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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e3181cfb901
Review Articles

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

Ip, Philip P. C. MBChB, FRCPath*; Tse, Ka Yu MBBS, MRCOG; Tam, Kar Fai MBBS, MRCOG

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Author Information

Departments of *Pathology

Obstetrics 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 figures can be viewed online in color at http://www.anatomicpathology.com.

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Abstract

Uterine smooth muscle tumors are classified 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 different 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 subclassification. 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 diffuse leiomyomatosis. Their clinicopathologic features, differential diagnoses, and management options based on findings in the previously reported cases will also be reviewed.

Uterine smooth muscle tumors are classified according to their pathologic features.1,2 Most diagnostic terminologies accurately reflect the morphology of the lesions, but they 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.3–5 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.

Table 1
Table 1
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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 classification 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, ≤10 mitotic figures (MFs)/10 high power fields (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 diffuse 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 ≥20/10 HPFs.2,7,8

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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 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

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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 diffuse moderate-to-severe atypia, a mitotic count of ≥10 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 first 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 leiomyosarcoma,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 different combinations that have been classified 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.

Table 2
Table 2
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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 diffuse 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 recurrence”2,8; 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 finding raises the possibility that the upper limit of the number of mitotic figures in LBNs is difficult to define. It may justify the inclusion of LBNs with any mitotic activity in the category of “atypical leiomyomas,” as defined in the current World Health Organization (WHO) classification.1

The varying outcomes for patients, who have “almost” pathologically identical atypical leiomyomas, may be partly explained by the subjective assessment of cytologic 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 difficult to confidently 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.

Figure 1
Figure 1
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Figure 2
Figure 2
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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 difficult and subjective. As both the nuclear pyknosis and the karyorhexis are common findings in LBNs,6 the degenerating nuclei undergoing apoptosis may have an appearance that mimics a mitotic figure, so-called “pseudoatypical mitosis” (Fig. 3).7,17 The use of immunohistochemical markers to confirm a true mitotic figure is thus helpful. Phosphohistone H3 is a recently described immunohistochemical marker that specifically identifies cells undergoing mitoses. Rapid identification 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 figures in uterine smooth muscle tumors.22

Figure 3
Figure 3
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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 differently.

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Behavior and Frequency of Recurrence

Comparison of different studies of STUMPs is difficult because of differing and evolving diagnostic criteria (as noted above); classification schemes of studies predating that of Bell et al in 1994 did not evaluate tumor cell necrosis,23–25 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 defined by the Stanford investigators,2 and in which there were sufficient 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 different diagnostic criteria was 7.3% (3 of 41 cases) and 26.7% (4 of 15 cases).10,25 Nonetheless, it may be difficult to interpret the recurrence rate from a large group of patients in a single study, when the definition 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.7,9,27–31 Although tumors regarded as STUMPs with recurrence are associated with diffuse immunoreactivity for p16 and p53,7,9,30 the number of cases in these studies are small, and further study is required to confirm 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
Table 3
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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 findings 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.

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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 effective, although in its absence, patients have also been reported to have an uneventful clinical course.2,12

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Smooth Muscle Tumor of Uncertain Malignant Potential: Epithelioid and Myxoid Differentiations

Malignant smooth muscle tumors with epithelioid or myxoid differentiation are less common than their spindle cell counterpart, and the diagnostic criteria predictive of malignancy are less well established. Malignant tumors of these differentiations 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 sufficient 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 sufficient to justify a diagnosis of malignancy.33

Owing to their rarity, STUMPs of either epithelioid or myxoid differentiation have not been specifically 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 finding of necrosis of an uncertain type and/or infiltrative border in a myxoid smooth muscle tumor without mitotic activity or nuclear atypia.

