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ACM

Advances in Clinical Medicine

2161-8712

Scientific Research Publishing

10.12677/ACM.2022.127896

ACM-53417

ACM20220700000_62172003.pdf

医药卫生

儿童EB病毒阳性T/NK细胞淋巴组织增殖性疾病21例临床病理特点及预后分析 Clinicopathological and Prognostic Analysis of 21 Children with Epstein-Barr Virus Positive T and NK-Cell Lymphoproliferative Disease

杨

梅

² ¹ 窦

颖

² ¹ 管

贤敏

² ¹ 郭

玉霞

² ¹ 温

贤浩

² ¹ 于

洁

² ¹

重庆医科大学附属儿童医院血液肿瘤中心，儿童发育疾病研究教育部重点实验室，国家儿童健康与疾病临床医学研究中心，儿童发育重大疾病国家国际科技合作基地，儿童学重庆市重点实验室，血液肿瘤中心，重庆

null

04 07 2022

12 07 6207 6214

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

目的：分析儿童EB病毒阳性T/NK细胞淋巴组织增殖性疾病临床病理特征及预后。方法：回顾性分析了21例儿童EB病毒阳性T/NK细胞淋巴组织增殖性疾病的临床病理资料，采用Kaplan-Meier法分析预后影响因素。结果：21例儿童EBV-T/NK-LPDs中男孩12例，女孩9例，发病年龄2~14岁(中位年龄8岁)。CAEBV 9例，HV-LPD 8例，CSEBV + TCL 4例，发病年龄分别为7~14岁(中位年龄10岁)，2~12岁(中位年龄6岁)、6~12岁(中位年龄8.5岁)。临床主要表现为发热(17/21)、肝脏肿大(15/21)、脾脏肿大(14/21)、淋巴结肿大(11/21)和皮疹(10/21)，伴全血细胞减少(10/21)、肝功能异常(9/21)、凝血功能障碍(7/21)、HLH (7/21)及肾功能异常(3/21)。21例患儿全血EBV-DNA拷贝数明显升高，超过104 copies/ml。组织病理特点为EB病毒感染的淋巴细胞增生，细胞形态多样。免疫组化：CD3、TIA-1阳性，部分合并CD56阳性。EBER原位杂交阳性。Ki-67增殖指数10%~90%。2例CAEBV、2例CSEBV + TCL及1例HV-LPD患儿检测到TCRγ基因克隆性重排。治疗策略包括抗病毒、糖皮质激素、联合化疗和HLH方案，1例患儿接受造血干细胞移植。随访20例患儿，随访时间0.3~59个月，死亡16例，存活4例。单因素分析结果：血小板减少(P = 0.013)、LDH升高(P = 0.003)、胆红素升高(P = 0)、肾功能异常(P = 0.02)、凝血功能障碍(P = 0)、合并HLH (P = 0)是预后不良的影响因素。结论：儿童EBV-T/NK-LPDs临床罕见，侵袭性强，接受抗病毒、糖皮质激素或按HLH方案治疗，病死率仍高。血小板减少、LDH升高、胆红素升高、肾功能异常、凝血功能障碍、合并HLH与不良预后相关。 Objective: To analyze the clinicopathological features and prognosis factors of Epstein-Barr virus positive T and NK-cell lymphoproliferative diseases of children. Methods: The clinicopathological data of 21 children with Epstein-Barr virus positive T and NK-cell lymphoproliferative diseases were retrospectively analyzed according to clinicopathological subtypes. Kaplan-Meier method was used to analyze the prognostic factors. Results: Among the 21 patients with this disease, 12 were males and 9 were females. And the age of onset ranged from 2 to 14 years (median onset age, 8 years), 9 of CAEBV, 8 of HV-LPD, and 4 of CSEBV + TCL. The onset ages were 7~14 years (median on-set age, 10 years), 2~12 years (median onset age, 6 years) and 6~12 years (median onset age, 8.5 years) separately. The main manifestations included fever (17/21), hepatomegaly (15/21), sple-nomegaly (14/21), lymphadenopathy (11/21) and rash (10/21). Laboratory examination showed pancytopenia (10/21), abnormal liver function (9/21), coagulation dysfunction (7/21), HLH (7/21) and abnormal kidney function (3/21). EBV genome lode in the peripheral blood of 21 patients was more than 104 copies/ml. Histopathology is characterized by EBV positive lymphocytes prolifera-tion with diverse morphology. The immunophenotype showed positive for CD3 and TIA-1(+), and partial positive for CD56. EBER-ISH positive cells were seen in all cases. The Ki-67 index was range from 10 % to 90 %. Clonal TCR-γ gene rearrangement was detected in 2 of CAEBV, 2 of CSEBV + TCL, and 1 of HV-LPD. The treatment strategies included antiviral, glucocorticoid, combined chemother-apy and HLH treatment regimen. One child received hematopoietic stem cell transplantation. 20 children were followed up with a follow-up time from 0.3 to 59 months, 16 children died, 4 children survived. Univariate analysis showed that thrombocytopenia (P = 0.013), elevated LDH (P = 0.003), elevated bilirubin (P = 0), renal dysfunction (P = 0.02), coagulation dysfunction (P = 0), and the presence of HLH (P = 0) were associated with poor prognosis. Conclusion: EBV-T/NK-LPDs of chil-dren is rare and aggressive. The outcome of antiviral therapy, glucocorticoid therapy alone or HLH treatment regimens, is unsatisfactory. Thrombocytopenia, elevated LDH, elevated bilirubin, ab-normal renal function, coagulation dysfunction and HLH are associated with poor prognosis.

