Expanding the molecular spectrum of gene fusions in endometrial stromal sarcoma: Novel subunits of the chromatin remodeling complexes PRC2 and NuA4/TIP60 as alternative fusion partners.

Endometrial stromal sarcomas (ESS) are morphologically and molecularly heterogeneous. We report novel gene fusions (EPC1::EED, EPC1::EZH2, ING3::PHF1) identified by targeted RNA sequencing in five cases. The ING3::PHF1-fusion positive ESS presented in a 58-year-old female as extrauterine mesocolonic, ovarian masses, and displayed large, monomorphic ovoid-to-epithelioid cells arranged in solid sheets. The patient remained alive with disease 13 months after surgery. The three ESS with EPC1::EED occurred in the uterine corpus in patients with a median age of 58 years (range 27-62 years). One tumor showed a uniform epithelioid nested morphology, while the other two were composed of monomorphic spindle cells in fascicles with elevated mitotic figures, focal tumor cell necrosis, and lymphovascular invasion. At a median follow-up of 20 months, two patients developed local recurrence, including one with concomitant distant metastasis, while one patient remained free of disease. All three patients were alive at the last follow-up. The EPC1::EZH2-fusion positive ESS presented in a 52-year-old female in the uterus, and displayed uniform spindled cells arranged in short fascicles, with focally elevated mitotic activity but without necrosis. The patient remained free of disease 3 months after surgery. All cases were diffusely positive for CD10; four diffusely express estrogen and progesterone receptors. Our study expands the molecular spectrum of EPC1 and PHF1-related gene fusions in ESS to include additional novel subunits of the PRC2 and/or NuA4/TIP60 complexes. These cases displayed a monomorphic epithelioid or spindled phenotype, spanning low-grade and high-grade cytomorphology, all expressing CD10 and commonly ER and PR, and are prone to local and/or distant spread.

ZC3H7B-BCOR Fusion High-grade Endometrial Stromal Sarcoma With Morphologic Features of Low-grade Endometrial Stromal Sarcoma. A Case Report and Review of Literature.

High-grade endometrial stromal sarcomas with ZC3H7B-BCOR fusion are rare. They are predominantly located in the endomyometrium, with morphologic features characterized as haphazardly arranged fascicles of spindle cells with mild to moderate atypia, abundant myxoid matrix, high mitotic index, and tongue-like/pushing patterns of myometrial invasion. Furthermore, conventional or variant low-grade endometrial stromal sarcomas are often not present. Clinically, they present at a higher stage and are associated with worse prognosis compared with low-grade endometrial stromal sarcoma. Given the limited number of reported cases, we describe the case of a ZC3H7B-BCOR fusion high-grade endometrial stromal sarcoma initially diagnosed on the hysterectomy specimen as low-grade endometrial stromal sarcoma based on an endometrial stromal tumor showing tongue-like myometrial and lymphovascular invasion, minimal cytologic atypia, low-mitotic activity (0-1/10 high-power field), round/spindle cell component and immunohistochemical stain results (positive for CD10, estrogen receptor, progesterone receptor, and focally positive for cyclin D1). At the time of pathologic diagnosis, she was Stage Ia and managed conservatively. Subsequent molecular analysis revealed a ZC3H7B (exon 10)- BCOR (BCL-6 corepressor) (exon 7) gene fusion. On follow-up, she showed no evidence of disease at 37 months from the time of diagnosis. This case report expands the morphologic spectrum of ZC3H7B-BCOR fusion high-grade ESS, which includes an intramural location, morphologic and immunophenotypic features similar to LG-ESS, as well as the presence of round and spindle cell components. This case also underscores the value of molecular analysis in the proper classification of ESS.

Clinical features of uterine sarcomas presenting mainly with uterine masses: a retrospective study.

