Undifferentiated Endometrial Sarcoma Research Articles

Discrepancies in pathological diagnosis of endometrial stromal sarcoma: a multi-institutional retrospective study from the Japanese clinical oncology group

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that requires accurate pathological diagnosis for proper treatment. This study aimed to clarify the discrepancies in the pathological diagnosis of ESS and obtain practical clues to improve diagnostic accuracy. Between 2002 and 2015, 148 patients with low-grade ESS (LGESS), high-grade ESS (HGESS), undifferentiated endometrial sarcoma (UES), or undifferentiated uterine sarcoma (UUS) diagnosed at 31 institutions were included. We performed immunohistochemistry, real-time polymerase chain reaction for JAZF1-SUZ12 and YWHAE-NUTM2A/B, and break-apart fluorescent in situ hybridization for JAZF1, PHF1, and YWHAE. Central pathology review (CPR) was performed by six pathologists. After CPR, LGESS, HGESS, UES/UUS, and other diagnoses were confirmed in 72, 25, 16, and 31 cases, respectively. Diagnostic discrepancies were observed in 19.6% (18/92) of LGESS and 34% (18/53) of HGESS or UUS/UES. Adenosarcomas, endometrial carcinomas, carcinosarcomas, and leiomyosarcomas were common diagnostic pitfalls. JAZF1-SUZ12 transcript, PHF1 split signal, and YWHAE-NUTM2A/B transcript were mutually exclusively detected in 23 LGESS, 3 LGESS, and 1 LGESS plus 3 HGESS, respectively. JAZF1-SUZ12 and YWHAE-NUTM2A/B transcripts were detected only in cases with CPR diagnosis of LGESS or HGESS. The CPR diagnosis of LGESS, HGESS, and UUS was a significant prognosticator, and patients with LGESS depicted a favorable prognosis, while those with UUS showed the worst prognosis. Pathological diagnosis of ESS is often challenging and certain tumors should be carefully considered. The accurate pathological diagnosis with the aid of molecular testing is essential for prognostic prediction and treatment selection.

822TiP BFR ESS: A randomized phase II trial from the GSF/GETO French group evaluating the impact of interruption versus maintenance of aromatase inhibitors in patients with advanced or metastatic low grade endometrial stromal sarcoma after at least 3 years of therapy

Uterine sarcomas are rare tumors with an incidence of 1.7/100 000 women per year, including 20% of endometrial stromal sarcomas (ESS). Patients (pts) with low grade ESS (LGESS) have a good prognosis with 5-year overall survival rates ranging from 66 to 98%, depending on the stage of the disease. Unlike undifferentiated endometrial sarcoma (UES), which behave aggressively, LGESS are indolent. For advanced or metastatic stage, hormonal therapy (HT) is the standard of care. The use of HT for advanced or metastatic disease is recommended based on retrospective data from small series providing evidence that HT have an anti-tumor activity on LGESS.

Imaging in gynecological disease (15): clinical and ultrasound characteristics of uterine sarcoma.

To describe the clinical and ultrasound characteristics of uterine sarcomas. This was a retrospective multicenter study. From the databases of 13 ultrasound centers, we identified patients with a histological diagnosis of uterine sarcoma with available ultrasound reports and ultrasound images who had undergone preoperative ultrasound examination between 1996 and 2016. As the first step, each author collected information from the original ultrasound reports from his/her own center on predefined ultrasound features of the tumors and by reviewing the ultrasound images to identify information on variables not described in the original report. As the second step, 16 ultrasound examiners reviewed the images electronically in a consensus meeting and described them using predetermined terminology. We identified 116 patients with leiomyosarcoma, 48 with endometrial stromal sarcoma and 31 with undifferentiated endometrial sarcoma. Median age of the patients was 56 years (range, 26-86 years). Most patients were symptomatic at diagnosis (164/183 (89.6%)), the most frequent presenting symptom being abnormal vaginal bleeding (91/183 (49.7%)). Patients with endometrial stromal sarcoma were younger than those with leiomyosarcoma and undifferentiated endometrial sarcoma (median age, 46 years vs 57 and 60 years, respectively). According to the assessment by the original ultrasound examiners, the median diameter of the largest tumor was 91 mm (range, 7-321 mm). Visible normal myometrium was reported in 149/195 (76.4%) cases, and 80.0% (156/195) of lesions were solitary. Most sarcomas (155/195 (79.5%)) were solid masses (> 80% solid tissue), and most manifested inhomogeneous echogenicity of the solid tissue (151/195 (77.4%)); one sarcoma was multilocular without solid components. Cystic areas were described in 87/195 (44.6%) tumors and most cyst cavities had irregular walls (67/87 (77.0%)). Internal shadowing was observed in 42/192 (21.9%) sarcomas and fan-shaped shadowing in 4/192 (2.1%). Moderate or rich vascularization was found on color-Doppler examination in 127/187 (67.9%) cases. In 153/195 (78.5%) sarcomas, the original ultrasound examiner suspected malignancy. Though there were some differences, the results of the first and second steps of the analysis were broadly similar. Uterine sarcomas typically appear as solid masses with inhomogeneous echogenicity, sometimes with irregular cystic areas but only very occasionally with fan-shaped shadowing. Most are moderately or very well vascularized. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