儿童EB病毒阳性T/NK细胞淋巴组织增殖性疾病，慢性活动性EB病毒感染，种痘水疱病样淋巴组织增生性疾病，儿童系统性EB病毒阳性T细胞淋巴瘤，预后 , Epstein-Barr Virus Positive T and NK-Cell Lymphoproliferative Diseases of Children Chronic Active Epstein-Barr Virus Infection Hydroa Vacciniforme-Like Lymphoproliferative Disorder Systemic Epstein-Barr Virus Positive T-Cell Lymphoma of Childhood Prognosis

摘要

关键词

儿童EB病毒阳性T/NK细胞淋巴组织增殖性疾病，慢性活动性EB病毒感染，种痘水疱病样淋巴组织增生性疾病，儿童系统性EB病毒阳性T细胞淋巴瘤，预后

Clinicopathological and Prognostic Analysis of 21 Children with Epstein-Barr Virus Positive T and NK-Cell Lymphoproliferative Disease<sup> </sup>

Mei Yang, Ying Dou, Xianmin Guan, Yuxia Guo, Xianhao Wen, Jie Yu^*

Department of Hematology and Oncology, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Center of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Hematology Oncology Department, Chongqing

Received: Jun. 6^th, 2022; accepted: Jun. 29^th, 2022; published: Jul. 8^th, 2022