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Intravenous Leiomyomatosis
Description and Terminology

Intravenous leiomyomatosis (IVL) is defined as intravascular proliferation of a benign-appearing smooth muscle tumor in the absence of, or beyond the confines 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 confined 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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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 worm-like 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 identified 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 affected by IVL is typically enlarged and heavy, and the serosa is often bosselated. Typically, the myometrium is affected by multiple leiomyomas of varying sizes with IVL found either focally or diffusely (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, firm and rubbery, gelatinous and translucent, even hemorrhagic and calcified depending on the presence of edema or degenerative changes (Fig. 4B).34

Figure 4
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Microscopically, the intravascular tumor nodules are found outside the confines 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 floating within the lumen or adhered to the intima.

Figure 5
Figure 5
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Unusual Morphologic Features and Differential 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

Table 4
Table 4
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Figure 6
Figure 6
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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 differentiation may be difficult, 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.

Figure 7
Figure 7
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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 differential diagnoses on “cellular and highly cellular leiomyoma” below). The majority of cellular IVLs has absent-to-mild atypia, although it may occasionally be moderate.40 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.

Figure 8
Figure 8
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IVL with bizarre nuclei is distinguished from leiomyosarcoma by the absence of mitotic figures. 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 difficult. Myxoid IVL should be mitotically inactive and devoid of atypia with no infiltrative 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.

Figure 9
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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

Figure 10
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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 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

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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.36,45–48

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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

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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 fibroids 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 fibroids.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.53–66 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.67–69 One case has been reported in which the patient presented with symptoms related to empyema and pleural effusion.70 The usual chest radiologic finding includes multiple and bilateral 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

Figure 11
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Although some investigators consider BMLs as multifocal hyperplastic or neoplastic proliferations of smooth muscle in response to hormonal stimulation,71–74 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,35,37,38,49,75–78 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 profile 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).

Figure 12
Figure 12
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Unusual Morphologic Features and Differential 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 finding of heterologous elements, such as adipose tissue, in an otherwise bland-looking BML, is of no additional adverse clinical consequences.81

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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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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 firm, 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 difficulty or misdiagnosis. The patient's drug history is 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.11,85–89 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 artificial 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 conflicting; some investigators found no light microscopic differences between treated versus untreated tumors,91,92 whereas others have reported increased cellularity in GnRH-a-treated lesions,89,93 a finding 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 finding 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 significant nuclear atypia, necrosis of an uncertain type, and a high mitotic count equivocal for diagnosis of a leiomyosarcoma.

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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.6,98–101 In the earlier edition of the WHO classification, bizarre leiomyoma was defined as “a leiomyoma containing giant cells with pleomorphic nuclei with little or no mitotic activity.”102 In the current WHO classification, bizarre leiomyoma is grouped under the heading “atypical leiomyoma” (see also above section on “the controversy of atypical leiomyoma”).1

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Typical Clinical and Pathologic Features

The clinical presentation and gross features of LBNs do not usually differ 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, 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 diffuse 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).

Figure 13
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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

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Unusual Morphologic Features and Differential Diagnoses

The differential 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 14
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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 figures can often be a focal finding, 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

Figure 15
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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

Figure 16
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Mitotically Active Leiomyoma
Description and Terminology

Mitotically active leiomyomas are defined as smooth muscle tumors with ≥5 to 15 MFs/10 HPFs. They are also referred to as leiomyomas with increased mitotic index.2

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Typical Clinical and Pathologic Features

These do not differ from ordinary leiomyomas in any gross or microscopic aspects, except for their higher mitotic count. Most importantly, they should not have significant cytologic atypia and should be devoid of tumor cell necrosis. If this is not the case, STUMP or even leiomyosarcoma should be considered.3–5

Mitotically active leiomyomas are related to the mitogenic effect 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 influence of exogenous hormones.107,108 A case of mitotically active leiomyoma in a postmenopausal woman taking tamoxifen has nonetheless been reported.109

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Unusual Morphologic Features and Differential 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 Bell's 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 ≥15 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

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Cellular and Highly Cellular Leiomyoma
Description and Terminology

Cellular leiomyomas (CLs) are defined as leiomyomas that are “significantly” 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

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Typical Clinical and Pathologic Features

The presenting symptoms do not differ from those of patients with typical leiomyomas. On gross examination, CLs and HCLs are more often soft and fleshy 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).

