—  SHORT COURSE #25  —

Mesenchymal Tumors of the Corpus and Glandular Lesions of the Cervix

Case 2 - Mesenchymal Tumors of the Corpus

Marisa R. Nucci and Esther Oliva


I) Smooth Muscle Tumors

Leiomyoma Variants
Typical leiomyomas are the most frequent among smooth muscle tumors. They are present in 25% of women of reproductive age. Although most of these tumors do not pose diagnostic difficulties on gross or microscopic examination, a number of leiomyoma variants can be misinterpreted as a leiomyosarcoma or even as some other type of uterine neoplasm because their unusual macroscopic or microscopic features such as ill-defined borders, fleshy areas, hemorrhage or marked cellularity.

A. Cellular and Highly Cellular Leiomyomas
Cellular leiomyomas are defined by the World Health Organization as otherwise typical leiomyomas that are "significantly" more cellular than the normal myometrium. The diagnostic threshold for "significant" cellularity should be that cellular leiomyomas do not account for more than 5% of leiomyomas in one's practice. On gross examination, cellular leiomyomas may resemble typical leiomyomas but often have a more fleshy, tan-brown to yellow sectioned surface. Hemorrhage or infarct-type necrosis or both are present in a minority of cases. These tumors almost always have < 5MFs/10HPFs and they are cytologically bland.

A small subgroup of cellular leiomyomas has a cellularity that is comparable to that seen in endometrial stromal tumors. These tumors are termed highly cellular leiomyomas. They may be confused with endometrial stromal nodules when well circumscribed or with low-grade endometrial stromal sarcomas when their borders are irregular, as they frequently are. On gross examination many of them have a somewhat different consistency and color from that of conventional leiomyoma, on average being softer and having a tendency to be yellow or yellow-tan, rather than white like the usual leiomyoma. Findings that help in the differential diagnosis with an endometrial stromal neoplasm are: a) the focal merging of the highly cellular areas with fascicular areas of characteristic smooth muscle neoplasia in most of the cases; b) the finding of large thick muscular wall blood vessels in contrast to the arterioles of an endometrial stromal neoplasm; c) the presence in many tumors of cleft-like spaces, some apparently representing compressed vessels, others apparently the result of edema; d) and strong and multifocal or diffuse immunoreactivity for desmin. Although there is controversy on desmin immunoreactivity in endometrial stromal tumors in the literature, in our experience endometrial stromal tumors only show focal desmin positivity that in many occasions is related to smooth muscle differentiation.

Another problematic aspect of some cellular and highly cellular leiomyomas is brisk mitotic activity. However, this is a well-known histologic feature relatively recently described in conventional leiomyomas. When this occurs in a highly cellular leiomyoma it should receive the designation of "mitotically active cellular leiomyoma" or "highly cellular mitotically active leiomyoma."

B. Leiomyomas with Bizarre Nuclei
These tumors have been referred to as "symplastic", "atypical", or "bizarre" leiomyoma, or as we prefer, "leiomyoma with bizarre nuclei". They usually occur in women of reproductive age. Downes and Hart reported the largest series of these tumors with 24 cases. Grossly these tumors usually resemble conventional leiomyomas, but they may show yellow to tan areas, areas of hemorrhage, focal softening, cavitation or myxoid change. In their series cellularity ranged from slight as seen in conventional leiomyomas (21%) to high as seen in highly cellular leiomyomas (21%). The defining feature of these neoplasms is the presence of bizarre pleomorphic cells usually with abundant eosinophilic cytoplasm with prominent nuclear pseudoinclusions and atypical nuclei, which can be distributed throughout the tumor, or may form discrete foci with a uni- or multifocal distribution. Most of these cells are multinucleated but they also can be mononucleated. Often the nuclei are pyknotic with dense smudged chromatin. Karyorrhectic nuclei simulating abnormal mitotic figures are often seen. Other worrisome nuclear features include the finding of prominent nucleoli, coarse chromatin and finally the presence of mitotic counts up to 7MFs/10HPF by the highest count method in some tumors as reflected by the Downes and Hart series. However in the same series the mitotic count by the average method ranged from 0 to 2.8 MFs/10HPFs (mean 0.8). In these cases it is very important to recognize that the areas not involved by the bizarre cells show bland cytologic features even when the bizarre cells are more diffusely arranged (as they are in 50% of the cases).

All the studies in the literature, including the Downes and Hart series, which had complete follow-up (mean 11 years), have shown that leiomyomas with bizarre nuclei have a benign clinical course. Only a small number of cases treated by myomectomy, however, have had long-term follow-up.

Leiomyomas with bizarre nuclei are distinguished from leiomyosarcoma by an absence of tumor cell necrosis and mitotic counts of < 10MFs/10HPFs. Downes and Hart found that the combination of aneuploidy and high MIB-1 activity is rare in bizarre leiomyomas, and a diagnosis of bizarre smooth muscle tumor should be made with caution when these features are seen.

C. Mitotically Active Leiomyomas
Otherwise typical or cellular leiomyomas with 5 to 15 MFs/10 HPFs (or even 19 in one series) have a benign course even after myomectomy, provided that they are benign by other criteria. The terms "mitotically active leiomyoma" or "leiomyoma with increased mitotic index" have been applied to such tumors. Otherwise typical tumors in this group that have 20 or more MF/10 HPFs are so rare that they are referred to by Bell et al as "leiomyoma with increased mitotic index but experience limited". At least 60% of mitotically active leiomyomas were submucosal in one study. In two series, a diagnosis of mitotically active leiomyoma was allowable only in the absence of nuclear pleomorphism, although the presence of mild nuclear atypia should not exclude the diagnosis. In as many as 15% of these tumors there is microscopic vascular invasion within the confines of the tumor. Most mitotically active leiomyomas lack worrisome features, but in one series almost 40% of the tumors had soft, fleshy or cystic areas and 20% of them were focally hemorrhagic. In contrast to leiomyosarcomas, these tumors almost always occur in women of reproductive age and are typically associated with the secretory phase of the menstrual cycle, pregnancy, or the use of exogenous hormones, consistent with the mitogenic effect of progestins on uterine leiomyomas.

D. Leiomyomas with Hormone-related Changes
Leiomyomas from pregnant patients or those on progestins may be misinterpreted as leiomyosarcoma. There may be a history of rapid growth of the leiomyoma (which also may occur with clomiphene or tamoxifen therapy), causing a clinical suspicion of sarcoma. On pathological examination, the pregnancy or progestin-related changes include hemorrhage, edema, myxoid change, focal hypercellularity, nuclear pleomorphism, and increased mitotic activity. A dusky red discoloration, so-called red degeneration, although observed occasionally in non-pregnant patients (such as those on oral contraceptives), is characteristic of pregnancy. The cause of the lesion is unclear, but it appears to be the result of variable degrees of infarction, hemorrhage with subsequent hemolysis, and hyalinization within a leiomyoma. Because of these pregnancy-related changes and the rarity of leiomyosarcomas in the reproductive age group, a diagnosis of uterine leiomyosarcoma should be rendered with caution in a pregnant patient or one on hormonal medication.

The synonymous designations "apoplectic leiomyoma" and "hemorrhagic cellular leiomyoma" refer to a characteristic constellation of changes within leiomyomas in women taking oral contraceptives or who are pregnant. Patients can present during pregnancy or the puerperium with acute abdominal signs secondary to rupture of the tumor into the peritoneal cavity. On gross examination, hemorrhage within one or more leiomyomas, which may be accompanied by cystic change, is the cardinal feature. Microscopic examination reveals densely cellular proliferations of smooth muscle cells surrounding stellate zones of recent hemorrhage. The cells lack malignant nuclear features, but as many as 8 MFs/10 HPFs have been encountered in some cases. As one moves away from the closest areas to hemorrhage, the cellularity and mitotic activity decrease. This zonation phenomenon is very characteristic of these tumors. Vascular alterations, including intimal myxoid change and fibrosis, medial hypertrophy, fibrinoid necrosis, and thrombosis, can be encountered within the leiomyomas or the surrounding myometrium.

Some of the findings in apoplectic leiomyomas also occur in leiomyomas treated with gonadotropin-releasing hormone agonists (GnRHa), agents that are used to reduce the size of leiomyomas prior to their removal. Although some studies have found no significant microscopic differences between GnRHa-treated leiomyomas and controls, most studies have found an increased frequency of one or more of the following features: irregular borders, focal increased cellularity, hyalinization, infarct-type necrosis, smaller cell size, larger collagen fibers, and vascular changes including fewer vessels, decreased vessel diameter, mural thickening, myxoid change, fibrinoid change, intimal or medial fibrosis, luminal narrowing, and thrombosis. Surprisingly, no study has demonstrated any difference in the mitotic rate between leiomyomas removed during treatment and those from untreated women. In contrast, leiomyomas removed several weeks after withdrawal of GnRHa treatment can have increased mitotic activity. Rare GnRHa treated smooth muscle tumors are unexpectedly found to be a leiomyosarcoma.

E. Hydropic and Hyaline Degeneration Within Leiomyomas
The deposition of collagen, referred to in the older literature as "hyaline degeneration", or in this era, as fibrosis or hyalinization, is a very common finding in leiomyomas of all types, especially in postmenopausal women in whom uterine leiomyomas shrink in size and can become completely or almost completely replaced by fibrous tissue. In such cases dystrophic calcification is common and can be extensive. Hyalinization in leiomyomas can sometimes result in peculiar patterns, including a compartimentalization of residual smooth muscle cells resulting in epithelial-like patterns, a finding that should not lead to a diagnosis of epithelioid leiomyoma. Hydropic degeneration is another common degenerative change in leiomyomas that can result in diagnostic problems especially if confused with myxoid change. One of the few places where this change is mentioned, although not specifically termed "hydropic degeneration", is in the classic work of Kelly and Cullen who devoted a chapter to hyaline and cystic degeneration within leiomyomas and indicated that hyaline degeneration typically proceeds "liquefaction", their term for what we refer to as hydropic change. The watery edematous change sometimes erroneously led the pathologist to consider, or make, the diagnosis of myxoid leiomyosarcoma or intravenous leiomyomatosis on gross examination. If marked, this hydropic change may result in cystic degeneration. Potential problems associated with this hydropic change are: a) characteristic perinodular disposition of the hydropic change that may mimic the appearance of intravenous leiomyomatosis both grossly and microscopically, potential problems being accentuated by the fact that the smooth muscle component in that low malignant potential lesion often has hydropic change. In contrast to intravenous leiomyomatosis, immunohistochemical stains for endothelial markers confirm the absence of endothelial cells around the nodules or lining the pseudovascular spaces; b) extension of the hydropic change beyond the confines of the leiomyoma suggesting the infiltration of a myxoid leiomyosarcoma; and c) extensive or subtotal obliteration of the usual architecture of the leiomyoma, often accompanied by numerous thick walled blood vessels that may obscure the smooth muscle nature of the neoplasm.

F. Myxoid Leiomyomas
Myxoid leiomyomas are rare. This term should be reserved for leiomyomas characterized by abundant, acellular, pale staining material rich in acid mucins that can be confirmed by alcian blue or colloidal iron stains. Myxoid leiomyomas, which may be encountered during pregnancy, are usually grossly well circumscribed and can resemble extrauterine myxomas, being composed of homogeneous, soft, gray, jelly-like material. On microscopic examination they have well-circumscribed margins although they may cause the false impression of pseudoinfiltration if the periphery of the leiomyoma shows a more conventional appearance and these areas are interpreted as normal myometrium. The neoplastic cells may be elongated or may be stellate in shape and widely separated by the extracellular material and if the myxoid change is diffuse it may result in a microscopic appearance indistinguishable from a myxoma, and distinction may require immunohistochemical or ultrastructural confirmation. The cytologic features are bland and mitotic figures are rare. The distinction between myxoid leiomyoma and myxoid leiomyosarcoma may be difficult in curettage specimens. In a recent study conducted by Atkins et al, in the absence of tumor cell necrosis or severe cytologic atypia, a mitotic index of <2 MFs /10 HPFs favored a benign myxoid smooth muscle tumor.

