{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T18:19:27Z","timestamp":1764181167675,"version":"3.46.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Criteria for malignancy in smooth muscle tumors vary by anatomic site. However, establishment of the primary site is not always possible preoperatively in the pelvis and retroperitoneum of female patients. Estrogen receptor (ER) expression rates in non-gynecologic smooth muscle tumors remain a subject of debate. We sought to study a cohort of well-characterized neoplastic and non-neoplastic non-gynecologic smooth muscle in both sexes to explore the utility of ER status in determination of site of origin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>A retrospective search was performed for cases of non-gynecologic leiomyosarcoma. Only cases where the site of origin could be confirmed by radiologic features, intraoperative findings, and\/or gross description were included. Non-neoplastic non-gynecologic smooth muscle tissues were also collected. A representative section from each specimen was immunostained for ER. ER expression was scored as follows:\u2009&lt;\u20091% (0), 1\u201325% (1\u2009+), 26\u201350% (2\u2009+),\u2009&gt;\u200950% (3\u2009+). Specimens were considered ER positive if \u2265 1% of tumor cells showed at least moderate nuclear staining for the antibody. Clinical data, including follow-up, was collected.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sixty-six cases of non-gynecologic leiomyosarcoma (36 females, 30 males) were identified, arising from large\/medium blood vessels of the retroperitoneum\/pelvis (23), subfascial soft tissue of the extremities, chest or trunk (17), suprafascial soft tissue of the extremities, chest or trunk (11), genitourinary tract (6), and gastrointestinal tract (9). FNCLCC grading was as follows: Grade 1 in 10 cases (15.2%), Grade 2 in 39 cases (59.1%), and Grade 3 in 17 cases (25.8%). ER expression was detected in 11 of 66 (17%) of non-gynecologic leiomyosarcoma. Follow-up was available in 64 patients (0 to 163\u00a0months, median 23\u00a0months); 6 patients developed local recurrence, 26 patients developed distant metastasis, and 12 patients died of disease. When cases were categorized into two groups based on gender, 9\/36 (25.0%) of female tumors were ER-positive compared to 2\/30 (6.7%) of male cases, and the difference was statistically significant (Fisher's exact test,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009\n                      <jats:italic>0.046<\/jats:italic>\n                      ). Leiomyosarcomas arising from large\/medium vessels of the retroperitoneum\/pelvis were significantly more likely to express ER (7\/23, 30.4%) than those from other non-gynecologic sites (4\/43, 9.3%) (Fisher's exact test,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009\n                      <jats:italic>0.035<\/jats:italic>\n                      ). There was no correlation between ER status and FNCLCC grade or outcome. Out of a total of 43 non-neoplastic smooth muscle tissues, 14 (33.3%) tissue samples were positive for ER expression. Analysis by site showed that non-neoplastic smooth muscle arising from retroperitoneal\/pelvic vessels was significantly more likely to express ER (10\/16, 62.5%) compared to other non-gynecologic sites (4\/27, 14.9%) (Fisher's exact test,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009\n                      <jats:italic>0.002<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ER expression may be present in both neoplastic and non-neoplastic smooth muscle at non-gynecologic sites. Extra-gynecologic leiomyosarcoma arising in female patients and from retroperitoneum\/pelvic vasculature are more likely to show ER expression compared to male patients and other non-gynecologic sites, respectively. These findings limit the utility of ER expression in determining the site of origin when evaluating smooth muscle neoplasms of the pelvis and retroperitoneum.