含微乳头及实体亚型的临床早期浸润性肺腺癌研究进展.pdf

2023,43(6)http:/J Clin Pathol Res 临床与病理杂志含微乳头及实体亚型的临床早期浸润性肺腺癌研究进展张新迪，何春明，王擎 综述 孙志勇，赵晓菁 审校（上海交通大学医学院附属仁济医院胸外科，上海 200127）摘 要 在早期(III)浸润性肺腺癌患者中，高级别病理亚型尤其是微乳头状为主型腺癌(micropapillary predominant adenocarcinoma，MPA)和实体为主伴黏液分泌型腺癌(solid predominant adenocarcinoma with mucin production，SPA)对患者预后有显著的负面效应，容易复发、局部侵犯以及远处转移。与其他病理亚型相比，MPA/SPA有明显的基因突变。通过放射组学构建的影像诊断预测模型可以精准预测肺结节的高危亚型成分。对可疑的含有高级别亚型成分的总直径2 cm的周围型肺癌，优先行肺叶切除术以避免复发。术后病理证实为IB期，合并胸膜侵犯、气道播散或其他高危因素者，结合患者基因突变类型，可考虑行辅助治疗以提高远期生存率。关键词 微乳头状为主型腺癌；实体为主伴黏液分泌型腺癌；预后；病理；肺腺癌；免疫治疗Research progress of micropapillary and solid subtypes in early-stage invasive lung adenocarcinomaZHANG Xindi,HE Chunming,WANG Qing,SUN Zhiyong,ZHAO Xiaojing(Department of Thoracic Surgery,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China)ABSTRACT High-grade pathological subtypes particularly the micropapillary predominant adenocarcinoma(MPA)and solid predominant adenocarcinoma with mucin production(SPA)types,have a significant negative prognostic effect in patients with early-stage(III)lung adenocarcinoma,leading to localized invasion,early recurrence,and distant metastasis.Compared to other lower grades subtypes,MPA/SPA has significant genetic mutations.Diagnostic imaging prediction models constructed by radiomics can accurately predict the high-grade subtypes component of lung nodules.Lobectomy is preferred for avoiding recurrence in suspected peripheral lung cancers suspected to containin high-grade DOI：10.11817/j.issn.2095-6959.2023.222409收稿日期(Date of reception)：2022-11-16第一作者(First author)：张新迪，Email:,ORCID:0000-0002-6348-7317通信作者(Corresponding author)：赵晓菁，Email:,ORCID:0000-0003-1858-2179基金项目(Foundation item)：国家自然科学基金(82072560)。This work was supported by the National Natural Science Foundation of China(82072560).1295临床与病理杂志,2023,43(6)http:/subtype components 2 cm in total diameter.With the pathological confirmation of stage IB,along with the presence of pleural invasion,airway dissemination,or other high-risk factors,adjuvant therapy may be considered in achieving long-term survival outcomes.The patient s genetic mutation type must also be taken into account when determining the appropriate adjuvant therapy to administer.KEY WORDS micropapillary predominant adenocarcinoma;solid predominant adenocarcinoma with mucin production;prognosis;pathology;lung adenocarcinoma;immunotherapy肺腺癌已成为非小细胞肺癌最常见的亚型，是全球癌症死亡的主要原因1-2。