翻译 | 周哲平
编写 | 孙晓冰
审核 | 吴 炯
系统性肥大细胞增多症伴t(8;21)(q22;q22)急性髓系白血病是2021年5月6日刊登在《Blood work images in hematology》上的一篇案例报道。
系统性肥大细胞增多症（SM）是一种罕见的克隆增生性血液肿瘤，95%病例由KIT D816V突变引起。KIT D816V在绝大多数SM的发病中扮演了极其重要的角色，它使得KIT基因异常活化，进而导致肥大细胞的调控失常和异常增殖，所以KIT D816V检测在SM的诊断、用药选择、预后评估等多个方面起到了不可或缺的作用。然而，它并非SM的专属，在急性髓系白血病（Acute Myeloid Leukemia，AML）等一些其他血液系统肿瘤中，KIT D816V检测同样拥有着较高的价值。
A 66-year-old woman with t(8;21)(q22;q22) therapy-related acute myeloid leukemia (AML) with molecular disease persistence after induction and consolidation chemotherapy (respectively, cytarabine/daunorubicin and cytarabine) underwent bone marrow (BM) examination to investigate a recent onset of pancytopenia.
1位伴有t(8;21)(q22;q22)治疗相关的急性髓系白血病(AML)的66岁妇女在诱导和巩固化疗(分别为阿糖孢苷/柔红霉素和阿糖孢苷)后，分子病持续存在，为调查研究近期发生的全血细胞减少而接受骨髓检查。
BM smears revealed myeloblasts (91%) and atypical mast cells (MCs) often hypogranulated with a bilobed nucleus (panels A-B: May-Grnwald-Giemsa stain, ×100 objective, original magnification ×1000).
骨髓涂片显示原始粒细胞(91%)和非典型肥大细胞(MCs)常有颗粒减少和双叶核 (图A-B:迈格吉染色，×100物镜，原图放大倍数×1000)。
注：迈格吉染色(MGG)由May-Grunwald染料和Giemsa染料组成。前者化学名为曙红亚甲基蓝Ⅱ，对胞质着色较好；后者对胞核着色较好。因此MGG染色，可兼两者的优点，常用于细胞涂片染色。
After reinduction chemotherapy, BM aspiration revealed a massive infiltrate of atypical MCs (70%) with few blasts (＜5%) (panel D: May-Grnwald-Giemsa stain, ×20 objective, original magnification ×200).
在诱导化疗后，骨髓穿刺发现大量非典型MCs浸润(70%)，原始细胞少量(＜5%)(图D: 迈格吉染色，×20物镜，原图放大倍数×200)。
The patient had skin lesions (not biopsied).
患者有皮肤病变(未活检)。
Flow cytometry analysis showed CD2/CD25-aberrant expression on MCs.
流式细胞仪检测发现MCs中CD2/CD25表达异常。
Serum tryptase level exceeded 200 ng/mL and molecular analysis by next-generation sequencing highlighted a KIT D816V mutation (variant allele frequency, 14%) that was absent at AML diagnosis. The diagnosis of systemic mastocytosis (SM) with an associated hematological neoplasm was confirmed.
血清胰蛋白酶水平超过200 ng/mL，通过二代测序技术（NGS）的检测发现了一个在AML诊断中不存在的KIT D816V突变(变异等位基因频率为14%)。系统性肥大细胞增多症(SM)与相关血液肿瘤的诊断得到证实。
注：类胰蛋白酶水平在大多数SM患者中则升高。然而，在多达10%的SM患者中(伴或不伴MPCM/UP)，类胰蛋白酶水平<20ng/mL【1，2】。KIT的激活突变与CM和SM的发病机制相关【3-6】。
Fluorescent in situ hybridization analysis on BM smears showed 2 t(8;21)(q22; q22) with RUNX1-RUNX1T1 rearrangements in 47% of tetraploid nucleated cells (panel C: fluorescent in situ hybridization analysis, ×100 objective, original magnification
×1000; red arrows, RUNX1 gene; light green arrows, RUNX1T1 gene; yellow arrows, RUNX1- RUNX1T1 fusion signals), indicating its presence in the MC compartment. This result favors a common origin for MCs and myeloblasts.
骨髓涂片荧光原位杂交分析显示在MC中47%的四倍体细胞中有2组t(8;21)(q22; q22) 伴RUNX1-RUNX1T1重排(图C:FISH分析，×100物镜，原图放大倍数×1000;红色箭头表示RUNX1基因;浅绿色箭头表示RUNX1T1基因;黄色箭头表示RUNX1- RUNX1T1融合信号)。结果支持MCs与原始粒细胞有共同的起源。
SM associated with t(8;21)(q22;q22) AML is an extremely rare variant of SM with an associated hematological neoplasm with a poor prognosis. The patient relapsed with MC persistence despite treatment including midostaurin.
