CREB family (CREB1, ATF1, and CREM) gene fusions are defining markers in diverse mesenchymal neoplasms (clear cell sarcoma, angiomatoid fibrous histiocytoma, and others). However, neoplasms harboring EWSR1-CREM/FUS-CREM fusions are rare and poorly characterized. We describe two cases (55-year-old male with 7.5 cm renal mass and 32-year-old female with 5.5 cm mesenteric mass) illustrating their misleading immunophenotypes. Histologically, both showed eosinophilic and focally clear epithelioid cells arranged into sheets, nests, and trabeculae. Immunohistochemistry showed ALK, EMA, and AE1/AE3 immunoreactivity suggesting ALK-rearranged renal cell carcinoma (Case 1) and coexpression of keratin, EMA, synaptophysin, and chromogranin-A, suggesting neuroendocrine neoplasm (Case 2). Targeted RNA sequencing revealed EWSR1-CREM (Case 1) and FUS-CREM (Case 2) fusions. These cases add to the spectrum of CREM fusion-positive intra-abdominal epithelioid neoplasms. Their unusual immunophenotype and unexpected sites represent major pitfalls, underline a wide differential diagnosis, and emphasize the value of molecular testing in correctly diagnosing them.

CREB ​​家族（CREB1、ATF1和CREM）基因融合是多种间充质肿瘤（透明细胞肉瘤、血管瘤样纤维组织细胞瘤等）中的标志物。然而，具有EWSR1-CREM/FUS-CREM融合的肿瘤很少见且特征不明确。我们描述了两个病例（55 岁男性，肾肿块 7.5 厘米，32 岁女性，肠系膜肿块 5.5 厘米），说明了它们的误导性免疫表型。组织学上，两者均显示嗜酸性和局部透明的上皮样细胞排列成片状、巢状和小梁状。免疫组织化学显示 ALK、EMA 和 AE1/AE3 免疫反应性提示ALK-重排肾细胞癌（病例1）和角蛋白、EMA、突触素和嗜铬粒蛋白-A的共表达，提示神经内分泌肿瘤（病例2）。靶向 RNA 测序显示EWSR1-CREM（案例 1）和FUS-CREM（案例 2）融合。这些病例增加了CREM融合阳性腹内上皮样肿瘤的谱系。它们不寻常的免疫表型和意想不到的部位代表了主要缺陷，强调了广泛的鉴别诊断，并强调了分子检测在正确诊断它们方面的价值。