EP33.14: Undifferentiated endometrial sarcoma presenting as a vaginal mass: a rare report

EP33.14: Undifferentiated endometrial sarcoma presenting as a vaginal mass: a rare report

Undifferentiated endometrial sarcoma of the cervix: a case report

Undifferentiated endometrial sarcoma is an aggressive sarcoma. The authors report a case of such a large tumor arising from the cervix in a 53-year-old multiparous woman presenting with urinary retention and vaginal bleeding. Ultrasound and Doppler imaging revealed a large mass about 13.3×7.6 cm in the cervix. MRI revealed a large polypoid heterogeneous hyperintensity tumor (12.2×8.2 cm) in the cervix with vaginal lumen protrusion and urinary bladder compression. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The pathology revealed FIGO Stage IIb. Adjuvant radiotherapy and chemotherapy with doxorubicin were given. The patient tolerated the treatment well, and so far she has no evidence of recurrence.

Prognostic factors associated with uterine sarcomas: the experience of a single institution

Uterine sarcomas are infrequent and heterogeneous mesenchymal tumours, associated with aggressive characteristics and a poor clinical outcome. The aim of the study is to describe the prognostic factors associated with uterine sarcomas. The clinical records between 2000 and 2014 of women diagnosed with uterine sarcomas and initially treated surgically were reviewed. A histological comparison was performed. The overall survival (OS) and disease-free survival (DFS) were calculated and compared. Seventy-three women had surgery (12.3% had endometrial stromal sarcomas, 24.7% undifferentiated endometrial sarcomas, 49.3% leiomyosarcomas and 13.7% other subtypes). Complete cytoreduction had a mean DFS of 25.1 months, while the incomplete cytoreduction averaged in a DFS of 4.33 months (p = .04). The median five–year OS with a complete cytoreduction was not reached; the incomplete cytoreduction OS was 10.1 months (p = .002). Our data suggests that undifferentiated endometrial sarcomas have the lowest DFS (p = .004); while OS was negatively influence by stage IV (p < .001).Impact statementWhat is already known about this subject? Uterine sarcomas compared with the more common endometrial carcinomas (epithelial neoplasms), behave aggressively and are associated with a poorer prognosis. The rarity of uterine sarcoma has made it difficult to perform large studies to identify risk factors.What do the results of this study add? Complete cytoreduction improves the DFS and OS and may be a valuable prognostic factor. Poorer DFS and OS prognosis was observed in undifferentiated endometrial sarcomas.What are the implications of these findings for clinical practice and/or further research? Our results demonstrate the importance of an early diagnosis, and thus an early identification of disease that benefits from complete cytoreduction regardless of histology. For the advanced clinical stage of uterine sarcomas further research is necessary and participation in clinical trials should be encouraged.

Uterine sarcomas.

