—  SHORT COURSE #21  —

Mesenchymal Neoplasms of the Female Genital Tract

Case 4 - Low-Grade Endometrial Stromal Sarcoma With Extensive Glandular Differentiation

Teri Longacre, Esther Oliva and Robert Soslow


Introduction
Endometrial stromal tumors are the second most common category of mesenchymal tumors of the uterus. They are typically composed of neoplastic cells that resemble the endometrial stromal cells of the proliferative endometrium. In the uterus they are divided into two main categories, endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (ESS), the latter being by far more common (constituting 10-15% of uterine malignancies with a mesenchymal component).

Clinical Features
These tumors are more commonly seen in late reproductive age or peri-menopausal women and some of them have been reported in association with a hyperestrogenic state. Patients commonly present with abnormal uterine bleeding or pelvic pain, but patients are not infrequently asymptomatic. Of note, extrauterine pelvic extension at presentation is found in up to 1/3 of patients and rarely, the patient presents with tumor at a metastatic site such as the ovary. In such cases it is always important to ask the surgeon if he/she has examined the uterus and about any relevant previous clinical history.

Pathologic Features
Most tumors show a nodular or diffuse permeation of the myometrium, including worm-like plugs of tumor in myometrial or parametrial veins, although some tumors are deceptively well circumscribed from the surrounding tissues on gross examination. They typically have a soft, fleshy, bulging, and tan to yellow cut surface. They may show areas of cyst formation, hemorrhage, and necrosis. On low-power examination, the tumor characteristically permeates the myometrium as irregular tongues. Extrauterine veins and lymphatics are frequently invaded. The tumors are cellular ("blue"), the cells grow in sheets, they have scant cytoplasm and uniform, oval to spindle-shaped nuclei with a tiny nucleolus as seen in endometrial stromal-type cells. The cells focally may whorl around small vessels reminiscent of the arterioles seen in the proliferative phase of the endometrium. This is a very characteristic feature of all endometrial stromal tumors, (ESN and ESS), but it is often not very striking. Significant degrees of nuclear atypia are absent and mitotic rates are usually <3/10HPFs; higher rates do not exclude this diagnosis. It is important to keep in mind that mitoses are no longer used to differentiate between low-grade and high-grade endometrial stromal sarcoma. Tumors with the typical morphology of endometrial stromal tumors and characteristic tongue-like growth should be classified as low-grade ESSs regardless of their mitotic counts because the prognosis of these tumors is similar. In contrast, pleomorphic tumors with an endometrial origin but lacking endometrial stromal differentiation should be classified as poorly differentiated endometrial sarcomas as they are associated with a very poor prognosis.

Other microscopic features that may be seen include collagen bands, focal thickening of the vessels wall secondary to hyalinization, foamy histiocytes (isolated in between neoplastic stromal cells or in compact groups) and cholesterol clefts. Both ESS and ESN may show: a) smooth muscle metaplasia; b) myxoid and fibrous background; c) sex cord-like differentiation; d) endometrioid glandular differentiation; e) clear or eosinophilic, granular cell change; f) rhabdoid appearance; g) rhabdomyoblastic differentiation; h) fatty differentiation; and i) bizarre nuclei.

a) Smooth muscle differentiation: In general it is required that the smooth muscle component occupy at least 30% of the neoplasm to merit this categorization. On gross examination, 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. On microscopic examination, the endometrial stromal component shows the characteristic cells and associated arterioles. The smooth muscle component may show nodules with central hyalinization ("starburst" pattern) that merge with disorganized short fascicles of smooth muscle or long fascicles of mature-appearing smooth muscle. If smooth muscle differentiation is present in an ESN, a not uncommon pitfall in the evaluation of the margin 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, an ESN with a well circumscribed margin may be misinterpreted as an invasive endometrial stromal tumor--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. For prognostic purposes these tumors should be reported as ESNs or ESSs with smooth muscle differentiation (depending on the margins). The designation mixed endometrial stromal-smooth muscle tumor may be given in parentheses. Any other unusual features of either component can be recorded in a notation. It is important to keep in mind that the recurrences may show endometrial stroma, smooth muscle or both components. We do not use the term "stromomyoma" because this term implies a benign tumor.

