{"paper_id":"6c99f947-7064-4786-8078-ce5e58f5b119","body_text":"Review began\n 04/26/2021 \nReview ended\n 04/29/2021 \nPublished\n 05/02/2021\n© Copyright \n2021\nAnees et al. This is an open access article\ndistributed under the terms of the\nCreative Commons Attribution License\nCC-BY 4.0., which permits unrestricted\nuse, distribution, and reproduction in any\nmedium, provided the original author and\nsource are credited.\nA Rare Case of Intestinal Low-Grade Endometrial\nStromal Sarcoma With Glandular Differentiation\nand Associated Endometriosis\nAzka Anees \n \n, \nKhurram Siddique \n \n, \nHisham \nAbouzeid \n \n, \nSami Titi \n1.\n Histopathology, Northern Care Alliance National Health Service (NHS) Trust, Oldham, GBR \n2.\n Colorectal Surgery,\nNorthern Care Alliance National Health Service (NHS) Trust, Oldham, GBR \n3.\n Obstetrics and Gynaecology, Northern\nCare Alliance National Health Service (NHS) Trust, Oldham, GBR\nCorresponding author: \nAzka Anees, \nazka.asquare.anees@gmail.com\nAbstract\nEndometrial stromal sarcoma is a rare tumour. It is even rarer to find it arising in the background of\nendometriosis in an extrauterine location. This case report describes a case of missed diagnosis of intestinal\nextra-uterine endometrial stromal sarcoma associated with endometriosis, and the subsequent presentation\nwith distant metastases. The potential pitfalls are highlighted and differential diagnoses are discussed.\nCategories:\n Pathology\nKeywords:\n endometrial stromal sarcoma, endometriosis, extra-uterine stromal sarcoma, liver metastasis, small\nintestine\nIntroduction\nEndometriosis is quite common in the reproductive age group with a reported incidence of 10% \n[1]\n. Of all\nthese cases, intestinal involvement is seen in 3% to 37% \n[2,3]\n. Malignant transformation in endometriosis\nhas been well-documented but is rare, only occurring in 0.7%-0.1% of cases \n[2]\n. It is believed that any type\nof tumour found in the endometrium can also arise from endometriosis \n[4]\n, the most common ones being\nendometrioid and clear-cell type carcinomas \n[5]\n. It is exceedingly rare to see an extrauterine endometrial\nstromal sarcoma (ESS) arising from endometriosis \n[4]\n.\nESS is characterized by cells that resemble proliferative phase endometrial stromal cells. It usually originates\nfrom the uterine corpus, but may be seen in extra-uterine locations \n[6]\n. ESS arising from endometriosis has\nbeen reported to be an indolent tumour with a very good prognosis. However, high-grade cases have a\npoorer prognosis with a mean survival of 53 months \n[7]\n. Even low-grade tumours can present with late\nrecurrences up to three decades after diagnosis \n[8]\n. They can also rarely metastasize to other organs \n[9]\n and\ntreatment becomes especially problematic in cases with disseminated disease.\nWe report a case of missed diagnosis of intestinal extra-uterine endometrial sarcoma associated with\nendometriosis, and subsequent presentation with distant metastases.\nCase Presentation\nA 46-year-old female patient was admitted to the hospital with abdominal pain and vomiting and had a CT\nscan of the pelvis which showed a complex adnexal mass and large mixed density mesenteric lesion in\nassociation with small bowel loops (20 x 15 cm). The patient underwent laparotomy where the mesenteric\ntumour and small bowel loop were excised and sent for histological examination along with a clinical\ndiagnosis of possible mesenteric lymphangioma or endometriotic cyst. There was no definite adnexal mass\nfound during surgery and liver and rest of the bowel were unremarkable.\nThe histological examination of the mesenteric mass showed benign-looking endometrial type glands\nsurrounded by monotonous endometrial stromal cells which revealed no obvious cytological atypia (Figure\n1\n). Immunohistochemistry for CD10 highlighted the endometrial stromal cells and an initial diagnosis of\nendometriosis was made based on the overall appearance (Figure \n1\n, inset).\n1\n2\n3\n1\n \n Open Access Case\nReport\n \nDOI:\n 10.7759/cureus.14801\nHow to cite this article\nAnees A, Siddique K, Abouzeid H, et al. (May 02, 2021) A Rare Case of Intestinal Low-Grade Endometrial Stromal Sarcoma With Glandular\nDifferentiation and Associated Endometriosis. Cureus 13(5): e14801. \nDOI 10.7759/cureus.14801\n\nFIGURE\n 1: (H&E, 10X): Microscopic appearance of mesenteric mass in\nsmall bowel showing monotonous stroma and endometrial type glands.