G. Leiomyomas with Heterologous Elements
Typical leiomyomas may contain mature heterologous elements, a finding with no clinical significance. The most common of those are lipoleiomyomas. Rare leiomyomas have contained bone, cartilage, skeletal muscle, or epithelial elements. In the latter circumstance the differential diagnosis includes adenomatoid tumor, especially because adenomatoid tumor usually is associated with prominent smooth muscle hyperplasia, however adenomatoid tumor is poorly circumscribed and exhibits a variety of characteristic patterns. Schwannoma-like leiomyomas, with palisading nuclei and Antoni A and B-like patterns within the tumors, are on ultrastructural examination leiomyomas devoid of schwannian differentiation.

H. Leiomyomas with Hematopoietic Cells
Some leiomyomas contain prominent numbers of inflammatory cells of hematopoietic type. "Pyomyomas" are the result of bacterial infection within a leiomyoma. Pathological examination reveals a leiomyoma with abscess cavities and large numbers of neutrophils; bacteria may be demonstrable. Rarely leiomyomas contain massive lymphoid infiltrates that may be confused with lymphoma or inflammatory pseudotumor that on rare occasion may involve the uterus. One example of a uterine leiomyoma with foci of extramedullary hematopoiesis has been reported in a woman with no evidence of systemic disease. Typical leiomyomas may contain numerous histiocytes and striking collections of mast cells, eosinophils or both.

I. Leiomyosarcomas
Leiomyosarcomas account for approximately 45% of uterine sarcomas. The vast majority affect women over the age of 40. Patients frequently present with abnormal vaginal bleeding, pain or both. Although rapid enlargement of a myometrial tumor suggests leiomyosarcoma, a similar finding occurs in leiomyomas in women taking oral contraceptives as mentioned previously and on occasion in patients with apparently typical leiomyomas with no obvious predisposing cause. In rare patients, the presenting manifestations are related to tumor rupture (and hemoperitoneum), extrauterine extension (present in one-third to one-half of cases), or metastases.

Leiomyosarcomas are typically large solitary masses with a mean diameter of 10 cm, however, 25% of the tumors were < 5 cm in one series. Approximately two-thirds of leiomyosarcomas are intramural, one-fifth submucosal, and one-tenth subserosal; 5% arise in the cervix. They are almost always less circumscribed than leiomyomas and cannot be shelled out from the adjacent myometrium. The cut surface is typically bulging, soft, fleshy and focally necrotic and hemorrhagic without the appearance of a typical leiomyoma, although as noted previously some leiomyoma variants may have some of these worrisome features. For this reason thorough sampling for microscopic examination is recommended any time a smooth muscle tumor has an unusual gross appearance (at least one section per centimeter in diameter). In 90% of cases, leiomyosarcomas are either the only mass, or when associated with leiomyomas (as they often are), the largest mass. Convincing examples of leiomyosarcoma arising in a typical leiomyoma or leiomyoma variant, however, are rare. Most leiomyosarcomas of the uterus are obviously malignant on microscopic examination, and exhibit:

Hypercellularity of at least moderate degree
Diffuse moderate to marked nuclear atypia
High mitotic rate (10 or more MFs /10 HPFs; 90% have > 15 MFs/10 HPFs)

Tumor cell necrosis, which is characterized by an abrupt transition from the viable cells to the necrotic cells without an interposed zone of granulation tissue or fibrous tissue. Preserved nuclei with marked pleomorphism and hyperchromasia can still be seen within the necrotic areas and there is a perivascular growth of the viable tumor cells. Tumor cell necrosis is highly characteristic of leiomyosarcomas. This type of necrosis should be distinguished from infarct-type necrosis that may be seen in benign or malignant smooth muscle tumors. The latter is characterized by the presence of a transition zone between the necrotic and the viable tumor that is composed of granulation tissue or fibrous or hyalinized tissue depending of the age of the infarct. The necrotic tissue has a mummified and homogeneous appearance, areas of hemorrhage are common, and no perivascular growth of tumor cells is seen. In the experience of Bell et al. any of the two last three criteria warrant a diagnosis of leiomyosarcoma. In some cases, the distinction between early infarct-type necrosis and tumor cell necrosis may be difficult. There is a third type of necrosis, ulcerative necrosis, which typically involves the ulcerated surface of a submucosal smooth muscle tumor and it is surrounded by prominent numbers of inflammatory cells, especially neutrophils, and may be seen in benign and malignant smooth muscle tumors.

Rare leiomyosarcomas have contained a prominent component of osteoclastic-type giant cells. In some cases, the giant cell component of the tumor resembled a benign or malignant giant cell tumor of bone or a giant cell variant of malignant fibrous histiocytoma. Rare "xanthomatous leiomyosarcomas" which can be focally or diffusely yellow, contain large cells with abundant cytoplasm, lipid vacuoles, and multiple or multilobulated nuclei sometimes disposed in a wreath-like arrangement. The xanthomatous cells are disposed in solid sheets or are intimately admixed with smooth muscle cells.

Leiomyosarcomas are aggressive tumors. In a large Gynecology Oncology Group (GOG) study, the recurrent rate was 71%. The first recurrence was in the lung in 40% of cases, whereas was in the pelvis in only 13% of the patients. The survival rates in most series are 15% to 25%, with a median survival of only 10 months in one study. There has been no consistency among various studies with respect to showing a correlation between survival and patient age (or menopausal status), clinical stage, tumor size, type of border (pushing versus infiltrative), the presence or absence of necrosis, mitotic rate, degree of nuclear pleomorphism, and vascular invasion. One study, however, found tumor size to be a major prognostic parameter: five of eight patients with tumors < 5 cm in diameter survived, whereas all the patients with tumors > 5 cm in diameter died from tumor. Similarly, in another study confined to leiomyosarcomas with metastases, almost 80% of the tumors were >5 cm.

Myxoid Leiomyosarcomas
This is a rare variant of leiomyosarcoma that can create diagnostic problems because its myxoid appearance and usually low mitotic rates can lead to a misdiagnosis of a benign tumor. These tumors have ranged from 5 to 16 cm in diameter and typically have a gelatinous cut surface and often a deceptively well-circumscribed border.

On microscopic examination, however, the tumors typically infiltrate the myometrium in irregular tongues, and in some cases, myometrial veins. Most or all the tumors are characterized by an abundant paucicellular myxoid matrix that is weakly basophilic or eosinophilic, weakly positive with the periodic acid-Schiff and mucicarmine methods, and strongly positive with alcian blue and colloidal iron staining. The tumor cells may be uniformly distributed throughout the myxoid stroma, arranged in fascicles, or may surround cavities filled with myxoid material. Most of the tumor cells have scanty cytoplasm, with oval, spindle, or stellate nuclei with inapparent nucleoli and, with rare exceptions, a mitotic rate of only 0 to 2 MFs/10 HPFs. The tumor cells usually exhibit only focal mild to moderate nuclear pleomorphism; occasional multinucleated cells may be present. Non-myxoid areas, which are present to a variable degree, usually exhibit greater degrees of nuclear pleomorphism and mitotic activity and architectural and cytologic features that help establish the smooth muscle nature of the neoplastic cells.

Recurrent tumor, distant metastases, or both have appeared in most of the reported cases with follow-up data. In some cases, the recurrent tumor in the abdominal cavity has mimicked the appearance of pseudomyxoma peritonei. In contrast to typical leiomyosarcoma, the postoperative interval to recurrence or metastases may be as long as 10 years.

It is important to distinguish myxoid leiomyosarcoma from myxoid leiomyoma as discussed earlier. Myxoid leiomyosarcoma should also be distinguished from myxoid endometrial stromal sarcoma as discussed later.

J. Smooth Muscle Tumors of Low or Uncertain Malignant Potential
Uterine smooth muscle tumors neither benign nor malignant were subdivided in the study by Bell et al. into three groups. The first group, "atypical leiomyoma with low risk of recurrence", was characterized by diffuse moderate to severe atypia, <10 MFs/ 10 HPFs, and no tumor cell necrosis. Only one of 46 such tumors was clinically malignant. The second group, "atypical leiomyoma but experience limited", was characterized by focal moderate to severe atypia, <20 MFs/ 10 HPFs, and no tumor cell necrosis. There were only five cases in this group and all were clinically benign. Three of the five tumors had <5 MFs/ 10 HPFs and would be considered leiomyomas with bizarre nuclei by most investigators. The other two tumors had 10-19 MFs/10 HPFs. The last group, "smooth muscle tumors of low malignant potential," had tumor cell necrosis, <10 MFs/ 10 HPFs, and absent to mild atypia. One of four tumors in this group was clinically malignant, again underscoring the importance of tumor cell necrosis. Rare smooth muscle tumors exhibiting yet other combinations of worrisome findings not included in the above groups are best referred to as "smooth muscle tumors of uncertain malignant potential" (STUMPs).

K. Epithelioid Smooth Muscle Tumors
The World Health Organization defines epithelioid smooth muscle tumors as neoplasms composed of cells resembling epithelial cells. Different terms have been used in the literature to designate these tumors. The term "leiomyoblastoma" has been used by some authors for tumors composed of cells containing abundant eosinophilic cytoplasm, but this term is incorrect because it implies a tumor composed of primitive cells. Tumors that are predominantly composed of cells with abundant clear cytoplasm have been designated "clear cell leiomyoma/ leiomyosarcoma". In our opinion, the best designation for all these tumors is that of epithelioid smooth muscle tumors. "Plexiform leiomyoma" or "plexiform tumorlet" refers to a microscopic tumor, less than 1 cm in size with a predominant plexiform pattern. They are frequently multiple. Rare examples of intravenous leiomyomatosis are composed predominantly or exclusively of epithelioid cells, as discussed under that heading. The designation "epithelioid" should not be applied loosely to smooth muscle tumors in which epithelial-like aggregation of cells results from hyalinization, hydropic or other stromal changes, something that is quite common.

The clinical presentation of epithelioid smooth muscle tumors does not differ significantly from that of typical leiomyomas or leiomyosarcomas. Plexiform tumorlets are usually asymptomatic. Grossly these tumors may resemble typical leiomyomas but they may be fleshy due to their increased cellularity (lacking a whorled cut surface), poorly circumscribed, and contain foci of hemorrhage and necrosis. Some tumors have overtly malignant features on gross examination. Plexiform tumorlets are typically microscopic, although rarely are recognized grossly as small leiomyomas, and are frequently multiple. Although more common in the myometrium, plexiform tumorlets may occasionally involve, or be confined to, the endometrium. Occasional epithelioid smooth muscle tumors have arisen within the cervix.

On microscopic examination epithelioid smooth muscle tumors most frequently show a diffuse growth of tumor cells, but they can also form nests, cords or occasionally pseudoglandular spaces. Stromal hyalinization may be slight and focal, or marked and diffuse, particularly in association with a plexiform pattern, and rare tumors have had a myxoid stroma. The cytoplasm is usually eosinophilic and granular, but may be clear, and in about 25% of the cases the entire tumor is composed of clear cells (clear cell leiomyoma/leiomyosarcoma). The round or angular nucleus is typically central but may be eccentric, occasionally resulting in a signet-ring appearance. Immunohistochemically these tumors are more frequently positive for keratins and are less frequently positive for muscle markers than non-epithelioid smooth muscle tumors.

