肾上腺累及的弥漫性大B细胞淋巴瘤患者临床病理特征、基因突变谱及预后分析

doi:10.3969/j.issn.1674-8115.2025.09.011

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (9): 1194-1201.doi: 10.3969/j.issn.1674-8115.2025.09.011

肾上腺累及的弥漫性大B细胞淋巴瘤患者临床病理特征、基因突变谱及预后分析

何嘉音, 陈思远, 施晴, 张慕晨, 易红梅, 董磊, 钱樱(), 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，医学基因组学国家重点试验室，上海血液学研究所，上海 200025

收稿日期:2025-05-05 接受日期:2025-06-19 出版日期:2025-09-28 发布日期:2025-09-30
通讯作者: 钱　樱，主治医师，学士；电子信箱：ljj10395502@163.com。
许彭鹏，主任医师，博士；电子信箱：pengpeng_xu@126.com。
基金资助:
国家自然科学基金(82130004);国家自然科学基金(81830007);国家自然科学基金(81670176);国家自然科学基金(82070204);上海交通大学医学院“双百人”项目(20230013)

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

HE Jiayin, CHEN Siyuan, SHI Qing, ZHANG Muchen, YI Hongmei, DONG Lei, QIAN Ying(), WANG Li, CHENG Shu, XU Pengpeng(), ZHAO Weili

Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology, Shanghai 200025, China

Received:2025-05-05 Accepted:2025-06-19 Online:2025-09-28 Published:2025-09-30
Contact: QIAN Ying, E-mail: ljj10395502@163.com.
XU Pengpeng, E-mail: pengpeng_xu@126.com.
Supported by:
National Natural Science Foundation of China(82130004);“Two-hundred Talents” Program of Shanghai Jiao Tong University School of Medicine(20230013)

摘要/Abstract

摘要：

目的·探究弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）且伴有肾上腺累及的患者的临床病理特征、基因突变谱及其预后影响因素。方法·纳入上海交通大学医学院附属瑞金医院2002年3月—2022年12月收治的105例肾上腺累及的初诊DLBCL患者，对其临床病理资料、分子遗传学特征及预后因素开展回顾性队列研究。采用靶向测序技术（包含152个淋巴瘤相关基因）分析患者基因突变结果。结果·患者的中位年龄为62（15~82）岁，男女比例为2.3∶1；其中63例（60.0%）患者年龄在60岁以上，22例（21.0%）美国东部肿瘤协作组（Eastern Cooperative Oncology Group，ECOG）评分≥2分，87例（82.9%）Ann Arbor分期为Ⅲ~Ⅳ期，92例（87.6%）血清乳酸脱氢酶（lactate dehydrogenase，LDH）水平高于参考值上限，84例（80.0%）存在≥2处结外器官受累，67例（63.8%）为非生发中心B细胞亚型（non germinal center B-cell，non-GCB），95例（90.5%）国际预后指数达到或超过2分。患者的中位随访时间为28.3（0.7~191.9）个月，2年的总生存（overall survival，OS）率和无进展生存（progression-free survival，PFS）率分别是68.3%和53.1%，5年OS率和PFS率分别为52.6%和44.0%。93例患者（88.6%）进行了疗效评估，其中62例（66.7%）达到完全缓解。单因素和多因素Cox分析显示，年龄60岁以上是PFS不良预后因素，ECOG评分≥2分是OS与PFS的不良预后因素。46例肾上腺累及的DLBCL患者的靶向基因测序显示KMT2D（lysine methyltransferase 2D；n=17，37%）、PIM1（Pim-1 proto-oncogene，serine/threonine kinase；n=17，37%）、MYD88（MYD88 innate immune signal transduction adaptor；n=15，33%）、CD79B（CD79b molecule；n=13，28%）和BTG2（BTG anti-proliferation factor 2；n=10，22%）存在高频突变。结论·年龄60岁以上是肾上腺累及的DLBCL患者PFS的不良预后因素，ECOG评分2分及以上是该类患者OS与PFS的不良预后因素。KMT2D、PIM1、MYD88、CD79B、BTG2是肾上腺累及的DLBCL患者的常见高频突变基因，患者MCD亚型的比例增加。

关键词: 弥漫性大B细胞淋巴瘤, 结外, 肾上腺, 临床病理特征, 基因突变, 预后因素

Abstract:

Objective ·To analyze the clinicopathologic characteristics, gene mutation profile, and prognostic factors of patients with adrenal diffuse large B-cell lymphoma (DLBCL). Methods ·From March 2002 to December 2022, a total of 105 patients with adrenal DLBCL admitted to Ruijin Hospital, Shanghai Jiao Tong University School of Medicine were retrospectively analyzed for their clinicopathological data, survival outcomes, and prognostic factors. Patients' gene mutation profiles were evaluated by targeted sequencing of 152 lymphoma-related genes. Results ·The median age of the patients was 62 (15‒82) years and the male-to-female ratio was 2.3∶1. Among them, 63 patients (60.0%) were over 60 years old, 22 patients (21.0%) had an Eastern Cooperative Oncology Group (ECOG) performance status of two or higher, 87 patients (82.9%) were staged Ann Arbor Ⅲ‒Ⅳ, 92 patients (87.6%) had elevated serum lactate dehydrogenase (LDH) levels (above the upper limit of reference), 84 patients (80.0%) had extranodal invasion in at least two organs, 67 patients (63.8%) were of non-germinal center B-cell (non-GCB) origin, and 95 patients (90.5%) had an international prognosis index (IPI) scored over 2. With a median follow-up of 28.3 (0.7‒191.9) months, the estimated 2-year overall survival (OS) rate and progression-free survival (PFS) rate were 68.3% and 53.1%, respectively. The estimated 5-year OS rate and PFS rate were 52.6% and 44.0%, respectively. Among 93 patients who could be evaluated for clinical outcomes, 62 (66.7%) got a complete response (CR). Univariate analysis and multivariate Cox analysis revealed that age over 60 years was an adverse prognostic factor for PFS, and ECOG performance status of two or higher was an adverse prognostic factor for both OS and PFS. Targeted gene sequencing in 46 adrenal diffuse DLBCL patients showed high mutation frequencies in lysine methyltransferase 2D (KMT2D; n=17, 37%), Pim-1 proto-oncogene, serine/threonine kinase (PIM1; n=17, 37%), MYD88 innate immune signal transduction adaptor (MYD88; n=15, 33%), CD79b molecule (CD79B; n=13, 28%), and BTG anti-proliferation factor 2 (BTG2; n=10, 22%). Conclusion ·Age over 60 years is an adverse prognostic factor for PFS, and ECOG performance status of two or higher is an adverse prognostic factor for both OS and PFS in patients with adrenal DLBCL. Patients exhibited high frequencies of KMT2D, PIM1, MYD88, CD79B, and BTG2 mutations, as well as an increased proportion of the MCD-like subtype.

Key words: diffuse large B-cell lymphoma (DLBCL), extranodal, adrenal gland, clinicopathologic characteristic, gene mutation, prognostic factor

中图分类号:

R733.4

何嘉音, 陈思远, 施晴, 张慕晨, 易红梅, 董磊, 钱樱, 王黎, 程澍, 许彭鹏, 赵维莅. 肾上腺累及的弥漫性大B细胞淋巴瘤患者临床病理特征、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): 1194-1201.

HE Jiayin, CHEN Siyuan, SHI Qing, ZHANG Muchen, YI Hongmei, DONG Lei, QIAN Ying, WANG Li, CHENG Shu, XU Pengpeng, ZHAO Weili. Clinicopathologic characteristics, gene mutation profile, and prognostic analysis of patients with adrenal diffuse large B-cell lymphoma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1194-1201.

图/表 5

表1 105例肾上腺累及DLBCL患者的临床病理特征

Tab 1 Clinicopathologic characteristics of 105 patients with adrenal DLBCL

Characteristic	n (%)
Gender
Male	73 (69.5)
Female	32 (30.5)
Age
≤60 years	42 (40.0)
>60 years	63 (60.0)
ECOG score
0‒1 score	83 (79.0)
≥2 score	22 (21.0)
Ann Arbor stage
Ⅰ‒Ⅱ	18 (17.1)
Ⅲ‒Ⅳ	87 (82.9)
Serum LDH
Normal	13 (12.4)
Elevated	92 (87.6)
Extranodal involvement
0‒1	21 (20.0)
≥2	84 (80.0)
IPI
0‒1 score	10 (9.5)
2‒5 score	95 (90.5)
Pathological subtype
DLBCL, NOS	101 (96.2)
HGBCL with MYC and BCL-2/BCL-6 rearrangement	3 (2.9)
Intravascular large B-cell lymphoma	1 (0.9)
Hans classification
GCB	27 (25.7)
non-GCB	67 (63.8)
Unknown	11 (10.5)
MYC and BCL⁃2 double expressor
Yes	27 (25.7)
No	45 (42.9)
Unknown	33 (31.4)

图1 肾上腺累及DLBCL患者的总体生存（A）和无进展生存（B）曲线Note： Shaded areas indicate the 95%CI.

