{"paper_id":"a3a9d939-8edb-4304-96df-87eaf8d54a82","body_text":"Altal et al. J Med Case Reports          (2021) 15:262  \nhttps://doi.org/10.1186/s13256-021-02838-x\nCASE REPORT\nComplete remission of advanced low-grade \nendometrial stromal sarcoma after aromatase \ninhibitor therapy: a case report\nOmar F. Altal1*, Ahmed H. Al Sharie2, Omar M. Halalsheh3, Nour Tashtush4, Sarat Shaban4, \nMahmoud Alfaqih5 and Abdelwahab Aleshawi4 \nAbstract \nBackground: Low-grade endometrial stromal sarcoma is a rare neoplastic growth in the uterine cavity, representing \nless than 1% of uterine tumors. Such tumors usually affect premenopausal and perimenopausal women, with a mean \nage of 46 years. Treatment generally starts with surgical resection of the tumor, followed by chemotherapy, radio-\ntherapy, or hormonal therapy.\nCase presentation: In the current report, we again present a case of low-grade endometrial stromal sarcoma in a \n51-year-old Mediterranean woman presenting with abdominopelvic pain. Computed tomography scan revealed a \nprimary uterine tumor measuring 17 × 9 × 9 cm metastasizing to the lungs, bladder, and ureteral orifice, along with \nlymphovascular involvement. The patient underwent total abdominal hysterectomy, omentectomy, and lymph node \ndissection. Estrogen deprivation was accomplished by bilateral salpingo-oophorectomy. Lifelong hormonal therapy \nconsisting of letrozole 2.5 mg per day was prescribed, which demonstrated remarkable efficacy, resulting in a partial \nremission of lung metastasis within 8 months after surgery. Full remission was observed after 18 months of hormo-\nnal therapy, with no recurrence. Another scan was performed after 2.5 years, revealing complete remission with no \nrecurrence.\nConclusion: We again report a case of complete remission of low-grade endometrial stromal sarcoma after surgi-\ncal removal of the tumor along with first-line hormonal therapy without the use of chemotherapy or radiotherapy, \nemphasizing the role of hormonal therapy in the treatment of such tumors.\nKeywords: Endometrial stromal sarcoma, Case report, Hormonal therapy, Letrozole, Complete remission\n© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco \nmmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\nEndometrial stromal sarcoma (ESS) is a rare neoplastic \ngrowth originating from the mesenchymal elements of \nthe endometrium [1]. It usually affects women between \nthe ages of 40 and 50 [2]. ESS are characterized by their \naggressiveness, poor prognosis, and high recurrence \nrate [3]. Low-grade ESS is associated with better prog -\nnosis than high-grade ESS, with higher survival rates \n[4]. Histological features of ESS include a heavily packed \ncellular population of oval, round, or spindle-like struc -\ntures with small thick-walled blood vessels [5]. Several \nimmunohistochemical markers have been identified for \nthe diagnosis of ESS including vimentin, smooth muscle \nactin (SMA), desmin, S-100, ionized calcium-binding \nadaptor molecule 1 (IBA1), and CD10 [6]. The detection \nof YWHAE-FAM22 translocation by molecular studies \naugmented with immunohistochemistry can differentiate \nbetween high- and low-grade ESS, and has replaced the \nOpen Access\n*Correspondence:  altal_omar@yahoo.com\n1 Department of Obstetrics & Gynecology, Faculty of Medicine, Jordan \nUniversity of Science and Technology, King Abdullah University Hospital, \nP . O. Box: 3030, Irbid 22110, Jordan\nFull list of author information is available at the end of the article\n\nPage 2 of 6Altal et al. J Med Case Reports          (2021) 15:262 \nuse of mitotic indices as a differentiation parameter [7]. \nThe prognostic factors of ESS are still controversial, and \nmainly depend on the stage at the time of presentation \nas assessed by the International Federation of Gynecol -\nogy and Obstetrics (FIGO) staging of ESS [8]. Treatment \ntypically