{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:27:36Z","timestamp":1778858856896,"version":"3.51.4"},"reference-count":25,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Avera Cancer Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lymphovascular invasion (LVSI) is defined as the presence of tumor cells within a definite endothelial-lined space (lymphatics or blood vessels) in the organ surrounding invasive carcinoma. The presence of LVI is associated with an increased risk of lymph nodes and distant metastases. Lymphovascular invasion is described as cancer within blood or lymph vessels and is an independent risk factor for metastasis, recurrence, and mortality. This study aims to present the marker-based immunohistological characterization of cells around LVSI in a high-grade adenocarcinoma of the endometrium to build a cellular atlas of cells of LVSI. A cellular characterization of the cells around lymphovascular space invasion in a 67-year-old female patient with invasive high-grade serous endometrial adenocarcinomas is presented. Resected tumor tissue from a consented patient with invasive high-grade serous endometrial adenocarcinoma was obtained within an hour of surgery. The expressions of the epithelial markers (CK8, 18, and EpCAM), LCA (leukocyte common antigen) marker (CD45), proliferation marker (Ki67), apoptosis markers (cleaved PARP and cleaved caspase3), immune cell markers (CD3, CD4, CD8, CD56, CD68, CD163, FoxP3, PD-1, PD-L1), pro-inflammatory marker (IL-12-RB2), and fibroblast\/mesenchyme markers (S100A7, SMA, and TE-7) of the resected tissue on the IHC stains were evaluated and scored by a pathologist. Acknowledging the deterministic role of LVSI in a high-grade adenocarcinoma of the endometrium, our study presents the first marker-based immunohistological atlas of the tumor and TME compartments in the context of epithelial cell markers, proliferation markers, apoptosis markers, macrophage markers, and fibroblast markers. Our study demonstrates that an aggressive disease like a high-grade adenocarcinoma of the endometrium inflicts the pro-metastatic event of LVSI by involving the immune landscape of both tumor and TME. This study demonstrates, for the first time, that the tumor cells within LVSI are positive for IL-12R-B2 and S100A4.<\/jats:p>","DOI":"10.3390\/ijms25063441","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T04:36:31Z","timestamp":1710822991000},"page":"3441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Atlas of Tumor and Tumor Microenvironment Cells of Lymphovascular Space Invasion (LVSI) in High-Grade Serous Endometrial Adenocarcinoma: A Case Study"],"prefix":"10.3390","volume":"25","author":[{"given":"Raed","family":"Sulaiman","sequence":"first","affiliation":[{"name":"Department of Pathology, Avera Cancer Institute, Sioux Falls, SD 57108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Dale","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqian","family":"Lin","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9405-5464","authenticated-orcid":false,"given":"Jennifer C.","family":"Aske","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kris","family":"Gaster","sequence":"additional","affiliation":[{"name":"Assistant VP Outpatient Cancer Clinics, Avera Cancer Institute, Sioux Falls, SD 57108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Starks","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Avera Cancer Institute, Sioux Falls, SD 57108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis Rojas","family":"Espaillat","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Avera Cancer Institute, Sioux Falls, SD 57108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pradip","family":"De","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57108, USA"},{"name":"Department of Internal Medicine, University of South Dakota SSOM, Sioux Falls, SD 57108, USA"},{"name":"Viecure, Greenwood Village, CO 80111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5533-8784","authenticated-orcid":false,"given":"Nandini","family":"Dey","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57108, USA"},{"name":"Department of Internal Medicine, University of South Dakota SSOM, Sioux Falls, SD 57108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.3802\/jgo.2021.32.e11","article-title":"Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer","volume":"32","author":"Tortorella","year":"2021","journal-title":"J. Gynecol. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.ygyno.2021.04.029","article-title":"Uterine serous carcinoma","volume":"162","author":"Bogani","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1158\/1940-6207.CAPR-11-0499","article-title":"Uterine serous carcinoma: Increased familial risk for lynch-associated malignancies","volume":"5","author":"Dewdney","year":"2012","journal-title":"Cancer Prev. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1097\/GRF.0b013e318218c755","article-title":"Uterine papillary serous carcinoma","volume":"54","author":"Moore","year":"2011","journal-title":"Clin. Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/PGP.0000000000000113","article-title":"Significance of lymphovascular space invasion in uterine serous carcinoma: What matters more; extent or presence?","volume":"34","author":"Winer","year":"2015","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ygyno.2017.07.119","article-title":"Extent of lymphovascular space invasion may predict lymph node metastasis in uterine serous carcinoma","volume":"147","author":"Qian","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_8","first-page":"1531","article-title":"BRCA germline mutations in women with uterine serous carcinoma\u2014Still a debate","volume":"20","author":"Lavie","year":"2010","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sulaiman, R., De, P., Aske, J.C., Lin, X., Dale, A., Koirala, N., Gaster, K., Espaillat, L.R., Starks, D., and Dey, N. (2023). Tumor-TME Bipartite Landscape of PD-1\/PD-L1 in Endometrial Cancers. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311079"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ygyno.2011.09.017","article-title":"Lymphovascular space invasion is an independent risk factor for nodal disease and poor outcomes in endometrioid endometrial cancer","volume":"124","author":"Guntupalli","year":"2012","journal-title":"Gynecol. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.ygyno.2022.01.013","article-title":"Lymphovascular space invasion in endometrial carcinoma: A prognostic factor independent from molecular signature","volume":"165","author":"Raffone","year":"2022","journal-title":"Gynecol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"762329","DOI":"10.3389\/fonc.2021.762329","article-title":"Association of Myometrial Invasion With Lymphovascular Space Invasion, Lymph Node Metastasis, Recurrence, and Overall Survival in Endometrial Cancer: A Meta-Analysis of 79 Studies With 68,870 Patients","volume":"11","author":"Wang","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/his.13871","article-title":"Reproducibility of lymphovascular space invasion (LVSI) assessment in endometrial cancer","volume":"75","author":"Peters","year":"2019","journal-title":"Histopathology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rafiee, A., and Mohammadizadeh, F. (2023). Association of Lymphovascular Space Invasion (LVSI) with Histological Tumor Grade and Myometrial Invasion in Endometrial Carcinoma: A Review Study. Adv. Biomed. Res., 12.","DOI":"10.4103\/abr.abr_52_23"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sulaiman, R., De, P., Aske, J.C., Lin, X., Dale, A., Vaselaar, E., Ageton, C., Gaster, K., Espaillat, L.R., and Starks, D. (2022). Identification and Morphological Characterization of Features of Circulating Cancer-Associated Macrophage-like Cells (CAMLs) in Endometrial Cancers. Cancers, 14.","DOI":"10.3390\/cancers14194577"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sulaiman, R., De, P., Aske, J.C., Lin, X., Dale, A., Vaselaar, E., Koirala, N., Ageton, C., Gaster, K., and Plorde, J. (2022). A Laboratory-Friendly CTC Identification: Comparable Double-Immunocytochemistry with Triple-Immunofluorescence. Cancers, 14.","DOI":"10.3390\/cancers14122871"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"823","DOI":"10.3892\/or.2018.6471","article-title":"Estrogen-related receptor gamma promotes the migration and metastasis of endometrial cancer cells by targeting S100A4","volume":"40","author":"Hua","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.3892\/or.2016.4760","article-title":"S100A4 promotes endometrial cancer progress through epithelial-mesenchymal transition regulation","volume":"35","author":"Hua","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/s41374-019-0359-x","article-title":"S100A4\/non-muscle myosin II signaling regulates epithelial-mesenchymal transition and stemness in uterine carcinosarcoma","volume":"100","author":"Tochimoto","year":"2020","journal-title":"Lab. Investig."},{"key":"ref_20","first-page":"12168","article-title":"Addressing activation of WNT beta-catenin pathway in diverse landscape of endometrial carcinogenesis","volume":"13","author":"De","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/ni1102-991","article-title":"Cancer immunoediting: From immunosurveillance to tumor escape","volume":"3","author":"Dunn","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.coi.2014.01.004","article-title":"New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape","volume":"27","author":"Mittal","year":"2014","journal-title":"Curr. Opin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: Integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1600-065X.2011.01007.x","article-title":"Shifting the equilibrium in cancer immunoediting: From tumor tolerance to eradication","volume":"241","author":"Quezada","year":"2011","journal-title":"Immunol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1159\/000494515","article-title":"Combined Effect of IL-12Rbeta2 and IL-23R Expression on Prognosis of Patients with Laryngeal Cancer","volume":"50","author":"Tao","year":"2018","journal-title":"Cell Physiol. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/6\/3441\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:15:45Z","timestamp":1760105745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/6\/3441"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,19]]},"references-count":25,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25063441"],"URL":"https:\/\/doi.org\/10.3390\/ijms25063441","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,19]]}}}