uterine smooth muscle tumors

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Uterine Smooth Muscle Tumors Other Than the OrdinaryLeiomyomas and Leiomyosarcomas: A Review of Selected

Variants With Emphasis on Recent Advances and UnusualMorphology 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 classified according totheir morphologic features that include architecture, growth pattern,cellular characteristics and constituents of the intercellular stroma.While terminologies used for the pathologic diagnosis of varioussubtypes may be eloquent and histologically accurate, some of theseare confusing for the clinician and may also be open to interpretationby different pathologists: the labeling of atypical leiomyomas epito-mizes this intricate system. Clinically, it is probably more useful toclassify them as either tumors with or tumors without recurrentand/or metastatic potential. The term atypical leiomyoma has beenused to label tumors that have a low risk of recurrence and issynonymous with benign tumors. The latter are known variously asleiomyoma with bizarre nuclei, symplastic leiomyoma, or pleomor-phic leiomyoma. Variants of benign uterine smooth muscle tumors,such as mitotically active leiomyoma, cellular and highly cellularleiomyoma, epithelioid leiomyoma, and myxoid leiomyoma eachhave distinctive hallmarks that enable subclassification. Nevertheless,they may occasionally possess one or more unusual features that arecause for alarm. Tumors that have a dissecting growth pattern, with

or without extrauterine extension, may mimic malignancy bothgrossly and microscopically. The current review discusses the patho-logic diagnosis of and terminology applied to selected variants ofuterine smooth muscle tumors other than the ordinary leiomyomasand leiomyosarcomas with emphasis on unusual reported featuresthat may indicate malignancy. This includes an update on uterinesmooth muscle tumor of uncertain malignant potential (STUMP),intravenous leiomyomatosis, benign metastasizing leiomyoma, anddiffuse leiomyomatosis. Their clinicopathologic features, differen-tial diagnoses, and management options based on findings in thepreviously 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 leio-

myoma, intravenous leiomyomatosis, benign metastasizing leio-

myoma, diffuse leiomyomatosis

(Adv Anat Pathol 2010;17:91112)

Uterine smooth muscle tumors are classified according totheir pathologic features.1,2 Most diagnostic termino-logies accurately reflect the morphology of the lesions, but they

provide little relevant clinical details or prognostic informa-tion to guide postoperative management. An example ofthis includes the mitotically active leiomyoma in which thehigh proliferative rate alone has little impact on the recur-

rence potential.35

The term atypical leiomyoma is evenmore confusing; it is used by some to label smooth muscletumors with a low risk of recurrence,2 but for others, it isused interchangeable with a benign tumor containing micro-scopically atypical cells that are clinically inconsequential.6

Clinically, it is probably more useful to classify them astumors with or without (or little) recurrent and/ormetastatic potential. A summary is listed in Table 1.

UTERINE SMOOTH MUSCLE TUMORS WITHRECURRENT AND/OR METASTATIC POTENTIAL

Uterine Smooth Muscle Tumor of Uncertain

Malignant Potential (STUMP): Standard(Spindle Cell) Smooth Muscle Differentiation

Description and TerminologyThe World Health Organization classification indi-

cates that a uterine smooth muscle tumor that cannot bediagnosed unequivocally as benign or malignant should betermed smooth muscle tumor of uncertain malignant potential(STUMP).1 The current approach to diagnosis was derivedby the Stanford investigators after studying 213 cases ofproblematic uterine smooth muscle tumors.2 In that study,although they did not use the term STUMP, they deli-neated 4 histologic subgroups of uterine smooth muscletumors that had a low or uncertain malignant potential: (1)atypical leiomyoma with limited experience, if the tumorshowed focal or multifocal moderate-to-severe atypia,r10 mitotic figures (MFs)/10 high power fields (HPFs) andno tumor cell necrosis; (2) smooth muscle tumor with lowmalignant potential, if the tumor showed tumor cellnecrosis, but absent-to-mild atypia and


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age at presentation is similar to those with leiomyosarco-mas and benign leiomyomas,9 patients diagnosed withSTUMP and a subsequent recurrence appear to be youngerthan those with an uneventful follow-up. In two studies, themean age of patients with recurrent disease was 44.5 and33.7 years, respectively, compared with 47.5 and 43.9 yearsin those without.7,10

Pathologic Diagnosis of STUMPThe histologic diagnosis of malignant uterine smooth

muscle tumors is usually based on the Stanford criteria,as noted above. This involves an assessment of a combina-tion of three histologic features, including atypia, mitoticrate, and type of necrosis.1,2 A leiomyosarcoma usuallyexhibits diffuse moderate-to-severe atypia, a mitotic countof Z10 MFs/10 HPFs, and tumor cell necrosis. A tumorwith any 2 of these features is clinically malignant oftenenough to warrant a diagnosis of leiomyosarcoma. As theStanford study2 was the first to appreciate that the type ofnecrosis in a uterine SMT was of crucial importance;studies that preceded it did not evaluate the presence orabsence of tumor cell necrosis.

If a tumor shows any unusual combinations of the 3features that do not satisfy the Stanford criteria for leio-

myosarcoma,2 a diagnosis of uterine smooth muscle tumorof uncertain malignant potential (STUMP) is appropriate.1

Examples of such ambiguity include presence of borderlinemitotic count (around 8 or 9 per 10HPFs) in a tumorwith moderate-to-severe atypia and absence of tumor cellnecrosis7; 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 ormitotic activity.7,11 Cases with different combinations thathave been classified as STUMPs are listed in Table 2,although it is not exhaustive. Other investigators haveincluded tumors with any other unusual histologic features,although the number of such cases reported is too small, andtheir true recurrence rate is unknown.

