intravenous Leiomyomatosis
Description and Terminology
Intravenous leiomyomatosis (IVL) is dened as intravascular proliferation of a benign-appearing smooth muscle
tumor in the absence of, or beyond the connes of a leiomyoma. Almost all the involved vessels are veins, or rarely,
lymphatics. Intraarterial growth has not been described.34
IVL should be distinguished from leiomyoma with
vascular invasion. The latter refers to microscopic intravascular growth conned to an ordinary leiomyoma that is
usually clinically inconsequential, although there are apparently no large series with long-term follow-up. Occasional
cases of leiomyoma with vascular invasion have been
associated with benign metastasizing leiomyoma, whereas
others may represent an early stage of an IVL.35

Typical Clinical and Pathologic Features


Most patients with IVL are of reproductive age,
although some cases in older patients in their eighties have
been described.34 The majority presents with symptoms
similar to those with ordinary leiomyomas. Some may present
with recurrent leiomyomas after repeated myomectomies.36
A minority of patients initially present with symptoms
related to cardiovascular involvement.
IVL may be suspected intraoperatively, when wormlike or nodular plugs are found in pelvic veins in descending
order of frequency: broad ligament, uterus, ovaries, and
vagina. Rarely, involvement of the inferior vena cava is identied during hysterectomy. Extrauterine involvement occurs
in approximately 30% of cases, discovered either intraoperatively or by postoperative imaging studies after a pathologic diagnosis of IVL. In some cases the clinical impression
during an operation can be leiomyosarcoma with vascular
involvement.34,37 Rarely, they are discovered many years
after hysterectomy.
IVL is usually diagnosed after pathologic examination
of uterus.38 A uterus aected by IVL is typically enlarged
and heavy, and the serosa is often bosselated. Typically, the
myometrium is aected by multiple leiomyomas of varying
sizes with IVL found either focally or diusely (Fig. 4A). The
irregular tumorous nodules are often seen as worm-like
plugs protruding from the cut-ends of the myometrial or
broad ligament veins. Similar to ordinary leiomyoma, the
appearance of the tumor in IVL is highly variable: soft and
spongy, rm and rubbery, gelatinous and translucent, even
hemorrhagic and calcied depending on the presence of
edema or degenerative changes (Fig. 4B).34
Microscopically, the intravascular tumor nodules are
found outside the connes of 1 or more leiomyomas and are
surrounded by endothelial cells. They are usually composed
of mitotically inactive spindle cells devoid of cytologic atypia
(Fig. 5). IVL involving the extrauterine vessels or heart may
be free oating within the lumen or adhered to the intima.

Unusual Morphologic Features and Dierential


Diagnoses
IVL may resemble any of the benign variants of
leiomyomas (Table 4). These include cellular leiomyomas,
leiomyomas with bizarre nuclei, myxoid leiomyomas,
epithelioid leiomyomas, and lipoleiomyomas (Fig. 6).34
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FIGURE 4. A, Intravenous leiomyomatosis. Nodules of tumor have distended the parametrial veins. B, The worm-like plugs appearance
of intravenous leiomyomatosis. Note hydropic change in the central tumor nodule. C, Histology (H&E stain) of an epithelioid
intravenous leiomyomatosis with endometrial tissue. The endometrial gland is dilated (arrow). D, Benign metastasizing leiomyoma.
Resected lung segment showing multiple subpleural white-colored tumor nodules. E, Benign metastasizing leiomyoma may undergo
hydropic and/or cystic change. F, Leiomyoma with red degeneration. The beefy red appearance is owing to hemorrhage and infarction.
G, Leiomyoma with bizarre nuclei. The gross appearance may seem to be atypical. H, Leiomyoma with skeletal muscle-like and
rhabdoid cells (H&E stain).

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FIGURE 5. Intravenous leiomyomatosis. The intravascular polypoid tumor has a clefted contour and contains numerous thickwalled blood vessels.

On rare occasions, intravascular endometrial tissue


can be seen. The intravascular tumor may comprise spindle
or epithelioid smooth muscle cells with thick-walled blood
vessels that merge with endometrial glands and stroma
(Fig. 4C).38 Distinction of this intravenous adenomyosis
from endometrial stromal sarcoma with glandular dierentiation may be dicult, as the latter often shows
prominent intravascular growth (Fig. 7).39 Features that
favor an endometrial stromal sarcoma include endometrial
involvement, permeative myometrial invasion by tongues of
extravascular tumor, predominance of endometrial stroma
over smooth muscle, and presence of atypia and high
mitotic activity in the neoplastic endometrial stromal cells.
Cellular IVL is most likely to be confused with an
endometrial stromal sarcoma (Fig. 8). It is distinguished by
the features described in the preceding paragraph (see also
dierential diagnoses on cellular and highly cellular leiomyoma below). The majority of cellular IVLs has absentto-mild atypia, although it may occasionally be moderate.40

Uterine Smooth Muscle Tumors

FIGURE 6. Cellular intravenous lipoleiomyomatosis.

They generally have a mitotic count of 1 or 2 per 10 HPFs,


but may have up to 4 MFs/10 HPFs.38 None of these
features has been associated with more aggressive behavior.

