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北京大学学报（医学版） ›› 2021, Vol. 53 ›› Issue (2): 246-254. doi: 10.19723/j.issn.1671-167X.2021.02.003

• 论著 • 上一篇    下一篇

18F-FDG PET/CT半定量参数、表皮生长因子受体和间变淋巴瘤激酶基因突变对肺腺癌患者预后评估的价值

廖栩鹤1,王荣福1,Δ(),刘萌1,Δ(),陈雪祺1,熊焰2,农琳2,殷雷1,张炳晔1,杜毓菁1   

  1. 1.核医学科, 北京大学第一医院 北京 100034
    2.病理科, 北京大学第一医院 北京 100034
  • 收稿日期:2019-02-25 出版日期:2021-04-18 发布日期:2021-04-21
  • 通讯作者: 王荣福,刘萌 E-mail:rongfu_wang@163.com;louisa_liu@bjmu.edu.cn
  • 基金资助:
    十二五国家科技支撑项目(2014BAA03B03);北京大学临床医学+X青年专项(PKU2018LCXQ012);北京大学第一医院自然科学基金(2017QN14)

Semiquantitative parameters of 18F-FDG PET/CT, gene mutation states of epidermal growth factor receptor and anaplastic lymphoma kinase in prognosis evaluation of patients with lung adenocarcinoma

LIAO Xu-he1,WANG Rong-fu1,Δ(),LIU Meng1,Δ(),CHEN Xue-qi1,XIONG Yan2,NONG Lin2,YIN Lei1,ZHANG Bing-ye1,DU Yu-jing1   

  1. 1. Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China
    2. Department of Pathology, Peking University First Hospital, Beijing 100034, China
  • Received:2019-02-25 Online:2021-04-18 Published:2021-04-21
  • Contact: Rong-fu WANG,Meng LIU E-mail:rongfu_wang@163.com;louisa_liu@bjmu.edu.cn
  • Supported by:
    National Science and Technology Support Program for the “12th Five-Year Plan”(2014BAA03B03);Cli-nical Medicine Plus X-Young Scholars Project of Peking University(PKU2018LCXQ012);Science Foundation of Peking University First Hospital(2017QN14)

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摘要：

目的: 评估18F-FDG PET/CT半定量参数、表皮生长因子受体(epidermal growth factor receptor,EGFR)和间变淋巴瘤激酶(anaplastic lymphoma kinase,ALK)基因突变状态对肺腺癌患者预后评估的价值。方法: 回顾性收集84名肺腺癌患者术前18F-FDG PET/CT半定量参数,EGFR及ALK基因突变检查结果。18F-FDG PET/CT半定量参数分别为:最大标准化摄取值(maximum standardized uptake value,SUVmax)、平均标准化摄取值(average of standardized uptake value,SUVmean)、肿瘤代谢体积(metabolic tumor volume,MTV)和总糖酵解量(total lesion glycolysis,TLG)。连续变量用ROC曲线分析法转为分类变量,生存分析采用Cox比例风险回归分析,生存曲线经Log-rank检验和Kaplan-Meier法获得。结果: 患者平均随访期31个月(24~58个月)。单因素分析显示,原发灶SUVmax、SUVmean、MTV及TLG与无进展生存期(progression-free survival,PFS)显著相关。多因素Cox比例风险回归分析显示,不论年龄、性别、合并症、EGFR或ALK基因突变与否及治疗情况,TLG(≥55.02,HR=4.965,95%CI:1.360~18.133)、TNM分期(Ⅲ/Ⅳ期,HR=7.811,95%CI:2.977~20.489)、胃泌素释放肽前体(pro-gastrin releasing peptide,proGRP)(≥45.65 ng/L,HR=4.070,95%CI:1.442~11.487)、组织多肽抗原(tissue polypeptide antigen,TPA)(≥68.20 U/L,HR=6.996,95%CI:1.458~33.574)、碱性磷酸酶(alkaline phosphatase,ALP)(≥82.50 IU/L,HR=4.160,95%CI:1.416~12.219)和活化部分凝血活酶时间比值(ratio of activated partial thromboplastin time,aPTTR)(≥1.16,HR=4.576,95%CI:1.913~10.946)为独立显著预后因素。EGFR(P=0.343)或ALK(P=0.608)基因突变状态均与PFS无显著相关。结论: 原发灶高水平18F-FDG PET/CT半定量参数(SUVmax、SUVmean、MTV和TLG)对肺腺癌患者具有不同程度的预后评估价值,TNM分期、proGRP、TPA、ALP和aPTTR均与PFS存在独立、显著关联,EGFR或ALK基因突变状态与PFS未见明确相关。

关键词: 肺肿瘤, 腺癌, 正电子发射断层显像术, 表皮生长因子受体, 间变淋巴瘤激酶

Abstract:

Objective: To explore the valuable predictors for evaluating progression-free survival (PFS) in patients with lung adenocarcinoma, we analyzed the potential roles of standardized uptake value (SUV)-derived parameters from 18F-FDG PET/CT, combining with the gene mutation states of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), and other clinical characteristics. Methods: Data of 84 lung adenocarcinoma patients pre-treated, who underwent 18F-FDG PET/CT scans, EGFR gene mutations test, ALK rearrangement assay and other relative tests, were retrospectively collected. Then a series of clinical parameters including EGFR/ALK mutation status and SUV-derived features [maximum standardized uptake value (SUVmax), average of standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)] were evaluated. Best possible cutoff points for all measuring parameters were calculated using receiver operating characteristic curve (ROC) analysis. Survival analysis was performed using Cox proportional hazards model to determine the prognostic markers for progression-free survival (PFS). Survival curves were obtained through Log-rank test and Kaplan-Meier curve. Results: The median follow-up period was 31 months (24 to 58 months). It was found that SUVmax (≥3.01), SUVmean (≥2.25), MTV (≥25.41 cm 3), and TLG (≥55.02) of the primary tumors were significantly associated with PFS in univariate Cox proportional hazards regression. Then regardless of age, gender, co-morbidity, EGFR/ALK mutation status, and treatment program, TLG (≥ 55.02, HR=4.965, 95%CI: 1.360-18.133), TNM stage (Ⅲ/Ⅳ, HR=7.811, 95%CI: 2.977-20.489), pro-gastrin releasing peptide (proGRP) (≥45.65 ng/L, HR=4.070, 95%CI: 1.442-11.487), tissue polypeptide antigen (TPA) (≥68.20 U/L, HR=6.996, 95%CI: 1.458-33.574), alkaline phosphatase (ALP) (≥82.50 IU/L, HR=4.160, 95%CI: 1.416-12.219) and ratio of activated partial thromboplastin time (aPTTR) (≥1.16: HR=4.58, 95%CI: 1.913-10.946) showed the independently relevant to PFS through multivariate Cox proportional hazards analysis. The EGFR mutant (P=0.343) and ALK rearrangement (P=0.608) were not significant either in survival analysis. Conclusion: High SUV-derived parameters (SUVmax, SUVmean, MTV and TLG) might provide prognostic value to some extent. Especially, TLG, and other clinical features [TNM stage, proGRP, TPA, ALP, and aPTTR] could be independently and significantly associated with PFS of lung adenocarcinoma patients. However, EGFR/ALK gene status could not be effectively relevant to PFS in lung adenocarcinoma patients.

Key words: Lung neoplasms, Adenocarcinoma, Positron-emission tomography, Epidermal growth factor receptor, Anaplastic lymphoma kinase

中图分类号: 

  • R734.2

表1

肺腺癌患者单因素和多因素Cox比例生存分析结果"

