1157645 review-article20232023 TAM0010.1177/17588359231157645Therapeutic Advances in Medical OncologyJA Pérez-Fidalgo, E Ortega Therapeutic Advances in Medical Oncology Review Uterine sarcomas: clinical practice Ther Adv Med Oncol 2023, Vol. 15: 1­–19 guidelines for diagnosis, treatment, DOI: 10.1177/ https://doi.org/10.1177/17588359231157645 https://doi.org/10.1177/17588359231157645 17588359231157645 and follow-up, by Spanish group for © The Author(s), 2023. Article reuse guidelines: sagepub.com/journals- research on sarcomas (GEIS) permissions Jose Alejandro Pérez-Fidalgo, Eugenia Ortega, Jordi Ponce, Andres Redondo, Isabel Sevilla, Claudia Valverde, Josep Isern Verdum , Enrique de Alava, Mar Galera López, Gloria Marquina and Ana Sebio Abstract: Uterine sarcomas are very infrequent and heterogeneous entities. Due to its rarity, pathological diagnosis, surgical management, and systemic treatment are challenging. Treatment decision process in these tumors should be taken in a multidisciplinary tumor board. Available evidence is low and, in many cases, based on case series or clinical trials in Correspondence to: which these tumors have been included with other soft tissue sarcoma. In these guidelines, Jose Alejandro we have tried to summarize the most relevant evidence in the diagnosis, staging, pathological Pérez-Fidalgo Oncology and Hematology disparities, surgical management, systemic treatment, and follow-up of uterine sarcomas. Department, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario, CIBERONC Keywords: adenosarcoma, endometrial stromal sarcoma, guidelines, leiomyosarcoma, Spain, Avda Blasco Ibañez PEComa, uterine sarcoma 17, Valencia, 46010, Spain japfidalgo@msn.com Eugenia Ortega Received: 12 July 2022; revised manuscript accepted: 30 January 2023. Medical Oncology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain Jordi Ponce Introduction Diagnosis and staging of uterine sarcomas Gynecology Department, Hospital Universitario Uterine sarcomas are uncommon soft tissue Specific clinical and radiological criteria to differ- de Bellvitge. IDIBELL. malignancies with an annual incidence of 0.36– entiate uterine sarcomas from benign uterine leio- Universidad de Barcelona, Barcelona, Spain 0.64 cases per 100.000 women in the United myomas are lacking. In both entities, abnormal Andres Redondo States.1 Diagnosis and pathological classification vaginal bleeding, pelvic pain, and abdominal Medical Oncology of uterine sarcomas is a challenge. The most fre- mass are the most common symptoms. A rapidly Department, Hospital Universitario La Paz- quent subtypes are leiomyosarcoma (LMS), fol- growing uterine fibroid in a peri-menopausal or IdiPAZ, Madrid, Spain lowed by endometrial stromal sarcoma (ESS) and postmenopausal woman should raise suspicion of Isabel Sevilla undifferentiated uterine sarcoma (UUS). sarcoma.3 Clinical and Translational Research Histological grade deeply impacts on prognosis in Cancer/Instituto and clinical behavior. While high-grade ESSs The first approach to diagnosis is usually a pelvic de Investigaciones Biomédicas de Málaga (HG-ESS) are generally highly aggressive, low- ultrasound followed by pelvic magnetic resonance (IBIMA)/Hospitales grade ESSs (LG-ESSs) have an indolent behav- imaging (MRI).4 Algorithms may help to differ- Universitarios Regional and Virgen de la Victoria ior. LG-ESSs have a 5-year survival rate and a entiate atypical leiomyomas from uterine sarco- de Málaga, Málaga, Spain 5-year disease-specific survival of 80–100%.2 mas on MRI,5 and 18-fluorine-fluorodeoxyglucose Claudia Valverde Treatment decision-making in patients with these positron emission tomography/computed tomog- Medical Oncology Department, Vall d’Hebron tumors is complex. The level of evidence is often raphy (18F-FDG PET-CT) can be useful to dis- University Hospital, low and mainly based on retrospective series or tinguish between the two entities. There are no Barcelona, Spain Josep Isern Verdum case reports. The aim of these guidelines is to specific serum tumor markers. An endometrial or Radiotherapy Department, summarize evidence available to date and guide transvaginal biopsy can be attempted to obtain Hospital de la Santa Creu i Sant Pau, Universitat decision-making concerning treatment for uterine histological diagnosis but its sensitivity is low.6 Autònoma de Barcelona, sarcomas. Diagnosis is often reached after analysis of a Barcelona, Spain journals.sagepub.com/home/tam 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Medical Oncology Volume 15 Enrique de Alava surgical specimen. Transabdominal biopsy and Table 1. Levels of evidence. Institute of Biomedicine of morcellation are discouraged as they could carry Sevilla (IBiS), Virgen del I Evidence from at least one large Rocio University Hospital / a high risk of peritoneal dissemination [IVA].7 randomized controlled trial of good CSIC/University of Sevilla/ CIBERONC, Sevilla, Spain methodological quality (low potential for Department of Normal The most widely used staging systems are those bias) or meta-analyses of well-conducted and Pathological Cytology of the Federation of Gynecology and Obstetrics randomized trials without heterogeneity and Histology, School of Medicine, University of (FIGO) and the American Joint Committee on Cancer8 (Table 1). For distance staging, a CT II Small randomized trials or large Seville, Seville, Spain randomized trials with a suspicion of bias Mar Galera López scan should be performed [IA]. (lower methodological quality) or meta- Medical Oncology Department, Hospital analyses of such trials with demonstrated General Universitario Pelvic ultrasound and MRI are usually the first heterogeneity Gregorio Marañón, Madrid, Spain approach to diagnosis [IIIA]. A 18F-FDG PET-CT can be useful to distinguish malignancy III Prospective cohort studies Gloria Marquina Department of Medical [VC]. Transabdominal biopsy and morcellation IV Retrospective cohort studies or case– Oncology, Hospital Clinico San Carlos, Madrid, IdISSC, are discouraged due to the risk of dissemination control studies Spain [IVA]. A CT scan is the preferred procedure for Department of Medicine, staging [IA]. V Studies without control group, case School of Medicine, reports, expert opinions Complutense University (UCM), Madrid, IdISSC, Spain Grade of recommendation Ana Sebio Pathology and molecular diagnosis Medical Oncology Uterine sarcomas a highly heterogeneous group of