BACKGROUND: Uterine sarcomas are uncommon mesenchymal tumors of the uterus. The clinical problem is that the features of uterine sarcomas can sometimes mimic uterine fibroids. This study aims to investigate the clinical characteristics of patients with uterine sarcomas who were preoperative presenting mainly with uterine masses. METHODS: A retrospective analysis of patients who underwent gynecological surgery for uterine sarcomas at the Obstetrics & Gynecology Hospital of Fudan University, between January 2016 and December 2021. RESULTS: Over the 5-year period, 277 patients were final diagnosed of uterine sarcomas. A total of 162 patients were preoperatively diagnosed as uterine fibroids for surgical treatment, the majority of whom were diagnosed of uterine leiomyosarcoma (uLMS) (49/162) and low-grade endometrial stromal sarcoma (LG-ESS) (100/162). Ninety people underwent total hysterectomy and bilateral salpingo-oophorectomy (TH + BSO), while 72 underwent myomectomy followed by supplemental TH + BSO. The group with direct hysterectomy had a higher average age than the group with prior myomectomy (47.20 ± 8.94 vs. 40.86 ± 5.88, p < 0.001). Among patients preoperatively diagnosed as uterine fibroids, patients with uLMS had a higher proportion of previous myomectomy (26.53% vs. 5.00%, p < 0.001), a larger uterine mass diameter on ultrasound (8.38 ± 3.39 cm vs. 6.41 ± 1.92 cm, p < 0.001), and richer hypervascularity (34.69% vs. 18%, p = 0.024) compared with LG-ESS. CONCLUSIONS: Analysis of our data showed that a large proportion of uterine sarcomas, especially uLMS and LG-ESS, present mainly with uterine masses. Ultrasound features including a large uterine mass diameter and rich hypervascularity, and with a history of myomectomy may alert clinicians in suspicion of uLMS when compared with LG-ESS.

Clinical characteristics and prognosis analysis of uterine sarcoma: a single-institution retrospective study.

BACKGROUND: Uterine sarcomas are rare and aggressive gynaecologic malignancies, characterized by a relatively high recurrence rate and poor prognosis. The aim of this study was to investigate the clinicopathological features and explore the prognostic factors of these malignancies. METHODS: This was a single-institution, retrospective study. We reviewed the medical records of 155 patients with pathologically confirmed uterine sarcomas including uterine leiomyosarcoma (ULMS), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), undifferentiated uterine sarcoma (UUS) and adenosarcoma (AS) between 2006 and 2022. A total of 112 patients who underwent surgery between January 2006 and April 2019 were included in the survival analysis. The current study recorded the clinicopathological, treatment and outcome data to determine clinical characteristics and survival. RESULTS: The most common histopathological type was ULMS (63/155, 40.64%), followed by LG-ESS (56/155, 36.13%) and HG-ESS (16/155, 10.32%). The mean age at diagnosis of all patients was 49.27±48.50 years and 32.90% (51/155) of patients were postmenopausal. Fifteen patients underwent fast-frozen sectioning, 63(54.78%) were diagnosed with malignancy, 29(25.22%) were highly suspected of malignancy that needed further clarification and 23(14.84%) were diagnosed with benign disease. A total of 124(80%) patients underwent total hysterectomy (TH) and salpingo-oophorectomy. Multivariate analyses showed that histological type and tumour size were independent prognostic factors both for overall survival (OS) (p<0.001 and P=0.017, respectively) and progression-free survival (PFS) (p<0.001 and P=0.018, respectively). Tumour stage was only significantly associated with PFS (P=0.002). Elevated preoperative NLR, PLR and postmenopausal status were significantly correlated with shorter PFS and OS in univariate analysis, but no statistically significant difference was found in multivariate analysis. CONCLUSIONS: In patients with uterine sarcoma, in comparison to LMS and LG-ESS, UUS and HG-ESS tend to present as more aggressive tumour with poorer outcomes. Furthermore, larger tumour (>7.5 cm) were an important predictor of shorter PFS and OS.

Primary characteristics and outcomes of newly diagnosed low-grade endometrial stromal sarcoma.