\nInset: (CD10, 10X): CD10 showed diffuse positive staining in stromal\ncells of small bowel mesenteric mass.\nThe patient recovered well after surgery and was discharged in a satisfactory condition. However, after 14\nmonths from the first admission, she presented to the accident and emergency department (A&E) with\nabdominal pain.\nCT scan of the chest, abdomen, and pelvis was done which showed cystic solid liver lesions, pulmonary\nmicronodules, omental infiltration, and soft tissue deposits. A suspicion of metastatic malignancy was\nraised at this point and correlation with the previous histology examination of the mesenteric mass was\nadvised.\nAn ultrasound-guided liver biopsy was performed and sent for histology. The liver biopsy showed complete\nreplacement by spindle cells with a positive expression for CD10 and ER (Figure \n2\n, insets). No normal liver\nparenchyma was identified. The stains for MNF116, D2-40, calretinin, AE1-3, Desmin, S100, CD34, CK7,\nCK20, Melan A, CD117, p53, and beta-catenin were negative.\n2021 Anees et al. Cureus 13(5): e14801. DOI 10.7759/cureus.14801\n2\n of \n6\n\nFIGURE\n 2: (H&E, 20X): Microscopic appearance of liver biopsy which\nshows complete replacement by tumour cells. Inset (top): Diffuse\nstrong positivity for CD10 in liver biopsy. Inset (bottom): Diffuse strong\npositivity for ER in liver biopsy.\nIt was noted that the changes were of similar appearance to the stromal changes in the small bowel\nresection received earlier. A possible diagnosis of a stromal component in endometriosis or ESS was\nconsidered. After external review, it was agreed that the liver biopsy contained ESS and the appearances\nwere in keeping with those of metastatic ESS in which the tumour is of uniform “low grade” appearance.\nThis led to a diagnostic review of the small bowel resection reported previously. It was agreed that it\ncontained definite endometriosis. In addition, there were features of associated ESS. There were admixed\nendometrial glands within the sarcoma which were presumed to represent endometrioid differentiation\nwithin stromal sarcoma. Mitotic activity was infrequent (<5 mitoses per 10HPF). A focus of lymphovascular\ninvasion was also noted in the review (Figure \n3\n).\n2021 Anees et al. Cureus 13(5): e14801. DOI 10.7759/cureus.14801\n3\n of \n6\n\nFIGURE\n 3: (H&E, 10 X): Vascular thrombi of tumour in section from\nsmall bowel mesenteric mass. The endometrial stromal sarcoma is seen\non the left side of the image (arrow head) with a large vessel containing\ntumour thrombi on the right (arrow).\nA final diagnosis of low-grade ESS with relatively prominent endometrioid glandular differentiation and\nassociated endometriosis was given.\nDiscussion\nThis case is being highlighted to discuss its complexity and associated pitfalls. The case was discussed at a\ndiscrepancy meeting in the histopathology department and there was consensus that this case was\nchallenging. None of the participants had come across such a case in their career. In addition to the rarity of\nthe disease, incomplete clinical details on the request form (sent with specimen), without any suspicion of\nmalignancy, from the surgeons contributed to the missed diagnosis. The presence of this information may\nhave supported a diagnosis of malignancy at the time of the original pathology report. It was agreed that\nvigilance is required when dealing with extrauterine endometriosis and in particular when the stromal\ncomponent shows exaggeration and prominent expansion.\nESS is a rare tumour with about 80 cases reported so far \n[10,11]\n. A case series from M D Anderson Cancer\nCentre, Texas, reports the largest number of such cases. This case series described the most common sites of\nESS as the abdominal peritoneum and bowel wall. It was reported that half of these sarcoma cases were\nassociated with endometriosis.\nThe development of malignancy in endometriosis was studied quite early. In 1925, Sampson \n[12]\n reported\nthe first case series of malignancy arising from endometriosis and recommended three criteria for its\ndiagnosis: (1) examples of endometriosis in close proximity to the tumour; (2) no other primary site of\nmalignancy, and (3) histological appearance compatible with the origin from endometriosis. These are\nhelpful criteria and easily applicable in routine practice.