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摘要: 目的 探索非霍奇金淋巴瘤(non-Hodgkin lymphoma，NHL)中弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma，DLBCL)患者与其他类型NHL患者的临床、实验室检查的特征和代谢差异。方法 2018年8月—2023年6月在南京大学医学院附属鼓楼医院收取新鲜组织97例，其中健康人淋巴结增生组织26例，NHL淋巴瘤组织71例。该研究对71例NHL患者的临床资料及实验室特征进行了回顾性分析。同时采用气相色谱-质谱分析(GC/MS)方法，对健康人淋巴结增生组织及NHL淋巴瘤组织进行了非靶向代谢组学分析，并对NHL及DLBCL、其他类型B细胞非霍奇金淋巴瘤(B-cell non-Hodgkin lymphoma，B-NHL)、T细胞非霍奇金淋巴瘤(T-cell non-Hodgkin lymphoma，T-NHL)与健康人之间的具体差异代谢物进行了通路富集分析。结果 71例NHL患者淋巴瘤组织与26例健康人淋巴结增生组织2组间的年龄(P=0.439)及性别(P=0.069)分布差异无统计学意义。71例NHL患者的临床及实验室特征回顾性分析结果显示：DLBCL患者与其他类型B-NHL及T-NHL患者之间在年龄、性别、分期、国际预后指数(International Prognostic Index，IPI)评分等方面差异无统计学意义，但DLBCL较其他类型B-NHL的治疗效果及生存情况不佳。DLBCL与其他类型B-NHL和T-NHL患者比较，除C反应蛋白水平差异有统计学意义外，其余血常规及生化指标亦差异无统计学意义。与其他类型B-NHL比较，DLBCL易出现CD30、MYC、BCL6、MUM1和Ki67的阳性表达，两者之间差异有统计学意义(P＜0.05)；与T-NHL比较，DLBCL易出现CD79a、MYC、BCL2和MUM1的阳性表达，两者之间差异有统计学意义(P＜0.05)。非靶向代谢组学分析发现：NHL患者与健康人存在明显的代谢差异，且DLBCL与其他类型B-NHL和T-NHL之间也存在明显的代谢差异。与健康人比较，DLBCL组织中有12个上调的差异代谢物，主要富集在丙酮酸、柠檬酸循环及甘油脂类代谢途径上；其他类型B-NHL组织中共有19个差异代谢物，其中有14个下调代谢物和5个上调代谢物，富集在磷脂酰乙醇胺生物合成、苯丙氨酸和酪氨酸代谢、苹果酸-天冬氨酸穿梭及葡萄糖-丙氨酸循环代谢途径上；而T-NHL有10个上调的差异代谢物，富集在苹果酸-天冬氨酸穿梭、糖原生成及磷酸戊糖途径代谢途径上。结论 该研究回顾了NHL的临床及实验室特征，并为NHL/DLBCL的代谢性发病机制提供了新的线索，为其临床诊断和药物开发提供了新的思路。Abstract: Objective To explore the features of clinical and laboratory tests, and metabolic differences between patients with diffuse large B-cell lymphoma(DLBCL) in non-Hodgkin lymphoma(NHL) and patients with other types of NHL.Methods From August 2018 to June 2023, 97 fresh tissues were collected from Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, including 26 healthy lymph node hyperplasia tissues and 71 NHL lymphoma tissues. The clinical data and laboratory features of 71 patients with NHL were retrospectively analyzed. Meanwhile, the non-targeted metabolomics of hyperplasia lymph node tissues and NHL lymphoma tissues were analyzed by gas chromatography-mass spectrometry(GC/MS), and the pathways enrichment between NHL and DLBCL, other types of NHL and healthy people were analyzed.Results There was no significant difference in age(P=0.439) and sex(P=0.069) between 71 NHL patients and 26 healthy subjects. Retrospective analysis of clinical and laboratory characteristics of 71 NHL patients showed that: there was no statistical difference in age, sex, stage, IPI score between patients with DLBCL and patients with other types of B-cell non-Hodgkin lymphoma(B-NHL) and T-cell non-Hodgkin lymphoma(T-NHL), but DLBCL had poor therapeutic effect and survival compared with other types of B-NHL. Compared with other types of B-NHL and T-NHL patients, DLBCL showed no statistical difference in blood routine and biochemical indexes except for C-reactive protein level. Compared with other types of B-NHL, DLBCL was more likely to show positive expressions of CD30, MYC, BCL6, MUM1 and Ki67, and the difference was statistically significant (P < 0.05). Compared with T-NHL, DLBCL was more likely to show positive expressions of CD79a, MYC, BCL2 and MUM1, and the differences between the two were statistically significant (P < 0.05). Non-targeted metabolomic analysis revealed significant metabolic differences between tissues of NHL patients and healthy individuals, as well as between DLBCL and other types of B-NHL and T-NHL. Compared with healthy people, there were 12 upregulated differential metabolites in DLBCL tissues, which were mainly concentrated in pyruvate, citric acid cycle and glycine metabolism pathway. There were 19 different metabolites in B-NHL tissues, including 14 down-regulated and 5 up-regulated metabolites, which were concentrated in phosphatidylethanolamine biosynthesis, phenylalanine and tyrosine metabolism, malate-aspartate shuttle and glucose-alanine cyclic metabolic pathways. However, T-NHL has 10 upregulated differential metabolites in malate-aspartate shuttle, gluconeogenesis and pentose phosphate pathway.Conclusion This study reviewed the clinical and laboratory features of NHL, and provided new clues for the metabolic pathogenesis of NHL/DLBCL, and provided new ideas for clinical diagnosis and drug development.
