Abstract
单核细胞增加的慢性粒细胞白血病临床少见，与慢性粒-单核细胞白血病难以鉴别。1例31岁男性患者，以全身疼痛起病，初步诊断为慢性粒单核细胞白血病，经融合基因和染色体等检查最终确诊为慢性粒细胞白血病。除了典型的Ph染色体外，还发现罕见的染色体易位t(2; 7)(p13; p22)。流式细胞学检测单核细胞亚群有助于鉴别诊断，融合基因与单核细胞增加的关系尚不明确。采用酪氨酸激酶抑制剂或者异基因造血干细胞移植治疗。
Keywords: 慢性粒细胞白血病, 慢性粒-单核细胞白血病, 染色体易位t(2, 7)(p13, p22)
Abstract
Chronic myeloid leukemia with a significant increase of monocytes is rare and difficult to identify from chronic myelo-monocytic leukemia in clinic. A 31-year-old male patient with systemic pain was initially diagnosed as chronic myelo-monocytic leukemia, who was finally diagnosed as chronic myeloid leukemia by fusion gene and chromosome examination. In addition to the typical Ph chromosome, a rare chromosome translocation t(2; 7)(p13; p22) was observed. The detection of monocyte subsets by multi-parameter flow cytometry is a diagnostic marker to distinguish the above 2 diseases. The relationship between fusion genes and mononucleosis is not clear. Tyrosine kinase inhibitors or allogeneic hematopoietic stem cell transplantation can be used in the treatment for this disease.
Keywords: chronic myeloid leukemia, chronic myelomonocytic leukemia, chromosome translocation t(2, 7) (p13, p22)
慢性粒细胞白血病(chronic myeloid leukemia，CML)是一种常见的骨髓增殖性肿瘤(myelopro-liferative neoplasms，MPN)。CML的主要特征为不成熟粒细胞显著增加、脾大、BCR-ABL融合基因及Ph染色体阳性。单核细胞增加在CML中十分罕见。目前国外有少量关于单核细胞增加的初诊CML的报道[1-10]，但其临床、病理及发病机制等还需探讨。现报道中南大学湘雅医院(以下简称我院)初诊的此类患者1例，并复习相关文献。
1. 临床资料
患者，男，31岁，2019年12月17日左右无明显诱因出现全身疼痛，以双臀部及肩部为主，疼痛时影响活动，休息后无明显缓解。半月后疼痛加剧，伴胸闷、气促，无胸痛、呕吐、头晕、腹泻。1998年曾因外伤致右肘关节骨折，行“固定复位术”。2019年12月29日入我院急诊，体格检查显示：右上肢肘关节曲面及双手静脉输液处可见大片瘀斑、肝肋下2横指、脾脏肋下平脐。血常规检查显示：白细胞(WBC)为236.5×109/L，血红蛋白(Hb)为107 g/L，血小板(PLT)为47×109/L。乳酸脱氢酶(lactate dehydrogenase，LDH)为2 243 U/L。B超显示左锁骨上窝多发淋巴结大、肝大(肋下缘24 mm)、脾大(肋下缘平脐)。外周血涂片显示：WBC分布增加，分类单核细胞增加(44%)，可见幼稚单核细胞；可见少量(3%)幼粒细胞及嗜碱细胞。骨髓细胞学显示：骨髓增生明显活跃，粒状核细胞系(以下简称粒系)增生活跃(57.5%)，可见巨形杆状核细胞、巨形晚幼粒细胞等粒系类巨变；红细胞系(以下简称红系)增生受抑(0.5%)，淋巴细胞减低，单核细胞增生明显活跃(37%)，幼稚单核细胞及不成熟单核细胞增加。全片见1个颗粒型巨核细胞，血小板少见。