Fig 1 OS (A) and PFS (B) curves in patients with adrenal DLBCL

表2 肾上腺累及DLBCL患者OS与PFS的单因素分析

Tab 2 Univariate analysis of OS and PFS in patients with adrenal DLBCL

Item	OS		PFS
Item	HR (95%CI)	P value	HR (95%CI)	P value
Age (>60 years)	1.915 (0.983‒3.732)	0.056	1.957 (1.074‒3.566)	0.028
ECOG score≥2	2.332 (1.214‒4.480)	0.009	2.083 (1.128‒3.847)	0.016
Ann Arbor Ⅲ‒Ⅳ	0.969 (0.463‒2.028)	0.933	1.017 (0.510‒2.025)	0.962
Elevated LDH	1.844 (0.658‒5.167)	0.244	2.355 (0.849‒6.533)	0.100
ENI≥2	1.499 (0.667‒3.370)	0.327	1.732 (0.816‒3.676)	0.153
Hans (non-GCB)	0.733 (0.360‒1.493)	0.392	0.775 (0.413‒1.455)	0.428
MYC and BCL2 double expressor	1.108 (0.492‒2.494)	0.805	1.005 (0.486‒2.078)	0.990

图2 ECOG评分<2或≥2的肾上腺累及DLBCL患者的总生存（A）和无进展生存（B）

Fig 2 OS (A) and PFS (B) of adrenal DLBCL patients with ECOG performance status above or under two

图3 肾上腺累及的DLBCL患者的基因突变图谱Note： PRDM1—PR/SET domain 1; CARD11—caspase recruitment domain family member 11; CREBBP—CREB-binding lysine acetyltransferase; DTX1—deltex E3 ubiquitin ligase 1; HIST1H1E—H1.4 linker histone, cluster member; IGLL5—immunoglobulin lambda-like polypeptide 5; MPEG1—macrophage-expressed 1; TMSB4X—thymosin beta 4 X-linked; CCND3—cyclin D3; DUSP2—dual specificity phosphatase 2; IRF4—interferon regulatory factor 4; LRP1B—LDL receptor-related protein 1B; TNFAIP3—TNF alpha-induced protein 3; ARID1A—AT-rich interaction domain 1A; ATM—ATM serine/threonine kinase; B2M—beta-2-microglobulin; BTG1—BTG anti-proliferation factor 1; CIITA—class II major histocompatibility complex transactivator; HIST1H1C—H1.2 linker histone, cluster member; KMT2C—lysine methyltransferase 2C; NOTCH2—Notch receptor 2; SOCS1—suppressor of cytokine signaling 1; ZNF608—zinc finger protein 608; BCL6—BCL6 transcription repressor; EBF1—EBF transcription factor 1; MYC—MYC proto-oncogene, bHLH transcription factor; NFKBIE—NFKB inhibitor epsilon; SGK1—serum/glucocorticoid-regulated kinase 1; TBL1XR1—TBL1X/Y-related 1; TET2—tet methylcytosine dioxygenase 2; CD58—CD58 molecule; CD70—CD70 molecule; DDX3X—DEAD-box helicase 3 X-linked; EP300—EP300 lysine acetyltransferase; EZH2—enhancer of zeste 2 polycomb repressive complex 2 subunit; FBXW7—F-box and WD repeat domain-containing 7; FOXO1—forkhead box O1; GNA13—G protein subunit alpha 13; KLHL6—kelch-like family member 6; MTOR—mechanistic target of rapamycin kinase; PCLO—piccolo presynaptic cytomatrix protein; PTPN6—protein tyrosine phosphatase non-receptor type 6; STAT3—signal transducer and activator of transcription 3; TP53—tumor protein p53; UBE2A—ubiquitin conjugating enzyme E2 A; ZFP36L1—ZFP36 ring finger protein-like 1; ACTB—actin beta; CD36—CD36 molecule (CD36 blood group); CD79A—CD79a molecule; CHD2—chromodomain helicase DNA-binding protein 2; CIC—capicua transcriptional repressor; EGR2—early growth response 2; FAS—Fas cell surface death receptor; FGFR3—fibroblast growth factor receptor 3; FOXC1—forkhead box C1; GRHPR—glyoxylate and hydroxypyruvate reductase; HLA-B—major histocompatibility complex, class I, B; ITPKB—inositol-trisphosphate 3-kinase B; KLHL14—kelch-like family member 14; LYN—LYN proto-oncogene, Src family tyrosine kinase; NOL9—nucleolar protein 9; NOTCH1—Notch receptor 1; NRAS—NRAS proto-oncogene, GTPase; OSBPL10—oxysterol-binding protein-like 10; PIK3CD—phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta; PIM2—Pim-2 proto-oncogene, serine/threonine kinase; POSTN—periostin; ROBO2—roundabout guidance receptor 2; SETD1B—SET domain containing 1B, histone lysine methyltransferase; TNFRSF14—TNF receptor superfamily member 14.

