▌江苏省南京市第一医院病理科杨路路 译；黄文斌 校

CIC重排的未分化圆形细胞肉瘤是一种罕见的新的疾病，主要发生于儿童和年轻人。该肿瘤具有原始的小圆细胞形态和CIC基因重排（19q13.2上的CIC基因与4q35.2或10q26.3上的DUX4基因融合）。由于CIC重排的未分化圆形细胞肉瘤具有侵袭性临床行为和潜在的治疗意义，因此，对这种新的软组织肿瘤准确诊断非常重要。该肿瘤的明确诊断需要分子病理学明确。一些研究发现PEA3亚家族基因，特别是ETV4（属于ETS转录因子家族）在CIC重排未分化圆形细胞肉瘤中表达上调。

本文我们进行了详细的免疫组化研究了ETV4在CIC重排的未分化圆形细胞肉瘤及其可能的拟似病变（尤其是Ewing肉瘤）中表达。该项研究共包括17例CIC重排的未分化圆形细胞肉瘤和110例形态学类似于CIC重排的未分化圆形细胞肉瘤的肉瘤：Ewing肉瘤43例、腺泡状横纹肌肉瘤25例、差分化圆形细胞滑膜肉瘤20例、促结缔组织增生性小圆细胞肿瘤10例、BCOR-CCNB3肉瘤5例、淋巴母细胞性淋巴瘤5例和横纹肌样瘤2例。

结果发现所有CIC重排的未分化圆形细胞肉瘤（核芯针活检和开放活检）均显示弥漫强阳性ETV4表达。而在110例类似CIC重排的未分化圆形细胞肉瘤中，仅有6例（Ewing肉瘤4例、腺泡状横纹肌肉瘤1和促结缔组织增生性小圆细胞肿瘤1例）局灶（<5％肿瘤细胞）和弱阳性ETV4核表达，所有其他肿瘤均不表达ETV4。75%（9/12）CIC重排的未分化圆形细胞肉瘤显示WT1（C-末端）核表达，胞质WT1（C-末端）表达见于14例（14/17），1例同时细胞核和细胞浆表达。70例非CIC重排的未分化圆形细胞肉瘤中，7例（10%）阳性表达WT1（C-末端），其中3例（腺泡状横纹肌肉瘤1例、促结缔组织增生性小圆细胞肿瘤2例）呈弥漫性（>50%）核强阳性（3+）表达，4例（Ewing肉瘤3例、腺泡状横纹肌肉瘤1例）呈局灶性（<50%）核表达，3例Ewing肉瘤显示局灶性“逗点样”WT1（N-末端）阳性。

这些结果提示ETV4免疫组化有助于CIC重排的未分化圆形细胞肉瘤的诊断（与没有分子标记的肉瘤相关易位），它是一种区分CIC重排的未分化圆形细胞肉瘤与其拟似病变的敏感和特异性标记物。WT1（C-末端）而不是WT1（N-末端）可作为ETV4免疫标记的补充用于CIC重排的未分化圆形细胞肉瘤的诊断和鉴别诊断。

Guellec SL, Velasco V, Pérot G, et al. ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions. Mod Pathol. 2016 Dec;29(12):1523-1531.

Subsets of primitive round-cell sarcomas remain difficult to diagnose and classify. Among these is a rare roundcell sarcoma that harbors a CIC gene rearrangement known as CIC-rearranged undifferentiated round-cell sarcoma, which is most commonly fused to the DUX4 gene. Owing to its aggressive clinical behavior and potential therapeutic implications, accurate identification of this novel soft tissue sarcoma is necessary. Definitive diagnosis requires molecular confirmation, but only a few centers are as yet able to perform this test. Several studies have shown that PEA3 subfamily genes, notably ETV4 (belonging to the family of ETS transcription factors), are upregulated in CIC-rearranged undifferentiated round-cell sarcomas.

We performed a detailed immunohistochemical analysis to investigate ETV4 expression in CIC-rearranged undifferentiated round-cell sarcomas and their potential mimics (especially Ewing sarcomas). The study cohort included 17 cases of CIC-rearranged undifferentiated round-cell sarcomas, and 110 tumors that morphologically mimic CIC-rearranged undifferentiated round-cell sarcomas: 43 Ewing sarcomas, 25 alveolar rhabdomyosarcomas, 20 poorly differentiated round-cell synovial sarcomas, 10 desmoplastic round-cell tumors, 5 BCOR-CCNB3 sarcomas, 5 lymphoblastic lymphomas, and 2 rhabdoid tumors.

All CIC-rearranged undifferentiated round-cell sarcomas (on core needle biopsies and open biopsies) were ETV4-positive with a strong diffuse nuclear pattern. Among the other 110 tumors, only six cases (four Ewing sarcomas, one alveolar rhabdomyosarcoma, and one desmoplastic round-cell tumor) showed focal (o5% of tumor cells) and very weak nuclear expression of ETV4; all other tumors were completely negative for ETV4. 

We conclude that systematic immunohistochemical analysis of ETV4 makes it possible to diagnose undifferentiated round-cell sarcomas (with no molecular markers for sarcoma-associated translocation) such as CIC-rearranged undifferentiated round-cell sarcoma.