The Controversy of Atypical LeiomyomaThe use of the term atypical leiomyoma is not

universal among pathologists, and the natural history ofsuch tumors remains controversial. Histologically, tumorsthat fall into this category are those with diffuse or multi-focal moderate-to-severe atypia and no tumor cell necrosis.Tumors with these features, and


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atypia and mitotic count. The microscopic description ofbizarre tumor cells by the Stanford investigators2 andDownes and Hart6 in their respective papers, are almostidentical. The former consider these as malignant, whereasthe latter consider these as degenerative. It would beextremely difficult to confidently distinguish malignantfrom degenerative by light microscopic examination ofthese cells alone, when in fact, the cellular morphology isequally ominous in atypical leiomyomas with low risk ofrecurrence and LBNs (Figs. 1, 2). For LBNs, although thebizarre cells are said to array against a background of moreuniform, bland myoma cells, atypical leiomyomas that werefollowed by a recurrence have often been noted to havethese cells scattered multifocally in a background of tumor

cells lacking atypia.7 Bizarre cells have been shown to haveincreased global methylation of DNA suggesting that thebizarre nuclear atypia may represent abundant hetero-chromatin with associated inactivated DNA.16 This observa-tion was nonetheless made in LBNs with benign outcome; itwould be useful to carry out DNA methylation studies inatypical leiomyomas that were followed by a recurrence.

The most important feature that distinguishes an atypicalleiomyoma with low risk of recurrence (or STUMP) from aLBN is the mitotic count. Reliable mitosis counting in suchtumors is nonetheless difficult and subjective. As both thenuclear pyknosis and the karyorhexis are common findingsin LBNs,6 the degenerating nuclei undergoing apoptosismay have an appearance that mimics a mitotic figure, so-called

pseudoatypical mitosis (Fig. 3).7,17 The use of immuno-histochemical markers to confirm a true mitotic figure isthus helpful. Phosphohistone H3 is a recently described

FIGURE 1. Leiomyoma with bizarre nuclei. The tumor cells haveeosinophilic cytoplasm and bizarrely shaped, multilobated ormultinucleated nuclei. The chromatin is often smudged andoften has cytoplasmic pseudoinclusions.

FIGURE 2. Atypical leiomyoma with low risk of recurrence (smoothmuscle tumor of uncertain malignant potential). The tumor cells areequally bizarre as those in leiomyoma with bizarre nuclei; additio-nally, there are more than 2 to 9 mitotic figures per 10 high powerfields, and sometimes including atypical mitoses (centre).

FIGURE 3. Leiomyoma with bizarre nuclei. Degenerating nucleimay have an appearance that mimics a mitotic figure, so-calledpseudoatypical mitosis.

Adv Anat Pathol Volume 17, Number 2, March 2010 Uterine Smooth Muscle Tumors

r 2010 Lippincott Williams & Wilkins www.anatomicpathology.com |93


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immunohistochemical marker that specifically identifiescells undergoing mitoses. Rapid identification of mitoseshas been reported in breast carcinomas,18 ovarian serousadenocarcinomas,19 meningiomas,20 and astrocytomas21 inwhich an accurate mitotic count is crucial. PhosphohistoneH3 has recently been shown to be a more sensitive and

reliable marker for highlighting true mitotic figures in uterinesmooth muscle tumors.22

Irrespective of the ongoing debate that surroundslabeling of these atypical leiomyomas, on a practical level,it is more important for the clinician to clarify with thepathologist whether the atypical uterine smooth muscle tumorrepresents a benign tumor (LBN) or a STUMP, as these aremanaged quite differently.

Behavior and Frequency of RecurrenceComparison of different studies of STUMPs is diffi-

cult because of differing and evolving diagnostic criteria

(as noted above); classification schemes of studies predat-ing that of Bell et al in 1994 did not evaluate tumor cellnecrosis,2325 whereas other studies have scant informationabout 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 samediagnostic criteria for STUMPs as defined by the Stanfordinvestigators,2 and in which there were sufficient clinicalfollow-up information and pathologic details for compari-son, reveals a recurrence rate of approximately 11% (10 of91 cases) (Table 2).2,7,9,12,14,15 A more recent study bythe 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 2other studies that used different diagnostic criteria was7.3% (3 of 41 cases) and 26.7% (4 of 15 cases). 10,25 None-theless, it may be difficult to interpret the recurrence ratefrom a large group of patients in a single study, when thedefinition of STUMP is so variable.

It is conceivable that some tumors regarded asSTUMPs are underdiagnosed leiomyosarcomas. Alterna-tively, others may be variants of leiomyomas with unusualpathologic features. Emerging evidence has shown thatSTUMPs that recur likely represent a form of borderlinetumor or a low-grade leiomyosarcoma.7 Despite applyingthe Stanford 3-feature criteria, it is not always possible topredict whether a STUMP will recur until a recurrence has

developed. Recent studies have suggested the use of immuno-histochemical stains, including p16, p53, MIB-1, Twist, bcl-2,estrogen and progesterone receptors to identify uterinesmooth muscle tumors with a higher risk of recurrence.7,9,2731

Although tumors regarded as STUMPs with recurrence areassociated with diffuse immunoreactivity for p16 and p53,7,9,30

the number of cases in these studies are small, and furtherstudy is required to confirm the reliability of employing suchmarkers.

In patients with a high-grade leiomyosarcoma, theclinical course is often aggressive with early recurrenceand metastases. In contrast, in those with STUMPs, tumorgrowth is slower and recurrence is often delayed, onaverage, 51 months (range 15 to 108 mo) after the initial

diagnosis.2,7,9,12,14,15 The clinical course is often prolongedwith a median survival of 61.5 months (range 40 to 108 mo)(Table 3). T

ABLE

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;NA,Notavailable;SMT-LMP,smoothmuscleoflowmalignant

potential;STUMP,smoothmuscletumorofuncertain

malignantpotential.

Ip et al Adv Anat Pathol Volume 17, Number 2, March 2010

94 |www.anatomicpathology.com r 2010 Lippincott Williams & Wilkins


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Proposed Follow-up PlanA paucity of cases means there is limited experience on

which to base standard guidelines for follow-up. On thebasis of the findings discussed here, the follow-up intervalfor patients who have STUMP diagnosed in hysterectomyspecimens should probably be a minimum of every 6 months

until the 5th year and, thereafter, annual surveillance for afurther 5 years. Each visit should include symptom check-ing and a general and pelvic examination. Imaging studiesshould be conducted at least once a year; chest X-rayshould be done to exclude metastasis; pelvic ultrasoundscan, computed tomography or magnetic resonance imag-ing may be used to detect any new lesions. For STUMPsdiagnosed in myomectomy specimens, hysterectomy shouldbe the treatment of choice for those who have completedtheir family, as recurrent uterine tumors have been repor-ted.13 These patients should be followed-up postoperativelyas suggested earlier. For those who wish to preserve fertility,successful pregnancy after myomectomy have been descri-bed,13 but these patients should be informed of the

likelihood of recurrence and be followed-up vigilantly withimaging studies.

