肺癌经气腔播散的研究进展

宋书珲, 李文雅

宋书珲, 李文雅. 肺癌经气腔播散的研究进展[J]. 实用临床医药杂志, 2022, 26(3): 144-148. DOI: 10.7619/jcmp.20214565
引用本文: 宋书珲, 李文雅. 肺癌经气腔播散的研究进展[J]. 实用临床医药杂志, 2022, 26(3): 144-148. DOI: 10.7619/jcmp.20214565
SONG Shuhui, LI Wenya. Research progress on spread through air spaces in lung cancer[J]. Journal of Clinical Medicine in Practice, 2022, 26(3): 144-148. DOI: 10.7619/jcmp.20214565
Citation: SONG Shuhui, LI Wenya. Research progress on spread through air spaces in lung cancer[J]. Journal of Clinical Medicine in Practice, 2022, 26(3): 144-148. DOI: 10.7619/jcmp.20214565

肺癌经气腔播散的研究进展

基金项目: 

辽宁省教育厅科学研究基金资助项目 QN2019003

详细信息
    通讯作者:

    李文雅, E-mail: 41578203@qq.com

  • 中图分类号: R734.2;R445.2

Research progress on spread through air spaces in lung cancer

  • 摘要: 目前, 肺癌经气腔播散(STAS)的发生机制仍不明确。本研究对近年来关于STAS发生机制、诊断方式、预后影响、治疗方案选择的最新成果予以综述,为临床医生、研究人员快速了解相关研究进展以及为该领域的未来研究提供导向参考。
    Abstract: At present, the mechanism of spread through air spaces (STAS) in lung cancer is still unclear. In this study, the latest achievements on the pathogenesis, diagnostic methods, prognostic impact and treatment options of STAS in the past few years were reviewed, so as to provide guidance and reference for clinicians and researchers, and to quickly understand the relevant research progress and future researches in this field.
  • 肺癌是人类最常见的癌症之一,也是癌症死亡的主要原因[1]。近年来,肺癌发病率和病死率在全球范围内持续上升,相关研究集中在肺癌早期诊断与综合治疗措施探讨方面。肺癌经气腔播散(STAS)或肺泡腔内播散作为肺癌的一种侵袭模式,与肺癌的预后、治疗选择等密切相关。本文就该领域的最新研究进行综述,现报告如下。

    2011年国际肺癌研究协会/美国胸科学会/欧洲呼吸学会(IASLC/ATS/ERS)国际肺腺癌多学科新分类发布后,关于肺腺癌的一系列新的病理形态学特征及其与预后的相关性被关注[2]。肺癌传统的转移方式包括淋巴转移、血行转移、胸膜播散。2015年,世界卫生组织(WHO)正式提出STAS这一新的转移方式[3]。关于STAS的亚型分类, WHO将其分为微乳头簇型、实巢型、单个细胞型。2017年, URUGA H等[4]对STAS进行了半定量评估,将微乳头簇型或实巢型占优势的STAS分类为无STAS、低STAS(1~4组微乳头状或实巢状占优势的STAS)或高STAS(≥5组STAS)。单个细胞型占优势的STAS分为无STAS、低STAS(1~4个肿瘤细胞)或高STAS(≥5个肿瘤细胞)。

    自STAS被WHO明确提出以来,关于其具体发生机制仍存在争议,争论的主要焦点在于STAS究竟是一种人为结果还是自然发生的病理过程[5]

    相关研究表明不能排除胸腔镜手术或病理组织切片处理过程中人为造成STAS的可能。一项关于肺神经内分泌肿瘤的研究[6]中发现增生的肺神经内分泌细胞(NE细胞)通过气腔播散、空间移动很可能通过刀、外科医生或其他方式人为地发生。而一项对51个手术肺标本的系列研究[7]发现STAS的发生不是人为事件,而是在外科手术前自然产生的。关于STAS是否有可能是一种人为因素造成的结果目前尚存在争议,相关方面研究只是临床观察到结果进行统计学分析探讨手术或病理标本处理是否与STAS存在相关性,随机对照试验(RCT)研究较少,是否是人为因素引起STAS还缺乏有力证据,未来还需进一步探讨。

    对于STAS分子机制的阐释越来越受到关注,较多的研究集中在STAS与上皮间质转化(EMT)和肿瘤免疫微环境上。2020年LIU A等[8]研究表明STAS与Twist和Slug两种转录因子的过表达相关,其表达上调引起EMT相关蛋白E-cadherin表达减弱, N-cadherin、vi-mentin及Snail表达增强,引发EMT, 进而引起STAS发生增加。2021年IKEDA T等[9]研究表明在切除的肺癌中,具有上皮表型的肿瘤中STAS的发生率低于非上皮表型(包括间质型和介于上皮间质中间的类型)的肿瘤,进一步证实STAS的发生与上皮间质转化相关。此外,一些研究还发现了许多与STAS发生相关的分子,如(α-平滑肌肌动蛋白)α-SAM阳性癌症相关成纤维细胞(CAFs)、β连环蛋白、黏蛋白21(MUC21)[10]等。通过抑制细胞-细胞、细胞-基质间黏附使肺癌细胞不粘连等多种机制,进而引发STAS的发生。一项研究[11]分别讨论了肺腺癌和肺鳞癌中与STAS的相关分子。在肺腺癌中, STAS的存在与野生型EGFR、ALK和ROS1重排、低E-cadherin表达以及高vi-mentin和Ki67表达相关。在肺鳞癌中, STAS与低E-钙粘蛋白表达和高波形蛋白和存活蛋白表达相关。

