恶性胸膜间皮瘤(MPM)分期的研究进展

复旦学报(医学版)

2019, Vol. 46

Issue (1): 108-113 DOI: 10.3969/j.issn.1672-8467.2019.01.019

Contents PDF Abstract Full text Fig/Tab

引用本文

王帅, 马可, 詹成, 蒋伟, 王群. 恶性胸膜间皮瘤(MPM)分期的研究进展[J]. 复旦学报医学版, 2019, 46(1): 108-113.

WANG Shuai, MA Ke, ZHAN Cheng, JIANG Wei, WANG Qun. Research progress on staging of malignant pleural mesothelioma (MPM)[J]. Fudan University Journal of Medical Sciences, 2019, 46(1): 108-113.

恶性胸膜间皮瘤(MPM)分期的研究进展

王帅 (综述), 马可 , 詹成 (审校), 蒋伟 , 王群

复旦大学附属中山医院胸外科上海 200032

收稿日期：2017-05-10

基金项目：上海市青年科技英才扬帆计划(17YF1402400);国家自然科学基金(81401875, 81472225)

摘要：恶性胸膜间皮瘤(malignant pleural mesothelioma, MPM)是一种高度侵袭性的肿瘤。目前对于MPM缺乏大规模的临床研究, 诊治经验较局限, MPM的分期仍处于探索阶段。一方面, MPM具有特殊的肿瘤生长及转移模式; 另一方面, 准确评估肿瘤的侵犯范围非常困难。肿瘤分期对于指导相应的治疗计划及预测患者预后有重要的作用, 因此, 临床上MPM的分期一直是研究焦点。本文对MPM分期的发展历史及最新研究进展进行综述。

关键词：胸膜间皮瘤肿瘤分期预后

Research progress on staging of malignant pleural mesothelioma (MPM)

WANG Shuai , MA Ke , ZHAN Cheng , JIANG Wei , WANG Qun

Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

Foundation item: This work was supported by Shanghai Sailing Program of Skilled Youth Personnel (17YF1402400) and the National Natural Science Foundation of China (81401875, 81472225)

Corresponding author: ZHAN Cheng, E-mail: czhan10@fudan.edu.cn.

Abstract: Malignant pleural mesothelioma (MPM) is a kind of highly invasive tumor.At present, the experience on the diagnosis and treatment of MPM is limited with a lack of large-scale clinical study.Thus staging of MPM need further exploratory research.On the one hand, the pattern of MPM growth and metastasis is quite special.On the other hand, accurate assessment of tumor invasion is very difficult.However, tumor staging plays an extremely important role in guiding the treatment and predicting the prognosis.Therefore, staging of MPM is still the focus of clinical research.In this review, we will summarize the development history and the latest research advances on staging of MPM.

Key words: pleural mesothelioma tumor stage prognosis

恶性胸膜间皮瘤(malignant pleural mesothelioma, MPM)起源于胸膜间皮细胞, 是一种特殊类型的高侵袭性肿瘤。MPM可发生于胸膜的任何部分, 发病年龄常见于40~60岁。国外流行病学数据表明, MPM发病率呈上升趋势^[1]。我国尚无大规模的统计学资料, 文献报道MPM在我国的发病率有很大的地区差异性, 在1~6/100万之间, 低于国外平均水平^[2]。MPM的发病与石棉暴露有直接关系, 国外大多数国家已经禁止应用石棉, 而我国仍是石棉最大消费国。从石棉暴露到发病, 大概有35年的潜伏期。学者估计在未来的20年中, MPM的发病将迅速增加, 成为公众健康难题^[3]。但是, MPM的临床资料有限, 诊断困难, 多为经验性治疗, 有关MPM的许多问题目前仍处于探索期。其中MPM分期一直是研究最热、争议最多的议题。

MPM沿着脏层胸膜或者壁层胸膜弥漫性生长, 并且侵袭周围组织。由于胸膜的解剖结构、位置和MPM的特殊生长方式, 准确估计肿瘤大小和局部侵犯范围非常困难, 因此MPM分期与其他恶性肿瘤不同, 不能盲目套用其他肿瘤的原发肿瘤-淋巴结-远处转移(tumor-node-metastasis, TNM)分期方法。虽然MPM患者整体预后非常差, 而且缺乏标准的治疗方案, 但是通过根治性切除和规范化疗, 仍可以延长部分患者的生存时间^[4]。而MPM的准确分期有助于判断预后及选择治疗方案, 因此对MPM患者的准确分期尤为重要。

