多发肺结节的基础研究和临床治疗进展
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摘要
肺癌是世界上发病率和死亡率最高的肿瘤。随着多层螺旋计算机断层扫描(computed tomography,CT)技术的发展和肺癌筛查的广泛开展,越来越多的肺结节被发现,其中不少是多发肺结节,这些结节在病理学上常被诊断为多原发肺腺癌。对于具有不同影像学特征的多发结节,首选处理方法不尽相同,且每个肺结节的处理方法仍存在很大争议。近年来多发肺结节各病灶的演进及病灶间的相互影响机制,病灶内和病灶间肿瘤细胞在基因组学方面的同质性和异质性也备受关注。本文从组织病理学、基因组学、外科处理等多方面综合论述多发肺结节的研究进展。
Lung cancer leads to the highest cancer-related morbidity and mortality worldwide. With the development of multi-slice spiral computed tomography technology and the implement of lung cancer screening, more and more lung nodules have been discovered, many of which are multiple pulmonary nodules. These pulmonary nodules are usually diagnosed as multiple primary lung adenocarcinomas from a pathological perspective. For multiple nodules with different imaging features, the preferred treatment methods are different, and the treatment of each lung nodule is still controversial. In recent years, the interactions between multiple lesions and the evolution of the lesions as well as the inter-tumoral and intratumoral homogeneity and heterogeneity of the genomics also arouse attention. Our review gathered the research progress in multiple pulmonary nodules from the points of histopathology, genomics and surgical management.
Lung cancer leads to the highest cancer-related morbidity and mortality worldwide. With the development of multi-slice spiral computed tomography technology and the implement of lung cancer screening, more and more lung nodules have been discovered, many of which are multiple pulmonary nodules. These pulmonary nodules are usually diagnosed as multiple primary lung adenocarcinomas from a pathological perspective. For multiple nodules with different imaging features, the preferred treatment methods are different, and the treatment of each lung nodule is still controversial. In recent years, the interactions between multiple lesions and the evolution of the lesions as well as the inter-tumoral and intratumoral homogeneity and heterogeneity of the genomics also arouse attention. Our review gathered the research progress in multiple pulmonary nodules from the points of histopathology, genomics and surgical management.
引文
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3 Schneider F,Dacic S.Histopathologic and molecular approach to staging of multiple lung nodules.Translat Lung Cancer Res,2017,6(5):540.doi:10.21037/tlcr.2017.06.11
4 Liu M,He WX,Song N.Discrepancy of epidermal growth factor receptor mutation in lung adenocarcinoma presenting as multiple ground-glass opacities.Eur J Cardio-Thoracic Surg,2016,50(5):913.doi:10.1093/ejcts/ezw113
5 Kobayashi Y,Mitsudomi T,Sakao Y,et al.Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules:the differences between nodules with and without growth.Ann Oncol,2015,26:156-161.doi:10.1093/annonc/mdu505
6 Yatabe Y,Borczuk AC,Powell CA.Do all lung adenocarcinomas follow a stepwise progression?Lung Cancer,2011,74:711.doi:10.1016/j.lungcan.2011.05.021
7 Izumchenko E,Chang X,Brait M,et al.Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA.Nat Commun,2015,6:8258.doi:10.1038/ncomms9258
