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肺癌是在中国乃至全世界发病率最高的恶性肿瘤,也是癌症患者死亡的首要原因[1]。在肺癌的所有病理类型中,非小细胞肺癌(non-small cell lung cancer,NSCLC)约占80%[2],70%的NSCLC患者在初诊时已进展到中晚期,数据显示,中晚期NSCLC患者的5年生存率仅为16%[3]。目前,化疗及分子靶向药物治疗已成为此类患者的主要治疗手段[4],在一定程度上可以控制疾病的进展,对患者的生存期及生存率有一定的积极影响。然而在实际临床工作中,患者发生获得性耐药从而导致病情进展的情况难以避免,这就促使临床工作者开始寻求其他有效的治疗手段[5]。近年来,肿瘤的免疫疗法兴起,其对NSCLC具有良好的治疗效果[6],其中以程序性死亡受体1(programmed death-1,PD-1)/程序性死亡受体配体1(programmed death-ligand 1,PD-L1)为代表的免疫检查点抑制剂在临床治疗中表现出良好的疗效[7]。
PD-L1作为一种跨膜糖蛋白,由290个氨基酸组成,属于B7-28超家族成员,PD-L1蛋白可在乳腺癌和NSCLC等多种恶性肿瘤细胞中过表达[8-9]。18F-FDG PET/CT作为一种将功能代谢显像与解剖结构显像相结合的影像检查方法,既能获得肿瘤组织结构的解剖信息,又可通过量化葡萄糖代谢获得肿瘤组织的代谢信息,其将PET与CT的优劣势互补,广泛应用于恶性肿瘤的诊断、疗效评价及预后评估[10]。本研究主要通过对NSCLC病灶PD-L1蛋白的表达水平与18F-FDG PET/CT的代谢指标进行分析,探讨二者之间是否存在一定的关系。
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本研究中入组的55例NSCLC患者的肺结节均为实性结节;有肺门及纵隔高代谢淋巴结者31例、无肺门及纵隔高代谢淋巴结者24例;原发灶分期中,T1期36例、T2期12例、T3期3例、T4期4例;临床分期中,Ⅰ期10例、Ⅱ期31例、Ⅲ期8例、Ⅳ期6例。根据PD-L1蛋白表达情况进行的分组结果:PD-L1阳性组34例、阴性组21例,腺癌患者PD-L1蛋白表达阳性率为50.00%(21/42),鳞癌患者PD-L1蛋白表达阳性率为100%(13/13);PD-L1阳性组患者中,PD-L1蛋白高表达组13例、低表达组21例,高表达组中腺癌患者占38.46%(5/13),鳞癌患者占61.54%(8/13)。典型病例的组织病理学检查图见图1。
图 1 非小细胞肺癌患者(男性,70岁,TPS=90%)的组织病理学检查图
Figure 1. Histopathological examination images of non-small cell lung cancer patient (male, 70 years old, TPS=90%)
由表1可知,存在肺门及纵隔高代谢淋巴结的患者PD-L1蛋白表达阳性率高于无肺门及纵隔高代谢淋巴结的患者,且差异有统计学意义(χ2=10.668,P=0.001);而患者PD-L1蛋白表达情况在不同性别、年龄、癌组织是否累及胸膜以及肿瘤原发灶分期亚组之间的差异均无统计学意义(χ2=0.083~2.902,均P>0.05)。
一般资料 PD-L1蛋白表达情况[例(%)] χ2值 P值 阳性 阴性 年龄(岁) 0.083 0.774 ≥60 30(55) 14(25) <60 4(7) 7(13) 性别 2.902 0.088 男 24(44) 10(18) 女 10(18) 11(20) 有无肺门及纵隔高代谢淋巴结 10.668 0.001 有 25(45) 6(11) 无 9(17) 15(27) 癌组织是否累及胸膜 2.006 0.157 是 7(13) 8(14) 否 27(49) 13(24) 肿瘤原发灶分期 0.536 0.464 T1期 21(38) 15(27) >T1期 13(24) 6(11) 注:PD-L1为程序性死亡受体配体1 表 1 55例非小细胞肺癌患者的一般资料及其与PD-L1蛋 白表达之间的相关性
Table 1. General information of 55 patients with non-small cell lung cancer and its correlation with programmed death-ligand 1 protein expression
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55例患者中,PD-L1蛋白表达阳性组的SUVmax为12.58±6.35,阴性组为5.60±4.83,阳性组SUVmax高于阴性组,且差异有统计学意义(t=2.576,P<0.05)。由图2可见,当SUVmax=5.15时,约登指数(灵敏度+特异度−1)最大(0.520),灵敏度和特异度分别为85.3%和66.7%。以SUVmax=5.15为临界值,高SUVmax组36例、低SUVmax组19例,高SUVmax组患者PD-L1蛋白表达阳性率为80.56%(29/36),PD-L1蛋白表达阳性的TPS为12.50%±3.21%;低SUVmax组患者PD-L1蛋白表达阳性率为28.16%(5/19),PD-L1蛋白表达阳性的TPS为1.28%±0.46%;高SUVmax组患者PD-L1蛋白表达阳性率及TPS均更高,且差异均有统计学意义(χ2=15.500,t=2.671,均P<0.05)。Pearson相关分析结果显示,病灶SUVmax与PD-L1蛋白表达阳性的TPS呈正相关(r=0.604,P<0.001)。典型病例的18F-FDG PET/CT图像见图3。
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55例患者的原发病灶的MTV和TLG分别为3.66(1.35,11.07)cm3和16.20(5.20,72.30) g,PD-L1蛋白表达阳性组的MTV及TLG分别为5.46(1.68,12.70) cm3和37.65(8.73,94.18) g,阴性组分别为1.56(0.71,6.00) cm3和5.90(3.55,40.75) g,Spearman秩相关分析结果显示,MTV和TLG与PD-L1蛋白表达阳性的TPS均无相关性(r=0.083,P=0.563;r=0.102,P=0.476)。
