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

doi:10.3969/j.issn.1674-8115.2024.01.007

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (1): 64-71.doi: 10.3969/j.issn.1674-8115.2024.01.007

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

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

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实验室，上海血液学研究所，上海 200025

收稿日期:2023-06-01 接受日期:2023-10-25 出版日期:2024-01-28 发布日期:2024-02-28
通讯作者: 许彭鹏 E-mail:14743888962@163.com;pengpeng_xu@126.com
作者简介:杜沚珊（2000—），女，硕士生；电子信箱：14743888962@163.com。
基金资助:
国家自然科学基金(82130004);上海交通大学医学院“双百人”项目(20230013)

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

DU Zhishan(), WANG Yue, SHI Ziyang, SHI Qing, YI Hongmei, DONG Lei, 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:2023-06-01 Accepted:2023-10-25 Online:2024-01-28 Published:2024-02-28
Contact: XU Pengpeng E-mail:14743888962@163.com;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·探究甲状腺弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）临床病理特征、基因突变谱及预后相关因素。方法·回顾性分析2003年11月—2021年12月上海交通大学医学院附属瑞金医院收治的66例初次诊断为甲状腺DLBCL患者［原发甲状腺DLBCL 23例（34.8%），继发甲状腺DLBCL 43例（65.2%）］的临床病理资料，并进行生存和预后因素分析。其中40例甲状腺DLBCL患者进行了靶向测序（55个淋巴瘤相关基因）以评估基因突变情况。结果·继发甲状腺DLBCL患者Ann Arbor分期Ⅲ~Ⅳ期（P=0.000）、乳酸脱氢酶（lactate dehydrogenase，LDH）升高（P=0.043）、结外器官受累数目≥2个（P=0.000）、非生发中心来源（non-GCB）（P=0.030）、MYC和BCL2蛋白双表达（double expression，DE）（P=0.026）、国际预后指数3~5分（P=0.000）的比例高于原发甲状腺DLBCL患者，其接受甲状腺手术切除的比例（P=0.012）低于原发甲状腺DLBCL患者。原发甲状腺DLBCL患者完全缓解（complete response，CR）率高于继发患者（P=0.039）。55例患者（83%）接受以利妥昔单克隆抗体联合环磷酰胺、阿霉素、长春新碱及泼尼松（R-CHOP）为基础的一线治疗方案，其中原发甲状腺DLBCL患者预期5年无进展生存（progress free survive，PFS）率95.0%，高于继发患者的49.7%（P=0.010）。单因素分析显示：Ann Arbor Ⅲ~Ⅳ期（HR=4.411，95%CI 1.373~14.170）、LDH升高（HR=5.500，95%CI 1.519~19.911）、non-GCB（HR=5.291，95%CI 1.667~16.788）、DE（HR=6.178，95%CI 1.813~21.058）是甲状腺DLBCL患者PFS的不良预后因素；Ann Arbor Ⅲ~Ⅳ期（HR=7.088，95%CI 0.827~60.717）、LDH升高（HR=6.982，95%CI 0.809~60.266）、DE（HR=18.079，95%CI 1.837~177.923）是总生存（overall survival，OS）时间的不良预后因素。多因素分析显示：Ann Arbor Ⅲ~Ⅳ期（HR=4.693，95%CI 1.218~18.081）和LDH升高（HR=5.058，95%CI 1.166~21.941）是甲状腺DLBCL患者PFS的独立不良预后因素。靶向测序结果显示，TET2（n=14，35%）、KMT2D（n=13，32%）、TP53（n=11，28%）、GNA13（n=10，25%）、KMT2C（n=9，22%）突变频率>20%，且TP53突变是甲状腺DLBCL患者PFS的不良预后因素（P=0.000）。结论·原发甲状腺DLBCL生存情况优于继发甲状腺DLBCL。Ann Arbor Ⅲ~Ⅳ期、LDH升高、non-GCB、DE（MYC和BCL2）是影响甲状腺DLBCL患者的不良预后因素。TET2、KMT2D、TP53、GNA13、KMT2C是甲状腺DLBCL中常见的高突变基因，TP53突变的患者预后不佳。

关键词: 甲状腺, 弥漫性大B细胞淋巴瘤, 临床病理特征, 基因突变谱, 预后分析

Abstract:

Objective ·To analyze the clinicopathologic characteristics, gene mutation profile, and prognostic factors of thyroid diffuse large B-cell lymphoma (DLBCL). Methods ·From November 2003 to December 2021, a total of 66 patients with thyroid DLBCL [23 cases (34.8%) with primary thyroid DLBCL, and 43 cases (65.2%) with secondary thyroid DLBCL] admitted to Ruijin Hospital, Shanghai Jiao Tong University School of Medicine were retrospectively analyzed for their clinicopathological data, survival and prognostic factors. Gene mutation profiles were evaluated by targeted sequencing (55 lymphoma-related genes) in 40 patients. Results ·Compared to primary thyroid DLBCL, secondary thyroid DLBCL had advanced ratio of Ann Arbor stage Ⅲ?Ⅳ (P=0.000), elevated serum lactate dehydrogenase (LDH) (P=0.043), number of affected extranodal involvement ≥2 (P=0.000), non-germinal center B cell (non-GCB) (P=0.030), BCL-2/MYC double expression (DE) (P=0.026), and international prognostic index (IPI) 3?5 -scores (P=0.000). The proportion of patients who underwent thyroid surgery (P=0.012) was lower than that of patients with primary thyroid DLBCL. The complete remission (CR) rate in primary thyroid DLBCL patients was higher than that in secondary thyroid DLBCL patients (P=0.039). Fifty-five patients (83%) received rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-based first-line regimen. The estimated 5-year progression free survival (PFS) rate of primary thyroid DLBCL patients was 95.0%, higher than the 49.7% of the secondary patients (P=0.010). Univariate analysis showed that Ann Arbor Ⅲ?Ⅳ (HR=4.411, 95%CI 1.373?14.170), elevated LDH (HR=5.500, 95%CI 1.519?19.911), non-GCB (HR=5.291, 95%CI 1.667?16.788), and DE (HR=6.178, 95%CI 1.813?21.058) were adverse prognostic factors of PFS in patients with thyroid DLBCL. Ann Arbor Ⅲ?Ⅳ (HR=7.088, 95%CI 0.827?60.717), elevated LDH (HR=6.982, 95%CI 0.809?60.266), and DE (HR=18.079, 95%CI 1.837?177.923) were adverse prognostic factors of overall survival (OS). Multivariate analysis showed that Ann Arbor Ⅲ?Ⅳ (HR=4.693, 95%CI 1.218?18.081) and elevated LDH (HR=5.058, 95%CI 1.166?21.941) were independent adverse prognostic factors of PFS in patients with thyroid DLBCL. Targeted sequencing data showed mutation frequency >20% in TET2 (n=14, 35%), KMT2D (n=13, 32%), TP53 (n=11, 28%), GNA13 (n=10, 25%), KMT2C (n=9, 22%), and TP53 were adverse prognostic factors of PFS in patients with thyroid DLBCL (P=0.000). Conclusion ·Patients with primary thyroid DLBCL have better PFS and OS than those with secondary thyroid DLBCL. Ann Arbor Ⅲ?Ⅳ, elevated LDH, non-GCB, and DE (MYC and BCL2) are adverse prognostic factors in thyroid DLBCL. TET2,KMT2D, TP53, GNA13, and KMT2C are commonly highly mutated genes in thyroid DLBCL, and the prognosis of patients with TP53 mutations is poor.

Key words: thyroid, diffuse large B-cell lymphoma (DLBCL), clinicopathologic characteristic, gene mutation profile, prognostic analysis

中图分类号:

R733.4

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.

DU Zhishan, WANG Yue, SHI Ziyang, SHI Qing, YI Hongmei, DONG Lei, WANG Li, CHENG Shu, XU Pengpeng, ZHAO Weili. Clinicopathologic characteristics, gene mutation profile and prognostic analysis of thyroid diffuse large B-cell lymphoma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(1): 64-71.

图/表 5

表1 原发和继发甲状腺DLBCL患者临床病理特征分析

Tab 1 Analysis of clinicopathologic characteristics in patients with primary and secondary thyroid DLBCL

Characteristic	Primary thyroid DLBCL (n=23)	Secondary thyroid DLBCL (n=43)	χ²	P value
Gender/n(%)			0.303	0.582
Male	7 (30.4)	16 (37.2)
Female	16 (9.6)	27 (62.8)
Age/n(%)			0.422	0.516
≤60 years	11 (47.8)	17 (39.5)
>60 years	12 (52.2)	26 (60.5)
ECOG score/n(%)			0.229	0.632
0‒1 score	21 (91.3)	36 (83.7)
≥2 score	2 (8.7)	7 (16.3)
Ann Arbor stage/n(%)			33.226	0.000
Ⅰ‒Ⅱ	23 (100)	11 (25.6)
Ⅲ‒Ⅳ	0 (0)	32 (74.4)
LDH/n(%)			4.108	0.043
Normal	14 (60.9)	15 (34.9)
Elevated	9 (39.1)	28 (65.1)
Extranodal involvement/n(%)			26.012	0.000
0‒1	23 (100)	15 (34.9)
≥2	0 (0)	28 (65.1)
Hans/n(%)			4.694	0.030
GCB	18/21 (85.7)	24/41 (58.5)
non-GCB	3/21 (14.3)	17/41 (41.5)
DE/n(%)			4.933	0.026
Yes	1/17 (5.9)	14/35 (40.0)
No	16/17 (94.1)	21/35 (60.0)
IPI/n(%)			12.476	0.000
0‒2 score	20 (87.0)	18 (41.9)
3‒5 score	3 (13.0)	25 (58.1)
Thyroidectomy/n(%)			6.242	0.012
Yes	11 (47.8)	8 (18.6)
No	12 (52.2)	35 (81.4)

图1 原发甲状腺DLBCL和继发甲状腺DLBCL患者的PFS（A）和OS（B）曲线Note： Survival analysis of 55 patients based on R-CHOP.

