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Treatment of low-grade endometrial stromal sarcoma in a nulligravid woman

      Abstract

      A 32 year-old nulligravid woman with a uterine mass underwent exploratory laparotomy with myomectomy. Final pathology revealed a low-grade endometrial stromal sarcoma (ESS) with positive margins. She subsequently underwent definitive robotic hysterectomy and bilateral salpingectomy with ovarian preservation. She was diagnosed with a stage IB low-grade ESS. She is currently undergoing observation. Discussion of classification, surgical options, and adjuvant therapy is presented.

      1. Presentation of case

      A 32-year-old nulligravid woman presented to her primary OBGYN for a routine gynecologic exam. The patient reported cyclic pelvic pain and occasional bloating, but otherwise denied vaginal bleeding, discharge, and early satiety. She was found to have an enlarged uterus on bimanual exam. Family history was notable for the patient's mother having been diagnosed with a retroperitoneal liposarcoma. A pelvic ultrasound was performed, which revealed an 11 × 8 × 8 cm uterus with a heterogeneous mass filling the entire uterus. The endometrial stripe was 2 mm and the ovaries were normal appearing with small follicles. An MRI confirmed an enlarged, lobulated uterus with a 10 × 7 × 12 cm intramural mass. The mass enhanced fairly homogenously with internal areas suggestive of degenerative changes. An endometrial biopsy was performed and showed no evidence of malignancy; however, there was scant material in the specimen. The primary working diagnosis was a degenerating uterine fibroid.
      After extensive counseling regarding the risks and benefits of fertility preservation, the patient underwent a myomectomy via a Pfannenstiel incision. At the time of surgery, she was found to have a fundal uterine mass measuring approximately 14 × 6 cm. Several other small whorled nodules clinically consistent with leiomyoma were noted, each <1 cm. The rest of her pelvic organs and abdomen appeared normal. After the dominant mass and other palpable uterine masses were removed, the uterus was repaired in multiple layers. She was discharged on postoperative day two without any complications.
      Pathology returned as a low-grade endometrial stromal sarcoma (ESS). The size of the tumor measured 12.7 cm in its greatest dimension and there were positive margins present. The patient was counseled on options of close observation, additional tumor resection, and definitive hysterectomy. In order to maximize oncologic outcomes, the patient elected to undergo hysterectomy. Due to concerns related to the side-effects of surgical menopause, the patient desired ovarian preservation. The decision was made to proceed with a robotic-assisted laparoscopic hysterectomy and bilateral salpingectomy with ovarian preservation. She was found to have small and large bowel adhesions to her previous myomectomy scar. Her tubes and ovaries appeared normal and there was no other disease noted in the pelvis and abdomen. The patient was discharged on postoperative day one.
      Pathology from the follow-up hysterectomy specimen was notable for a 1.3 cm nodule with residual low-grade ESS; the surgical margins were uninvolved. Final pathology was consistent with stage IB due to tumor limited to the uterus and a combined tumor size of 14 cm. Hormonal therapy with an aromatase inhibitor was considered but the patient opted for observation. At her three-month follow-up, the patient's primary symptoms were vaginal dryness and dyspareunia which improved with vaginal estrogen cream. Follow-up CT scans of the chest, abdomen, and pelvis showed no evidence of disease and the patient is without evidence of disease at 18 months.

      2. Epidemiology of endometrial stromal sarcoma

      ESS tumors are rare and account for <10% of uterine mesenchymal neoplasms and <2% of all uterine neoplasms [
      • Ali R.H.
      • et al.
      Endometrial stromal tumours revisited: an update based on the 2014 WHO classification.
      ]. The annual incidence is estimated to be 1–2 per million women [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ]. The mean age of diagnosis is 50 years old and premenopausal women comprise up to half of affected patients [
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ]. Due to limitations with preoperative imaging and endometrial sampling to accurately diagnose ESS, the usual presentation is abnormal uterine bleeding or incidental pathologic finding at hysterectomy performed for suspected benign disease, such as fibroids. The majority of cases present with early stage disease [
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ]. Approximately 30–50% of patients will experience recurrence or metastasis after surgical management, including both pelvic and/or extrapelvic locations [
      • Cheng X.
      • et al.
      Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy.
      ]. Recurrences typically have an indolent course and can occur up to 20 years later [
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ].

