Frutos Díaz-Alejo Jesús, Prieto-Potín Iván, Manso Rebeca, Rodríguez Marta, Rebollo-González Marcos, Díaz de la Pinta Francisco Javier, Morales-Gallego Miriam, Rodríguez-Pinilla Socorro María, Onaindia Arantza
Pathology Department, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain.
Pathology Department, Osakidetza Basque Health Service, Araba University Hospital, 01070 Vitoria-Gasteiz, Spain.
Int J Mol Sci. 2025 Jun 19;26(12):5871. doi: 10.3390/ijms26125871.
Anaplastic Large Cell Lymphoma (ALCL) represents a diverse group of mature T-Cell Lymphomas unified by strong CD30 expression but with different molecular and clinical subtypes. This review summarizes recent molecular advances in ALCL, highlighting key discoveries that have refined its classification, diagnosis, and therapeutic strategies. ALCL comprises four major entities: systemic ALK-positive ALCL, systemic ALK-negative ALCL, Breast Implant-Associated ALCL (BIA-ALCL), and primary cutaneous ALCL. Each subtype exhibits unique phenotypes, along with cytogenetic and molecular alterations that affect clinical outcomes. Nevertheless, different oncogenic mechanisms mediate STAT3 activation. In ALK-positive ALCL, ALK fusion proteins drive oncogenesis via constitutive activation of STAT3 and other signaling pathways. ALK-negative ALCL comprises heterogeneous genetic subtypes, in which JAK/STAT3 pathway alterations and novel gene fusions are gaining recognition as potential therapeutic targets. This review emphasizes the need for integrative molecular diagnostics to improve stratification of ALCL subtypes and targeted treatment approaches. Future research should focus on elucidating the biological mechanisms underlying these alterations and on translating molecular insights into clinical practice.
间变性大细胞淋巴瘤（ALCL）是一组成熟T细胞淋巴瘤，其共同特征是CD30强表达，但具有不同的分子和临床亚型。本综述总结了ALCL最近的分子进展，重点介绍了在其分类、诊断和治疗策略方面取得的关键发现。ALCL包括四个主要类型：系统性ALK阳性ALCL、系统性ALK阴性ALCL、乳房植入物相关ALCL（BIA-ALCL）和原发性皮肤ALCL。每个亚型都表现出独特的表型，以及影响临床结果的细胞遗传学和分子改变。然而，不同的致癌机制介导STAT3激活。在ALK阳性ALCL中，ALK融合蛋白通过STAT3和其他信号通路的组成性激活驱动肿瘤发生。ALK阴性ALCL包括异质性遗传亚型，其中JAK/STAT3通路改变和新的基因融合正逐渐被视为潜在的治疗靶点。本综述强调了综合分子诊断对于改善ALCL亚型分层和靶向治疗方法的必要性。未来的研究应集中于阐明这些改变背后的生物学机制，并将分子见解转化为临床实践。
