Advances in Clinical Medicine
Vol. 12  No. 07 ( 2022 ), Article ID: 53479 , 7 pages
10.12677/ACM.2022.127901

血清标志物与弥漫大B细胞淋巴瘤预后关系的研究进展

付滕1,杨香会1,张海亚1,王彦丽2,李丽2,接贵涛2*

1潍坊医学院,山东 潍坊

2临沂市中心医院血液科,山东 临沂

收稿日期:2022年6月8日;录用日期:2022年7月1日;发布日期:2022年7月11日

摘要

弥漫大B细胞淋巴瘤是最常见的非霍奇金淋巴瘤,具有高度异质性。利妥昔单抗时代,患者的治愈率得到很大的提高,但仍有部分患者出现耐药或早期复发,传统的预后评估手段在新时期受到了极大的挑战。近些年,血清标志物因其易获得、便于动态评估和价格低廉等优势,在DLBCL的预后评估中的作用受到关注。本文就初诊及治疗过程中患者的外周血淋巴细胞/单核细胞比值(LMR)、β2微球蛋白(β2MG)、红细胞沉降率(ESR)、红细胞分布宽度(RDW)做一综述。

关键词

弥漫大B细胞淋巴瘤,血清标志物,预后

Research Advances in the Relationship between Serum Markers and the Prognosis of Diffuse Large B-Cell Lymphoma

Teng Fu1, Xianghui Yang1, Haiya Zhang1, Yanli Wang2, Li Li2, Guitao Jie2*

1Weifang Medical University, Weifang Shandong

2Department of Hematology, Linyi Central Hospital, Linyi Shandong

Received: Jun. 8th, 2022; accepted: Jul. 1st, 2022; published: Jul. 11th, 2022

ABSTRACT

Diffuse large B-cell lymphoma is the most common non-Hodgkin lymphoma and is highly heterogeneous. In the era of rituximab, the cure rate of patients has been greatly improved, but some patients still develop drug resistance or early recurrence, and the traditional prognostic evaluation methods have been greatly challenged in the new period. In recent years, the role of serum markers in the prognosis assessment of DLBCL has attracted attention because of its advantages of easy availability, easy dynamic assessment and low price. In this paper, the peripheral blood lymphocyte/monocyte ratio (LMR), β2 microglobulin (β2MG), erythrocyte sedimentation rate (ESR), and red blood cell distribution width (RDW) of patients during initial diagnosis and treatment are reviewed.

Keywords:Diffuse Large B-Cell Lymphoma, Serum Markers, Prognosis

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma, DLBCL)是来源于B淋巴细胞的恶性肿瘤,为最常见的非霍奇金淋巴瘤(non Hodgkin lymphoma, NHL),占NHL的25%~50% [1]。DLBCL在细胞起源、分子遗传学特征、临床表现、治疗效果、预后以及转归等方面均呈现明显异质性 [2],目前标准一线化疗R-CHOP (利妥昔单抗、环磷酰胺、阿霉素、长春新碱、强的松)方案能治愈半数以上的患者,但仍有约40%患者出现初治耐药/难治或病灶消退后短期复发 [3]。因此明确预后因素,在诊断初期发现高风险患者、给予个体化分层治疗对延长生存期、改善生活质量具有重要意义。国际预后指数(international prognostic index, IPI)是目前DLBCL应用最广泛的预后评价系统。但IPI评分是在利妥昔单抗应用于临床之前提出来的,传统化疗方案加入利妥昔单抗之后,各危险组的生存得到改善,IPI评分预后价值下降 [2] [3]。因此确定新的预后标志物至关重要,目前基因表达谱、免疫组化等分子预后因素及PET-CT检查等也有助于判断其预后,但因以上检查成本过高,在临床上较难推广。寻找有效且容易在临床开展的预后指标具有重要意义。

肿瘤的发生发展与机体对肿瘤细胞的免疫反应、肿瘤细胞本身的分子和生物学机制及肿瘤生长的微环境均存在密切的关系。Iwahori等人研究表明外周血中的炎症指标和肿瘤浸润淋巴细胞(TILs)在功能及免疫表型上存在一定的相似性,该研究提示我们血清标志物在肿瘤的发生发展过程中可以起到预测作用 [4]。本文就外周血中淋巴细胞/单核细胞比值(LMR)、β2微球蛋白(β2MG)、红细胞沉降率(ESR)、红细胞分布宽度(RDW)与DLBCL患者预后关系的研究进展作一综述。