      3. Pathology of endometrial stromal sarcoma

      A single fragment of disrupted soft tissue labeled as “uterine fibroid” was examined (12.7 × 7.7 × 5.2 cm). Sectioning revealed yellow multi-nodular tissue and low power microscopic examination showed a tumor with irregular tongues and islands of highly cellular tissue infiltrating the myometrium (Fig. 1). Collagen bands and areas of diffuse hyalinization were present (Fig. 2). The tumor extended to the margins of resection. On high power magnification, tumor cells had uniform oval to spindle nuclei with scant cytoplasm resembling proliferative phase endometrial stroma (Fig. 3). Rare mitoses were identified and the stroma had multiple small arterioles and capillaries with collagen bands surrounding the tumor cells. The tumor was positive for CD10, WT-1, estrogen and progesterone receptors. Residual tumor in the hysterectomy specimen showed similar findings.
      Fig. 1
      Fig. 1Low-grade endometrial stromal sarcoma with irregular tongues of highly cellular tissue infiltrating myometrium (H&E stain, 40× magnification).
      Fig. 2
      Fig. 2Collagen bands surrounding tumor cells were present (H&E stain, 200× magnification).
      Fig. 3
      Fig. 3High power examination shows tumor with uniform oval to spindle shape nuclei with scant cytoplasm resembling proliferative phase endometrial stroma (H&E stain, 400× magnification).

      4. Molecular characteristics

      The majority of ESS are estrogen and progesterone receptor positive. They are typically reactive for CD10 and smooth muscle actin. Several genetic abnormalities have been reported in low-grade ESS. The most common rearrangement (50%) is a gene translocation involving the short arm of chromosome 7 and the long arm of chromosome 17 t (7;17); this results in the fusion of JAZF1 and SUZ12 genes [
      • Huang H.Y.
      • et al.
      Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial stromal neoplasms with classic and variant histology: evidence for genetic heterogeneity.
      ,
      • Oliva E.
      • et al.
      High frequency of JAZF1-JJAZ1 gene fusion in endometrial stromal tumors with smooth muscle differentiation by interphase FISH detection.
      ,
      • Hoang L.
      • et al.
      Endometrial stromal sarcomas and related neoplasms: new developments and diagnostic considerations.
      ]. The JAZF1/SUZ12 protein has not been found in other uterine sarcomas. Although recent advances have expanded our understanding of the molecular characteristics of ESS tumors, further research is needed to better understand the molecular pathways and optimize targeted treatment strategies. These tumors are routinely diagnosed using histologic criteria; however, next generation sequencing assays may assist in the identification of ESS with unusual location or morphology.

      5. Classification system

      Endometrial stromal tumors are a subset of uterine mesenchymal neoplasms that account for <10% of uterine sarcomas and approximately 1% of all uterine malignant neoplasms. The terminology and classification system of endometrial stromal neoplasms has changed numerous times. The 2014 World Health Organization (WHO) classifies these tumors into four categories: (a) endometrial stromal nodule, (b) low-grade endometrial stromal sarcoma, (c) high-grade endometrial stromal sarcoma, and (d) undifferentiated uterine sarcoma [
      • Ali R.H.
      • et al.
      Endometrial stromal tumours revisited: an update based on the 2014 WHO classification.
      ,
      • Conklin C.M.
      • et al.
      Endometrial stromal tumors: the new WHO classification.
      ,
      • Lee C.H.
      • et al.
      Endometrial stromal sarcoma–the new genetic paradigm.
      ]. One of the important highlights of the updated guidelines was the re-introduction of high-grade ESS as a distinct entity. The diagnosis of mesenchymal tumors can be challenging due to overlapping histopathologic appearance of the lesions [
      • Nucci M.R.
      • et al.
      Practical issues related to uterine pathology: endometrial stromal tumors.
      ]. Distinction between benign endometrial stromal nodule (well circumscribed stromal nodule with <3 mm projections) and low-grade ESS in biopsy/curettage specimen cannot be made with certainty in the absence of lymphovascular invasion. Highly cellular leiomyoma should also be considered during histologic evaluation. High-grade ESS shows a destructive growth pattern with a various mixture of high-grade and low-grade tumor components. Mitotic activity is striking and typically >10 per 10 HPF. Necrosis is usually present. The College of American Pathologists uses the American Joint Committee on Cancer (AJCC) pathologic stage classification (pTNM, AJCC 8th Edition) for endometrial stromal sarcoma.
      In our patient, lymphovascular invasion was noted with irregular tongues and islands of highly cellular tissue infiltrating the myometrium. The tumor cells had uniform nuclei with scant cytoplasm resembling proliferative phase endometrial stroma. Rare mitoses were identified. The pathologic findings were consistent with low-grade ESS.

