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   中国临床医学  2022, Vol. 29 Issue (6): 957-961      DOI: 10.12025/j.issn.1008-6358.2022.20220554
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原发性肺淋巴上皮瘤样癌的临床特征及预后
李芳1,2 , 程莉莎1,2 , 甘荷霞1,2 , 苏志敏1,2 , 张秀萍1,2 , 李智勇1,2 , 王志明1,2,3     
1. 复旦大学附属中山医院厦门医院肿瘤内科, 厦门 361015;
2. 厦门市恶性肿瘤综合治疗临床医学研究中心, 厦门 361015;
3. 复旦大学附属中山医院肿瘤内科, 上海 200032
摘要目的: 探讨原发性肺淋巴上皮瘤样癌的临床特征、治疗及预后。方法: 回顾性分析2015年1月至2019年12月在复旦大学附属中山医院厦门医院及复旦大学附属中山医院诊治的39例原发性肺淋巴上皮瘤样癌患者的临床资料,并进行总结。结果: 19例(48.7%)患者体检时发现肿瘤,症状无特异性。83.9%(26/31)患者程序性死亡配体1(PD-L1)阳性,97.2%(35/36)患者EB病毒编码的小RNA(Epstein-Barr virus encoded small RNA,EBER)阳性。基因检测发现1例合并ROS-1基因重排,未检测到EGFR基因突变及ALK基因重排。64.1%(25/39)患者进行手术治疗,无法手术的患者采取多学科综合诊治策略。中位随访33.7(23.4, 47.7)个月,中位生存时间未达到。4例患者死亡,其中1例合并ROS-1基因重排,生存期24.4个月;另3例生存期为49.7、25.3、69.7个月。相关性分析显示PD-L1表达情况不是生存时间的独立影响因素。结论: 原发性肺淋巴上皮瘤样癌是一种罕见类型的肺恶性肿瘤,发生与EB病毒密切相关,PD-L1高表达,肺癌驱动基因突变少见,临床发现时分期常较早,采用以手术为主的多学科综合诊治策略,多数患者预后较好。
关键词原发性肺淋巴上皮瘤样癌    EB病毒    预后    ROS-1基因重排    
Clinical features and outcome of primary pulmonary lymphoepithelioma-like carcinoma
LI Fang1,2 , CHENG Li-sha1,2 , GAN He-xia1,2 , SU Zhi-min1,2 , ZHANG Xiu-ping1,2 , LI Zhi-yong1,2 , WANG Zhi-ming1,2,3     
1. Department of Medical Oncology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen 361015, Fujian, China;
2. Xiamen Clinical Research Center for Cancer Therapy, Xiamen 361015, Fujian, China;
3. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Abstract: Objective: To investigate the clinical characteristics, treatment, and prognosis of primary pulmonary lymphoepithelioma-like carcinoma. Methods: Clinical data of 39 patients with primary pulmonary lymphoepithelioma-like carcinoma and were hospitalized in Xiamen Branch, Zhongshan Hospital, Fudan University and Zhongshan Hospital, Fudan Universtity from January 2015 to December 2019 were retrospectively analyzed. Results: Symptoms were not specific, and 48.7%(19/39) patients were found by physical examination. 83.9% (26/31) patients were PD-L1 positive, and 97.2% (35/36) patients were Epstein-Barr virus encoded small RNA (EBER) positive. Genetic testing found that 1 patient had ROS-1 rearrangement, but no EGFR mutation and ALK rearrangement were detected. 64.1% (25/39) patients underwent surgical treatment, and the patients who could not be operated were treated with multidisciplinary comprehensive treatment strategy. The median follow-up time was 33.7(23.4, 47.7) months, and the median survival time was not reached in all patients. Four patients died, of whom, one patient had a ROS-1 mutation with a survival time of 24.4 months; the survival time of the other 3 patients was 49.7, 25.3, 69.7 months respectively. Correlation analysis showed that the expression of PD-L1 was not an independent risk factor of survival time. Conclusion: Primary pulmonary lymphoepithelioma-like carcinoma is a rare type of primary lung cancer. It's occurrence is closely related to the Epstein-Barr virus. Lung cancer driver gene mutations are rare. A multidisciplinary comprehensive diagnosis and treatment strategy based on surgery is offen adopted. Most patients have a good prognosis.
Key words: primary pulmonary lymphoepithelioma-like carcinoma    Epstein-Barr virus    prognosis    ROS-1 gene rearrangement    