TABLE 4. Morphologic Variants of Intravenous Leiomyomatosis


(IVL)
Cellular IVLbizarre nuclei
IVL with bizarre nuclei
Epithelioid IVL (eosinophilic cell)
Epithelioid IVL (clear cell)
Epithelioid IVL with bizarre nuclei
Myxoid IVL
Intravenous lipoleiomyomabizarre nuclei
IVL with endometrial tissue
IVL as a component of dissecting/cotelydenoid dissecting
leiomyoma

2010 Lippincott Williams & Wilkins

FIGURE 7. Endometrial stromal sarcoma with glandular differentiation. Distinction from intravenous leiomyomatosis with
endometrial tissue (intravenous adenomyosis) may be difficult.

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FIGURE 8. Cellular intravenous leiomyomatosis. Note the presence of thick-walled blood vessels, which helps to distinguish it
from endometrial stromal sarcoma.

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Volume 17, Number 2, March 2010

FIGURE 9. Epithelioid intravenous leiomyomatosis. The tumor is


mitotically inactive and devoid of tumor cell necrosis. Rarely, it
may contain bizarre tumor cells, as seen in leiomyoma with
bizarre nuclei.

IVL with bizarre nuclei is distinguished from leiomyosarcoma by the absence of mitotic gures. Additionally, the
latter do not usually show grossly visible vascular invasion.38
Coard and Fletcher reported a uterine leiomyosarcoma
with unusually striking vascular involvement resembling
IVL (intravenous leiomyosarcomatosis). The extravascular
tumor also had a combination of moderate-to-marked atypia,
more than 10 MFs/10 HPFs and tumor cell necrosis.41
Rarely, an IVL may be myxoid (myxoid IVL).38 Such
diagnosis should nonetheless be cautious, as myxoid
smooth muscle tumors are often hypocellular (see section
on myxoid leiomyoma), and distinguishing myxoid IVL
from myxoid leiomyosarcoma is extremely dicult. Myxoid
IVL should be mitotically inactive and devoid of atypia
with no inltrative myometrial myxoid smooth muscle
tumor elsewhere in the uterus.
Epithelioid IVL should be distinguished from epithelioid
leiomyosarcoma. Although epithelioid IVL may occasionally
contain cells with bizarre nuclei (Fig. 9), the absence of a high
mitotic count and tumor cell necrosis distinguishes it from a
leiomyosarcoma with vascular invasion.
IVL may also coexist or be as a component of dissecting leiomyoma or cotelydonoid leiomyoma (Fig. 10). Extravascular tumors in such cases are often more hydropic.42

Behavior and Frequency of Recurrence


Although histologically benign, IVL can occasionally
recur because of its unusual intravascular growth pattern.
In some cases, it extends into extrauterine pelvic vessels,
and the residual intravascular tumor may continue to grow
very slowly such that recurrence may not appear for years
after hysterectomy. Detection of persistent or recurrent
tumors has been reported to occur between 7 months to 15

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FIGURE 10. Dissecting leiomyoma with intravenous leiomyomatosis. The irregular tumor dissects through the myometrium
associated with 2 small foci of intravascular tumor (arrows).
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years (median, 2.5 y) after hysterectomy.34 In approximately


70% of the patients, the initial presentation was related to
inferior vena cava and cardiac involvement. The remaining patients had a pelvic mass. The risk of recurrence for
IVL is low, likely much less than 5% (personal communication, Dr Philip B. Clement).17 One hospital-based study
of 22 cases of IVL found no cardiovascular recurrence after
a mean follow-up of 7.5 years.37

Management
Treatment of IVL is surgical. If complete excision of
the tumor is not possible, ligation of the vein distal to the
tumor has been suggested to prevent tumor growth along
the inferior vena cava.43 IVL are usually hormone receptor
positive, and because the diagnosis is usually made in a
hysterectomy specimen, subsequent bilateral oophorectomy
is recommended, if it has not already been done.34 It may
be prudent to do a posthysterectomy MRI scan of the pelvis
to check for any residual intravascular tumor followed by
an annual scan for a few years in case there is any residual
microscopic tumor that may continue to grow.44,45
The treatment of recurrent IVL is surgical in which the
extrauterine tumors are removed, when technically feasible.
The use of GnRH-a, tamoxifen, and aromatase inhibitors
has been successful in some cases, in which resection was
not possible.36,4548

Benign Metastasizing Leiomyoma


Description and Terminology
Benign metastasizing leiomyoma (BML) is a condition
in which single or multiple morphologically benign smooth
muscle tumors are found in extrauterine locations, especially the lungs, in women with a history of typical uterine
leiomyomas. BML should only be diagnosed after a uterine
or extrauterine leiomyosarcoma has been excluded, or on
the assumption that any preexistent uterine leiomyoma has
been thoroughly sampled with no histologic evidence of
malignancy.
BML seems to be a tumor with benign histology but
with the biologic behavior of a malignant tumor. Although
most patients with persistent pulmonary disease have an
indolent clinical course, the tumors may continue to grow
and result in respiratory failure and death.49 For this
reason, some investigators have proposed that BMLs
should be regarded as STUMPs.50

FIGURE 11. CT scan of thorax from a patient with benign


metastasizing leiomyoma. Multiple nodules of various sizes are
distributed throughout both lungs.