      6. Role of imaging

      The majority of patients with ESS will present with abnormal bleeding, pelvic pressure, or an enlarged uterus. Frequently a benign leiomyoma is suspected in asymptomatic or premenopausal patients. ESS tumors have a non-specific appearance on transvaginal ultrasound, typically characterized as a heterogeneous hypoechoic endometrial mass, which can show extensive myometrial involvement. On MRI, these masses consist of worm-like projections in the vessels or myometrium which are best visualized on diffuse weighted imaging. The diagnosis of ESS is often made after a hysterectomy; therefore, postoperative imaging with either CT or MRI is important to evaluate for extrauterine disease even if intraoperative assessment is negative.

      7. Surgical staging and ovarian preservation

      Since an accurate diagnosis of ESS requires the evaluation of vasculature and invasion of the myometrium, diagnosis is not typically made with endometrial sampling. In patients with a preoperative diagnosis of low-grade ESS as determined by myomectomy, surgical resection with hysterectomy and bilateral salpingo-oophorectomy is the gold standard for treatment and staging [
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ]. ESS is surgically staged using the FIGO staging system for uterine sarcomas. The majority of patients are diagnosed with stage 1 or II disease [
      • Chan J.K.
      • et al.
      Endometrial stromal sarcoma: a population-based analysis.
      ,
      • Shah J.P.
      • et al.
      Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma.
      ].
      Although surgical staging of uterine sarcomas can include lymph node assessment, reported rates of nodal metastasis in low-grade ESS range from 7% to 10% in population-based and multi-institutional studies [
      • Chan J.K.
      • et al.
      Endometrial stromal sarcoma: a population-based analysis.
      ,
      • Shah J.P.
      • et al.
      Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma.
      ]. Data are mixed as to whether positive lymph node status is a predictor of poorer outcomes [
      • Chan J.K.
      • et al.
      Endometrial stromal sarcoma: a population-based analysis.
      ,
      • Shah J.P.
      • et al.
      Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma.
      ,
      • Leath III, C.A.
      • et al.
      A multi-institutional review of outcomes of endometrial stromal sarcoma.
      ]. Routine performance of lymphadenectomy has not been shown to confer a survival benefit [
      • Chan J.K.
      • et al.
      Endometrial stromal sarcoma: a population-based analysis.
      ,
      • Shah J.P.
      • et al.
      Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma.
      ,
      • Barney B.
      • et al.
      Does radiotherapy or lymphadenectomy improve survival in endometrial stromal sarcoma?.
      ]. For patients in whom early stage disease is suspected without clinically suspicious lymph nodes, routine lymphadenectomy is not recommended [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ,
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ,
      • Shah J.P.
      • et al.
      Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma.
      ,
      • Barney B.
      • et al.
      Does radiotherapy or lymphadenectomy improve survival in endometrial stromal sarcoma?.
      ]. Furthermore, when the diagnosis occurs incidentally after hysterectomy for benign indications, reoperation to perform lymphadenectomy is not indicated.
      Because ESS often occurs in premenopausal women, the question of whether to preserve the ovaries in order to delay the negative long-term effects of early menopause is an important one [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ]. Two studies using the SEER database have demonstrated no overall survival benefit in patients with low-grade ESS who underwent oophorectomy compared to those who did not [
      • Chan J.K.
      • et al.
      Endometrial stromal sarcoma: a population-based analysis.
      ,
      • Shah J.P.
      • et al.
      Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma.
      ]. The majority of patients who underwent ovarian sparing surgery in these studies were early stage and premenopausal. However, because ESS is a hormonally sensitive cancer for which adjuvant progestin or anti-estrogen therapy may be recommended in advanced stage and recurrent disease, the benefit of oophorectomy in women must also be weighed against the risk of early menopause [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ]. The ovaries can be retained in appropriately selected and counseled premenopausal patients with stage I disease who want to preserve hormonal function. Amant and colleagues propose that ovary-sparing surgery be considered for patients age 35 or younger with a small tumor [
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ]. Similarly, for a patient in whom ESS is diagnosed after hysterectomy without oophorectomy the same principles can apply. Early stage, premenopausal patients do not necessarily require reoperation for oophorectomy if a diagnosis of ESS comes unexpectedly after hysterectomy.

