{"paper_id":"8fa5f452-8ffe-4a65-b137-630e86ee844a","body_text":"www.kjco.org  73\nINTRODUCTION\nLow-grade endometrial stromal sarcoma (ESS) is typically a uter-\nine mesenchymal neoplasm but it may also occur in extrauterine \nsites. Extrauterine ESS (EESS) is rare and the exact incidence is un-\nknown. The majority of these cases are associated with endometri-\nosis and have a relatively higher tendency to disseminate than \nuterine ESS. The commonest extrauterine site of origin is the gas-\ntrointestinal tract, but cases from the pelvis, sciatic nerve, vulva and \nretroperitoneum have also been reported [1]. ESS arising in the va-\ngina is a rare entity. The diagnosis may be difficult owing to associ-\nated endometriosis that presents with similar clinical features. W e \nreport a case of low-grade EESS arising in vaginal endometriosis. \nThis case merits mention because of the difficulty in diagnosis due \nto overlapping clinical features and response to medical therapy, \ntimely management, and good survival outcomes. An informed \nwritten consent was obtained from the patient for the publication \nof this report.\nCASE REPORT\nA 38-year-old P2L2 patient presented with complaints of dyspa-\nreunia, dysmenorrhea, and painful defecation for a year, along \nwith blood-mixed vaginal discharge for 3 months. Her systemic \nexamination was normal. On per speculum examination, the cer-\nvix was normal but multiple brownish irregular nodules were seen \nin posterior vaginal fornix. On bimanual examination, fixed ten-\nder nodules were felt in the posterior fornix with irregularity in the \noverlying vaginal mucosa. The uterus was retroverted, nor -\nmal-sized with restricted mobility. Examination during menstrua-\ntion noted the presence of blood-mixed mucoid discharge from \nthe nodules in the posterior fornix (Fig. 1A). With clinical suspi-\ncion of vaginal endometriosis, imaging and biopsy were per -\nCase\nReport\nKorean Journal of Clinical Oncology 2023;19:73-79\nhttps://doi.org/10.14216/kjco.23013\npISSN 1738-8082 ∙ eISSN 2288-4084\nLow-grade extrauterine endometrial stromal \nsarcoma arising from vaginal endometriosis: a case \nreport and literature review\nSeema Singhal1, Aarthi S Jayraj1,2, Ekta Dhamija3, Sachin Khurana4\n1Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India  \n2Department of Gynecologic Oncology, James Cook University Hospital, South Tees NHS Foundation Trust, Middlesbrough, UK \n3Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India \n4Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India\nExtrauterine endometrial stromal sarcoma arising from malignant transformation of the vagina is an extremely rare condition. The diagnosis is \noften difficult as the symptomatology and pathological features overlap with that of pelvic endometriosis. A 38 years old female presented with \ncomplaints of dyspareunia, dysmenorrhea, and painful defecation along with blood-stained vaginal discharge for a year. Examination revealed the \npresence of multiple brownish irregular nodules in posterior vaginal fornix and fixed tender nodules which on biopsy revealed florid vaginal \nendometriosis. She improved symptomatically on medical therapy. After 18 months of diagnosis, she presented again with a necrotic growth in \nposterior fornix, which on repeat biopsy revealed a low-grade endometrial stromal sarcoma. Laparotomy revealed a 7×5 cm mass in the pouch of \nDouglas, infiltrating the posterior vaginal wall and rectum. A complete cytoreductive surgery with retrograde hysterectomy, excision of posterior \nvaginal wall and rectosigmoid resection was done. The patient is disease-free at a follow-up of 65 months.