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00428-025-04300-5","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T06:09:39Z","timestamp":1763791779000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Estrogen receptor expression by immunohistochemistry is not specific to gynecologic-type smooth muscle"],"prefix":"10.1007","author":[{"given":"Rayan","family":"Sibira","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Vu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Daniels","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariya","family":"Farooqui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine K.","family":"Dermawan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen J.","family":"Fritchie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,22]]},"reference":[{"issue":"10","key":"4300_CR1","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1097\/PAS.0000000000000249","volume":"38","author":"S Croce","year":"2014","unstructured":"Croce S, Young RH, Oliva E (2014) Uterine leiomyomas with bizarre nuclei: a clinicopathologic study of 59 cases. Am J Surg Pathol 38(10):1330\u20131339. https:\/\/doi.org\/10.1097\/PAS.0000000000000249","journal-title":"Am J Surg Pathol"},{"issue":"11","key":"4300_CR2","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1097\/00000478-199711000-00001","volume":"21","author":"KA Downes","year":"1997","unstructured":"Downes KA, Hart WR (1997) Bizarre leiomyomas of the uterus: a comprehensive pathologic study of 24 cases with long-term follow-up. Am J Surg Pathol 21(11):1261\u20131270. https:\/\/doi.org\/10.1097\/00000478-199711000-00001","journal-title":"Am J Surg Pathol"},{"key":"4300_CR3","doi-asserted-by":"publisher","unstructured":"Wile AG, Evans HL, Romsdahl MM (1981) Leiomyosarcoma of soft tissue: a clinicopathologic study. Cancer 48(4):1022\u20131032. https:\/\/doi.org\/10.1002\/1097-0142(19810815)48:4%3C1022::aid-cncr2820480429%3E3.0.co;2-5","DOI":"10.1002\/1097-0142(19810815)48:4%3C1022::aid-cncr2820480429%3E3.0.co;2-5"},{"issue":"1","key":"4300_CR4","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/0046-8177(89)90207-4","volume":"20","author":"KR Cho","year":"1989","unstructured":"Cho KR, Woodruff JD, Epstein JI (1989) Leiomyoma of the uterus with multiple extrauterine smooth muscle tumors: a case report suggesting multifocal origin. Hum Pathol 20(1):80\u201383. https:\/\/doi.org\/10.1016\/0046-8177(89)90207-4","journal-title":"Hum Pathol"},{"issue":"11","key":"4300_CR5","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1097\/00000478-200111000-00002","volume":"25","author":"E Paal","year":"2001","unstructured":"Paal E, Miettinen M (2001) Retroperitoneal leiomyomas: a clinicopathologic and immunohistochemical study of 56 cases with a comparison to retroperitoneal leiomyosarcomas. Am J Surg Pathol 25(11):1355\u20131363. https:\/\/doi.org\/10.1097\/00000478-200111000-00002","journal-title":"Am J Surg Pathol"},{"issue":"11","key":"4300_CR6","first-page":"1001","volume":"12","author":"UN Rao","year":"1999","unstructured":"Rao UN, Finkelstein SD, Jones MW (1999) Comparative immunohistochemical and molecular analysis of uterine and extrauterine leiomyosarcomas. Mod Pathol 12(11):1001\u20131009","journal-title":"Mod Pathol"},{"issue":"4","key":"4300_CR7","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1097\/00129039-200412000-00008","volume":"12","author":"TW Kelley","year":"2004","unstructured":"Kelley TW, Borden EC, Goldblum JR (2004) Estrogen and progesterone receptor expression in uterine and extrauterine leiomyosarcomas: an immunohistochemical study. Appl Immunohistochem Mol Morphol 12(4):338\u2013341. https:\/\/doi.org\/10.1097\/00129039-200412000-00008","journal-title":"Appl Immunohistochem Mol Morphol"},{"issue":"12","key":"4300_CR8","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1038\/modpathol.2009.122","volume":"22","author":"CH Lee","year":"2009","unstructured":"Lee CH, Turbin DA, Sung YCV et al (2009) A panel of antibodies to determine site of origin and malignancy in smooth muscle tumors. Mod Pathol 22(12):1519\u20131531. https:\/\/doi.org\/10.1038\/modpathol.2009.122","journal-title":"Mod Pathol"},{"issue":"18","key":"4300_CR9","doi-asserted-by":"publisher","first-page":"4186","DOI":"10.1002\/cncr.24486","volume":"115","author":"JC Carvalho","year":"2009","unstructured":"Carvalho