肺受累弥漫大B细胞淋巴瘤临床病理特征、基因突变谱及预后分析

doi:10.3969/j.issn.1674-8115.2025.09.013

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (9): 1214-1220.doi: 10.3969/j.issn.1674-8115.2025.09.013

肺受累弥漫大B细胞淋巴瘤临床病理特征、基因突变谱及预后分析

陈思远, 施晴, 付迪, 王黎, 程澍, 许彭鹏(), 赵维莅

上海交通大学医学院附属瑞金医院血液科，组学与疾病全国重点实验室，上海血液学研究所，上海 200025

收稿日期:2025-03-10 接受日期:2025-05-19 出版日期:2025-09-28 发布日期:2025-09-30
通讯作者: 许彭鹏，教授，博士；电子信箱：pengpeng_xu@126.com。
基金资助:
国家自然科学基金(82370187);上海交通大学医学院“双百人”项目(20230013)

Clinicopathologic characteristics, gene mutation profile, and prognostic analysis of diffuse large B-cell lymphoma with lung involvement

CHEN Siyuan, SHI Qing, FU Di, WANG Li, CHENG Shu, XU Pengpeng(), ZHAO Weili

Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Omics and Diseases; Shanghai Institute of Hematology, Shanghai 200025, China

Received:2025-03-10 Accepted:2025-05-19 Online:2025-09-28 Published:2025-09-30
Contact: XU Pengpeng, E-mail: pengpeng_xu@126.com.
Supported by:
National Natural Science Foundation of China(82370187);“Two-hundred Talents” Program of Shanghai Jiao Tong University School of Medicine(20230013)

摘要/Abstract

摘要：

目的·探究肺受累弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）的临床病理特征、基因突变谱及真实世界生存预后。方法·纳入2003年8月至2022年12月于上海交通大学医学院附属瑞金医院初诊且经病理检查确诊为DLBCL并伴有肺受累的110例患者的临床资料，进行临床特征分析。对其中88例接受利妥昔单抗联合环磷酰胺、多柔比星/表柔比星、长春新碱及泼尼松（rituximab, cyclophosphamide, doxorubicin/epirubicin, vincristine, and prednisone，R-CHOP）为基础一线治疗方案的患者进行疗效评估、生存分析及单因素、多因素预后分析。共74例患者接受了55个淋巴瘤相关基因的靶向DNA测序和基因突变评估。结果·110例患者中，>60岁72例（65.5%），女性52例（47.3%），Ann Arbor分期Ⅲ~Ⅳ期92例（83.6%），美国东部肿瘤协作组（Eastern Cooperative Oncology Group，ECOG）评分≥2分20例（18.2%），乳酸脱氢酶（lactate dehydrogenase，LDH）水平升高75例（68.2%），结外器官受累数目≥2个79例（71.8%），生发中心B细胞亚型32例（31.4%），双表达淋巴瘤22例（26.8%），双打击淋巴瘤4例（4.6%）。在接受以R-CHOP为基础的一线治疗方案的患者中，客观缓解率（objective response rate，ORR）为68.2%，5年无进展生存（progression free survival，PFS）率为43.7%，5年总生存（overall survival，OS）率为65.4%。单因素分析显示，LDH升高及ECOG评分≥2为肺受累DLBCL患者PFS及OS的不良预后因素；在高频突变中，PIM1及CD79B基因突变为患者PFS的不良预后因素。多因素分析显示，LDH升高为肺受累DLBCL患者PFS（HR=2.47，95%CI 1.28~4.77）及OS（HR=2.71，95%CI 1.21~6.07）的独立不良预后因素。靶向测序结果表明，PIM1（25.7%）、MYD88（24.3%）、TP53（18.9%）、CD79B（17.6%）、KMT2D（17.6%）、TNFAIP3（16.2%）为突变频率超过15%的高频突变。结论·LDH升高为肺受累DLBCL患者PFS及OS的独立不良预后因素；肺受累DLBCL患者中PIM1、MYD88、TP53、CD79B、KMT2D、TNFAIP3等基因突变频率较高。

关键词: 弥漫大B细胞淋巴瘤, 肺, 基因突变, 预后

Abstract:

Objective ·To investigate the clinicopathologic features, gene mutation profile, and real-world survival prognosis of diffuse large B-cell lymphoma (DLBCL) with pulmonary involvement. Methods ·The clinical data of 110 patients with newly diagnosed, pathologically confirmed DLBCL and pulmonary involvement at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, between August 2003 and December 2022 were retrospectively collected and analyzed. Evaluation of the efficacy of treatment, survival analyses, and univariate and multivariate analyses were performed in 88 patients who received a first-line regimen based on rituximab in combination with cyclophosphamide, doxorubicin/epirubicine, vincristine, and prednisone (R-CHOP). A total of 74 patients underwent targeted DNA sequencing of 55 lymphoma-related genes and were evaluated for mutations. Results ·Among the 110 patients, 72 (65.5%) were >60 years old, 52 (47.3%) were female, 92 (83.6%) presented with Ann Arbor stage Ⅲ‒Ⅳ, 20 (18.2%) had ECOG scores≥2, 75 (68.2%) had elevated lactate dehydrogenase (LDH) levels, 79 (71.8%) had ≥2 extranodal involvements, 32 (31.4%) were classified as germinal center B-cell subtype, 22 (26.8%) were diagnosed with double expressor lymphoma, and 4 (4.6%) with double-hit lymphoma. Among the patients treated with R-CHOP-based first-line regimens, the objective response rate (ORR) was 68.2%, the 5-year progression-free survival (PFS) rate was 43.7%, and the 5-year overall survival (OS) rate was 65.4%. Univariate analysis showed that elevated LDH and ECOG score≥2 were poor prognostic factors for PFS and OS, and mutations in PIM1 and CD79B were poor prognostic factors for PFS among high-frequency mutations. Multivariate analysis showed that elevated LDH was an independent adverse prognostic factor for PFS (HR=2.47, 95%CI 1.28‒4.77) and OS (HR=2.71, 95%CI 1.21‒6.07). Targeted sequencing results showed that PIM1 (25.7%), MYD88 (24.3%), TP53 (18.9%), CD79B (17.6%), KMT2D (17.6%), and TNFAIP3 (16.2%) were the high-frequency mutations with mutation rates over 15%. Conclusion ·Elevated LDH is an independent adverse prognostic factor for PFS and OS in DLBCL with pulmonary involvement. Mutations in PIM1, MYD88, TP53, CD79B, KMT2D, and TNFAIP3 are frequently observed in this population.

Key words: diffuse large B-cell lymphoma (DLBCL), lung, gene mutation, prognosis

中图分类号:

R733.4

陈思远, 施晴, 付迪, 王黎, 程澍, 许彭鹏, 赵维莅. 肺受累弥漫大B细胞淋巴瘤临床病理特征、基因突变谱及预后分析[J]. 上海交通大学学报（医学版）, 2025, 45(9): 1214-1220.

CHEN Siyuan, SHI Qing, FU Di, WANG Li, CHENG Shu, XU Pengpeng, ZHAO Weili. Clinicopathologic characteristics, gene mutation profile, and prognostic analysis of diffuse large B-cell lymphoma with lung involvement[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1214-1220.

图/表 6

参考文献 17

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Clinical characteristic	Total (n=110)	Primary lung involvement (n=31)	Secondary lung involvement (n=79)	P value
Gender/n (%)				0.883
Female	52 (47.3)	15 (48.4)	37 (46.8)
Male	58 (52.7)	16 (51.6)	42 (53.2)
Age/n (%)				0.752
>60 years	72 (65.5)	21 (67.7)	51 (64.6)
≤60 years	38 (34.5)	10 (32.3)	28 (35.4)
ECOG score/n (%)				0.147
≥2	20 (18.2)	3 (9.7)	17 (21.5)
0‒1	90 (81.8)	28 (90.3)	62 (78.5)
Ann Arbor stage/n (%)				<0.001
Ⅰ‒Ⅱ	18 (16.4)	15 (48.4)	3 (3.8)
Ⅲ‒Ⅳ	92 (83.6)	16 (51.6)	76 (96.2)
Elevated LDH/n (%)	75 (68.2)	17 (54.8)	58 (73.4)	0.060
Extranodal lesion/n (%)				<0.001
≥2	79 (71.8)	0 (0.0)	69 (87.3)
1	31 (28.2)	31 (100.0)	10 (12.7)
IPI/n (%)				<0.001
0‒1	13(11.8)	13 (41.9)	0 (0)
2	19(17.3)	11 (35.5)	8 (10.1)
3	34(30.9)	6 (19.4)	29 (36.7)
4‒5	44(4.0)	1 (3.2)	42 (53.2)
Hans type/[n/N (%)]				0.044
GCB	32/102 (31.4)	13/28 (46.4)	19/74 (25.7)
non-GCB	70/102 (68.6)	15/28 (53.6)	55/74 (74.3)
DE lymphoma/[n/N (%)]	22/82 (26.8)	5/22 (22.7)	17/60 (28.3)	0.612
DH lymphoma/[n/N (%)]	4/87 (4.6)	0/23 (0)	4/64 (6.3)	0.220