starts with surgical removal of the tumor, and \nadjuvant methods including chemotherapy, radiotherapy, \nand hormonal therapy can be utilized [8]. In the current \nreport, we describe the complete remission of metasta -\nsized low-grade ESS after surgical removal of the neo -\nplasm followed by hormonal therapy. To the best of our \nknowledge, few cases have been reported of complete \nremission of advanced metastasized low-grade ESS after \nsurgical and hormonal therapy alone, without the need \nfor chemotherapy or radiotherapy. This case report was \nwritten in accordance with the CARE guidelines for case \nreports [9].\nCase presentation\nA 51-year-old married Mediterranean woman with a \nnonsignificant past medical history presented to our \ncenter through the outpatient clinic, complaining of \nmenorrhagia and abdominal pain for the past 2  weeks. \nThe pain was radiating to the back and  was associated \nwith loss of appetite and stress incontinence. The patient \nreported no episodes of dysmenorrhea. She had no \nremarkable surgical history prior to her current symp -\ntoms and no family history of malignancies. The physical \nexamination revealed no significant findings. Ultrasonog-\nraphy revealed multiple uterine masses and polyps along \nwith an enlarged uterus and thin endometrial lining.\nBasic laboratory investigations were performed and \nall were within the normal range except for complete \nblood count, which indicated microcytic hypochromic \nanemia. She was suspected of having uterine fibroids. \nAccordingly, hysteroscopy along with dilation and curet -\ntage (D&C) was performed. Operative findings included \na 22-week-sized uterus that was deviated to the left side. \nIn addition, cystocele and rectocele were noted, both \nassessed as grade II. Hysteroscopy findings included \nmultiple uterine fibroids and polyps. Endometrial biopsy \nrevealed infarcted endometrial polyps. Plasma tumor \nmarkers were evaluated to rule out any possible malig -\nnancies. Results indicated high levels of lactate dehydro -\ngenase (LDH: 441 U/L), alpha-fetoprotein (AFP: 1.9 ng/\nmL), and CA-125 (106.8 U/mL), along with normal val -\nues for beta-human chorionic gonadotropin (β-hCG), \ncancer antigen (CA) 15-3, CA 19-9, and carcinoembry -\nonic antigen (CEA). Abdominal and pelvic computed \ntomography (CT) scan showed an irregular hypodense \nlesion in the uterus containing an area of necrosis meas -\nuring 17 × 9 × 9 cm, suggesting a primary uterine tumor \n(Fig. 1a–c). CT scan also revealed wall thickening in the \nright posterolateral aspect of the urinary bladder, with \nfilling defect and wall irregularity causing severe hydro -\nnephrosis on the right side (Fig.  1b). Enlarged lymph \nnodes were seen in both the external and internal iliac \nregions, the largest measuring 1.3 cm.\nUltrasonography-guided biopsy under aseptic condi -\ntions with the application of local anesthetic was used \nto take six true-cut biopsies for the same mass seen on \nthe CT scan. Histopathological examination showed a \nhypercellular spindle cell lesion, with some of the cells \nhaving nuclei resembling those of smooth muscle origin \n(Fig. 2a–c). Mild cellular pleomorphism along with non -\nsignificant count of mitotic figures was observed. Thick-\nwalled spindly blood vessels were seen in the background. \nImmunohistochemical studies revealed that the spindle \ncell population was positive for CD10, SMA, and estro -\ngen receptor (ER) but negative for CD34, CD117, epithe -\nlial membrane antigen (EMA), and desmin, as shown in \nFig. 2d–f. A diagnosis  of low-grade ESS was established.