根据2021年世界卫生组织(World Health Organization，WHO)肺癌分类，肺浸润性非黏液腺癌的常见亚型包括5个组织病理亚型：贴壁状为主型腺癌(lepidic predominant adenocarcinoma，LPA)、腺 泡 状 为 主 型 腺 癌(acinar predominant adenocarcinoma，APA)、乳头状为主型腺癌(papillary predominant adenocarcinoma，PPA)、微乳头状为主型腺 癌(micropapillary predominant adenocarcinoma，MPA)及实体为主伴黏液分泌型腺癌(solid predominant adenocarcinoma with mucin production，SPA)3-5。肺腺癌高级别病理亚型主要包括MPA、SPA以及复杂腺体模式(complex glandular pattern，CGP)。在2015版的WHO分类中，对CGP有所认知，但决定不创建一个新的亚型，而是将其描述为浸润性肺腺癌高级别模式的一种，2020 年国际肺癌研究协会(International Association for the Study of Lung Cancer，IASLC)将其纳入浸润性肺腺癌的术后病理分级系统6。研究7-10报道：肺腺癌的高级别病理亚型作为主要成分存在时(5%)，具有快速转移潜力，患者预后较差且易复发。此外，近期研究9发现当高级别病理亚型作为次要成分出现时(成分0.5,mGGO,pT2N0M0,IB,micropapillary and acinar predominant,STAT(+)and visceral pleura invasion,FDG hypermetabolism with SUVmax=2.6.E,K:HE,0.5;F,L:HE,20.SPA:Solid predominant adenocarcinoma with mucin production;MPA:Micropapillary predominant adenocarcinoma;CTR:Consolidation tumor ratio;FDG:Fluorodeoxyglucose;SUVmax:Maximum standard uptake value;mGGO:Mixed ground glass opacity;STAT:Signal transducer and activator of transcription;HE:Hematoxylin and eosin.1298含微乳头及实体亚型的临床早期浸润性肺腺癌研究进展 张新迪，等近年来已经有许多针对高级别病理亚型的放射学定性研究，主要用于术前辅助病理亚型定性，指导手术方式的选择和术后的个性化治疗。有研究36通过传统的影像形态特征和放射学特征来构建影像学诊断模型，与传统影像形态特征相比，这些放射学特征具有更高的诊断价值，如灰度共生矩阵、灰度行程矩阵、灰度区域大小矩阵、高强度组分、低强度组分等。He等37根据以上放射学特征构建一个机器预测模型，该模型针对高纯度病理亚型的肺腺癌表现出强烈的放射组学值分层，为准确的病理亚型分型和肿瘤亚区域的图像分割提供基础信息。在上述研究基础上Chen等38改进预测模型，建立一种基于最大似然估计法的“近纯”肿瘤亚型(“近纯”主要亚型成分70%肿瘤体积)的预测模型，具有高度的敏感度和中度的特异度。通过对肿瘤区域内的每个体素进行补丁式的高级似然预测，然后根据该区域的体积百分比阈值确定高级别亚型的存在。在CT图像上评估实变/肿瘤比率，应用放射学侵袭性(实变/肿瘤比率0.5)进行预测。使用“近纯”的放射组学特征和逐块图像分析证明高危亚型(MPA/SPA)检测的高灵敏度和中等水平的特异性。但不足之处在于以“近纯”成分替代100%的亚型成分，相应的影像区域内可能包括一部分非肿瘤部分，如间质增生、肺纹理等。3 基因组学特征 3.1 免疫检查点表达水平已有研究39-40证实：程序性死亡受体配体 1(programmed death-ligand 1，PD-L1)作为免疫治疗的生物标志物，与中级别病理亚型(APA/PPA)和低级别病理亚型(LPA)相比，PD-L1表达水平与高级别病理亚型(MPA/SPA)呈显著正相关，且PD-L1在SPA中的表达水平显著高于其他亚型。在另一项实验9证实SPA成分存在组(5%)和MPA成分存在组的PD-L1表达水平略高于SPA、MPA成分阴性组，但差异无统计学意义。Zhang等41通过二代测序方法描绘MPA的免疫微环境景观，发现在MPA与T细胞浸润程度和PD-L1的表达水平呈正相关，推测MPA的肿瘤细胞可能通过 T 细胞的免疫抑制作用来促进免疫逃逸。因此针对程序性死亡-1(programmed death-1，PD-1)/PD-L1的免疫疗法可能有利于MPA/SPA亚型的患者预后。3.2 靶向基因突变3.2.1 致癌驱动基因突变3.2.1.1 KRAS目前研究42证实致癌基因的突变频率与整个肿瘤中MPA成分的占比有关。Rekhtman等43研究深度分析高级别病理亚型与常见的几个基因突变的关系，表明实体模式和KRAS突变之间的关联，以及肿瘤中实体模式的比例与KRAS突变频率之间的正相关性：增高的实体亚型比例与更高的KRAS突变频率相关。即使SPA的KRAS突变率高，目前仍缺乏对KRAS突变有效的治疗。3.2.1.2 EGFRRekhtman 等43在观察 SPA 的增量和 EGFR 突变率的关系时发现EGFR突变频率在MPA/PPA/APA中较高，在SPA中较低。另外，从来自3个不同人群的4项研究44-47中得出结论：LPA成分与EGFR突变呈正相关。LPA可作为EGFR突变的预测因子，并且EGFR突变的LPA阳性患者可受益于相应的靶向药物。因此，从靶向治疗的角度来看，SPA中EGFR的低突变率和 KRAS 的高突变率是靶向治疗的挑战，MPA则是EGFR靶向治疗的良好候选者。