Treatment for Recurrent STUMPSTUMPs may recur as STUMPs2,10,15 or as leiomyo-

sarcomas.7,10,12,14 The treatment of choice for recurrence issurgical excision with the majority of patients prescribedsome form of single or combined additional therapy, suchas pelvic irradiation,2,7 chemotherapy (such as doxorubicinand cisplatin),2,7,10 medroxyprogesterone,9,10,14 and gonado-tropin-releasing hormone analogue (Table 3).15 Additionaltherapy seems to be effective, although in its absence,patients have also been reported to have an uneventful

clinical course.

2,12

Smooth Muscle Tumor of Uncertain MalignantPotential: Epithelioid and MyxoidDifferentiations

Malignant smooth muscle tumors with epithelioid ormyxoid differentiation are less common than their spindlecell counterpart, and the diagnostic criteria predictive ofmalignancy are less well established. Malignant tumorsof these differentiations usually show a lesser degree ofcytologic atypia and lower mitotic counts required for adiagnosis of leiomyosarcoma compared with the spindlecell type. For example, in epithelioid smooth muscle tumorswith moderate-to-severe atypia, a mitotic count of more

than 5 per 10 HPFs is sufficient for the diagnosis of epithelioidleiomyosarcoma32; similarly, for myxoid leiomyosarcoma,the presence of as few as more than 2 MFs/10HPFs intumors devoid of atypia or tumor cell necrosis is oftensufficient to justify a diagnosis of malignancy.33

Owing to their rarity, STUMPs of either epithelioid ormyxoid differentiation have not been specifically studied,and the behavior of these lesions is virtually unknown.Currently, as for their spindle cell counterpart, there areno universally accepted criteria for the diagnosis of epithe-lioid STUMP, and none so-far have been described for themyxoid variant. The proposed criteria for epithelioid STUMPare tumors with 2 or more of the subsequent features: sizemore than 6 cm, 2 to 4 MFs/10 HPFs, moderate-to-severe

atypia, and tumor cell necrosis.1 For myxoid STUMP, thepossible criteria for making such a diagnosis include findingof necrosis of an uncertain type and/or infiltrative border in

a myxoid smooth muscle tumor without mitotic activity ornuclear atypia.

Intravenous Leiomyomatosis

Description and Terminology

Intravenous leiomyomatosis (IVL) is defined as intra-vascular proliferation of a benign-appearing smooth muscletumor in the absence of, or beyond the confines of a leio-myoma. Almost all the involved vessels are veins, or rarely,lymphatics. Intraarterial growth has not been described.34

IVL should be distinguished from leiomyoma withvascular invasion. The latter refers to microscopic intra-vascular growth confined to an ordinary leiomyoma that isusually clinically inconsequential, although there are appa-rently no large series with long-term follow-up. Occasionalcases of leiomyoma with vascular invasion have beenassociated with benign metastasizing leiomyoma, whereasothers may represent an early stage of an IVL.35

Typical Clinical and Pathologic FeaturesMost patients with IVL are of reproductive age,

although some cases in older patients in their eighties havebeen described.34 The majority presents with symptomssimilar to those with ordinary leiomyomas. Some may presentwith recurrent leiomyomas after repeated myomectomies.36

A minority of patients initially present with symptomsrelated to cardiovascular involvement.

IVL may be suspected intraoperatively, when worm-like or nodular plugs are found in pelvic veins in descendingorder of frequency: broad ligament, uterus, ovaries, andvagina. Rarely, involvement of the inferior vena cava is identi-fied during hysterectomy. Extrauterine involvement occursin approximately 30% of cases, discovered either intra-operatively or by postoperative imaging studies after a patho-logic diagnosis of IVL. In some cases the clinical impressionduring an operation can be leiomyosarcoma with vascularinvolvement.34,37 Rarely, they are discovered many yearsafter hysterectomy.

IVL is usually diagnosed after pathologic examinationof uterus.38 A uterus affected by IVL is typically enlargedand heavy, and the serosa is often bosselated. Typically, themyometrium is affected by multiple leiomyomas of varyingsizes with IVL found either focally or diffusely (Fig. 4A). Theirregular tumorous nodules are often seen as worm-likeplugs protruding from the cut-ends of the myometrial orbroad ligament veins. Similar to ordinary leiomyoma, theappearance of the tumor in IVL is highly variable: soft andspongy, firm and rubbery, gelatinous and translucent, evenhemorrhagic and calcified depending on the presence ofedema or degenerative changes (Fig. 4B).34

Microscopically, the intravascular tumor nodules arefound outside the confines of 1 or more leiomyomas and aresurrounded by endothelial cells. They are usually composedof mitotically inactive spindle cells devoid of cytologic atypia(Fig. 5). IVL involving the extrauterine vessels or heart maybe free floating within the lumen or adhered to the intima.

Unusual Morphologic Features and DifferentialDiagnoses

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 appearanceof intravenous leiomyomatosis. Note hydropic change in the central tumor nodule. C, Histology (H&E stain) of an epithelioidintravenous 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 undergohydropic 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 andrhabdoid cells (H&E stain).




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On rare occasions, intravascular endometrial tissuecan be seen. The intravascular tumor may comprise spindle

or epithelioid smooth muscle cells with thick-walled bloodvessels that merge with endometrial glands and stroma(Fig. 4C).38 Distinction of this intravenous adenomyosisfrom endometrial stromal sarcoma with glandular differ-entiation may be difficult, as the latter often showsprominent intravascular growth (Fig. 7).39 Features thatfavor an endometrial stromal sarcoma include endometrialinvolvement, permeative myometrial invasion by tongues ofextravascular tumor, predominance of endometrial stromaover smooth muscle, and presence of atypia and highmitotic activity in the neoplastic endometrial stromal cells.

Cellular IVL is most likely to be confused with anendometrial stromal sarcoma (Fig. 8). It is distinguished bythe features described in the preceding paragraph (see alsodifferential diagnoses on cellular and highly cellular leio-myoma 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/10HPFs.38 None of thesefeatures has been associated with more aggressive behavior.

FIGURE 5. Intravenous leiomyomatosis. The intravascular poly-poid tumor has a clefted contour and contains numerous thick-walled blood vessels.