Because of the rarity of these tumors, criteria predictive of malignant behavior, which has occurred in 12 to 40% of the reported tumors, are less well established for epithelioid smooth muscle tumors than for spindle-cell smooth muscle tumors. Kurman and Norris studied a series of 26 of these tumors and although they found some overlapping microscopic features between benign and malignant epithelioid smooth muscle tumors concluded that the presence of clear cytoplasm, expansile margin, extensive hyalinization and absence of extensive necrosis were parameters associated with a favorable prognosis and tumors that exhibited 5 or more mitosis should be designated as epithelioid leiomyosarcomas. In contrast, Prayson, Goldblum and Hart did not find a single histologic feature predictive of outcome. They concluded that clinically malignant tumors in their series showed grade 3 nuclei, mitotic activity higher than 3/10 HPFs and tumor cell necrosis. Atkins et al. recently studied 32 epithelioid smooth muscle tumors and concluded that in the absence of tumor cell necrosis, cytologic atypia or a mitotic index >5 MFs/10 HPFs warranted a diagnosis of malignancy. In the largest series up to date only published as an abstract, a series of 80 of these tumors were studied. Mitotic activity was the most important microscopic parameter in patients with stage I epithelioid smooth muscle tumors (tumors confined to the uterus). In that series, tumors with 2 to 4 MFs/10 HPFs were malignant in half of the cases. For this reason extensive sampling is very important in these tumors as well as close follow-up of patients with epithelioid smooth muscle tumors with any significant mitotic activity specially if they show other atypical microscopic features. Patients may die from tumor, often after multiple recurrences, >5 or even >10 years after hysterectomy.

The differential diagnosis of epithelioid smooth muscle tumors includes primary endometrial carcinomas and metastatic carcinomas; especially those composed of eosinophilic or clear cells. Many such carcinomas, however, exhibit, at least focally, overt glandular or squamous differentiation. In some cases, immunohistochemical or ultrastructural studies may be needed to facilitate the diagnosis. Primary cervical or metastatic epithelioid malignant melanomas, especially amelanotic examples, can be excluded by their immunoreactivity for S-100 and HMB-45 and lack of reactivity for smooth muscle markers. Features favoring or establishing a diagnosis of placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT) versus epithelioid leiomyosarcoma include a history of a recent pregnancy, an elevated serum hCG level, an infiltrative growth pattern with tumor cells penetrating between myometrial smooth muscle bundles (PSTT), prominent vascular involvement (PSTT), fibrinoid change in vessel walls, and immunoreactivity for inhibin, placental lactogen, or hCG. Low-grade endometrial stromal sarcoma belongs in the differential diagnosis in the rare cases of multiple plexiform tumorlets, which can have an irregular contour and extensively involve the myometrium, resulting in an infiltrative pattern. The epithelioid appearance of most or all the cells, the presence of moderate amounts of eosinophilic cytoplasm, the absence of typical cells of endometrial-stromal type, desmin-immunoreactivity, and an absence of the characteristic vascular invasion of low-grade endometrial stromal sarcoma facilitates the distinction from endometrial stromal sarcoma in such cases.

Diagnostic criteria for uterine smooth muscle tumors (Bell et al.)

MI<20 /10 HPFs, no tumor cell necrosis, no atypia, or no more than mild cytologic atypia: LEIOMYOMA WITH INCREASED MITOTIC ACTIVITY.
MI>20 /10 HPFs, no tumor cell necrosis, no atypia or no more than mild cytologic atypia: LEIOMYOMA WITH INCREASED MITOTIC ACTIVITY BUT EXPERIENCE LIMITED.
MI<10 /10 HPFs, no tumor cell necrosis, but with focal moderate to severe cytologic atypia: ATYPICAL LEIOMYOMA WITH LIMITED EXPERIENCE.
0< MI<10 /10 HPFs, no tumor cell necrosis, but with diffuse moderate to severe cytologic atypia: ATYPICAL LEIOMYOMA WITH LOW RISK OF RECURRENCE.
MI<10/ 10 HPFs, with tumor cell necrosis and no to mild cytologic atypia: SMOOTH MUSCLE TUMOR OF LOW MALIGNANT POTENTIAL.
MI>10 /10 HPFs, no tumor cell necrosis, but with diffuse moderate to severe cytologic atypia: LEIOMYOSARCOMA
Any MI with tumor cell necrosis, with diffuse or focal moderate to severe cytologic atypia: LEIOMYOSARCOMA.
MI>10/10 HPFs, with tumor cell necrosis, no to mild atypia: LEIOMYOSARCOMA.



L. Smooth Muscle Tumors with Unusual Growth Patterns
It has already been noted that occasional leiomyoma variants, especially highly cellular leiomyomas, may have irregular borders with the surrounding myometrium, a finding that has no prognostic significance. Other benign smooth muscle tumors of the uterus may have worrisome growth patterns that may suggest leiomyosarcoma, but lack the cardinal histologic features of the later. Peritoneal leiomyomatosis is not discussed here because it is a primary peritoneal lesion.

Diffuse Uterine Leiomyomatosis
This rare lesion is characterized by symmetrical uterine enlargement due to the presence of countless, confluent, leiomyomatous nodules within the myometrium. The clinical presentation is similar to that of patients with typical uterine leiomyomas. Microscopic examination reveals that the nodules, including many not appreciable grossly, consist of cytologically benign, typically cellular, mitotically inactive smooth muscle. A focal proliferation of perivascular smooth muscle cells has been encountered within the nodules and occasionally, the intervening myometrium. The differential diagnosis includes rare cases of uterine involvement by lymphangioleiomyomatosis, usually in patients with tuberous sclerosis. In such cases, the myometrium is usually grossly normal but it is involved by numerous microscopic ill-defined nodules of smooth muscle surrounding lymphatics and protruding into their lumens. The smooth muscle cells of lymphangioleiomyomatosis are immunoreactive for HMB-45.

Dissecting Leiomyoma
Rare leiomyomas, including hydropic leiomyomas and intravenous leiomyomatosis (discussed below), may have a dissecting growth pattern. Grossly, dissecting leiomyomas are often lobulated with irregular, indistinct margins. On microscopic examination, columns of neoplastic smooth muscle dissect into the surrounding myometrium, or occasionally, into the broad ligament.

One type of dissecting leiomyoma is the cotylenoid dissecting leiomyoma ("Stenberg tumor"). Their clinical presentation is identical to that of typical leiomyomas. Follow-up in three cases revealed a benign clinical course. The most distinctive feature of these tumors is their appearance at laparoscopy and on gross examination as congested exophytic placental-like masses extending from the uterus into the broad ligament and pelvic cavity. Microscopic examination reveals a sinuous dissecting pattern at the periphery of the tumors, micronodules of smooth muscle with a swirling (rather than fascicular) growth pattern, marked vascularity, and extensive hydropic and hyaline degeneration.

Leiomyoma with Vascular Invasion
This term has been applied to rare otherwise typical leiomyomas or leiomyoma variants with microscopic intravascular growth confined to the tumor. In many patients, this intravascular growth is likely inconsequential, although no large series of these tumors with long-term follow-up has been reported. Several cases, however, have been associated with benign smooth muscle nodules in the lungs ("benign metastasizing leiomyoma", see below) while some cases may represent an early stage of intravenous leiomyomatosis.

Intravenous Leiomyomatosis
Intravenous leiomyomatosis is defined as the presence of intravenous proliferations of benign-appearing smooth muscle in the absence of, or outside the confines of, a leiomyoma. The clinical presentation is usually similar to that of typical uterine leiomyomas. Extrauterine venous involvement, which occurs in about 30% of cases, is usually confined to the pelvis, but occasionally tumor can extend into the inferior vena cava and reach the right side of the heart, sometimes with fatal results. In rare cases, patients with intact uteri and no pelvic manifestations present with cardiac involvement. Extrauterine extension may be diagnosed intraoperatively, on gross examination of the hysterectomy specimen, on postoperative imaging studies, or in some cases not until many years after hysterectomy when the patient presents with recurrent tumor, as discussed below. Rare patients have had a solitary metastases (lungs, pelvic lymph nodes) ("benign metastasizing leiomyoma").

The uterus is usually enlarged and bosselated with multinodular, rubbery, gray-white myometrial masses, at least some of which form worm-like plugs of tumor within myometrial or parametrial vessels, although this feature is often not appreciated on initial gross examination. Typical or hydropic leiomyomas are also usually present, but occasionally all discernible tumor is intravascular. On microscopic examination, the intravascular tumor (which is unsheathed by endothelial cells) usually, at least focally, resembles a typical leiomyoma, but rarely has the appearance of a leiomyoma variant, including cellular leiomyoma, leiomyoma with bizarre nuclei, lipoleiomyoma, myxoid leiomyoma, or epithelioid leiomyoma. The intravascular tumor often has a clefted or lobulated contour, extensive hydropic change or hyalinization, and a content of numerous thick-walled vessels, features that may obscure its smooth muscle nature. Mitotic figures are usually rare, but cellular intravenous leiomyomatosis may contain up to 4MFs/ 10 HPFs.

The intravascular tumor of intravenous leiomyomatosis should not be confused with typical leiomyomas that are partially surrounded by compressed vascular spaces or typical leiomyomas with artifactual retraction from the surrounding myometrium. Stains for endothelial antigens may be useful in problematic cases. Two other lesions in the differential diagnosis, leiomyoma with vascular invasion and leiomyoma with perinodular hydropic change, have been discussed earlier. Low-grade endometrial stromal sarcoma, in contrast to cellular intravenous leiomyomatosis, usually lacks thick-walled vessels, lobulation, and hydropic degeneration in its intravascular extensions, and usually involves the endometrium as well as the myometrium.

Rare patients experience pelvic or cardiac recurrences, as many as 15 years after hysterectomy, from continued growth of residual intravenous tumor. In some such cases, an initial diagnosis of a primary cardiac tumor is made, especially in women in whom the diagnosis was missed on a hysterectomy specimen. In women in whom the diagnosis of intravenous leiomyomatosis is made on a hysterectomy specimen, postoperative ultrasonic or magnetic resonance imaging studies may be useful in detecting and monitoring the growth of residual intravascular tumor. GnRH-agonists may be useful in controlling unresectable tumor.

Benign Metastasizing Leiomyoma
This disorder is characterized by the presence of single or multiple extrauterine nodules, usually pulmonary; composed of benign-appearing smooth muscle in women who have had typical uterine leiomyomas, or rarely leiomyomas with vascular invasion or intravenous leiomyomatosis. Other sites that may be involved in the presence or absence of pulmonary involvement include retroperitoneal and mediastinal lymph nodes, soft tissue and bone. The uterine tumors often have been removed by hysterectomy years earlier. The diagnosis of benign metastasizing leiomyoma should be rendered only in cases in which the uterine tumors have been thoroughly sampled to exclude leiomyosarcoma. An extrauterine leiomyosarcoma (gastrointestinal tract, retroperitoneum) should also be excluded. The pulmonary tumors, which may be as large as 10 cm in diameter but are usually smaller, are circumscribed; solid or solid and cystic with fluid-filled cysts lined by entrapped bronchioalveolar epithelium. The presence of estrogen and progesterone receptors in the metastatic tumor, a reduction in their size during pregnancy, and a cessation in their growth or complete regression after oophorectomy or the menopause, indicate hormone dependence in at least some cases.

Although some investigators argue that cases of "benign metastasizing leiomyoma" represent hormonally induced hyperplastic primary pulmonary lesions, the rarity of smooth muscle proliferations in the absence of uterine leiomyomas, the association of the pulmonary lesions and uterine leiomyomas with vascular invasion or intravenous leiomyomatosis, and the occasional involvement of pelvic lymph nodes indicate that the pulmonary nodules are likely metastatic from the uterine tumors in most cases.

Peritoneal Parasitic Leiomyoma
The term "parasitic" leiomyoma has been applied to otherwise unremarkable, usually solitary (one or occasionally a few), leiomyomas or leiomyoma variants attached to the pelvic peritoneum in women who usually have uterine leiomyomas. The peritoneal tumors in such cases are presumed to originate from subserosal pedunculated uterine leiomyomas that become attached to, and vascularized by, the pelvic peritoneum, eventually loosing their attachment to the uterus. Tumors within the broad ligament (intraligamentous leiomyomas) are likely primary in that site in most cases.