\nKeywords: Endometrial stromal sarcoma, Endometriosis, Dyspareunia, Dysmenorrhea, Case reports\nReceived: Jul 17, 2023 Revised: Dec 4, 2023 Accepted: Dec 5, 2023\nCorrespondence to: Aarthi S Jayraj\nDepartment of Gynecologic Oncology, James Cook University Hospital, \nSouth Tees NHS Foundation Trust, Middlesbrough, UK \nTel: +44-1642-54858\nE-mail: aarthisjayraj91@gmail.com\nCopyright © 2023 Korean Society of Surgical Oncology\nThis is an Open Access article distributed under the terms of the Creative Commons Attri-\nbution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which \npermits unrestricted non-commercial use, distribution, and reproduction in any medium, \nprovided the original work is properly cited.\n\n\n74  Korean Journal of Clinical Oncology\nformed. Computed tomography pelvis showed normal uterus and \nadnexa with nodularity and thickening of posterior vaginal fornix \nwith ill-defined planes posteriorly with rectum (Fig. 1B). Biopsy of \nthe irregular nodular areas in posterior fornix showed proliferative \nendometrial glands and cellular stroma suggestive of extrauterine \nendometriosis (Fig. 1C). \nThe patient opted for medical therapy and was started on le -\nuprolide acetate 3.75 mg intramuscular injection monthly for 3 \nmonths. There was a significant improvement in her symptoms \nwith disappearance of the vaginal forniceal lesions. Thereafter, the \npatient was started on depot intramuscular injection of medroxy-\nprogesterone acetate 150 mg every 3 monthly for 12 months. Eigh-\nteen months after diagnosis, she presented again with blood-mixed \nvaginal discharge for 3 months with dyspareunia and dyschezia. \nOn per speculum examination, there was an irregular exophytic \nnecrotic growth in posterior vaginal fornix. The cervix appeared \nA B C\nFig. 1. (A) Image showing raised irregular areas in posterior fornix on speculum examination. (B) Computed tomography pelvis axial image \nshowing ill-defined planes of posterior wall of vagina with the rectosigmoid. (C) Biopsy from posterior fornix shows presence of endometrial \nglands and stroma suggestive of endometriosis (hematoxylin and eosin stain, ×100).\nFig. 2. (A) T2 weighted magnetic resonance imaging image of pelvis showing heterogeneously enhancing mass of 7×6 cm at posterior vagi-\nnal wall with exophytic component and necrosis with diffusion restriction and loss of fat planes with the rectosigmoid colon. (B) En bloc \nspecimen of excised tumor along with uterus, ovaries, rectum, vagina and rectosigmoid colon up to perineum.\nA B\n\nSeema Singhal et al. • ESS from vaginal endometriosis\nwww.kjco.org  75\ntubes and ovary were normal with no evidence of endometriosis. \nThe tumor cells were immunopositive for CD10, ER, PR and focal-\nly for cyclin D1 and desmin, while negative for SMA, consistent \nwith a diagnosis of ESS (Fig. 3). There were foci of endometriosis \nfound embedded within the periphery of the tumor. The patient re-\ncovered uneventfully and was discharged on third postoperative \nday. The patient was diagnosed with stage IIIA low grade, EESS of \nthe vagina and was started on the aromatase inhibitor anastrozole 1 \nmg daily. The patient was followed up in a combined oncology clin-\nic every month for the first 3 months; 3 monthly till 2nd year and 6 \nmonthly till the 5th year. At every visit, a careful evaluation of symp-\ntoms was done, thorough clinical examination was performed and \nimaging was advised accordingly. She also underwent dual-energy \nX-ray absorptiometry scan every 1–2 yearly to monitor bone min-\neral density. She was on calcium and vitamin D supplementation \nand was provided advice on a healthy lifestyle and importance of \nregular physical exercise. At 65 months follow-up, the patient is dis-\nease-free. W e plan to continue anastrozole therapy till disease pro-\ngression or development of significant toxicity in terms of osteope-\nnia/osteoporosis.