OBJECTIVE: To assess potential predictive variables for nodal metastasis and survival outcomes in patients with newly diagnosed, low-grade endometrial stromal sarcoma. METHODS: We performed a single-institution, retrospective analysis of consecutive patients with newly diagnosed, low-grade endometrial stromal sarcoma who presented between January 1, 1980 and December 31, 2019 and underwent hysterectomy at our institution or presented within 3 months of primary surgery elsewhere before recurrence. Patients who presented to our institution only at recurrence were excluded. Patients with <3 months of follow-up were excluded from survival analyses. RESULTS: We identified 127 consecutive patients for analysis. Median age at diagnosis was 48 years (range 19-88 years); 91 (74.6%) of 127 were pre-menopausal; and 74 (58.3%) of 127 had uterine-confined, stage I tumors. Of 56 patients (44.1%) who underwent lymph node sampling, 10 (17.9%) had nodal metastasis. Of the 10 with nodal metastasis, 1 (10%) did not have lymphadenopathy or extra-uterine disease, 4 (40%) had lymphadenopathy only, 1 (10%) had extra-uterine disease only, and 4 (40%) had both. Among the 29 patients without apparent extra-uterine disease or gross lymphadenopathy, there was one occult lymph node metastasis (3.4%). Gross lymphadenopathy at time of surgery was predictive for lymph node metastasis (p<0.001). Median follow-up was 69 months (range 4-336) for the 95 patients included in the survival analyses. The 5-year progression-free survival and disease-specific survival rates were 79.8% and 90.8%, respectively. Patients with stage I tumors had longer progression-free survival than those with stage II-IV disease (p<0.001); there was no difference in disease-specific survival (p=0.63). Post-operative observation versus adjuvant therapy with hormone blockade or radiation therapy did not result in progression-free survival differences for stage I or completely resected stage II-IV disease (p=0.50 and p=0.81, respectively). Similarly, there was no disease-specific survival difference for completely resected stage II-IV disease (p=0.3). CONCLUSIONS: Lymph node dissection in patients with low-grade endometrial stromal sarcoma should be reserved for those with clinically suspicious lymphadenopathy. Disease stage correlated with progression-free survival but not disease-specific survival. Post-operative therapy did not improve progression-free survival or disease-specific survival.

Primary ovarian endometrioid stromal sarcoma presenting with reno-ureteral colic.

BACKGROUND: Endometrioid Stromal Sarcomas are an infrequent group of mesenchymal tumors that we must take into account in the differential diagnosis despite representing only 0.2% of tumors of the female genital tract, as they can go unnoticed until advanced stages. CASE PRESENTATION: Fifty-fourth year-old woman referred from the Urology department due to incidental finding of adnexal mass in MRI during examination after renoureteral colic, in the case of a 50 mm solid cystic mass in LE. MT were within the normal range, and the CT scan observed this mass in contact with the left ureter. The surgery was completed with hysterectomy and contralateral adnexectomy without incident and chemotherapy treatment was not added. The pathological result was ovarian tissue with low-grade endometrial sarcoma. Currently, after two years of follow-up, the patient remains stable without any recurrence of disease. CONCLUSIONS: Endometrioid stromal sarcomas are rare tumors that originate in the endometrial stroma, the ovarian location being rare. Management lies in surgical treatment, and adjuvant therapy is sometimes necessary in advanced stages.

An extremely rare disconnection of the external iliac artery and novel collateral remodeling in an endometrial stromal sarcoma woman.

BACKGROUND: Injury to the external iliac artery can have serious consequences and can be extremely challenging for surgeons. Here, we report a patient with bizarre disconnection of the external iliac artery during a laparoscopic operation. CASE PRESENTATION: On May 27, 2020, during a laparoscopic pelvic lymphadenectomy operation to treat endometrial stromal sarcoma, we encountered an unusual anatomy: abnormal disconnection of the left external iliac artery in a 26-year-old female patient. The proximal and distal ends of the left external iliac artery demonstrated old narrowing without active bleeding, and the distance between the two disconnected ends was more than 3 cm. The scenario was surprising to all the staff in the operating theater. After a comprehensive assessment of skin temperature, arterial pulsation and arterial blood flow, a multidisciplinary team determined that collateral circulation of the left lower limb had been established and could meet the blood supply of the lower limbs, which was also confirmed three times by computed tomography angiography and Doppler ultrasound of the blood vessels in the abdomen and lower limbs. Sixteen months after the operation, the patient had no obvious abnormality, and the daily activities of the left lower limb were not affected. Follow-up after treatment for the patient is still in progress. CONCLUSIONS: We describe the details of the whole case of disconnection of the external iliac artery. We hope to summarize the experience and lessons learned through this case and a relevant literature review to improve the safety and orderliness of our future clinical work.