3.2.2 其他突变位点3.2.2.1 细胞间质表皮转化因子细胞间质表皮转化因子(cellular-mesenchymal epithelial transition factor，c-Met)在肿瘤侵袭和肿瘤细胞运动等进展过程中具有重要作用。Koga等12发现高水平的磷酸化c-Met蛋白与MPA成分和淋巴结转移相关。与c-Met低表达的患者相比，c-Met高表达的IA期肿瘤患者预后较差(5年生存率：51.3%)。此外，在LPA阳性患者中，c-Met的高表达与淋巴浸润有关。这些发现表明c-Met的激活与MPA的肿瘤进展和促进淋巴浸润的生物学行为之间存在联系。3.2.2.2 SMARCA4(BRG1)/SMARCA2(BRM)染色质交换型转换/蔗糖不发酵(switch/sucrose non-fermentable，SWI/SNF)相关基质关联肌动蛋白依赖性调节因子亚家族A成员(SWI/SNF-related,matrix-associated,actin-dependent regulator of chromatin subfamily A member，SMARCA)4/SMARCA2所编码的蛋白质是SWI/SNF蛋白质家族的成员，具有解螺旋酶和ATP酶活性，被认为是通过改变某些基因周围 的 染 色 质 结 构 来 调 节 这 些 基 因 的 转 录48。Matsubara等49发现Brahm相关基因1(Brahma-related gene 1，BRG1)或 Brahma 同系物(Brahma homolog，BRM)表达缺失或二者同时缺失在SPA中较为常见，1299临床与病理杂志,2023,43(6)http:/并与甲状腺转录因子低表达、支气管上皮细胞低的分化水平及患者不良预后相关，且BRG1的缺失与LPA成分的缺失相关，与EGFR突变相互排斥。3.2.2.3 低密度脂蛋白受体相关蛋白1B低 密 度 脂 蛋 白 受 体 相 关 蛋 白 1B(low-density lipoprotein receptor-related protein 1B，LRP1B)编码一类低密度脂蛋白受体，在细胞发挥正常功能和细胞生长发育过程中发挥重要作用，LRP1B突变是促进肺癌发生的重要一环50。Ding等50发现LRP1B突变与 APA、LPA 和 细 支 气 管 肺 泡 癌(bronoloalveolar carcinoma，BAC)亚型呈负相关，与SPA呈正相关，且在I期病变中，SPA较MPA具有更复杂的突变谱，LRP1B的突变率更高；SPA患者PD-L1阳性成分占比和肿瘤比例评分(tumor proportion score，TPS)显著增高。此外，LRP1B作为重要的抑癌基因，其突变水平与较高的肿瘤新生抗原负荷和肿瘤突变负荷相关，肿瘤浸润的免疫细胞更为丰富，免疫应答状态和免疫治疗反应也较好51-52。目前，针对LRP1B位点的免疫治疗方法，在非小细胞肺癌和黑色素瘤患者中也被确定，SPA结合LRP1B突变的患者，可以从免疫治疗中获益40。4 治疗方案 4.1 手术治疗肺腺癌的组织学构成往往不是单一成分，包含其他不同组织学亚型，而且MPA或SPA亚型与淋巴结转移和不良预后有关，5年复发风险高。因此不能只根据肺癌主要病理类型决定手术方式及辅助治疗方案。目前已有许多针对MPA手术方法选择的临床研究，如Nitadori等53研究表明2 cm的早期肺腺癌，以MPA为主的患者行亚肺叶切除术(肺楔形切除或肺段切除)，术后复发的风险更高。存在 MPA的患者与无MPA成分存在(MPA成分5%即认为存在)的患者相比，MPA成分存在与否是接受局部切除术后累及复发率的独立预测因素。相反地，接受肺叶切除的患者无论是否存在MPA成分，累计发病率比值差异均无统计学意义。此外，存在MPA成分的患者，在接受局部切除后(亚肺叶切除术)，容易发生局部复发(63.4%)，且当手术切缘1 cm时，局部复发风险增加。这可能是由于在行局部切除时手术 边 缘 不 够 充 分 或 淋 巴 结 清 扫 有 限 所 致。与Nitadori等53研究结果稍有差别的是，Yao等54研究表明：MPA成分5%的患者，行肺楔形切除术后，复发率显著高于行解剖性肺叶(段)切除术者，且MPA成分0.5，总直径2 cm 的周围型肺癌，优先行肺叶切除术，肺段切除是可选的，不推荐楔形切除术，并强调早期(术前或术中快速冰冻)发现 MPA 成分的重要性。SPA 亚型相较于 MPA 亚型，属于低分化病理类型，恶性程度较 MPA 更高，也应行解剖性肺叶(段)切除术，但尚无相关临床研究支持，未来需要进一步证实。4.2 辅助治疗含高危因素的IB期患者术后辅助治疗的问题是目前胸外科领域充满争议的话题之一。MPA或SPA的患者生存率较低，随着低剂量胸部CT的普及，I1300含微乳头及实体亚型的临床早期浸润性肺腺癌研究进展 张新迪，等期患者目前已经成为临床外科治疗的主要人群。IA期患者相比IB期患者预后明显较好，且现有临床研究60证明无需术后辅助治疗改善预后。但IB期具有高危因素的患者术后是否需要辅助化学治疗存在明显争议。高危因素包括：低分化肿瘤(肺神经内分泌肿瘤但不包括分化良好的神经内分泌肿瘤)、血管侵犯、肺楔形切除、肿瘤直径4 cm、脏层胸膜受累、淋巴结状态不明。2020年美国国文综合癌症网络非小细胞肺癌指南指出高危IB期患者术后建议辅助化学治疗。含有MPA/SPA成分的早期肺腺癌患者在接受亚肺叶切除治疗时，局部复发率较高，但可能通过辅助化学治疗改善54。与非高级别病理亚型为主的患者相比，以MPA或SPA模式为主的患者从辅助化学治疗中明显获益61。但在Yanagawa等62研究中，无论辅助化学治疗如何，MPA或SPA成分是否存在，患者的PFS和总生存率差异无统计学意义。据 Warth 等1报道SPA亚型的患者接受辅助放射治疗后预后有所改善。