military nodules ranging from several millimeters to 10


centimeters (Figs. 4D, E and Fig. 11).49 When BMLs occur in
extrapulmonary locations, the presenting symptoms are
usually related to the mass lesion.65,66
Although some investigators consider BMLs as multifocal hyperplastic or neoplastic proliferations of smooth

Typical Clinical and Pathologic Features


Patients are usually of late reproductive age, but
occasionally they are postmenopausal.50,51 Almost all
cases of BMLs have been described in women with a
history of prior hysterectomy for uterine broids with or
without subsequent hormone replacement therapy.52 In
the largest series, the metastatic lesions were discovered
after a median interval of 14.9 years after the initial
removal of uterine broids.49 The most commonly
involved extrauterine location is the lung, but abdominopelvic and mediastinal lymph nodes, soft tissue,
striated muscle, and bone have also been described.5366
Lung lesions are often discovered incidentally with chest
X-rays, and rarely do patients present with respiratory
symptoms, such as dyspnoea, cough, or chest pain.6769 One
case has been reported in which the patient presented with
symptoms related to empyema and pleural eusion.70 The
usual chest radiologic nding includes multiple and bilateral
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FIGURE 12. Benign metastasizing leiomyoma. Proliferation of


mitotically inactive spindle tumor cells lacking atypia or tumor
cell necrosis. Note the entrapped bronchioles (arrows).

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muscle in response to hormonal stimulation,7174 there is


increasing evidence that many are a result of vascular or
lymphatic dissemination from uterine leiomyomas. This is
evidenced by case reports in which BMLs coexisted with
leiomyomas with vascular invasion and/or IVLs,35,37,38,49,7578
and from the results of clonality studies. Patton et al50 and
Tietze et al,79 respectively, found identical patterns of
androgen receptor allelic inactivation and X-chromosome
inactivation between the pulmonary and uterine lesions
indicating that these are indeed clonal. Nucci et al80 showed
a distinctive cytogenetic prole of BMLs that was found only
in a subset (3%) of uterine leiomyomas not present in other
types of benign or malignant tumors.
Microscopically, the lesions resemble a benign uterine
leiomyoma. They are usually normocellular, mitotically
inactive, and devoid of atypia or tumor cell necrosis and
express both estrogen and progesterone receptors.49 They
may show hydropic change, as in the uterine leiomyoma. In
addition, pulmonary lesions often show entrapment of
bronchioalveolar epithelium characterizing the slow growth
of the tumors (Fig. 12).

Unusual Morphologic Features and Dierential


Diagnoses
BMLs should not show worrisome histologic features,
such as atypia, high mitotic count, or tumor cell necrosis.
Retrospective review of the histology of the uterine lesion in
such cases is essential, and may lead to discovery of a
poorly sampled STUMP or leiomyosarcoma.
The nding of heterologous elements, such as adipose
tissue, in an otherwise bland-looking BML, is of no
additional adverse clinical consequences.81

Management
BMLs are slow-growing and hormone-sensitive. Bilateral
oophorectomy should thus be considered in patients
who still have unresected ovaries.56,82 If the patients are
symptomatic, metastatic lesions should, wherever possible,
be resected. If the tumors are not resectable, or if the
patient refuses surgery, hormonal therapy including gonadotropin-releasing hormone analogue (GnRH-a), progestin, aromatase inhibitor (such as anastrozole), and a
selective estrogen receptor modulator (such as raloxifene)
may prevent further growth of the tumors.83,84

UTERINE SMOOTH MUSCLE TUMORS WITH


LITTLE OR NO RECURRENT AND/OR
METASTATIC POTENTIAL
These include leiomyoma variants with diagnostic
terms accurately describing the unusual gross or histologic
features. They may be considered atypical to a pathologist,
because they have certain characteristics that may mimic
malignancy. Clinically, they are benign and are managed
in the same way as ordinary leiomyomas. Although any of
the variants may recur after myomectomy, recurrence with
distant metastasis after hysterectomy is rare.
The typical gross appearance of a leiomyoma is rm,
spherical, circumscribed, and bulging, when sectioned. The
cut surface is often grey-white with a whorled appearance.
It is important to be aware of the range of possible morphologic changes that ischemia, hormonal, and drug treatment may induce, as their presence may cause diagnostic
diculty or misdiagnosis. The patients drug history is

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often overlooked, especially, when it is not included on the


pathology request form. Progestogens, oral contraceptives,
and tranexamic acid may induce hemorrhage and/or
necrosis in leiomyomas (Fig. 4F). Cases of GnRH-a
associated necrosis have also been described.11,8589 If the
time interval between drug administration and leiomyoma
removal is short, drug-induced necrosis may be of the early
infarct type that may mimic tumor cell necrosis, or be
labeled as necrosis of an uncertain type. This will lead to a
diagnosis of STUMP.11,90
GnRH-a is sometimes used to create a temporary
articial menopause that leads to the shrinkage of large
uterine leiomyomas. This facilitates their surgical removal
and prevents excessive bleeding. Reports on the range of
histologic changes associated with GnRH-a are conicting;
some investigators found no light microscopic dierences
between treated versus untreated tumors,91,92 whereas others
have reported increased cellularity in GnRH-a-treated
lesions,89,93 a nding supported by studies that included
the use of morphometry in their methodology.94,95 Degeneration and loss of cytoplasmic organelles and/or alteration
of extracellular matrix has been proposed as the mechanism
underlying the reduction of leiomyoma size.94,96 It is thus
reasonable to assume that the loss of cell volume or
extracellular matrix may result in crowding of nuclei.
Additionally, leiomyomas removed several weeks after
cessation of GnRH-a may show increased mitotic activity
(corresponding to regrowth of the tumor observed clinically).85
The nding of any unusual features other than those
described in the subsequent sections requires thorough
sampling of the tumor; usually, 1 block per cm of tissue
should be selected for microscopic examination. If a tumor
has an unusual combination of any of the 3 features that
give cause for concern, STUMP is an appropriate diagnosis. Such features include signicant nuclear atypia, necrosis
of an uncertain type, and a high mitotic count equivocal for
diagnosis of a leiomyosarcoma.

