儿童成熟B细胞非霍奇金淋巴瘤临床特点和预后分析

目的探讨儿童成熟B细胞非霍奇金淋巴瘤(B-NHL)患儿的临床特征、疗效、生存情况，以及预后相关危险因素。 方法选择2010年1月至2018年12月，四川大学华西第二医院收治的67例儿童B-NHL患儿为研究对象。其中，伯基特淋巴瘤/L3急性淋巴细胞白血病(BL/L3-ALL)、弥漫大B细胞淋巴瘤(DLBCL)及其他B-NHL(病理检查结果为骨髓B淋巴细胞高增殖活性，除外上述2种B-NHL)分别为51、11及5例，将其分别纳入BL组、DLBCL组及其他B-NHL组。采用回顾性分析方法，收集3组患儿的临床病例资料，包括确诊年龄、性别、临床特征、实验室检查结果、B-NHL临床分期、治疗与随访结果及预后等。对本组67例B-NHL患儿进行生存分析，如2年和5年总体生存(OS)率、无事件生存(EFS)率。3组患儿的生存曲线比较，采用Cox比例风险回归模型进行分析。根据既往研究结果，并结合临床经验及B-NHL患儿预后影响因素的单因素分析结果，对B-NHL患儿预后影响因素，进行多因素非条件logistic回归分析。本研究遵循的程序符合2013年修订的《世界医学协会赫尔辛基宣言》要求。3组患儿病程比较，差异无统计学意义(P>0.05)。 结果①患儿年龄、性别：67例B-NHL患儿确诊时，中位年龄为7.0岁(1.8～14.6岁)；其中男性患儿为48例(71.6%)，女性为19例(28.4%)，男、女患儿比为2.5∶1。3组患儿的年龄、性别构成比比较，差异均有统计学意义(χ²＝8.054、8.677，P＝0.018、0.013)，并且DLBCL组患儿年龄和男性患儿所占比例，分别大于或高于BL组，差异亦均有统计学意义(Z＝2.866、P＝0.004，χ²＝3.892、P＝0.049)。②B-NHL原发部位及骨髓和CNS受累情况：化疗前，67例B-NHL患儿均完成影像学、骨髓穿刺涂片及脑脊液检查。BL组中，BL/L3-ALL原发部位位于腹腔者最多，占39.2%(20/51)，DLBCL组患儿中，DLBCL原发部位位于外周淋巴结为主，占45.5%(5/11)，其他B-NHL组患儿中，原发部位位于腹腔者最多，占60.0%(3/5)。此外，11例患儿存在骨髓和CNS受累(均为BL组患儿)。③实验室检查结果：39例(58.2%)患儿血清LDH水平升高，中位血清LDH水平为498 U/L(153～6 640 U/L)。BL组患儿Bcl-6阳性表达率(86.4%，38/44)和C-MYC基因重排阳性率(96.3%，26/27)，均显著高于DLBCL组的54.5%(6/11)和0，并且差异均有统计学意义(χ²＝6.960、26.527，P＝0.031、<0.001)。④临床分期：3组患儿的临床分期构成比比较，差异有统计学意义(χ²＝13.949、P＝0.012)。BL组患儿临床分期为Ⅲ/Ⅳ期所占比例(80.4%，41/51)，均显著高于DLBCL组的36.4%(4/11)，并且差异有统计学意义(χ²＝6.740、P＝0.009)。⑤随访结果：对67例患儿随访截至时间为2019年3月1日，中位随访时间为49个月(2～104个月)，完全缓解(CR)为49例，部分缓解(PR)为7例，进展/复发为9例(5例死亡、3例失访、1例经治疗后无病存活)，其他原因所致患儿死亡为2例(1例因严重感染放弃治疗而死亡，1例化疗疗程结束后死亡)。⑥生存情况：67例B-NHL患儿的2年OS率、EFS率分别为88.8%、85.7%，5年OS率、EFS率分别为88.8%、83.2%。3组患儿5年OS率和5年EFS率组间分别比较，差异均无统计学意义(P>0.05)。67例患儿的中位复发时间为9个月(2～37个月)，2年、5年累积复发率(CIR)分别为11.3%、13.9%。存在骨髓/CNS受累患儿的5年OS率(71.6%)和5年EFS率(59.7%)，均显著低于无骨髓/CNS受累者的92.2%和87.6%，并且差异均有统计学意义(χ²＝5.001、6.319，P＝0.025、0.012)。⑦单因素分析：复发/进展和非复发/进展患儿的单因素分析结果显示，复发/进展患儿骨髓/CNS受累者所占比例和肿瘤裂解综合征发生率分别为50.0%(4/8)和25.0%(2/8)，显著高于非复发/进展患儿的11.9%(7/59)和1.7%(1/59)，二者比较，差异有统计学意义(χ²＝4.946、P＝0.026；P＝0.036)；复发/进展患儿2个疗程内达CR率(12.5%，1/8)显著低于非复发/进展患儿(69.5%，41/59)，二者比较，差异亦有统计学意义(χ²＝9.782、P＝0.002)。⑧多因素分析：结合已有研究结果及临床经验，以及单因素分析结果，对B-NHL患儿预后影响因素的多因素非条件logistic回归分析结果显示，骨髓/CNS受累(OR＝6.536，95%CI：1.085～39.380，P＝0.040)和2个疗程内未达CR(OR＝14.682，95%CI：1.582～136.240，P＝0.018)是B-NHL患儿疾病复发/进展的独立危险因素。 结论儿童B-NHL以病理类型为BL最为常见，原发部位位于回盲部最为常见；其次为DLBCL，其原发部位位于外周淋巴结最为常见。骨髓/CNS受累和2个疗程未达CR是B-NHL患者发生复发/进展的危险因素。尽管B-NHL患儿2年EFS及5年EFS均>80%，但是，临床分期为Ⅳ期及进展/复发的B-NHL患儿的预后仍然尚待提高。

Clinical characteristics and prognosis of mature B-cell non-Hodgkin lymphoma in children

