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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.
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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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
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
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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
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
Size
Age (cm) Cellularity
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
4
5.8
NA
4
10
NA
Outcome
(mo)
(74)
(40)
(36)
(68)
(>108)
(60)
50
39
NA
46
33
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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
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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.
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.
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
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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).
r
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
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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
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FIGURE 15. Leiomyoma with bizarre nuclei with skeletal musclelike and rhabdoid cells.
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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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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
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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.
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
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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
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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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