\nnormal. On bimanual examination, a hard fixed mass was felt pos-\nteriorly in the rectovaginal septum. The uterus was normal in size \nwith restricted mobility. On rectal examination, the mucosa was \nfree with external compression by the mass. A repeat biopsy from \nnecrotic growth in the posterior fornix was suggestive of low-grade \nESS. Magnetic resonance imaging showed a T1 isointense and T2 \nheterogeneously enhancing hyperintense mass of 7× 6 cm in the \nrectovaginal septum with an exophytic component and necrosis \nwith diffusion restriction (Fig. 2A). \nThe patient was taken up for laparotomy. Intraoperatively, the \npouch of Douglas was obliterated by a fixed mass of 7× 5 cm arising \nfrom the posterior vaginal wall and rectovaginal septum filling the \npouch of Douglas, encasing the left ureter and invading the recto-\nsigmoid. Inferiorly, the tumor was extending almost up to 4–5 cm \nfrom the anal sphincter. A retrograde hysterectomy with excision of \nposterior vaginal wall, abdominoperineal resection of rectosigmoid \ncolon and a permanent end colostomy was performed (Fig. 2B). \nGross histopathological examination of the specimen showed a 7.5\n× 5.5× 3 cm grey-white tumor involving the rectovaginal septum, \ninfiltrating the serosal aspect of rectosigmoid, posterior myometri-\num up to endometrium isthmus and part of cervix. The cut end of \nvaginal cuff, colonic and rectal margins were free of tumor. Bilateral \nA\nC D E\nB\nFig. 3. (A) Sections from the uterine tumor show proliferation of endometrial stromal cells in a sheet-like pattern with formation of whorls \naround arterioles suggestive of low-grade endometrial stromal sarcoma (hematoxylin and eosin staining, ×100). (B) The tumor cells are oval \nto spindle-shaped and show mild nuclear atypia and fine nuclear chromatin (hematoxylin and eosin stain, ×200). The tumor cells are immu-\nnopositivity for CD10 (C), ER (D), and PR (E). (C-E) Immunohistochemical staining, ×200.\n\n76  Korean Journal of Clinical Oncology\nTable 1. Review of cases reporting endometrial stromal sarcoma in vagina\nAuthor Age \n(yr)\nClinical \npresentation\nPrevious \nhistory of \nhormonal \ntherapy\nSize of \ntumor \n(cm)\nSite of \ntumor\nAssociation \nwith \nendometriosis\nStage Treatment Hormonal \ntherapy Immunohistochemistry Margins\nFollow \nup \n(mo)\nRFS (mo) OS \n(mo) Comments\nBerkowitz, \n1978 [3]\n57 Intermittent \nvaginal bleeding, \nnodule\nYes 8 Vaginal apex Yes II Exploratory \nlaparotomy+\nradical \nvaginectomy+\nradiotherapy\n- - - 18 18 18 H/o TAH+\nBSO 15 yr \nago- no \nmalignancy\nUlbright, \n1981 [4]\n32 Vaginal nodule - 2.5 Right lateral \nvagina\nNo I TAH+BSO+\nresection of \nthe mass\n- - - 36 36 36 -\nKondi-\nPaphitis, \n1998 [5]\n45 Vaginal discharge, \nnodules\n- 2 Posterior vagina Yes II Excision of tumor - Vimentin+Desmin,\nsmooth muscle actin, \nfactor VIII, EMA and LCA –\nFree 36 36 36 -\nChang, \n2000 [6]\n34 - - - - No - TAH+BSO+\nLND+partial \nvaginectomy+RT\n- - - 18 18 18 -\nCorpa, \n2004 [7]\n40 Periurethral vaginal \nnodule\nNo 2 Periurethral No I Excision of the \nnodule\n- CD10, ER, PR+Desmin, \nactin, S-100 protein, \nand cytokeratin –\n- 38 38 38 -\nMasand, \n2013 [1]\n52 Pelvic mass - Pelvis, round \nligament, \nvagina\nYes IVB Surgery+\nchemoradiation\n- - - 96 Yes 96 Died of \ndisease\n51 - - Vagina