8 Chuang JC,Shrager JB,Wakelee HA,et al.Concordant and discordant EGFR mutations in patients with multifocal adenocarcinomas:implications for EGFR targeted therapy.Clin Therap,2016,38(7):1567-1576.doi:10.1016/j.clinthera.2016.06.005
9 Yamasaki M,Takeshima Y,Fujii S,et al.Correlation between genetic alterations and histopathological subtypes in bronchiolo-alveolar carcinoma and atypical adenomatous hyperplasia of the lung.Pathol Int,2010,50(10):778-785.doi:10.1046/j.1440-1827.2000.01123.x
10 Takamochi K,Ogura T,Suzuki K,et al.Loss of heterozygosity on chromosomes 9q and 16p in aty pical adenomatous hy perplasia concomitant with adenocarcinoma of the lung.Am J Pathol,2001,159(5):1941-1948.doi:10.1016/S0002-9440(10)63041-6
11 Yang Y,Yang Y,Zhou X,et al.EGFR L858R mutation is associated with lung adenocarcinoma patients with dominant ground-glass opacity.Lung Cancer,2015,87(3):272-277.doi:10.1016/j.lungcan.2014.12.016
12 Hsu KH,Chen KC,Yang TY,et al.Epidermal growth factor receptor mutation status in stage I lung adenocarcinoma with different image patterns.J Thorac Oncol,2011,6(6):1066-1072.doi:10.1097/JTO.0b013e31821667b0
13 Kim EA,Johkoh T,Lee KS,et al.Quantification of ground-glass opacity on high-resolution CT of small peripheral adenocarcinoma of the lung:pathologic and prognostic implications.AJR Am J Roentgenol,2001,177(6):1417-1422.doi:10.2214/ajr.177.6.1771417
14 Liu Y,Zhang J,Li L,et al.Genomic heterogeneity of multiple synchronous lung cancer.Nat Commun,2016,7:13200.doi:10.1038/ncomms 13200
15 Campbell PJ,Yachida S,Mudie LJ,et al.The patterns and dynamics of genomic instability in metastatic pancreatic cancer.Nature,2010,467(7319):1109-1113.doi:10.1038/nature09460
16 Ding L,Ellis MJ,Li S,et al.Genome remodelling in a basal-like breast cancer metastasis and xenograft.Nature,2010,464(7291):999-1005.doi:10.1038/nature08989
17 Vignot S,Frampton GM,Soria JC,et al.Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer.J Clin Oncol,2013,31(17):2167-2172.doi:10.1200/JCO.2012.47.7737
18 Hua B,Wang Z,Wang Y,et al.Detection and clinical significance of intratumoral EGFR mutational heterogeneity in chinese patients with advanced non-small cell lung cancer.PLoS One,2013,8(2):e54170.doi:10.1371/journal.pone.0054170
19 Chen ZY,Zhong WZ,Zhang XC,et al.EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas.Oncologist,2012,17(7):978-985.doi:10.1634/theoncologist.2011-0385
20 Ma P,Ma P,Fu Y,et al.Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer.Nat Commun,2017,8(1):823.doi:10.1038/s41467-017-00963-0
21 Tanvetyanon T,Finley DJ,Fabian T,et al.Prognostic factors for survival afer complete resections of synchronous lung cancers in multiple lobes:pooled analysis based on individual patient data.Ann Oncol,2013,24(4):889-894.doi:10.1093/annonc/mds495
22 Dai C,Ren Y,Xie H,et al.Clinical and radiological features of synchronous pure ground-glass nodules observed along with operable non-small cell lung cancer.J Surg Oncol,2016,113(7):738-744.doi:10.1002/jso.24235
23 Sihoe ADL,Schil PV.Non-small cell lung cancer:when to offer sublobar resection.Lung Cancer,2014,86(2):115-120.doi:10.1016/j.lungcan.2014.09.004