2. 淋巴细胞/单核细胞比值(LMR)

单核细胞从骨髓进入外周血时仍是一种尚未成熟的细胞,可以分化为巨噬细胞和树突状细胞。正常的单核细胞可以诱导淋巴细胞产生特异性免疫性反应、对抗细胞内致病菌和寄生虫、识别并杀伤肿瘤细胞;当分化为巨噬细胞时,可以吞噬、清除受伤、衰老的细胞及其碎片。但在肿瘤细胞和基质细胞分泌的趋化因子的驱使下,募集到肿瘤组织内,分化成为肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs),成为肿瘤组织中最丰富的免疫细胞群。TAMs促进肿瘤血管生成和抑制免疫应答,从而促进肿瘤的生长和发育并失去杀伤肿瘤细胞的能力 [5] [6] [7]。淋巴细胞由淋巴器官产生,在机体内起到免疫监视的作用,用过诱导毒性细胞死亡、破环残留的恶性细胞从而在肿瘤免疫防御中发挥重要作用。当淋巴细胞数量减少时,机体对抗肿瘤细胞的能力降低,从而促进肿瘤的复发和转移。有研究表明,在免疫受损的人群中(包括移植后患者和感染人类免疫缺陷病毒的患者等),淋巴瘤的发病率升高。淋巴细胞减少是反映机体免疫功能低下的指标,是DLBCL的不良预后因素 [5] [8] [9] [10]。因此,绝对淋巴细胞计数(absolute lymphocyte count, ALC)的降低和绝对单核细胞计数(absolute monocyte count, AMC)升高都可以成为DLBCL患者的不良预后。外周血淋巴细胞与单核细胞比值(lymphocyte to monocyte ratio, LMR)将机体的免疫能力与肿瘤微环境联系起来,LMR的降低是DLBCL预后的不利因素。蔡春颖等选取NHL患者56例,以LMR中位值2.17为阈值,单因素分析PFS的影响因素包括IPI、ALC、LMR、血小板绝对计数;OS的影响因素包括IPI、外周血中性粒细胞、淋巴细胞绝对数以及初诊时的LDH。多因素分析PFS的影响因素为LMR,LMR ≥ 2.17组的2年PFS显著高于LMR < 2.17组。OS的影响因素包括LMR和IPI,LMR ≥ 2.17组2年OS显著高于LMR小于2.17组 [11]。Leyre Bento等回顾性研究包括992例接受R-CHOP治疗的DLBCL患者,在多因素分析中,LMR、年龄、RDW等与PFS独立相关 [12]。Shujuan Zhou等人通过回顾性173例DLBCL患者在初诊和一线治疗完成时的LMR,发现LMR < 3.2的患者PFS和OS率显著低于LMR ≥ 3.2的患者。对初诊时LMR < 3.2的94例患者行单因素分析发现,无论LMR是否升高,治疗完成后的LMR、B症状和疾病处于III/IV期均与PFS和OS显著相关;行多因素分析发现,一线治疗结束后LMR值未升高是OS和PFS的独立预测因子。无论LMR是否达到截断值,相对于初诊时LMR的升高是有利临床预后 [13]。刘琦、张素芳等人认为LMR结合肿瘤负荷(如LDH)能更有效预测DLBCL患者的预后 [5] [8]。目前,关于LMR在DLBCL预后中的研究较多,大部分认为LMR对患者的预后有显著影响,但也不乏一些相反的结论 [14] [15]。受到研究纳入患者的年龄、治疗方案、纳入研究病例数不足等的影响,LMR的截断值目前缺乏统一性,但是随着样本量的扩充,LMR未来可以作为一种简单、廉价的工具,在DLBCL预后研究中发挥重要作用。

3. β2微球蛋白(β2MG)