b) Myxoid and/or fibrous background. As a consequence of the presence of myxoid or collagenous background these tumors tend to be hypocellular in contrast to most endometrial stromal tumors. In case of an ESS, the tumor still shows the typical permeative growth, the arterioles, and in most cases areas of conventional endometrial stromal neoplasia. As with endometrial stromal tumors with smooth muscle differentiation, these tumors may also cause diagnostic problems when they metastasize, particularly to the lung, where a myxoid/fibrous appearance can predominate. It is important to note that in some instances this appearance will be encountered in metastatic sites, but not in the primary tumor.

c) Sex cord-like differentiation. It is characterized by 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. This morphology overlaps with that seen in a uterine tumor resembling an ovarian sex cord stromal tumor, but differs from the latter because conventional areas of endometrial stromal neoplasia are typically found. This finding does not have any prognostic significance.

d) Endometrioid glandular differentiation.  The endometrioid-like glands can be 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.

Differential Diagnosis

Low-grade endometrial stromal sarcoma vs endometrial stromal nodule
First of all, it is important to keep in mind that ESN and ESS have identical histologic appearance, thus, 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 such that the pathologist can appreciate the margins of the lesion. Distinction between an ESN and an ESS is primarily based on the presence of infiltrative margins or vascular permeation in ESS, which in most cases can only be established in a hysterectomy specimen. Only small ESNs are likely to be diagnosable with confidence on a curettage, an important issue when the patient is in her reproductive age and desires to preserve her uterus. In these women a combination of diagnostic imaging and hysteroscopy may be useful in monitoring the growth of the lesion and in occasional cases local excision has been successful. The same rules apply when fragments of tumor seen in the curettage specimen are predominantly composed of sex cord-like elements. In those cases the differential diagnosis includes a uterine tumor resembling an ovarian sex cord tumor and a conventional EST with sex cord-like differentiation. Although the former in most cases is well circumscribed, the pathologist needs to evaluate margins in order to properly sub-classify the tumor and for this reason a hysterectomy is usually the treatment of choice.

Secondly, as mentioned earlier, some ESSs may be grossly well circumscribed and may be thought to represent an ESN. In such cases it is extremely important to generously sample the tumor-myometrium interface to detect areas of clear-cut invasion. Finally, recently, we have reported a series of 50 ESNs including 3 tumors that did not fulfill the criteria for ESN but still did not have the overt permeative growth seen in ESS. As these tumors are associated with a much more limited infiltration of the myometrium, it may be hypothesized that they would have a much better prognosis. However, follow-up in these 3 cases was limited, thus limiting our ability to establish firm conclusions regarding their prognosis. For the moment these tumors have been descriptively referred to as "endometrial stromal tumors with limited infiltration" until more information is obtained regarding their prognosis.

Low-grade endometrial stromal tumor vs cellular endometrial polyp
Endometrial polyps may be fragmented in curettage specimens and some of the fragments may consist of cellular stroma only. Although endometrial stromal tumors 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 a benign polyp in which vessels, if prominent, tend to be larger, thick-walled, and irregularly distributed.

Low-grade endometrial stromal sarcoma 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. Other helpful features to establish the diagnosis of adenomyosis with sparse glands or intravascular adenomyosis include: a) the absence of other typical morphologic features of ESS; b) the presence of typical areas of adenomyosis elsewhere, c) the absence of a mass; and d) the postmenopausal age of the patients.