Objective To study clinical features and prognosis of childhood mature B-cell non-Hodgkin lymphoma(B-NHL).Methods Sixty-seven cases of pathologically-confirmed B-NHL from January 2010 to December 2018 in West China Second University Hospital,Sichuan University were enrolled in this retrospective study.According to different pathological types,they were divided into Burkitt lymphoma(BL)group(n=51),diffuse large B-cell lymphoma(DLBCL)group(n=11)and other B-NHL group(n=5,pathological examination results were high proliferative activity B cell lymphoma).The retrospective analysis method was used to collect the clinical data of these subjects,including age,gender,clinical characteristics,laboratory examination results,clinical stages,treatment results and follow-up.Kaplan-Meier method was used to analyze the survival of children with B-NHL in this group,such as 2-year and 5-year overall survival(OS)rate and event-free survival(EFS)rate,and Cox propertional hazards model was used to compare OS and EFS curves among three groups.According to previous research results,combined with clinical experience and single factor analysis results of clinical factors affecting the prognosis of children with B-NHL,multivariate non-conditional logistic analysis was carried out on the influencing factors of prognosis of children with B-NHL.This study was in line with the requirements of World Medical Association Declaration of Helsinki revised in 2013.There was no significant difference among 3 groups in the course of the diseases(P>0.05).Results①The median age of 67 children with B-NHL was 7 years old(1.8-14.6 years old).Among them,48 cases(71.6%)were boys,and 19 cases(28.4%)were girls,and the ratio of boys to girls was 2.5∶1.There was statistically significant differences in age and gender ratio among three groups(χ2=8.054,8.677;P=0.018,0.013).The age and the proportion of boys in DLBCL group were older and higher than those in BL group,respectively,and the differences were statistically significant(Z=2.866,P=0.004;χ2=3.892,P=0.049).②All of the 67 cases completed imaging examination,bone marrow smear and cerebrospinal fluid examination before chemotherapy.The primary tumor sites in BL group tended to be more common in the abdomen,while peripheral lymph nodes were more commonly involved at disease onset in DLBCL group.In addition,11 children had bone marrow and CNS involvement(all children in the BL group).③Laboratory findings showed that 39 cases(58.2%)had elevated serum LDH levels,with a median serum LDH level of 498 U/L(153-6640 U/L).The positive expression rate of Bcl-6(86.4%,38/44)and the positive rate of C-MYC gene rearrangement(96.3%,26/27)in BL group were significantly higher than those of 54.5%(6/11)and 0 in DLBCL group,and the differences were statistically significant(χ2=6.960,26.527;P=0.031,<0.001).④There was a significant difference in the constituent ratio of different clinical stages among 3 groups(χ2=13.949,P=0.012).The proportion of children with clinical stageⅢ/Ⅳin BL group(80.4%,41/51)was significantly higher than those of 36.4%(4/11)in DLBCL group,and the difference was statistically significant(χ2=6.740,P=0.009).