原发性肺淋巴上皮瘤样癌(primary pulmonary lymphoepithelioma-like carcinoma, PPLELC)是一种罕见的原发性肺癌亚型,以大量淋巴细胞浸润为典型特征,组织学上类似于未分化的鼻咽癌,预后较其他肺部恶性肿瘤好[1-2]。2015年WHO将其归于肺部肿瘤其他未分类癌。PPLELC在1987年由Begin等[3]首次发现,与EB病毒(Epstein-Barr virus,EBV)感染相关[4]。由于发病率低,国内外对其报道较少,目前无标准治疗方式,均为经验性治疗,因此仍然存在争议。本研究回顾性分析了39例PPLELC的临床特点、治疗方案及预后等情况。

1 资料与方法 1.1 研究对象

回顾性收集复旦大学附属中山医院厦门医院及复旦大学附属中山医院2015年1月至2019年12月收治的PPLELC患者的临床资料。所有患者均具有完整的病史资料和病理学标本。所有患者的诊断符合PPLELC诊断标准[5]。排除合并其他肿瘤的病例2例,共39例PPLELC纳入分析。本研究经医院伦理委员会审批(B2022-002),患者知情同意并签署知情同意书。

1.2 观察指标及随访

收集患者的性别、年龄、居住地、分期、转移部位、吸烟史、症状,程序性死亡配体1(programmed death-ligand 1,PD-L1)、肺癌驱动基因、Ki-67、EBV编码的小RNA(Epstein-Barr virus encoded small RNA,EBER)表达水平,治疗方式及生存情况等资料。其中,肿瘤细胞阳性比例评分(tumor cell proportion score, TPS)≥5%定义为PD-L1阳性。肺癌驱动基因改变包括表皮生长因子受体(epithelial growth factor receptor,EGFR)基因突变、间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)基因重排、ROS-1基因重排。通过住院病史、门诊病史及电话随访获得患者生存情况。随访截止时间为2021年7月1日。

1.3 统计学处理

所有分析均采用SPSS 22.0进行。连续变量以x±sMP25, P75)表示,分类变量以n(%)表示。采用Kaplan-Meier生存曲线分析生存情况。采用双侧检验。检验水准(α)为0.05。

2 结果 2.1 人口学特征

39例患者中,男性20例(51.3%)、女性19例(48.7%),年龄38~82岁,平均(58.3±10.4)岁;均来自华东地区,其中浙江省11例、江苏省10例、上海市9例、福建省5例、江西省3例、安徽省1例。有吸烟史者10例(25.6%)。

2.2 临床特征

19例(48.7%)患者无症状,体检时发现;20例患者有症状,其中12例表现为咳嗽,其余8例表现为咳痰、胸闷、胸痛、咯血、乏力、颈部淋巴结肿大。起病时临床分期:Ⅰ期12例(30.7%),Ⅱ期8例(20.5%),Ⅲ期15例(38.5%),Ⅳ期4例(10.3%)。常见转移部位为肺门、纵膈和锁骨上淋巴结(共7例,43.6%),骨转移患者1例(2.6%),肝转移患者2例(5.1%)。

2.3 病理及基因特征

镜下可见肿瘤细胞呈巢状或片状排列,细胞呈圆形或椭圆形,大小不等,细胞质淡染或呈弱嗜酸性;核大深染,呈空泡征,形态不规则,可见少量嗜酸性核仁;间质内可见大量淋巴细胞及浆细胞浸润(图 1)。Ki-67占20%~90%,其中Ki-67>30%的患者占89.7%(34/39)。31例患者进行了PD-L1检测,其中26例(83.9%)为PD-L1阳性。36例患者进行了EBER检测,其中35例(97.2%)为阳性。所有患者进行了肺癌驱动基因检测,其中1例合并ROS-1基因重排,未发现EGFR基因突变及ALK基因重排。

