Division of Hematopathology.
Department of Laboratory Medicine and Pathology, Division of Genetics.
Am J Surg Pathol. 2021 Apr 1;45(4):550-557. doi: 10.1097/PAS.0000000000001614.
Anaplastic large cell lymphomas (ALCLs) are broadly classified into ALK-positive and ALK-negative. ALK-negative ALCL is composed of DUSP22-rearranged, TP63-rearranged, and triple-negative cases. While lymphoid enhancer-binding factor (LEF1) plays a crucial role in T-cell maturation, limited data exist on its expression in T-cell lymphomas, including ALCL. We characterized the expression of LEF1 in ALCL by immunohistochemistry. LEF1 nuclear expression in the neoplastic cells was graded as negative (0), weak (1+), intermediate (2+), or strong (3+), with the percentage of LEF1-positive neoplastic cells recorded. A total of 45 ALCL cases were evaluated, of which 16 were DUSP22-rearranged. About 93.8% (15/16) DUSP22-rearranged cases showed strong expression of LEF1 in >75% tumor cells, compared with 3.4% (1/29) non-DUSP22-rearranged ALCL (P<0.0001). The striking association of LEF1 protein overexpression with DUPS22 rearrangement in ALCL was further confirmed by a gene expression profiling study which revealed significantly higher LEF1 expression in DUSP22-rearranged ALCL compared with other ALCL subtypes (P=0.0001). Although LEF1 is a nuclear mediator of the Wnt/β-catenin pathway, CTNNB1 RNA and protein levels were not overexpressed in LEF1-positive cases, suggesting the LEF1 overexpression in ALCL may not be involved in the Wnt/β-catenin pathway. The strong and uniform LEF1 expression pattern has a high positive predictive value (93.8%) and high negative predictive value (96%) for DUSP22 rearrangement in ALK-negative ALCL. The combination of characteristic morphologic and molecular features of DUSP22-rearranged cases with the high LEF1 expression further emphasizes that DUSP22-rearranged ALCL represents a distinct clinicopathologic subset of ALCL.
间变性大细胞淋巴瘤（ALCL）广泛分为ALK 阳性和ALK 阴性。ALK 阴性 ALCL 由 DUSP22 重排、TP63 重排和三阴性病例组成。虽然淋巴增强因子结合因子（LEF1）在 T 细胞成熟中发挥着关键作用，但关于其在 T 细胞淋巴瘤中的表达，包括 ALCL，数据有限。我们通过免疫组织化学方法对 ALCL 中 LEF1 的表达进行了特征描述。肿瘤细胞中 LEF1 的核表达被评为阴性（0）、弱阳性（1+）、中等强度（2+）或强阳性（3+），并记录 LEF1 阳性肿瘤细胞的百分比。共评估了 45 例 ALCL 病例，其中 16 例为 DUSP22 重排。与非 DUSP22 重排的 ALCL（3.4%，1/29）相比，约 93.8%（15/16）的 DUSP22 重排病例中>75%的肿瘤细胞显示出强烈的 LEF1 表达（P<0.0001）。通过基因表达谱研究进一步证实了 LEF1 蛋白过表达与 ALCL 中 DUSP22 重排的显著相关性，该研究表明 DUSP22 重排的 ALCL 中 LEF1 的表达明显高于其他 ALCL 亚型（P=0.0001）。尽管 LEF1 是 Wnt/β-catenin 通路的核中介物，但 LEF1 阳性病例中 CTNNB1 RNA 和蛋白水平并未过表达，提示 ALCL 中的 LEF1 过表达可能不涉及 Wnt/β-catenin 通路。ALK 阴性 ALCL 中 DUSP22 重排的 LEF1 强而均匀的表达模式具有高阳性预测值（93.8%）和高阴性预测值（96%）。DUSP22 重排病例的特征形态和分子特征与 LEF1 高表达的结合进一步强调了 DUSP22 重排的 ALCL 代表了 ALCL 的一个独特的临床病理亚群。