II) Endometrial Stromal Tumors

A. Endometrial Stromal Nodule (ESN)
The most important single criterion for its diagnosis is the finding of a non-infiltrative border of the tumor on microscopic examination. It is allowed the presence of focal irregularities in the form of lobulated or finger-like projections into the adjacent myometrium that do not exceed 3 mm. No vascular invasion should be seen.

B. Endometrial Stromal Sarcoma (ESS)
Low-grade ESS accounts for 10-15% of uterine malignancies with a mesenchymal component. Extrauterine pelvic extension at presentation is found in up to 1/3 of the patients. Rarely, the patient presents with tumor at a metastatic site such as the ovary. Grossly there is a nodular or diffuse permeation of the myometrium, including worm-like plugs of tumor in myometrial or parametrial veins. The cut surface is soft, fleshy, bulging, and tan to yellow. On microscopic examination the tumor permeates the myometrium as irregular tongues. Myometrial as well as extrauterine veins and lymphatics are frequently invaded. The tumors are cellular with uniform, oval to spindle-shaped cells of endometrial stromal-type. Significant degrees of nuclear atypia are absent. Mitotic rates are usually <3/10HPFs but higher rates do not exclude this diagnosis. Mitosis are no longer used to differentiate between low-grade and high-grade ESSs. Tumors with the typical morphology of endometrial stromal tumors (EST) and characteristic tongue-like growth should be classified as low-grade ESSs regardless of their mitotic counts because the prognosis in these tumors is similar. In contrast tumors with an endometrial origin but lacking endometrial stromal differentiation should be classified as poorly differentiated endometrial sarcomas. Low-grade ESSs have a low malignant potential.

C. Endometrial Stromal Nodule vs Endometrial Stromal Sarcoma:
The differential diagnosis between ESN and ESS is not possible in a curettage specimen except in the rare case in which the former is completely curetted during the procedure.

D. Endometrial Stromal Tumors vs Cellular Endometrial Polyps
Endometrial polyps may be fragmented in curettage specimens and some of the fragments may consist of cellular stroma only. Although ESTs may arise in endometrial polyps, in such cases one sees an expansile growth of endometrial stroma with the typical vascular network, which contrasts with the more compact, atrophic appearance of the endometrial stroma of the polyp in which vessels, if prominent, tend to be larger, thick-walled, and irregularly distributed.

E. Endometrial Stromal Tumors vs Adenomyosis with Sparse Glands and Intravascular Adenomyosis
Adenomyosis with a scant glandular component or in which adenomyotic foci are present in vascular spaces or associated with intravascular endometrial tissue may cause concern for a low-grade ESS. On gross examination adenomyosis occurs as an incidental finding, produces an ill-defined nodularity or asymmetric thickening of the uterine wall. There is a zonation phenomenon within the adenomyotic foci with a less cellular central area surrounded by a more cellular periphery composed of a rim of endometrial stroma, smooth muscle or both, and the atrophic appearance of the stromal nests and cells that lack nuclear atypia and mitotic activity are in contrast with the expansile growth of the stromal nests and proliferative appearance of the cells in ESS. The absence of other morphologic features seen in ESS, the presence of typical areas of adenomyosis elsewhere, and the postmenopausal age of the patients helps in the differential diagnosis.

F. Endometrial Stromal Tumors vs Intravascular Endometrial Tissue, and Menses-associated Cellular Stroma
Intravascular menstrual endometrium if composed of only stromal cells may cause problems in the differential diagnosis with ESS. The stromal cells form tight clusters of small spindle cells with hyperchromatic nuclei and a high nuclear/cytoplasmic ratio. Some of the nests may have a necrotic appearance and in other areas they may be surrounded by a cuff of larger cuboidal to low columnar epithelial cells with more abundant eosinophilic cytoplasm. These clusters of cells are frequently associated with neutrophils and lymphocytes.

G. Endometrial Stromal Tumors vs Highly Cellular Leiomyomas (HCL)
It has already been discussed.

H. Endometrial Stromal Sarcoma vs Intravenous Leiomyomatosis (IVL)
IVL may cause confusion with an ESS mainly because of its prominent intravascular growth. The marked cellularity of some cases of IVL resembling a HCL may increase confusion with ESSs. Helpful features include a clefted or lobulated contour of the intravascular masses, a focal fascicular architecture, cells with blunt-ended nuclei, prominent thick-walled vessels and hydropic change. Finally, if a tumor shows vascular permeation, a useful diagnostic feature of some cases of IVL is that the tumor cells may be seen not only in vascular lumina but also beneath the vascular endothelium and "colonizing" the walls of veins. Although cardiac involvement is seen in up to 40% of cases of IVL, low-grade ESSs may also have it although infrequently.

I. Fibrous-myxoid Endometrial Stromal Tumors vs Other Mesenchymal Tumors
ESTs may undergo extensive fibrous and or myxoid change. The most frequent and problematic differential diagnosis pertains to smooth muscle tumors including myxoid leiomyomas, the rare myxoid variant of IVL and myxoid leiomyosarcomas. Helpful features in establishing the diagnosis of myxoid/fibroblastic EST are a frequent presentation as an endometrial polypoid mass, a prominent multinodular or tongue-like pattern of myometrial infiltration, the focal presence of typical endometrial stromal neoplasia with characteristic arterioles, and the absence or minimal staining for desmin in most cases.

J. Miscellaneous Other Problems in the Differential of Pure Endometrial Stromal Tumors
If tissue sample is small and shows crush artifact, metastatic breast cancer or lymphoma may be in the differential. The history as well as immunohistochemistry will facilitate the diagnosis.

K. Endometrial Stromal Tumors with Smooth Muscle Differentiation (EST-SMD)
In general it is required that the smooth muscle component occupy at least 30% of the neoplasm to merit this categorization. Grossly some of these tumors contain one or more tan to yellow, soft nodules alternating with firm, white whorled nodules or they are embedded in or at the periphery of paler, firmer tissue. The endometrial stromal component has the characteristic cell type and arterioles. The smooth muscle component may show nodules with central hyalinization ("starburst" pattern) that merge with disorganized short fascicles of smooth muscle or long mature fascicles of smooth muscle. An unusual pitfall in the evaluation of these tumors is posed by the irregular interdigitation of both components, particularly when the smooth muscle is mature and relatively well organized. If the latter is misconstrued as myometrial muscle, a well-circumscribed tumor may be misinterpreted as an invasive EST and hence an ESS. It is crucial to appreciate that in such cases one is examining regions with divergent differentiation within the mass itself rather than invasion. EST-SMD should be distinguished from adenomyomas, pure ESTs, and UTROSCTs. Recurrences may show an EST, smooth muscle or both components. For prognostic purposes these tumors should be reported as ESNs or ESSs with smooth muscle differentiation (depending on the margins) with the designation mixed endometrial stromal-smooth muscle tumor given in parentheses with any other unusual features of either component recorded in a notation. We do not use the term "stromomyoma" because this term implies a benign tumor.

L. Endometrial Stromal Tumors with Sex Cord-like Differentiation.


M. Endometrial Stromal Tumors with Endometrioid Glandular Differentiation
The epithelial component may resemble endometrioid glands, either benign or malignant. The origin of the glands has been attributed to entrapment of non-neoplastic endometrial or adenomyotic glands or epithelial differentiation in these neoplasms. These rare neoplasms should be distinguished from adenomyosis and endometriosis, and indeed some (perhaps most) cases of "aggressive endometriosis" in our opinion probably represent ESSs with endometrioid gland differentiation. Mullerian adenosarcoma should also be included in the differential diagnosis. The latter, however, shows a more uniform distribution of the glands within the stromal component as well as intraglandular polypoid stromal projections and periglandular stromal condensation. In addition adenosarcomas are more circumscribed and less often have vascular invasion.

N. Uterine Tumor Resembling Ovarian Sex-cord Tumor (UTROSCT)
The term "uterine tumor resembling ovarian sex-cord tumor" was applied by Clement and Scully to a heterogeneous group of uncommon neoplasms characterized by pure or prominent microscopic patterns that resemble those of ovarian sex-cord tumors. Several tumors reported in the older literature as "granulosa cell tumors" of the uterus belong in this category. The histologic appearance of some of these neoplasms merges imperceptibly with that of ESTs exhibiting less than predominant sex cord-like differentiation. The designation UTROSCT should be restricted to tumors with prominent sex cord-like differentiation in which there is no conspicuous endometrial stromal background.

In the initial paper describing this entity, the neoplasms were considered in two categories, group 1 and group 2, the former usually having infiltrating margins and the latter being relatively or completely well-circumscribed. We would currently elect to consider the group 1 neoplasms ESSs with sex cord-like differentiation, an entity referred to above. As alluded to in that portion of this manuscript, an argument can be made for viewing some of the group 2 cases as ESNs with massive sex cord-like differentiation, but as their histogenesis is usually not provable as being unequivocally of endometrial stromal origin, it is our current convention to retain their placement in the descriptive category of UTROSCTs. Patients with UTROSCTs are in the reproductive and postmenopausal age groups, with an age range of 16 to 73 (mean, 47) years. The presenting clinical manifestations are usually abnormal vaginal bleeding, uterine enlargement ascribed to "fibroids" or a pelvic mass, or both; occasional patients have had pelvic pain or discomfort or have been asymptomatic.

On gross examination, UTROSCTs are generally solid, round, well-circumscribed myometrial masses that range from 0.7 cm to 20 cm in diameter (mean, 6 cm); rare tumors have been predominantly cystic. UTROSCTs are usually mural, but are occasionally submucosal or subserosal; the submucosal and subserosal tumors may be polypoid, and in such cases, focal hemorrhage is sometimes encountered within them. Rare tumors have been located predominantly within the endometrium or endocervix. The cut surfaces are often yellow, but occasionally gray to tan, and are soft, fleshy and homogeneous without the whorled pattern of a leiomyoma.

The cardinal features on microscopic examination are a variety of epithelial and stromal patterns that create a resemblance to those of ovarian sex-cord tumors, especially granulosa cell and Sertoli cell tumors, alone or in combination. Anastomosing cords one to two cells in width, broad trabeculae, small nests, sertoliform or retiform tubular structures, Call-Exner-like bodies, and diffuse sheets of uniform cells reminiscent of a diffuse adult granulosa cell tumor may be seen. The epithelial-like cells vary from small, round, and regular with scanty cytoplasm to large with abundant eosinophilic, clear, or foamy cytoplasm that is often lipid-rich. The nuclei are generally small and regular with little pleomorphism and indistinct nucleoli. Nuclear grooves are rare or absent and mitotic figures are typically scarce. The fibrous stroma ranges from scanty to abundant and from moderately cellular to hypocellular and hyalinized. An occasional striking feature in some cases of UTROSCT is the presence of conspicuous mature smooth muscle between the sex cord-like elements. The nature of this smooth muscle component has not been extensively studied. It is possible that in some cases it is metaplastic but in the majority of cases, in our opinion, it has an appearance indistinguishable from that of normal myometrium, which it probably represents in many, perhaps most, cases. Although this, therefore, presumably represents "myometrial invasion" by the tumor, it does not have any significant adverse prognostic implications and it is our practice when this muscle is incorporated within an otherwise typical UTROSCT to consider it part and parcel of the neoplasm and not to use terminology such as "with myometrial invasion" which might be confusing and sound ominous to the treating physician. Leydig cell-like or theca cell-like differentiation has not been observed in UTROSCTs, although lipid-laden stromal cells of questionable origin have been present in some cases as noted above.

Assessing the prognosis of these tumors from the literature is difficult because most of the reported series include circumscribed tumors and infiltrating tumors with the features of ESSs without distinction between them. UTROSCTs should be considered tumors of low-malignant potential unless small and well circumscribed in which instance, for practical purposes, they are benign.