\nSubsequently, right double-J (DJ) stent insertion was \nperformed. The operative findings included a mass \naround the right ureteral orifice with multiple varicosi -\nties and neovascularization around and in the bladder, \nFig. 1 Transverse (a), sagittal (b), and coronal (c) computed tomography scans showing a primary uterine mass as pointed by the white arrow\n\nPage 3 of 6\nAltal et al. J Med Case Reports          (2021) 15:262 \n \nrespectively. Microscopic examination of bladder biopsy \nshowed fragments of urothelial mucosa infiltrated by \nnodules of small monotonous round cell tumor. The \ntumor cells were immunoreactive against CD10 and ER \nbut negative for keratin 20 (CK20), CD34, cyclin D1, \nand SMA. The results were consistent with the diagno -\nsis of ESS. Chest CT scan showed a left lower lobe nod -\nule peripherally mostly representing a malignant deposit \n(Fig.  3a). Pulmonary embolism (PE) in the secondary \nand tertiary branches of the right pulmonary artery was \nobserved incidentally, with elevated D-dimer (4.1  μg/\nmL) and fibrinogen (598 mg/dL). In addition, CT angio -\ngram confirmed the diagnosis of acute PE. The patient \nstarted therapeutic doses of enoxaparin (100  mg, every \n12 hours), after which she underwent staging laparotomy. \nOperative findings included uterus (22  weeks in size) \nwith tumor invading the right fallopian tube and adher -\nent to the right pelvic side wall and the right side of the \nbladder wall. Total abdominal hysterectomy (TAH) and \nbilateral salpingo-oophorectomy (BSO), omentectomy, \nand lymph node dissection were performed. Biopsies \nwere taken from the uterus, both ovaries, both fallopian \ntubes, omentum, and right external iliac lymph node, \nwhich all confirmed the diagnosis of low-grade ESS with \nlymphovascular invasion.\nHormonal therapy with letrozole 2.5 mg daily was ini -\ntiated. The patient was then discharged with a 10-day \nFig. 2 Histopathological investigations of six true-cut biopsies for the same mass seen on computed tomography scan. Hematoxylin and eosin \n(H&E) stains for different samples (a–c) illustrating hypercellular spindle cell lesions, with the nuclei of some cells resembling those of smooth \nmuscle origin, with mild cellular pleomorphism and nonsignificant count of mitotic figures. The cellular population was positive for CD10 (d), \nsmooth muscle actin (e), and estrogen receptor (f)\nFig. 3 Transverse computed tomography image showing lung \nmetastasis as pointed by the black arrow (a). Partial remission of the \nmetastasized tumor was achieved after 8 months of letrozole 2.5 mg \nper day (b). Complete remission was observed after 18 months (c) \nand 2.5 years (d) with the same therapeutic regimen\n\nPage 4 of 6Altal et al. J Med Case Reports          (2021) 15:262 \ncourse of clindamycin and lifelong enoxaparin treatment. \nShe was followed up in the outpatient clinic with right \nDJ stent exchange every 3  months. Partial remission of \nlung metastasis was achieved after 8  months of hormo -\nnal therapy, which was confirmed by a clean CT image \n(Fig.  3b). After 18 months, another chest CT was con -\nducted and revealed complete resolution of the metasta -\nsis (Fig. 3c). Another chest and abdominopelvic CT scan \nwere performed after 2.5 years form the surgery, which \nalso confirmed the full remission of ESS as shown in \nFig. 3d for the lung metastasis and Fig.  4a, b for the pri -\nmary lesion.\nDiscussion\nESS is an extremely rare uterine malignancy, constituting \n0.2% of all genital tract neoplasms, with an incidence of 2 \nper million women worldwide [10]. Such uterine tumors \nare aggressive in nature and associated with poor prog -\nnosis and high rates of recurrence, and can affect women \nof both reproductive and postmenopausal age [3]. \nAccording to the World Health Organization (WHO), \nESS is categorized into low- and high-grade ESS along \nwith nodular and undifferentiated forms of the neo -\nplasm; the classification is based on the morphology and \nthe prognosis of the tumor as well as cellular cytogenetic \nproperties [7].