FIGURE 6. Cellular intravenous lipoleiomyomatosis.

TABLE 4. Morphologic Variants of Intravenous Leiomyomatosis(IVL)

Cellular IVLbizarre nucleiIVL with bizarre nucleiEpithelioid IVL (eosinophilic cell)Epithelioid IVL (clear cell)Epithelioid IVL with bizarre nucleiMyxoid IVLIntravenous lipoleiomyomabizarre nuclei

IVL with endometrial tissueIVL as a component of dissecting/cotelydenoid dissectingleiomyoma

FIGURE 7. Endometrial stromal sarcoma with glandular differ-entiation. Distinction from intravenous leiomyomatosis withendometrial tissue (intravenous adenomyosis) may be difficult.




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IVL with bizarre nuclei is distinguished from leiomyo-sarcoma by the absence of mitotic figures. Additionally, the

latter do not usually show grossly visible vascular invasion.38

Coard and Fletcher reported a uterine leiomyosarcomawith unusually striking vascular involvement resemblingIVL (intravenous leiomyosarcomatosis). The extravasculartumor 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 Suchdiagnosis should nonetheless be cautious, as myxoidsmooth muscle tumors are often hypocellular (see sectionon myxoid leiomyoma), and distinguishing myxoid IVLfrom myxoid leiomyosarcoma is extremely difficult. MyxoidIVL should be mitotically inactive and devoid of atypiawith no infiltrative myometrial myxoid smooth muscletumor elsewhere in the uterus.

Epithelioid IVL should be distinguished from epithelioidleiomyosarcoma. Although epithelioid IVL may occasionallycontain cells with bizarre nuclei (Fig. 9), the absence of a highmitotic count and tumor cell necrosis distinguishes it from aleiomyosarcoma with vascular invasion.

IVL may also coexist or be as a component of dissect-ing leiomyoma or cotelydonoid leiomyoma (Fig. 10). Extra-vascular tumors in such cases are often more hydropic.42

Behavior and Frequency of RecurrenceAlthough 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 yearsafter hysterectomy. Detection of persistent or recurrenttumors has been reported to occur between 7 months to 15

FIGURE 10. Dissecting leiomyoma with intravenous leiomyoma-tosis. The irregular tumor dissects through the myometriumassociated with 2 small foci of intravascular tumor (arrows).

FIGURE 8. Cellular intravenous leiomyomatosis. Note the pre-sence of thick-walled blood vessels, which helps to distinguish itfrom endometrial stromal sarcoma.

FIGURE 9. Epithelioid intravenous leiomyomatosis. The tumor ismitotically inactive and devoid of tumor cell necrosis. Rarely, itmay contain bizarre tumor cells, as seen in leiomyoma withbizarre nuclei.




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years (median, 2.5 y) after hysterectomy.34 In approximately70% of the patients, the initial presentation was related toinferior vena cava and cardiac involvement. The remain-ing patients had a pelvic mass. The risk of recurrence forIVL is low, likely much less than 5% (personal commu-nication, Dr Philip B. Clement).17 One hospital-based study

of 22 cases of IVL found no cardiovascular recurrence aftera mean follow-up of 7.5 years.37

ManagementTreatment of IVL is surgical. If complete excision of

the tumor is not possible, ligation of the vein distal to thetumor has been suggested to prevent tumor growth alongthe inferior vena cava.43 IVL are usually hormone receptorpositive, and because the diagnosis is usually made in ahysterectomy specimen, subsequent bilateral oophorectomyis recommended, if it has not already been done.34 It maybe prudent to do a posthysterectomy MRI scan of the pelvisto check for any residual intravascular tumor followed byan 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 theextrauterine tumors are removed, when technically feasible.The use of GnRH-a, tamoxifen, and aromatase inhibitorshas been successful in some cases, in which resection wasnot possible.36,4548

Benign Metastasizing Leiomyoma

Description and TerminologyBenign metastasizing leiomyoma (BML) is a condition

in which single or multiple morphologically benign smoothmuscle tumors are found in extrauterine locations, espe-cially the lungs, in women with a history of typical uterine

leiomyomas. BML should only be diagnosed after a uterineor extrauterine leiomyosarcoma has been excluded, or onthe assumption that any preexistent uterine leiomyoma hasbeen thoroughly sampled with no histologic evidence ofmalignancy.

BML seems to be a tumor with benign histology butwith the biologic behavior of a malignant tumor. Althoughmost patients with persistent pulmonary disease have anindolent clinical course, the tumors may continue to growand result in respiratory failure and death.49 For thisreason, some investigators have proposed that BMLsshould be regarded as STUMPs.50

Typical Clinical and Pathologic Features

Patients are usually of late reproductive age, butoccasionally they are postmenopausal.50,51 Almost allcases of BMLs have been described in women with ahistory of prior hysterectomy for uterine fibroids with orwithout subsequent hormone replacement therapy.52 Inthe largest series, the metastatic lesions were discoveredafter a median interval of 14.9 years after the initialremoval of uterine fibroids.49 The most commonlyinvolved extrauterine location is the lung, but abdomi-nopelvic and mediastinal lymph nodes, soft tissue,striated muscle, and bone have also been described.5366

Lung lesions are often discovered incidentally with chestX-rays, and rarely do patients present with respiratorysymptoms, such as dyspnoea, cough, or chest pain.6769 One

case has been reported in which the patient presented withsymptoms related to empyema and pleural effusion.70 Theusual chest radiologic finding includes multiple and bilateral

military nodules ranging from several millimeters to 10centimeters (Figs. 4D, E and Fig. 11).49 When BMLs occur inextrapulmonary locations, the presenting symptoms areusually related to the mass lesion.65,66

Although some investigators consider BMLs as multi-focal hyperplastic or neoplastic proliferations of smooth

FIGURE 12. Benign metastasizing leiomyoma. Proliferation ofmitotically inactive spindle tumor cells lacking atypia or tumorcell necrosis. Note the entrapped bronchioles (arrows).

FIGURE 11. CT scan of thorax from a patient with benignmetastasizing leiomyoma. Multiple nodules of various sizes aredistributed throughout both lungs.




