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   复旦学报(医学版)  2019, Vol. 46 Issue (6): 829-833      DOI: 10.3969/j.issn.1672-8467.2019.06.019
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引用本文
陈晨, 周宇红, 顾思楠, 徐蓓, 陆维祺, 张新, 葛晓雯, 徐佳岱, 刘澎. 11例HIV阴性浆母细胞淋巴瘤(PBL)的临床特征分析[J]. 复旦学报医学版, 2019, 46(6): 829-833.
CHEN Chen, ZHOU Yu-hong, GU Si-nan, XU Bei, LU Wei-qi, ZHANG Xin, GE Xiao-wen, XU Jia-dai, LIU Peng. Clinical features of HIV-negative plasmablastic lymphoma (PBL): analysis of 11 cases[J]. Fudan University Journal of Medical Sciences, 2019, 46(6): 829-833.
11例HIV阴性浆母细胞淋巴瘤(PBL)的临床特征分析
陈晨1 ▲, 周宇红2 ▲, 顾思楠1 , 徐蓓2 , 陆维祺3 , 张新4 , 葛晓雯5 , 徐佳岱1 , 刘澎1     
1. 复旦大学附属中山医院血液科 上海 200032;
2. 复旦大学附属中山医院肿瘤内科 上海 200032;
3. 复旦大学附属中山医院普外科 上海 200032;
4. 复旦大学附属中山医院呼吸科 上海 200032;
5. 复旦大学附属中山医院病理科 上海 200032
收稿日期：2018-08-27
基金项目：国家自然科学基金（81570123）；上海市卫生系统优秀学科带头人计划（2017BR033）
摘要：回顾性分析复旦大学附属中山医院2007年1月至12月确诊的11例HIV阴性浆母细胞淋巴瘤（plasmablastic lymphoma，PBL）患者的临床特点、治疗及预后，以积累对疾病的临床诊治经验。其中男性8例，女性3例，中位年龄45岁，60岁以上5例，均为结外受累起病，其中6例胃肠道受累首发。Ann Arbor分期Ⅳ期9例，Ⅲ期1例，另1例未能分期。所有患者均表达浆细胞特异性标记，CD20阴性8例，弱阳性2例，中位Ki67为75%。7例患者采用CHOP样方案化疗，其中1例联合硼替佐米治疗，2例获得完全缓解；另4例患者中1例采用EPOCH治疗，疾病进展后失访，1例采用EP方案治疗，1例采用来那度胺为主方案治疗，1例采用中药治疗，均因疾病进展导致死亡。中位无进展生存时间4.9个月，中位生存时间7.8个月。11例HIV阴性PBL患者均为高度侵袭性，男性及老年易发，胃肠道易受累，CHOP样方案疗效不佳，早期治疗可改善预后。
关键词：浆母细胞淋巴瘤(PBL)    HIV阴性    临床特征    
Clinical features of HIV-negative plasmablastic lymphoma (PBL): analysis of 11 cases
CHEN Chen1 ▲, ZHOU Yu-hong2 ▲, GU Si-nan1 , XU Bei2 , LU Wei-qi3 , ZHANG Xin4 , GE Xiao-wen5 , XU Jia-dai1 , LIU Peng1     
1. Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
2. Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
3. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
4. Department of Respiratory, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
5. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Foundation item: This work was supported by the National Natural Science Foundation of China (81570123) and Shanghai Outstanding Academic Leaders Plan of Shanghai Municipal Health System (2017BR033)
Corresponding author: LIU Peng, E-mail:liu.peng@zs-hospital.sh.cn.
▲CHEN Chen and ZHOU Yu-hong contributed equally to this work
Abstract: To accumulate more experience on diagnose and treatment of HIV-negative plasmablastic lymphoma (PBL), clinical characteristcs, treatment options and prognosis of 11 HIV negative PBL cases, including 8 males and 3 females, were analysed retrospectively from Jan.2007 to Dec.2017 in Zhongshan Hospital, Fudan University.The median age was 45 years, and 5 patients were over 60 years old.These patients were all extra-nodal involvement as origin, and 6 cases were gastrointestinal involvement.According to Ann Arbor staging, 9 cases were at Ⅳ stage, 1 case was at Ⅲ stage, and the left one could not be staged.All patients' tumor cells expressed plasma cell-specific markers.Eight cases were CD20 negative, and 2 cases were weakly positive.The median Ki67 was 75%.Seven patients were treated with CHOP-like regimen, and 1 case of them was also treated with bortezomib, 2 cases of them achieved complete remission.Among the other 4 cases, 1 case treated with EPOCH was lost after disease progression, 1 case treated with EP regimen, 1 case treated with lenalidomide-based regimen, and 1 case treated with Chinese medicine treatment were all dead.The median progression-free survival time was 4.9 months, and the median survival time was 7.8 months.Therefore, HIV-negative PBL in our center was highly invasive, male and old were susceptible, and the gastrointestinal tract was easily involved.The efficacy of CHOP-like regimen was frustrating, but early treatment might be helpful.
Key words: plasmablastic lymphoma (PBL)    HIV-negative    clinical features    