      8. The impact of uterine morcellation

      In December 2017, the FDA released a white paper updating their 2014 safety communication discouraging the use of laparoscopic power morcellators in cases of presumed fibroids due to the risk of mechanical spread of cancerous tissue and potential for worse clinical outcomes if sarcoma is diagnosed [
      FDA updated assessment of the use of laparoscopic power morcellators to treat uterine fibroids.
      ]. Based on the FDA analysis of the existing literature, the prevalence of uterine sarcoma of any histological subtype is estimated to be between 1 in 225 to 1 in 580 women who undergo surgery for presumed fibroids [
      FDA updated assessment of the use of laparoscopic power morcellators to treat uterine fibroids.
      ]. While there is no controversy that morcellation should not be undertaken in cases of known malignancy, the diagnosis is often not known due to inherent limitations in endometrial sampling to diagnose sarcomas preoperatively. Various preoperative risk assessment protocols have been proposed and include a combination of clinical criteria such as age, menopausal status, rate of uterine growth, history of prior treatment (i.e., tamoxifen or pelvic radiation), hereditary conditions, and imaging scoring algorithms that use ultrasound and/or magnetic resonance imaging [
      • Sizzi O.
      • et al.
      Assessing the risk of laparoscopic morcellation of occult uterine sarcomas during hysterectomy and myomectomy: literature review and the ISGE recommendations.
      ]. However, these protocols do not fully exclude the possibility of occult malignancy. In cases where morcellation was performed for undiagnosed sarcoma, surgical reoperation should be considered to ensure that there are no malignant implants noted [
      • Mowers E.L.
      • et al.
      Effects of morcellation of uterine smooth muscle tumor of uncertain malignant potential and endometrial stromal sarcoma: case series and recommendations for clinical practice.
      ,
      • Zhang J.
      • et al.
      Clinical characteristics and management experrence of unexpected uterine sarcoma after myomectomy.
      ].
      Data for clinical outcomes after morcellation of previously undiagnosed ESS is variable and further limited by small sample sizes. A retrospective study conducted by the MITO group found no difference in survival outcomes in a group of 14 ESS patients when comparing morcellation vs. non-morcellation [
      • Raspagliesi F.
      • et al.
      Morcellation worsens survival outcomes in patients with undiagnosed uterine leiomyosarcomas: a retrospective MITO group study.
      ]. Another retrospective study of 50 ESS cases found that tumor morcellation was associated with worse disease-free survival (OR 4.03, 95% CI 1.06–15.30; p = 0.040) and abdominal/pelvic disease-survival (OR 5.06, 95% CI 1.02–25.04; p = 0.047) [
      • Park J.Y.
      • et al.
      The impact of tumor morcellation during surgery on the outcomes of patients with apparently early low-grade endometrial stromal sarcoma of the uterus.
      ]. The use of power morcellators has dramatically decreased over the last five years due to the concern of tumor dissemination in the case of an unrecognized uterine sarcoma, although the prevalence of uterine cancers in women who underwent morcellation was unchanged [
      • Wright J.D.
      • et al.
      Trends in use and outcomes of women undergoing hysterectomy with electric power morcellation.
      ].