JC, Thomas DG, Lucas DR (2009) Cluster analysis of immunohistochemical markers in leiomyosarcoma delineates specific anatomic and gender subgroups. Cancer 115(18):4186\u20134195. https:\/\/doi.org\/10.1002\/cncr.24486","journal-title":"Cancer"},{"issue":"3","key":"4300_CR10","doi-asserted-by":"publisher","first-page":"233","DOI":"10.5114\/pjp.2022.124478","volume":"73","author":"D Bay\u00e7elebi","year":"2022","unstructured":"Bay\u00e7elebi D, Kefeli M, Y\u0131ld\u0131z L, Karag\u00f6z F (2022) Comprehensive immunohistochemical analysis based on the origin of leiomyosarcoma. Pol J Pathol 73(3):233\u2013243. https:\/\/doi.org\/10.5114\/pjp.2022.124478","journal-title":"Pol J Pathol"},{"key":"4300_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2025.105757","volume":"157","author":"F Viehweger","year":"2025","unstructured":"Viehweger F, Gusinde J, Leege N et al (2025) Estrogen receptor expression in human tumors: A tissue microarray study evaluating more than 18,000 tumors from 149 different entities. Hum Pathol 157:105757. https:\/\/doi.org\/10.1016\/j.humpath.2025.105757","journal-title":"Hum Pathol"},{"issue":"1","key":"4300_CR12","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1097\/00004347-199901000-00004","volume":"18","author":"YL Zhai","year":"1999","unstructured":"Zhai YL, Kobayashi Y, Mori A et al (1999) Expression of steroid receptors, Ki-67, and p53 in uterine leiomyosarcomas. Int J Gynecol Pathol 18(1):20\u201328. https:\/\/doi.org\/10.1097\/00004347-199901000-00004","journal-title":"Int J Gynecol Pathol"},{"issue":"6","key":"4300_CR13","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1002\/cncr.20521","volume":"101","author":"MM Leitao","year":"2004","unstructured":"Leitao MM, Soslow RA, Nonaka D et al (2004) Tissue microarray immunohistochemical expression of estrogen, progesterone, and androgen receptors in uterine leiomyomata and leiomyosarcoma. Cancer 101(6):1455\u20131462. https:\/\/doi.org\/10.1002\/cncr.20521","journal-title":"Cancer"},{"issue":"1B","key":"4300_CR14","first-page":"729","volume":"23","author":"K Bodner","year":"2003","unstructured":"Bodner K, Bodner-Adler B, Kimberger O, Czerwenka K, Leodolter S, Mayerhofer K (2003) Estrogen and progesterone receptor expression in patients with uterine leiomyosarcoma and correlation with different clinicopathological parameters. Anticancer Res 23(1B):729\u2013732","journal-title":"Anticancer Res"},{"issue":"2","key":"4300_CR15","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.jsbmb.2003.11.013","volume":"88","author":"Y Kitaoka","year":"2004","unstructured":"Kitaoka Y, Kitawaki J, Koshiba H et al (2004) Aromatase cytochrome P450 and estrogen and progesterone receptors in uterine sarcomas: correlation with clinical parameters. J Steroid Biochem Mol Biol 88(2):183\u2013189. https:\/\/doi.org\/10.1016\/j.jsbmb.2003.11.013","journal-title":"J Steroid Biochem Mol Biol"},{"issue":"1","key":"4300_CR16","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.ygyno.2005.05.019","volume":"99","author":"SE Akhan","year":"2005","unstructured":"Akhan SE, Yavuz E, Tecer A et al (2005) The expression of Ki-67, p53, estrogen and progesterone receptors affecting survival in uterine leiomyosarcomas. A clinicopathologic study. Gynecol Oncol 99(1):36\u201342. https:\/\/doi.org\/10.1016\/j.ygyno.2005.05.019","journal-title":"Gynecol Oncol"},{"issue":"3","key":"4300_CR17","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.ygyno.2011.11.009","volume":"124","author":"MM Leitao","year":"2012","unstructured":"Leitao MM, Hensley ML, Barakat RR et al (2012) Immunohistochemical expression of estrogen and progesterone receptors and outcomes in patients with newly diagnosed uterine leiomyosarcoma. Gynecol Oncol 124(3):558\u2013562. https:\/\/doi.org\/10.1016\/j.ygyno.2011.11.009","journal-title":"Gynecol Oncol"},{"issue":"4","key":"4300_CR18","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1093\/ajcp\/aqw030","volume":"145","author":"B Davidson","year":"2016","unstructured":"Davidson B, Kj\u00e6reng ML, F\u00f8rsund M, Danielsen HE, Kristensen GB, Abeler VM (2016) Progesterone Receptor Expression Is an Independent Prognosticator in FIGO Stage I Uterine Leiomyosarcoma. Am J Clin Pathol 145(4):449\u2013458. https:\/\/doi.org\/10.1093\/ajcp\/aqw030","journal-title":"Am J Clin Pathol"},{"key":"4300_CR19","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.839005","volume":"13","author":"P Chen","year":"2022","unstructured":"Chen P, Li B, Ou-Yang L (2022) Role of estrogen receptors in health and disease. Front Endocrinol (Lausanne). 