Low-grade endometrial stromal sarcoma vs intravascular endometrial tissue, and menses-associated cellular stroma
Intravascular menstrual endometrium if only composed of stromal cells may cause problems in the differential diagnosis with an ESS. However, the stromal cells form tight clusters of small spindle cells with hyperchromatic nuclei showing high nuclear/cytoplasmic ratio. Some of the nests may have a necrotic appearance and/or 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.

Low-grade endometrial stromal tumor vs highly cellular leiomyoma (HCL)
Many highly cellular leiomyomas have a somewhat different consistency and color from that of conventional leiomyomas, on average being softer and having a tendency to be yellow or yellow-tan, closely resembling the gross appearance of endometrial stromal tumors. On microscopic examination, as their definition implies, they are as cellular as endometrial stromal tumors and they may have prominent vascularity as well as irregular margins with the surrounding stroma that would cause concern for an ESS. Histologic findings that favor a highly cellular leiomyoma include: a) focal merging of the highly cellular areas with typical fascicular areas of smooth muscle neoplasia in most of the cases, b) large thick muscular blood vessels in contrast to the arterioles seen in an endometrial stromal neoplasm, c) cleft-like spaces, some apparently representing compressed vessels, others apparently the result of edema, and d) strong and multifocal or diffuse immunoreactivity for smooth muscle markers including desmin and h-caldesmon.

Low-grade endometrial stromal sarcoma vs intravenous leiomyomatosis (IVL)
This entity may cause confusion with an ESS mainly because of its prominent intravascular growth especially and when the tumor is highly cellular, resembling HCL. Helpful features to establish the diagnosis of IVL include: a) clefted or lobulated contour of the intravascular masses, b) focal fascicular architecture, c) cells with blunt-ended nuclei, d) prominent thick-walled vessels, and e) 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. Cardiac involvement is seen in up to 40% of cases of IVL, but low-grade ESSs may also demonstrate this finding infrequently.

Low-grade endometrial stromal sarcoma vs high-grade endometrial sarcoma
The lack of specific evidence of endometrial stromal cell origin in most cases of high-grade endometrial sarcoma 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 extensive 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.

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.
  • It is important to keep in mind that common tumors outside the uterus may rarely occur in the uterus (primitive neuroectodermal tumors, lymphoma, others). Thus, if a tumor composed of small blue cells does not stain for the typical panel (CD10, desmin and h-caldesmon) used to differentiate endometrial stromal tumors from smooth muscle tumors (the two more common pure mesenchymal tumors) it is important to explore other diagnostic possibilities and perform appropriate studies (immunohistochemistry, cytogenetics, flow cytometry, others).

Endometrial stromal tumor with gland and/or smooth muscle vs endometrioid adenomyoma
Even though endometrioid adenomyoma contains endometrioid-type glands, endometrial-type stroma and smooth muscle as may be seen in endometrial stromal tumors, they typically show an orderly distribution of the three elements, where the glands are surrounded by variable amounts of endometrial stroma which in turn is surrounded by mature muscle with an appearance that differs from the metaplastic muscle seen in endometrial stromal tumors. Furthermore they are well-circumscribed tumors that in most cases have the gross appearance of a leiomyoma.

Fibrous-myxoid endometrial stromal tumor vs other mesenchymal tumors
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 endometrial stromal tumor include: a) frequent presentation as an endometrial polypoid mass, b) prominent multinodular or tongue-like pattern of myometrial infiltration, c) focal presence of typical endometrial stromal neoplasia with characteristic arterioles, and d) the absence or minimal staining for muscle markers in most cases (desmin and h-caldesmon).

Low-grade endometrial stromal sarcoma with extensive sex cord-like differentiation vs uterine tumor resembling a sex cord ovarian tumor (UTROSCT)
The diagnosis of UTROSCT should only be established when no clear-cut areas of endometrial stromal neoplasia are identified. Thus, extensive sampling is mandatory to identify any area with the pattern of typical endometrial stromal neoplasia. The distinction is important as patients with a UTROSCT have an excellent prognosis. Immunohistochemical stains are not helpful in this differential diagnosis.