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muscle in response to hormonal stimulation,7174 there isincreasing evidence that many are a result of vascular orlymphatic dissemination from uterine leiomyomas. This isevidenced by case reports in which BMLs coexisted withleiomyomas 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 ofandrogen receptor allelic inactivation and X-chromosomeinactivation between the pulmonary and uterine lesionsindicating that these are indeed clonal. Nucci et al80 showeda distinctive cytogenetic profile of BMLs that was found onlyin a subset (3%) of uterine leiomyomas not present in othertypes of benign or malignant tumors.

Microscopically, the lesions resemble a benign uterineleiomyoma. They are usually normocellular, mitoticallyinactive, and devoid of atypia or tumor cell necrosis andexpress both estrogen and progesterone receptors.49 Theymay show hydropic change, as in the uterine leiomyoma. Inaddition, pulmonary lesions often show entrapment ofbronchioalveolar epithelium characterizing the slow growth

of the tumors (Fig. 12).


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 insuch cases is essential, and may lead to discovery of apoorly sampled STUMP or leiomyosarcoma.

The finding of heterologous elements, such as adiposetissue, in an otherwise bland-looking BML, is of noadditional adverse clinical consequences.81

ManagementBMLs are slow-growing and hormone-sensitive. Bilateraloophorectomy should thus be considered in patientswho still have unresected ovaries.56,82 If the patients aresymptomatic, metastatic lesions should, wherever possible,be resected. If the tumors are not resectable, or if thepatient refuses surgery, hormonal therapy including gona-dotropin-releasing hormone analogue (GnRH-a), proges-tin, aromatase inhibitor (such as anastrozole), and aselective 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/ORMETASTATIC POTENTIALThese include leiomyoma variants with diagnostic

terms accurately describing the unusual gross or histologicfeatures. They may be considered atypical to a pathologist,because they have certain characteristics that may mimicmalignancy. Clinically, they are benign and are managedin the same way as ordinary leiomyomas. Although any ofthe variants may recur after myomectomy, recurrence withdistant metastasis after hysterectomy is rare.

The typical gross appearance of a leiomyoma is firm,spherical, circumscribed, and bulging, when sectioned. Thecut surface is often grey-white with a whorled appearance.It is important to be aware of the range of possible morpho-

logic changes that ischemia, hormonal, and drug treat-ment may induce, as their presence may cause diagnosticdifficulty or misdiagnosis. The patients drug history is

often overlooked, especially, when it is not included on thepathology request form. Progestogens, oral contraceptives,and tranexamic acid may induce hemorrhage and/ornecrosis in leiomyomas (Fig. 4F). Cases of GnRH-aassociated necrosis have also been described.11,8589 If thetime interval between drug administration and leiomyoma

removal is short, drug-induced necrosis may be of the earlyinfarct type that may mimic tumor cell necrosis, or belabeled as necrosis of an uncertain type. This will lead to adiagnosis of STUMP.11,90

GnRH-a is sometimes used to create a temporaryartificial menopause that leads to the shrinkage of largeuterine leiomyomas. This facilitates their surgical removaland prevents excessive bleeding. Reports on the range ofhistologic changes associated with GnRH-a are conflicting;some investigators found no light microscopic differencesbetween treated versus untreated tumors,91,92 whereas othershave reported increased cellularity in GnRH-a-treatedlesions,89,93 a finding supported by studies that includedthe use of morphometry in their methodology.94,95 Degene-

ration and loss of cytoplasmic organelles and/or alterationof extracellular matrix has been proposed as the mechanismunderlying the reduction of leiomyoma size.94,96 It is thusreasonable to assume that the loss of cell volume orextracellular matrix may result in crowding of nuclei.Additionally, leiomyomas removed several weeks aftercessation of GnRH-a may show increased mitotic activity(corresponding to regrowth of the tumor observed clini-cally).85

The finding of any unusual features other than thosedescribed in the subsequent sections requires thoroughsampling of the tumor; usually, 1 block per cm of tissueshould be selected for microscopic examination. If a tumorhas an unusual combination of any of the 3 features that

give cause for concern, STUMP is an appropriate diagno-sis. Such features include significant nuclear atypia, necrosisof an uncertain type, and a high mitotic count equivocal fordiagnosis of a leiomyosarcoma.

Leiomyoma With Bizarre Nuclei (LBN)

Description and TerminologyOnce regarded as in-situ leiomyosarcomas,97 these

tumors are now generally accepted as a clinically benignvariant of leiomyoma. They are also variously referred to asbizarre leiomyomas, symplastic leiomyomas, or pleomor-phic leiomyomas.6,98101 In the earlier edition of the WHOclassification, bizarre leiomyoma was defined as a leiomyoma

containing giant cells with pleomorphic nuclei with little orno mitotic activity.102 In the current WHO classification,bizarre leiomyoma is grouped under the heading atypicalleiomyoma (see also above section on the controversy ofatypical leiomyoma).1

Typical Clinical and Pathologic FeaturesThe clinical presentation and gross features of LBNs

do not usually differ from those of ordinary leiomyomasand will be of little concern to the gynecologist or patholo-gist, until they are examined microscopically. Occasionally,they may seem grossly atypical, being more yellow andtanned with hemorrhagic or myxoid change (Fig. 4G).

Most LBNs are less than 5.5 cm in diameter,6 and theyare characterized by the presence of large cells witheosinophilic cytoplasm and bizarrely shaped, multilobated,


100 | www.anatomicpathology.com r 2010 Lippincott Williams & Wilkins


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or multinucleated nuclei. The chromatin is often smudged,and there may be cytoplasmic pseudoinclusions. As notedearlier, this strikingly abnormal morphology is consi-dered as a degenerative, rather than neoplastic change.103

Although the distribution of these bizarre cells is describedto be diffuse or multifocal, most of these examples represent

cases seen in consultation practice. In the course of routinesurgical pathology, they are more commonly found asisolated foci distributed in a background of an otherwisetypical leiomyoma (Fig. 13).