MPM的早期分期 1976年, Butchart等^[5]根据29例接受胸膜外肺组织切除术(extrapleural pneumonectomy, EPP)的MPM患者临床特点, 提出了MPM的第1个分期系统。此系统按照肿瘤的局部侵犯程度和远处转移情况直接将MPM分为4期。虽然该研究样本量少, 术后并发症多并且患者的预后差, 但是Butchart分期系统仍然在临床上广泛应用。现在看来该分期系统略显粗糙, 但在当时医学影像学尚不发达的情况下, 该系统为MPM的手术治疗提供了重要的参考标准, 具有划时代意义。随后, 许多学者根据Butchart的四分期系统提出了不同的MPM分期。其中, Mattson等^[6]将ButchartⅠ期心包浸润患者归类到Ⅱ期。Dimitrov等^[7]提出Butchart Ⅰ期应根据肿瘤大小分为两类, Ⅱ期包括浸润胸内筋膜和肺, Ⅲ期包括胸壁和心包浸润, Ⅳ期包括纵隔、肺门淋巴结转移, 对侧胸膜浸润和胸腔外转移。这些分期方法分别从不同方面优化了Butchart的四分期系统, 但未有实质性改变。这些分期方法的不足之处在于:(1)对于原发MPM的侵袭部位不明确; (2)对MPM胸腔内转移范围的描述不完善; (3)MPM的淋巴结转移和血性转移特点未得到重视; (4) MPMⅡ期太宽泛而Ⅲ期又太狭隘; (5)分期系统与患者预后相关性差。

Sugarbaker等^[8]分析52例多学科治疗的MPM患者发现, 肺门、纵隔淋巴结转移的患者预后相对较差, 并于1993年提出了新的四分期系统:肺门、纵隔或同侧胸腔内淋巴结转移为Ⅱ期; 胸壁、心脏、食管或对侧结构受侵为Ⅲ期。与Butchart的四分期系统相比, 其最大的进步在于考虑到MPM淋巴结转移特点, 并对原发肿瘤胸腔内侵袭的结构进一步划分。在随后对183例经EPP完全切除MPM患者的随访分析显示, 该分期系统与患者预后有重要相关性^[9]。连续MPM病例分析表明, 分期系统Ⅰ~Ⅲ期患者分布较均匀^[9]。Sugarbaker分期系统建立在外科切除标本的病理研究基础之上, 准确应用该分期的前提是完全切除MPM, 且对淋巴结微转移和标本切缘进行详细评估。由于MPM患者预后差, 手术治疗效果有限, 术后并发症较多, 可完全切除MPM的患者较少, 因此MPM切除术式选择争议较大[EPP vs. 胸膜切除/剥脱术(pleurectomy/decortication, P/D)]。在免疫组织化学和医学电镜技术尚未在临床大规模应用时, 部分标本病理可能无法证实MPM是否侵犯淋巴结, 因此当时Sugarbaker分期的临床推广受到限制。

MPM的TNM分期 由于MPM特殊的肿瘤生长方式和胸膜淋巴引流, MPM的早期分期系统并未采用传统TNM方法。学者们曾普遍认为MPM患者的死因主要是局部肿瘤进展, 压迫和侵袭重要胸腔结构, 比如心脏、肺、食管和主动脉。而且胸膜的淋巴引流是多方向的, MPM的淋巴结转移模式也是多方向的, 对MPM的淋巴结转移的鉴定和分类较困难。早期对MPM的T分期研究较多, 而N分期知之甚少, 在这种情况下, TNM分期系统和四分期系统并没有实质性区别。然而, TNM分期的多维度评价可以更全面地反映肿瘤进展程度, 更准确地预测患者预后, 因此有必要对MPM进行TNM分期。