ABSTRACT

Objective: To analyze the clinicopathological features and prognosis factors of Epstein-Barr virus positive T and NK-cell lymphoproliferative diseases of children. Methods: The clinicopathological data of 21 children with Epstein-Barr virus positive T and NK-cell lymphoproliferative diseases were retrospectively analyzed according to clinicopathological subtypes. Kaplan-Meier method was used to analyze the prognostic factors. Results: Among the 21 patients with this disease, 12 were males and 9 were females. And the age of onset ranged from 2 to 14 years (median onset age, 8 years), 9 of CAEBV, 8 of HV-LPD, and 4 of CSEBV + TCL. The onset ages were 7~14 years (median onset age, 10 years), 2~12 years (median onset age, 6 years) and 6~12 years (median onset age, 8.5 years) separately. The main manifestations included fever (17/21), hepatomegaly (15/21), splenomegaly (14/21), lymphadenopathy (11/21) and rash (10/21). Laboratory examination showed pancytopenia (10/21), abnormal liver function (9/21), coagulation dysfunction (7/21), HLH (7/21) and abnormal kidney function (3/21). EBV genome lode in the peripheral blood of 21 patients was more than 10⁴ copies/ml. Histopathology is characterized by EBV positive lymphocytes proliferation with diverse morphology. The immunophenotype showed positive for CD3 and TIA-1(+), and partial positive for CD56. EBER-ISH positive cells were seen in all cases. The Ki-67 index was range from 10 % to 90 %. Clonal TCR-γ gene rearrangement was detected in 2 of CAEBV, 2 of CSEBV + TCL, and 1 of HV-LPD. The treatment strategies included antiviral, glucocorticoid, combined chemotherapy and HLH treatment regimen. One child received hematopoietic stem cell transplantation. 20 children were followed up with a follow-up time from 0.3 to 59 months, 16 children died, 4 children survived. Univariate analysis showed that thrombocytopenia (P = 0.013), elevated LDH (P = 0.003), elevated bilirubin (P = 0), renal dysfunction (P = 0.02), coagulation dysfunction (P = 0), and the presence of HLH (P = 0) were associated with poor prognosis. Conclusion: EBV-T/NK-LPDs of children is rare and aggressive. The outcome of antiviral therapy, glucocorticoid therapy alone or HLH treatment regimens, is unsatisfactory. Thrombocytopenia, elevated LDH, elevated bilirubin, abnormal renal function, coagulation dysfunction and HLH are associated with poor prognosis.

Keywords:Epstein-Barr Virus Positive T and NK-Cell Lymphoproliferative Diseases of Children, Chronic Active Epstein-Barr Virus Infection, Hydroa Vacciniforme-Like Lymphoproliferative Disorder, Systemic Epstein-Barr Virus Positive T-Cell Lymphoma of Childhood, Prognosis

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

2016年WHO淋巴肿瘤分类将慢性活动性EBV感染(Chronic active epstein-barr virus infection, CAEBV)和儿童系统性EBV阳性T细胞淋巴瘤(Systemic EBV-positive T-cell lymphoma of childhood, CSEBV + TCL)纳入EBV阳性T/NK细胞淋巴组织增殖性疾病(Epstein-barr virus positive T and NK-cell lymphoproliferative diseases, EBV-T/NK-LPDs) 。这是一类具有系统性炎症表现和肿瘤性质的异质性疾病 [ 1 ]。种痘水疱病样淋巴组织增生性疾病(Hydroa vacciniforme-like lymphoproliferative disorder, HV-LPD)和重度蚊虫叮咬过敏是CAEBV以皮疹为突出表现的临床病理亚型。HV-LPD预后优于CAEBV，但具有进展为CAEBV，甚至淋巴瘤的风险。CSEBV + TCL预后最差，急性起病后数天或数周死亡，常合并噬血细胞性淋巴组织细胞增生症(Hemophagocytic lymphohistiocytosis, HLH) [ 2 ]。目前，造血干细胞移植是提高儿童EBV-T/NK-LPDs生存率唯一有效的治疗方式。移植前控制疾病活动有助于提高患儿移植后存活率，采用Cooling化疗、CHOP化疗的完全缓解率仅为17%、13% [ 3 ] 化疗尚不能有效控制疾病活动 [ 4 ]。因此，本研究纳入21例儿童EBV-T/NK-LPDs临床病理资料，总结疾病活动特点、分析治疗及预后情况，以期为诊断和干预提供依据。

2. 资料与方法 2.1. 研究对象

我院2017年1月至2020年9月诊治的21例儿童EBV-T/NK-LPDs，其中2例患儿分别于2014年、2016年明确诊断。诊断标准：1) 侵袭性临床病程或持续性、反复性发作传染性单核细胞增多症样表现(如发热、淋巴结肿大、肝脾肿大等)超过3个月和/或皮肤反复丘疱疹、溃疡、凹陷性愈合瘢痕。2) 定量PCR检测全血存在高EB病毒载量(EBV-DNA ≥ 1 × 102.5 copies/ml)以及组织病理EBV编码的RNA (EBER)原位杂交阳性。3) 组织病理学结果疑诊或诊断为EBV-T/NK-LPDs。4) 除外潜在的免疫异常(免疫缺陷、自身免疫性疾病)和肿瘤。必须同时满足以上4条。