近期，一项荟萃分析63汇总6项研究结果表明与不进行术后化学治疗相比，术后化学治疗与更好的总生存率相关，术后化学治疗也显著提高IB期MPA/SPA患者的PFS(术后化学治疗与非术后化学治疗，RR=0.51，95%CI 0.400.64；P2 to 3 cmJ.J Thorac Oncol,2017,12(7):1052-1060.https:/doi.org/10.1016/j.jtho.2017.03.020.16Zhao Y,Wang R,Shen X,et al.Minor components of micropapillary and solid subtypes in lung adenocarcinoma are predictors of lymph node metastasis and poor prognosisJ.Ann Surg Oncol,2016,23(6):2099-2105.https:/doi.org/10.1245/s10434-015-5043-9.17Li C,Shen Y,Hu F,et al.Micropapillary pattern is associated with the development of brain metastases and the reduction of survival time in EGFR-mutation lung adenocarcinoma patients with surgeryJ.Lung Cancer,2020,141:72-77.https:/doi.org/10.1016/j.lungcan.2020.01.007.18Xu CH,Wang W,Wei Y,et al.Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification in stage IB lung adenocarcinomaJ.Eur J Surg Oncol,2015,41(10):1430-1436.https:/doi.org/10.1016/j.ejso.2015.06.004.19张欢,孙奉昊,陈振淙,等.I期肺腺癌中病理学亚型判断预后的价值分析J.中华外科杂志,2022,60(6):580-586.https:/doi.org/10.3760/112139-20211008-00474.ZHANG Huan,SUN Fenghao,CHEN Zhencong,et al.Validation of prognostic value of pathological staging in pathological stage I lung adenocarcinomaJ.Chinese Journal of Surgery,2022,60(6):580-586.https:/doi.org/10.3760/112139-20211008-00474.20Miyoshi T,Satoh Y,Okumura S,et al.Early-stage lung adenocarcinomas with a micropapillary pattern,a distinct pathologic marker for a significantly poor prognosisJ.Am J Surg Pathol,2003,27(1):101-109.https:/doi.org/10.1097/00000478-200301000-00011.21Travis WD,Brambilla E,Nicholson AG,et al.The 2015 World Health Organization classification of lung tumors:impact of genetic,clinical and radiologic advances since the 2004 classificationJ.J Thorac Oncol,2015,10(9):1243-1260.https:/doi.org/10.1097/JTO.0000000000000630.22Ohe M,Yokose T,Sakuma Y,et al.Stromal micropapillary component as a novel unfavorable prognostic factor of lung adenocarcinomaJ.Diagn Pathol,2012,7:3.https:/doi.org/10.1186/1746-1596-7-3.23Emoto K,Eguchi T,Tan KS,et al.Expansion of the concept of micropapillary adenocarcinoma to include a newly recognized 1302含微乳头及实体亚型的临床早期浸润性肺腺癌研究进展 张新迪，等filigree pattern as well as the classical pattern based on 1468 stage I lung adenocarcinomasJ.J Thorac Oncol,2019,14(11):1948-1961.https:/doi.org/10.1016/j.jtho.2019.07.008.24Zhu E,Xie H,Gu C,et al.Recognition of filigree pattern expands the concept of micropapillary subtype in patients with surgically resected lung adenocarcinomaJ.Mod