Leiomyoma With Bizarre Nuclei (LBN)


Description and Terminology
Once regarded as in-situ leiomyosarcomas,97 these
tumors are now generally accepted as a clinically benign
variant of leiomyoma. They are also variously referred to as
bizarre leiomyomas, symplastic leiomyomas, or pleomorphic leiomyomas.6,98101 In the earlier edition of the WHO
classication, bizarre leiomyoma was dened as a leiomyoma
containing giant cells with pleomorphic nuclei with little or
no mitotic activity.102 In the current WHO classication,
bizarre leiomyoma is grouped under the heading atypical
leiomyoma (see also above section on the controversy of
atypical leiomyoma).1

Typical Clinical and Pathologic Features


The clinical presentation and gross features of LBNs
do not usually dier from those of ordinary leiomyomas
and will be of little concern to the gynecologist or pathologist, until they are examined microscopically. Occasionally,
they may seem grossly atypical, being more yellow and
tanned with hemorrhagic or myxoid change (Fig. 4G).
Most LBNs are less than 5.5 cm in diameter,6 and they
are characterized by the presence of large cells with
eosinophilic cytoplasm and bizarrely shaped, multilobated,
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or multinucleated nuclei. The chromatin is often smudged,


and there may be cytoplasmic pseudoinclusions. As noted
earlier, this strikingly abnormal morphology is considered as a degenerative, rather than neoplastic change.103
Although the distribution of these bizarre cells is described
to be diuse or multifocal, most of these examples represent
cases seen in consultation practice. In the course of routine
surgical pathology, they are more commonly found as
isolated foci distributed in a background of an otherwise
typical leiomyoma (Fig. 13).
LBNs are reported to be clinically benign. Evans et al98
described 3 atypical leiomyomas that had 1, 0, and 0 MFs/
10 HPFs, respectively, and followed an uneventful clinical
course for 25, 10, and 11 years, respectively. Downes and
Hart studied 24 LBNs and found an average of 1.6 MFs/
10 HPFs using the highest count method, or 0.8 MFs/
10 HPFs using the average count method. Although 1 of the
tumors had 7 MFs/10 HPFs, none of them recurred after
a mean follow-up of 11.2 years.6 Przybora also described 15
cases of such tumors with no evidence of recurrence or
metastasis in 9 patients for whom follow-up data were
available. Follow-up was nonetheless short.97

Unusual Morphologic Features and Dierential


Diagnoses
The dierential diagnoses of LBNs include STUMP
and leiomyosarcoma. Unlike tumors that some investigators regard as STUMPs, as noted above, LBNs that are
thoroughly sampled for microscopic examination have very
low mitotic activity, and absence of tumor cell necrosis
although infarct type necrosis can be present (Fig. 14).

FIGURE 13. Leiomyoma with bizarre nuclei. In routine surgical


pathology practice, examples of this are usually tumors containing occasional focus (or foci) of bizarre cells in an otherwise
unremarkable leiomyoma.
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FIGURE 14. Leiomyoma with bizarre nuclei with infarct type


necrosis. The viable tumor is usually separated from the necrotic
cells (N) by a zone of reparative granulation tissue (R).

FIGURE 15. Leiomyoma with bizarre nuclei with skeletal musclelike and rhabdoid cells.

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Mitotically active leiomyomas are related to the


mitogenic eect of progesterone and thus usually diagnosed
in a uterus during the secretory phase of the menstrual
cycle. They commonly have a submucosal location and are
rarely seen in postmenopausal women, except under the
inuence of exogenous hormones.107,108 A case of mitotically active leiomyoma in a postmenopausal woman taking
tamoxifen has nonetheless been reported.109

Unusual Morphologic Features and Dierential


Diagnoses
Cytologically bland smooth muscle tumors without
tumor cell necrosis but a mitotic count more than 15 MFs/
10 HPFs are rarely reported in the literature, and their
behavior is therefore less certain. Two of the 91 patients in
Bells study of tumors that had a mitotic count of more
than 20 MFs/10 HPFs were alive without disease after 102
and 78 months, respectively.2 One patient with a similar
tumor in the study by Ip et al7 that had 20 MFs/10 HPFs
had an uneventful clinical course of 21 months. In view of
the scant information on uterine smooth muscle tumors in
which the only worrisome feature is a mitotic count
Z15 MFs/10 HPFs, they have been labeled as mitotically active leiomyomas with limited experience,2 although
they should now be appropriately considered as STUMPs
(Table 2).2,7
FIGURE 16. Lipoleiomyoma with bizarre nuclei.