13:839005. https:\/\/doi.org\/10.3389\/fendo.2022.839005","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"22","key":"4300_CR20","doi-asserted-by":"publisher","first-page":"4679","DOI":"10.1158\/1078-0432.CCR-23-0692","volume":"29","author":"R Sanfilippo","year":"2023","unstructured":"Sanfilippo R, Sbaraglia M, Fabbroni C et al (2023) Low-grade uterine leiomyosarcoma is highly sensitive to hormonal treatment. Clin Cancer Res 29(22):4679\u20134684. https:\/\/doi.org\/10.1158\/1078-0432.CCR-23-0692","journal-title":"Clin Cancer Res"},{"issue":"3","key":"4300_CR21","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/j.ygyno.2009.08.014","volume":"115","author":"YJ Ioffe","year":"2009","unstructured":"Ioffe YJ, Li AJ, Walsh CS et al (2009) Hormone receptor expression in uterine sarcomas: prognostic and therapeutic roles. Gynecol Oncol 115(3):466\u2013471. https:\/\/doi.org\/10.1016\/j.ygyno.2009.08.014","journal-title":"Gynecol Oncol"},{"issue":"4","key":"4300_CR22","doi-asserted-by":"publisher","first-page":"921","DOI":"10.3390\/cancers14040921","volume":"14","author":"E Maccaroni","year":"2022","unstructured":"Maccaroni E, Lunerti V, Agostinelli V et al (2022) New insights into hormonal therapies in uterine sarcomas. Cancers (Basel) 14(4):921. https:\/\/doi.org\/10.3390\/cancers14040921","journal-title":"Cancers (Basel)"},{"key":"4300_CR23","unstructured":"Guidelines Detail. NCCN. Accessed March 18, 2025. https:\/\/www.nccn.org\/guidelines\/guidelines-detail?category=1&id=1464"},{"issue":"4","key":"4300_CR24","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.3892\/ijo.2011.920","volume":"38","author":"A Valkov","year":"2011","unstructured":"Valkov A, Sorbye S, Kilvaer TK et al (2011) Estrogen receptor and progesterone receptor are prognostic factors in soft tissue sarcomas. Int J Oncol 38(4):1031\u20131040. https:\/\/doi.org\/10.3892\/ijo.2011.920","journal-title":"Int J Oncol"},{"issue":"6","key":"4300_CR25","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1245\/s10434-013-2876-y","volume":"20","author":"RA Gladdy","year":"2013","unstructured":"Gladdy RA, Qin LX, Moraco N, Agaram NP, Brennan MF, Singer S (2013) Predictors of survival and recurrence in primary leiomyosarcoma. Ann Surg Oncol 20(6):1851\u20131857. https:\/\/doi.org\/10.1245\/s10434-013-2876-y","journal-title":"Ann Surg Oncol"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-025-04300-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-025-04300-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-025-04300-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T18:15:58Z","timestamp":1764180958000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-025-04300-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,22]]},"references-count":25,"alternative-id":["4300"],"URL":"https:\/\/doi.org\/10.1007\/s00428-025-04300-5","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"type":"print","value":"0945-6317"},{"type":"electronic","value":"1432-2307"}],"subject":[],"published":{"date-parts":[[2025,11,22]]},"assertion":[{"value":"27 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interest"}},{"value":"The datasets generated during the current study are not publicly available due to patient confidentiality but are available from the corresponding author upon reasonable request.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This research was approved by the Institutional Review Board at the University of Minnesota and Cleveland Clinic.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"This study was presented in part at the 114th Annual Meeting of the United States and Canadian Academy of Pathology; March 2025, Boston, MA.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclaimer"}}]}}