Pathol,2021,34(5):883-894.https:/doi.org/10.1038/s41379-020-00711-8.25Nakamura H,Takagi M.Clinical impact of the new IASLC/ATS/ERS lung adenocarcinoma classification for chest surgeonsJ.Surg Today,2015,45(11):1341-1351.https:/doi.org/10.1007/s00595-014-1089-8.26Onozato ML,Kovach AE,Yeap BY,et al.Tumor islands in resected early-stage lung adenocarcinomas are associated with unique clinicopathologic and molecular characteristics and worse prognosisJ.Am J Surg Pathol,2013,37(2):287-294.https:/doi.org/10.1097/PAS.0b013e31826885fb.27Kuang M,Shen X,Yuan C,et al.Clinical significance of complex glandular patterns in lung adenocarcinoma:clinicopathologic and molecular study in a large series of casesJ.Am J Clin Pathol,2018,150(1):65-73.https:/doi.org/10.1093/ajcp/aqy032.28Morales-Oyarvide V,Mino-Kenudson M.Tumor islands and spread through air spaces:distinct patterns of invasion in lung adenocarcinomaJ.Pathol Int,2016,66(1):1-7.https:/doi.org/10.1111/pin.12368.29Boss Y,Gagn A,Althakfi W,et al.Prognostic value of complex glandular patterns in invasive pulmonary adenocarcinomasJ.Hum Pathol,2022,128:56-68.https:/doi.org/10.1016/j.humpath.2022.07.007.30Kadota K,Kushida Y,Kagawa S,et al.Cribriform subtype is an independent predictor of recurrence and survival after adjustment for the eighth edition of TNM staging system in patients with resected lung adenocarcinomaJ.J Thorac Oncol,2019,14(2):245-254.https:/doi.org/10.1016/j.jtho.2018.09.028.31Ding Q,Chen D,Wang X,et al.Characterization of lung adenocarcinoma with a cribriform component reveals its association with spread through air spaces and poor outcomesJ.Lung Cancer,2019,134:238-244.https:/doi.org/10.1016/j.lungcan.2019.06.027.32Zhang J,Liang Z,Gao J,et al.Pulmonary adenocarcinoma with a micropapillary pattern:a clinicopathological,immunophenotypic and molecular analysisJ.Histopathology,2011,59(6):1204-1214.https:/doi.org/10.1111/j.1365-2559.2011.04050.x.33Xu Y,Ji W,Hou L,et al.Enhanced CT-based radiomics to predict micropapillary pattern within lung invasive adenocarcinomaJ.Front Oncol,2021,11:704994.https:/doi.org/10.3389/fonc.2021.704994.34Cha MJ,Lee HY,Lee KS,et al.Micropapillary and solid subtypes of invasive lung adenocarcinoma:clinical predictors of histopathology and outcomeJ/OL.J Thorac Cardiovasc Surg,2014,147(3):921-928.e22022-12-22.https:/doi.org/10.1016/j.jtcvs.2013.09.045.35Lee HY,Jeong JY,Lee KS,et al.Histopathology of lung adenocarcinoma based on new IASLC/ATS/ERS classification:prognostic stratification