Low-grade endometrial stromal sarcoma with extensive sex cord-like differentiation vs epithelioid leiomyosarcoma
Epithelioid smooth muscle tumors may exhibit a sex cord-like pattern, although generally not as strikingly as in tumors of probable endometrial stromal cell derivation. Smooth muscle markers, epithelial markers as well as some sex cord markers may be present or lacking in both tumor types. Thus, the immunohistochemical findings must be evaluated in the light of conventional microscopy, as most epithelioid smooth muscle tumors will show at least focally a spindle cell component.

Low-grade endometrial stromal sarcoma with gland differentiation vs adenomyosis
Adenomyosis is typically an incidental finding that never presents as a mas,s as discussed earlier. Even though both entities show endometrial-type glands surrounded by endometrial-type stroma, the stroma in adenomyosis has an inactive appearance while in low-grade ESS show an expansile growth and a proliferative appearance of the stromal cells. Furthermore, low-grade ESS typically form a mass, and in some areas the tumor may show the more typical appearance without the glandular component.

Low-grade endometrial stromal sarcoma with gland differentiation vs low-grade mullerian adenosarcoma
Both tumors show endometrioid-type glands, endometrial-type stroma and both components infiltrate the myometrium. However, mullerian adenosarcoma 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, if they infiltrate do not show the typical tongue-like growth and less often have vascular invasion.

Metastatic low-grade endometrial stromal sarcoma to the ovary vs stromal or sex-cord stromal tumor
The findings of tumor outside the ovary as well as endometriosis favor the diagnosis of low-grade ESS. Immunohistochemical stains are of limited help. Sex cord but not pure stromal tumors may be positive for CD10, although the degree and extent of positivity is much less than that observed in endometrial stromal tumors. Furthermore, sex cord-like areas in endometrial stromal tumors stain similarly to sex cord stromal tumors. In these cases extensive sampling is required to show areas of conventional endometrial stromal neoplasia.

Metastatic low-grade endometrial stromal sarcoma vs solitary fibrous tumor
When low-grade ESS has a fibrous background and it is present in the lung or even in the peritoneum, one should consider a solitary fibrous tumor in the differential diagnosis. However, the latter is frequently associated with a more haphazard orientation of the tumor cells and a vascular component not only showing arterioles. These tumors may be positive for CD10 and estrogen and progesterone receptors, thus, these markers are not helpful in this differential diagnosis. CD34 may be of help in distinguishing these two tumors. 

Metastatic low-grade endometrial stromal sarcoma vs gastrointestinal stromal tumor
Even though these two entities have different histologic appearance, one may not think about the possibility of an endometrial stromal tumor when outside the uterus, especially as the histologic appearance may differ to some extent from that seen in typical tumors.

Immunohistochemical Features
Although in most instances the diagnosis of endometrial stromal tumors (EST) 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. 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. In the ovary, CD10 is positive in sex-cord stromal tumors, the latter usually showing weak and focal staining. For that reason, although CD10 is not widely used in the diagnosis of sex-cord stromal tumors, it is important to be aware of this finding.

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 tum ors, Hey! Our study was first J why did everyone like Nucci's better?? 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. Others have confirmed these findings.

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 and colleagues 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 and colleagues 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 isconsistent with the presence of steroid-producing cells and is supportive of their specialized gonadal stromal nature . Inhibin is the paramount marker for sex cord-stromal tumors of the ovary (I think Mike Deavers would disagree with you—what about calretinin?), however, remember that inhibin is not totally specific for sex cord-stromal tumors and that mesonephric tumors frequently show focal and weak positivity and that a minority of ovarian carcinomas have been reported to be also positive for α-inhibin.