诊断结论为慢性粒-单核细胞白血病(chronic myelo-monocytic leukemia，CMML)待排查，请结合临床及相关检查(图1)。流式细胞学检查显示：单核细胞比例增加(40.6%)，部分细胞CD13表达减弱，请结合临床及相关病理资料进行综合分析。初步诊断为骨髓增生异常/骨髓增殖性肿瘤(myelodysplastic/myeloproliferative neoplasm，MDS/MPN)，予以羟基脲治疗，并于2020年1月3日收入病房，继续完善相关检查。复查血常规检查显示：WBC为33.3×109/L，Hb为91 g/L，PLT为24×109/L。骨髓活检结果：HE及PAS染色示骨髓增生极度活跃(90%)，粒系、红系比增大，粒系各阶段可见，以中幼粒细胞及以下阶段为主，单核细胞易见，红系少见，巨核细胞偏少见，可见胞体小、分叶少的巨核细胞。网状纤维染色为MF-1级。小巨核细胞免疫酶标染色结果显示：正常巨核细胞79个，双巨核细胞6个，大单元核小巨核细胞26个，单元核小巨核细胞11个，全片巨核细胞122个。反转录PCR显示：BCR-ABL(p210)融合基因呈阳性，定量为76.77%。荧光原位杂交(fluorescence in situ hybridization，FISH)结果显示：BCR-ABL(p190/p200)融合基因(图2)。染色体核型：46，XY，t(9; 22)(q34; q11)[5]/47，XY，(2; 7)(p13; p22)，t(9; 22)(q34; q11)，+der(22) t(9, 22)(q34; q11)[15](图3)。结合临床及相关检查，最终诊断为CML，予以达沙替尼治疗，目前随访中。
图1.
骨髓细胞学检查(瑞氏吉姆萨染色，×1 000)
Figure 1 Cytology examination of bone marrow (Wright-Giemsa, ×1 000)
A: Immature monocytes are increased; B: There is myeloid dysplasia.
图2.
FISH检测结果
Figure 2 Result of FISH examination
BCR/ABL translocation probe shows that the proportion of yellow fusion signal is 95%.
图3.
骨髓染色体分析结果
Figure 3 Results of bone marrow chromosome analysis
Chromosome karyotype is 47, XY, t(2; 7)(p13; p22), t(9; 22)(q34; q11), +der(22) t(9, 22)(q34, q11).
2. 讨 论
CML是一种以外周血中性粒细胞增加、各阶段幼稚粒细胞和嗜碱性粒细胞增加及脾肿大为特征、起源于多能造血干细胞的克隆性疾病。单核细胞增加可见于多种良性及恶性疾病中，但单核细胞增加在初诊CML中罕见，笔者通过检索文献[1-10]，收集到14例(包括本病例为15例)单核细胞增加的初诊CML资料(表1)，患者多为男性，年龄9个月~76岁，平均外周血WBC为(19.6~236.5)×109/L，平均单核细胞百分比为6%~44%，平均单核细胞绝对计数为(2.5~104.1)×109/L，5例为BCR-ABL(p210)融合基因阳性，10例为BCR-ABL(p190)融合基因阳性；5例可见明显的病态造血。
表1.
15例初诊CML伴单核细胞增加
Table 1 Significant increase of monocytes in 15 patients with CML at initial diagnosis
| 病例 | 发表时间 | 性别/年龄 | 分期 | WBC/(×109·L-1) |
单核 细胞/% |
单核细胞绝对 计数/(×109·L-1) |
未成熟 粒细胞/% |
嗜碱性 粒细胞/% |
病态造血 | BCR-ABL的编码蛋白 | 染色体 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 本病例 | m/31Y | AP | 236.5 | 44.0 | 104.06 | 6.0 | 3.0 |
粒系 巨核系 |
p210 | Ph; t(2, 7)der(22) | |
| Inoue 等[1] | 2017年 | m/48Y | AP | 33.5 | 8.5 | 2.84 | 6.5 | 2.5 |
粒系 红系 巨核系 |
p210 | Ph |