24 Shimada Y,Saji H,Otani K,et al.Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities,and the management of their residual lesions.Lung Cancer,2015,88(2):174-180.doi:10.1038/s41467-017-00963-0
25 Battafarano RJ,Meyers BF,Guthrie TJ,et al.Surgical resection of multifocal non-small cell lung cancer is associated with prolonged survival.Ann Thorac Surg,2002,74(4):988-994.doi:10.1016/S0003-4975(02)03878-X
26 Jiang GN,Chen C,Zhu YM,et al.Shanghai pulmonary hospital experts consensus on the management of ground glass nodules suspected as lung adenocarcinoma(version 1).Zhongguo Fei Ai Za Zhi,2018,21(3):147-159.[姜格宁,陈昶,朱余明,等.上海市肺科医院磨玻璃结节早期肺腺癌的诊疗共识(第一版).中国肺癌杂志,2018,21(3):147-159.]doi:10.3779/j.issn.1009-3419.2018.03.05
27 Wang Q,Wei J,Xi J.Surgery for pulmonary multiple ground glass opacities.Chin J Lung Cancer,2016,19(6):355-358.[王群,蒋伟,奚俊杰.肺部多发磨玻璃影的外科治疗.中国肺癌杂志,2016,19(6):355-358.]doi:10.3779/j.issn.1009-3419.2016.06.11
28 Ye C,Wang J,Li W,et al.Novel strategy for synchronous multiple primary lung cancer displaying unique molecular profiles.Ann Thorac Surg,2016,101(2):e45-e47.doi:10.1016/j.athoracsur.2015.06.042
29 Zhang B,Zhu F,Ma X,et al.Matched-pair comparisons of stereotactic body radiotherapy(SBRT)versus surgery for the treatment of early stage nonsmall cell lung cancer:A systematic review and meta-analysis.Radiother Oncol,2014,112(2):250-255.doi:10.1016/j.radonc.201 4.08.031
30 Kelly P,Balter PA,Rebueno N,et al.Stereotactic body radiation therapy for patients with lung cancer previously treated with thoracic radiation.Int J Radiat Oncol Biol Physics,2010,78(5):1387-1393.doi:10.1016/j.ijrobp.2009.09.070
31 Sinha B,Mcgarry RC.Stereotactic body radiotherapy for bilateral primary lung cancers:the Indiana University experience.Int J Radiat Oncol Biol Physics,2006,66(4):1120-1124.doi:10.1016/j.ijropb.2006.06.042
32 Newman AM,Bratman SV,To J,et al.An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage.Nat Med,2014,20(5):548-554.doi:10.1038/nm.3519
33 Wang L,Ou ZX.Expression and diagnostic efficacy of serum exosome miR-184 in non-small cell lung cancer.Lanzhou Da Xue Xue Bao(Yi Xue Ban),2018,44(3):31-36.[王蕾,欧宗兴.血清外泌体miR-184在非小细胞肺癌中的表达水平及其诊断效能.兰州大学学报(医学版),2018,44(3):31-36.]doi:10.13885/j.issn.1000-2812.2018.03.005
34 Mei XY,Sun YJ,Xu MQ,et al.Research of loss of heterozygaity on chromosome 3p in non-small cell lung cancer.Zhongguo Fei Ai Za Zhi,2008,21(4):534-537.[梅新宇,孙余婕,徐美青,等.非小细胞肺癌3p染色体多区域杂合性缺失检测的研究.中国肺癌杂志,2008,11(4):534-537.]doi:10.3779/j.issn.1009-3419.2008.04.017
2 Zhou QH,Fan YG,Wang Y,et al.China national guideline of classification,diagnosis and treatment for lung nodules(2016 version).Zhongguo Fei Ai Za Zhi,2016,19(12):793-798.[周清华,范亚光,王颖,等.中国肺部结节分类、诊断与治疗指南(2016年版).中国肺癌杂志,2016,19(12):793-798.]doi:10.3779/j.issn.1009-3419.2016.12.12
3 Schneider F,Dacic S.Histopathologic and molecular approach to staging of multiple lung nodules.Translat Lung Cancer Res,2017,6(5):540.doi:10.21037/tlcr.2017.06.11
4 Liu M,He WX,Song N.Discrepancy of epidermal growth factor receptor mutation in lung adenocarcinoma presenting as multiple ground-glass opacities.Eur J Cardio-Thoracic Surg,2016,50(5):913.doi:10.1093/ejcts/ezw113