A Strong evidence of efficacy with a Department, Hospital de tumors both clinically and histologically. While substantial clinical benefit, strongly la Santa Creu i Sant Pau, Barcelona some tumors can be classified as simple genomic recommended Universitat Autònoma de sarcomas as they harbor specific gene fusions such B Strong or moderate evidence for efficacy Barcelona, Barcelona, Spain as endometrial stroma tumors, the most frequent with a limited clinical benefit generally Institut de Recerca subtype, leiomyosarcomas, has a complex karyo- recommended Biomèdica Sant Pau (IIB type comprising numerous structural aberrations. Sant Pau), Barcelona, Spain C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, Leiomyosarcomas etc.), optional Uterine leiomyosarcoma (uLMS) is a malignant mesenchymal tumor originating from myometrial D Moderate evidence against efficacy smooth muscle. Three main subtypes have been or for adverse outcome generally not described: spindle, epithelioid, and myxoid recommended leiomyosarcoma. E Strong evidence against efficacy or for adverse outcome, never recommended Spindle cell (conventional) tumors are typically Taken from Lee and Vielemeyer.9 cellular and composed of spindle-shaped cells with eosinophilic cytoplasm arranged in long, interlac- ing, often compact, but relatively disorganized fas- cicles. Nuclear pleomorphism is often striking, but appearance consisting of polygonal cells with a subset of tumors exhibits uniform cytological fea- eosinophilic or clear cytoplasm arranged in tures. Diagnosis of spindle leiomyosarcomas nested, corded, nodular, or diffuse patterns. requires the presence of two of three features: Positivity for CD10, EMA (Epithelial membrane tumor cell necrosis, marked cytological atypia, and antigen), and cytokeratin is common, with EMA ⩾4 mitoses/mm2 (equating to ⩾10 mitoses/10 and cytokeratin positivity being especially fre- HPF of 0.55 mm in diameter and 0.24 mm2 in quent in this subtype.10 area). Spindle cell uLMS express estrogen recep- tors (ERs) and progesterone receptors (PRs) in Myxoid tumors are often paucicellular and con- approximately 40–50% of cases. In addition, p16 tain abundant myxoid stroma. They may display and/or p53 overexpression is common. vague fascicular or nodular growth. The cells express desmin, h-caldesmon, and smooth muscle Epitheloid leiomyosarcomas is a variant com- actin, but this expression may be focal or weak if posed of more than 50% of cells with epithelioid the tumor is poorly differentiated or myxoid.11 2 journals.sagepub.com/home/tam JA Pérez-Fidalgo, E Ortega et al. High-grade uterine sarcomas Undifferentiated uterine sarcoma. UUS is a malig- High-grade sarcomas of the endometrium encom- nant mesenchymal tumor lacking evidence of spe- pass two distinct entities: high-grade ESS cific lines of differentiation. Diagnosis is therefore (HG-ESS) and UUS. based on exclusion. These sarcomas show no identi- fiable line of differentiation and are considered a het- High-grade ESS. HG-ESS is a malignant endo- erogeneous group. They typically display a metrial stromal tumor with uniform, high-grade destructive pattern of myometrial invasion. In the round and/or spindle morphology, sometimes past, they were classified as uniform or pleomorphic with a low-grade component. types.15 In tumors with uniform nuclear features, YWHAE-NUTM2 (FAM22) HG-ESS should be These tumors may show expansive, permeative, excluded. These tumors may be associated with a or infiltrative growth, and more than one pattern low-grade stromal component and express cyclin of invasion may be seen. They typically display D1. However, others with pleomorphic histology are lymphovascular invasion (LVSI), brisk mitotic also associated with a low-grade component and are activity, and necrosis. FISH HG-ESS can be clas- designated HG-ESS NOS. UUS typically consists of sified into the following: sheets of uniform or pleomorphic epithelioid and/or spindle cells associated with brisk mitotic activity. Necrosis and LVSI are commonly seen.16 Tumors 1) HG-ESS with YWHAE-NUTM2A/B fusion are often positive for p53 and p16, and some may displays round cells with eosinophilic cyto- show positivity for ER and/or PR, and variable posi- plasm and high-grade nuclei with irregular tivity for CD10.17 P53 mutation is normally seen in nuclear contours, vesicular chromatin, and fusion negative uterine sarcomas with the exception variably distinct nucleoli. They can also be of a small subset of NTRK1/3-positive sarcomas.18 associated with a fibromyxoid or conven- tional low-grade endometrial stromal com- YWHAE, JAZF1, and NTRK rearrangements ponent.8 The high-grade component is may underpin rare pleomorphic sarcomas that positive for cyclin D1, BCOR, KIT, CD56, should not be classified in this category.19 and CD99, and negative for DOG1.12 2) HG-ESS with ZC3H7B-BCOR fusion is typically positive for cyclin D1, whereas Low-grade uterine sarcomas only about 50% of cases express BCOR by LG-ESS is a malignant stromal tumor with cells IHC. This group typically shows diffuse resembling proliferative-phase endometrial CD10 positivity with variable ER and PR stroma and displaying infiltrative (permeative) positivity. Also focal expression of SMA growth with or without LVSI. and caldesmon can be shown but usually desmin is negative. Tumors may show pan- Microscopically, they show irregular, densely cel- TRK staining not related to NTRK rear- lular islands of tumor cells with a diffuse growth rangement.13 BCOR internal tandem that permeate the myometrium (tongue-like) and duplication (ITD) tumors have a different may be associated with LVSI. Cells have uniform, immunoprofile to ZC3H7B-BCOR tumors. oval-to-fusiform nuclei, with no or minimal atypia, They show less positivity for CD10 and are scant cytoplasm, and a delicate arteriolar network. diffusely positive for cyclin D1 and BCOR, Sometimes, tumor cells whorl around the vessels. but they are negative for ER and PR. The mitotic activity is usually low but can be Furthermore, they may express desmin but brisk.20 Hyaline plaques, foamy histiocytes, cystic are negative for SMA and caldesmon.14 change, and necrosis can be seen.21 Common var- 3) HG-ESS NOS is a high-grade sarcoma iant features include smooth muscle differentia- associated with a low-grade endometrial tion22 fibromyxoid/fibrous change,23,24 and sex stromal component.15 cord–like differentiation. Bizarre nuclei, epithe- lioid/rhabdoid