Sex cord-like patterns also may be seen in epithelioid smooth muscle tumors, although generally not as strikingly as in tumors of probable endometrial stromal cell derivation.The extent to which desmin positivity is allowable in uterine tumors resembling ovarian sex-cord tumors is still a matter of debate. We, and others allow its presence in such tumors, but this finding must be evaluated in the light of conventional light microscopic and other immunohistochemical findings. Further studies are indicated to establish the appropriate boundary between the classification of an epithelial-like tumor of the uterus as a uterine tumor resembling an ovarian sex-cord tumor and an epithelioid smooth muscle tumor.

O. Other Unusual Morphologic Features in Endometrial Stromal Neoplasms

  1. Epithelioid Appearance

  2. Granular Change

  3. Clear Cell Change

  4. Rhabdoid Appearance

  5. Skeletal Muscle

P. High-grade Endometrial Sarcoma
The lack of specific evidence of endometrial stromal cell origin in most cases precludes their placement in the endometrial stromal group of uterine tumors. Myometrial invasion is common but the intravascular worm-like plugs characteristic of low-grade ESS are usually absent. They have marked cellular pleomorphism, brisk mitotic activity and carry a very bad prognosis. These tumors should be diagnosed only after extensively sampling has excluded smooth or skeletal muscle differentiation or even small foci of carcinoma that would result in a diagnosis of MMMT. Occasional tumors have a component of low-grade ESS indicating that in those cases at least the high-grade component presumably is truly of endometrial stromal derivation.

Q. Immunohistochemical Profile of Endometrial Stromal Neoplasms
Although in most instances the diagnosis of endometrial stromal neoplasia is based on morphologic grounds alone, immunohistochemical stains may be helpful in the diagnosis of problematic cases. The neoplastic endometrial stromal cells are typically immunoreactive for vimentin, muscle-specific and smooth muscle actin, and keratin. This panel of antibodies, however, is not very sensitive in distinguishing ESTs from smooth muscle tumors, the commonest and most problematic group of tumors in the differential diagnosis. Desmin staining has been of help in our experience, but the frequency of desmin staining in ESTs and percentage of desmin positive tumor cells varies among studies. In the study by Franquemont et al., two of two ESNs were strongly and diffusely positive and 7 of 12 ESSs were immunoreactive for desmin, although the staining was diffuse in only four of them, and limited to scattered cells in the other three. Similarly, normal endometrial stromal cells were desmin positive in 9 of 10 cases. The staining was confined to scattered cells in 8 cases, but it was diffuse in the ninth. In some studies the sex cord-like elements in ESSs and UTROSCTs have been desmin-positive suggesting smooth muscle differentiation. More recent studies, however, have suggested that these elements represent sex cord differentiation as discussed below. Other studies have shown a frequency of desmin positivity ranging from 0 to 30% in typical ESS. In our laboratory, desmin has been focally positive in only 3 out of 29 ESTs studied, a finding we consider consistent with smooth muscle differentiation in ESTs as discussed earlier.

In recent years, a few other antibodies have been tested in ESTs:

CD10, initially described as tumor-specific antigen in acute lymphoblastic leukemia, was strongly and diffusely positive in 5/5 ESSs in a recent study. The normal endometrial stromal cells were also positive. Our very limited experience with this antibody confirms these results. In the study just cited only one of 16 malignant smooth muscle tumors including one from the uterus was positive for CD10. However, more recent studies have shown that smooth muscle tumors as well as mixed mullerian tumors (including adenosarcoma and malignant mixed mullerian tumor) or even rhabdomyosarcomas may be positive for CD10. For this reason this antibody should not be used in isolation when evaluating the origin of a mesenchymal tumor of the uterus.

h-caldesmon is also helpful in the differential diagnosis of ESTs versus smooth muscle tumors. h-caldesmon is a calcium, calmodulin, and actin-binding protein widely distributed in smooth and non-smooth muscle cells and is thought to regulate cellular contraction. Its isoform, high-molecular-weight caldesmon, is specific for smooth muscle cells and smooth muscle tumors and is never expressed in myofibroblasts. In a study of 9 ESTs and 15 benign and malignant smooth muscle tumors, Nucci et al found that all ESTs were negative for this antibody. In contrast all leiomyomas and leiomyosarcomas were positive, although staining was focal or confined to isolated cells in three leiomyosarcomas.

Inhibin is a gonadal hormone that acts as a suppressor in the synthesis and secretion of pituitary follicle stimulating hormone. It is a very useful marker for sex cord stromal tumors of the ovary although not pathognomonic. Inhibin has been negative in 20 ESSs of the ovary reported in different series from the literature. In the uterus, Baker et al studied the expression of inhibin in 10 ESTs with sex cord-like differentiation. It was positive in 3/10 of these tumors usually being focal and weak and confined to sex cord-like areas. Additionally, 5 of 5 UTROSCTs were positive for inhibin, although the staining varied from weak and punctate to diffuse and strong and was generally much stronger and more extensive in areas with prominent foam cells. Krishnamurthy et al. found that 3 of 7 UTROSCTs were inhibin positive, ranging from focal (1) to extensive (2). The authors concluded that the inhibin staining in certain areas of these tumors was indicative of true sex cord-like differentiation rather than smooth muscle differentiation. In the same study, 4 of seven UTROSCTs stained for Mart-1, an antigen expressed by normal melanocytes and melanocytic neoplasms, and steroid producing cells and tumors composed of such cells located in the adrenal cortex, ovary, and testis. The positive staining for Mart-1 in UTROSCTs is consistent with the presence of steroid-producing cells and is supportive of their specialized gonadal stromal nature.

CD99 was initially described as a marker for Ewing's sarcoma as well as primitive neuroectodermal tumors, but it also stains normal sex-cord elements as well as tumors derived from them. Loo et al. studied 5 ESSs, one of which had sex cord-like differentiation; positive staining for CD99 was confined to the sex-cord-like areas. In the series reported by Baker et al., only three of ten ESTs with a sex cord-like component were positive for CD99, with weak and focal positivity confined to the sex-cord areas. CD99 was positive in all 5 UTROSCTs in that series, ranging from weak and slightly punctate to intense and diffuse. In the series by Krishnamurthy et al, all 7 UTROSCTs were positive for CD99, ranging from one to three in intensity. In contrast, smooth muscle tumors have been negative for inhibin as well as for CD99 with the exception of one epithelioid smooth muscle tumor that showed weak positivity for this antigen. The combination of positive staining for keratin, desmin, and CD99 has been documented in granulosa cell tumors of the ovary and the same findings in ESSs with sex-cord-like differentiation and UTROSCTs support true sex-cord rather than smooth muscle differentiation.

CD34, a myeloid progenitor cell antigen present in endothelial cells and some other mesenchymal cells, including perivascular and periadnexal dermal fibroblasts, has been found to be present in the stromal cells of the basal endometrium but was negative in 6 ESSs tested. Additionally we found that CD34-staining was absent in 10 fibrous and myxoid ESTs. In contrast, Rizeq et al. found CD34 positivity in 36% of 22 conventional smooth muscle tumors with a spindle cell morphology and 6% of 36 epithelioid smooth muscle neoplasms, although normal myometrium in most cases did not stain for CD34. Furthermore, as previously noted in the rare cases in which the differential diagnosis includes a gastrointestinal stromal tumor, the latter frequently is positive for CD34 in contrast to EST.

c-kit, a well known marker for gastrointestinal stromal tumors, has been recently tested in endometrial stromal and smooth muscle neoplasms. In our study all endometrial stromal tumors where negative for c-kit and Klein and Kurman found that only 1/10 endometrial stromal sarcomas and 3/6 endometrial stromal nodules were positive for c-kit but no more than 5% of the cells stained with the antibody. In contrast to the homogenous results obtained in endometrial stromal tumors, the literature on smooth muscle tumors and c-kit is confusing. Some studies have shown that leiomyosarcomas are c-kit negative while others have reported variable degrees of positivity in malignant smooth muscle tumors and have even found correlation with prognosis.

Oxytocin, a neurohypophyseal peptide associated with muscle contraction during labor, is expressed in smooth muscle tumors but not in endometrial stromal tumors. In the study conducted by Loddenkemper and colleagues they found that oxytocin was present in all conventional and highly cellular leiomyomas as well as in all leiomyosarcomas while all nine ESS (9) were oxytocin negative. These authors postulate that this antibody may be used as part of the panel to distinguish ESTs from smooth muscle tumors.

Aromatase, participates in the extraovarian estrogen production via conversion of androgen to estrogen through the aromatase enzyme complex. Aromatase has been described in stromal cells of endometriosis, adenomyosis, endometrial carcinomas as well as ESSs. Reich and Regauer found that most low-grade ESSs expressed aromatase and little or no expression of aromatase tended to correlate with stage I disease.

Finally, numerous studies have shown that ESTs frequently contain estrogen and progesterone receptors, a finding that may have therapeutic and prognostic implications, although the presence of these receptors has limited utility in differential diagnosis inasmuch as these receptors may be found in many other epithelial and mesenchymal tumors of the uterus.

It is important to remember that one should not rely in one antibody but on a panel when trying to interpret mesenchymal tumors of the uterus.

III) References

    SMOOTH MUSCLE TUMORS

    General references:
    1. Clement PB. Pure mesenchymal tumors. In: Tumors and tumor-like conditions of the uterine corpus and cervix. PB Clement and RH Young, Eds. Churchill Livingstone 1993.pp 265-328.

    2. Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases. Am J Surg Pathol 18:535-558, 1994.

    3. Longrace TA, Hendrickson MR, Kempson RL. Predicting clinical outcome for uterine smooth muscle neoplasms with a reasonable degree of certainty. Adv Anat Pathol 4:95-104, 1997.

    4. Clement PB, Young RH. Mesenchymal and mixed epithelial-mesenchymal tumors of the uterine corpus and cervix. In: Atlas of Gynecologic surgical pathology. Philadelphia: WB Saunders 2000.pp 177-210.

    5. Clement PB. The pathology of uterine smooth muscle tumors and mixed endometrial stromal and smooth muscle tumors: A selected review with emphasis on recent advances. Int J Gynecol Pathol 19:39-55, 2000.

    6. Kempson RL, Hendrickson MR. Smooth muscle, endometrial stromal, and mixed mullerian tumors of the uterus. Mod Pathol 13:328-342, 2000.

    7. Robboy SJ, Bentley RC, Butnor K, Anderson MC. Pathology and pathophysiology of uterine smooth muscle tumors. Environ Health Perspect 2000;108:779-784.

    8. Wilkinson N, Rollason TP. Recent advances in the pathology of smooth muscle tumours of the uterus. Histopathology 39:331-341, 2001.

    9. Benda JA. Pathology of smooth muscle tumors of the uterine corpus. Clin Obstet Gynecol 44:350-63, 2001.

    10. Nielsen GP, Young RH. Mesenchymal tumors and tumor-like lesions of the female genital tract: a selective review with emphasis on recently described entities. Int J Gynecol Pathol 20:105-27, 2001.

    11. Oliva E, Clememt PB, Young RY. Mesenchymal tumors of the uterus: selected topics emphasizing diagnostic pitfalls. Current Diag Pathol 2002;8:268-282.
    Highly cellular leiomyoma:
    1. Oliva E, Young RH, Clement PB, Bhan AK, Scully RE. Cellular benign mesenchymal tumors of the uterus. A comparative morphologic and immunohistochemical analysis of 33 highly cellular leiomyomas and six endometrial stromal nodules, two frequently confused tumors. Am J Surg Pathol 19:757-768, 1995.
    Bizarre leiomyoma:
    1. Evans N. Malignant myomata and related tumors of the uterus. Report of 72 cases occurring in a series of 4000 operations for uterine fibromyomata. Surg Gynecol Obstet 30:225-239, 1920.