Unusual morphologic features of low-grade endometrial stromal sarcoma: A case report.

BACKGROUND: Endometrial stromal tumours are uncommon tumours of the uterus. They mainly occur in perimenopausal women. Tumours with typical clinicopathological features do not usually pose diagnostic problems. However, rare clinicopathological features can occur, and clinicians without significant experience may have difficulty diagnosing these tumours and managing these patients. METHODS: Herein, we report a case of endometrial stromal sarcoma that occurred in a 25-year-old woman. The pathological features, immunophenotype, treatment and prognosis were discussed. RESULTS: The tumour revealed morphological heterogeneity, and there were similar proliferative-type endometrial stromal cells, an extensive amount of mature adipose tissue, and prominent rhabdomyoblastic and smooth muscle cells. Histopathological and immunohistochemical studies confirmed low-grade endometrial stromal sarcoma with smooth muscle, adipocytic and rhabdomyoblastic differentiation (approximately 60% were differentiated tissues). The final treatment of the tumour was total abdominal hysterectomy with bilateral salpingo-oophorectomy. There was no evidence of recurrence for 109 months postoperatively. CONCLUSIONS: We found that low-grade endometrial stromal tumours with extensive adipocytic and prominent rhabdomyoblastic differentiation are misdiagnosed because they are infrequent. They must be differentiated from rhabdomyosarcoma with accurate identification of adipocytes, and long-term follow-up is needed.

Low-grade endometrial stromal sarcoma with intracaval or intracardiac extension: a retrospective study of eight cases.

PURPOSE: This study aimed to improve the knowledge of low-grade endometrial stromal sarcoma (LG-ESS) with intracaval or intracardiac extension and tried to identify the potential risk factors and optimal treatment method influencing prognosis. METHODS: We performed a retrospective review of eight LG-ESS patients with intracaval or intracardiac extension who underwent treatment at Peking Union Medical College Hospital between 2012 and 2020. RESULTS: The median age at diagnosis was 44 years, ranging from 28 to 56 years. Abnormal uterine bleeding was the most common intimal symptom (3/8), followed by low back discomfort (2/8), edema of the lower limbs (2/8), abdominal pain (1/8), and dyspnea (1/8). All patients underwent resection of the intravascular and extravascular portions of the tumor. Two patients were in stage IIIC, and six were in stage IVB. After surgery, four patients received adjuvant radiotherapy, of whom three also received letrozole. One patient was treated with letrozole alone, and one patient received medroxyprogesterone. The average follow-up time was 34.5 months, ranging from 6 to 98 months. No patients died or relapsed during the follow-up period. CONCLUSIONS: LG-ESS with intracaval or intracardiac extension is an uncommon type of tumor which is easily misdiagnosed and can only be diagnosed by histological evaluation after surgery. Complete tumoral excision followed by adjuvant therapy may benefit patient survival time. Long-term follow-up is essential due to the high rate of late recurrence.

[A Case of Solitary Liver Metastasis of Low-Grade Endometrial Stromal Sarcoma 31 Years after Resection of Primary Lesion].