change, endometrioid glands, and Demonstration of gene fusion or BCOR ITD pseudopapillae are uncommon.15,25,26 may be helpful for diagnosis. In this context. FISH could be recommended in any case with These tumors usually show diffuse, strong expres- unusual morphology or any high-grade or recur- sion of CD10, ER and PR, and focal cyclin D1 rent disease. positivity. Tumors may be positive for wide journals.sagepub.com/home/tam 3 Therapeutic Advances in Medical Oncology Volume 15 spectrum keratins.27 Desmin and h-caldesmon summarizes the most relevant alterations and dif- typically highlight smooth muscle differentia- ferences in the diagnosis of high grade and low tion28 and are often positive in sex cord–like ele- grade uterine sarcomas. ments, which also express inhibin, calretinin, melan-A, WT1, and CD99.29 Surgical management of early stages Demonstration of characteristic gene fusions may Surgery is the standard of care for uterine sarco- be helpful in selected cases. Two-thirds of mas regardless of grade. Complete resection of LG-ESS tumors harbor genetic fusions involving disease without fragmentation and with negative polycomb family genes.26 The most common of surgical margins is the gold standard for treat- these is JAZF1-SUZ12, followed by JAZF1- ment.34 Standard procedures include total hyster- PHF1, EPC1-PHF1, and MEAF6-PHF1.30,31 ectomy and bilateral salpingo-oophorectomy.35 MBTD1-EZHIP (CXorf67), BRD8-PHF1, In case of incidental diagnosis, a second surgery EPC2-PHF1, and EPC1-SUZ12 have also been should be evaluated to complete surgical treat- documented, but experience is limited (fewer ment.36,37 In case of a casual diagnosis after previ- than three cases of each have been reported to ous uterine morcellation, a second intervention date). may be required to complete the surgery, explore the abdominopelvic cavity, and collect peritoneal BRD8-PHF1 has also been implicated in high- biopsies.38 grade tumors.32 Ovarian-spearing surgery can be performed in LG-ESS with JAZF1 and PHF1 rearrangements, leiomyosarcoma in early stage disease and pre- although rare, can transform into high grade at menopausal women without compromising the time of diagnosis or years later. An increased survival.39 mitotic index, prominent nucleoli or nuclear enlargement can be seen in this transformation Systematic pelvic and para-aortic lymphadenec- underlying a more aggressive behavior.33 Table 2 tomy is not recommended. Lymph node Table 2. Main pathological and molecular alterations with diagnostic implications in uterine sarcomas. LG-ESS HG-ESS (YMHAE-altered) HG-ESS (BCOR-altered) Characteristics Uniform cells resembling May be associated with LG- Myxoid background, spindled proliferative-phase endometrial stroma ESS and round cell morphology ER/PR + − −/Focal (except areas of LGESS) CD10 + − ± Cyclin D1 − +++ +++ BCOR − + ± +++ (BCOR ITD) KIT − + Molecular alteration JAZF1/SUZ12 YMHAE/NUTM2A-B ZC3H7B/BCOR fusion JAZF1/PHF1 Fusion Or BCOR ITD fusions Prognosis Good Bad Bad ITD, internal tándem duplication. 4 journals.sagepub.com/home/tam JA Pérez-Fidalgo, E Ortega et al. resection seems to be beneficial only when pre- improved survival. Two phase III trials were pre- operative imaging or intra-operative findings sug- maturely closed due to low recruitment. In the first gest lymph node metastasis.42 one, the SARCGYN phase III trial, the authors compared adjuvant polychemotherapy based on In advanced disease, maximal cytoreduction, cisplatin, doxorubicin, and ifosfamide followed by when feasible, could significantly improve sur- radiation versus radiation alone. The study planned vival outcomes if the resection is R0. Residual to enroll 256 patients but only 81 patients were disease after surgery is an indicator of poor randomized and 19 of them were patients with car- prognosis.40,41 cinosarcomas. A benefit of adjuvant chemotherapy (CT) group was seen on 3-year disease-free sur- In LG-ESSs, total hysterectomy and bilateral sal- vival (DFS) (55% in CT-treated patients versus pingo-oophorectomy should be the recom- 41% in the control arm, p = 0.048) was reported mended treatment.43 Ovary-sparing procedures but with no impact on overall survival (OS).46 should only be considered in young women, depending on tumor hormonal receptor status, In the second one, a more recent study, patients and extensive counselling is advised.44 with stage I high-grade leiomyosarcoma were ran- domized to receive four cycles of gemcitabine/ Surgery is the standard of care in uterine sarco- docetaxel followed by four cycles of doxorubicin mas regardless of grade. Complete resection of versus observation. The study planned to enroll disease without fragmentation and with negative 216 patients but was prematurely closed after surgical margins is the gold standard for treat- only 38 patients were randomized. No differences ment [IIA]. In premenopausal uLMS patients, were found in OS or recurrence-free survival ovary-sparing procedures can be performed (RFS).47 No definitive results can be drawn from [IIIA]. In LG-ESS ER+, salpingo-oophorectomy these trials. Nevertheless, several phase II studies is the recommended treatment [IIIA]. have suggested that adjuvant chemotherapy pro- vides a benefit in uLMS compared to observation in historical controls. Various chemotherapy Surgical management of uterine schedules have been studied, such as anthracy- mass (unexpected sarcoma) clines in monotherapy or in combination with The risk of sarcoma is about 1/352 in patients other drugs, four cycles of gemcitabine/doc- undergoing laparoscopic hysterectomy, but a etaxel,48 and four cycles of gemcitabine/docetaxel thorough preoperative examination can help followed by four cycles of doxorubicin.49 decrease the number of undetected uterine sarco- mas. Several reports suggest patients with an Several retrospective studies suggest a potential unexpected uterine sarcoma who undergo mor- benefit of combining anthracyclines with ifosfa- cellation during surgery have worse prognosis mide in uLMS, but it cannot been ruled out that because this procedure may spread disease the benefit is mainly due to anthracyclines given through the abdominal cavity.45 It is therefore the concerns about ifosfamide effectivity in recommended that (1) morcellation should be LMS.50 The combination of anthracyclines with avoided if ultrasound shows oval shape, central dacarbazine has also shown to be effective in