    2. Downes KA, Hart WR. Bizarre leiomyomas of the uterus: A comprehensive pathologic study of 24 cases with long term follow-up. Am J Surg Pathol 21:1261-70,1997.

    3. Downes KA, Hart WR. Bizarre uterine leiomyomas: Ki-67 activity and DNA ploidy. Abstract. Mod Pathol 12: 116A, 1999.

    4. Ernst LM, Luo FF, Parkash V, Zheng W. Increased global DNA Methylation in Symplastic Leiomyomas. Abstract. Mod Pathol 2002; 15:196A.
    Mitotically active leiomyoma:
    1. O'Connor DM, Norris HJ. Mitotically active leiomyomas of the uterus. Hum Pathol 21:223-227, 1990.

    2. Perrone T, Dehner LP. Prognostically favorable "mitotically active" smooth muscle tumors of the uterus. A clinicopathologic study of 10 cases. Am J Surg Pathol 12:1-8,1988.

    3. Prayson RA, Hart WR. Mitotically active leiomyomas of the uterus. Am J Clin Pathol 97:14-20,1992.

    4. Dgani R, Piura B, Ben-Baruch G, Opne M, Glezerman M, Nass D, Czernobilsky B, Yanai-Inbar I, Elchalal U. Clinical-pathological study of uterine leiomyomas with high mitotic activity. Acta Obstet Gynecol Scand 1998;77:74-77.
    Leiomyomas with hormonal changes:
    1. Smiddy M, Silverberg S. Pathologic features of uterine leiomyomas following treatment with leuprolide acetate (abstract). Am J Clin Pathol 1992;97:448.

    2. Sreenan JJ, Prayson RA, Biscotti CV, Thornton MH, Easley KA, Hart WR. Histopathologic findings in 107 uterine leiomyomas treated with leuprolide acetate compared with 126 controls. Am J Surg Pathol 1996;20:427-432.

    3. Gutmann JN, Thornton KL, Diamond MP, Carcangiu ML. Evaluation of leuprolide acetate treatment on histopathology of uterine myomata. Fertil Steril 1994;61:622-626.

    4. August CZ, T. K, Meier L, Valle J. Histologic findings in uterine leiomyoma of women treated with gonadotropin-releasing hormone agonists (abstract). Am J Clin Pathol 1992;97:448.

    5. Colgan TJ, Pendergast S, LeBlanc M. The histopathology of uterine leiomyomas following treatment with gonadotropin-releasing hormone analogues. Hum Pathol 1993;24:1073-1077.

    6. Garcia A, De Torres I, Tarragona J, Vidal MT, Moragas MA. Quantitative study of morphologic changes in myomas treated with gonadotropin releasing hormones before surgery (abstract). Mod Pathol 1994;7:89A.

    7. Cohen D, Mazur MT, Jozefczyk MA, Badawy SZ. Hyalinization and cellular changes in uterine leiomyomata after gonadotropin releasing hormone agonist therapy. J Reprod Med 1994;39:377-380.

    8. Crow J, Gardner RL, McSweeney G, Shaw RW. Morphological changes in uterine leiomyomas treated by GnRH agonist goserelin. Int J Gynecol Pathol 1995;14:235-242.

    9. Rutgers JL, Spong CY, Sinow R, Heiner J. Leuprolide acetate treatment and myoma arterial size. Obstet Gynecol 1995;86:386-388.

    10. Demopoulos RI, Jones KY, Mittal KR, Vamvakas EC. Histology of leiomyomata in patients treated with leuprolide acetate. Int J Gynecol Pathol 1997;16:131-137.

    11. Kalir T, Goldstein M, Dottino P, et al. Morphometric and electron-microscopic analyses of the effects of gonadotropin-releasing hormone agonists on uterine leiomyomas. Arch Pathol Lab Med 1998;122:442-446.
    Hydropic leiomyomas:
    1. Clement PB, Young RH, Scully RE. Diffuse, perinodular, and other patterns of hydropic degeneration within and adjacent to uterine leiomyomas. Problems in differential diagnosis. Am J Surg Pathol 16:26-32, 1992 .
    Leiomyomas with heterologous elements and hematopoietic cells:
    1. Gisser SD, Young I. Neurilemoma-like uterine myomas: an ultrastructural reaffirmation of their non-Schwannian nature. Am J Obstet Gynecol 1977;129:389-392.

    2. Pritchard JG, Lowenstein MH, Silverman IJ, Brennan JC. Streptococcus milleri pyomyoma simulating infective endocarditis. Obstet Gynecol 1986;129:389-392.

    3. Ferry JA, Harris NL, Scully RE. Uterine leiomyomas with lymphoid infiltration simulating lymphoma. A report of seven cases. Int J Gynecol Pathol 1989;8:263-270.

    4. Gilks CB, Taylor GP, Clement PB. Inflammatory pseudotumor of the uterus. Int J Gynecol Pathol 1987;6:275-286.

    5. Schmid C, Beham A, Kratochvil P. Haematopoesis in a degenerating leiomyoma. Arch Gynecol Obstet 1991;248:81-86.

    6. Schmid C, Beham A, Kratochvil P. Haematopoesis in a degenerating leiomyoma. Arch Gynecol Obstet 1991;248:81-86.

    7. Adany R, Fodor F, Molnar P, Ablin RJ, Muszbek L. Increased density of histiocytes in uterine leiomyomas. Int J Gynecol Pathol 1990;9:137-144.

    8. Crow J, Wilkins M, Howe S, More L, Helliwell P. Mast cells in the female genital tract. Int J Gynecol Pathol 1991;10:230-237.

    9. Orii A, Mori A, Zhai YL, Toki T, Nikaido T, Fujii S. Mast cells in smooth muscle tumors of the uterus. Int J Gynecol Pathol 1998;17:336-342.

    10. Vang R, Medeiros LJ, Samoszuk , Daevers MT. Uterine leiomyomas with eosinophils: A clinicopathologic study of 3 cases. Int J Gynecol Pathol 2001;239-43.
    Leiomyosarcoma:
    1. Taylor HB, Norris HJ. Mesenchymal tumors of the uterus. IV. Diagnosis and prognosis of leiomyosarcomas. Arch Pathol 1966;82:40-44.

    2. Hart WR, Billman JK, Jr. A reassessment of uterine neoplasms originally diagnosed as leiomyosarcomas. Cancer 1978;41:1902-1910.

    3. Evans HL, Chawla SP, Simpson C, Finn KP. Smooth muscle neoplasms of the uterus other than ordinary leiomyoma. A study of 46 cases, with emphasis on diagnostic criteria and prognostic factors. Cancer 1988;62:2239-2247.

    4. Schwartz LB, Diamond MP, Schwartz PE. Leiomyosarcomas: clinical presentation. Am J Obstet Gynecol 1993;168:180-183.

    5. Major FJ, Blessing JA, Silverberg SG, et al. Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study. Cancer 1993;71:1702-1709.

    6. Barter JF, Smith EB, Szpak CA, Hinshaw W, Clarke-Pearson DL, Creasman WT. Leiomyosarcoma of the uterus: clinicopathologic study of 21 cases. Gynecol Oncol 1985;21:220-227.

    7. Larson B, Silfversward C, Nilsson B, Pettersson F. Prognostic factors in uterine leiomyosarcoma. A clinical and histopathological study of 143 cases. The Radiumhemmet series 1936-1981. Acta Oncol 1990;29:185-191.

    8. Jones MW, Norris HJ. Clinicopathologic study of 28 uterine leiomyosarcomas with metastasis. Int J Gynecol Pathol 1995;14:243-249.

    9. Atkins K, Bell S, Kempson M, Hendrickson M. Myxoid smooth muscle tumors of the uterus. Modern Pathol 2001;14:132A.

    10. King ME, Dickersin GR, Scully RE. Myxoid leiomyosarcoma of the uterus. A report of six cases. Am J Surg Pathol 1982;6:589-598.

    11. Chen KT. Myxoid leiomyosarcoma of the uterus. Int J Gynecol Pathol 1984; 3:389-392.

    12. Pounder DJ, Iyer PV. Uterineleiomyosarcoma with myxoid stroma. Arch Pathol Lab Med 1985;109:762-764.

    13. Salm R, Evans DJ. Myxoid leiomyosarcoma. Histopathology 1985;9:159-169.Peacock G, Archer S. Myxoid leiomyosarcoma of the uterus. Case report and review of the literature. Am J Obstet Gynecol 1989;160:1515-1519.

    14. Schneider D, Halperin R, Segal M, Maymon R, Bukovsky I. Myxoid leiomyosarcoma of the uterus with unusual malignant histologic pattern: a case report. Gynecol Oncol 1995;59:156-158.

    15. Bodner K, Bodner-Adler B, Kimberger O, Czerwenka K, Leodolter S, Mayerhofer K. Evaluating prognostic parameters in women with uterine leiomyosarcoma. A clinicopathologic study. J Reprod Med 2003;48:95-1000.

    16. Mayerhofer K, Obermair A, Windbichler G, Petru E, Kaider A, Hefler L, Czerwenka K, Leodolter S, Kainz C. Gynecol Oncol 74:196-201, 1999.

    17. Zhai YL, Kobayashi Y, Mori A, Orii A, Nikaido T, Konishi I, Fujii S. Expression of steroid receptors, Ki-67, and p53 in uterine leiomyosarcomas. Int J Gynecol Pathol 18:20-8, 1999.

    18. Rao UN, Finkelstein SD, Jones MW. Comparative immunohistochemical and molecular analysis of uterine and extrauterine leiomyosarcomas. Mod Pathol12:1001-9, 1999.

    19. Giuntoli RL, Metzinger DS, DiMarco CS, Cha SS, Sloan JA, Henney GL, Gostout BS. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol 2003;89:460-469.

    20. Hu J, Khanna V, Jones M, Surti U. Genomic alterations in uterine leiomyosarcomas: potential markers for clinical diagnosis and prognosis. Genes, Chromosomes Cancer 2001;31:117-124.

    21. Levy B, Mukherjee T, Hirschhorn K. Molecular cytogenetic analysis of uterine leiomyoma and leiomyosarcoma by comparative genomic hybridization. Cancer Genet Cytogenet 2000:121:1-8

    22. Leiato MM, Sonoda Y, Brennan MF, Barakat RR, Chi DS. Incidence of lymph node metastases in leiomyosarcoma of the uterus. Gynecol Oncol 2003:91:209-212.

    23. Dinh TA, Oliva E, Fuller AF, Lee H, Goodman A. The treatment of uterine leiomyosarcoma. Results from a 10-year experience (1990-1999) at the Massachusetts General Hospital. Gynecol Oncol 2004;92:648-652.
    Epithelioid smooth muscle tumors:
    1. Kurman RJ, Norris HJ. Mesenchymal tumors of the uterus. VI. Epithelioid smooth muscle tumors including leiomyoblastoma and clear-cell leiomyoma. A clinical and pathological analysis of 26 cases. Cancer 37:1853-65,1976.

    2. Prayson RA, Goldblum JR, Hart WR. Epithelioid smooth-muscle tumors of the uterus: A clinicopathologic study of 18 patients. Am J Surg Pathol 21:383-91,1997.

    3. Oliva E, Nielsen PG, Clement PB, Young RY, Scully RE. Epithelioid smooth muscle tumors of the uterus. A clinicopathologic analysis of 80 cases. Abstract. Mod Pathol 10:107A, 1997.

    4. Atkins K, Bell S, Kempson R, Hendrickson M. Epithelioid smooth muscle of the uterus. Mod Pathol2001; 14:132A.

    5. Kyriazis AP, Kyriazis AA. Uterine leiomyoblastoma (epithelioid leiomyoma) neoplasm of low-grade malignancy. A histopathologic study. Arch Pathol Lab Med 1992;116:1189-1191.

    6. Kaminski PF, Tavassoli FA. Plexiform tumorlet: a clinical and pathologic study of 15 cases with ultrastructural observations. Int J Gynecol Pathol 1984;3:124-134.

