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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 583-585

Endometrial stromal sarcoma: A rare tumor with therapeutic conundrums

1 Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi, India
2 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi, India

Date of Submission30-Jun-2020
Date of Decision06-Jul-2020
Date of Acceptance07-Jul-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Dinesh Chandra Doval
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_228_20

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How to cite this article:
Pasricha S, Doval DC. Endometrial stromal sarcoma: A rare tumor with therapeutic conundrums. Cancer Res Stat Treat 2020;3:583-5

How to cite this URL:
Pasricha S, Doval DC. Endometrial stromal sarcoma: A rare tumor with therapeutic conundrums. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 21];3:583-5. Available from: https://www.crstonline.com/text.asp?2020/3/3/583/295556

Endometrial stromal sarcomas (ESSs) are rare mesenchymal malignant tumors comprising less than 1% of all uterine malignancies. After leiomyosarcoma, they are the second most common tumors of mesenchymal origin. Conventionally, they have been classified as low-grade (LG) ESS and high-grade (HG) ESS tumors. However, as per the recent World Health Organization (WHO) classification of the tumors of the female reproductive organs, ESSs have been categorized as LG-ESS, HG-ESS, and undifferentiated stromal sarcomas (USSs), based on the extent of differentiation and the underlying genetic profile.[1],[2],[3],[4]

The most common presenting symptoms include pelvic pain and abnormal uterine bleeding. These tumors are often underdiagnosed or misdiagnosed preoperatively because of the lack of characteristic imaging features. Even endometrial curettings are not helpful in establishing the diagnosis as LG-ESS resembles the native endometrial stroma. The knowledge about the etiology, pathogenesis, natural course, predictive and prognostic factors, and precise optimal therapeutic strategies is still very limited.[2],[3],[5],[6]

The LG-ESSs are indolent tumors, often seen in the fifth decade of life. On histomorphological examination, they exhibit LG atypia with a low mitotic count without necrosis. These tumors show strong immunopositivity for the estrogen receptor (ER) and CD10 on immunohistochemistry (IHC). At the time of diagnosis, a vast majority (65%) of the cases have an International Federation of Gynecology and Obstetrics (FIGO) Stage I/II disease. The most important factor for prognosis is the disease stage; the 5-year overall survival (OS) rate is more than 90% in Stage I, while it decreases to 50% for Stage III/IV. Hysterectomy along with bilateral salpingo-oophorectomy (BSO) is the mainstay of treatment for LG-ESS. Recurrence may occur even after 10–20 years, thus necessitating long-term follow-up in these patients. The most common sites for recurrence are the pelvis and abdomen.[1],[7],[8],[9]

HG-ESS and USS are aggressive tumors, with more than 50% of the patients having advanced-stage disease. On microscopy, these tumors show HG atypia with a high mitotic count and are often associated with necrosis. These are also strongly positive for cyclin D1 and c-kit and negative for ER and CD10 on IHC. In addition, they are associated with early and more frequent recurrences and higher mortality.[1],[3],[7]

The study published by Rattan et al.[10] describes an institutional experience of the management of 23 patients with ESS over a period of 4.5 years. Of these, 65% (15) and 35% (8) of the patients had LG-ESS and HG-ESS, respectively. Of the patients with LG-ESS, 72% were postmenopausal and 53% presented with early-stage disease (Stage I/II). Among those with HG-ESS, 75% presented with advanced-stage disease (Stage II–IV), and there was no predilection of age with the menopausal status. Of all the patients, 65% (15) were referred cases and had received some form of treatment before presenting to the referral tertiary care center. All the patients underwent a total abdominal hysterectomy with BSO (TAH-BSO). Considering the lack of precise guidelines, the decision for adjuvant therapy was based on factors such as tumor grade, initial incomplete surgery, residual disease, lymph node positivity, and the presence of metastasis. As per convention, the adjuvant and aggressive treatments were used in the presence of extrauterine spread and HG tumors, respectively. Adjuvant therapy was given to 14 out of 23 patients (61%). Chemotherapy was given to seven patients of whom six had HG-ESS, while hormone therapy was given to nine patients of whom eight had LG-ESS. Adjuvant radiation was given to an almost equal number of patients with LG-ESS and HG-ESS. Extended surgery in the form of omentectomy or lymph node dissection was done in a majority of patients with HG-ESS, while it was performed in only 20% of those with LG-ESS. The median progression-free survival (PFS) was 8.5 months. The median OS for those with LG-ESS was not reached, while it was 25 months for those with HG-ESS. The difference in the OS was not significant between the two groups.