      9. Adjuvant treatment

      Hysterectomy with bilateral salpingo-oophorectomy is the mainstay of treatment, and achievement of negative margins is an important prognostic factor [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ,
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ,
      • Goff B.A.
      • et al.
      Uterine leiomyosarcoma and endometrial stromal sarcoma: lymph node metastases and sites of recurrence.
      ]. For patients with metastatic disease, cytoreductive surgery should be attempted with a goal of complete resection [
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ]. Recommendations for adjuvant treatment in patients with low-grade ESS depend on stage. For patients with completely resected stage I disease, observation is reasonable. Adjuvant hormonal therapy is recommended for patients with stage II to IV [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ]. As these tumors often express both estrogen receptors and progesterone receptors (in 70% and 95% of cases, respectively), hormonal therapy may lower the risk of recurrence [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ]. Although receptor status is not predictive of response to hormonal therapy, it may help the clinician decide which hormonal therapy to use. Aromatase inhibitors such as letrozole are the preferred hormonal agent; however, progestins such as medroxyprogesterone or megestrol acetate or gonadotropin-releasing hormone are also acceptable options [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ,
      • Spano J.P.
      • et al.
      Long-term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma.
      ]. Tamoxifen and oral estrogen are contraindicated in patients as this may stimulate tumor growth [
      • NCCN Guidelines Version 1.2018
      Endometrial carcinoma.
      ,
      • Pink D.
      • et al.
      Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: single center experience with 10 cases and review of the literature.
      ].
      Our patient did not desire adjuvant hormonal therapy due to the side-effects of low estrogen. Interestingly, she did experience vaginal dryness after surgery despite ovarian preservation. She was treated for a short period of time with vaginal estrogen with improvement in her symptoms. Most studies have shown that the risk of systemic absorption with vaginal estrogen is very low and does not increase the risk of breast cancer recurrence [
      • Le Ray I.
      • et al.
      Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case-control study.
      ]. Short-term therapy with vaginal estrogen for symptomatic, low-risk patients is reasonable with appropriate counseling.
      The role of adjuvant radiation therapy in low-grade ESS is controversial. While radiation therapy may provide improved local control, no prospective studies have demonstrated improved survival [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ,
      • Reed N.S.
      • et al.
      Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874).
      ]. Treatment of patients with metastatic or recurrent disease can be challenging. Due to the indolent nature of these tumors and tendency for late recurrence, surgical management can be considered for patients with disease amenable to complete resection. Adjuvant hormonal therapy can be used to prolong the recurrence-free interval following complete resection [
      • Amant F.
      • et al.
      Clinical management of uterine sarcomas.
      ]. Radiation therapy can be considered for patients with unresectable pelvic recurrence [
      • Rauh-Hain J.A.
      • et al.
      Endometrial stromal sarcoma: a systematic review.
      ].
      For patients with metastatic disease, hormonal therapy or systemic chemotherapy with a regimen active in uterine sarcomas should be considered. Options include doxorubicin, docetaxel and gemcitabine, or ifosfamide [
      • NCCN Guidelines Version 1.2018
      Endometrial carcinoma.
      ]. In a phase II study conducted by the Gynecologic Oncology Group, the overall response rate with single-agent ifosfamide in chemotherapy-naïve patients with recurrent or metastatic ESS was 33% [
      • Sutton G.
      • et al.
      Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group.
      ]; however, prospective data on use of chemotherapy in this population is limited. In 2016, the Federal Drug Administration (FDA) granted accelerated approval to olaratumab with doxorubicin for the treatment of patients with soft tissue sarcoma not amenable to curative treatment with radiotherapy or surgery. Olaratumab is a human anti-platelet-derived growth factor (PDGF) receptor α monoclonal antibody. Approval was based on data from a randomized, controlled, clinical trial involving 133 patients with metastatic soft tissue sarcoma. Patients were required to have a histologic type of sarcoma for which an anthracycline-containing regimen was appropriate, but had not been administered. 2% of the patients in the trial had ESS. This study achieved a significant improvement of 12 months in median overall survival, suggesting a potential shift in the treatment of soft tissue sarcoma [
      • Tap W.D.
      • et al.
      Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.
      ]. A study of 13 tissue samples of low-grade ESS found that expression of PDGF-α and PDGF-β were 33% and 36%, respectively [
      • Cheng X.
      • et al.
      Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy.
      ].

      10. Surveillance recommendations

      Patients with uterine sarcomas are recommended to undergo surveillance visits for symptom review and physical examination including pelvic exam. Use of cervical or vaginal cytology is not indicated. For low-risk disease, visits are recommended every 6 months for the first 2 years and then annually after 2 years [
      • Salani R.
      • et al.
      An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations.
      ]. For high-risk disease, visits are recommended every 3 months for the first 2 years, every 6 months for the next 3 years, and then annually thereafter. CT imaging of the chest, abdomen, and pelvis can be used for surveillance of uterine sarcoma every 6 to 12 months [
      • Salani R.
      • et al.
      An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations.
      ]. Prolonged use of routine surveillance imaging in patients with ESS may be of lower yield and it is reasonable to utilize imaging based upon clinical suspicion for possible recurrence.

      11. Summary

      Low-grade ESS is a rare uterine malignancy that generally is hormonally sensitive with an indolent course. The management of young patients desiring fertility can be challenging and extensive counseling is needed to carefully consider all options. It is clear that the prognosis of women with low-grade ESS is significantly better than other uterine sarcomas. Patients are at risk for late recurrences therefore long-term follow-up with pelvic exams and imaging is warranted. Hormonal therapy remains the mainstay for patients with advanced and recurrent disease.

      Disclosures

      None.