    2019年QIU X等[12]及2021年YOSHIDA C等[13]研究发现肿瘤微环境中CD68+TAM1和CD204+TAM的(TAMs)浸润与较高的肿瘤STAS率有关。

    随着关于STAS对肺癌病理分期以及预后影响的研究逐渐深入,临床医生认识到在治疗早期对肺癌患者STAS是否存在应有更加精准的诊断。近些年相关研究也集中在影像学、组织病理预测上。

    2018年KIM S K等[14]和DE MARGERIE-MELLON C等[15]提出相似观点,STAS在实体瘤中比在部分实体瘤或毛玻璃状病变中更常见。实性成分的总平均直径、长轴直径,以及实性成分直径占总平均直径的比率高是亚实性肺腺癌合并STAS的CT表现[15]。此外, STAS还与中央低衰减、支气管空气征、CT上的分叶状和毛刺状边缘、缺口的存在与否、肺内磨玻璃密度影相关[16]。2020年,有学者[17-18]提出开发和验证基于计算机断层扫描(CT)的放射组学模型,从而可以在术前预测肺腺癌的STAS, 提高术前诊断效能,进而选择合适的切除方法。

    2018年WALTS A E等[19]对是否可以在冰冻切片(FS) 中可靠地识别出STAS以帮助对肺叶或亚肺叶切除术的患者进行分层展开研究,得到结论FS对STAS检测的敏感性和阴性预测值过低,由此认为术中病理检测STAS对指导手术切除范围没有帮助。2020年KIMURA T等[20]提出基于小肺腺癌手术标本的新型Nakayama-Higashiyama印记细胞学分类(N-H分类),并阐明肺腺癌术中印记细胞学N-H分类与肿瘤的STAS状态密切相关,可作为STAS术中预测标志物。这种分类可能有助于术中STAS的检测和外科手术的决策过程。2021年VILLALBA J A等[21]进一步研究表明, FS对Ⅰ期肺腺癌的STAS检测具有高度特异性而敏感性较低。且STAS的专家观察者间一致性(IOA)在FS中一般,在讨论后仅略有改善。一系列连续的研究表明术中病理对于STAS的预测价值有限, N-H细胞学可能更有预测价值,仍需更灵敏的检测手段在术中对STAS做出更为准确的预测。还有学者[22]对术前支气管肺泡灌洗(BAL)或支气管冲洗(BW)细胞学标本与随后的肺腺癌手术切除标本进行比对,以了解术前细胞学是否可以预测STAS, 结论是单独的术前支气管细胞学并不能充分预测肿瘤STAS, 然而,其可能提供有关STAS对后续切除范围的有用信息。无论是影像学还是术中病理细胞学检测均对STAS术前或术中有一定的预测价值,后续研究可考虑建立术前术中STAS预测整合模型,从而利于术式选择。

    对于合并STAS的肺癌治疗措施,研究集中在外科手术策略的选择上。文献[23-29]报道,存在STAS并实施局部肺切除术(亚肺叶切除)的早期腺癌患者预后较实施肺叶切除术的患者差且有更高的术后复发风险。TOYOKAWA G等[30]对合并淋巴结转移的腺癌患者实施完全切除术后生存率的预后进行研究,发现在完全切除的腺癌伴有淋巴结转移中, STAS的存在也预示更加不良的RFS。但对于伴发STAS的肺腺癌手术方式,较大的切除范围(肺叶切除)已经逐渐得到了业界学者的充分认可。2020年SUH J W等[31]开发了一个流程图用于判断早期非小细胞癌的术式选择,结合CT二维肺内磨玻璃密度影(GGO)百分比、正电子发射CT上的SUV T/L比和贴壁为主模式来预测STAS, 得到STAS阳性的敏感性、特异性和阴性预测值分别为79.3%、68.5%和89.5%。该流程图可能有助于判断早期非小细胞癌患者是否可行亚肺叶切除术。

    STAS的伴发与肺癌治疗方式的选择一直是临床关注和有待进一步探讨的话题,但研究几乎集中在外科干预选择上,关于分子治疗新靶点的发现、射频消融以及不同放化疗方式对各类肺癌伴发STAS预后影响依然罕有研究报道,或许将成为今后对肺癌伴发STAS的一个有待开发探索的方向。