浆母细胞淋巴瘤(plasmablastic lymphoma, PBL)是一类罕见的弥漫大B细胞淋巴瘤。1997年, 首次由Delecluse报道了16例患者, 初发病灶均来自口腔, 其中15例为HIV阳性[1]。2016年, WHO将其归类为人类免疫缺陷综合征相关淋巴瘤, 认为与HIV和EB病毒感染有关, 或与其他免疫缺陷状态相关, 如服用免疫抑制剂、器官移植或老年相关免疫衰退等[2-4]。PBL恶性程度高、侵袭性强、预后差, 目前没有公认有效的治疗方案。近年关于HIV阴性PBL报道不断增加[5-8]。本文旨在对复旦大学附属中山医院诊断的11例HIV阴性PBL患者的临床特点、治疗及预后进行回顾性分析, 以期为疾病的诊治积累经验。

病例资料  以2007年1月至12月间我院诊断的11例PBL患者为研究对象, 通过对我院电子病历系统进行检索, 收集临床病史、实验室、影像学检查、病理资料及治疗情况。临床疗效评估参照2017年国际工作组共识淋巴瘤疗效评价标准(RECIL 2017)分为:完全缓解(complete remission, CR)、部分缓解(partial remission, PR)、轻微缓解(minor response, MR)、疾病稳定(stable disease, SD)和疾病进展(progressive disease, PD)。

随访和生存定义   通过我院住院部及门诊就诊记录进行患者随访, 对于无完整记录者进行电话、电子邮件及信函方式随访。随访截止时间为2018年5月31日, 中位随访时间为5.7(0.4~22.2)个月。总体生存时间(overall survival, OS)定义为确诊至死亡或末次随访时间, 无进展生存时间(progression-free survival, PFS)定义为确诊至疾病进展或末次随访时间。

临床特点  11例PBL患者均为HIV阴性, 其中男性8例, 女性3例。中位年龄45(31~69)岁, 60岁以上5例。11例均为结外器官受累起病:胃肠道6例, 骨骼3例, 肺和浆膜腔积液各2例, 肝脏、腿部软组织各1例, 无骨髓受累。初诊Ann-Arbor分期Ⅳ期9例, Ⅲ期1例, 1例未能分期。5例患者存在B组症状, 且不局限于Ⅳ期。初诊时11例患者的血清白蛋白均在30 g/L以上, 9例乳酸脱氢酶(lactate dehydrogenase, LDH)高于正常上限(≥215 U/L)。国际预后指数评分(international prognostic index score, IPI score):0~2分共3人, 3~5分共7人(表 1)。