5 Kobayashi Y,Mitsudomi T,Sakao Y,et al.Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules:the differences between nodules with and without growth.Ann Oncol,2015,26:156-161.doi:10.1093/annonc/mdu505
6 Yatabe Y,Borczuk AC,Powell CA.Do all lung adenocarcinomas follow a stepwise progression?Lung Cancer,2011,74:711.doi:10.1016/j.lungcan.2011.05.021
7 Izumchenko E,Chang X,Brait M,et al.Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA.Nat Commun,2015,6:8258.doi:10.1038/ncomms9258
8 Chuang JC,Shrager JB,Wakelee HA,et al.Concordant and discordant EGFR mutations in patients with multifocal adenocarcinomas:implications for EGFR targeted therapy.Clin Therap,2016,38(7):1567-1576.doi:10.1016/j.clinthera.2016.06.005
9 Yamasaki M,Takeshima Y,Fujii S,et al.Correlation between genetic alterations and histopathological subtypes in bronchiolo-alveolar carcinoma and atypical adenomatous hyperplasia of the lung.Pathol Int,2010,50(10):778-785.doi:10.1046/j.1440-1827.2000.01123.x
10 Takamochi K,Ogura T,Suzuki K,et al.Loss of heterozygosity on chromosomes 9q and 16p in aty pical adenomatous hy perplasia concomitant with adenocarcinoma of the lung.Am J Pathol,2001,159(5):1941-1948.doi:10.1016/S0002-9440(10)63041-6
11 Yang Y,Yang Y,Zhou X,et al.EGFR L858R mutation is associated with lung adenocarcinoma patients with dominant ground-glass opacity.Lung Cancer,2015,87(3):272-277.doi:10.1016/j.lungcan.2014.12.016
12 Hsu KH,Chen KC,Yang TY,et al.Epidermal growth factor receptor mutation status in stage I lung adenocarcinoma with different image patterns.J Thorac Oncol,2011,6(6):1066-1072.doi:10.1097/JTO.0b013e31821667b0
13 Kim EA,Johkoh T,Lee KS,et al.Quantification of ground-glass opacity on high-resolution CT of small peripheral adenocarcinoma of the lung:pathologic and prognostic implications.AJR Am J Roentgenol,2001,177(6):1417-1422.doi:10.2214/ajr.177.6.1771417
14 Liu Y,Zhang J,Li L,et al.Genomic heterogeneity of multiple synchronous lung cancer.Nat Commun,2016,7:13200.doi:10.1038/ncomms 13200
15 Campbell PJ,Yachida S,Mudie LJ,et al.The patterns and dynamics of genomic instability in metastatic pancreatic cancer.Nature,2010,467(7319):1109-1113.doi:10.1038/nature09460
16 Ding L,Ellis MJ,Li S,et al.Genome remodelling in a basal-like breast cancer metastasis and xenograft.Nature,2010,464(7291):999-1005.doi:10.1038/nature08989
17 Vignot S,Frampton GM,Soria JC,et al.Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer.J Clin Oncol,2013,31(17):2167-2172.doi:10.1200/JCO.2012.47.7737
18 Hua B,Wang Z,Wang Y,et al.Detection and clinical significance of intratumoral EGFR mutational heterogeneity in chinese patients with advanced non-small cell lung cancer.PLoS One,2013,8(2):e54170.doi:10.1371/journal.pone.0054170
19 Chen ZY,Zhong WZ,Zhang XC,et al.EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas.Oncologist,2012,17(7):978-985.doi:10.1634/theoncologist.2011-0385
20 Ma P,Ma P,Fu Y,et al.Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer.Nat Commun,2017,8(1):823.doi:10.1038/s41467-017-00963-0