2.2. 临床病理分型

结合2016年全国儿童EB病毒感染协作组提出的CAEBV诊断标准 [ 2 ] 和2016年版WHO淋巴肿瘤分类 [ 1 ] 进行临床病理分组，CAEBV 9例，HV-LPD 8例，CSEBV + TCL 4例。2例临床呈急性暴发性进展，1例未检测到TCR基因重排，1例无相关资料，发病后3个月内死亡，仍诊断为CSEBV + TCL。将以皮疹起病，病程中出现系统性炎症表现病例，诊断为HV-LPD。

2.3. 研究方法

收集资料包括患儿临床表现、血常规、肝肾功能、血脂、凝血功能、病毒抗体、外周血EBV-DNA、病理检查、EBER、T细胞受体重排、治疗方案及治疗后生存状态，随访截止日期为2020年12月1日，或直到发生死亡或失访。以此分析儿童EBV-T/NK-LPDs的临床病理特点及影响预后的因素。

2.4. 统计方法

使用SPSS 26.0软件进行数据统计分析。定性资料采用例数和百分比表示；3组临床病理分型间差异性比较采用Kruskal-Wallis H检验；预后的影响因素分析采用Kaplan-Meier法。P < 0.05有统计学差异。

3. 结果 3.1. 一般情况

21例来自西南地区的儿童EBV-T/NK-LPDs发病年龄2~14岁(中位年龄8岁)，男孩12例，女孩9例。CAEBV 9例，HV-LPD 8例，CSEBV + TCL 4例，发病年龄分别为7~14岁(中位年龄10岁)、2~12岁(中位年龄6岁)、6~12岁(中位年龄8.5岁) (表1)；发病年龄在各临床病理组间存在统计学差异(P = 0.041)，在CAEBV和HV-LPD间存在统计学差异(P = 0.034)。表1显示CAEBV、HV-LPD、CSEBV + TCL组内性别分布及发病年龄情况。

3.2. 临床表现

表1根据临床病理分组总结了21例儿童EBV-T/NK-LPDs的临床表现。主要为发热、肝脾肿大、淋巴结肿大和皮疹，7例患儿合并HLH。此外，4例CAEBV以腹痛、腹胀主要表现，可不伴发热。HV-LPD患儿皮疹均位于面部和/或双手，5例皮疹同时累及非光暴露部位，皮疹特点为丘疱疹、溃疡、脐凹样结痂以及色素沉着，4例伴面部肿胀；所有患儿均伴有不同程度的全身炎症表现。

Table 1 Clinical characteristics of EBV positive T/NK cell lymphoproliferative disease in 21 childre

	Clinical index	EBV-T/NK-LPDs (n = 21)	CAEBV (n = 9)	HV-LPD (n = 8)	CSEBV + TCL (n = 4)
General information	Sex (Boy: Girl)	4:3	7:2	1:3	3:1
	Age of onset > 8 years	12	7	3	2
Manifestation	Fever	17	7	6	4
	Lymphadenopathy	11	5	2	4
	Hepatomegaly	15	7	4	4
	Splenomegaly	14	7	3	4
	rash	10	2	8	0
	facial swelling	6	1	5	0
Laboratory examination	Pancytopenia	10	4	4	3
	Thrombocytopenia	11	4	4	3
	Abnormal liver function	9	4	4	1
	Bilirubin disorder	7	2	4	1
	LDH increased	11	5	4	2
	Coagulation disorders	7	2	3	2
	Abnormal renal function	3	2	1	0
Classification	T cell type	16	9	3	4
Complication	HLH	7	3	2	2
Prognosis	Death	16/20 (80%)	6/8 (75%)	6/8 (75%)	4/4 (100%)

表1. 21例儿童EBV阳性T/NK细胞淋巴组织增殖性疾病患儿临床特征

注：血小板减少：血小板计数 < 100 × 10⁹/L；全血细胞减少：血红蛋白计数 < 100 g/L，中性粒细胞计数 < 1.5 × 10⁹/L；肝功能异常：谷丙转氨酶水平至少连续2次升高到正常上限的2倍以上。胆红素代谢障碍：总胆红素 > 17.1 mg/dL；肾功能异常：血尿素氮 > 7.14 mmol/L和/或血肌酐 > 91 μmol/L；LDH升高：乳酸脱氢酶升高超过500 IU/L。