When a tumor contains strikingly bizarre cells that


resemble those in LBNs, and additionally, tumor cell necrosis,
it should be regarded as leiomyosarcoma, irrespective of the
mitotic count, according to the Stanford criteria.2 Necrosis
or mitotic gures can often be a focal nding, and the need
for adequate sampling should be reiterated.
LBNs may occasionally contain tumor cells with
abundant eosinophilic cytoplasm, including eosinophilic
cytoplasmic globules. Similar cellular changes in uterine
leiomyomas referred to as skeletal muscle-like and rhabdoid cells are not associated with clinically malignant
behavior, provided there are no worrisome microscopic
features (Fig. 4H and Fig. 15).104
Bizarre tumor cells have also been found in lipoleiomyomas (Fig. 16).105 Their presence in these tumors has no
bearing on their behavior. For liposarcomas that arise from
lipoleiomyomas, lipoblasts, a mitotic count of 3 to 7 per
10 HPFs and usually, tumor cell necrosis is present alongside tumor cells with bizarre nuclei.106

Mitotically Active Leiomyoma


Description and Terminology
Mitotically active leiomyomas are dened as smooth
muscle tumors with Z5 to 15 MFs/10 HPFs. They are also
referred to as leiomyomas with increased mitotic index.2

Typical Clinical and Pathologic Features


These do not dier from ordinary leiomyomas in any
gross or microscopic aspects, except for their higher mitotic
count. Most importantly, they should not have signicant
cytologic atypia and should be devoid of tumor cell
necrosis. If this is not the case, STUMP or even leiomyosarcoma should be considered.35

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Cellular and Highly Cellular Leiomyoma


Description and Terminology
Cellular leiomyomas (CLs) are dened as leiomyomas
that are signicantly more cellular than the surrounding
myometrium, often with crowding and overlapping of
nuclei.1 Highly cellular leiomyomas (HCLs) have an even
higher density of cells reminiscent of endometrial stromal
tumors.110

Typical Clinical and Pathologic Features


The presenting symptoms do not dier from those of
patients with typical leiomyomas. On gross examination,
CLs and HCLs are more often soft and eshy and appear
more tan or yellow and less circumscribed than the usual
leiomyomas (Fig. 17A).110 Microscopically, they are tumors
that are characterized by small cells with scanty cytoplasm
and oval-to-spindle nuclei and arranged in a fascicular pattern.
Intralesional thick-walled vessels and cleftlike spaces are common. The tumors often have an irregular border that merges
imperceptibly with the surrounding myometrium (Fig. 18).

Unusual Morphologic Features and Dierential


Diagnoses
The most important dierential diagnosis of CL and
HCL is leiomyosarcoma. Unlike leiomyosarcomas, these
benign and hypercellular variants of leiomyoma have no
tumor cell necrosis and lack signicant cytologic atypia.
Nonetheless, tumors containing focally bizarre cells, similar
to those in LBNs, have been described, although they are
not associated with malignancy.100,110,111
The average mitotic count for CLs and HCLs is
typically <1 MF/10 HPFs (and none are greater than 3 in
Hart and Billmans study);100 nonetheless, the biologic
behavior for similar tumors with more than 4 MFs/10 HPFs
is less certain. Perhaps for this reason, some investigators consider hypercellular smooth muscle tumors with
more than 4 MFs/10 HPFs as STUMPs.10 As for ordinary
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FIGURE 17. A, Highly cellular leiomyomas. The cut surface is soft, fleshy, and yellow or brown. The border is not well demarcated. Note
the cleft-like spaces between coalescing tumor nodules. B, Cotelydonoid dissecting leiomyoma. The grape-like appearance is owing to
the perinodular hydropic change subdividing the extrauterine tumor into numerous bulbous nodules. C, Dissecting leiomyoma. The
tumor is lobulated and shows irregular penetration of the myometrium. D, Cotelydonoid dissecting leiomyoma. The extrauterine tumor
has a placenta-like appearance. E, Myxoid leiomyoma. Myxoid (right) and nonmyxoid areas (left) often coexist. F, Myxoid leiomyoma.
The tumor has a gelatinous cut surface and irregular border with the adjacent myometrium (right). G, Histology of myxoid leiomyoma.
The tumor has a low cellularity (left image, H&E stain). The hyaluronic acid-rich stroma can be shown with alcian blue stain (right
image). H, Diffuse leiomyomatosis. The myometrium is involved by numerous tiny tumors and a few typical leiomyomas.

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FIGURE 18. Highly cellular leiomyoma. Note the presence of


cleft-like spaces and thick-walled blood vessels (top), and
irregularity of border in which the tumor cells melt into the
surrounding myometrium (bottom).