表 1 11例HIV阴性PBL患者临床特点及预后 Tab 1 Clinical characteristics and prognosis of 11 HIV-negative PBL cases
Parameters1234567891011
SexFemaleMaleMaleMaleMaleMaleMaleFemaleMaleMaleFemale
Age (y)4563423731696124696431
Primary
involved
site		StomachTonsilStomachRetroperitoneumOropharynxStomachStomachStomachLower
extremity		LungRetroperitoneum
Medical
history		Chronic
hepatitis
B		HypertensionHBV
carrier		NAChronic
hepatitis
B		NANANAPost-kidney
transplantation		NANA
Ann-Arbor
stage		ⅣⅢⅣⅣⅣⅣⅣⅣⅣNAⅣ
B symptomsNoYesNoYesNoNoYesYesYesNoNo
LDH
(U/L)		8815862636832801672 1544682572081 268
IPI score252351334/4
Other
extra-nodal
sites		NASmall intestineNASpine,
serous
effusion		CNS, cervical
spine,
bone kidney		NADuodenum,
lung		NABoneLungSerous
effusion,
liver
Albumin
(g/L)		3041353138413430304131
HIV-----------
Serum
EBV
load		---NA-NA---NANA
PBMC
EBV
load		-3.63×104-NA-NA--1.24×106NANA
Treatment
options		CHOP×3CHOP×1CHOP×6CHOP×1-
CHOPE×2-
ESHAP×1-
COPE-
BEAMD-
auto-HCT-
Thalidomide		RCD×2Bortezomib+
CHOP×3-
Bortezomib+
DICE×3-
radiotherapy-
GDP×1-
COEP×1		EPOCH
×3		Chinese
medicine		CHOP×6EP×3CHOPE×1
PFS (mo)2.80.422.23.82.46.02.34.914.87.81.9
End pointDeathAliveAliveNADeathDeathNADeathAliveDeathDeath
OS (mo)2.80.422.2NA2.612.3NA4.914.87.81.9
CNS:Central nervous system; LDH:Lactate dehydrogenase; EBV:Epstein-barr virus; IPI:International prognostic index; PFS:Progression free survival; OS:Overall survival; PBMC:Peripheral blood mononuclear cell; auto-HCT:Autologous hematopoietic cell transplantation; -:Negative; NA:Not available.1-11:Patient number.
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病理特点  11例患者的肿瘤细胞均为大而偏位的细胞核, 核仁显著, 胞质丰富, 嗜碱性, 形态学表现典型。病理形态及免疫表型详见图 1, 免疫组化表型详见表 2。CD20阴性8例, 弱阳性2例。CD79α阳性5例, 弱阳性2例, 阴性3例。所有患者均表达CD38或VS38C。CD138阳性4例, 阴性4例。λ阳性4例, 弱阳性1例, 阴性2例。κ弱阳性3例, 阴性4例。5例患者行EB病毒编码小RNA(EBV-encoded small RNA, EBER)原位杂交检测, 其中1例阳性。MUM-1阳性5例, 阴性2例PAX-5弱阳性2例, 阴性4例。IgM阳性4例, IgG弱阳性1例。CD3弱阳性5例, 阳性1例。CD30阳性1例, 弱阳性1例。10例患者行Ki67检测, 中位数为75%(30%~90%), 1例为30%, 余均在60%以上。

A:HE staining (×400);B-G:Immunohistochemistry with HE staining (×200). 图 1 HIV阴性PBL组织病理及免疫表型 Fig 1 Histopathologic features and immunophenotype of HIV-negative PBL
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表 2 11例HIV阴性PBL患者的病理特点 Tab 2 Pathological features of 11 HIV-negative PBL cases
Parameters1234567891011
CD20-Weak+----Weak+---NA
CD79α+++-+-+Weak+Weak+-NA
CD38+NA+NANANANA++NANA
VS38C++-+++NANANA++
CD138---NA+NA+-+NA+
Ki6780%90%70%NA30%90%80%90%60%70%NA
MycNA+NANA-NA++NANANA
κ-NA--Weak+Weak+NA-Weak+NANA
λ+NA-+Weak++NA+-NANA
EBER-NA-NA-NA--+NANA
CD3--Weak+-Weak+-+Weak+-NANA
CD30NANA+-NA-NAWeak+-NANA
MUM-1NA++-+-+NA+NANA
PAX-5Weak+-Weak+NANA--NA-NANA
IgMNANA+-++NA+NANANA
IgGNANA-Weak+--NA-NANANA
NA:Not available; +:Positive; -:Negative.EBER:EBV-encoded small RNA.
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疗效和预后  7例患者采用一线CHOP(环磷酰胺+表柔比星/脂质体阿霉素+长春地辛+泼尼松)样方案治疗(表 1), 其中1例联合硼替佐米治疗, 疗效:CR 2例, PD 5例。1例患者采用RCD方案治疗(来那度胺+环磷酰胺+地塞米松); 1例采用EPOCH方案治疗3个周期后失访; 1例因首发部位为肺, 于呼吸科诊治, 采用EP(依托泊苷+顺铂)方案治疗3个周期; 1例选择中药治疗, 疗效均为PD。中位PFS为4.9个月, 中位OS为7.8个月, 中位随访时间为5.7 (0.4~22.2)个月。

讨论  国外报道HIV阴性PBL有29%~37%与免疫抑制状态相关, 如实体器官移植、EB病毒感染、自身免疫性疾病、老年等, 其中移植后免疫异常占50%[9-11]。本中心11例患者中5例(45%)与免疫抑制状态相关, 比例高于国外报道。5例老年患者中, 1例为肾移植后服用免疫抑制剂伴EB病毒感染患者, 1例为EB病毒感染。国内其他中心的老年患者比例也较国外文献多, 存在各类免疫抑制疾病或医源性免疫抑制因素的患者较少[6, 12]。以此推测, 亚洲人群PBL发病与老龄引起的免疫衰退关系密切。