3.3. 实验室检查及病毒学检查

儿童EBV-T/NK-LPDs可累及造血系统、影响肝肾功能等单个或多个系统(表2)，其中乳酸脱氢酶升高明显，其中7例患儿LDH水平超过1000 IU/L。诊断时，19例患儿有EBV相关血清学检查资料，外周血EBV-DNA阳性率100 %，所有患儿EBV-DNA拷贝数均超过104 copies/ml，最高达108 copies/ml。此外，18例患儿EBV VCA-IgM均阴性，VCA-IgG均阳性，1例情况不详。

Table 2 Immunophenotype, EBER in situ hybridization, TCR rearrangement results (Total number of samples N = 29

Immunophenotype	n/N (%)
CD3+	24/24 (100%)
CD4+CD8+	20/20 (100%)
CD4+/CD8+ > 1	8/20 (40%)
CD4+/CD8+ < 1	6/20 (30%)
CD20+	7/21 (33.3%)
CD56+	8/21 (38.1%)
CD30+	10/18 (55.6%)
TIA-1+	18/18 (100%)
EBER positive	28/29 (96.6%)
EBER > 100个/HPF	8/29 (27.6%)
Ki-67 (%)	10%~90%
TCR positive	5/10 (50%)

表2. 免疫表型、EBER原位杂交、TCR重排结果(总样本数N = 29)

注：TIA-1：T细胞胞质内抗原-1。“+”表示阳性。

3.4. 组织病理结果

12份淋巴结标本(5例CAEBV、4例CSEBV + TCL、1例HV-LPD)的组织病理结果：淋巴结结构完整5份、淋巴结部分结构破坏5份，3份存在吞噬血细胞现象。可见淋巴细胞和/或组织细胞增生，增生细胞形态多样，可见大–中等类圆形细胞、小-中等细胞、淋巴样细胞及组织样细胞等，部分病例见淋巴滤泡缩小或被膜下窦、髓窦扩张。

累及皮肤的大多数病例有相似的组织病理表现，14份皮肤标本(8例HV-LPD、2例CAEBV)组织病理结果：真皮层及皮下组织内淋巴细胞或淋巴样细胞浸润，浸润深度不一，在6份可见淋巴细胞血管中心性浸润，3份可见皮肤附件周围淋巴细胞浸润。浸润细胞为小型或小–中型，1例为中–大型细胞。可见轻度异型性细胞浸润。偶有中性粒细胞、单核细胞、浆细胞和嗜酸性粒细胞等炎性细胞浸润。

11份骨髓标本(5例CAEBV、2例CSEBV + TCL、1例HV-LPD)的增殖病理结果相似，9份表现为有核细胞增生活跃，三系增生，6份可见淋巴组织细胞增生，4份存在吞噬现象。其中1例患儿病程进展时骨髓活检提示有核细胞增生减低。1例患儿骨髓活检可见微脓肿形成。

肝脏活检：炎性细胞浸润，细胞有轻度异型性。

结肠粘膜组织活检：炎性细胞及淋巴细胞浸润，可见中等偏大细胞异型细胞增生。

鼻咽部组织活检：弥漫性坏死，其间可见小灶肿瘤细胞，小–中等大小，胞浆稀少，核浓染，可见细胞浸润血管壁，核碎屑易见。

3.5. 免疫表型、EBER原位杂交、TCR重排

表2总结了免疫表型、EBER原位杂交、TCR重排结果(未纳入骨髓)。CD3及TIA-1阳性率为100% (24/24, 18/18)，CD20阳性率为33.3% (7/21)，CD56阳性率为38.1% (8/21)。CD30阳性率为55.6% (10/18)。20份标本同时表达CD4和CD8 (20/20)，其中CD4+/CD8+ > 1有8份，CD4+/CD8+ < 1有6份。除1例鼻咽部受累患儿的淋巴结组织病理检查EBER阴性，其余28份标本EBER均阳性。Ki-67增殖指数10%~90%。10例患儿接受TCR基因重排检测，5例检测到TCRγ基因克隆性重排(2例CAEBV、2例CSEBV + TCL、1例HV-LPD)。