    7. Mazur MT, Priest JB. Clear cell leiomyoma (leiomyoblastoma) of the uterus: ultrastructural observations. Ultrastruct Pathol 1986;10:249-251.

    8. Hyde KE, Geisinger KR, Marshall RB, Jones TL. The clear-cell variant of uterine epithelioid leiomyoma. An immunohistologic and ultrastructural study. Arch Pathol Lab Med 1989;113:551-553.

    9. Aida Y, Tadokoro M, Takeuchi E, et al. Myxoid variant of epithelioid leiomyosarcoma of the uterus. Acta Pathol Jpn 1991;41:778-783.

    10. Silva EG, Tornos C, Ordonez NG, Morris M. Uterine leiomyosarcoma with clear cell areas. Int J Gynecol Pathol 1995;14:174-178.

    11. Seidman JD, Thomas RM. Multiple plexiform tumorlets of the uterus. Arch Pathol Lab Med 1993;117:1255-1256.

    12. Kaminski PF, Tavassoli FA. Plexiform tumorlet: a clinical and pathologic study of 15 cases with ultrastructural observations. Int J Gynecol Pathol 1984;3:124-134.

    13. Ito H, Sasaki N, Miyagawa K, Tahara E. Bizarre leiomyoblastoma of the cervix uteri. Immunohistochemical and ultrastructural study. Acta Pathol Jpn 1986;36:1737-1745.

    14. Mazur MT, Priest JB. Clear cell leiomyoma (leiomyoblastoma) of the uterus: ultrastructural observations. Ultrastruct Pathol 1986;10:249-251.

    15. Hyde KE, Geisinger KR, Marshall RB, Jones TL. The clear-cell variant of uterine epithelioid leiomyoma. An immunohistologic and ultrastructural study. Arch Pathol Lab Med 1989;113:551-553.

    16. Seidman JD, Yetter RA, Papadimitriou JC. Epithelioid component of uterine leiomyosarcoma simulating metastatic carcinoma. Arch Pathol Lab Med 1992;116:287-290.

    17. Silva EG, Tornos C, Ordonez NG, Morris M. Uterine leiomyosarcoma with clear cell areas. Int J Gynecol Pathol 1995;14:174-178.

    18. Silva EG . Deavers MT, Bokurda DC, Malpica A Uterine leiomyosarcoma with clear cell areas. Reactivity with HMB-45 and the concept of PEComa. 2004;28:44-49.

    19. Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 1998;22:1393-1403.

    20. Vang R, Kempson RL. Perivascular epithelioid cell tumor (PEComa) of the uterus: A subset of HMB-45-positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors. Am J Surg Pathol 2002; 26:1-13.

    21. Young RH, Scully RE. Placental-site trophoblastic tumor: current status. Clin Obstet Gynecol 1984;27:248-257.

    22. Silva EG, Deavers MT, Bodurka D, Malpica A. Utrine epithelioid leiomyosarcomas with clear cells. Reactivity with HMB-45 and the concept of PEComa. Am J Surg Pathol 2004;28:244-249.

    23. Young RH, Scully RE. Oxyphilic tumors of the female and male genital tracts. Semin Diagn Pathol 1999;16:146-161.
    Other variants:
    1. Clement PB, Young RH. Diffuse leiomyomatosis of the uterus: a report of four cases. Int J Gynecol Pathol 1987;6:322-330.

    2. Lai FM, Wong FW, Allen PW. Diffuse uterine leiomyomatosis with hemorrhage. Arch Pathol Lab Med 1991;115:834-837.

    3. Mulvany NJ, Ostor AG, Ross I. Diffuse leiomyomatosis of the uterus. Histopathology 1995;27:175-179.

    4. Lack EE, Dolan MF, Finisio J, Grover G, Singh M, Triche TJ. Pulmonary and extrapulmonary lymphangioleiomyomatosis. Report of a case with bilateral renal angiomyolipomas, multifocal lymphangioleiomyomatosis, and a glial polyp of the endocervix. Am J Surg Pathol 1986;10:650-657.

    5. Gyure KA, Hart WR, Kennedy AW. Lymphangiomyomatosis of the uterus associated with tuberous sclerosis and malignant neoplasia of the female genital tract: a report of two cases. Int J Gynecol Pathol 1995;14:344-351.

    6. Roth LM, Reed RJ. Dissecting leiomyomas of the uterus other than cotyledonoid dissecting leiomyomas: a report of eight cases. Am J Surg Pathol 1999;23:1032-1039.

    7. Fukunaga M, Ushigome S. Dissecting leiomyoma of the uterus with extrauterine extension. Histopathology 1998;32:160-164.

    8. Roth LM, Reed RJ, Sternberg WH. Cotyledonoid dissecting leiomyoma of the uterus. The Sternberg tumor. Am J Surg Pathol 1996; 20:1455-1461.

    9. Kim MJ, Park YK, Cho JH. Cotyledonoid dissecting leiomyoma of the uterus: a cases report and review of the literature.J Korean Med Sci 2002;17:840-844.

    10. Canzonieri V, D'Amore ES, Bartoloni G, Piazza M, Blandamura S, Carbone A. Leiomyomatosis with vascular invasion. A unified pathogenesis regarding leiomyoma with vascular microinvasion, benign metastasizing leiomyoma and intravenous leiomyomatosis. Virchows Arch 1994; 425:541-545.

    11. Norris HJ, Parmley T. Mesenchymal tumors of the uterus. V. Intravenous leiomyomatosis. A clinical and pathologic study of 14 cases. Cancer 1975;36:2164-2178.

    12. Nogales FF, Navarro N, Martinez de Victoria JM, et al. Uterine intravascular leiomyomatosis: an update and report of seven cases. Int J Gynecol Pathol 1987;6:331-339.

    13. Clement PB. Intravenous leiomyomatosis of the uterus. Pathol Annu 1988;23:153-183.

    14. Clement PB, Young RH, Scully RE. Intravenous leiomyomatosis of the uterus. A clinicopathological analysis of 16 cases with unusual histologic features. Am J Surg Pathol 1988;12:932-945.

    15. Mulvany NJ, Slavin JL, Ostor AG, Fortune DW. Intravenous leiomyomatosis of the uterus: a clinicopathologic study of 22 cases. Int J Gynecol Pathol 1994;13:1-9.

    16. Tresukosol D, Kudelka AP, Malpica A, Varma DG, Edwards CL, Kavanagh JJ. Leuprolide acetate and intravascular leiomyomatosis. Obstet Gynecol 1995;86:688-692.

    17. Boyce CR, Buddhdev HN. Pregnancy complicated by metastasizing leiomyoma of the uterus. Obstet Gynecol 1973;42:252-258.

    18. Horstmann JP, Pietra GG, Harman JA, Cole NG, Grinspan S. Spontaneous regression of pulmonary leiomyomas during pregnancy. Cancer 1977;39:314-321.

    19. Tench WD, Dail D, Gmelich J, Matani N. Benign metastasizing leiomyomas: A review of 21 casses. Lab Invest 1978;38:37.

    20. Wolff M, Silva F, Kaye G. Pulmonary metastases (with admixed epithelial elements) from smooth muscle neoplasms. Report of nine cases, including three males. Am J Surg Pathol 1979;3:325-342.

    21. Cramer SF, Meyer JS, Kraner JF, Camel M, Mazur MT, Tenenbaum MS. Metastasizing leiomyoma of the uterus. S-phase fraction, estrogen receptor, and ultrastructure. Cancer 1980;45:932-937.

    22. Banner AS, Carrington CB, Emory WB, et al. Efficacy of oophorectomy in lymphangioleiomyomatosis and benign metastasizing leiomyoma. N Engl J Med 1981;305:204-209.

    23. Evans AJ, Wiltshaw E, Kochanowski SJ, Macfarlane A, Sears RT. Metastasizing leiomyoma of the uterus and hormonal manipulations. Case report. Br J Obstet Gynaecol 1986;93:646-648.

    24. Abell MR, Littler ER. Benign metastasizing uterine leiomyoma. Multiple lymph nodal metastases. Cancer 1975;36:2206-2213.

    25. Deppe G, Clachko M, Deligdisch L, Cohen CJ. Uterine fibroleiomyomata with aortic lymph node metastases. Int J Gynaecol Obstet 1980;18:1-3.

    26. Gatti JM, Morvan G, Henin D, Aboulker J, Nahum H, Glowinski J. Leiomyomatosis metastasizing to the spine. A case report. J Bone Joint Surg Am 1983;65:1163-1165.

    27. Rigaud C, Bogomoletz WV. Leiomyomatosis in pelvic lymph node. Arch Pathol Lab Med 1983;107:153-154.

    28. Barter JF, Szpak C, Creasman WT. Uterine leiomyomas with retroperitoneal lymph node involvement. South Med J 1987;80:1320-1322.

    29. Jautzke G, Muller-Ruchholtz E, Thalmann U. Immunohistological detection of estrogen and progesterone receptors in multiple and well differentiated leiomyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases. Pathol Res Pract 1996;192:215-223.

    30. Abu-Rustum NR, Curtin JP, Burt M, Jones WB. Regression of uterine low-grade smooth-muscle tumors metastatic to the lung after oophorectomy. Obstet Gynecol 1997;89:850-852.

    31. Horiuchi K, Yabe H, Mukai M, et al. Multiple smooth muscle tumors arising in deep soft tissue of lower limbs with uterine leiomyomas. Am J Surg Pathol 1998;22:897-901.

    32. Gal AA, Brooks JS, Pietra GG. Leiomyomatous neoplasms of the lung: a clinical, histologic, and immunohistochemical study. Mod Pathol 1989;2:209-216.

    ENDOMETRIAL STROMAL TUMORS

    General references:
    1. Hart WR, Yoonessi M. Endometrial stromatosis of the uterus. Obstet Gynecol 49:393-403,1977.

    2. Evans HL. Endometrial stromal sarcoma and poorly differentiated endometrial sarcoma. Cancer 50:2170-82,1982.

    3. Fekete PS, Vellios F. The clinical and histologic spectrum of endometrial stromal neoplasms: A report of 41 cases. Int J Gynecol Pathol 3:198-212,1984.

    4. Chang KL, Crabtree GS, Lim-Tan SK et al. Primary uterine endometrial stromal neoplasms. A clinicopathologic study of 117 cases. Am J Surg Pathol 14:415-438,1990.

    5. Kempson RL, Hendrickson MR. Pure mesenchymal neoplasms of the uterine corpus: Selected problems. Semin Diagn Pathol 5:172-198,1988.

    6. Clement PB, Young RH. Mesenchymal and mixed epithelial-mesenchymal tumors of the uterine corpus and cervix. In: Atlas of Gynecologic surgical pathology. Philadelphia: WB Saunders, 2000. pp 177-210.

    7. Clement PB. The pathology of uterine smooth muscle tumors and mixed endometrial stromal and smooth muscle tumors: A selected review with emphasis on recent advances. Int J Gynecol Pathol 19:39-55,2000.

    8. Kempson RL, Hendrickson MR. Smooth muscle, endometrial stromal, and mixed mullerian tumors of the uterus. Mod Pathol 13:328-342, 2000.

    9. Silverberg SG. Low-grade endometrial stromal sarcoma: a rare often puzzling diagnostic problem. Pathology Case Reviews 5:173-180, 2000.

    10. Oliva E, Clement PB, Young RH. Endometrial stromal tumors: An update on a group of tumors with a protean phenotype. Adv Anat Pathol 7:257-281, 2000.

    11. Dionigi A, Oliva E, Clement P, Young R. Endometrial stromal nodules and endometrial stromal tumors with limited infiltration: A clinicopathologic analysis of 50 cases. Am J Surg Pathol 2002;26:567-581.
    Problems in differential diagnosis in endometrial stromal tumors:
    1. Hattab Em, Allam-Nandyala P, Rhatigan RM. The stromal component of large endometrial polyps. Int J Gyn Pathol 18:332-337, 1999.