Fig 3 Gene mutation profiles in patients with adrenal DLBCL

参考文献 18

[1]	SWERDLOW S H, CAMPO E, PILERI S A, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms[J]. Blood, 2016, 127(20): 2375-2390.
[2]	SEHN L H, SALLES G. Diffuse large B-cell lymphoma[J]. N Engl J Med, 2021, 384(9): 842-858.
[3]	CHEN S Y, XU P P, FENG R, et al. Extranodal diffuse large B-cell lymphoma: clinical and molecular insights with survival outcomes from the multicenter EXPECT study[J]. Cancer Commun (Lond), 2025. DOI: 10.1002/cac2.70033.
[4]	OLLILA T A, OLSZEWSKI A J. Extranodal diffuse large B cell lymphoma: molecular features, prognosis, and risk of central nervous system recurrence[J]. Curr Treat Options Oncol, 2018, 19(8): 38.
[5]	LAURENT C, CASASNOVAS O, MARTIN L, et al. Adrenal lymphoma: presentation, management and prognosis[J]. QJM, 2017, 110(2): 103-109.
[6]	SWERDLOW S H, CAMPO E, HARRIS N L. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: International Agency for Research on Cancer, 2017.
[7]	CHESON B D, FISHER R I, BARRINGTON S F, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification[J]. J Clin Oncol, 2014, 32(27): 3059-3068.
[8]	ZHU J, MA J, Union for China Lymphoma Investigators of Chinese Society of Clinical Oncology. Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for malignant lymphoma 2021 (English version)[J]. Chin J Cancer Res, 2021, 33(3): 289-301.
[9]	ALTINMAKAS E, ÜÇıŞıK-KESER F E, JEFFREY MEDEIROS L, et al. CT and ¹⁸F-FDG-PET-CT findings in secondary adrenal lymphoma with pathologic correlation[J]. Acad Radiol, 2019, 26(6): e108-e114.
[10]	邓建华, 李汉忠. 原发性肾上腺淋巴瘤的诊断与临床处理[J]. 协和医学杂志, 2020, 11(1): 91-95.
	DENG J H, LI H Z. Diagnosis and clinical treatment of primary adrenal lymphoma[j]. Medical Journal Of Peking Union Medical College Hospital, 2020, 11(1): 91-95.
[11]	KIM Y R, KIM J S, MIN Y H, et al. Prognostic factors in primary diffuse large B-cell lymphoma of adrenal gland treated with rituximab-CHOP chemotherapy from the Consortium for Improving Survival of Lymphoma (CISL)[J]. J Hematol Oncol, 2012, 5: 49.
[12]	SHI Y K, HAN Y, YANG J L, et al. Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin: analysis of 1, 085 WHO classified cases in a single institution in China[J]. Chin J Cancer Res, 2019, 31(1): 152-161.
[13]	SHEN R, XU P P, WANG N, et al. Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B-cell lymphoma[J]. Clin Transl Med, 2020, 10(7): e221.
[14]	LIU Q X, ZHU Y, YI H M, et al. KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-β1 axis[J]. Int J Biol Sci, 2024, 20(10): 3972-3985.
[15]	SHEN R, FU D, DONG L, et al. Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma[J]. Signal Transduct Target Ther, 2023, 8(1): 145.
[16]	YOUNES A, SEHN L H, JOHNSON P, et al. Randomized phase Ⅲ trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma[J]. J Clin Oncol, 2019, 37(15): 1285-1295.
[17]	XU P P, SHI Z Y, QIAN Y, et al. Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: a phase 2, single-arm study[J]. Lancet Healthy Longev, 2022, 3(7): e481-e490.
[18]	MCDONNELL T, MULKERRIN E. Primary adrenal lymphoma[J]. N Engl J Med, 2021, 384(2): 165.