非小细胞肺癌PD-L1蛋白表达与18F-FDG PET/CT代谢指标的关系研究
Relationship between PD-L1 protein expression and 18F-FDG PET/CT metabolic markers in non-small cell lung cancer
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摘要:
目的 探讨非小细胞肺癌(NSCLC)组织中程序性死亡配体1(PD-L1)蛋白表达与18F-氟脱氧葡萄糖(FDG) PET/CT代谢指标之间的关系,为NSCLC的免疫治疗提供PET/CT代谢层面的理论依据。 方法 回顾性收集并分析2020年1月至2021年7月于青岛大学第三临床医学院(青岛市市立医院)行18F-FDG PET/CT检查并被组织病理学检查(穿刺活体检查或手术)结果证实的55例NSCLC患者的临床资料,其中男性34例、女性21例,年龄(66.5±9.3)岁。 18F-FDG PET/CT检查于治疗前进行,采用PET体积计算机辅助判读图像处理系统对肺癌原发病灶行代谢指标的测定,包括最大标准化摄取值(SUVmax)、病灶糖酵解总量(TLG)和肿瘤代谢体积(MTV)。以PD-L1蛋白表达阳性的肿瘤细胞比例分数(TPS)=1%为临界值,将患者分为PD-L1蛋白表达阳性组(TPS≥1%)和阴性组(TPS<1%);以PD-L1蛋白表达阳性的TPS=50%为临界值,将阳性组患者分为PD-L1蛋白高表达组(TPS≥50%)和低表达组(1%≤TPS<50%)。符合正态分布的计量资料的组间比较采用两独立样本t检验;计数资料的组间比较采用卡方检验;对病灶SUVmax与PD-L1蛋白表达情况的关系行Pearson相关分析;对病灶TLG和MTV与PD-L1蛋白表达情况的关系行Spearman秩相关分析。勾画受试者工作特征(ROC)曲线,以SUVmax的最佳临界值将入组患者分为高SUVmax组与低SUVmax组,观察2组的PD-L1蛋白表达情况。 结果 NSCLC病灶SUVmax与PD-L1蛋白表达阳性的TPS呈正相关(r=0.604,P<0.001);而MTV和TLG与TPS均无相关性(r=0.083、0.102,均P>0.05)。55例患者中,PD-L1蛋白表达阳性组34例、阴性组21例,阳性组SUVmax高于阴性组(12.58±6.35 对 5.60±4.83,t=2.576,P<0.05)。ROC曲线结果显示,以SUVmax=5.15为最佳临界值,高SUVmax组36例、低SUVmax组19例,2组PD-L1蛋白表达阳性率分别为80.56%(29/36)和28.16%(5/19),PD-L1蛋白表达阳性的TPS分别为12.50%±3.21%和1.28%±0.46%,高SUVmax组患者PD-L1蛋白表达阳性率及TPS均更高,且差异均有统计学意义(χ2=15.500,t=2.671,均P<0.05)。 结论 NSCLC患者18F-FDG PET/CT中SUVmax与PD-L1蛋白表达阳性的TPS呈正相关,可为NSCLC的免疫治疗提供依据。 -
关键词:
- 癌,非小细胞肺 /
- B7-H1抗原 /
- 正电子发射断层显像术 /
- 体层摄影术,X线计算机 /
- 最大标准化摄取值 /
- 肿瘤代谢体积 /
- 病灶糖酵解总量
Abstract:Objective To investigate the relationship between programmed death-ligand 1 (PD-L1) protein expression in non-small cell lung cancer (NSCLC) tissues and 18F-fluorodeoxyglucose (FDG) PET/CT metabolic markers and to provide theoretical basis for NSCLC immunotherapy on PET/CT metabolic level. Methods The clinical data of 55 patients with NSCLC who underwent 18F-FDG PET/CT from January 2020 to July 2021 in Third Clinical Medical College of Qingdao University (Qingdao Municipal Hospital) and confirmed by histopathological examination (biopsy or surgery) were retrospectively collected and analyzed, including 34 males and 21 females, aged (66.5±9.3) years. 18F-FDG PET/CT examination was performed before treatment. The metabolic parameters of primary lung cancer lesions were measured using the PET volume computed assisted reading (VCAR) image processing system, including maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and metabolic tumor volume (MTV). Taking the tumor proportion score (TPS) of tumor cells with a positive PD-L1 protein expression=1% as the threshold, patients were divided into positive PD-L1 protein expression group (TPS≥1%) and negative group (TPS<1%). With the threshold of TPS=50% for PD-L1 protein expression, patients in the positive group were divided into high PD-L1 protein expression group (TPS≥50%) and low expression group (1%≤TPS<50%). Two independent sample t-test was performed for the intergroup comparison of measurement data in accordance with normal distribution. Chi-square test was conducted for the intergroup comparison of counting data. Pearson correlation analysis was performed on the relationship between SUVmax and PD-L1 protein expression in lesions. Spearman rank correlation analysis was conducted on the relationship among TLG, MTV, and PD-L1 protein expression in lesions. The receiver operating characteristic (ROC) curve was drawn. Enrolled patients were divided into high and low SUVmax groups on the basis of the optimal critical value of SUVmax. PD-L1 protein expression was observed in both groups. Results A positive correlation was found between SUVmax and TPS of tumor cells with a positive PD-L1 protein expression in NSCLC lesions (r=0.604, P<0.001); no correlation was observed between MTV, TLG, and TPS (r=0.083, 0.102, both P>0.05). Among 55 patients, 34 were in the positive PD-L1 protein expression group and 21 in the negative group. The SUVmax in the positive group was higher than that in the negative group (12.58±6.35 vs. 5.60±4.83, t=2.576, P<0.05). The ROC curve results revealed that with SUVmax=5.15 as the optimal critical value, 36 cases were found in the high SUVmax group and 19 cases in the low SUVmax group. The positive expression rates of PD-L1 protein in the two groups were 80.56% (29/36) and 28.16% (5/19). The TPS of tumor cells with a positive PD-L1 protein expression were 12.50%±3.21% and 1.28%±0.46%, respectively. Patients in the high SUVmax group had a higher positive expression rates of PD-L1 protein and TPS, and the differences were statistically significant (χ2=15.500, t=2.671, both P<0.05). Conclusion A positive correlation is found between SUVmax in 18F-FDG PET/CT and TPS of tumor cells with a positive PD-L1 protein expression in patients with NSCLC, which can provide evidence for NSCLC immunotherapy. -
表 1 55例非小细胞肺癌患者的一般资料及其与PD-L1蛋 白表达之间的相关性
Table 1. General information of 55 patients with non-small cell lung cancer and its correlation with programmed death-ligand 1 protein expression
一般资料 PD-L1蛋白表达情况[例(%)] χ2值 P值 阳性 阴性 年龄(岁) 0.083 0.774 ≥60 30(55) 14(25) <60 4(7) 7(13) 性别 2.902 0.088 男 24(44) 10(18) 女 10(18) 11(20) 有无肺门及纵隔高代谢淋巴结 10.668 0.001 有 25(45) 6(11) 无 9(17) 15(27) 癌组织是否累及胸膜 2.006 0.157 是 7(13) 8(14) 否 27(49) 13(24) 肿瘤原发灶分期 0.536 0.464 T1期 21(38) 15(27) >T1期 13(24) 6(11) 注:PD-L1为程序性死亡受体配体1 -
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