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表 1 71例NHL患者的临床特征
例(%) 患者特征 DLBCL
(n=23)其他类型B-NHL
(n=33)T-NHL
(n=15)年龄/岁 64(58~70) 59(52~61) 56(52~65) 性别 女 9(39.1) 17(51.5) 5(33.3) 男 14(60.9) 16(48.5) 10(66.7) 诊断 初诊 19(82.6) 31(93.9) 15(100.0) 复发 4(17.4) 2(6.1) 0 分期 Ⅰ/Ⅱ期 8(34.8) 11(33.3) 3(20.0) Ⅲ/Ⅳ期 15(65.2) 22(66.7) 12(80.0) IPI评分 1~2分 11(47.8) 12(37.5) 8(53.3) 3~4分 12(52.2) 21(62.5) 7(46.7) 化疗 是 18(78.3) 23(69.7) 11(73.3) 否 5(21.7) 10(30.3) 4(26.7) 疗效评价 缓解 9/18(50.0) 16/23(69.6)1) 6/11(54.5) 稳定 0 2/23(8.7)1) 1/11(9.1) 进展 9/18(50.0) 5/23(21.7)1) 4/11(36.4) 生存情况 生存 11(47.8) 24(72.7)1) 5(33.3) 死亡 12(52.2) 9(27.3)1) 10(66.7) 与DLBCL组比较，1) P < 0.05。 
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表 2 71例NHL患者的实验室检查
X±S 实验室指标 DLBCL(n=23) 其他类型B-NHL(n=33) T-NHL(n=15) 血红蛋白/(g/L) 119.5±23.3 115.0±25.9 120.5±20.0 白细胞/(×109/L) 5.4±1.7 14.2±23.2 6.9±6.0 红细胞/(×1012/L) 4.1±0.7 3.9±0.8 4.2±0.6 血小板计数/(×109/L) 227.5±99.3 185.4±99.9 209.8±120.4 淋巴细胞/(×109/L) 1.2±0.5 9.7±22.4 0.9±0.5 葡萄糖/(mmol/L) 5.2±1.1 5.1±1.8 5.3±1.1 甘油三酯/(mmol/L) 1.2±0.5 1.1±0.8 1.4±0.3 血清总胆固醇/(mmol/L) 3.6±1.2 4.0±1.2 3.5±0.7 白蛋白/(g/L) 38.5±5.1 37.4±4.4 36.1±4.3 谷丙转氨酶/(U/L) 18.9±11.6 18.9±15.5 17.2±6.9 谷草转氨酶/(U/L) 29.6±24.9 23.9±15.9 27.8±14.2 总胆红素/(μmol/L) 10.2±4.9 8.4±4.2 10.5±3.9 直接胆红素/(μmol/L) 2.7±1.1 2.1±0.8 2.9±1.7 乳酸脱氢酶/(U/L) 364.6±298.9 230.2±97.8 359.8±141.6 CRP/(mg/L) 12.8±15.7 11.5±17.0 44.4±57.31) 血肌酐/(μmol/L) 65.8±15.1 61.2±16.1 58.4±14.4 eGFR/(mL/min) 110.1±22.6 112.7±23.0 115.6±31.3 与DLBCL组比较，1)P < 0.05。
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