LBNs are reported to be clinically benign. Evans et al98

described 3 atypical leiomyomas that had 1, 0, and 0 MFs/10HPFs, respectively, and followed an uneventful clinicalcourse for 25, 10, and 11 years, respectively. Downes andHart studied 24 LBNs and found an average of 1.6MFs/10HPFs using the highest count method, or 0.8 MFs/10 HPFs using the average count method. Although 1 of thetumors had 7 MFs/10 HPFs, none of them recurred aftera mean follow-up of 11.2 years.6 Przybora also described 15cases of such tumors with no evidence of recurrence or

metastasis in 9 patients for whom follow-up data wereavailable. Follow-up was nonetheless short.97


The differential diagnoses of LBNs include STUMPand leiomyosarcoma. Unlike tumors that some investiga-tors regard as STUMPs, as noted above, LBNs that arethoroughly sampled for microscopic examination have verylow mitotic activity, and absence of tumor cell necrosisalthough infarct type necrosis can be present (Fig. 14).

FIGURE 13. Leiomyoma with bizarre nuclei. In routine surgicalpathology practice, examples of this are usually tumors contain-ing occasional focus (or foci) of bizarre cells in an otherwiseunremarkable leiomyoma.

FIGURE 14. Leiomyoma with bizarre nuclei with infarct typenecrosis. The viable tumor is usually separated from the necroticcells (N) by a zone of reparative granulation tissue (R).

FIGURE 15. Leiomyoma with bizarre nuclei with skeletal muscle-like and rhabdoid cells.




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When a tumor contains strikingly bizarre cells thatresemble 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 Necrosisor mitotic figures can often be a focal finding, and the needfor adequate sampling should be reiterated.

LBNs may occasionally contain tumor cells withabundant eosinophilic cytoplasm, including eosinophiliccytoplasmic globules. Similar cellular changes in uterineleiomyomas referred to as skeletal muscle-like and rhab-doid cells are not associated with clinically malignantbehavior, provided there are no worrisome microscopicfeatures (Fig. 4H and Fig. 15).104

Bizarre tumor cells have also been found in lipoleio-myomas (Fig. 16).105 Their presence in these tumors has nobearing on their behavior. For liposarcomas that arise fromlipoleiomyomas, lipoblasts, a mitotic count of 3 to 7 per

10 HPFs and usually, tumor cell necrosis is present along-side tumor cells with bizarre nuclei.106

Mitotically Active Leiomyoma

Description and TerminologyMitotically active leiomyomas are defined as smooth

muscle tumors with Z5 to 15 MFs/10 HPFs. They are alsoreferred to as leiomyomas with increased mitotic index.2

Typical Clinical and Pathologic FeaturesThese do not differ from ordinary leiomyomas in any

gross or microscopic aspects, except for their higher mitoticcount. Most importantly, they should not have significant

cytologic atypia and should be devoid of tumor cellnecrosis. If this is not the case, STUMP or even leiomyo-sarcoma should be considered.35

Mitotically active leiomyomas are related to themitogenic effect of progesterone and thus usually diagnosedin a uterus during the secretory phase of the menstrualcycle. They commonly have a submucosal location and arerarely seen in postmenopausal women, except under theinfluence of exogenous hormones.107,108 A case of mitoti-

cally active leiomyoma in a postmenopausal woman takingtamoxifen has nonetheless been reported.109


Cytologically bland smooth muscle tumors withouttumor cell necrosis but a mitotic count more than 15 MFs/10 HPFs are rarely reported in the literature, and theirbehavior is therefore less certain. Two of the 91 patients inBells study of tumors that had a mitotic count of morethan 20 MFs/10 HPFs were alive without disease after 102and 78 months, respectively.2 One patient with a similartumor in the study by Ip et al7 that had 20 MFs/10 HPFshad an uneventful clinical course of 21 months. In view of

the scant information on uterine smooth muscle tumors inwhich the only worrisome feature is a mitotic countZ15MFs/10 HPFs, they have been labeled as mitoti-cally active leiomyomas with limited experience,2 althoughthey should now be appropriately considered as STUMPs(Table 2).2,7

Cellular and Highly Cellular Leiomyoma

Description and TerminologyCellular leiomyomas (CLs) are defined as leiomyomas

that are significantly more cellular than the surroundingmyometrium, often with crowding and overlapping ofnuclei.1 Highly cellular leiomyomas (HCLs) have an even

higher density of cells reminiscent of endometrial stromaltumors.110

Typical Clinical and Pathologic FeaturesThe 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 appearmore tan or yellow and less circumscribed than the usualleiomyomas (Fig. 17A).110 Microscopically, they are tumorsthat are characterized by small cells with scanty cytoplasmand oval-to-spindle nuclei and arranged in a fascicular pattern.Intralesional thick-walled vessels and cleftlike spaces are com-mon. The tumors often have an irregular border that mergesimperceptibly with the surrounding myometrium (Fig. 18).


The most important differential diagnosis of CL andHCL is leiomyosarcoma. Unlike leiomyosarcomas, thesebenign and hypercellular variants of leiomyoma have notumor cell necrosis and lack significant cytologic atypia.Nonetheless, tumors containing focally bizarre cells, similarto those in LBNs, have been described, although they arenot associated with malignancy.100,110,111

The average mitotic count for CLs and HCLs istypically


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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. Notethe cleft-like spaces between coalescing tumor nodules. B, Cotelydonoid dissecting leiomyoma. The grape-like appearance is owing tothe perinodular hydropic change subdividing the extrauterine tumor into numerous bulbous nodules. C, Dissecting leiomyoma. Thetumor is lobulated and shows irregular penetration of the myometrium. D, Cotelydonoid dissecting leiomyoma. The extrauterine tumorhas 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 (rightimage). H, Diffuse leiomyomatosis. The myometrium is involved by numerous tiny tumors and a few typical leiomyomas.




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leiomyomas though, CLs and HCLs may also be subjected

to the mitogenic effect of progesterone, and under thesecircumstances, they should probably still be regarded asmitotically active cellular leiomyomas and mitotically activehighly cellular leiomyomas, respectively, rather thanSTUMPs, unless the mitotic count is more than 15 per10 HPFs.