SM伴t(8;21)(q22;q22) AML是一种极其罕见的伴有相关的血液肿瘤SM的变异型，预后较差。尽管患者接受了包括米哚妥林在内的治疗，MC仍持续存在，疾病复发。
肥大细胞增多症
肥大细胞在一个或多个器官系统中的克隆性、肿瘤性增殖而引起的。它的特征是异常的肥大细胞浸润，通常包含多焦点的致密团簇或内聚性聚集体。2017年WHO标准主要分为三类：
1.皮肤肥大细胞增生症（Cutaneous mastocytosis）
2.系统性肥大细胞增生症（Systemic mastocytosis）
3.肥大细胞肉瘤（Mast cell sarcoma）
系统性肥大细胞增多症(SM)
一种罕见的血液肿瘤，WHO分类系统将SM分为5个亚型，其中后三者被称为晚期SM（Adv SM），五种亚型的治疗和预后不同。
SM亚型
SM诊断
主要基于世界卫生组织（WHO）拟定的标准，包括骨髓肥大细胞形态、基因检测、免疫表型和生化指标这四方面【15】。
SM的WHO诊断标准
伴发其他克隆性血液病的系统性肥大细胞增多症（SM-AHN）
SM-AHN患者除SM外，还满足WHO分类所定义的其他相关血液肿（AHN）标准【7,8】。大多数SM-AHN患者都是在50-60岁期间诊断的，通常是为评估血液系统异常而发现【9,10】。约90%的病例中，AHN为髓系起源：通常是骨髓增殖性肿瘤（MPN），如慢性髓系白血病、原发性骨髓纤维化、特发性血小板增多症、真性红细胞增多症、慢性嗜酸性粒细胞白血病；MDS；不可归类的MDS/MPN，如慢性粒-单核细胞白血病【11】。罕见的情况下也可以是急性髓系白血病、继发性急性白血病或淋巴细胞增生性疾病(如多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤)【12,13】，该病例则是SM伴t(8;21)(q22;q22) AML。
KIT D816V突变
绝大多数SM患者都存在KIT基因的突变，其中最常见的就是KIT D816V突变,在SM辅助诊断中占据了重要的地位，大多数SM患者的外周血中都可检出KIT D816V激活突变，提示SM具有多能造血克隆特性【14,15】。KIT D816V突变检测还可以用于识别其他血液肿瘤性疾病合并SM，有回顾性研究对40例t(8;21) (q22;q22) AML患者进行了KIT突变分析，同样发现了4例SM，其中3例为KIT D816V突变，研究人员建议通过形态学、免疫表型分析和KIT突变分析检查所有t(8;21) AML患者是否合并SM【16】，KIT D816V突变对inv(16)(p13;q22)、t(16;16)(p13;q22)和t(8;21)(q22;q22)AML患者预后有影响，突变预示着更高的复发率和更差的预后水平【17-19】。
正文原文所述，“该病例是SM伴t(8;21)(q22;q22) AML，是一种极其罕见的SM变异型，伴有相关的血液肿瘤，预后较差。”
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[1] Escribano L, Alvarez-Twose I, Sánchez-Muñoz L, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009; 124:514.
[2] Bonadonna P, Gonzalez-de-Olano D, Zanotti R, et al. Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations. J Allergy Clin Immunol Pract 2013; 1:474.
[3] Valent P, Sperr WR, Schwartz LB, Horny HP. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol 2004; 114:3.
[4] Galli SJ, Tsai M, Wershil BK. The c-kit receptor, stem cell factor, and mast cells. What each is teaching us about the others. Am J Pathol 1993; 142:965.
[5] Furitsu T, Tsujimura T, Tono T, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest 1993; 92:1736.
[6] Akin C. Molecular diagnosis of mast cell disorders: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn 2006; 8:412.
[7] Metcalfe DD. Classification and diagnosis of mastocytosis: current status. J Invest Dermatol 1991; 96:2S.
[8] Horny HP, Sotlar K, Sperr WR, Valent P. Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: a histopathological challenge. J Clin Pathol 2004; 57:604.
[9] Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113:5727.
[10] Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol 2015; 90:250.
[11] Wimmer J, Hurstel R. Systemic mastocytosis with an associated t(8;21)(q22;q22) acute myeloid leukemia. Blood 2021; 137:2564.
[12] Parker RI. Hematologic aspects of systemic mastocytosis. Hematol Oncol Clin North Am 2000; 14:557.
[13] Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition. IARC, Lyon, 2017.
[14] Nagata H, Worobec AS, Oh CK, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A 1995; 92:10560.
[15] Yavuz AS, Lipsky PE, Yavuz S, et al. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood 2002; 100:661.
[16] Johnson RC, Savage NM, Chiang T, et al. Hidden mastocytosis in acute myeloid leukemia with t(8;21)(q22;q22). Am J Clin Pathol. 2013;140(4):525-535.
[17]中华医学会血液学分会. 中国成人急性髓系白血病（非急性早幼粒细胞白血病）诊疗指南2021年版.2021
[18] Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
[19] Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia. 2013;27(9):1891-1901.