with functional and metabolic imaging biomarkersJ.J Magn Reson Imaging,2013,38(4):905-913.https:/doi.org/10.1002/jmri.24080.36Yang SM,Chen LW,Wang HJ,et al.Extraction of radiomic values from lung adenocarcinoma with near-pure subtypes in the International Association for the Study of Lung Cancer/the American Thoracic Society/the European Respiratory Society(IASLC/ATS/ERS)classificationJ.Lung Cancer,2018,119:56-63.https:/doi.org/10.1016/j.lungcan.2018.03.004.37He B,Song Y,Wang L,et al.A machine learning-based prediction of the micropapillary/solid growth pattern in invasive lung adenocarcinoma with radiomicsJ.Transl Lung Cancer Res,2021,10(2):955-964.https:/doi.org/10.21037/tlcr-21-44.38Chen LW,Yang SM,Wang HJ,et al.Prediction of micropapillary and solid pattern in lung adenocarcinoma using radiomic values extracted from near-pure histopathological subtypesJ.Eur Radiol,2021,31(7):5127-5138.https:/doi.org/10.1007/s00330-020-07570-6.39Hazim A,Majithia N,Murphy SJ,et al.Heterogeneity of PD-L1 expression between invasive and lepidic components of lung adenocarcinomasJ.Cancer Immunol Immunother,2021,70(9):2651-2656.https:/doi.org/10.1007/s00262-021-02883-x.40Li Y,Tan Y,Hu S,et al.Targeted sequencing analysis of predominant histological subtypes in resected stage I invasive lung adenocarcinomaJ.J Cancer,2021,12(11):3222-3229.https:/doi.org/10.7150/jca.51405.41Zhang S,Xu Y,Zhao P,et al.Integrated analysis of genomic and immunological features in lung adenocarcinoma with micropapillary componentJ.Front Oncol,2021,11:652193.https:/doi.org/10.3389/fonc.2021.652193.42Zhang Y,Wang R,Cai D,et al.A comprehensive investigation of molecular features and prognosis of lung adenocarcinoma with micropapillary componentJ.J Thorac Oncol,2014,9(12):1772-1778.https:/doi.org/10.1097/JTO.0000000000000341.43Rekhtman N,Ang DC,Riely GJ,et al.KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinomaJ.Mod Pathol,2013,26(10):1307-1319.https:/doi.org/10.1038/modpathol.2013.74.44Song Z,Zhu H,Guo Z,et al.Correlation of EGFR mutation and predominant histologic subtype according to the new lung adenocarcinoma classification in Chinese patientsJ.Med Oncol,2013,30(3):645.https:/doi.org/10.1007/s12032-013-0645-1.45Li H,Pan Y,Li Y,et al.Frequency of well-identified oncogenic driver mutations in lung adenocarcinoma of smokers varies with histological subtypes and graduated smoking doseJ.Lung Cancer,2013,79(1):8-13.https:/doi.org/10.1016/j.lungcan.2012.09.018.46Russell