Characteristics Univariate analysis Multivariate Cox proportional hazards regression
HR (95%CI) P value HR (95%CI)* P value
Demographic characteristics
Age (continuous) 0.959 (0.906-1.016) 0.158
Gender 0.871a
Male 0.872 (0.475-1.880) 0.872b 0.832 (0.302-2.292) 0.721
Female Reference Reference
Weight loss 0.033a
Not more than 5% Reference
≥ 5% 2.260 (1.037-4.924) 0.040b
Co-morbidity 0.425a
None Reference Reference
One co-morbidity 0.934 (0.451-1.936) 0.854b 1.000 (0.383-2.612) 0.999
≥ Two co-morbidities 0.494 (0.164-1.490) 0.211b 1.828 (0.455-7.349) 0.396
Treatment 0.129a
Surgeryc 1.106 (0.149-8.220) 0.922b 13.258 (1.056-166.519) 0.045
TKIsd 3.275 (0.381-28.150) 0.280b 7.060 (0.510-97.748) 0.145
Surgery+TKIse 1.805 (0.163-20.036) 0.630b 12.513 (0.570-274.469) 0.109
Other treatmentf Reference Reference
SUVs characteristics
SUVmax 0.001a
<3.01 Reference
≥3.01 12.541 (1.708-92.070) 0.013b
SUVmean 0.003a
<2.25 Reference
≥2.25 4.198 (1.468-12.004) 0.007b
MTV/cm3 <0.001a
<25.41 Reference Reference
≥25.41 3.613 (1.751-7.456) <0.001b 0.313 (0.084-1.160) 0.082
TLG <0.001a
<55.02 Reference Reference
≥55.02 4.497 (2.061-9.815) <0.001b 4.965 (1.360-18.133) 0.015
Driver gene mutation status
EGFR/ALK 0.171a
Wild type Reference Reference
EGFR+ 1.450 (0.720-2.921) 0.298b 1.663 (0.581-4.755) 0.343
ALK+ 0.281 (0.037-2.107) 0.217 0.535 (0.049-5.819) 0.608
Morphological parameters
Primary tumor size/mm <0.001a
<26.50 Reference
≥26.50 3.850 (1.773-8.358) 0.001b
Solidity 0.002a
Part-solid/non-solid 0.269 (0.109-0.660) 0.004b
Solid Reference
Stage
TNM stage <0.001a
Ⅰ/Ⅱ Reference
Ⅲ/Ⅳ 5.291 (2.423-11.553) <0.001b 7.811 (2.977-20.489) <0.001
T stage 0.001a
Tis/Tia/T1/T2 Reference
T3/T4 3.153 (1.539-6.460) 0.002b
N stage <0.001a
N0 Reference
N1/N2/N3 5.814 (2.489-13.585) <0.001b
M stage <0.001a
M0 Reference
M1 3.274 (1.619-6.621) 0.001b
Blood test
proGRP/(ng/L) 0.035a
<45.65 Reference Reference
≥45.65 2.059 (1.029-4.123) 0.041b 4.070 (1.442-11.487) 0.008
Characteristics Univariate analysis Multivariate Cox proportional hazards regression
HR (95%CI) P value HR (95%CI)* P value
TPA/(U/L) 0.010a
<68.20 Reference Reference
≥68.20 3.585 (1.253-10.258) 0.017b 6.996 (1.458-33.574) 0.015
CEA/(μg/L) <0.001a
<6.15 Reference
≥6.15 3.764 (1.843-7.684) <0.001b
CYFRA21-1/(μg/L) 0.014a
<3.14 Reference
≥3.14 2.324 (1.156-4.675) 0.018b
NSE/(μg/L) 0.001a
<15.27 Reference
≥15.27 3.198 (1.570-6.515) 0.001b
WBC/(×109/L) 0.017a
<6.35 Reference
≥6.35 2.236 (1.127-4.438) 0.021b
ALP/(IU/L) 0.002a
<82.50 Reference Reference
≥82.50 3.089 (1.467-6.502) 0.003b 4.160 (1.416-12.219) 0.010
PT/s 0.029a
<10.25 Reference
≥10.25 2.765 (1.059-7.220) 0.038b
PTR 0.029a
<1.015 Reference
≥1.015 2.765 (1.059-7.220) 0.038b
PA/% 0.004a
<107.50 4.975 (1.499-16.516) 0.009b
≥107.50 Reference
aPTT 0.004a
<33.95 Reference
≥33.95 2.600 (1.306-5.177) 0.007b
aPTTR 0.001a
<1.16 Reference Reference
≥1.16 2.905 (1.455-5.797) 0.002b 4.576 (1.913-10.946) 0.001
FIB/(g/L) 0.013a
<2.77 Reference
≥2.77 2.893 (1.190-7.034) 0.019b

图1

多因素预后模型入选参数的Kaplan-Meier曲线(P值为Log-rank检验)"

图2

SUVmax、SUVmean和MTV的Kaplan-Meier曲线(P值为Log-rank检验)"

图3

65岁女性,肺腺癌Ⅲb期,TLG=56.83,proGRP=66.36 ng/L,TPA=76.10 U/L,ALP=91.00 IU/L,aPTTR=1.22。治疗前18F-FDG PET/CT [CT (A)、PET (B)]和胸部薄层屏气CT(C)显示原发灶位于右肺上叶尖段,原发灶SUVs增高,SUVmax=5.97,SUVmean=3.54, MTV=16.04 cm3。患者经右肺上叶切除,原发灶病理检查提示浸润性肺腺癌(D,HE染色),基因检测示EGFR 19号外显子缺失突变(E,免疫组织化学染色)和ALK蛋白表达阴性(F,免疫组织化学染色)。术后患者未接受其他治疗,定期随访,18个月后经18F-FDG PET/CT复查示:右肺门、纵隔、腹膜后、肠系膜多发肿大高代谢淋巴结,较前明显增大,葡萄糖代谢程度明显增高[腹膜后淋巴结:术前PET(G)和CT(H)、随访PET(K)和CT(L)];腰4右侧椎弓根新发骨质破坏伴葡萄糖代谢增高灶[术前PET(I)和CT(J)、随访PET(M)和CT(N)],病灶经持续随访证实为复发"

图4

59岁女性,肺腺癌Ⅰa3期,TLG=18.61,proGRP=33.77 ng/L,TPA=33.61 U/L,ALP=50.00 IU/L,aPTTR=0.92。治疗前18F-FDG PET/CT[CT(A)和PET(B)]和胸部薄层屏气CT(C)显示原发灶位于左肺上叶尖后段,原发灶SUVs偏低,SUVmax=2.84,SUVmean=1.64,MTV=11.33 cm3。患者经左肺上叶切除,原发灶病理检查提示浸润性肺腺癌(D, HE染色),基因检测示EGFR 19号外显子缺失突变(E, 免疫组织化学染色)和ALK蛋白表达阴性(F, 免疫组织化学染色)。术后患者未接受其他治疗,定期随访至2018年4月未见复发或转移,PFS为42.50个月"

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