Uterine sarcomas account for approximately 3%-7% of all uterine cancers. Since carcinosarcomas are currently classified as metaplastic carcinomas, leiomyosarcomas remain the most common subtype. Exclusion of several histologic variants of leiomyoma, as well as atypical smooth muscle tumors (so-called "smooth muscle tumors of uncertain malignant potential"), has highlighted that the vast majority of leiomyosarcomas are high-grade tumors associated with poor prognosis even when apparently confined to the uterus. Low-grade endometrial stromal sarcomas are indolent tumors associated with long-term survival. High-grade endometrial stromal sarcomas and undifferentiated endometrial sarcomas behave more aggressively than tumors showing nuclear uniformity. Adenosarcomas have a favorable prognosis except for tumors showing myometrial invasion or sarcomatous overgrowth. The prognosis for carcinosarcomas (which are considered here in a postscript fashion) is usually worse than that for grade 3 endometrial carcinomas. Tumor stage is the single most important prognostic factor for uterine sarcomas.

High Grade Uterine Sarcoma with Concurrent Metastatic Adenocarcinoma to the Uterus: A Case Report

Uterine cancer remains a relatively common cancer among women accounting for 3.6% of all new cancer cases in the United States. Uterine sarcomas are a rare subset of uterine malignancies arising from mesenchymal origin and account for 3 to 7% of all uterine cancers. Sarcomas possess a diverse array of clinical and histopathologic features which can make it difficult to delineate between the various classifications including: Leiomyosarcoma, endometrial stromal sarcoma, undifferentiated endometrial sarcoma, and smooth muscle tumors of uncertain malignant potential (STUMP).

Genomic profiling identifies GPC5 amplification in association with sarcomatous transformation in a subset of uterine carcinosarcomas.

Uterine carcinosarcoma, also known as Malignant Mixed Müllerian Tumour, is a high‐grade biphasic neoplasm composed of sarcomatous elements thought to originate via transdifferentiation from high‐grade endometrial carcinoma. To identify molecular factors contributing to the histogenesis of this tumour, we analyzed DNA extracted from matched carcinoma and sarcoma components from 12 cases of carcinosarcoma by a molecular inversion probe microarray to assess genomic copy number alterations (CNAs) and allelic imbalances. Widespread CNAs were identified in tumours with serous histology in the carcinoma component (9/12), while the remaining three cases with endometrioid carcinoma were near‐diploid. Quantification of the extent of genomic aberrations revealed a significant increase in sarcoma relative to carcinoma in tumours with well‐delineated histologic components. Focal amplification of 13q31.3 was identified in 6/12 profiled tumours, of which four harboured the aberration exclusively in the sarcoma component. This result was verified by fluorescence in situ hybridization against GPC5, the only gene situated within the minimal region of amplification. In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of GPC5 (GPC5/CEP13 ratio ≥ 2.2) was identified in 11/97 (11.3%) cases (9/64 carcinosarcoma, 1/3 rhabdomyosarcoma, 1/21 leiomyosarcoma, 0/8 adenosarcoma, 0/1 undifferentiated endometrial sarcoma) and an additional 4 (2.8%) cases had low level gains (GPC5/CEP13 ratio ≥1.5 but <2.2). The functional relevance of Glypican‐5, the gene product of GPC5, in regulating differentiation and lineage commitment was demonstrated in an endometrial carcinoma cell line in vitro. In conclusion, we identified GPC5 amplification as a molecular event mediating epithelial‐mesenchymal transdifferentiation in a subset of uterine carcinosarcomas.

OP20.03: Ultrasound features of endometrial stromal sarcomas

To describe the ultrasound findings of endometrial stromal sarcomas. This is a retrospective study. Patients with a histological diagnosis of endometrial stromal sarcoma (ESS) who had undergone preoperative ultrasound examination were identified from the databases of 13 tertiary ultrasound centres. The tumours were described by the principal investigator at each contributing centre on the basis of ultrasound images and ultrasound reports using definitions and parameters previously agreed upon in a consensus meeting. We identified 79 women with a histological diagnosis of endometrial stromal sarcomas, 48 of whom (60.8%) had low grade endometrial stromal sarcoma (EES) and 31 (39.2%) undifferentiated endometrial stromal sarcoma (UES). Seven (8.9%) women were asymptomatic (incidental finding), whilst the remaining complained of abnormal vaginal bleeding (62%) and/or abdominal pain and distension. The median largest diameter was 68 mm (range 12-210 mm) for EESs and 70 mm (7-250 mm) for UESs. The tumour appeared heterogeneous in (34/48) 71% of EESs and (24/31) 87% of UESs. Cystic areas with irregular contour were observed in 11/48 (23%) of EESs and in 12/31 (38.7%) of UESs respectively. Irregular border was present in (19/48) 40% of EESs and (23/31) 74% of UESs. In (37/48) 77% of EESs and (23/31) 87% of UESs no shadowing was observed. Most tumours (48/76, 61%) were moderately or very well vascularised whilst 28/76 (36.8%) were minimal or no vascularised on colour or power Doppler ultrasound. Uterine lesion with heterogeneous echotexture, internal irregular cyst areas and no shadowing should raise the suspicion of uterine sarcomas. No substantial differences were observed between EESs and UESs, but a regular border seems to be more common in EESs. The absence of vascularisation within the lesion cannot exclude malignancy.