Fig 1 PFS (A) and OS (B) curves in patients with primary and secondary thyroid DLBCL

表2 影响甲状腺DLBCL患者预后的单因素分析

Tab 2 Univariate analysis in patients with thyroid DLBCL

Item	PFS		OS
Item	HR (95%CI)	P value	HR (95%CI)	P value
Gender	1.593 (0.558‒4.544)	0.380	1.638 (0.330‒8.117)	0.542
Age>60 years	1.699 (0.565‒5.113)	0.340	5.647 (0.635‒50.183)	0.084
ECOG score≥2 score	2.932 (0.640‒13.426)	0.146	2.940 (0.343‒25.216)	0.302
Ann Arbor stage Ⅲ‒Ⅳ	4.411 (1.373‒14.170)	0.007	7.088 (0.827‒60.717)	0.037
LDH elevated	5.500 (1.519‒19.911)	0.004	6.982 (0.809‒60.266)	0.040
Extranodal involvement≥2	2.505 (0.867‒7.235)	0.079	3.248 (0.593‒17.788)	0.151
non-GCB	5.291 (1.667‒16.788)	0.002	3.066 (0.597‒15.744)	0.159
DE	6.178 (1.813‒21.058)	0.001	18.079 (1.837‒177.923)	0.001
Thyroidectomy	0.259 (0.058‒1.162)	0.058	0.377 (0.044‒3.226)	0.354

图2 甲状腺DLBCL患者的基因突变图谱Note： TET2—tet methylcytosine dioxygenase 2; KMT2D—lysine methyltransferase 2D; TP53—tumor protein p53; GNA13—G protein subunit α13; KMT2C—lysine methyltransferase 2C; BTG2—BTG anti-proliferation factor 2; FOXO1—forkhead box O1; SGK1—serum/glucocorticoid regulated kinase 1; SOCS1—suppressor of cytokine signaling 1; TNFRSF14—TNF receptor superfamily member 14; ATM—ATM serine/threonine kinase; CCND3—cyclin D3; EBF1—EBF transcription factor 1; EZH2—enhancer of zeste 2 polycomb repressive complex 2 subunit; PIM1—Pim-1 proto-oncogene, serine/threonine kinase; B2M—β2-microglobulin; CREBBP—CREB binding protein; DDX3X—DEAD-box helicase 3 X-linked; DTX1—deltex E3 ubiquitin ligase 1; MYD88—MYD88 innate immune signal transduction adaptor; ARID1A—AT-rich interaction domain 1A; BTG1—BTG anti-proliferation factor 1; CARD11—caspase recruitment domain family member 11; CD70—CD70 molecule; DUSP2—dual specificity phosphatase 2; HIST1H1E—H1.4 linker histone, cluster member; MYC—MYC proto-oncogene, bHLH transcription factor; NFKBIE—NFKB inhibitor epsilon; TMSB4X—thymosin β4 X-linked; ZFP36L1—ZFP36 ring finger protein-like 1; ZNF608—zinc finger protein 608; BCL6—BCL6 transcription repressor; CD58—CD58 molecule; NOTCH1—notch receptor 1; PTPN6—protein tyrosine phosphatase non-receptor type 6; TBL1XR1—TBL1X/Y-related 1; TNFAIP3—TNFα-induced protein 3; TSC2—TSC complex subunit 2; CIITA—class Ⅱ major histocompatibility complex transactivator; EP300—E1A binding protein p300; FAS—Fas cell surface death receptor; IRF4—interferon regulatory factor 4; IRF8—interferon regulatory factor 8; mTOR—mechanistic target of rapamycin kinase; STAT3—signal transducer and activator of transcription 3; FBXW7—F-box and WD repeat domain containing 7; HIST1H1C—H1.2 linker histone, cluster member; LYN—LYN proto-oncogene, Src family tyrosine kinase; MAPK7—mitogen-activated protein kinase 7; MPEG1—macrophage-expressed 1; STAT6—signal transducer and activator of transcription 6.

Fig 2 Gene mutation profiles in thyroid DLBCL patients

图3 甲状腺DLBCL患者 TP53 基因的突变状态与PFS（A）和OS（B）的关系

Fig 3 PFS (A) and OS curves (B) in patients with thyroid DLBCL TP53 gene mutation

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[15]	叶欣，周晓云，杨莉，王杰，何奇. 不同年龄范围界定下的年轻乳腺癌患者的临床病理特征及预后分析[J]. 上海交通大学学报（医学版）, 2020, 40(3): 351-.

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

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

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