HCLs may also be confused with endometrial stromaltumors. The latter usually have small arterioles encircled byfusiform tumor cells, absence of thick-walled blood vessels,and sharply circumscribed margins (Fig. 19). Use of a panelof immunohistochemical stains, such as h-caldesmon,desmin, and CD10, can usually distinguish between the 2conditions. HCLs usually express h-caldesmon and desmin,whereas endometrial stromal tumors express CD10.112,113

Dissecting Leiomyoma, Cotelydenoid DissectingLeiomyoma, and Cotelydenoid Leiomyoma

Description and TerminologyA dissecting leiomyoma is characterized by an unusual

pattern of growth in which the tumor permeates throughthe myometrium. It may extend beyond the uterus and involvethe pelvis, including the broad ligament, and sometimes,owing to the commonly associated edema and congestion,give rise to a characteristic gross appearance reminiscentof the cotelydons of a placenta. This has been describedas cotyledenoid dissecting leiomyoma (Sternberg tu-mor).114,115 These tumors are probably identical with theso-called grapelike leiomyoma described in older studies

(Fig. 17B).116,117When a dissecting leiomyoma arises subserosally in the

uterus and involves the broad ligament without the accom-

panying intramyometrial dissecting growth, the term

cotelydenoid leiomyoma is appropriate.

118

Typical Clinical and Pathologic FeaturesThese tumors affect women in their reproductive age or

those who are perimenopausal. The clinical presentation andgross pathologic features are similar to that of the usualleiomyomas, although the intrauterine component is usuallymore lobulated and has irregular and, sometimes, indistinctmargins (Fig. 17C).117 Microscopically, elongated nodules orlong columns of tumors can be found dividing throughbundles of smooth muscle of the myometrium (Fig. 20).

Cotyledenoid dissecting leiomyomas (and cotelyde-noid leiomyomas) are red, purple, exophytic and multi-nodular and are usually large (mean 17.7 cm). They commonly

have extensive pelvic involvement and may simulate amalignant lesion intraoperatively. They may promptthe surgeon to request frozen section to exclude malignancy(Fig. 17D).114,119121 Microscopically, the tumor nodulesshow a sinuous dissecting pattern into the myometrium andbeyond separated by edematous and richly vascularizedstroma. 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


It is conceivable that any of the cytologic variationsin an ordinary leiomyoma may be seen in these dissecting

leiomyomas. To date, none of the reported cases have beenassociated with microscopic worrisome features, includingthe combinations of nuclear atypia, high mitotic activity,

FIGURE 18. Highly cellular leiomyoma. Note the presence ofcleft-like spaces and thick-walled blood vessels (top), andirregularity of border in which the tumor cells melt into thesurrounding myometrium (bottom).

FIGURE 19. A, Endometrial stromal nodule. Note presence ofsmall arterioles surrounded by fusiform tumor cells and sharpdemarcation from the myometrium on right, in contrast to ahighly cellular leiomyoma (Fig. 18).




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and/or tumor cell necrosis. Of the 8 dissecting leiomyomacases reported by Roth and Reed, 1 tumor had a high

cellularity (cellular dissecting leiomyoma) and was followedby an uneventful postoperative course.117 Another casereport of a dissecting leiomyoma was associated withresidual tumor postoperatively, although there was nofurther increase in size after 15 months of follow-up.119

IVL may be a component of any of these 3 dissectingleiomyoma variants;42,122 however, follow-up informationon these cases, is limited. It is reasonable that patients whohave tumors with this unusual growth pattern be managedin the same manner as those with IVLs without this feature.

Myxoid Leiomyoma

Description and Terminology

Myxoid leiomyomas are leiomyomas that contain abun-dant acellular stroma that appears pale or basophilic andsemitransparent on routine hematoxylin and eosin stainedsections. The myxoid change is the accumulation of hyal-uronic acid-rich glycosaminoglycans that can be confirmedby special stains, such as alcian blue. This ensures distinctionfrom the more common hydropic change with which it isoften confused (Figs. 17E, F, G).123 Hydropic change is anaccumulation of edematous fluid and of no clinical signi-ficance. Myxoid change can be a focal finding in up to 12%of benign leiomyomas, especially surrounding zones of aninfarct124 and may also be associated with pregnancy.86

Typical Clinical and Pathologic Features

Myxoid leiomyomas are usually gelatinous, but thisappearance is rarely diffuse or pure. More commonly, thegelatinous foci alternate with nonmyxoid white to grey

FIGURE 20. Dissecting leiomyoma. Tongues of tumor (T) dissectbetween myometrial smooth muscle. Noted hydropic changewithin the tumor nodules.

FIGURE 21. Cotelydonoid dissecting leiomyoma. The tumornodules are often strikingly congested and hydropic.

FIGURE 22. Cotelydonoid dissecting leiomyoma. The spindledtumor cells are usually arranged in a swirling, rather than afascicular growth pattern and separated by a hydropic stroma.




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areas, sometimes with areas of gross necrosis and hemorr-hage. Although malignant tumors may have a grossly decep-tive circumscribed border,33 the finding of an ill-defined orinfiltrative border should prompt extensive sampling fromthe surrounding myometrium. An infiltrative border isknown to be associated with malignant behavior in myxoid

smooth muscle tumors, but in one study, one-third of benigncases also showed this feature.33 Histologically, the myxoidzones are often hypocellular, with the spindle or stellatetumor cells spread throughout the basophilic matrix.


Pathologic assessment of malignancy is more difficultin myxoid smooth muscle tumors. The myxoid foci mayabut a nonmyxoid area within the tumor, creating a pseudo-invasive histologic appearance. Careful gross evaluation andblock coding for tissue sampled at the periphery of thetumor is therefore necessary.125

In tumors that are extensively myxoid, the cellularity is

often low and the tumor cells are widely separated resultingin a lower mitotic count. The cells may be more oval orstellate with less cytoplasm and the atypia is less conspicuous.Sometimes, even the recognition of their smooth musclenature may be difficult, and confirmation with immuno-stains such as desmin and h-caldesmon is necessary. Tumorcell necrosis is also less often encountered in malignanttumors. For these reasons, the diagnostic threshold for diagno-sis of myxoid leiomyosarcomas is different from that ofconventional leiomyosarcomas (see preceding section onmyxoid smooth muscle tumor of uncertain malignantpotential). The finding of areas of conventional leiomyo-sarcoma, vascular invasion, and irregular infiltrating bor-ders often helps make the distinction but extensive sampling

is often necessary.