      References

        • Ali R.H.
        • et al.
        Endometrial stromal tumours revisited: an update based on the 2014 WHO classification.
        J. Clin. Pathol. 2015; 68: 325-332
        • Rauh-Hain J.A.
        • et al.
        Endometrial stromal sarcoma: a systematic review.
        Obstet. Gynecol. 2013; 122: 676-683
        • Amant F.
        • et al.
        Clinical management of uterine sarcomas.
        Lancet Oncol. 2009; 10: 1188-1198
        • Cheng X.
        • et al.
        Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy.
        Gynecol. Oncol. 2011; 121: 323-327
        • Huang H.Y.
        • et al.
        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: 224-232
        • Oliva E.
        • et al.
        High frequency of JAZF1-JJAZ1 gene fusion in endometrial stromal tumors with smooth muscle differentiation by interphase FISH detection.
        Am. J. Surg. Pathol. 2007; 31: 1277-1284
        • Hoang L.
        • et al.
        Endometrial stromal sarcomas and related neoplasms: new developments and diagnostic considerations.
        Pathology. 2018; 50: 162-177
        • Conklin C.M.
        • et al.
        Endometrial stromal tumors: the new WHO classification.
        Adv. Anat. Pathol. 2014; 21: 383-393
        • Lee C.H.
        • et al.
        Endometrial stromal sarcoma–the new genetic paradigm.
        Histopathology. 2015; 67: 1-19
        • Nucci M.R.
        • et al.
        Practical issues related to uterine pathology: endometrial stromal tumors.
        Mod. Pathol. 2016; 29: S92-103
        • Chan J.K.
        • et al.
        Endometrial stromal sarcoma: a population-based analysis.
        Br. J. Cancer. 2008; 99: 1210-1215
        • Shah J.P.
        • et al.
        Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma.
        Obstet. Gynecol. 2008; 112: 1102-1108
        • Leath III, C.A.
        • et al.
        A multi-institutional review of outcomes of endometrial stromal sarcoma.
        Gynecol. Oncol. 2007; 105: 630-634
        • Barney B.
        • et al.
        Does radiotherapy or lymphadenectomy improve survival in endometrial stromal sarcoma?.
        Int. J. Gynecol. Cancer. 2009; 19: 1232-1238
      1. FDA updated assessment of the use of laparoscopic power morcellators to treat uterine fibroids.
        • Sizzi O.
        • et al.
        Assessing the risk of laparoscopic morcellation of occult uterine sarcomas during hysterectomy and myomectomy: literature review and the ISGE recommendations.
        Eur. J. Obstet. Gynecol. Reprod. Biol. 2018; 220: 30-38
        • Mowers E.L.
        • et al.
        Effects of morcellation of uterine smooth muscle tumor of uncertain malignant potential and endometrial stromal sarcoma: case series and recommendations for clinical practice.
        J. Minim. Invasive Gynecol. 2015; 22: 601-606
        • Zhang J.
        • et al.
        Clinical characteristics and management experrence of unexpected uterine sarcoma after myomectomy.
        Int. J. Gynaecol. Obstet. 2014; 130: 195-199
        • Raspagliesi F.
        • et al.
        Morcellation worsens survival outcomes in patients with undiagnosed uterine leiomyosarcomas: a retrospective MITO group study.
        Gynecol. Oncol. 2017; 144: 90-95
        • Park J.Y.
        • et al.
        The impact of tumor morcellation during surgery on the outcomes of patients with apparently early low-grade endometrial stromal sarcoma of the uterus.
        Ann. Surg. Oncol. 2011; 18: 3453-3461
        • Wright J.D.
        • et al.
        Trends in use and outcomes of women undergoing hysterectomy with electric power morcellation.
        JAMA. 2016; 316: 877-878
        • Goff B.A.
        • et al.
        Uterine leiomyosarcoma and endometrial stromal sarcoma: lymph node metastases and sites of recurrence.
        Gynecol. Oncol. 1993; 50: 105-109
        • Spano J.P.
        • et al.
        Long-term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma.
        Med. Oncol. 2003; 20: 87-93
        • NCCN Guidelines Version 1.2018
        Endometrial carcinoma.
        (Available from:)
        • Pink D.
        • et al.
        Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: single center experience with 10 cases and review of the literature.
        Gynecol. Oncol. 2006; 101: 464-469
        • Le Ray I.
        • et al.
        Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case-control study.
        Breast Cancer Res. Treat. 2012; 135: 603-609
        • Reed N.S.
        • et al.
        Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874).
        Eur. J. Cancer. 2008; 44: 808-818
        • Sutton G.
        • et al.
        Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group.
        Obstet. Gynecol. 1996; 87: 747-750
        • Tap W.D.
        • et al.
        Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.
        Lancet. 2016; 388: 488-497
        • Salani R.
        • et al.
        An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations.
        Gynecol. Oncol. 2017; 146: 3-10