Calretinin has been shown to be highly sensitive but not as specific marker as inhibin for sex cord -stromal tumors. Some sex cord-stromal tumors that are negative for inhibin may be calretinin positive. Calretinin is also positive in fibromas of the ovary. This antibody is expressed in non-neoplastic ovarian sex cord-stromal cells, but also in secretory endometrial stromal cells. There is limited experience with ESTs at the moment, although some ESTs have reported to be calretinin positive. Moreover, other tumors may stain for calretinin including leiomyosarcomas, mesonephric tumors as well as endometrioid carcinomas of the ovary and endometrium and for that reason positive calretinin immunoreactivity should be used in the appropriate context.

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 and colleagues 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 and colleagues, 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 and colleagues, 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.CD99 reacts with normal sertoli and granulosa cells and it is marker for sex-cord stromal tumors. The degree of expression may be related to the degree of tumor differentiation and the staining may be membranous or cytoplasmic. It has been shown that CD99 is much less sensitive and less specific than inhibin in the diagnosis of sex cord-stromal tumors.

Mart-1 (Melan A, A103) is typically positive in steroid cell tumors but also in other sex cord -stromal tumors, including Sertoli-Leydig cell tumors, adult and juvenile granulosa cell tumors, and even in the fibroma-thecoma category of ovarian tumors, although experience is very limited. Endometrial/ioid stromal tumors have been shown to be negative for Mart-1, with the exception of sex-cord areas that may be positive.

WT-1 Nonneoplastic endometrial stroma as well as endometrial stromal tumors are WT-1 positive .  However, smooth muscle tumors, the most problematic tumors in the differential diagnosis of endometrial stromal tumors are also positive for this antibody.

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 and colleagues 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. CD34 may be helpful in cases of metastatic ESS to lungs where the differential diagnosis is mainly with solitary fibrous tumors, the latter typically positive for this marker.

C-KIT, a well known marker for gastrointestinal stromal tumors and it has been to be the most useful immunohistochemical marker for gastrointestinal stromal tumors and it is typically positive in 72-100% of these tumors. It 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, progesterone and androgen receptors, findings 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.

Cytogenetic Features
At least 60 to 70% of typical low-grade EESs show the t(11;17), involving JAZF1 and JJAZ1 translocation, including tumors with smooth muscle metaplasia, fibrous and/or myxoid background or sex cord-like differentiation. The prevalence of this translocation is much lower in so-called high-grade endometrial stromal sarcoma.

Prognosis and Treatment
As in most cases it is impossible to separate between an endometrial stromal nodule and a low-grade endometrial stromal sarcoma in a curettage specimen, the optimal treatment is always hysterectomy accompanied by bilateral salpingo-oophorectomy because these tumors are often hormone sensitive and it has been shown that patients retaining their ovaries have a much higher risk of recurrence (up to 100%). The 5-year survival rate is approximately 80-90% and the 10-year survival is a bit lower (about 70%). Patients who present with Stage I (organ confined) disease have better prognosis, with a 5-year survival close to 100% and a 10-year survival around 90%. In contrast, patients who present with high-stage ESSs have only a 40% survival that remains constant at 10 years. Therefore, patients who present with low-stage tumors probably continue to experience recurrence decades after diagnosis whereas patients diagnosed with high stage tumors experience recurrence and frequently die of disease within 5 years of diagnosis.
  • Stage is therefore the most powerful prognostic factor in endometrial stromal sarcomas.

References

General:
  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 of 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. Endometrial tissue 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.

  9. Baker PM, Moch H, Oliva E. Unusual morphologic features of endometrial stromal tumors: a report of 2 cases. Am J Surg Pathol. 2005;29:1394-8.

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.

  2. Irving JA, Carinelli S, Prat J. Uterine tumors resembling ovarian sex cord tumors are polyphenotypic neoplasms with true sex cord differentiation. Mod Pathol. 2006;19:17-24.