\nAs seen from the case above, the diagnosis of low-grade ESS with prominent glandular differentiation is\ndifficult, especially when the primary presentation is in the intestine. It can be confused with many other\nlesions, some of which will be discussed below.\nThe main diagnostic difficulty in our case was the differentiation between endometriosis and ESS with\nextensive glandular differentiation. This is understandably difficult and some light is shed on this topic by a\nresearch article by McCluggage et al. \n[13]\n. This article studies the unusual occurrence of ESSs with extensive\nendometrioid glandular differentiation and highlights the heterologous morphology of these tumours, with\nsome cases showing glands throughout the neoplasm, and others with areas of typical ESS without glands.\nGlands were seen only in the recurrent tumour in one case. The article also highlights the increased chances\nof initial misdiagnosis and delayed diagnosis causing patient harm, much like our case. Few characteristic\nmorphologic features have been defined which can be helpful in the diagnosis of this challenging entity.\nThese include invasive “tongues” of tumour at the periphery of the neoplasm, short fascicles or sheets of\nmonotonous plump spindle cells, and prominent arterioles \n[14]\n.\n2021 Anees et al. Cureus 13(5): e14801. DOI 10.7759/cureus.14801\n4\n of \n6\n\nAnother important differential for our case was stromal endometriosis, which is known to simulate a\nsarcoma \n[15]\n. Stromal endometriosis is a well-circumscribed lesion composed of endometrial stroma type\ncells with absent or very scant endometrial glands. The predominance of stroma and lack of endometrial\nglands can lead to confusion with several neoplasms, particularly low-grade ESS.\nAggressive endometriosis is another entity commonly confused with extrauterine ESSs \n[16]\n. This\ndifferentiation is particularly problematic as aggressive endometriosis is known to disseminate to different\norgans. Intravascular intrusion, perineural space invasion, and involvement of lymph nodes have also been\ndocumented in these cases \n[17]\n. A useful histological clue to indicate a diagnosis of aggressive endometriosis\nover ESS is the presence of endometrial stroma with glands that show normal cyclical changes according to\nthe menstrual cycle. There should be no stromal overgrowth and p53 overexpression should be\ndemonstrable on immunohistochemistry in cases of aggressive endometriosis \n[16]\n.\nOther differential diagnoses of primary extrauterine stromal sarcoma in the intestine include\ngastrointestinal stromal tumour (GIST) and Mullerian adenosarcoma with sarcomatous overgrowth. GIST is\nreported as the most prevalent stromal tumour in the intestine. It is important to differentiate ESS from\nGIST as the management route for both of these tumours is completely different. GISTs are well-\ncircumscribed and have pushing borders in contrast to ESS which is invasive. Positive\nimmunohistochemistry with c-kit is usually confirmatory for a diagnosis of GIST.\nA less common condition that can be included in the differential diagnosis is Mullerian adenosarcoma with\nsarcomatous overgrowth. The main histological clue to this diagnosis is the presence of different kinds of\nMullerian epithelium. Other findings are periglandular cellular stromal condensation and extension of\ncellular stroma into the lumen of glands.\nConclusions\nThe diagnosis of intestinal low-grade ESS with endometrioid glandular differentiation and associated\nendometriosis is difficult with a high likelihood of misdiagnosis and delayed diagnosis. A careful\nmorphological and immunohistochemical examination is the key to the correct diagnosis.\nAdditional Information\nDisclosures\nHuman subjects:\n Consent was obtained or waived by all participants in this study. \nConflicts of interest:\n In\ncompliance with the ICMJE uniform disclosure form, all authors declare the following: \nPayment/services\ninfo:\n All authors have declared that no financial support was received from any organization for the\nsubmitted work. \nFinancial relationships:\n All authors have declared that they have no financial\nrelationships at present or within the previous three years with any organizations that might have an\ninterest in the submitted work. \nOther relationships:\n All authors have declared that there are no other\nrelationships or activities that could appear to have influenced the submitted work.\nReferences\n1\n. \nHoloch KJ, Lessey BA: \nEndometriosis and infertility\n. 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