\nClinical presentation of ESS varies according to the \naffected area, but patients commonly complain of \nabdominal pain, vaginal bleeding, vomiting, diarrhea, \nconstipation, hematuria, and increased urinary frequency \nand urgency with incontinence [11]. The pathogenesis \nof ESS includes gene rearrangement, loss of tumor sup -\npressor genes, microsatellite instability, and loss of het -\nerozygosity [12]. Some reports suggest that prolonged \nexposure to endogenous or exogenous estrogens along \nwith tamoxifen treatment can play an important role in \nthe development of the tumor [13, 14].\nTreatment for ESS starts with surgical removal of the \nneoplasm and the associated invaded tissues [8]. Since \nthe histopathological profile suggests a nonsignificant \ncount of mitotic figures, the neoplasm will respond \npoorly to chemotherapeutic agents [15]. However, \nresponsiveness to chemotherapy was described previ -\nously in a reported case suggesting total remission of \nESS following a combination of chemotherapeutic agents \n[16]. On the other hand, some studies suggest a beneficial \noutcome for radiotherapy against high-grade ESS, while \nothers report a nonsignificant effect against low- or high-\ngrade forms of ESS [15, 17]. ESS can express estrogen \nreceptor (ER) and progesterone receptors (PR), which \ncan be effectively used as a target to suppress the growth \nof the neoplasm [18]. The suggested protocol is treatment \nwith aromatase inhibitors with or without gonadotropin-\nreleasing hormone (GnRH) if the cellular population is \nER-positive; if the tumor is positive for both ER and PR, \nprogestins can be used [19]. GnRH is used without any \ncombination if the tumor is positive only for PR [19]. \nEstrogen deprivation after BSO can be very useful, espe -\ncially for metastasized ESS [20]. Hormonal therapy has \nproved to be an effective tool against ESS, with improved \nlong-term survival [21, 22]. Several chemotherapeutic \nregimens have been introduced for the treatment of ESS \nincluding carboplatin or gemcitabine plus docetaxel [23, \n24]. In addition, pazopanib, a selective multi-targeted \nreceptor tyrosine kinase inhibitor, has been shown to be \nan efficient agent for ESS [25–27].\nOur patient complained of abdominal pain and menor -\nrhagia, which are typical presentations for ESS, and since \nshe was in her early 50s, she was prone to such neoplas -\ntic growth [2]. What is unique about our case is that the \npatient experienced a full neoplastic remission after a \ncombination of surgical removal of the tumor and hor -\nmonal therapy including estrogen deprivation by BSO and \na course of letrozole as previously described. Despite ESS \naggressiveness and the extensive metastatic spread across \nthe bladder, ureteral orifice, and lung with lymphovascular \ninvolvement, full remission was observed 18 weeks after \nsurgery, which was confirmed by a clear CT scan. Several \ncases reports have demonstrated the importance of hor -\nmonal therapy in the management of ESS. Alkasi et al. \nreported long-term survival of a 28-year-old patient with \nmetastatic ESS treated with goserelin and anastrozole after \nsurgical intervention [28]. A similar report by Spano et al. \ndescribed total response in two women with ESS and lung \nmetastasis after surgical removal of the tumor followed by \ntreatment with aminoglutethimide, an aromatase inhibi -\ntor [21]. Leunen et al. described outstanding response to \nletrozole in a 76-year-old patient with a huge pelvic mass \naccompanied by post-renal kidney failure [29]. Hormonal \ntherapy has also proved effective in the case of neoplastic \nFig. 4 Transverse (a) and coronal (b) computed tomography images \nshowing full neoplastic remission after 18 months of letrozole 2.5 mg \nper day without any evidence of a primary uterine tumor marked by \nthe dashed circle\n\nPage 5 of 6\nAltal et al. J Med Case Reports          (2021) 15:262 \n \nrecurrence, where Shoji et al. reported that anastrozole \nimproved prognosis in a case of recurrent low-grade ESS \nin a 34-year-old woman [30]. Hormonal therapy has also \nbeen used to shrink the tumor before surgical resection, \nas reported in the case of a 47-year-old woman with low-\ngrade ESS [31]. Despite complete remission of ESS, such \ntumors carry a high risk of recurrence even after two dec-\nades of treatment, as reported by Gangireddy et al., which \nhighlights the importance of regular follow-ups [32].