FIGURE 19. A, Endometrial stromal nodule. Note presence of


small arterioles surrounded by fusiform tumor cells and sharp
demarcation from the myometrium on right, in contrast to a
highly cellular leiomyoma (Fig. 18).

leiomyomas though, CLs and HCLs may also be subjected


to the mitogenic eect of progesterone, and under these
circumstances, they should probably still be regarded as
mitotically active cellular leiomyomas and mitotically active
highly cellular leiomyomas, respectively, rather than
STUMPs, unless the mitotic count is more than 15 per
10 HPFs.
HCLs may also be confused with endometrial stromal
tumors. The latter usually have small arterioles encircled by
fusiform tumor cells, absence of thick-walled blood vessels,
and sharply circumscribed margins (Fig. 19). Use of a panel
of immunohistochemical stains, such as h-caldesmon,
desmin, and CD10, can usually distinguish between the 2
conditions. HCLs usually express h-caldesmon and desmin,
whereas endometrial stromal tumors express CD10.112,113

panying intramyometrial dissecting growth, the term


cotelydenoid leiomyoma is appropriate.118

Dissecting Leiomyoma, Cotelydenoid Dissecting


Leiomyoma, and Cotelydenoid Leiomyoma
Description and Terminology
A dissecting leiomyoma is characterized by an unusual
pattern of growth in which the tumor permeates through
the myometrium. It may extend beyond the uterus and involve
the pelvis, including the broad ligament, and sometimes,
owing to the commonly associated edema and congestion,
give rise to a characteristic gross appearance reminiscent
of the cotelydons of a placenta. This has been described
as cotyledenoid dissecting leiomyoma (Sternberg tumor).114,115 These tumors are probably identical with the
so-called grapelike leiomyoma described in older studies
(Fig. 17B).116,117
When a dissecting leiomyoma arises subserosally in the
uterus and involves the broad ligament without the accom-

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Typical Clinical and Pathologic Features


These tumors aect women in their reproductive age or
those who are perimenopausal. The clinical presentation and
gross pathologic features are similar to that of the usual
leiomyomas, although the intrauterine component is usually
more lobulated and has irregular and, sometimes, indistinct
margins (Fig. 17C).117 Microscopically, elongated nodules or
long columns of tumors can be found dividing through
bundles of smooth muscle of the myometrium (Fig. 20).
Cotyledenoid dissecting leiomyomas (and cotelydenoid leiomyomas) are red, purple, exophytic and multinodular and are usually large (mean 17.7 cm). They commonly
have extensive pelvic involvement and may simulate a
malignant lesion intraoperatively. They may prompt
the surgeon to request frozen section to exclude malignancy
(Fig. 17D).114,119121 Microscopically, the tumor nodules
show a sinuous dissecting pattern into the myometrium and
beyond separated by edematous and richly vascularized
stroma. They are often strikingly hydropic and hyalinized.
The spindled tumor cells are usually arranged in a swirling,
rather than a fascicular growth pattern (Figs. 21, 22).115

Unusual Morphologic Features and Dierential


Diagnoses
It is conceivable that any of the cytologic variations
in an ordinary leiomyoma may be seen in these dissecting
leiomyomas. To date, none of the reported cases have been
associated with microscopic worrisome features, including
the combinations of nuclear atypia, high mitotic activity,
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FIGURE 20. Dissecting leiomyoma. Tongues of tumor (T) dissect


between myometrial smooth muscle. Noted hydropic change
within the tumor nodules.

Uterine Smooth Muscle Tumors

FIGURE 22. Cotelydonoid dissecting leiomyoma. The spindled


tumor cells are usually arranged in a swirling, rather than a
fascicular growth pattern and separated by a hydropic stroma.

and/or tumor cell necrosis. Of the 8 dissecting leiomyoma


cases reported by Roth and Reed, 1 tumor had a high
cellularity (cellular dissecting leiomyoma) and was followed
by an uneventful postoperative course.117 Another case
report of a dissecting leiomyoma was associated with
residual tumor postoperatively, although there was no
further increase in size after 15 months of follow-up.119
IVL may be a component of any of these 3 dissecting
leiomyoma variants;42,122 however, follow-up information
on these cases, is limited. It is reasonable that patients who
have tumors with this unusual growth pattern be managed
in the same manner as those with IVLs without this feature.

Myxoid Leiomyoma
Description and Terminology
Myxoid leiomyomas are leiomyomas that contain abundant acellular stroma that appears pale or basophilic and
semitransparent on routine hematoxylin and eosin stained
sections. The myxoid change is the accumulation of hyaluronic acid-rich glycosaminoglycans that can be conrmed
by special stains, such as alcian blue. This ensures distinction
from the more common hydropic change with which it is
often confused (Figs. 17E, F, G).123 Hydropic change is an
accumulation of edematous uid and of no clinical signicance. Myxoid change can be a focal nding in up to 12%
of benign leiomyomas, especially surrounding zones of an
infarct124 and may also be associated with pregnancy.86

Typical Clinical and Pathologic Features


FIGURE 21. Cotelydonoid dissecting leiomyoma. The tumor
nodules are often strikingly congested and hydropic.
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Myxoid leiomyomas are usually gelatinous, but this


appearance is rarely diuse or pure. More commonly, the
gelatinous foci alternate with nonmyxoid white to grey
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areas, sometimes with areas of gross necrosis and hemorrhage. Although malignant tumors may have a grossly deceptive circumscribed border,33 the nding of an ill-dened or
inltrative border should prompt extensive sampling from
the surrounding myometrium. An inltrative border is
known to be associated with malignant behavior in myxoid
smooth muscle tumors, but in one study, one-third of benign
cases also showed this feature.33 Histologically, the myxoid
zones are often hypocellular, with the spindle or stellate
tumor cells spread throughout the basophilic matrix.