1485P - Localized undifferentiated endometrial sarcomas (LUES): Results of a French Sarcoma Group (FSG) retrospective series of 39 patients (pts)

Background: UES are tumors of very bad prognosis. Although large surgical resection is the cornerstone of curative intent treatment, the optimal post-operative strategy remains unclear. Methods: We conducted a retrospective analysis of LUES pts (Stade I-III) over the last 8 years in 10 FSG centers, from Netsarc and RRePs databases. Results: Thirty-nine pts with primary LUES treated from 2008 to 2016 were included, with median age of 61 years (range, 43-80), and median ECOG of 0 (range, 0-3). Metrorrhagia, abdominal pain, and pelvic mass bleeding were the most common symptoms. The locoregional extension report usually included: gynecological examination (71%), and/or pelvic MRI (83%) and/or abdomino-pelvic CT scan (43%). The remote extension report was performed preoperatively for only 17/39 (50%) pts. Among 39 LUES, 24 (67%) were stage I, 3 (8%) stage II and 9 (25%) stage III. All the patients were operated on and surgical procedures were radical hysterectomy and bilateral oophorectomy for 26/39 (70%).Tumor resections were mostly R0, 23/39 (74%) and R1, 6/39 (19%). Tumor rupture occurred in 6 pts. For 7/39 LUES there was a positivity of hormonal receptors and/or cyclin D1. Twenty-two (56%) received post-operative radiotherapy (11 of them with complementary brachytherapy) and 11 (31%) adjuvant chemotherapy. With a median follow-up of 33 months (0.3-112), 17/39 pts are alive, 21/39 (54%) relapsed (7 local relapse and 13 metastases). The 3- and 5-year Overall Survival (OS) rates are 49.8% and 31.1% respectively. Median OS and Relapse-Free Survival (RFS) are 32.7 (16.3-49.1) and 23 (4.4-41.6) months, respectively. In univariate analysis; early FIGO stage (p < 0.0001), complete resection (R0-R1 vs R2; p = 0.027), ECOG (p = 0.02) and adjuvant radiotherapy (p < 0.0001) were associated with a better OS; vascular invasion (p = 0.024) and adjuvant radiotherapy (p = 0.021) were associated with a better RFS. Conclusions: Treatment of primary LUES is radical hysterectomy and bilateral oophorectomy. Adjuvant radiotherapy appears beneficial for RFS and OS. The FIGO stage seems to have an impact on OS. A prospective study could be carried out to validate this therapeutic management. Legal entity responsible for the study: invalid Funding: None Disclosure: All authors have declared no conflicts of interest.

Undifferentiated endometrial sarcomas (UES): Results of a French sarcoma group (FSG) retrospective series of 52 patients (pts).