图 1 典型PPLELC病灶病理图 A:苏木精-伊红(H-E)染色,PPLELC肿瘤细胞呈实性排列,细胞异型,核仁明显,间质富含淋巴细胞;B:免疫荧光染色,肿瘤细胞EBER弥漫强阳性表达;C~F:免疫组化染色(Max Vision法),肿瘤细胞PD-L1高表达(C)、低表达(D),肿瘤组织间质内PD-1阳性的免疫细胞丰富(E)或较少(F)。Original magnification: ×200。
2.4 治疗情况

39例患者中,有25例(64.1%)进行手术治疗,其中3例进行术前新辅助化疗,4例进行术后辅助放化疗;不能进行手术患者14例,其中4例患者行放化疗,6例患者单纯行化疗,2例接受放疗联合免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)治疗(ICIs分别为帕博利珠单抗和信迪利单抗),1例ROS-1基因重排的患者接受克唑替尼靶向治疗,1例患者未治疗。化疗方案以含铂类双药方案为主(17例,43.6%),其中紫杉醇联合顺铂方案最为常用(12例,70.6%),其次为吉西他滨联合铂类化疗方案(3例,17.6%)和培美曲塞联合铂类化疗方案(2例,11.8%)。

2.5 预后情况

截至2021年7月1日,随访1~72个月,中位随访33.7(23.4,47.7)个月。随访结束时,存活27例、死亡4例,失访8例,中位生存期(median overall survival,mOS)未达到。4例死亡患者中,1例为合并ROS-1基因重排者,生存期为24.4个月;另3例存活时间分别为49.7、25.3、69.7个月。

2.6 PD-L1阳性与阴性表达患者生存分析

Kaplan-Meier生存曲线(图 2)显示:PD-L1阳性表达患者与PD-L1表达阴性患者mOS差异无统计学意义(49.73个月vs 69.73个月,HR=3.981,95%CI 0.14~112.20,P=0.417)。

图 2 PD-L1阳性与阴性表达PPLELC患者的Kaplan-Meier生存曲线
3 讨论

PPLELC发病率低,国内外报道较少,亚洲报道病例相对较多;我国报道的病例多来自广东、香港、台湾地区[6-8]。本研究患者均来自华东地区,平均年龄为(58.3±10.4)岁,约75%患者不吸烟,与既往报道相一致。既往研究[9-10]显示,女性发病率略高于男性,本研究男女性患者比例差异无统计学意义,可能与样本量少有关。

EGFR、ALK、ROS-1等肺癌驱动基因突变在PPLELC患者中少见。EGFR基因突变比例相对其他驱动基因多见,占2.4%~19.6%[11-15];ALK基因重排少见,仅占0~6.5%[13, 15-16]。既往未见PPLELC患者合并ROS-1基因重排的报道。本研究首次报道1例合并ROS-1基因重排病例,丰富了PPLELC的基因数据。

3.1 PD-L1表达及相关治疗

PD-L1表达水平与患者预后密切相关[17]。PPLELC患者PD-L1表达阳性率较高(30%~75.8%)[14, 16, 18-19],本研究中83.9%(26/31)患者PD-L1表达阳性,略高于既往报道。PPLELC患者PD-L1表达情况与预后的关系尚不明确。Jiang等[18]发现,PD-L1表达阳性PPLELC患者较阴性者有更长的无进展生存期和OS;另一些研究[14-16]则发现,PD-L1高表达患者较低表达者无病生存期短。而本研究显示PD-L1表达情况不影响PPLELC患者OS,但完成随访的患者未达到mOS。PD-L1表达对生存的影响有待进一步验证。

PD-L1阳性表达是否为PPLELC患者ICIs治疗反应较高的预测因子,目前研究较少。部分研究[19-21]显示,PD-L1阳性的PPLELC患者对PD-1单抗反应良好,最佳疗效为病理学完全缓解[21];而另一项病例报道显示,PD-L1阳性PPLELC患者使用PD-1单抗后出现超进展和免疫相关性肠炎[22];1例PPLELC胸膜及淋巴结转移患者使用PD-L1单抗后获得部分缓解[23]。本研究有2例Ⅳ期PD-L1阳性患者采用PD-1单抗联合放疗方案,分别随访30、39个月,疾病均未进展,显示了良好的疾病控制。