No - Surgery - - - - - - Lost to \nfollow-up\n40 Vaginal bleeding - Vagina, pelvis No III Surgery+\nchemotherapy+\nhormonal \ntherapy\n- - - 9 Yes 9 Alive with \ndisease\n44 Vaginal bleeding - Vagina, colon Yes IVA Surgery+\nchemotherapy\n- - - 36 Yes \n(dedifferentia\nted tumor)\n36 Died of \ndisease\n49 Pelvic pain and \nmenorrhagia\n- Ovary, uterine \nserosa, vagina, \nurinary bladder, \ncolon, \nhypogastric LN\nYes IVB Surgery+\nchemotherapy+\nhormonal \ntherapy\n- - - 84 Yes 84 Alive with \nno evidence \nof disease\n(Continued to the next page)\n\nSeema Singhal et al. • ESS from vaginal endometriosis\nwww.kjco.org  77\nAuthor Age \n(yr)\nClinical \npresentation\nPrevious \nhistory of \nhormonal \ntherapy\nSize of \ntumor \n(cm)\nSite of \ntumor\nAssociation \nwith \nendometriosis\nStage Treatment Hormonal \ntherapy Immunohistochemistry Margins\nFollow \nup \n(mo)\nRFS (mo) OS \n(mo) Comments\nLiu, 2013 [8] 32 Postcoital bleeding No 1 Middle and \nupper right \nposterior \nvaginal wall\nNo I TAH+BSO+partial \nvaginectomy+\n6 cycles of \nchemotherapy \n(PAC)\n- CD10, ER, PR and \nVimentin+desmin, \nmuscle actin, S-100 –\nFree 18 18 18 -\nRivard, 2015 \n[9]\n43 Asymptomatic No 5 Vaginal introitus Yes I Surgery - - - - - - -\nWang, 2015\n[10]\n40 Vaginal discharge, \nmass\n- 5 Left vagina, \nbladder, rectum\nNo IVA Radiotherapy MPA - NA 12 Disease \nprogressed \nduring therapy\n12 Died of \ndisease\n32 Mass - 1.5 Right lower \nthird of vagina\nNo I TAH+BSO+wide \nlocal excision\nFree 21 21 21 -\nSanverdi,\n2016 [11]\n46 Postcoital \nvaginal bleeding, \npain, constipation, \nmass\nNo 7 Posterior fornix Yes II TAH+BSO+partial \nvaginectomy\n- CD10 (+), ER (+), PR (+), \nand vimentin (+)\nFree 22 22 22 Elevated preop \nCA125 at \n75 IU/mL\nAbu Jamea, \n2017 [12]\n58 Vaginal heaviness, \nmass\nNo 3 Left vagina No I TAH+BSO+LND Letrozole \n2.5 mg\nVimentin, CD10, ER, PR, \nfocal CD99+h-\nCaldesmon, calponin, \ndesmin, smooth mus- \ncle actin, CD68, CD34, \nBcl-2, NSE, S100 protein, \ncyclin-D1, GFAP, HMB45, \ninhibin, EMA & \nsynaptophysin –\n- 7 7 7 -\nZou, 2020 \n[13]\n61 - - - - - I Surgery - - - 12 - 12 Alive with \ndisease\nTang, 2020 \n[14]\n74 Irregular vaginal \nbleeding, mass\nNo 6 Left vagina No - Partial \nvaginectomy\n- Beta-catenin, ER, PR, \nvimentin+; CD10, EMA, \nCD31, CD34, CD117,CD99, \nSMA, desmin, h-caldesmon, \nS-100, MelanA, &HMB45 –\nFree 46 46 46 -\nWu, 2022 \n[15]  \n- - - - - Yes - Surgery+RT - - - - - - -\nPresent case 38 Pain Yes 7 Posterior fornix Yes IIIA TAH+BSO+\nvaginectomy+\nrectosigmoid \nresection\nAnastrozole \n1 mg\nCD10, ER, PR and focally \nfor cyclin D1 and \ndesmin+; SMA –\nFree 65 65 65 -\nRFS, recurrence-free survival; OS, overall survival; TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; EMA, epithelial membrane antigen; LCA, leucocyte common antigen (CD45); LND, \nlymphadenectomy; ER, estrogen receptor; PR, progesterone receptor; LN, lymph node; PAC, cisplatin, doxorubicin, and cyclophosphamide; MPA, medroxyprogesterone acetate; CA125, cancer antigen 125; RT, \nradiotherapy; SMA, smooth muscle antigen.\nTable 1. Continued\n\n78  Korean Journal of Clinical Oncology\nDISCUSSION\nMalignant transformation of long-standing endometriosis occurs \nin 0.7% to 1% of cases and the most common histopathology is ad-\nenocarcinoma, particularly of the endometrioid or clear cell sub-\ntype. Rarely endometriotic foci can give rise to ESS. EESS arising \nfrom endometriosis is an extremely rare condition, reported only \nin few case reports. The symptoms of ESS and endometriosis are \nsimilar and depend on the site of involvement. \nEESS can arise as a primary