The study highlights the incidence, clinicopathological features, and experience in the management of this rare malignancy comprising a heterogeneous group of patients. The disease-related mortality in all the cases was attributed to the omental and visceral metastases, regardless of the grade of the tumor. The greatest therapeutic challenge that the authors faced was management of the referred patients who had already been treated in an non-oncology institute. This was largely due to the fertility issues of the premenopausal patients, therapeutic choice, and the lack of an experienced site-specific oncology team. However, this study has its limitations that need to be addressed. This was a single-institutional retrospective study with a small sample size, which dilutes the statistical significance of the prognostic and predictive parameters. Moreover, a significant proportion of the cases were already treated before being referred to the tertiary care center, and hence, the study was predisposed to a selection bias.

Horng et al.[8] performed a systematic review of uterine ESS. For LG-ESS, the most important prognostic factor is the disease stage, and the preferred treatment modality is TAH-BSO, which could play an important role in causing cessation of the hormone production. In the studies reviewed, although lymphadenectomy provided prognostic information, it did not provide any survival benefit to the patients with LG-ESS. With regard to the management of residual or recurrent disease with postoperative adjuvant therapy, aromatase inhibitors were the therapeutic choice.[2],[8],[11] HG-ESS typically presented at an advanced stage (FIGO II–IV) and had a considerably shorter PFS and OS. Moreover, they were frequently associated with early recurrences. In case of extensive disease, apart from TAH-BSO, whenever feasible, an extended debulking surgery with extensive lymphadenectomy was recommended. In view of the increased recurrence and visceral metastasis associated with the extensive disease in HG-ESS, cytotoxic chemotherapy in the form of doxorubicin, ifosfamide, and cisplatin along with radiation therapy has been recommended and found to increase the 3-year survival rate.

Zhang et al.[3] retrospectively evaluated 40 patients with HG-ESS with median PFS and OS of 9 and 24 months, respectively, and reported that 72.5% and 47.5% of the patients relapsed and died, respectively. The chemotherapeutic regimen comprised combinations of cisplatin, epirubicin, and ifosfamide; cisplatin and epirubicin; ifosfamide and paclitaxel; and cisplatin and paclitaxel. The authors concluded that patients with early-stage disease could benefit from a multimodality treatment using a combination of surgery, radiotherapy, and chemotherapy.

Seagle etal.[7] evaluated the prodigious data (National Cancer Database Study) from 2414 patients with LG-ESS and 1383 patients with HG-ESS. The 5-year survival of patients with HG-ESS was significantly inferior to that of LG-ESS (32.6% vs. 90.5%, P < 0.001). The median survival for patients with HG-ESS was only 19.9 months. For those with LG-ESS, advanced age and increased tumor size were associated with decreased survival. Similarly, for those with HG-ESS, nodal or distant metastasis, exclusion of lymphadenectomy, and pathologically positive surgical margins were associated with a poor prognosis (P < 0.001, for all parameters). The use of adjuvant chemotherapy (P < 0.001) and radiotherapy (P < 0.001) were associated with an increased survival in patients with HG-ESS.