3.6. 治疗及随访

21例患儿接受治疗方案如下：糖皮质激素联合抗病毒治疗4例，单用糖皮质激素治疗3例、干扰素-α和/或更昔洛韦等抗病毒治疗3例，采用HLH方案治疗5例，采用LDEP、CHOP或SMILE联合化疗治疗2例。其中1例经糖皮质激素联合依托泊苷治疗后仍持续进展的HV-LPD患儿，进行了异基因造血干细胞移植。3例患儿确诊后放弃治疗。

共随访20例患儿，随访时间0.3~59个月，16例患儿死亡。另外4例患儿在7~59个月的随访期内存活。其中，CAEBV死亡6例、HV-LPD死亡6例、CSEBV + TCL 4例均死亡。16例死亡患儿的中位生存时间为16.5个月(0.3~161个月)。其中，CAEBV、HV-LPD、CSEBV + TCL中位生存时间分别是9个月(7~25个月)、60个月(24~16个月)、2.5个月(0.3~6个月)。生存时间在3组临床病理分型间存在统计学差异(P = 0.002)，在CSEBV + TCL与HV-LPD间有统计学差异(P = 0.001)。主要死亡原因为多器官功能衰竭以及合并HLH。

3.7. 预后的影响因素分析

对21例患儿的临床资料进行单因素分析，包括发病年龄 > 8岁、性别、面部肿胀、血小板减少、肝功能异常、胆红素升高、肾功能异常、LDH升高、凝血功能障碍、合并HLH，结果显示儿童EBV-T/NK-LPDs预后不良与血小板减少(P = 0.013)、LDH升高(P = 0.003)、胆红素升高(P = 0)、肾功能异常(P = 0.02)、凝血功能障碍(P = 0)、合并HLH (P = 0)有关(P < 0.05)。

4. 讨论

儿童EBV-T/NK-LPDs临床罕见，系EBV感染T/NK细胞后克隆性增殖并浸润组织器官导致。可呈良性自限性或恶性肿瘤性临床表现，主要发生在亚洲及拉丁美洲 [ 4 ]。大多数情况下，该病易反复发作且可能逐渐进展，当出现全身性炎症表现时，炎症活动难以控制，一旦进展至EBV相关的淋巴瘤或HLH，死亡率极高 [ 5 ]。本研究随访20例患儿，共死亡16例。国内类似研究随访33例患儿，死亡31例。可见该病严重影响儿童生存，亟待相关临床研究提供进一步诊断及治疗指南。

儿童EBV-T/NK-LPDs临床特点为反复发作性或持续性传单样表现，以发热、肝脾肿大、淋巴结肿大为主；种痘样皮疹是累及皮肤的重要表现。出现系统性炎症表现时，易累及造血系统、影响肝脏功能 [ 3 ] [ 6 ]。本研究中部分病例以消化道症状起病，以腹胀、腹痛为主。国内既往报道过相似病例，患者出现溃疡性结肠炎样表现，通过病理活检证实与EBV感染相关 [ 7 ]，最终诊断为儿童EBV-T/NK-LPDs。该类临床表现不具特异性，因此，通过血液及病理活检确定EBV感染及明确EBV感染的淋巴细胞亚型至关重要 [ 1 ]。本研究检测到19例患儿全血EBV-DNA拷贝数均明显升高，可高达108 copies/ml。通过EBER联合免疫组化检测EBV感染的淋巴细胞亚型，也可采用外周血通过磁珠分选或流式细胞术检测EBV感染淋巴细胞表型 [ 3 ] [ 6 ]。