disease as a result of metaplasia of \nsub-coelomic mesenchyme or secondarily from malignant trans-\nformation of pre-existent endometriosis. It may not always be pos-\nsible to differentiate primary EESS from secondary EESS. Accord-\ning to Sampson criteria, to diagnose endometriosis-associated ma-\nlignancy, the following points should be met: (1) demonstration of \nbenign endometriotic foci in the proximity of the malignant tu-\nmor; (2) no other primary site for the tumor; or (3) histology of tu-\nmor consistent with origin from an endometriotic foci [2]. Our \ncase met all of Sampson’s criteria (presence of multiple endometri-\notic foci in the periphery of the tumor, presence of tumor in rec-\ntovaginal septum and posterior vaginal wall excluding any other \nsource of primary origin, histopathological examination consistent \nwith that of ESS arising from endometriosis) suggesting that the \ninitial vaginal endometriosis had undergone malignant transfor-\nmation into low-grade ESS subsequently. It has also been noted \nthat it is not always necessary to identify a focus of endometriosis \nnear the tumor because growth of tumor may destroy the transi-\ntional areas of endometriosis. Therefore, any tumor of histological \ntype known to be associated with endometriosis occurring at an \nunusual age and at an uncommon site may point towards the diag-\nnosis of malignant transformation even without a demonstrable \nfocus of endometriosis in real time. \nOne of the most important differential diagnoses to be consid-\nered is gastrointestinal stromal tumor (GIST). GIST s are rounded \nsmooth tumors, arising as an endoluminal, exophytic growth. \nThey are immune positive for CD117 and DOG-1. In compari-\nson, the characteristic appearance of gastrointestinal tract ESS is \nthat of an extrinsic mass that may involve the complete thickness \nof rectal wall with luminal protrusion. The presence of invasive \ntongues of tumor at the periphery of the neoplasm, short fascicles \nor sheets of monotonous plump spindle cells and prominent arte-\nrioles favor the diagnosis of ESS. \nMost common site of origin of EESS are the ovaries. Only few \ncases were reported arising from the vagina (T able 1) [1,3-15]. ESSs \nare characterized by the presence of the fusion of JAZF1 and \nSUZ12 (JJAZ1) genes resulting from translocation of t(7,17)\n(p15;q21). But, in contrast, EESS rarely harbors this genetic abnor-\nmality. \nThe factors that lead to malignant transformation in endometri-\nosis are not clear. Exogenous hormone therapy with estrogen was \nconsidered as a potential contributing factor for the development \nof the colonic ESS in a few case reports. Conversely, hormonal \ntherapy may have checked the tumor growth as medroxyproges-\nterone acetate is known to achieve tumor control in already diag-\nnosed cases of ESS. Our patient was given hormonal treatment \nwith gonadotropin-releasing hormone (GnRH) analogs and pro-\ngesterone as she was initially diagnosed to have deeply infiltrating \nrectovaginal endometriosis. Low-grade ESS is a slow growing neo-\nplasm and the management is primarily surgical with the aim of \ncomplete cytoreduction. The most important prognostic variable \nis stage with 5-year survival rates as good as 90% to 100% for stage \n1 and reduced to 50% for advanced stage disease. A systematic re-\nview on EESS has revealed that small size of the tumor and hor-\nmonal therapy were predictors of a good survival, while the role of \nchemotherapy or radiation does not seem to affect survival. In cas-\nes of disseminated intraperitoneal disease survival rates as low as \n12% have been