  3. De Leval L, Waltregni D, Dupuis LM, Boniver J, Oliva E. Uterine Tumors Resembling Ovarian Sex-Cord Tumors. A study of 13 cases showing a diverse phenotypic profile. Modern Pathol 2006, 19:176A.

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. McCluggage WG, Cromie AJ, Bryson C, Traub AI. Uterine endometrial stromal sarcoma with smooth muscle and glandular differentiation. J Clin Pathol. 2001;54:481-3.

  3. Levine PH, Abou-Nassar S, Mittal K. Extauterine low-grade endometrial stromal sarcoma with florid endometrioid glandular differentiation. Int J Gynecol Pathol 2001;20:395-398.

Immunohistochemistry:
  1. Baker PM, Oliva E. Immunohistochemistry as a tool in the differential diagnosis of ovarian tumors: an update. Int J Gynecol Pathol. 2005;24:39-55.

  2. McGluggage WG. Immunohistochemical and functional biomarkers of value in female genital tract lesions. Int J Gynecol Pathol. 2006;25:101-20.

  3. McGluggage WG, Young RH. Immunohistochemistry as a diagnostic aid in the evaluation of ovarian tumors. Semin Diagn Pathol. 2005;22:3-32.

  4. Abrams J, Talcott J, Corson JM. Pulmonary metastases in patients with low-grade characterization. Am J Surg Pathol 13:133-140, 1989.

  5. Bhargava R, Shia, Hummer AJ, Thaler HT, Tornos C, Soslow RA Distinction of endometrial stromal sarcomas from 'hemangiopericytomatous' tumors using a panel of immunohistochemical stains. Mod Pathol. 2005;18:40-7.

  6. 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.

  7. 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.

  8. 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.

  9. De Leval L, Waltregny D, Boniver J, Young RH, Castronovo V, Oliva E. Use of histone deacetylase 8 (HDAC8), a new marker of smooth muscle differentiation, in the classification of mesenchymal tumors of the uterus. Am J Surg Pathol. 2006;30:319-27.

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

  11. 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.

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

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

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

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

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

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

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

  26. 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.

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

  28. 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.

  29. 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.

  30. Sumathi VP, Al-Hussaini M, Conolly LE, Fullerton M, McCluggage WG. Endometrial stromal neoplasms are immunoreactive with WT-1 antibody. Int J Gynecol Pathol. 2004;23:241-7.

  31. 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.

  32. 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.

  33. 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..

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

  35. 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.

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

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

  38. 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.

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

  40. 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.

  41. 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.

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

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

  44. 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.

  45. Mount SL, Eltabbakh GH, Cooper K. Recent "non-gynecological" immunohistochemical markers in diagnostic ovarian pathology. Current Diagnostic Pathol 2003; 9:11-18.

  46. McCluggage WG. Recent advances in immunohistochemistry in gynecological pathology. Histopathology 2002; 40:309-326.

  47. McCluggage WG. Recent advances in immunohistochemistry in the diagnosis of ovarian neoplasms. J Clin Pathol 2000; 53:327-334.

  48. Rossi G, Cavazza A, Longo L, Maiorana A. Localized pleural metastatic adenosarcoma of the uterine cervix mimicking a malignant solitary fibrous tumor: CD10 has no value in differential diagnosis. Histopathology 2002; 41:82-88.

  49. Oliva E, Garcia Miralles N, Vu Q, Young RH. CD10 expression in sex cord-stromal tumors and steroid cell tumors of the ovary. Int J Gynecol Pathol (in press).

  50. Ordi J, Nogales FF, Palacin A, Marquez M, Pahisa J, Vanrell JA, Cardesa A. Mesonephric carcinoma of the uterine corpus: CD10 expression as evidence of mesonephric differentiation. Am J Surg Pathol 2001; 25:1540-1545.

  51. Mikami Y, Hata S, Kiyokawa T, Manabe T. Expression of CD10 in Malignant Mullerian Mixed Tumors and Adenosarcomas: An immunohistochemical Study. Mod Pathol 2001;15:923-930.

