Rudelius Martina, Weinberg Olga K, Niemeyer Charlotte M, Shimamura Akiko, Calvo Katherine R
Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Virchows Arch. 2023 Jan;482(1):113-130. doi: 10.1007/s00428-022-03447-9. Epub 2022 Nov 29.
Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200-1228, 2022).
更新伴有胚系易感性的血液系统肿瘤、儿童骨髓增生异常综合征（MDS）和青少年骨髓单核细胞白血病（JMML）的分类对于诊断、治疗、研究和临床试验至关重要。下一代测序技术的进步导致了越来越多基因的发现，这些基因在胚系状态下发生突变并遗传时，易引发血液淋巴系统肿瘤的发生。本综述涵盖了伴有胚系易感性的髓系和淋巴细胞肿瘤分类的最新进展，总结了重要的遗传和表型信息、相关实验室检测以及病理骨髓特征。基因分为三大类，包括：（1）与先天性疾病无关的基因，如CEBPA、DDX41和TP53；（2）与血小板减少或血小板功能障碍相关的基因，如RUNX1、ANKRD26和ETV6；（3）与影响多个器官系统的先天性疾病相关的基因，如GATA2、SAMD9和SAMD9L，以及与经典骨髓衰竭综合征和JMML相关的遗传性基因突变，还有唐氏综合征。创建了一个胚系易感性基因的临时类别，以识别随着越来越多证据表明可能在未来修订分类中正式纳入的基因，因为大量支持数据不断出现。我们还详细介绍了儿童骨髓增生异常综合征（MDS）分类的进展，将儿童难治性血细胞减少症（RCC）的定义扩大到包括伴有胚系易感性患者中MDS的早期表现。最后，介绍了青少年骨髓单核细胞白血病分类的更新内容，从遗传学角度将JMML定义为一种具有经典RAS通路突变的骨髓增殖性/骨髓增生异常性疾病。具有与JMML重叠特征但不携带RAS通路突变的疾病被分类为类JMML。本综述基于Arber等人报道的髓系和淋巴系肿瘤国际共识分类（ICC）（《血液》140(11):1200 - 1228, 2022）。