    2. Goldblum JR, Clement PB, Hart WR. Adenomyosis with sparse glands. A potential mimic of low-grade endometrial stromal sarcoma. Am J Clin Pathol 103:218-223,1995.

    3. Banks ER, Mills SE, Frierson HF. Uterine intravascular menstrual endometrium simulating malignancy. Am J Surg Pathol 15:407-412, 1991.

    4. Sahin AA, Silva EG, Landon G, Ordonez NG, Gershenson DM. Endometrialtissue in myometrial vessels not associated with menstruation. Int J Gyn Pathol 8:139-146,1989.

    5. Oliva E, Young RH, Clement PB, Bhan AK, Scully RE. Cellular benign mesenchymal tumors of the uterus. A comparative morphologic and immunohistochemical analysis of 33 highly cellular leiomyomas and six endometrial stromal nodules, two frequently confused tumors. Am J Surg Pathol 19:757-768, 1995.

    6. Clement PB, Young RH, Scully RE. Intravenous leiomyomatosis of the uterus: a clinicopathologic analysis of 16 cases with unusual histologic features. Am J Surg Pathol 12:932-945, 1988.

    7. Young RH, Prat J, Scully RE. Endometrioid stromal sarcomas of the ovary. A clinicopathologic analysis of 23 cases. Cancer 53: 1143-1155, 1984.

    8. Young RH, Scully RE. Sarcomas metastatic to the ovary: a report of 21 cases. Int J Gynecol Pathol 9:231-252, 1990.
    Mixed endometrial stromal and smooth muscle tumors:
    1. Oliva E, Clement PB, Young RH, Scully RE. Mixed endometrial stromal and smooth muscle tumors of the uterus: A clinicopathologic study of 15 cases. Am J Surg Pathol 22:997-1005,1998.

    2. Schammel DP, Silver SA, Tavassoli FA. Combined endometrial stromal/smooth muscle neoplasms. A clinicopathologic study of 38 cases. Abstract. Mod Pathol 12:124A, 1999.

    3. Gilks CB, Clement PB, Hart WR, Young RH. Uterine adenomyomas excluding atypical polypoid adenomyomas and adenomyomas of endocervical type: a clinicopathologic study of 30 cases of an underemphasized lesion that may cause diagnostic problems with brief consideration of adenomyomas of other female genital tract sites. Int J Gyn Pathol 19:195-205, 2000.
    Myxoid and fibrous endometrial stromal tumors:
    1. Oliva E, Clement PB, Young RH, Scully RE. Myxoid and fibrous endometrial stromal tumors of the uterus: A report of ten cases. Int J Gynecol Pathol 18:310-319, 1999.

    2. Yilmaz A, Rush DS, Soslow RA. Endometrial stromal sarcomas with unusual histologic features. A report of 24 primary and metastatic tumors emphasizing fibroblastic and smooth muscle differentiation. Am J Surg Pathol 2002;26:1142-1150.

    3. Kasashima S, Kobayashi M, Yamada M, Oda Y. Myxoid endometrial stromal sarcoma of the uterus. Pathol Int 2003;53:637-641.
    Uterine tumors resembling ovarian sex cord stromal tumors:
    1. Clement PB, Scully RE: Uterine tumors resembling ovarian sex-cord tumors. A clinicopathologic analysis of fourteen cases. Am J Clin Pathol 66:512-525, 1976.
    Endometrial stromal tumors with gland differentiation:
    1. Clement PB, Scully RE. Endometrial stromal sarcomas of the uterus with extensive endometrioid glandular differentiation: a report of three cases that caused problems in differential diagnosis. Int J Gynecol Pathol 11:163-173, 1992.

    2. Levine PH, Abou-Nassar S, Mittal K. Extauterine low-grade endometrial stroaml sarcoma with florid endometrioid glandular differentiation. Int J Gynecol Pathol 2001;20:395-398.
    Immunohistochemistry:
    1. Abrams J, Talcott J, Corson JM. Pulmonary metastases in patients with low-grade characterization. Am J Surg Pathol 13:133-140, 1989

    2. Devaney K, Tavassoli FA. Immunohistochemistry as a diagnostic aid in the interpretation of unusual mesenchymal tumors of the uterus. Arch Pathol Lab Med 4:225-231, 1991.

    3. Lillemoe TJ, Perrone T, Norris HJ, Dehner LP: Myogenous phenotype of epithelial-like areas in endometrial stromal sarcomas. Arch Pathol Lab Med 115:215-219, 1991.

    4. Franquemont DW, Frierson HF Jr, Mills SE: An immunohistochemical study of normal endometrial stroma and endometrial stromal neoplasms. Evidence for smooth muscle differentiation. Am J Surg Pathol 15:861-870, 1991.

    5. Farhood AI, Abrams J. Immunohistochemistry of endometrial stromal sarcoma. Hum Pathol 1991;22:224-230.

    6. Rizeq MN, van de Rijn M, Hendrickson MR, Rouse RV. A comparative immunohistochemical study of uterine smooth muscle neoplasms with emphasis on the epithelioid variant. Hum Pathol 25: 671-677, 1994.

    7. Lindenmayer AE, Miettinen M. Immunophenotypic features of uterine stromal cells. CD34 expression in endocervical stroma. Virchows Arch 426: 457-460, 1995.

    8. Loo KT, Leung AK, Chan JK. Immunohistochemical staining of ovarian granulosa cell tumours with MIC2 antibody. Histopathology 27: 388-390, 1995.

    9. Matias-Guiu X, Prat J. Alpha-inhibin immunostaining in diagnostic pathology. Adv Anat Pathol 5: 263-267, 1998.

    10. Kommoss F, Oliva E, Bhan AK, Young RH, Scully RE. Inhibin expression in ovarian tumors and tumor-like lesions: an immunohistochemical study. Mod Pathol 11: 656-664, 1998.

    11. Krishnamurthy S, Jungbluth AA, Busam KJ, Rosai J. Uterine tumors resembling ovarian sex-cord tumors have an immunophenotype consistent with true sex-cord differentiation. Am J Surg Pathol 22: 1078-1082, 1998.

    12. Horiuchi A, Nikaido T, Ito K, Zhai Y, Orii A, Taniguchi S, Toki T, Fujii S. Reduced expression of calponin h1 in leiomyosarcoma of the uterus. Lab Invest 78:839-846, 1998.

    13. Baker RJ, Hildebrandt RH, Rouse RV, Hendrickson MR, Longacre TA. Inhibin and CD99 (MIC2) expression in uterine stromal neoplasms with sex-cord-like elements. Hum Pathol 30: 671-679, 1999.

    14. Chu P, Arber DA. Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms. Frequent expression in renal cell carcinoma and endometrial stromal sarcoma. Am J Clin Pathol 113: 374-382, 2000.

    15. Toki T, Shimizu M, Takagi Y, Ashida T, Konishi I. CD10 is a marker for normal and neoplastic endometrial stromal cells. Int J Gynecol Pathol 2002;21:41-47.

    16. Nucci MR, O'Connell JT, Cviko A, Sun D, Quade BJ. h-Caldesmon expression distinguishes endometrial stromal neoplasms from smooth muscle tumors. Am J Surg Pathol 2001;25:445-63.

    17. Watanabe K, Tajino T, Sekiguchi M, Suzuki T. h-Caldesmon as a specific marker for smooth muscle tumors. Comparison with other smooth muscle markers in bone tumors. Am J Clin Pathol 113:663-668, 2000.

    18. Layfield LJ, Liu K, Dodge R, Barsky SH. Uterine smooth muscle tumors: utility of classification by proliferation, ploidy, and prognostic markers versus traditional histopathology. Arch Pathol Lab Med 1.24: 221-7, 2000.

    19. Chu PG, Arber DA, Weiss LM, Chang KL. Utility of CD10 in distinguishing between endometrial stromal sarcoma and uterine smooth muscle tumors: an immunohistochemical comparison of 34 cases. Mod Pathol 14:465-71, 2001.

    20. McCluggage WG. Value of inhibin staining in gynecological pathology. Int Gynecol Pathol 20:79-85, 2001.

    21. McCluggage WG, Sumathi VP, Maxwell P. CD10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms. Histopathology 39:273-8, 2001.

    22. Nixon B, Agoff S, Grieco V, Garcia R, Gown A. The use of immunohistochemistry to distinguish endometrial stromal sarcoma from cellular leiomyoma. Mod Pathol 14:142A, 2001.

    23. Rush DS, Tan J, Baergen RN, Soslow RA. h-Caldesmon, a novel smooth muscle-specific antibody, distinguishes between cellular leiomyoma and endometrial stromal sarcoma. Am J Surg Pathol 25:253-8, 2001.

    24. Oliva, E, Young RH, Amin MB, Clement PB. An immunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus. A study of 54 cases emphasizing the importance of using a panel because of overlap in immunoreactivity for individual antibodies. Am J Surg Pathol 26:403-412,2002.

    25. Wang L, Felix JC, Lee JL, Tan PY, Tourgeman DE, O'Meara AT, Amezcua CA. The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus. Gynecol Oncol 2003;90:402-406.

    26. Winter WE, Seidman JD, Krivac TC, Chauhan S, Carlson JW, Rose GS, Birrer MJ. Clinicopathological analysis of c-kit expression in carcinosarcomas and leiomyosarcomas of the uterine corpus. Gynecol Oncol 2003;91:3-8.

    27. Klein WM, Kurman RJ. The lack of expression of c-kit protein (CD117) in mesenchymal tumors of the uterus and ovary. Int Gyn Pathol, 203;22:181-184..

    28. Srodon M, Kurman RJ. CD10, desmin, and caldesmon in differentiating uterine stromal from smooth muscle tumors. Mod Pathol 2002;15:211A.

    29. Wang L, Felix JC, Amezcua CA. The pattern of expression of c-kit and CD10 may aid in the diagnostic distinction among uterine mesenchymal neoplasms. Mod Pathol 2002;15:213A.

    30. Sabini G, Chumas JC, Mann WJ. Steroid hormone receptors in endometrial stromal sarcomas. A biochemical and immunohistochemical study. Am J Clin Pathol 1992;97:381-386.

    31. Ghofrani M, Jain SR, Hui P, Zheng W, Parkash V. Immunohistochemical markers for the diagnosis of uterine mesenchymal neoplasms. Mod Pathol 2002;15:197A.

    32. Wang L, Felix JC, Lee JL, Tan PY, Tourgeman DE, O'Meara AT, Amezcua CA. The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus. Gynecol Oncol 2003;90:402-406.

    33. Raspollini MR, Villanucci A, Amunni G, Paglierani M, Taddei A, Taddei GL. J Chemot 2003;15:81-84.

    34. Leath Ca, Straughn JM, Conner MG, Barnes MN, Alvarez RD, Partridge EE, Huh WK. Immunohistochemical evaluation of the c-kit proto-oncogene in sarcomas of the uterus: a case series. J Reprod Med 2004;49:71-75.

    35. Loddenkemper C, Mechsner S, Fos HD, Dallenbach F, Anagnostopoulus I, Ebert A, Stein H. Use of oxytocin receptor expression in distinguishing between uterine smooth muscle tumors and endometrial stromal sarcoma. Am J Surg Pathol 2003;27:1458-1462.

    36. Reich O, Regauer S. Aromatase expression in low-grade endometrial stromal sarcomas: an immunohistochemical study. Mod Pathol 2004;17:104-108.

    37. Leunen M, Breugelmans M, De Sutter P, et al. Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole. Gynecol Oncol 2004;95:769-71

    38. Bodner K, Bodern-Adler B, Kimberger O, Czerwenka K, Leodolter S, Mayerhofer K. Estrogen and progesterone receptor expression in patients with uterine leiomyosarcoma and correlation with different clinicopathologic parameters. Anticancer Research 2003;23:729-732.