β2MG存在于几乎所有有核细胞的膜表面,在白细胞表面尤其丰富,白细胞膜的更新和转变是血清β2MG的主要来源,形成主要组织相容性复合体I类抗原的轻链亚单位 [16] [17]。β2MG广泛参与癌细胞生存、增殖、凋亡甚至转移的功能调节 [18]。脑脊液β2MG水平用于评估与中枢神经系统有关的疾病;血液或尿素中β2MG的异常水平与多种疾病有关,例如一些急性和慢性炎症、肝或肾功能障碍、一些病毒感染和几种恶性肿瘤 [19] [20] [21]。自20世纪60年代末发现β2MG以来,血清β2MG水平已被广泛用于评估其对多种血液病的预后价值 [22]。众所周知,多发性骨髓瘤患者血清β2MG水平的测定被认为是分期和临床治疗的关键,然而,它在预测DLBCL患者临床预后方面的作用尚未得到广泛研究。Kanemasa等 [23] 研究发现,DLBCL患者血清中β2MG水平升高与B症状、PS > 1、晚期、结外疾病、LDH水平升高、IPI和NCCN-IPI中高风险患者相关。该研究通过使用ROC曲线,确定β2MG水平的最具辨别力的临界值为3.2 mg/L,AUC值为0.831。另外,该研究还发现β2MG水平与DLBCL患者的化疗反应、OS和PFS显著相关,β2MG ≥ 3.2 mg/L与β2MG < 3.2 mg/L的患者相比,β2MG ≥ 3.2 mg/L患者化疗后的完全缓解率显著降低以及OS和PFS也显著降低。因此β2M水平对DLBCL患者的预后具有一定的提示作用。血清β2MG水平已被证明是多种组织学亚型淋巴瘤的一个强有力的预后因素。然而,除滤泡性淋巴瘤外,该标记物尚未被纳入临床使用的淋巴瘤预后模型 [24]。DLBCL具有明显的异质性,目前的指标体系还有改进的余地,血清β2MG水平可能有助于提供更好的预后信息。Chen等 [25] 基于血清β2MG水平、外周血中性粒细胞计数(ANC)、外周血单核细胞计数(AMC)、PS和结外病变五个参数建立新的预后模型,通过该模型对817例新诊断DLBCL患者的预后进行评估,研究发现,包括β2MG水平在内的新风险模型有效地分层了DLBCL患者的生存率,其预后评估能力优于IPI,更好地将新诊断的DLBCL患者分为各种风险类别。由此可见,血清β2M水平是一个重要的观察和判断指标,在反映DLBCL患者预后及疗效方面有一定意义。除此之外,将血清β2MG水平纳入并更新目前临床使用的DLBCL预后模型将更准确的评估DLBCL的预后和指导治疗。

4. 红细胞沉降率(ESR)

红细胞沉降率(erythrocyte sedimentation rate, ESR)是红细胞的沉降速度,在机体正常状态下ESR处于稳定状态,当出现感染、脓毒症、恶性肿瘤及自身免疫系统疾病时,ESR会发生变化 [26]。大进多数肿瘤的发生与机体的炎症存在一定的相关性,非特异性炎症通过诱变微环境或促基因突变参与了癌症的发展过程。C反应蛋白与急性炎症反应相关,ESR与慢性炎症反应相关,而持续的慢性炎症在肿瘤进程中发挥更为关键的作用。有研究表示ESR的升高与霍奇金淋巴瘤、乳腺癌、胶质瘤、胃癌、大肠癌、前列腺癌、肾细胞癌及蕈样真菌病的不良预后相关 [27]。章尤权等人通过对81例DLBCL患者的ESR等指标进行分析发现较高水平的ESR较正常组OS和PFS更短,单因素回归分析中证明较高水平的ESR是影响DLBCL患者OS和PFS的危险因素;多因素回归分析较高水平的ESR不是OS的独立危险因素,但是DLBCL患者PFS的独立危险因素 [28]。Shuang Wu等人首次通过对182例DLBCL患者的ESR与临床特征进行分析,设定ESR的截断值为37.5 mm/h,对ESR进行动态评估,发现CR/PR患者初诊时的ESR低于截断值,并在治疗中一直低于截断值,而SD/PD患者的ESR高于截断值或在治疗后升高。多因素分析认为ESR时DLBCL的OS和PFS的独立预后因素 [29]。Rotaru等人一项为49例的小样本研究认为ESR在DLBCL中的预后价值仍不确定,其结果可能受样本量的限制 [30]。目前关于ESR在DLBCL预后中的研究相对较少,受到研究群体及研究对象数量的限制,关于ESR对DLBCL预后的影响存在争议,但因ESR的廉价、易获得性,使得在日后的DLBCL动态监测中发挥不可否认的作用。