本中心男性患者占72%, 明显高于女性, 与国外文献报道一致[10]。就诊时Ann-Arbor分期Ⅳ期、LDH升高及IPI评分中高危以上者居多, 提示肿瘤负荷高, 疾病进展快。文献报道HIV阴性PBL结外受累广泛, 异质性强[6, 11-13], 国内其他中心的病例初诊累及部位多样。本中心11例患者均为结外受累起病, 胃肠道受累者最多(55%)。本中心患者起病更隐匿, 初诊Ⅳ期患者明显多于其他中心, 在各中心治疗方案相似的情况下, 可能是导致患者中位OS及中位随访时间较其他中心短的原因, 可见早期治疗的重要性。

11例患者形态学表现典型。免疫表型CD38、VS38C或CD138中至少有1项浆细胞标记物阳性, 5例患者表达MUM-1, 少有PAX-5表达, 与既往报道一致[10], 18%的患者CD20局灶阳性, 较文献报道(10%)略高[14]。既往报道[4]HIV阳性PBL患者EBER阳性率约为75%, 移植后PBL为67%, 其余(不包括自身免疫性疾病或医源性免疫抑制因素)为50%。本中心除1例移植后患者EBER阳性, 其余5例患者均为阴性, 比例较低。

1例患者(编号5) Ki67检测为30%, 余均在60%以上, 可见肿瘤增殖迅速, 侵袭性强。虽然该患者Ki67表达仅30%, 但临床进展迅速, 结外器官广泛累及, 侵袭性极强, 考虑Ki67表达量低与病灶快速增殖引起组织坏死及抗原脱落有关。鉴于HIV阴性PBL与浆母细胞样浆细胞瘤之间存在鉴别难点[15], 该患者采用两者兼顾的RCD方案(来那度胺+环磷酰胺+地塞米松)进行治疗。1例患者(编号11)因腹膜占位于外科就诊, 起病时ECOG评分为3分, 一般情况差, 无法耐受手术。肿块包绕大血管介入超声下穿刺风险极大, 故取腹水脱落细胞行肠衣包埋, 未进行Ki67等免疫表型检测。但肿瘤细胞形态典型, 浆细胞相关免疫表型阳性, 临床特征符合PBL诊断。

PBL的自然病程极短, HIV阳性PBL中位OS为3个月, HIV阴性为4个月[16]。化疗可延长生存, 但目前无标准疗法[10]。本中心7例患者采用CHOP及CHOP样方案治疗, 仅2例存活。NCCN指南[17]指出HIV阳性PBL患者使用CHOP及CHOP样方案并不合适, 推荐剂量调整的EPOCH、Hyper-CVAD、CODOX-M/IVAC等更强效的化疗方案, 同时推荐CR后行自体干细胞移植。较HIV阳性PBL, HIV阴性PBL预后更差[7], 中位OS仅为9个月, 2年OS为10%, 本中心数据与文献相仿。国人HIV阴性PBL患者中老年人较多, 对于强化疗多难以耐受, 因而HIV阴性PBL的治疗方案仍需进一步探索。文献报道过硼替佐米或来那度胺治疗PBL取得良好疗效的病例[18-19], 本中心各有1例患者使用, 均未能获得长期存活, 说明PBL患者存在异质性。

综上所述, 本中心HIV阴性PBL表现为老年、男性患者居多, 起病时肿瘤负荷高, 结外受累部位胃肠道比例高, 病情进展快, 预后差, 早期治疗可延长生存。传统CHOP及CHOP样方案疗效不尽人意, 有待进一步探索新型治疗方案。

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文章信息

陈晨, 周宇红, 顾思楠, 徐蓓, 陆维祺, 张新, 葛晓雯, 徐佳岱, 刘澎
CHEN Chen, ZHOU Yu-hong, GU Si-nan, XU Bei, LU Wei-qi, ZHANG Xin, GE Xiao-wen, XU Jia-dai, LIU Peng
11例HIV阴性浆母细胞淋巴瘤(PBL)的临床特征分析
Clinical features of HIV-negative plasmablastic lymphoma (PBL): analysis of 11 cases
复旦学报医学版, 2019, 46(6): 829-833.
Fudan University Journal of Medical Sciences, 2019, 46(6): 829-833.
Corresponding author
LIU Peng, E-mail:liu.peng@zs-hospital.sh.cn.
基金项目
国家自然科学基金（81570123）；上海市卫生系统优秀学科带头人计划（2017BR033）
Foundation item
This work was supported by the National Natural Science Foundation of China (81570123) and Shanghai Outstanding Academic Leaders Plan of Shanghai Municipal Health System (2017BR033)

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