A 73-year-old woman was referred to our hospital after a liver tumor was discovered during an abdominal ultrasonography. Thirty-one years ago, she underwent a total hysterectomy for uterine myoma and was diagnosed with a leiomyoma. Twenty years ago, she underwent a bilateral oophorectomy for an ovarian tumor and was diagnosed with a luteinized theca cell tumor accompanied by sclerosing peritonitis. A CT scan and MRI revealed a 65-mm tumor in the S6-7 of the liver. There was no sign of any lesions other than in the liver, and TACE was performed for suspected hepatocellular carcinoma. However, a favorable treatment outcome was unable to be obtained and a posthepatic segmental resection was performed. Histopathological morphology suggested a similarity to endometrial stromal cells and, considering the history of myoma of the uterus and ovarian tumor, immunohistological staining was carried out. The myoma of the uterus and the ovarian and liver tumors were all CD10(+), α⊖SMA(-), MIB-1 index 3%. The uterine myoma, which was initially operated on, was rediagnosed as a low-grade endometrial stromal sarcoma. After 11 years, ovarian metastasis was observed, and after 31 years liver metastasis occurred. Examples of resection of liver metastasis of endometrial stromal sarcoma are extremely rare and, we will include a review of the literature in this report.

Metastatic endometrial stromal sarcoma: A rare cause of right-sided intracardiac mass.

The endometrial stromal sarcoma (EES) is a rare uterine malignancy and its intracardiac metastasis are exceedingly rare. We report a case of a 53-year-old female patient diagnosed with a metastatic tumor of a ESS in the right side of the heart, who underwent successful surgical resection and initiated chemotherapy with docetaxel and gemcitabine. At a 9-month follow-up, the patient was in New York Heart Association-Class I, without any further complications.

Effect of bilateral salpingo-oophorectomy on the overall survival of premenopausal patients with stage I low-grade endometrial stromal sarcoma; a National Cancer Database analysis.

OBJECTIVES: Investigate the prevalence of bilateral salpingo-oophorectomy (BSO) for women ≤50 years with early stage low-grade endometrial stromal sarcoma (LGESS) and its impact on overall survival (OS). METHODS: Women ≤50 years, diagnosed with stage I LGESS and managed with hysterectomy between 2004 and 2015 were identified from the National Cancer Database. Patient demographics were recorded and compared with the chi-square test. OS for patients diagnosed between 2004 and 2014 with at least one month of follow-up was assessed using Kaplan-Meier curves, and compared with the log-rank test. RESULTS: A total 743 patients with a median age of 44 years met the inclusion criteria. Use of radiatiotherapy (9%), chemotherapy (0.8%) and hormonal therapy (11%) was infrequent. BSO was performed in 541 (72.8%) patients. Patients who had ovarian preservation (OP) were younger (median age 43 vs 45 years, p < 0.001), less likely to have comorbidities (6.9% vs 12.4%, p = 0.034), or undergo LND (30.7% vs 44.4%, p = 0.001). There were no differences between the two groups in terms of substage or patient race. Five year OS rates for patients who did (n = 490) and did not (n = 191) undergo BSO were 96.2% and 97.1% and there was no difference in OS, p = 0.50. Even after controlling for presence of comorbidities performance of BSO was not associated with better survival (HR: 1.28, 95% CI: 0.51, 3.19). CONCLUSIONS: Ovarian function was preserved in approximately one third of women ≤50 years with stage I LGESS with no clear detriment to overall survival. As BSO is associated with long term health effects in this patient population OP could be considered in selected women with stage I LGESS.

Endometrial stromal sarcoma: A review of rare mesenchymal uterine neoplasm.

OBJECTIVE: This review aims to analyze the pathological aspects, diagnosis and treatment of rare mesenchymal uterine tumors. METHODS: On August 2019, a systematic review of the literature was done on Pubmed, MEDLINE, Scopus, and Google Scholar search engines. The systematic review was carried out in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes statement (PRISMA). The following words and key phrases have been searched: "endometrial stromal sarcoma", "low-grade endometrial stromal sarcoma", "high-grade endometrial stromal sarcoma", "uterine sarcoma", "mesenchymal uterine tumors" and "uterine stromal sarcoma". Across these platforms and research studies, five main aspects were analyzed: the biological characteristics of the neoplasms, the number of cases, the different therapeutic approaches used, the follow-up and the oncological outcomes. RESULTS: Of the 94 studies initially identified, 55 were chosen selecting articles focusing on endometrial stromal sarcoma. Of these fifty-five studies, 46 were retrospective in design, 7 were reviews and 2 randomized phases III trials. CONCLUSION: Endometrial stromal sarcomas are rare mesenchymal uterine neoplasms and surgery represents the standard treatment. For uterus-limited disease, the remove en bloc with an intact resection of the tumor (without the use of morcellation) is strongly recommended. For advanced-stage disease, the standard surgical treatment is adequate cytoreduction with metastatectomy. Pelvic and para-aortic lymphadenectomy is not recommended in patients with Low-grade Endometrial Stromal Sarcoma (ESS), while is not clear whether cytoreduction of advanced tumors improves patient survival in High-grade ESS. Administration of adjuvant radiotherapy or chemotherapy is not routinely used and its role is still debated.