Clinical characteristic	Total (n=110)	Primary lung involvement (n=31)	Secondary lung involvement (n=79)	P value
Gender/n (%)				0.883
Female	52 (47.3)	15 (48.4)	37 (46.8)
Male	58 (52.7)	16 (51.6)	42 (53.2)
Age/n (%)				0.752
>60 years	72 (65.5)	21 (67.7)	51 (64.6)
≤60 years	38 (34.5)	10 (32.3)	28 (35.4)
ECOG score/n (%)				0.147
≥2	20 (18.2)	3 (9.7)	17 (21.5)
0‒1	90 (81.8)	28 (90.3)	62 (78.5)
Ann Arbor stage/n (%)				<0.001
Ⅰ‒Ⅱ	18 (16.4)	15 (48.4)	3 (3.8)
Ⅲ‒Ⅳ	92 (83.6)	16 (51.6)	76 (96.2)
Elevated LDH/n (%)	75 (68.2)	17 (54.8)	58 (73.4)	0.060
Extranodal lesion/n (%)				<0.001
≥2	79 (71.8)	0 (0.0)	69 (87.3)
1	31 (28.2)	31 (100.0)	10 (12.7)
IPI/n (%)				<0.001
0‒1	13(11.8)	13 (41.9)	0 (0)
2	19(17.3)	11 (35.5)	8 (10.1)
3	34(30.9)	6 (19.4)	29 (36.7)
4‒5	44(4.0)	1 (3.2)	42 (53.2)
Hans type/[n/N (%)]				0.044
GCB	32/102 (31.4)	13/28 (46.4)	19/74 (25.7)
non-GCB	70/102 (68.6)	15/28 (53.6)	55/74 (74.3)
DE lymphoma/[n/N (%)]	22/82 (26.8)	5/22 (22.7)	17/60 (28.3)	0.612
DH lymphoma/[n/N (%)]	4/87 (4.6)	0/23 (0)	4/64 (6.3)	0.220

Index	Total (n=110)	R-CHOP treatment group (n=88)	Non-R-CHOP treatment group (n=22)	P value
CR/n (%)	58 (52.7)	51 (58.0)	7 (31.8)	0.028
PR/n (%)	13 (11.8)	9 (10.2)	4 (18.2)	0.301
OR/n (%)	71 (64.5)	60 (68.2)	11 (50.0)	0.111
SD/n (%)	15 (13.6)	13 (14.8)	2 (9.1)	0.530
PD/n (%)	24 (21.8)	15 (17.0)	9 (40.9)	0.015

Index	Total (n=110)	R-CHOP treatment group (n=88)	Non-R-CHOP treatment group (n=22)	P value
CR/n (%)	58 (52.7)	51 (58.0)	7 (31.8)	0.028
PR/n (%)	13 (11.8)	9 (10.2)	4 (18.2)	0.301
OR/n (%)	71 (64.5)	60 (68.2)	11 (50.0)	0.111
SD/n (%)	15 (13.6)	13 (14.8)	2 (9.1)	0.530
PD/n (%)	24 (21.8)	15 (17.0)	9 (40.9)	0.015

Variable	PFS		OS
Variable	HR (95%CI)	P value	HR (95%CI)	P value
Male	1.02 (0.61‒1.71)	0.942	0.99 (0.53‒1.84)	0.975
Age>60 years	1.21 (0.70‒2.09)	0.487	1.69 (0.85‒3.37)	0.132
Elevated LDH	2.74 (1.44‒5.22)	0.002	3.00 (1.36‒6.61)	0.007
ECOG score≥2	2.22 (1.21‒4.07)	0.010	2.27 (1.10‒4.67)	0.027
Ann Arbor stage Ⅲ‒Ⅳ	1.38 (0.62‒3.05)	0.427	1.82 (0.65‒5.12)	0.255
Extranodal lesion≥2	1.33 (0.74‒2.41)	0.339	1.40 (0.68‒2.87)	0.362
Non-GCB type	1.46 (0.80‒2.66)	0.214	1.46 (0.70‒3.03)	0.311
DE lymphoma	1.20 (0.59‒2.46)	0.616	1.68 (0.70‒4.06)	0.246
DH lymphoma	1.80 (0.43‒7.55)	0.421	1.69 (0.22‒12.83)	0.610
PIM1 mutation	4.18 (1.93‒9.05)	<0.001	1.40 (0.45‒4.33)	0.556
MYD88 mutation	1.01 (0.43‒2.38)	0.978	0.85 (0.28‒2.62)	0.778
TP53 mutation	1.19 (0.48‒2.94)	0.713	1.25 (0.36‒4.38)	0.130
CD79B mutation	2.60 (1.14‒5.93)	0.023	2.26 (0.79‒6.49)	0.723
KMT2D mutation	1.21 (0.46‒3.20)	0.697	0.69 (0.16‒3.04)	0.625
TNFAIP3 mutation	0.14 (0.02‒1.04)	0.421	0.27 (0.04‒2.01)	0.610

肺受累弥漫大B细胞淋巴瘤临床病理特征、基因突变谱及预后分析

Clinicopathologic characteristics, gene mutation profile, and prognostic analysis of diffuse large B-cell lymphoma with lung involvement

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