e17109 Background: UES are rare tumors of very poor prognosis. Although large surgical resection is the cornerstone of curative intent treatment, the optimal post-operative strategy remains unclear. Methods: We conducted a retrospective analysis of UES pts over the last 8 years in 10 FSG centers, from Netsarc and RRePs databases. Results: Fifty-two pts with primary UES treated from 2008 to 2016 were included. The median age was 59 years (range, 42-82), and median ECOG was 0 (range, 0-3): 33 were localized (FIGO I-III) and 19 metastatic at diagnosis. Metrorrhagia, abdominal pain, and pelvic mass bleeding were the most common symptoms. Surgical procedures were radical hysterectomy and bilateral adnexectomy for 23/33 (70%) of localized and 11/19 (58%) of metastatic UES. Metastases were identified post operatively for 9/19 pts. In the localized group, 19 pts (58%) received radiotherapy, 10 (30%) complementary brachytherapy and 9 (27%) adjuvant chemotherapy. In the metastatic group, 16/19 (84%) received chemotherapy (polyCT, n=11). With a median follow-up of 28 months (0.3-112),24/52 pts are alive, 18/33 (58%) localized pts relapsed with 6 local relapses and 11 metastases. The 3- and 5-year Overall Survival (OS) rates were 40.7% and 29.1% respectively, for the whole group. In the localized group; median OS and Relapse-Free Survival (RFS) were 32.7 (23.3-42.1) and 22.9 months (2.3-43.7). In univariate analysis; early FIGO stage (p &lt;0.0001), complete resection (R0-R1 vs R2; p=0.015) and adjuvant radiotherapy (p=0.001) were associated with a better OS; complete resection (p=0.021) and adjuvant radiotherapy (p=0.026) were associated with a better RFS. In the metastatic group, median OS was 16.4 months (12.0-20.7). In univariate analysis, no significant prognostic factor was retrieved neither on OS nor on RFS. Conclusions: Treatment of primary UES is radical hysterectomy and bilateral adnexectomy. Adjuvant radiotherapy appears beneficial for RFS. Due to the rarity and complexity of UES, referring patients to expert sarcoma centers is highly recommended.

Investigation of New Therapeutic Targets in Undifferentiated Endometrial Sarcoma

Background: Undifferentiated endometrial sarcoma (UES) is a very rare subtype of uterine sarcoma, which has no consensus on the treatment. We investigated the expression of potential new therapeutic targets in UES to improve its aggressive clinical course and poor survival outcome. Methods: The immunohistochemical expressions of vascular endothelial growth factor (VEGF), c-KIT, c-ABL, platelet derived growth factor receptor (PDGFR), protein kinase B (AKT1), mammalian target of rapamycin, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER2), Wilms tumor (WT1), aromatase inhibitor (CYP19A1), and histone deacetylase (HDAC) series in 10 UES patients were assessed using tissue microarrays. Results: Strongly positive immunoreactivities were observed for VEGF, AKT1, and HDAC2/7 in 8 (80.0%) tumors; for CYP19A1 and HDAC6 in 9 (90%) tumors; and for HDAC1/4/8 in 10 (100%) tumors. Strong expression of CYP19A1 and HDAC6 was associated with distant recurrence (p = 0.030, both), and expression of WT1 indicated a more advanced stage (p = 0.033). UES treated with adjuvant therapy showed better disease-free and overall survivals (both 0 vs. 33.3%, p = 0.003). Conclusion: VEGF, AKT1, CYP19A1, and the HDAC1/2/4/6/7/8 series show an especially high frequency of strong immunoreactivity in UES and can be considered potential therapeutic targets.

Systemic therapy for endometrial stromal sarcomas: current treatment options.

Uterine endometrial stromal sarcomas including true low-grade endometrial stromal sarcoma (LG-ESS) and high-grade (HG-ESS) or undifferentiated endometrial sarcoma (UES) constitute a group of rare, aggressive malignancies. Most LG-ESSs express steroid receptors. Surgery is the principal primary therapy for endometrial stromal sarcomas and should be considered in all cases. These malignancies are relatively radio- and chemoresistant. Chemotherapy is used in recurrent and advanced HG-ESS and UES. Currently, the combination of gemcitabine and docetaxel is considered the most effective regimen, but at the expense of substantial toxicity. In steroid receptor positive advanced LG-ESS hormonal therapy, mainly with progestins, allows in some patients for a long-term survival. Aromatase inhibitors seem to be equally effective as first- and subsequent-line of treatment, and are well tolerated. The role of molecular-targeted therapies in endometrial stromal sarcomas remains to be established.

Undifferentiated endometrial sarcoma: Does adjuvant treatment impact outcomes of stage I disease?

Undifferentiated endometrial sarcoma: Does adjuvant treatment impact outcomes of stage I disease?

European Society of Gynecological Oncology Statement on Fibroid and Uterine Morcellation.