肾上腺累及的弥漫性大B细胞淋巴瘤患者临床病理特征、基因突变谱及预后分析

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

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 5

参考文献 18

相关文章 15

编辑推荐

Metrics

[1]	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.
[2]	刘晓黎, 曹立. 肾上腺脑白质营养不良最新治疗研究进展[J]. 上海交通大学学报（医学版）, 2025, 45(1): 95-100.
[3]	王博恩, 陈思远, 施晴, 张慕晨, 易红梅, 董磊, 王黎, 程澍, 许彭鹏, 赵维莅. 肾脏累及的弥漫性大B细胞淋巴瘤患者临床病理特征[J]. 上海交通大学学报（医学版）, 2024, 44(9): 1162-1168.
[4]	宋一凡, 江林昊, 杨谦梓, 罗艳. 右美托咪定的中枢神经作用机制研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(5): 626-634.
[5]	周凌云, 陈海飞. 多发性骨髓瘤伴心脏淀粉样变性并继发性肾上腺皮质功能减退症1例[J]. 上海交通大学学报（医学版）, 2024, 44(4): 537-542.
[6]	韦柳彤, 赖东梅. 慢性应激与卵巢功能减退的相关性研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(12): 1601-1606.
[7]	詹湉柳, 严子航, 吴近近, 陈浩, 陈丽君, 陈轶维, 傅立军. 18例Barth综合征患儿的临床和遗传学特征分析[J]. 上海交通大学学报（医学版）, 2024, 44(11): 1406-1413.
[8]	杜沚珊, 王玥, 石子旸, 施晴, 易红梅, 董磊, 王黎, 程澍, 许彭鹏, 赵维莅. 甲状腺弥漫性大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）, 2024, 44(1): 64-71.
[9]	刘桃桃, 刘晓黎, 邬静莹, 倪瑞隆, 张梦圆, 季杜欣, 张梅, 曹立. 成人脑型肾上腺脑白质营养不良的临床及遗传学特征[J]. 上海交通大学学报（医学版）, 2023, 43(5): 592-599.
[10]	朱啸巍, 钟平, 曹立, 栾兴华. 腓骨肌萎缩症合并小脑性共济失调的临床及遗传学特点[J]. 上海交通大学学报（医学版）, 2023, 43(3): 350-357.
[11]	张漪蓉, 魏玮庆, 马皎, 张雪. 靶向SOX9调控弥漫性大B细胞淋巴瘤代谢重编程的研究[J]. 上海交通大学学报（医学版）, 2023, 43(10): 1236-1244.
[12]	赵洁, 姜言, 郝思国. 弥漫大B细胞淋巴瘤患者临床特征及预后分析[J]. 上海交通大学学报（医学版）, 2023, 43(10): 1282-1288.
[13]	邢正文, 吴滢, 王雪莉, 王庆煜, 王文婷, 李治, 张彬, 金晶. 8例儿童卵巢颗粒细胞瘤临床病理特征及预后分析[J]. 上海交通大学学报(医学版), 2022, 42(2): 192-196.
[14]	李雅慧, 王依闻, 谢利娟. SAMD9基因新发突变引起新生儿MIRAGE综合征1例[J]. 上海交通大学学报（医学版）, 2022, 42(11): 1644-1648.
[15]	徐天雪, 钱樱, 刘占云, 蔡刚, 吴英理, 李军民, 沈志祥, 周励. 伊马替尼治疗慢性髓系白血病达无治疗缓解的效果观察[J]. 上海交通大学学报（医学版）, 2022, 42(10): 1413-1419.