    自STAS作为肺癌的一种新转移途径被WHO提出后,大量的研究集中在了肺癌合并STAS对于患者无复发生存(RFS)和总生存期(OS)等相关预后指标的影响以及不同手术方式对预后的影响上。

    在肺腺癌中, 2017年就有研究[32]对不同肿块最大直径合并STAS对预后分层影响情况进行了分类阐述: ①肿块径大于2~3 cm且存在STAS的患者预后情况与IB期无STAS的腺癌患者相似。②在肿块最大径≤2 cm的患者中, STAS未对预后有显著影响。而同年的另一项研究[4]却表明Ⅰ期肺腺癌(最大径≤2 cm)合并较显著STAS也提示RFS更差。2018年LEE J S等[33]研究进一步证实STAS还与肺腺癌胸内和胸外的复发有关。2020年LEE M A等[34]研究表明与其他亚型相比,肺浸润性黏液腺癌(IMA)显示出更高的STAS发生率,且在IMA中,伴有STAS也是一个独立的不良预后预测因子。2021年有关研究[35]探讨了肺内GGO与STAS之间的关系,以及对Ⅰ期肺腺癌预后的影响,发现STAS与GGO都是Ⅰ期肺腺癌预后的重要预测因子。此外, GGO成分对预后的有利影响大于STAS的不利影响,表明GGO是Ⅰ期肺腺癌更为权重可靠的预后预测因子。

    在其他病理类型的肺癌以及肺转移瘤方面也有探讨STAS与不良预后的关联性的研究。2017年的一项研究[36]表明STAS是肺鳞状细胞癌(SQCC)中最具有预后意义的组织学检查结果之一,肿瘤STAS是已切除SQCC患者RFS的独立预测因子[37], 并且与肿瘤侵袭性相关。2018年YANAGAWA N等[38]又进一步将STAS对不同分期的SQCC预后影响进行了分类阐述,证实了STAS与Ⅰ期SQCC的复发和较差的生存相关,但在Ⅱ期和Ⅲ期SQCC中没有对预后产生显著影响。近年又有学者针对肺神经内分泌肿瘤和类癌中STAS与其预后的关联进行研究,结果显示在肺神经内分泌肿瘤(NETs)患者中, STAS与早期远处转移和更高的肺癌特异性累积死亡率(LC-CID)相关。在大细胞神经内分泌癌(LCNEC)或小细胞肺癌(SCLC)患者中, STAS都是一个独立的不良预后因素[39]。2019年ALTINAY S等[40]研究证实了STAS的存在也是肺非典型类癌(ACs)的一个相关不良预后因素。在肺多形性癌中STAS与手术切除后的高复发率和较差的生存率相关[41]。2020年TAKEDA-MIYATA N等[42]评估STAS对结直肠癌肺转移的预后意义,发现STAS与结直肠癌肺转移的预后不佳和手术边缘复发有关。

    近年来,关于STAS对肺癌预后影响的研究较多,从最早对腺癌的研究逐渐扩展到鳞癌、小细胞癌等各种病理类型; 研究深度也从单一的STAS的影响逐渐深入到与多种其他相关预后因素进行整合比较。2019年,有学者[43]提出建立一个由STAS和其他病理特征,包括肺浸润性腺癌的脏层胸膜浸润(VPI)、血管浸润(VI) 和组织学亚型(HS)组成的肺腺癌预后模型。还有学者[12]推荐以STAS和基质细胞为变量的列线图作为评估肺腺癌患者预后的实用模型,从而更好地预测肺腺癌患者的生存情况。总而言之, STAS对肺癌预后的不良影响已经得到共识,后续的研究可进一步整合细分STAS对不同病理类型、分期的影响,从而建立更加完善、客观、科学的肺癌预后模型。

    STAS可发生在除腺癌外多种病理类型的肺癌中(包括鳞癌、类癌、小细胞癌、大细胞癌等),其存在对肺癌患者的预后有不利影响。术前或术中对STAS是否存在进行评价有利于外科术式的合理选择。临床可通过影像学(CT、正电子发射CT)配合术中组织病理学(FS)、细胞学检查(BAL、BW)等多种方式综合检查进行更加准确科学的预测,但还需进一步建立对于STAS早期诊断的系统模型。对于存在STAS的早期肺癌患者建议进行更大范围的切除(肺叶切除)。STAS的发生机制还存在争议,究竟STAS是否是一种人为“伪影”仍需进一步论证,但随着STAS相关细胞分子的检出,可考虑进一步尝试筛查相关作用靶点的药物进行肿瘤内科治疗并探讨相关药物、介入治疗等新疗法对于伴发STAS肺癌患者的预后改善情况,以完善对于伴发STAS肺癌的综合治疗模式。

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出版历程
  • 收稿日期:  2021-11-19
  • 网络出版日期:  2022-03-10
  • 发布日期:  2022-02-14

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