由于目前缺乏大规模临床研究数据支持,PPLELC患者可使用的ICIs无高级别循证医学证据,既往病例报道[19-23]及本研究中使用的ICIs包括纳武利尤单抗、帕博利珠单抗、信迪利单抗、阿替利珠单抗,均起到了一定的治疗效果。由于需要使用ICIs治疗的Ⅳ期PPLELC患者数量较少,治疗方案及效果有待进一步验证。对于PPLELC患者,在缺乏循证医学证据情况下,可以参照非小细胞肺癌临床研究证据或既往病例报道选用ICIs。

3.2 EBER表达及相关治疗

EBV是一种含双链DNA的疱疹病毒,感染后可能引起传染性单核细胞增多症、鼻咽癌、伯基特淋巴瘤等疾病。在亚洲国家,淋巴上皮瘤样癌的发生与EBV感染密切相关[4]。血清EBV滴度与PPLELC的肿瘤负荷及病程相关,也是监测PPLELC病情的重要指标[24]。EBER是一种在宿主细胞中大量表达的非编码小RNA,是EBV的表达产物,促进B淋巴细胞增殖,上调原癌基因抗细胞凋亡水平及胰岛素样生长因子1分泌,进而促进肿瘤的发生发展[25]。EBER在50%~94% PPLELC患者中表达阳性[4, 10]。本研究97.2%(35/36)患者EBER阳性,略高于既往报道。患者均来自长江以南的华东地区,而华东为EBV感染多发地区。既往报道[26-28]显示,EBER阳性肿瘤患者起病年龄晚,预后较EBER阴性肿瘤患者好。本研究PPLELC患者EBER阳性率高,预后良好,与既往报道[26-28]的EBER阳性肿瘤生物学行为相近。

大多数PPLELC患者在疾病早期确诊,接受手术治疗[29]。EBER阳性PPLELC进展慢,以邻近淋巴结转移为主,广泛播散少见,因此选用手术治疗。晚期肿瘤一般采用联合治疗方式(化疗、免疫治疗、放疗、外科手术)[5]。关于PPLELC的化疗方案,目前尚缺乏共识,多采用以铂类为基础的方案,如铂类联合5-氟尿嘧啶、紫杉醇、多西他赛或吉西他滨[8];部分患者能从放疗中获益。ICIs在鼻咽癌等EBER阳性肿瘤中应用越来越广泛,而EBER阳性PPLELC有相似的发病机制及生物学行为,因此ICIs可能是PPLELC潜在的治疗药物。近期研究[19-21, 23]均显示,PPLELC患者对ICIs有较好的治疗反应。但这些文献纳入病例数较少,因此ICIs对PPLELC的治疗效果有待进一步明确。本研究患者以手术治疗为主(25例,64.1%),对无法手术的患者采用放疗和(或)化疗,可联用ICIs;化疗方案采用以铂类为基础的方案,多联合紫杉醇或培美曲塞。

综上所述,PPLELC无明显性别差异,与吸烟无关,临床症状和影像学表现缺乏特异性,诊断主要依赖于病理学检查。PPLELC与EBV感染有关,PD-L1高表达。PPLELC患者多在疾病早期确诊,病灶相对局限,侵袭、转移过程缓慢,大多数患者预后良好。ICIs可能成为PPLELC的重要治疗药物。为更全面了解PPLELC,需积累更多病例,总结诊治经验。

利益冲突:所有作者声明不存在利益冲突。

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文章信息

引用本文
李芳, 程莉莎, 甘荷霞, 苏志敏, 张秀萍, 李智勇, 王志明. 原发性肺淋巴上皮瘤样癌的临床特征及预后[J]. 中国临床医学, 2022, 29(6): 957-961.
LI Fang, CHENG Li-sha, GAN He-xia, SU Zhi-min, ZHANG Xiu-ping, LI Zhi-yong, WANG Zhi-ming. Clinical features and outcome of primary pulmonary lymphoepithelioma-like carcinoma[J]. Chinese Journal of Clinical Medicine, 2022, 29(6): 957-961.
通信作者(Corresponding authors).
王志明, Tel: 021-64041990, E-mail: wang.zhiming@zs-hospital.sh.cn.
基金项目
复旦大学附属中山医院厦门医院孵化课题(2019ZSXMYS10)
Foundation item
Supported by Incubation Program of Xiamen Branch, Zhongshan Hospital, Fudan University (2019ZSXMYS10)

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