Unusual Morphologic Features and Dierential


Diagnoses
Pathologic assessment of malignancy is more dicult
in myxoid smooth muscle tumors. The myxoid foci may
abut a nonmyxoid area within the tumor, creating a pseudoinvasive histologic appearance. Careful gross evaluation and
block coding for tissue sampled at the periphery of the
tumor is therefore necessary.125
In tumors that are extensively myxoid, the cellularity is
often low and the tumor cells are widely separated resulting
in a lower mitotic count. The cells may be more oval or
stellate with less cytoplasm and the atypia is less conspicuous.
Sometimes, even the recognition of their smooth muscle
nature may be dicult, and conrmation with immunostains such as desmin and h-caldesmon is necessary. Tumor
cell necrosis is also less often encountered in malignant
tumors. For these reasons, the diagnostic threshold for diagnosis of myxoid leiomyosarcomas is dierent from that of
conventional leiomyosarcomas (see preceding section on
myxoid smooth muscle tumor of uncertain malignant
potential). The nding of areas of conventional leiomyosarcoma, vascular invasion, and irregular inltrating borders often helps make the distinction but extensive sampling
is often necessary.

FIGURE 23. Plexiform tumorlet.

the tumors. The cells usually have eosinophilic and granular


cytoplasm (Fig. 24). Occasionally, the tumor may comprise
entirely cells with clear cytoplasm.

Epithelioid Leiomyoma
Description and Terminology
This subtype of benign uterine smooth muscle tumors
is dened by the presence of rounded or polygonal cells that
have a microscopic appearance of epithelial cells in at
least 50% of the tumor. In the literature, they are referred
variously as leiomyoblastomas and clear cell leiomyoma.32,98,101,126,127 The former, an outmoded terminology,
is no longer in general use, as it incorrectly implies a highly
malignant tumor composed of primitive small round
tumor cells.85,98,126 Plexiform leiomyomas are epithelioid
leiomyomas in which the tumor cells are arranged in cords
and nests separated by a hyalinized stroma; those <1 cm in
size are known as plexiform tumorlets.128,129

Typical Clinical and Pathologic Features


The clinical presentation of epithelioid leiomyomas
does not dier signicantly from that of typical leiomyomas. On gross examination, although the majority of these
tumors have a whorled cut surface, nonetheless, some are
poorly circumscribed, eshy with areas of hemorrhage or
necrosis that can mimic a leiomyosarcoma.85 Plexiform
tumorlets are often asymptomatic, discovered incidentally
during microscopic examination, and are often multiple
(Fig. 23).128,129
Histologically, the tumor cells are arranged in sheets,
cords, or nests with variable degrees of stromal hyalinization.
A background spindle cell component coexists in 50% of

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FIGURE 24. Epithelioid leiomyoma. The appearance is almost


identical to sheets of epithelial cells.
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Unusual Morphologic Features and Dierential


Diagnoses
Epithelioid dierentiation may constitute part of, or
be a predominant cellular component of IVL. Tumors with
such features should be managed in the same manner as
ordinary IVL (see preceding section on IVL).
As for ordinary leiomyomas, epithelioid leiomyomas
may contain tumor cells with bizarre nuclei that are
degenerative in nature (Fig. 25). When unaccompanied by
mitotic activity or tumor cell necrosis, these tumors are
reported to follow a benign clinical course.32,105 Lipoleiomyoma may also contain tumor cells arranged in a
plexiform pattern (plexiform lipoleiomyoma); this has no
bearing on the clinical behavior.130
Two epithelioid smooth muscle tumors containing
osteoclastic-type giant cells are reported to be clinically
malignant. In addition, they both have other features of
malignancy, including tumor cell necrosis and a high mitotic
count.32,131
In rare cases, tumors may have epithelioid cells
arranged in cords or nests scattered among a background
of ordinary leiomyoma, potentially mimicking metastatic
carcinoma.132 Immunohistochemical study is necessary under
such circumstances. Unfortunately, the tumor cells in epithelioid smooth muscle tumors often express cytokeratins
(as in carcinomas) and less often myogenic markers, such as
desmin. Histone deacetylase 8 has recently been shown to
be a superior smooth muscle marker for epithelioid smooth
muscle tumors compared with desmin or h-caldesmon.133
Epithelioid smooth muscle tumors that are composed
of clear cells may be immunoreactive for HMB-45 in onethird of cases, and these show overlapping morphology with perivascular epithelioid cell tumors (Fig. 26).
The latter are associated with tuberous sclerosis and/or

FIGURE 26. Epithelioid leiomyoma. Tumors composed entirely


of clear cells.

lymphangioleiomyomatosis and one-third are found to be


clinically malignant.134137
Epithelioid leiomyomas should have absent or mild
atypia (grade 1), r2 MFs/10 HPFs and no tumor cell
necrosis. Presence of bizarre cells (as noted above) should
not be included in the grading of atypia. Clinically
malignant epithelioid smooth muscle tumors normally have
grade 2 to 3 nuclear features and more than 5 MFs/
10 HPFs, often with tumor cell necrosis.32,126,138,139 Tumors
that do not satisfy benign or malignant criteria can be
appropriately labeled as epithelioid STUMPs (see preceding
sections on STUMPs) and be managed accordingly.