reported. Late recurrences are common, even with \nearly-stage tumors, mandating a long time follow-up for these pa-\ntients. \nIn conclusion, being an extrauterine foci of endometriosis, any \nprimary tumor of the endometrium might arise from endometri-\nosis. A practicing gynecologist should keep this rare possibility in \nmind while medically treating long-standing cases of deeply infil-\ntrating endometriosis. Features suggestive of malignant transfor-\nmation include worsening symptoms, development of resistance \nto a previously responsive medical treatment or sudden increase in \nsize.\nCONFLICT OF INTEREST\nNo potential conflict of interest relevant to this article was reported.\nFUNDING\nNone.\n \nORCID \nSeema Singhal https://orcid.org/0000-0002-8644-7684\nAarthi S Jayraj https://orcid.org/0000-0002-6913-6876\nEkta Dhamija https://orcid.org/0000-0001-8265-9674\nSachin Khurana https://orcid.org/0000-0002-6308-5481\n\nSeema Singhal et al. • ESS from vaginal endometriosis\nwww.kjco.org  79\nREFERENCES \n1. Masand RP , Euscher ED, Deavers MT , Malpica A. Endometrioid \nstromal sarcoma: a clinicopathologic study of 63 cases. Am J Surg \nPathol 2013;37:1635-47.\n2. Alcazar JL, Guerriero S, Ajossa S, Parodo G, Piras B, Peiretti M, et \nal. Extragenital endometrial stromal sarcoma arising in endometri-\nosis. Gynecol Obstet Invest 2012;73:265-71.\n3. Berkowitz RS, Ehrmann RL, Knapp RC. Endometrial stromal sar-\ncoma arising from vaginal endometriosis. Obstet Gynecol 1978; \n51(1 Suppl):34s-7s.\n4. Ulbright TM, Kraus FT . Endometrial stomal tumors of extra-uter-\nine tissue. Am J Clin Pathol 1981;76:371-7.\n5. Kondi-Paphitis A, Smyrniotis B, Liapis A, Kontoyanni A, Deligeor-\ngi H. Stromal sarcoma arising on endometriosis: a clinicopatholog-\nical and immunohistochemical study of 4 cases. Eur J Gynaecol \nOncol 1998;19:588-90.\n6. Chang YC, W ang TY , Tzen CY . Endometrial stromal sarcoma of \nthe vagina. Zhonghua Yi Xue Za Zhi (T aipei) 2000;63:714-9.\n7. Corpa MV , Serafini EP , Bacchi CE. Low-grade endometrial stromal \nsarcoma presenting as vaginal nodule. Ann Diagn Pathol 2004;8: \n295-8.\n8. Liu Z, Ding J, Li X, Y u K. Endometrial stromal sarcoma arising in \nvagina. Int J Clin Exp Pathol 2013;6:2997-3002.\n9. Rivard C, Carter JS, Downs LS Jr. Low-grade endometrial stromal \nsarcoma primarily arising in the vagina: a case report. J Reprod \nMed 2015;60:433-5.\n10. W ang Y , Huang YW , Li YF . Primary vaginal sarcoma: experience of \na regional cancer center in China. J Obstet Gynaecol Res 2015;41: \n1463-8.\n11. Sanverdi I, T emizkan O, V ural F , Koc N, Polat M. Primary vaginal \nendometrial stromal sarcoma associated with endometriosis: a \ncase report with a review of the literature. Eur J Gynaecol Oncol \n2016;37:717-21.\n12. Abu Jamea GA, Al Rikabi AC, Akkour K. Primary low-grade en-\ndometrial stromal sarcoma arising in the vagina: report of an un-\nusual case and literature review. J Surg Case Rep 2017;2017:rjx238.\n13. Zou Y , T urashvili G, Soslow RA, Park KJ, Croce S, McCluggage \nWG, et al. High-grade transformation of low-grade endometrial \nstromal sarcomas lacking YWHAE and BCOR genetic abnormali-\nties. Mod Pathol 2020;33:1861-70.\n14. T ang Y , Chen Y , Tian L, Chen J, Y ang P , Zhang D, et al. V aginal low-\ngrade endometrial stromal sarcoma: an extremely rare case report \nand review of the literature. Int J Gynecol Pathol 2020;39:447-51.\n15. W u Y , Li N, Zhang R, Bai P . Primary low-grade extrauterine endo-\nmetrial stromal sarcoma: analysis of 10 cases with a review of the \nliterature. W orld J Surg Oncol 2022;20:17.","source_license":"CC0","license_restricted":false}