Figure 17
Figure 17
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Figure 18
Figure 18
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Unusual Morphologic Features and Differential Diagnoses

The most important differential diagnosis of CL and HCL is leiomyosarcoma. Unlike leiomyosarcomas, these benign and hypercellular variants of leiomyoma have no tumor cell necrosis and lack significant 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 Billman's 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 leiomyomas though, CLs and HCLs may also be subjected to the mitogenic effect 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

Figure 19
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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 accompanying intramyometrial dissecting growth, the term cotelydenoid leiomyoma is appropriate.118

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Typical Clinical and Pathologic Features

These tumors affect 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).

Figure 20
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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).114,119–121 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

Figure 21
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Figure 22
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Unusual Morphologic Features and Differential 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, 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.

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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 confirmed 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 fluid and of no clinical significance. Myxoid change can be a focal finding 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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Typical Clinical and Pathologic Features

Myxoid leiomyomas are usually gelatinous, but this appearance is rarely diffuse or pure. More commonly, the gelatinous foci alternate with nonmyxoid white to grey areas, sometimes with areas of gross necrosis and hemorrhage. Although malignant tumors may have a grossly deceptive circumscribed border,33 the finding of an ill-defined or infiltrative border should prompt extensive sampling from the surrounding myometrium. An infiltrative 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.

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Unusual Morphologic Features and Differential Diagnoses

Pathologic assessment of malignancy is more difficult 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 difficult, and confirmation 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 different from that of conventional leiomyosarcomas (see preceding section on myxoid smooth muscle tumor of uncertain malignant potential). The finding of areas of conventional leiomyosarcoma, vascular invasion, and irregular infiltrating borders often helps make the distinction but extensive sampling is often necessary.

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Epithelioid Leiomyoma
Description and Terminology

This subtype of benign uterine smooth muscle tumors is defined 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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Typical Clinical and Pathologic Features

The clinical presentation of epithelioid leiomyomas does not differ significantly from that of typical leiomyomas. On gross examination, although the majority of these tumors have a whorled cut surface, nonetheless, some are poorly circumscribed, fleshy 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

Figure 23
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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 the tumors. The cells usually have eosinophilic and granular cytoplasm (Fig. 24). Occasionally, the tumor may comprise entirely cells with clear cytoplasm.

Figure 24
Figure 24
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Unusual Morphologic Features and Differential Diagnoses

Epithelioid differentiation 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

Figure 25
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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 one-third of cases, and these show overlapping morphology with perivascular epithelioid cell tumors (Fig. 26). The latter are associated with tuberous sclerosis and/or lymphangioleiomyomatosis and one-third are found to be clinically malignant.134–137

Figure 26
Figure 26
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Epithelioid leiomyomas should have absent or mild atypia (grade 1), ≤2 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.

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Diffuse Leiomyomatosis
Description and Terminology

Diffuse 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, confluent 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 uterus”140, “myomatosis”141 and “complete fibromyomatosis of the corpus uteri”142.

Each individual nodule in DL has been shown to be of different clonal origin, as shown by the presence of nonrandom X-chromosome inactivation involving different alleles between each lesion.143 Some cases have been reported to occur in association with Alport's syndrome.144

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Typical Clinical and Pathologic Features

DL affects women in their reproductive years: patient age ranges from 28 through 42 years.145,146 Although the 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 affected uterus is symmetrically enlarged and the serosa is often bosselated (Fig. 27). The myometrium typically contains numerous ill-defined 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 significant 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 calcification have not been described.145,147

Figure 27
Figure 27
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Figure 28
Figure 28
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Unusual Morphologic Features and Differential Diagnoses

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

Figure 29
Figure 29
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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 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 differential 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.

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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 ineffective 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 fibroids with or without prior GnRH-a treatment.148,149

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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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Back to Top | Article Outline
Keywords:

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; diffuse leiomyomatosis

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