\nWe report yet another case of complete neoplastic \nremission of low-grade ESS with extensive metastasis to \nthe lungs, bladder, and ureter along with lymphovascular \ninvolvement after surgical and hormonal therapy, in hopes \nof expanding the knowledge about such rare neoplasms.\nConclusion\nIn the current case, we reported a 51-year-old woman diag-\nnosed with low-grade ESS, where the neoplasm had started \nas a primary uterine tumor measuring 17 × 9 × 9 cm and \nhad metastasized to the bladder, ureteral orifice, and exter-\nnal and internal iliac lymph nodes. Malignant depositions \nwere also observed in the lung. The patient achieve total \nremission of the neoplasm, which suggests an excellent \nsynergistic effect between surgical intervention and hor -\nmonal therapy that includes letrozole 2.5 mg per day. Fur-\nther studies and trials  are needed to establish a protocol \nfor treatment of such tumors.\nAbbreviations\nESS: Endometrial stromal sarcoma; SMA: Smooth muscle actin; IBA1: Ionized \ncalcium-binding adaptor molecule 1; FIGO: International Federation of Gyne-\ncology and Obstetrics; D&C: Dilation and curettage; LDH: Lactate dehydro-\ngenase; AFP: Alpha-fetoprotein; β-hCG: Beta-human chorionic gonadotropin; \nCEA: Carcinoembryonic antigen; CT: Computed tomography; ER: Estrogen \nreceptor; PR: Progesterone receptor; DJ: Double-J; PE: Pulmonary embolism; \nTAH: Total abdominal hysterectomy; BSO: Bilateral salpingo-oophorectomy.\nAcknowledgements\nThe authors wish to thank Khawla Mhedat for her valuable help in obtaining \nthe histopathological images. In addition, the authors wish to thank Yazan O. \nAl Zu’bi for his help during the preparation of this manuscript.\nAuthors’ contributions\nOFA, OMH, and AA were responsible for the treatment and care of the patient \nincluding diagnostics. AHA, NT, SS, and MA wrote the manuscript. All authors \nrevised the final version of the report. All authors read and approved the final \nmanuscript.\nFunding\nNo funding.\nAvailability of data and materials\nNot applicable.\nDeclarations\nEthics approval and consent to participate\nEthical approval for case reports is waived by the institutional review board \n(IRB) in the King Abdullah University Hospital (KAUH). Consent to participate is \nnot applicable.\nConsent for publication\nWritten informed consent was obtained from the patient for publication of \nthis case report and any accompanying images. A copy of the written consent \nis available for review by the Editor-in-Chief of this journal.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthor details\n1 Department of Obstetrics & Gynecology, Faculty of Medicine, Jordan Univer-\nsity of Science and Technology, King Abdullah University Hospital, P . O. Box: \n3030, Irbid 22110, Jordan. 2 Faculty of Medicine, Jordan University of Science & \nTechnology, Irbid 22110, Jordan. 3 Department of General Surgery and Urology, \nFaculty of Medicine, Jordan University of Science & Technology, Irbid 22110, \nJordan. 4 Intern, King Abdullah University Hospital, Jordan University of Sci-\nence & Technology, Irbid 22110, Jordan. 5 Department of Physiology, Faculty \nof Medicine, Jordan University of Science & Technology, Irbid, Jordan. \nReceived: 20 March 2020   Accepted: 29 March 2021\nReferences\n 1. Dahhan T, Fons G, Buist MR, ten Kate FJW, van der Velden J. 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