| Dass等[2] | 2011年 | m/37Y | AP | 19.6 | 23.0 | 4.50 | 12.0 | 5.0 |
红系 巨核系 |
p210 | NR |
| Gupta等[3] | 2010年(病例1) | m/19M | CP | 40.0 | 12.0 | 4.8 | 6.0 | 3.0 | 无 | p210 | 46, XY |
| Gupta等[3] | 2010年(病例2) | m/9M | CP/AP | 38.0 | 16.0 | 6.08 | 7.0 | 2.0 | 无 | p210 |
无分 裂象 |
| Hur等[4] | 2002年 | f/66Y | CP | 34.6 | 9.0 | 3.11 | 13.0 | 0 | NR | p190 | Ph |
| Ravandi等[5] | 1999年(病例1) | NR/43Y | AP | 128.5 | 16.0 | 20.56 | NR | 3.0 | NR | p190 | Ph |
| Ravandi等[5] | 1999年(病例2) | NR/70Y | CP | 50.0 | 14.0 | 7.00 | NR | 2.0 | NR | p190 | Ph |
| Ravandi等[5] | 1999年(病例3) | NR/49Y | AP | 163.0 | 14.0 | 22.82 | NR | 13.0 | NR | p190 | Ph |
| 病例 | 发表时间 | 性别/年龄 | 分期 | WBC/(×109·L-1) |
单核 细胞/% |
单核细胞 绝对计数/ (×109·L-1) |
未成熟 粒细胞/% |
嗜碱性粒细胞/% | 病态造血 | BCR-ABL的编码蛋白 | 染色体 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Ravandi等[5] | 1999年(病例4) | NR/76Y | CP | 25.0 | 10.0 | 2.50 | NR | 8.0 | NR | p190 | Ph |
| Ohno等[6] | 1998年 | m/49Y | CP | 73.9 | 32.0 | 23.64 | 25.0 | 1.0 |
红系 巨核系 |
p190 | Ph |
| Melo等[7] | 1994年 | m/52Y | CP | 32.5 | 19.0 | 6.18 | 16.0 | 0 |
红系 巨核系 |
p190 | Ph |
| Nakamura等[8] | 1993年 | m/65Y | CP/AP | 174.4 | 22.0 | 38.37 | 27.0 | 4.0 | NR | p190 | Ph |
| Guo等[9] | 1993年 | m/52Y | CP | 180.0 | 6.0 | 10.80 | 24.0 | 13.0 | NR | p190 | Ph |
| Selleri等[10] | 1990年 | f/44Y | CP | 56.8 | 12.0 | 6.80 | 19.0 | 2.0 | NR | p190 | Ph |
Y：岁，M：月，f：女性，m：男性，CP：慢性期，AP：加速期，NR：无记录。Gupta等报道了2个病例；Ravandi等报道了4个病例。
包括CML在内的MPN侧重于骨髓的增殖，而MDS/MPN则强调有增殖的同时存在病态改变。国际形态学专家组[11]将单核细胞分为4种亚型：原始单核细胞、幼稚单核细胞、不成熟单核细胞及成熟单核细胞。不成熟单核细胞的鉴定及其与幼单核细胞的区别对于区分急性髓系白血病(acute myeloid leukemia，AML)和伴原始细胞增多的CMML至关重要[11]。本例患者幼稚单核细胞及不成熟单核细胞明显增加，同时粒系和巨核系可见明显的病态造血，因此最初的诊断是CMML。Nafe等[12-13]发现在CML中能观察到胞体较小的巨核细胞，甚至微小巨核细胞。Bain等[14]报道1例CML患者存在嗜碱性粒细胞发育异常，包括胞质可见空泡、核过分叶、颗粒减少等。Rajpal等[15]发现CML患者外周血粒细胞发育异常，包括细胞核分叶不良、颗粒减少、染色质异常浓集，并认为发育不良是CML加速期的特征。包括本例在内的5例CML均可见病态造血，由此可见部分CML患者骨髓中可以有不同程度的病态造血。同时，MPN可以伴有单核细胞增加，尤其是原发性血小板增多症(essential thrombocythemia，ET)(约见于20%的患者)和骨髓纤维化(myelofibrosis，MF)(约见于15%的患者)，这样便使诊断时难以区分MPN和CMML[16-17]。