The genetic profile of ESS has been described in the latest WHO classification of ESS. Most cases of LG-ESS harbor translocations such as t(7;17)(p21;q15) with fusion such as JAZFI–SUZ12 and JAZF1–PHF1. HG-ESS typically harbors the genomic rearrangement t(10;17) that leads to a fusion of YWHAE and FAM22 genes. These tumors are associated with an aggressive clinical course and frequent recurrences. Their overall outcome appears to be between that of LG-ESS and USS. More recently, a subset of HG-ESS has been identified harboring the ZC3H7B-BCOR gene fusion resulting from t(X; 22)(p11;q13) and is found to be associated with early recurrence and mortality.[1],[12],[13]

In conclusion, ESSs, although rare, are still the second most common malignant mesenchymal tumor of the uterine corpus associated with significant morbidity and mortality. However, standard guidelines regarding the selection and extent of adjuvant treatment, including the selection of a chemotherapy regimen, have not yet been established. Hence, further multicenter trials involving a larger cohort of patients along with research focused on the molecular pathogenesis will help in formulating the standard guidelines along with improving the management of this malignancy.

  References Top

Oliva E, Carcangiu ML, Carinelli SG, Ip P, Loening T, Longacre TA, et al. Mesenchymal tumors, endometrial stromal and related tumors. In: Kurman RJ, Carcangiu ML, Herrington CS, Young RH, editors. WHO Classification of Tumors of Female Reproductive Organs. 4th ed. Lyon (France): International Agency for Research on Cancer; 2014. p. 141-5.  Back to cited text no. 1
Puliyath G, Nair MK. Endometrial stromal sarcoma: A review of the literature. Indian J Med Paediatr Oncol 2012;33:1-6.  Back to cited text no. 2
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Zhang YY, Li Y, Qin M, Cai Y, Jin Y, Pan LY. High-grade endometrial stromal sarcoma: A retrospective study of factors influencing prognosis. Cancer Manag Res 2019;11:831-7.  Back to cited text no. 3
Desar IM, Ottevanger PB, Benson C, van der Graaf WT. Systemic treatment in adult uterine sarcomas. Crit Rev Oncol Hematol 2018;122:10-20.  Back to cited text no. 4
Puliyath G, Nair MK. Endometrial stromal sarcoma: A review of the literature. Indian J Med Paediatr Oncol 2012;33:1-6.  Back to cited text no. 5
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Thiel FC, Halmen S. Low-grade endometrial stromal sarcoma-A review. Oncol Res Treat 2018;41:687-92.  Back to cited text no. 6
Seagle BL, Shilpi A, Buchanan S, Goodman C, Shahabi S. Low-grade and high-grade endometrial stromal sarcoma: A National Cancer Database study. Gynecol Oncol 2017;146:254-62.  Back to cited text no. 7
Horng HC, Wen KC, Wang PH, Chen YJ, Yen MS, Ng HT, et al. Uterine sarcoma Part II-Uterine endometrial stromal sarcoma: The TAG systematic review. Taiwan J Obstet Gynecol 2016;55:472-9.  Back to cited text no. 8
Mbatani N, Olawaiye AB, Prat J. Uterine sarcomas. Int J Gynaecol Obstet 2018;143 Suppl 2:51-8.  Back to cited text no. 9
Rattan R, Thakur P, Gupta A, Miriyala R, Ballari N, Rai B. Endometrial stromal sarcoma: A Retrospective analysis of tertiary care experience from India. Cancer Res Stat Treat 2020:3;489-94.  Back to cited text no. 10
Ryu H, Choi YS, Song IC, Yun HJ, Jo DY, Kim S, et al. Long-term treatment of residual or recurrent low-grade endometrial stromal sarcoma with aromatase inhibitors: A report of two cases and a review of the literature. Oncol Lett 2015;10:3310-4.  Back to cited text no. 11
Lewis N, Soslow RA, Delair DF, Park KJ, Murali R, Hollmann TJ, et al. ZC3H7B-BCOR high-grade endometrial stromal sarcomas: A report of 17 cases of a newly defined entity. Mod Pathol 2018;31:674-84.  Back to cited text no. 12
Lee CH, Mariño-Enriquez A, Ou W, Zhu M, Ali RH, Chiang S, et al. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: A histologically high-grade and clinically aggressive tumor. Am J Surg Pathol 2012;36:641-53.  Back to cited text no. 13


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