本研究发现儿童EBV-T/NK-LPDs病理学特点为受累组织淋巴细胞浸润，可累及皮肤、淋巴结、骨髓、肝脏、消化道、鼻咽部组织。浸润的细胞大小不一，部分可见轻度异型性。与既往研究结果相似 [ 8 ]。日本关于CAEBV的全国、多中心研究显示 [ 3 ] [ 9 ]，EBV主要感染T细胞或NK细胞。本研究结果显示大多数病例为EBV感染的T细胞表型，其余部分CD56阳性的病例被鉴定为T细胞和NK细胞的混合型。研究表明，CAEBV-T细胞表型预后较差 [ 9 ]。

此外，本研究中3例CSEBV + TCL全部死亡。CSEBV + TCL需与其他亚型EBV-T/NK-LPDs鉴别，但临床上与EBV-HLH难以完全区分。本研究中3例CSEBV + TCL在发病以后3月内死亡，另1例发病后6月内死亡，其中一半患儿合并HLH。在既往一些研究中，并未严格将两者区分 [ 10 ] [ 11 ]，均采用HLH方案治疗，但临床结局均差。所以，将CSEBV + TCL与EBV-HLH区别开来，有利于选择合适的治疗策略改善预后。既往研究认为TCR基因克隆性检测有助于鉴别，但在EBV-HLH中TCR基因克隆性检测也可呈阳性 [ 10 ] [ 11 ]，该方法存在局限性。因此，有研究提出异常染色体核型可能是鉴别的依据，因为存在异常染色体核型患儿死亡率为100% [ 12 ]，突出CSEBV + TCL的恶性肿瘤性特点。

在治疗方面，尚未建立儿童EBV-T/NK-LPDs的标准治疗策略。在美国，Jeffrey I Cohen等人采用大剂量激素，更昔洛韦与组蛋白去乙酰化酶抑制剂或硼替佐米联合使用，可暂时缓解病情 [ 13 ]，为患儿赢得移植的时间。在日本，主要采用SAWADA等人 [ 14 ] 建议的化疗方案，主要包括糖皮质激素、依托泊苷联合环孢素A (Cooling方案)，环磷酰胺、阿霉素、长春新碱联合泼尼松龙(CHOP方案)，但临床完全缓解率仅为17%、13%。与本研究采用激素、或依照HLH方案治疗，观察到的临床结局相似。研究表明，接受化疗、化疗联合移植和仅接受移植的系统性CAEBV患儿的3年总体生产率分别为0、65%、82% [ 3 ]。异基因造血干细胞移植是唯一有效提高患者的生存率的方法。因此，参考日本学者推荐化疗联合异基因造血干细胞移植的三步治疗策略 [ 3 ]，2021年王天有等人制定了我国CAEBV的治疗规范，该方案是否适用于我国患儿还有待进一步研究。

近年来，Chon J提出白人患者的预后优于非白人患者，较少合并全身炎症表现，血液中EBV DNA拷贝数更低，NK细胞水平更高。与此同时，国内有研究指出中国HV-LPD患儿可仅采用保守治疗方案，如糖皮质激素、干扰素，化疗不推荐为常规推荐 [ 15 ] [ 16 ]。但在本研究中，HV-LPD患儿合并系统性炎症表现，采用抗病毒联合激素、HLH方案治疗，6例患儿死亡，对于处于疾病进展的HV-LPD患儿，可能需要参考CAEBV的治疗策略。该病有进展至淋巴瘤的风险，目前预测病情进展的指标尚不明确。

5. 结论

本研究通过Kaplan-Meier分析，发现多个因素与预后不良相关，既往文献显示血小板减少、肝功能损害、LDH升高、合并HLH、发病年龄 > 15岁是影响患儿预后的主要因素 [ 17 ]。目前，造血干细胞移植是唯一可行的治愈该病的方法，对于合并危险因素患儿，可能需要尽早开始和完成造血干细胞移植。

文章引用

杨梅,窦颖,管贤敏,郭玉霞,温贤浩,于洁. 儿童EB病毒阳性T/NK细胞淋巴组织增殖性疾病21例临床病理特点及预后分析Clinicopathological and Prognostic Analysis of 21 Children with Epstein-Barr Virus Positive T and NK-Cell Lymphoproliferative Disease[J]. 临床医学进展, 2022, 12(07): 6207-6214. https://doi.org/10.12677/ACM.2022.127896

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