21 Tanvetyanon T,Finley DJ,Fabian T,et al.Prognostic factors for survival afer complete resections of synchronous lung cancers in multiple lobes:pooled analysis based on individual patient data.Ann Oncol,2013,24(4):889-894.doi:10.1093/annonc/mds495
22 Dai C,Ren Y,Xie H,et al.Clinical and radiological features of synchronous pure ground-glass nodules observed along with operable non-small cell lung cancer.J Surg Oncol,2016,113(7):738-744.doi:10.1002/jso.24235
23 Sihoe ADL,Schil PV.Non-small cell lung cancer:when to offer sublobar resection.Lung Cancer,2014,86(2):115-120.doi:10.1016/j.lungcan.2014.09.004
24 Shimada Y,Saji H,Otani K,et al.Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities,and the management of their residual lesions.Lung Cancer,2015,88(2):174-180.doi:10.1038/s41467-017-00963-0
25 Battafarano RJ,Meyers BF,Guthrie TJ,et al.Surgical resection of multifocal non-small cell lung cancer is associated with prolonged survival.Ann Thorac Surg,2002,74(4):988-994.doi:10.1016/S0003-4975(02)03878-X
26 Jiang GN,Chen C,Zhu YM,et al.Shanghai pulmonary hospital experts consensus on the management of ground glass nodules suspected as lung adenocarcinoma(version 1).Zhongguo Fei Ai Za Zhi,2018,21(3):147-159.[姜格宁,陈昶,朱余明,等.上海市肺科医院磨玻璃结节早期肺腺癌的诊疗共识(第一版).中国肺癌杂志,2018,21(3):147-159.]doi:10.3779/j.issn.1009-3419.2018.03.05
27 Wang Q,Wei J,Xi J.Surgery for pulmonary multiple ground glass opacities.Chin J Lung Cancer,2016,19(6):355-358.[王群,蒋伟,奚俊杰.肺部多发磨玻璃影的外科治疗.中国肺癌杂志,2016,19(6):355-358.]doi:10.3779/j.issn.1009-3419.2016.06.11
28 Ye C,Wang J,Li W,et al.Novel strategy for synchronous multiple primary lung cancer displaying unique molecular profiles.Ann Thorac Surg,2016,101(2):e45-e47.doi:10.1016/j.athoracsur.2015.06.042
29 Zhang B,Zhu F,Ma X,et al.Matched-pair comparisons of stereotactic body radiotherapy(SBRT)versus surgery for the treatment of early stage nonsmall cell lung cancer:A systematic review and meta-analysis.Radiother Oncol,2014,112(2):250-255.doi:10.1016/j.radonc.201 4.08.031
30 Kelly P,Balter PA,Rebueno N,et al.Stereotactic body radiation therapy for patients with lung cancer previously treated with thoracic radiation.Int J Radiat Oncol Biol Physics,2010,78(5):1387-1393.doi:10.1016/j.ijrobp.2009.09.070
31 Sinha B,Mcgarry RC.Stereotactic body radiotherapy for bilateral primary lung cancers:the Indiana University experience.Int J Radiat Oncol Biol Physics,2006,66(4):1120-1124.doi:10.1016/j.ijropb.2006.06.042
32 Newman AM,Bratman SV,To J,et al.An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage.Nat Med,2014,20(5):548-554.doi:10.1038/nm.3519
33 Wang L,Ou ZX.Expression and diagnostic efficacy of serum exosome miR-184 in non-small cell lung cancer.Lanzhou Da Xue Xue Bao(Yi Xue Ban),2018,44(3):31-36.[王蕾,欧宗兴.血清外泌体miR-184在非小细胞肺癌中的表达水平及其诊断效能.兰州大学学报(医学版),2018,44(3):31-36.]doi:10.13885/j.issn.1000-2812.2018.03.005
34 Mei XY,Sun YJ,Xu MQ,et al.Research of loss of heterozygaity on chromosome 3p in non-small cell lung cancer.Zhongguo Fei Ai Za Zhi,2008,21(4):534-537.[梅新宇,孙余婕,徐美青,等.非小细胞肺癌3p染色体多区域杂合性缺失检测的研究.中国肺癌杂志,2008,11(4):534-537.]doi:10.3779/j.issn.1009-3419.2008.04.017