ret- necrosis, high blood flow, fast growth within rospective studies in metastatic disease.51 3 months or rapid postmenopausal growth are seen on ultrasound; (2) when planning a power Despite the lack of prospective randomized data, the morcellation, a preoperative endometrial biopsy poor prognosis of uLMS has led to a clear increase in with hysteroscopy is mandatory and a myoma the use of adjuvant chemotherapy in localized uLMS ultrasound-guided Trucut biopsy should be con- over the last decade.52 Adjuvant chemotherapy sidered; and (3) fibroids from myomectomy options should be individually evaluated by a multi- should be morcellated in endobag containers. disciplinary tumor board and discussed with the patient. If considered appropriate, antracyclines should be the backbone chemotherapy. Adjuvant therapies Uterine leiomyosarcomas High-grade ESS and UUS There is no clear evidence that the administration Few prospective data are available regarding the of adjuvant chemotherapy is associated with role of adjuvant CT in HG-ESS and UUS. journals.sagepub.com/home/tam 5 Therapeutic Advances in Medical Oncology Volume 15 Observation should be the standard of care, but I/II uterine sarcoma. Adjuvant pelvic irradiation due to the poor prognosis adjuvant CT can be with 50.4 Gy improved local control in a patient considered in selected cases.53 population with various sarcoma entities, but in the subgroup of leiomyosarcomas (n = 99), no Adjuvant CT in high-grade uterine sarcomas is effect was found nor in the rate of local recurrence not the standard of care [ID]. In FIGO stage I, (20% with versus 24% without RT) nor in the OS adjuvant CT should not be recommended [IB]. rate. Nevertheless, due to the poor prognosis of the disease, adjuvant CT (including antracyclines) Pelvic local recurrence in early stage high-grade could be considered in selected patients with uterine sarcomas occurs in 14–34% at 5 years53,58,59 FIGO II-III stage [IVC]. and favorable local control following adjuvant pelvic RT has been reported in retrospective series.60 In these studies, RT was associated with Low-grade uterine sarcoma a lower rate of local relapse, with no clear impact To date, adjuvant treatment with endocrine ther- on survival. apy in low-grade endometrial stroma sarcoma (LG-ESS) has only been evaluated in retrospec- A retrospective analysis of 3650 patients of whom tive studies. Beck et al described a recurrence rate the majority were carcinosarcoma, up to 529 of 50% for all patients (38.5% for stage I) without patients had uterine leiomyosarcoma. In this adjuvant treatment. This decreased to 33% cohort, those patients treated with adjuvant RT (14.3% for stage I) for those treated with adju- had a 5-year locoregional failure-free survival vant progestins.54 Another cohort of LG-ESS rates of 98% (N = 131) versus only 85% in those found a reduction in the risk of relapse in patients without adjuvant RT (N = 398) (p < 0.01).61 receiving megestrol acetate (31% versus 67%).55 More recently, Comert et al. described a global In a recent study that used a propensity score recurrence rate of 27%; while 0% in patients who approach to reduce comparison biases, adjuvant had adjuvant therapy versus 38.5% in those who RT provided a benefit in terms of local control. did not.56 In addition, Leath et al. showed a trend However, no impact was seen on overall or can- to a better OS with adjuvant progestin, with a cer-specific mortality.62 median of 94 months versus 72 months in those who did not receive this treatment.41 A recently published meta-analysis confirmed that adjuvant RT does not reduce the recurrence Despite the lack of prospective data, due to the rate in early-stage uLMS patients.63 consistent reduction in the recurrence rate observed in retrospective studies, adjuvant hor- For HG-ESS and UUS patients, retrospective monal treatment could be recommended in data from the French Sarcoma Group showed LG-ESS [IVB]. Given the lack of strong evidence, that adjuvant RT appears to improve overall sur- however, no recommendation regarding duration vival. Malouf et al.40 observed that patients who can yet be given. Observation is also an option, received postoperative RT had better DFS than particularly for stage I tumors. patients who did not, suggesting that RT could be considered depending on risk factors such as tumor size, involvement of margins, and/or num- Adjuvant radiotherapy ber of positive lymph nodes removed. High-grade uterine sarcoma Adjuvant radiotherapy (RT) has not demon- Low-grade uterine sarcoma strated a statistically significant increase in terms As far as LG EES patients are concerned, only a of survival versus observation in early-stage high- few small retrospective studies are available to grade uterine sarcomas. Therefore, its use cannot date, and data mining of large databases has iden- be considered a standard of care. tified a lower rate of local relapse after RT.64 A ret- rospective comparative study on the use of pelvic In the only phase III randomized study (EORTC radiation in patients with uterine sarcoma included 55874)57 published to date, the rate of pelvic recur- 361 patients with EES (109 treated with adjuvant rence after adjuvant RT was compared with obser- RT and 252 patients with no further treatment). In vation in 224 surgically treated patients with stage this cohort of EES, adjuvant RT increased 5-year 6 journals.sagepub.com/home/tam JA Pérez-Fidalgo, E Ortega et al. local-regional failure-free survival rates from 93% Postoperative RT after complete resection of a to 97% (p < 0.05); however, data regarding tumor local recurrence could be considered. [IVB]. grade was not available.61 Because of the evidence based on retrospective designs, unclear data and long-term side effects of adjuvant RT this treat- Low-grade uterine sarcoma ment is generally not indicated. Despite its indolent behavior, recurrence occurs in up to one-third of LG-ESS patients.21 Median Adjuvant RT in high-grade uterine sarcomas is time to recurrence in early stages ranges from 5 to not standard of care [ID]. Adjuvant RT can be 9 years compared to <1 year for stages III or IV.71 considered in selected patients with risk factors This highlights the need for a long follow-up. such as cervical, parametrial, or serosal involve- Recurrences are generally limited to the pelvis or ment, or incomplete resection, after discussion abdomen but distant metastases are also possi- with