  52. Zheng W, Senturk BZ, Parkash V. Inhibin immunohistochemical staining: A practical approach for the surgical pathologist in the diagnoses of ovarian sex cord-stromal tumors. Adv Anat Pathol 2003; 10:27-38.

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

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

  55. McCluggage WG, Maxwell P, Sloan JM. Immunohistochemical staining of ovarian granulosa cell tumors with monoclonal antibody against inhibin. Hum Pathol 1997;28:1034-1038.

  56. Riopel MA, Perlman EJ, Seidman JD, Kurman RJ, Sherman ME. Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord-stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas. Int J Gynecol Pathol 1998;17:46-53.

  57. Rishi M, Howard LN, Bratthauer GL, Tavassoli FA. Use of monoclonal antibody against human inhibin as a marker for sex cord-stromal tumors of the ovary. Am J Surg Pathol 1997;21:583-589.

  58. Stewart CJ, Jeffers MD, Kennedy A. Diagnostic value of inhibin immunoreactivity in ovarian gonadal stromal tumours and their histological mimics. Histopathology 1997;31:67-74.

  59. Matias-Guiu X, Pons C, Prat J. Mullerian Inhibiting substance, Inhibin, and CD99 xpression in sex cord-stromal tumors and endometrioid ovarian carcinomas resembling sex cord-stromal tumors. Hum Pathol 1998; 29:840-845.

  60. Kommoss F, Oliva E, Young RH, Bittinger F, Kirkpatrick CJ, Schmidt D. Expression of Mullerian Inhibiting Substance, CD99, and HEA125 in ovarian tumors. German J Obstet Gynecol 2001; 61:274-279.

  61. Gordon MD, Corless C, Renshaw AA, Beckstead J. CD99, Keratin, and Vimentin taining of Sex Cord-Stromal Tumors, normal ovary and testis. Mod Pathol 1998; 11:769-773.

  62. 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 1999;30:671-679.

  63. Movahedi-Lankarani S, Kurman RJ. Calretinin, a more sensitive but less specific marker than inhibin for ovarian sex cord-stromal neoplasms. An immunohistochemical study of 215 cases. Am J Surg Pathol 2002; 26:1477-1483.

  64. Deavers MT, Malpica A, Liu J, Broaddus R, Silva EG. Ovarian sex cord-stromal tumors: 64. an immunohistochemical study including a comparison of calretinin and inhibin. Mod Pathol 2003; 16:584-590.

  65. Reich O, Regauer S. Aromatase expression in low-grade endometrial stromal sarcomas: an immunohistochemical study. Mod Pathol. 2004;17:104-8.

Cytogenetics:
  1. Oliva E, de Leval L, Soslow RA, Herens C. Interphase FISH Detection of JAZF1-JJAZ1 Gene fusion in Endometrial Stromal Tumors with Smooth muscle differntiation. Am J Surg Pathol (in press).

  2. Nucci M. Harburger D, Koontz J, Dal Cin PD, Sklar J. Molecular Analysis of the JAZF1-JJAZ1 Gene Fusion by RT-PCR and Fluorescence In Situ Hybridization in Endometrial Stromal Neoplasms. Am J Surg Pathol. 2007;31:65-70.

  3. Hrzenjak A, Moinfar F, Tavassoli FA, Strohmeir B, Kremser ML, Zadloukal K, Denk HJAZF1/JJAZ1 gene fusion in endometrial stromal sarcomas: molecular analysis by reverse transcriptase-polymerase chain reaction optimized for paraffin-embedded tissue. J Mol Diagn. 2005;7:388-95.

  4. Huang HY, Ladanyi M, Soslow RA. Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial stromal neoplasms with classic and variant histology: evidence for genetic heterogeneity. Am J Surg Pathol. 2004 ;28:224-32.