Impact of oophorectomy and hormone suppression in low grade endometrial stromal sarcoma: A multicenter review.

OBJECTIVES: Low grade endometrial stromal sarcoma (LG-ESS) is a rare cancer with an indolent course. We aimed to assess the effectiveness of adjuvant hormonal suppression (HT) with or without oophorectomy (BSO) in prolonging progression free survival (PFS) and overall survival (OS) in patients with LG-ESS. METHODS: We performed a multi-institutional retrospective review of patients treated for low grade LG-ESS from 1985 to 2014. Demographics, treatment and recurrence data were abstracted from medical records. Pathologic diagnosis was confirmed by a gynecologic pathologist. Long-term patient-reported outcomes were obtained via mailed survey. RESULTS: One-hundred-twelve patients underwent surgery for LG-ESS; 59 had postoperative data with a median follow-up of 55months (1-325months). The mean age at diagnosis was 48.5years (22-82years). Forty-nine (61%) had stage I disease. The most common presenting symptoms were abnormal uterine bleeding (38%) and pelvic mass (17%). Seventy-one (63%) patients had BSO at the time of diagnosis. Of the 59 patients with postoperative follow-up information, 49 (73%) underwent BSO, 26 (44%) received HT, 20 (33%) were expectantly managed, and 6 (10%) received chemotherapy, radiation or both. Median PFS for the entire group was 53months and OS was 63months. PFS for those who underwent BSO compared with those who retained their ovaries was 38 vs 11months, p=0.071. PFS for HT vs no HT was 28 vs 23months, p=0.77. CONCLUSIONS: Consistent with prior series, our results support BSO to prolong PFS in LG-ESS but are limited by sample size. Larger studies with more complete follow-up are needed to determine the effect of adjuvant hormonal suppression.

Efficacy of Hyperthermic Intraperitoneal Chemotherapy and Cytoreductive Surgery in the Treatment of Recurrent Uterine Sarcoma.

OBJECTIVE: Uterine sarcomas (USs) are characterized by poor response to systemic chemotherapy and high recurrence rates. This study evaluates whether the use of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) confers survival benefit in comparison with conventional treatment modalities in patients with recurrent US. METHODS/MATERIALS: A retrospective analysis of patients with recurrent US at a single institution for an 11-year study period was performed. All women with a pathologic diagnosis of leiomyosarcoma, adenosarcoma, endometrial stromal sarcoma, or undifferentiated US were identified. Overall and disease-free survival was estimated using Kaplan-Meier method. Comparisons between the study groups were performed with the log-rank test and Cox regression. RESULTS: A total of 26 patients were identified. Five patients received chemotherapy and/or radiotherapy without surgical intervention, 14 patients underwent surgery alone or a combination of surgery and adjuvant systemic chemotherapy, and 7 patients received cytoreductive surgery with HIPEC. There was no treatment-related mortality in any group, and only 1 patient had grade III-IV surgical complications. Median disease-free survival was 2.4 months for patients with nonsurgical treatments, 5.3 months for patients treated with conventional surgery, and 11.3 months for patients treated with HIPEC. Median overall survival was 35.9 months for patients treated with conventional surgery and 43.8 months for patients treated with HIPEC. CONCLUSIONS: Our study is the first to compare survival outcomes of HIPEC versus conventional therapies for recurrent US and is suggestive of treatment benefit. Further studies with more patients and longer follow-up to evaluate the role of HIPEC in management of this disease are warranted.