the patient [IVC]. ble.72 Locoregional and distant relapses can be managed with local therapies. Locoregional relapses after fertility-sparing are common but Local management of oligometastatic can be safely managed through surgery, without or locally recurrent disease affecting survival.44,73,74 High-grade uterine sarcomas Complete surgical removal of metastatic lesions Retrospective studies suggest that complete increased survival in several retrospective series – resection of metastases can increase survival in some including other uterine sarcomas.75,76 selected cases of uLMS.65,66 Five-year survival rates of 58% have been reported in isolated lung RT or ablation could also be considered on an metastases and rates of 30–50% in isolated liver individual basis but data supporting these thera- metastases. In a single-center study in MSKCC pies is scarce. with 62 uLMS patients, most of whom had abdomino-pelvic or lung metastases, the most Whenever possible, resection of local or distant important prognostic factor for survival was com- recurrences of LG-ESS should be recommended plete resection, with no benefit for postoperative [IVB]. chemotherapy.67 Peritoneal sarcomatosis from uterine sarcoma, Systemic treatment for advanced or specially leiomyosarcoma, could also benefit from recurrent disease: Chemotherapy complete resection if R0 resection can be achieved.68 High-grade uterine sarcoma First-line treatment. Evidence for the use of CT Prognostic factors identified in several studies in uterine sarcomas is scarce and mainly extracted include histology, number of metastases, a dis- from studies including other soft tissue sarcomas ease-free interval longer than 12–18 months, no (STSs). Nevertheless, in a national database extrapulmonary metastases, histological grade, study, first-line CT in uLMS showed a survival size of metastases, and complete resection.69 benefit of 8 months for patients receiving this treatment.34 CT achieves a response rate between In HG-ESS and US, resection of metastases is 17% and 25%. Table 3 summarizes the most rel- not usually considered due to their aggressive evant trials in first- or second-line settings. clinical course. Stereotactic RT can be proposed in some cases in oligometastic disease, providing Single-agent doxorubicin has been the accepted disease control with acceptable toxicity. This is of standard of care for first-line STS and uterine sar- particular interest when surgery is not feasible.70 comas. Despite attempts to improve the results Local recurrence should be treated surgically if with the addition of other drugs, such as ifosfa- R0 resection can be achieved, and postoperative mide,77 or testing other combinations, such as RT could be recommended. gemcitabine–docetaxel78 no benefit of the combi- nation over single-agent doxorubicin was seen. Surgical resection of metastatic (particularly lung) or local recurrent disease should be consid- However, a recent randomized phase III trial ered by a multidisciplinary tumor board [IVB]. compared the combination of doxorubicin plus journals.sagepub.com/home/tam 7 Therapeutic Advances in Medical Oncology Volume 15 Table 3. Staging of uterine sarcoma. chemotherapy has shown to increase toxicity with- out any benefit on overall survival.80 Stage Description Leyomiosarcomas/ESS Adenosarcoma Ifosfamide, either as a single agent or combined with another agent, is not commonly recom- I Limited to the uterus mended in uLMS based on retrospective data.51 IA Tumor ⩽ 5 cm Limited to the endometrium and/ However, a single arm prospective phase II study or endocervix that examined the role of first-line ifosfamide in CT-naïve ESS patients showed a response rate of IB Tumor >5 cm Invading < 50% myometrium 33%.81 IC – Invading > 50% myometrium Table 4 summarizes first-line systemic treatment II Extending beyond the uterus but within the pelvis options for high-grade uterine sarcoma. IIA Involving adnexa In fit patients with uLMS the combination of IIB Involving other pelvic tissues doxorubicin plus trabectedin should be the pre- ferred first-line chemotherapy, particularly when III Infiltrating abdominal tissues obtaining a response is relevant (IA). Nevertheless, single agent doxorubicin and doxorubicin-dacar- IIIA 1 site bazine are valuable alternatives. IIIB >1 site In non-uLMS histologies, single-agent doxoru- IIIC Regional lymph nodes metastases bicin should be considered standard (IB). However, anthracycline-based combinations IVA Invading bladder or rectum (with ifosfamide or dacarbazine) are valuable IVB Distant metastases options when obtaining a response is relevant. Second and later lines. Trabectedin was first approved for STSs in Europe following two phase trabectedin (3-h infusion) followed by mainte- II trials.82,83 It was recently compared with dacar- nance trabectedin for up to 17 cycles versus doxo- bazine in a phase III trial in metastatic liposar- rubicin alone for six cycles in first line in patients coma and leiomyosarcoma patients. In a post-hoc with advanced or recurrent LMS. uLMS was a analysis, progression-free survival (PFS) favored stratification factor. The combination showed a trabectedin, especially in uLMS patients, with a relevant improvement in PFS [13.5 versus clinical benefit rate of 31% versus 18% but no dif- 7.3 months; adjusted hazard ratio (HR) = 0.38, ference in OS.88 A benefit with the latter strategy 0.27–0.55].79 Moreover, the response rate was was seen in a phase II randomized trial that com- also superior for the combination (38% versus pared intermittent versus continuous administra- 13%), with a median follow up of 37 months. OS tion of trabectedin in patients achieving disease was 24.1 months in the standard group versus control.85 30.5 m in the experimental arm; HR: 0.73 [95% confidence interval (CI): 0.49–1.12]. Toxicity, Gemcitabine-based combinations are commonly particularly hematological and gastrointestinal, used. In a phase II trial conducted by the Spanish was higher in the trabectedin–doxorubicin arm. Sarcoma Group (GEIS) in STS, including uter- Based on these results, a combination of trabect- ine sarcomas, the combination of gemcitabine edin + doxorubicin should be the first-line regi- and dacarbazine showed a superior response to men of choice for fit patients. dacarbazine alone (49% versus 25%), PFS (4.2 months versus 2 months; 0.58; 95% CI, 0.39– In uLMS patients, the combination of doxorubicin- 0.86; p < 