5. 红细胞分布宽度(RDW)

红细胞分布宽度(red blood cell distribution width, RDW)是红细胞体积变异性的常规生物标志物,也是红细胞内稳态的指标 [31]。它反映了红细胞生成受损和红细胞存活异常,与炎症、营养不良和肾功能受损以及促红细胞生成素(EPO)生成不足有关 [32] [33]。慢性炎症反应和营养不良可以抑制红细胞生成,缩短红细胞在血液中的存活时间,从而导致RDW的增加 [34]。RDW被认为是一种炎症相关标志物。炎症是癌症发生和发展的关键调节因素 [35]。肿瘤微环境中炎症细胞分泌的大量肿瘤分泌因子和细胞因子可以影响肿瘤细胞的增殖、存活、耐药性和迁移,所以癌症相关炎症被认为是肿瘤发展和进展的标志性特征 [36]。另外,癌症患者的营养异常可导致各种矿物质和维生素(如铁、叶酸和维生素B12)的缺乏。众所周知,RDW受这些矿物质和维生素缺乏的影响 [37]。因此,在炎症反应中起关键作用的RDW因其与炎症和癌症之间的联系而备受关注。实验室血液分析仪自动报告的这一简单参数可能有多种临床应用。一些研究调查了RDW在恶性肿瘤患者中的预后价值,例如,较高的RDW水平也与晚期癌症和转移显著相关 [38] [39]。另外,越来越多的证据表明,RDW水平升高与各种癌症的不良预后相关,包括食管癌 [40]、胃肠道肿瘤 [41]、肝癌 [42]、肺癌 [43] 和血液系统恶性肿瘤 [44]。目前多项研究表明RDW增加与DLBCL预后较差相关。Zhou等 [45] 对161例DLBCL患者的RDW与临床特征之间的相关性进行了评估。该研究发现,将14.1%视为RDW的临界值,高水平RDW与更频繁的B症状、更高的IPI评分、更多的结外疾病部位以及较低的ECOG评分相关。另外,RDW高的患者OS较短(2年OS率53.6%对83.6%,P < 0.001),PFS)较短(2年PFS率44.7%对81.8%,P < 0.001)。该研究证明,高RDW提示DLBCL患者预后不良。相同的是,Periša等人 [46] 以及Li等人 [47] 的研究同样证明了该结论,不同的是以上两项研究的RDW的临界值分别为15%和14.35%,但临界值彼此之间相差不大。因此,目前认为RDW是DLBCL患者的一个容易获得且廉价预后标志物,只是具体的诊断临界值尚需进一步探索。

6. 展望

综上所述,DLBCL作为一种具有异质性的恶性肿瘤,虽然其预后评价系统较为完善,但随着免疫治疗时代的发展,既往的IPI评分已经不完全适用于R-CHOP方案下DLBCL的评价。校正后的R-IPI、NCCN-IPI虽较之前改善,但受到经济情况及患者病情状况的限制,一些检查,如PET-CT、骨髓穿刺等不能完成。因此寻找一种便捷、经济、灵敏度高的评价指标尤为重要,外周血的检查数据因其便宜、易获取可用于动态监测。目前有研究表明LMR、ESR、β2MG、RDW等实验室指标对血液系统恶性肿瘤的预后及动态监测起指导作用。受到样本量的限制,目前外周血实验室指标缺乏统一的截断值,但随着前瞻性、大样本、多中心研究的进行,外周血生物标志物在DLBCL的治疗监测及预后评价起重要作用。

基金项目

基于石墨烯量子点多循环扩增计数DNA化学发光检测淋巴瘤ctDNA的研究(编号:ZR201911070516)。

文章引用

付 滕,杨香会,张海亚,王彦丽,李 丽,接贵涛. 血清标志物与弥漫大B细胞淋巴瘤预后关系的研究进展
Research Advances in the Relationship between Serum Markers and the Prognosis of Diffuse Large B-Cell Lymphoma[J]. 临床医学进展, 2022, 12(07): 6239-6245. https://doi.org/10.12677/ACM.2022.127901

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  48. NOTES

    *通讯作者。

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