Recently, there has been an intense discussion about the issue of fibroid and uterine morcellation in relation to the risk of unrecognized uterine sarcoma spread. Morcellation can negatively influence the prognosis of patients, and transecting the specimen into pieces prevents the pathologist from performing proper disease staging. Many societies have published their statements regarding this issue. The European Society for Gynecological Oncology has established a working group of clinicians involved in diagnostics and treatment of oncogynecological patients to provide a statement from the oncological point of view. Leiomyosarcomas and undifferentiated endometrial sarcomas have generally dismal prognosis, whereas low-grade endometrial stromal sarcomas and adenosarcomas have variable prognosis based on their stage. A focus on the detection of patients at risk of having a sarcoma should be mandatory before every surgery where morcellation is planned by evaluation of risk factors (African American descent, previous pelvic irradiation, use of tamoxifen, rapid lesion growth particularly in postmenopausal patients) and exclusion of patients with any suspicious ultrasonographic signs. Preoperative endometrial biopsy should be mandatory, although the sensitivity to detect sarcomas is low. An indication for myomectomy should be used only in patients with pregnancy plans; otherwise en bloc hysterectomy is preferred in both symptomatic and postmenopausal patients. Eliminating the technique of morcellation could lead to an increased morbidity in low-risk patients; therefore, after thorough preoperative evaluation and discussion with patients, morcellation still has its place in the armamentarium of gynecologic surgery.

Outcome and prognosis in uterine sarcoma and malignant mixed Mullerian tumor.

There is low evidence regarding the optimal treatment in patients with uterine sarcomas and malignant mixed Mullerian tumors (MMMTs). This study provides an overview of experience at our center with patients diagnosed with uterine sarcoma and MMMT, in relation to the clinical management and outcome. The medical records for 143 patients with low-grade endometrial stromal sarcoma (ESS), leiomyosarcoma (LMS), and high-grade (undifferentiated) endometrial sarcoma (UES) and MMMT were reviewed. All available clinical and pathological data were collected and analyzed. Putative prognostic factors were entered into a multivariate analysis using a Cox proportional hazards ratio model, and survival data were calculated. The 5-year overall survival rates were significantly different between patients with ESS, LMS, and UES and MMMT (86 vs. 40 vs. 57 vs. 45%; P<0.001). The multivariate analysis showed that the patients' age, higher FIGO stage (III-IV), a history of smoking, prior pelvic radiation, diabetes, and residual tumor after surgery were associated with a poorer overall survival. Histological subtypes of LMS (HR 4.68; 95% CI 1.35-16.17), UES (HR 1.21; 95% CI 0.26-5.77) and MMMT (HR 1.63; 95% CI 0.42-6.43) were also associated with a poorer overall survival than ESS (P=0.008). Adjuvant therapies showed no associations with overall survival. Adjuvant therapy has so far not shown any overall survival benefit, and the focus is therefore on primary surgery. In future studies, the entities should be investigated separately in relation to prognostic factors and effective therapeutic management.

Bilateral Ovarian Mass: Low-Grade Endometrial Stromal Sarcoma—a Rare Entity

Abstract Background: An endometrial stromal tumor is a histopathologic entity characterized by a monomorphus population of blunt, spindle-to-oblong–shaped cells with scant cytoplasm in an abundant reticulin framework. This entity was first described in 1908, and was well-characterized by Norris and Taylor in 1966. It is classified as: (1) a benign stromal nodule; (2) a low-grade endometrial stromal sarcoma; or (3) an undifferentiated endometrial sarcoma. Endometrial stromal sarcomas usually arise from the uterine corpus. The most common extrauterine site is the ovary. Case: A 50-year-old female presented clinically with an abdominal lump. Radiologic findings were inconclusive and suggestive of a bilateral ovarian mass. Microscopic examination revealed a circumscribed tumor composed of uniform cells, having scanty cytoplasm, and having uniform nuclei showing nest and sex-cord differentiation that was seen blending with intervening stromal cells. Results: Immunoreactivity of tumor cells for cluster of diffe...

Cytologic Features of Metastatic Endometrial Stromal Sarcoma and Undifferentiated Endometrial Sarcoma

Cytologic Features of Metastatic Endometrial Stromal Sarcoma and Undifferentiated Endometrial Sarcoma

Uterine sarcomas.

Uterine sarcomas.