0.005) and OS (16.8 months versus dacarbazine may also be an option. In a retrospec- 8.2 months; HR, 0.56; 95% CI, 0.36–0.90; tive study, this combination showed a longer OS p < 0.014). Histotype leiomyosarcoma and com- (median 36.8 months) and a higher response rate bination treatment were significantly favorable (30.6%) than the combination of doxorubicin-ifos- prognostic factors for PFS. Furthermore, the reg- famide or doxorubicine alone.51 Nevertheless, in imen is well tolerated, and has high compliance prospective trials, anthracycline-based combination despite extensive prior treatment exposure.86 8 journals.sagepub.com/home/tam JA Pérez-Fidalgo, E Ortega et al. Combining gemcitabine with docetaxel is also an indolent tumors with a low disease burden and option and has been evaluated in several phase II high hormonal receptor positivity [IIIC]. studies that included uLMS.84 Gemcitabine monotherapy could be an option in selected Targeted therapy patients. NTRK fusions. NTRK rearrangements have also been described in uterine tumors arising Pazopanib is an oral antiangiogenic therapy tar- mainly in the uterine cervix of premenopausal geting VEGFR. The phase III Palette trial87 ran- women.93,94 They exhibit features fibrosarcoma domized STS patients who had been treated with and although few cases have been published to at least one previous line including anthracyclines date, they might benefit from targeted therapy.95 to received pazopanib 800 mg once daily or pla- cebo. In all, 372 patients were included, approxi- NTRK inhibitors larotrectinib96 and entrectinib96 mately 40% of whom had leiomyosarcoma. With have shown activity in several tumor types harbor- pazopanib, the median PFS increased from ing NTRK fusions. Larotrectinib achieved an 1.6 months (placebo arm) to 4.6 months (pazo- ORR of 75% and entrectinib achieved an ORR of panib arm) with an HR = 0.31 (95% CI: 0.24– 57%. Both drugs also showed a high proportion of 0.40). A subgroup analysis confirmed that the patients maintained prolonged responses. In these efficacy of pazopanib in uLMS appears to be sim- trials, only the entrectinib trial enrolled uterine ilar than in the non-uterine LMS subgroup.89 sarcomas, one adenosarcoma and one ESS. Table 2 summarizes second-line systemic treat- Recently, an NTRK fusion-positive uterine spin- ment options for high-grade uterine sarcoma. dle cell sarcoma with features of fibrosarcoma was described.93 Such tumors harbor NTRK1 Trabectedin, gemcitabine combinations (prefer- and NTRK3 rearrangements, suggesting a poten- ably with dacarbazine), and pazopanib are second tial benefit from NTRK inhibitors. and further-line options depending on the first- line chemotherapy regimen received. ALK fusions. Inflammatory myofibroblastic tumors (IMTs) can arise in the uterus. Differ- Endocrine therapy. Data supporting endocrine ential diagnoses must be made with endometrial therapy in HG-uterine sarcoma are scarce and stromal tumors and also with myxoid variants restricted to uLMS and aromatase inhibitors of uterine smooth muscle tumors. IMTs can (AI). In one retrospective study, 40 patients, 50% exhibit ALK rearrangements, however, as in of whom were ER+, were treated with AI. A par- other STS IMTs, not all are ALK-rearranged.97 tial response was achieved in 9% of patients (all ALK-rearranged locally advanced or metastatic ER-positive) and 32% achieved stable disease IMTs tumors might be treated with crizo- (SD).90 In another retrospective study including tinib. In a single arm phase II study, the objec- 16 patients who had ER+/PR+ tumors and tive response rate to crizotinib was 66.7% and received AI, the response rate was 12.5%, whereas median PFS was 18 months for the patients with the clinical benefit reached 62.5% (partial ALK fusions.98 response and SD of at least 6 months). Six of these patients received another AI (exemestane) NTRK fusion testing could be considered in uterine as second-line treatment, achieving a 1-year pro- sarcoma. Patients with NTRK-positive tumors gression-free rate of 80%.91 should be offered an NTRK inhibitor [IIIA]. A phase II non-randomized trial evaluated letro- zole in 27 ER+/PR+ patients with unresectable Low-grade uterine sarcoma uLMS. The 12-week PFS rate was 50%, and the LG-ESS is characterized by high expression of SD rate was 54%, without any objective response.92 ER and PR. Therefore, despite the lack of pro- However, three patients who expressed hormonal spective randomized data, treatment with AI and receptors in over 90% of tumor cells continued progestins are commonly used in an advanced or letrozol for at least 24 weeks. recurrent disease setting. Due to a better toxicity profile, AI is preferred as first-line hormonal ther- Endocrine therapy with AI may be a reasonable apy. The use of tamoxifen is contraindicated in option for some patients with advanced ER/ uterine sarcomas expressing hormonal receptors PR-positive uLMS, particularly those who have due to its endometrial proliferative effect.99 journals.sagepub.com/home/tam 9 Therapeutic Advances in Medical Oncology Volume 15 Table 4. Most relevant prospective trials with systemic agents including uterine sarcoma patients. Chemotherapy agents Inclusion Phase N (uLMS) RR % PFS OS (months) (months) First-line studies 80Sutton 1996 uLMS II 34 30.3 4 – Doxo + ifosfamide 77Judson 2014 STS III 455 14 versus 27 4.6 versus 12.8 versus Doxo versus Doxo + ifosfamide 7.4 14.3 (113 LMS) 78GeDDisSeddon Doxo 75 mg/m2 versus STS III 257 (71) – 23.3 versus 76.3 versus 2017 gemcitabine 650 mg/m2 d1 & 23.7 weeks 67.3 weeks 8 + Docetaxel 75 mg/m2 d8/21 d 80LMS-04 Pautier LMS III 150 (67) 38 versus 13 13.5 versus 30.5 versus Doxo 60 mg/m2 + Trabectedin ESMO2021 1.1 mg/m2 iv 3 h/21 d versus Doxo 7.3 24.1 75 mg/m2 81Sutton 1996 Ifosfamide 1.5 mg/m2 d1-5/21 d ESS II 31 33 3 – Second and further lines 85Le Cesne 2005 Trabectedin 1.5 mg/m2 24 h iv/21 d STS II 104 56 (CBR) LMS PFS 6 m 9.2 (43 LMS) 29% 86Garcia del Muro STS II 109 12 versus 4 4.2 versus 2 16.8 versus DTIC 500 mg/m2+ Gemcitabine JCO2011 1800 mg/m2 iv/14 d versus 8.2 DTIC1000 mg/m2/21 d (32 LMS) 85Hensley 2017 Trabectedin 1.5 mg/m2 24 h iv/21 d LMS and III 577 (232) 11 versus 9 4 versus 1.5 13.4 versus (uLMS post versus DTIC 1 gr/21 d LPS 12.9 hoc) CBR uLMS (31 versus 18 uLMS uLMS) 86 Le Cesne 2015 Trabectedin 1.5 mg/m2 STS II 56 (21 LMS) PFS 6 m OS 12 m 24 h/21 d × 6cycles versus continuous 23.1 versus 73.3 versus 51.9% 