Diffuse Leiomyomatosis
Description and Terminology
Diuse leiomyomatosis (DL) is a rare lesion with less
than 20 cases reported in the literature, and is characterized
by extensive involvement of the myometrium by countless,
conuent proliferating smooth muscle nodules.1 The cervix
appears to be spared. In the older literature, cases with
similar pathologic features were variously referred to as
general myomatous tendency of the uterus140, myomatosis141 and complete bromyomatosis of the corpus
uteri142.
Each individual nodule in DL has been shown to be
of dierent clonal origin, as shown by the presence of
nonrandom X-chromosome inactivation involving dierent
alleles between each lesion.143 Some cases have been
reported to occur in association with Alports syndrome.144

Typical Clinical and Pathologic Features


FIGURE 25. Epithelioid leiomyoma with bizarre nuclei. Some of
the bizarre cells concentrate around blood vessels.
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DL aects women in their reproductive years: patient


age ranges from 28 through 42 years.145,146 Although the
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FIGURE 27. Diffuse leiomyomatosis. The serosa is often


congested and bosselated. Note the absence of cervical involvement.

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FIGURE 29. Diffuse leiomyomatosis. Compressed vascular spaces


between tumor nodules may mimic intravenous leiomyomatosis.

clinical symptoms are identical to those of women with


ordinary leiomyomas, rapid uterine enlargement has been
described.147 Diagnosis can usually be made by ultrasound
scan, in which the innumerable small myometrial tumors
can be detected.148,149
The aected uterus is symmetrically enlarged and the
serosa is often bosselated (Fig. 27). The myometrium
typically contains numerous ill-dened nodules <1 cm in
size merging with one another and with the surrounding
myometrium. Occasional larger, more circumscribed typical leiomyoma can be found (Fig. 17H). Histologically, the
tumorous nodules are usually hypercellular and merge
imperceptibly to adjacent nodules and myometrial smooth
muscle (Fig. 28). As in an ordinary leiomyoma, the nodules
lack signicant atypia or tumor cell necrosis, and are
usually very low in mitotic activity. Apart from hyalinization, degenerative changes such as hydropic and myxoid
change, hemorrhage or calcication have not been
described.145,147

Unusual Morphologic Features and Dierential


Diagnoses

FIGURE 28. Diffuse leiomyomatosis. Multiple highly cellular


tumor nodules (T) merging with one another without a welldefined boundary.

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Blood vessels between tumor nodules may sometimes


be compressed, a feature that may be confused with IVL
(Fig. 29).38 Unlike DL, the tumor nodules in IVL are
usually more hydropic, and surrounded by endothelial
cells.147
Occasional tumors may show perivascular condensation of the tumor cells similar to that described for
endometrial stromal tumors.142,147 The latter are nonetheless usually diagnosed in older women (range 31 to 86 y
of age, median, 53).150 Unlike DL, endometrial stromal
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sarcomas usually involve the endometrium, and the tumor


nodules often show abrupt transition as opposed to
merging imperceptibly to the surrounding myometrium.
Finding of other features of endometrial stromal tumors
described above supports the latter diagnosis. (see under
dierential diagnoses of cellular and highly cellular
leiomyomas above).
Extrauterine extension of DL with involvement of the
ovaries and parametrium has been described in 1 case
report in which the tumor showed no worrisome microscopic features and there was no vascular invasion. The
patient showed no evidence of residual disease 6 months
after surgery.146
Although most investigators found DL a benign
condition,145,147 its relationship with BML is unknown.
Thomas et al151 described a patient in whom DL caused
uterine rupture during pregnancy, and incidental discovery
of BMLs involving the iliac bones and vertebral bodies. The
histology of all lesions was benign, and the tumor expressed
estrogen and progesterone receptors. All the bony lesions
regressed spontaneously during the post-partum period.

Management
As DL is rare, there is no consensus on management.
Owing to the extensiveness of the condition, and the fact
that the tumor cells merge imperceptibly with the surrounding myometrium, myomectomy is ineective and patients
inevitably develop persistent disease. Additionally, severe
intraoperative hemorrhage is a risk.152,153 Uterine conservation with uterine arterial embolization or GnRH-a has
been successful in some cases.154,155
Patients with DL are said to be more likely to have a
distorted uterine cavity, and hence infertility problems.156
Nonetheless, pregnancy has been achieved after hysteroscopic resection of submucosal broids with or without
prior GnRH-a treatment.148,149
ACKNOWLEDGMENTS
The authors thank Dr Philip B. Clement (Department of
Pathology, University of British Columbia, Vancouver Hospital and Health Science Centre, Vancouver, Canada) for his
advices and comments on this review, and for allowing study
and photography of his consultation cases; The authors also
thank Dr Robert H. Young (Department of Pathology, Harvard
Medical School, Massachusetts General Hospital, Boston,
MA), Dr Victor Tang (Department of Pathology, Pamela
Youde Nethersole Hospital, Hong Kong), and Dr Tina Lam
(Department of Diagnostic Radiology, Queen Mary Hospital, Hong Kong) for their generosity in contributing gross and
radiologic photos.
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