{"title":"Immunohistochemical evaluation of CREM in CREB-rearranged mesenchymal tumors and their mimics.","authors":"Shogo Nishino, Hirokazu Sugino, Yasuhito Arai, Natsuko Hama, Tatsuhiro Shibata, Shuhei Osaki, Seiichi Yoshimoto, Yasushi Yatabe, Taisuke Mori, Akihiko Yoshida","doi":"10.1007/s00428-025-04207-1","DOIUrl":null,"url":null,"abstract":"<p><p>Fusion genes between the FET (EWSR1/FUS) and CREB (CREB1, ATF1, CREM) families characterize many tumor types, including mesenchymal entities. Herein, we tested the diagnostic utility of CREM (C-terminus) immunohistochemistry using 51 CREB-rearranged mesenchymal tumors and 159 tumors of 14 mimicking entities. Staining was considered positive if nuclear staining of moderate or strong intensity was observed in at least 10% of the tumor cells. Among the 51 CREB-rearranged tumors, CREM was at least focally positive in 39 tumors (76.5%), diffusely (≥ 50%) positive in 31 tumors (60.8%), and diffuse strong staining was observed in 23 tumors (45.1%). Diffuse strong reactivity was observed in nearly all angiomatoid fibrous histiocytoma (11 of 12 tumors), intracranial FET::CREB mesenchymal neoplasms (2 of 2 tumors), and unclassifiable sarcomas (2 of 2 tumors, including 1 case with SMARCA2::CREM). However, the positivity was more limited in clear cell sarcoma (15 of 20 tumors), keratin-positive malignant FET::CREB tumors in the abdomen (5 of 8 tumors), and gastrointestinal neuroectodermal tumors (4 of 7 tumors). Two separately evaluated CRTC1-rearranged tumors (CRTC1::TRIM11 and CRTC1::SS18) demonstrated diffuse strong positivity. Among the 159 tumors in the comparison cohort, CREM was at least focally positive in 33 (20.8%) tumors, diffusely positive in 19 tumors (11.9%), and diffusely and strongly positive in 5 tumors (3.1%). CREM demonstrated moderate sensitivity and specificity for the diagnosis of CREB-rearranged mesenchymal tumors as a whole cohort, and its overall utility in predicting CREB fusion is limited. However, CREM staining may be useful in a few specific contexts, such as when angiomatoid fibrous histiocytoma is suspected.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Virchows Archiv","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00428-025-04207-1","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Fusion genes between the FET (EWSR1/FUS) and CREB (CREB1, ATF1, CREM) families characterize many tumor types, including mesenchymal entities. Herein, we tested the diagnostic utility of CREM (C-terminus) immunohistochemistry using 51 CREB-rearranged mesenchymal tumors and 159 tumors of 14 mimicking entities. Staining was considered positive if nuclear staining of moderate or strong intensity was observed in at least 10% of the tumor cells. Among the 51 CREB-rearranged tumors, CREM was at least focally positive in 39 tumors (76.5%), diffusely (≥ 50%) positive in 31 tumors (60.8%), and diffuse strong staining was observed in 23 tumors (45.1%). Diffuse strong reactivity was observed in nearly all angiomatoid fibrous histiocytoma (11 of 12 tumors), intracranial FET::CREB mesenchymal neoplasms (2 of 2 tumors), and unclassifiable sarcomas (2 of 2 tumors, including 1 case with SMARCA2::CREM). However, the positivity was more limited in clear cell sarcoma (15 of 20 tumors), keratin-positive malignant FET::CREB tumors in the abdomen (5 of 8 tumors), and gastrointestinal neuroectodermal tumors (4 of 7 tumors). Two separately evaluated CRTC1-rearranged tumors (CRTC1::TRIM11 and CRTC1::SS18) demonstrated diffuse strong positivity. Among the 159 tumors in the comparison cohort, CREM was at least focally positive in 33 (20.8%) tumors, diffusely positive in 19 tumors (11.9%), and diffusely and strongly positive in 5 tumors (3.1%). CREM demonstrated moderate sensitivity and specificity for the diagnosis of CREB-rearranged mesenchymal tumors as a whole cohort, and its overall utility in predicting CREB fusion is limited. However, CREM staining may be useful in a few specific contexts, such as when angiomatoid fibrous histiocytoma is suspected.
期刊介绍:
Manuscripts of original studies reinforcing the evidence base of modern diagnostic pathology, using immunocytochemical, molecular and ultrastructural techniques, will be welcomed. In addition, papers on critical evaluation of diagnostic criteria but also broadsheets and guidelines with a solid evidence base will be considered. Consideration will also be given to reports of work in other fields relevant to the understanding of human pathology as well as manuscripts on the application of new methods and techniques in pathology. Submission of purely experimental articles is discouraged but manuscripts on experimental work applicable to diagnostic pathology are welcomed. Biomarker studies are welcomed but need to abide by strict rules (e.g. REMARK) of adequate sample size and relevant marker choice. Single marker studies on limited patient series without validated application will as a rule not be considered. Case reports will only be considered when they provide substantial new information with an impact on understanding disease or diagnostic practice.