85.2% 84Hensley 2008 Gemcitabine 900 mg/m2 d1 & d8 uLMS II 51 27 5.4 14.7 90 min+ Docetaxel 100 mg/m2 d8/3w CBR, clinical benefit rate; DTIC, dacarbazine; ESS, endometrial stromal sarcoma; LMS, leyomiosarcoma; OS, overall survival; PFS, progression-free survival; RR, response rate; STS, soft tissue sarcoma; uLMS, uterine leyomiosarcoma. Many retrospective series have reported the effec- 4 years.91 A Dutch series with 11 patients treated tivity of progestins and AI in the first-line setting. with AI and megestrol showed a response rate of The Royal Marsden study included 13 patients 82% with a median duration of response of who were treated mainly with AI (11 patients 48 months.100 A response rate of 77.7% was also with AI and 2 patients with progestins) and found reported by Loffe et al. in 18 LG-ESS patients a response rate of 46.2% and a median PFS of treated with hormonal therapy.101 10 journals.sagepub.com/home/tam JA Pérez-Fidalgo, E Ortega et al. Recently, a basket single arm trial of anastrozole in Adjuvant pelvic RT is not recommended for uter- first-line positive ER/PR gynecological cancers ine adenosarcoma, because no survival benefit enrolled 15 LG-ESS patients. Response rate in has been proven.107 The role of adjuvant CT is the setting of this clinical trial was 26.7% and SD uncertain as adenosarcomas have been frequently was achieved in 46.7% of the patients. Median excluded from clinical trials. PFS was not reached and PFS was 73.3%, 73.3%, and 66% at 6, 12, and 18 months, respectively.102 ER/PR positivity could be used as a predictive biomarker for response to hormonal therapy but In a second-line setting in the Royal Marsden evidence is limited to case reports or case series in study, patients receiving second-line hormonal the adjuvant and advanced setting (V, B). therapy had a median PFS of 3 years and a 2-year Endocrine therapy should be limited to low-grade PFS of almost 90%. adenosarcomas. Based on a few individual case reports, other hor- There is no standard treatment for advanced/ monal therapies., include GnRH analogues or recurrent disease. CT or endocrine therapy can fulvestrant.103 Fulvestrant is currently under eval- be considered (V, A) and in selected cases surgery uation in the FUCHSia phase II trial. could be an option (V, A). Regarding CT doxoru- bicin-based regimens,108 gemcitabine/doc- Upon progression to hormonal therapies or in etaxel, and trabectedin110 have been described 109 case of no expression of hormonal receptors, in case reports and case series. chemotherapy regimens used in other STSs might be employed but such practice has only been A retrospective review showed an increase in PFS described in a few case reports. in patients treated with doxorubicin and ifosfa- mide compared to those receiving doxorubicin Treatment with AI or progestins is recommended alone or other regimens.111 as first-line treatment. Due to their better toxicity profile, AI are preferred as first- line hormonal therapy (IIIA). Perivascular epithelioid cell tumors Perivascular epithelioid cell tumors are ultra-rare vascular neoplasms that can arise in multiple Other infrequent subtypes: Adenosarcoma, locations including the uterus. The mainstay of PEComa, uterine tumor resembling ovarian treatment consists of hysterectomy plus bilateral sex cord tumor oophorectomy. There are no data to support adjuvant treatment either with systemic treatment Uterine adenosarcoma or RT. In the metastatic setting, due to the mTOR Uterine adenosarcoma is a rare entity, accounting pathway activation in these tumors, mTOR inhib- for approximately 5–9% of uterine sarcomas and itors such as sirolimus are the preferred treatment only about 0.2% of all uterine neoplasms.104,105 choice (III-A). Recently, the phase II single arm Most patients with adenosarcoma are diagnosed AMPEC trial evaluating nab-sirolimus revealed a with stage I disease and have a 5-year OS of 39% response rate for the overall population and 60–80%. 89% for the patients with TSC2 mutation. The duration of response also correlated with the Uterine adenosarcoma is considered a biphasic mutational status.112 STS treatment regimens tumor because of the presence of benign epithe- might be an option as second-line and further line lial elements combined with a malignant mesen- therapies but low responses and short PFS are to chymal component. Sarcomatous overgrowth is be expected.113 (IV-B). associated with worse prognosis. The standard treatment is hysterectomy with Uterine tumor resembling ovarian bilateral salpingo-oophorectomy given the risk of sex cord tumors local spread to the adnexa and ovaries. Uterine tumor resembling ovarian sex cord Lymphadenectomy is not recommended as the tumors (UTROSCT) represent fewer than 1% of incidence of nodal metastasis is very low.106 uterine mesenchymal tumors and their etiology is journals.sagepub.com/home/tam 11 Therapeutic Advances in Medical Oncology Volume 15 unknown. These rare tumors affect the uterine LGESS is usually a slow-growing malignancy corpus (intramural or submucosal), and occa- with an indolent course. Several studies suggest sionally the cervix in middle-aged peri-menopau- that up to 80% of recurrences can be detected by sal women. They usually present with abnormal routine radiographic surveillance.75 vaginal bleeding or pelvic pain. Based on expert opinion, a CT scan of chest, UTROSCT are generally benign but sometimes abdomen, and pelvis is recommended every have malignant potential and may recur. Those 3–6 months for the first 3 years, and then every more aggressive subtypes have been associated 6–12 months for the next 2 years. Annual or bian- with extensive rhabdoid differentiation and nual imaging should be considered thereafter for GREB1 and ESR1-NCOA2 fusions.114–117 an additional 5 years. [VB.]