Selimoglu-Buet等[18-19]利用多参数流式细胞术检测外周血单核细胞亚群，认为CMML患者CD14+/CD16-这类经典型单核细胞亚群有所增加，其百分比大于94%时能快速准确地区分CMML及单核细胞增加的MPN。Hudson等[20]则进一步证实：CD14-/CD16+非经典型单核细胞的定量检测可以在临床实践中作为CMML在血液及骨髓标本中的诊断标志。因此，流式细胞术检测骨髓及外周血单核细胞亚群可能成为鉴别CMML和MPN的重要依据。单核细胞亚群的流式细胞术检测与骨髓形态学、分子生物学相结合，将有助于提高该病诊断的准确性。
BCR基因位于22号染色体长臂(q11)，因其断裂点不一，BCR-ABL融合基因及其蛋白质产物呈现多样性。当断裂点位于22号染色体的主要断裂区(major breakpoint cluster region，M-bcr)的外显子e12~e16(新命名为b1~b5)之间时，形成转录产物e13a2(b2a2)及e14a2(b3a2)[21-22]，其最终产物为p210胞浆质蛋白质。当断裂点少见地发生在上游次要断裂区(minor breakpoint cluster region，m-bcr)时，形成转录产物e1a5[4, 23]，则编码p190胞质蛋白质。当断裂点更少见地位于微小断裂区时，形成转录产物e19a2[23-25]等，编码p230胞质蛋白质。Nakamura等[8, 10]先后报道了融合基因(p190)阳性的CML伴有单核细胞增加，而Melo等[7]认为融合基因p190导致了单核细胞增加而非融合基因p210，这个观点亦与少数报道[5-6]相一致。然而，2010年Gupta等[3]报道了2例儿童融合基因p210阳性的CML伴单核细胞增加，并均被怀疑患有幼年型粒单核细胞白血病(juvenile myelomonocytic leukemia，JMML)。Inoue等[1-2]报道了2例成人男性融合基因p210阳性的CML伴单核细胞增加的患者，之前均被误诊为CMML。本病例患者最终亦诊断为融合基因p210阳性的CML，且单核细胞比例甚高，因此，笔者认为单核细胞增加与CML融合基因亚型之间的关系仍有待进一步研究。
随着病程的进展，CML分为慢性期、加速期和急变期[26]。随着慢性期向急变期的过渡，60%~80%的患者出现了典型的Ph染色体以外的染色体改变，如双Ph染色体、+8或+19三体、等臂17染色体[27]。在本例患者中，除了典型的Ph染色体改变外，还检测到额外的染色体易位t(2; 7)(p13; p22)和双Ph染色体。笔者查阅文献发现：目前仅有1例CML患者在使用伊马替尼治疗后有2号和7号染色体易位，并且通过FISH和高分辨率阵列验证的多色波段技术(high resolution array-proven multicolor banding，aMCB)证实其易位位点为(p13.1; p21.3)[28]。本例染色体位点暂未被FISH或aMCB证实，这种CML罕见的染色体易位，加上明显的单核细胞增加及发育不良的具体机制及临床意义有待进一步阐明。
目前，CML慢性期(除合并妊娠外)的一线治疗为酪氨酸激酶抑制剂(tyrosine kinase inhibitor，TKI)[29]。TKI治疗以BCR-ABL融合基因为靶点，使80%~90%的CML患者获得分子生物学及细胞遗传学缓解，并显著提高患者的生存质量和生存寿命[30-31]，这些患者的生存寿命可与年龄相匹配的普通人群预期寿命相当[32]，对于多种TKI耐药或服药后不能恢复正常造血的少数初次CML慢性期患者推荐异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation，HSCT)[29]。CML进展为加速期的应视为高风险患者，如果TKI效果不理想，应考虑HSCT[29]。对于正在进展或者已经进展为急变期的患者，任何目前可用的TKI治疗的长期预后都很差[33]，在病情得到初步控制后应尽一切努力提供HSCT，如患者在移植前再次转为慢性期则可以改善移植效果[34-35]。本例患者给予达沙替尼治疗，目前在随访中。
综上所述，单核细胞显著增加的初诊CML伴染色体易位t(2; 7)(p13; p22)目前十分罕见，缺乏对其认识，该病的临床特点、治疗方案及预后需要更多病例支持，其发病机制更需进一步明确。
利益冲突声明
作者声称无任何利益冲突。
原文网址
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