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<p>Fusion genes between the FET (<i>EWSR1</i>/<i>FUS</i>) and CREB (<i>CREB1</i>, <i>ATF1</i>, <i>CREM</i>) families characterize many tumor types, including mesenchymal entities. Herein, we tested the diagnostic utility of CREM (C-terminus) immunohistochemistry using 51 <i>CREB</i>-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 <i>CREB</i>-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 <i>SMARCA2</i>::<i>CREM</i>). 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 <i>CRTC1</i>-rearranged tumors (<i>CRTC1</i>::<i>TRIM11</i> and <i>CRTC1</i>::<i>SS18</i>) 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 <i>CREB</i>-rearranged mesenchymal tumors as a whole cohort, and its overall utility in predicting <i>CREB</i> fusion is limited. However, CREM staining may be useful in a few specific contexts, such as when angiomatoid fibrous histiocytoma is suspected.</p>

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Immunohistochemical evaluation of CREM in CREB-rearranged mesenchymal tumors and their mimics

  • 期刊论文

  • 发表日期：

    2025年8月23日

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  • Shogo Nishino,
  • Hirokazu Sugino,
  • Yasuhito Arai,
  • Natsuko Hama,
  • Tatsuhiro Shibata,
  • Shuhei Osaki,
  • Seiichi Yoshimoto,
  • Yasushi Yatabe,
  • Taisuke Mori,
  • Akihiko Yoshida

摘要

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.