. Long-term clinical surveillance is also recommended (VB). Morphologically, UTROSCT display patterns that resemble those of ovarian sex cord tumors, without a component of recognizable endometrial Declarations stroma.118 UTROSCT are usually well-defined and grow in sheets, cords, nests, insulae, trabecu- Ethics approval and consent to participate lae, or tubules. Mitotic figures and necrosis are As this is a clinical guidelines by a group of experts infrequent. Their immunohistochemical profile no informed consent was needed and no Ethical exhibits variable positivity for sex cord markers Committee approval has been submitted. (inhibin, calretinin, WT1, CD56, CD99, SF1, FOXL2, and melan-A), epithelial markers (pan- Consent for publication cytokeratin, EMA), smooth muscle markers Not applicable. (actin, desmin, and h-caldesmon) and miscella- neous markers (ER, PR, CD10). Author contribution(s) Jose Alejandro Pérez-Fidalgo: Conceptua­ The staging strategy is similar to that of other lization; Methodology; Project administration; uterine sarcomas. Hysterectomy ± bilateral sal- Writing – original draft; Writing – review & pingo-oophorectomy is usually the treatment of editing. choice [VA], although fertility-preserving surgery Eugenia Ortega: Conceptualization; Writing – has been successfully reported in younger original draft; Writing – review & editing. women.119 Jordi Ponce: Conceptualization; Writing – origi- Adjuvant treatment is generally not recom- nal draft. mended, and recommended first-line CT is dox- Andres Redondo: Conceptualization; Writing – orubicin. Other combinations include original draft. carboplatin–gemcitabine or bleomycin, etoposide and cisplatin, but evidence to support these alter- Isabel Sevilla: Conceptualization; Writing – native regimens is lacking.120 original draft. Claudia Valverde: Conceptualization; Writing – original draft. Follow-up strategy For high-grade sarcomas, follow-up should Josep Isern Verdum: Conceptualization; include physical examination and imaging every Writing – original draft. 3–4 months for the first 2–3 years, every Enrique de Alava: Conceptualization; Writing 6 months for the following 5 years, and annually – original draft. thereafter. Imaging should include a CT scan of chest, abdomen and pelvis, with or without pel- Mar Galera López: Conceptualization; Writing vic MRI121 [VA]. A PET-CT can be useful. A – original draft. chest X-ray could be considered instead of a CT Gloria Marquina: Conceptualization; Writing scan after 5 years of surveillance to reduce radia- – original draft. tion exposure.122 Patients should be informed about symptoms that could suggest recurrence Ana Sebio: Conceptualization; Project adminis- and the importance of seeking prompt medical tration; Writing – original draft; Writing – review attention. & editing. 12 journals.sagepub.com/home/tam JA Pérez-Fidalgo, E Ortega et al. Acknowledgements declares to be member and president of the Group None. GEIS. J Isern deckares a Grant contract from Pharmamar, Funding and support for travel/meeting from Pharmamar. The authors disclosed receipt of the following financial support for the research, authorship, E de Alava declares consulting fees from Roche, and/or publication of this article: Authors received honoraria for speakers bureaus from Lilly, Bayer no funding from any company. English language and Merck and support for travel/meetings from revision was funded by the Hospital Sant Pau of Pharmamar and Roche. Barcelona. M Galera declares honoraria for speaker´s bureaus from MSD and Pharmamar and support for travel Competing interests /meetings from Pharmamar, MSD and Lilly and JA Perez Fidalgo declares receiving honoraria as receipt of material support from Pharmamar. speaker from Astrazeneca, MSD, Clovis, Pharmamar and GSK, as advisor from G Marquina declares payment for speakers Astrazeneca, GSK, Abilify pharma, Azierta and bureaus from Astrazeneca, GSK, Clovis, MSD, clovis and funding for travel and/or meeting from Medicamenta, Fundacion SEOM, Eisai, Astrazeneca, MSD, GSK and Pharmamar. He Pharmamar, Bayer, Lilly, Tropos formacion, also declares research support to his institution Tactics, Fundacion investigación HM hospitales, from GSK, Astrazeneca and Pharmamar. He also Globalianxia, Publicidad Permanyer, Transworld declares to be member of the executive commit- editors, Outcomes 10, Claris 2 Gmbh, Pharmore. tees of GEIS and GEICO. She also declares support for travel/meetings from Astrazeneca, GSK, Clovis, MSD, ESGO, SEOM, E Ortega declares conflict of interest with GSK, SECT,Pharmamar, Grupo de estudios oncologi- Astrazeneca, Clovis, Merck, Pharmamar and cos,, Meidcamenta. Participation in advisory MSD for speakers bureau and from Merck and boards from Deciphera, GSK, Azierta, MSD for travel/meetings and fro advisory board Boehringer, Pfizer and Pharmamar. She also from Eisai. declares bo be member fo SGO scientific com- J Ponce declares no conflict of interest mittee (observer), EOTTD executive committee, EORTC STBSG executive committee, and A Redondo declares honoraria for speakers EORTC GCG young representative in ENGOT bureau from Astrazeneca, GSK, Clovis, and and GCIG. MSD. He also has received payment for advisory boards for Astrazeneca, GSK, Clovis, MSD and A Sebio declares consulting fees from pharmamar Boehringer and travel/meeting expenses from and Boehringer-Ingelheim, honororaria for speak- Astrazeneca and Clovis. ers bureaus from Pharmamar, Eisai, Merck and Lilly and support for attending travel/meetings I Sevilla declares payment for speakers bureaus from Pharmamar, Eisai, Merck, Amgen, Roche, from AAA, Novartis, Pharmamar, Ipsen, Pfizer, Lilly. She declares to be member of the GEIS Amgen and Bayer. Support for travel/meetings executive committee from AAA, Novartis, Pharmamar, Ipsen, Boehringer, Advanz Pharma, Esteve Availability of data and materials Pharmaceuticals, Amgen and Bayer. Honoraria for participating in Advisory boards from AAA, Not applicable. Novartis, Pharmamar, Ipsen, Boehringer, Advanz Pharma, Esteve Pharmaceuticals, Amgen and ORCID iD Bayer. She also declares being member of the Josep Isern Verdum https://orcid.org/0000- GEIS and GETNE executive committees. 0002-0974-3615 C Valverde declares honoraria for consulting or advisory boards from Pharmamar, Boehringer, Bayer, Deciphera and Philogen. Support for References travel/meetings from Pharmamar, Boehringer 1. Toro JR, Travis LB, Hongyu JW, et al. Incidence and Bayer and Research funding grants to her patterns of soft tissue sarcomas, regardless of institution from Pharmamar, Boehringer, Baryer, primary site, in the surveillance, epidemiology Deciphera, Philogen, Novartis and Pfizer. She and end results program, 1978-2001: an analysis journals.sagepub.com/home/tam 13 Therapeutic Advances in Medical Oncology Volume 15 of 26,758 cases. Int J cancer 2006; 119: 2922– 14. Lewis N, Soslow RA, Delair DF, et al. ZC3H7B- 2930. BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity. 2. Seagle BLL, Shilpi A, Buchanan S, et al. 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