Epithelioid Leiomyoma

Description and TerminologyThis subtype of benign uterine smooth muscle tumors

is defined by the presence of rounded or polygonal cells thathave a microscopic appearance of epithelial cells in atleast 50% of the tumor. In the literature, they are referredvariously as leiomyoblastomas and clear cell leiomyo-ma.32,98,101,126,127 The former, an outmoded terminology,is no longer in general use, as it incorrectly implies a highlymalignant tumor composed of primitive small roundtumor cells.85,98,126 Plexiform leiomyomas are epithelioid

leiomyomas in which the tumor cells are arranged in cordsand nests separated by a hyalinized stroma; those


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Epithelioid differentiation may constitute part of, orbe a predominant cellular component of IVL. Tumors withsuch features should be managed in the same manner asordinary IVL (see preceding section on IVL).

As for ordinary leiomyomas, epithelioid leiomyomasmay contain tumor cells with bizarre nuclei that aredegenerative in nature (Fig. 25). When unaccompanied bymitotic activity or tumor cell necrosis, these tumors arereported to follow a benign clinical course.32,105 Lipoleio-myoma may also contain tumor cells arranged in aplexiform pattern (plexiform lipoleiomyoma); this has nobearing on the clinical behavior.130

Two epithelioid smooth muscle tumors containingosteoclastic-type giant cells are reported to be clinicallymalignant. In addition, they both have other features ofmalignancy, including tumor cell necrosis and a high mitoticcount.32,131

In rare cases, tumors may have epithelioid cells

arranged in cords or nests scattered among a backgroundof ordinary leiomyoma, potentially mimicking metastaticcarcinoma.132 Immunohistochemical study is necessary undersuch circumstances. Unfortunately, the tumor cells in epi-thelioid smooth muscle tumors often express cytokeratins(as in carcinomas) and less often myogenic markers, such asdesmin. Histone deacetylase 8 has recently been shown tobe a superior smooth muscle marker for epithelioid smoothmuscle tumors compared with desmin or h-caldesmon.133

Epithelioid smooth muscle tumors that are composedof clear cells may be immunoreactive for HMB-45 in one-third of cases, and these show overlapping morpho-logy with perivascular epithelioid cell tumors (Fig. 26).The latter are associated with tuberous sclerosis and/or

lymphangioleiomyomatosis and one-third are found to beclinically malignant.134137

Epithelioid leiomyomas should have absent or mild

atypia (grade 1), r2 MFs/10HPFs and no tumor cellnecrosis. Presence of bizarre cells (as noted above) shouldnot be included in the grading of atypia. Clinicallymalignant epithelioid smooth muscle tumors normally havegrade 2 to 3 nuclear features and more than 5 MFs/10 HPFs, often with tumor cell necrosis.32,126,138,139 Tumorsthat do not satisfy benign or malignant criteria can beappropriately labeled as epithelioid STUMPs (see precedingsections on STUMPs) and be managed accordingly.

Diffuse Leiomyomatosis

Description and TerminologyDiffuse leiomyomatosis (DL) is a rare lesion with less

than 20 cases reported in the literature, and is characterizedby extensive involvement of the myometrium by countless,confluent proliferating smooth muscle nodules.1 The cervixappears to be spared. In the older literature, cases withsimilar pathologic features were variously referred to asgeneral myomatous tendency of the uterus140, myoma-tosis141 and complete fibromyomatosis of the corpusuteri142.

Each individual nodule in DL has been shown to beof different clonal origin, as shown by the presence ofnonrandom X-chromosome inactivation involving differentalleles between each lesion.143 Some cases have beenreported to occur in association with Alports syndrome.144

Typical Clinical and Pathologic FeaturesDL affects women in their reproductive years: patient

age ranges from 28 through 42 years.145,146 Although theFIGURE 25. Epithelioid leiomyoma with bizarre nuclei. Some ofthe bizarre cells concentrate around blood vessels.

FIGURE 26. Epithelioid leiomyoma. Tumors composed entirelyof clear cells.




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clinical symptoms are identical to those of women withordinary leiomyomas, rapid uterine enlargement has been

described.147 Diagnosis can usually be made by ultrasoundscan, in which the innumerable small myometrial tumorscan be detected.148,149

The affected uterus is symmetrically enlarged and theserosa is often bosselated (Fig. 27). The myometriumtypically contains numerous ill-defined nodules


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sarcomas usually involve the endometrium, and the tumornodules often show abrupt transition as opposed tomerging imperceptibly to the surrounding myometrium.Finding of other features of endometrial stromal tumorsdescribed above supports the latter diagnosis. (see underdifferential diagnoses of cellular and highly cellular

leiomyomas above).Extrauterine extension of DL with involvement of the

ovaries and parametrium has been described in 1 casereport in which the tumor showed no worrisome micro-scopic features and there was no vascular invasion. Thepatient showed no evidence of residual disease 6 monthsafter surgery.146

Although most investigators found DL a benigncondition,145,147 its relationship with BML is unknown.Thomas et al151 described a patient in whom DL causeduterine rupture during pregnancy, and incidental discoveryof BMLs involving the iliac bones and vertebral bodies. Thehistology of all lesions was benign, and the tumor expressedestrogen and progesterone receptors. All the bony lesions

regressed spontaneously during the post-partum period.

ManagementAs DL is rare, there is no consensus on management.

Owing to the extensiveness of the condition, and the factthat the tumor cells merge imperceptibly with the surround-ing myometrium, myomectomy is ineffective and patientsinevitably develop persistent disease. Additionally, severeintraoperative hemorrhage is a risk.152,153 Uterine conser-vation with uterine arterial embolization or GnRH-a hasbeen successful in some cases.154,155

Patients with DL are said to be more likely to have adistorted uterine cavity, and hence infertility problems.156

Nonetheless, pregnancy has been achieved after hystero-

scopic resection of submucosal fibroids with or withoutprior GnRH-a treatment.148,149

ACKNOWLEDGMENTS

The authors thank Dr Philip B. Clement (Department ofPathology, University of British Columbia, Vancouver Hospi-tal and Health Science Centre, Vancouver, Canada) for hisadvices and comments on this review, and for allowing studyand photography of his consultation cases; The authors alsothank Dr Robert H. Young (Department of Pathology, HarvardMedical School, Massachusetts General Hospital, Boston,MA), Dr Victor Tang (Department of Pathology, PamelaYoude Nethersole Hospital, Hong Kong), and Dr Tina Lam

(Department of Diagnostic Radiology, Queen Mary Hospi-tal, Hong Kong) for their generosity in contributing gross andradiologic photos.

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