⑤All the 67 cases were followed up until March 1,2019.The median follow-up time was 49 months(2-104 months).Complete remission(CR)was achieved in 49 cases,partial remission(PR)in 7 cases,progression/recurrence in 9 cases(5 cases died,3 cases were lost visit to follow-up,1 case survived without disease).Other causes of death were 2 cases(1 case died of severe infection after giving up treatment,1 case died after the end of chemotherapy course).⑥The 2-year OS and EFS rates of the 67 cases were 88.8%and 85.7%,respectively,and the 5-year OS and EFS rates were 88.8%and 83.2%,respectively.There were no significant differences in 5-year OS rate and 5-year EFS rate among three groups(P>0.05).The median time to recurrence was 9 months(2-37 months),and the 2-year and 5-year cumulative incidence of relapse(CIR)were 11.3%and 13.9%,respectively.In addition,the 5-year OS rate(71.6%)and 5-year EFS rate(59.7%)in patients with bone marrow/CNS involvement were significantly lower than those of 92.2%and 87.6%in patients without bone marrow/CNS involvement,and the differences were statistically significant(χ2=5.001,6.319,P=0.025,0.012).⑦The results of univariate analysis for children with recurrence/progression and non-recurrence/progression showed that the proportion of bone marrow/CNS involvement and the incidence rate of tumor lysis syndrome in children with recurrence/progression were 50.0%(4/8)and 25.0%(2/8),respectively,which were significantly higher than those of 11.9%(7/59)and 1.7%(1/59)in children without recurrence/progression,and the differences were statistically significant(χ2=4.946,P=0.026;P=0.036);the CR rate(12.5%,1/8)within 2 courses in children with recurrence/progression was significantly lower than that of 69.5%(41/59)in children without recurrence/progression,and the difference was also statistically significant(χ2=9.782,P=0.002).⑧Combined with the results of existing studies and clinical experience,as well as the results of above univariate analysis,the results of multivariate non-conditional logistic analysis of prognostic factors in children with B-NHL showed that bone marrow/CNS involvement(OR=6.536,95%CI:1.085-39.380,P=0.040)and failure to achieve CR within 2 courses of treatment(OR=14.682,95%CI:1.582-136.240,P=0.018)were independent risk factors for disease relapse/progression in children with B-NHL.Conclusions BL is the most common type of B-NHL in children,with the ileocecum as the prevalent site of tumor primaries.While DLBCL is the second most common type of B-NHL,which commonly occurs in the peripheral lymph node.Involvements of bone marrow/CNS,and incomplete response within 2 courses of chemotherapy may predict poor prognosis of patients.The clinical outcomes of B-NHL children with stageⅣand relapsed/progressive B-NHL remain to be improved.