Chahinian等^[10]于1983年首次尝试将TNM分期应用于MPM。Chahinian分期系统将原发肿瘤详细划分为4个阶段:T1~T4, 淋巴结转移分为4个阶段:N0~N3, 血性转移和胸腔外淋巴结转移视为M1。总体分期为:Ⅰ期, T1N0M0;Ⅱ期, T1-2N1M0或者T2N0M0;Ⅲ期, T3N0-3M0或者T1-3N2-3M0;Ⅳ期, T4N0-3M0或者T1-4N0-3M1。Chahinian综合分析已有的分期系统并结合自己的临床经验提出的分期系统在当时并未引起重视。直到1995年, 国际胸膜间皮瘤小组(International Mesothelioma Interest Group, IMIG)发布了MPM的TNM国际分期标准, 该分期被UICC和AJCC采纳后, MPM的TNM分期才逐渐被临床医师接受^[11]。该分期系统综合考虑原发肿瘤、淋巴结转移和血行转移特点, 反映了MPM的自然史。与Chahinian分期不同的是:该分期系统将T分期进一步细化, 将T1分为T1a和T1b;当肿瘤为T1~T3时, N1和N2患者为Ⅲ期; T4、N3或者M1患者为Ⅳ期。IMIG分期系统的特点是将支气管肺淋巴结、肺门淋巴结、隆凸下淋巴结、内乳淋巴结、锁骨上淋巴结或者斜角肌淋巴结转移划入不同的分期。

大部分MPM患者在初诊时就已经是晚期, 早期MPM患者非常少。随着MPM发病率的增加和诊断技术的进步, 越来越多的MPM患者在早期即可被诊断。在胸腔镜下, 部分患者表现为肿瘤局限在壁胸膜, 而脏胸膜正常, 这些极早期MPM患者手术完全切除率高, 且预后相对较好。IMIG分期系统将Ⅰ期患者分为ⅠA期(T1aN0M0), ⅠB期(T1bN0M0), 以进一步对Ⅰ期患者采取针对性治疗, 并准确预测患者生存时间。T4表示局部进展晚期MPM, 一般认为是不适合手术治疗, 多数上皮型MPM患者在M1之前, 就已经进展至T4, T4与M1的生存时间无显著性差异, 因此IMIG分期系统认为T4与M1均属Ⅳ期。

在IMIG分期系统基础上, UICC发布了MPM最新的TNM分期^[12-14](表 1)。该系统的T分期与IMIG分期系统无实质性改变, 仍将原发肿瘤局部进展分为T1~T4。在N分期, UICC分期系统更加重视区域淋巴结概念, 将支气管肺淋巴结、肺门淋巴结转移、纵隔淋巴结、内乳淋巴结、隔上淋巴结和锁骨上淋巴结定义为区域淋巴结; 将非区域淋巴结转移定义为M1。对于部分原发于壁胸膜和隔胸膜的MPM患者, 由于局部肿瘤的直接侵袭, 内乳淋巴结受累(N2)可能早于支气管肺淋巴结或肺门淋巴结(N1)转移。因此系统性淋巴结评估对MPM的分期十分重要^[15]。现在学者普遍认为淋巴结转移是MPM患者预后的不良因素, 在手术中也强调对纵隔淋巴结的清扫, 但是MPM的淋巴结转移发生率和转移途径仍然未知。UICC分期系统对N的定义与非小细胞肺癌相似(表 1)。与非小细胞肺癌不同的是, MPM的N1与N2患者的预后无显著性差异(N3患者预后最差)^[16]。在对MPM的淋巴结转移研究不足的情况下, UICC分期暂时将N1、N2均划入Ⅲ期, N3划入Ⅳ期。这种N分期的目的是为以后MPM淋巴结转移研究制定国际标准, 利于多中心大样本研究。此分期系统仍将MPM分为4期(表 1)。与早期的分期系统相比, UICC制定的TNM分期对MPM的纵隔内侵袭结构和淋巴结转移的规定更加具体。早期的MPM分期认为局限在胸腔内的肿瘤均为早期(Ⅰ期或Ⅱ期), 胸腔外结构受累则是进展期疾病(Ⅲ期或Ⅳ期); 最新的TNM分期认为, 胸壁、心脏、纵隔和对侧胸膜受累已是进展期疾病(Ⅲ期或Ⅳ期)。此种分期为MPM的多学科治疗提供了重要参考标准:对于Ⅰ期或Ⅱ期患者采用手术切除为主的综合治疗; 对于Ⅲ期或Ⅳ期患者采用以化、放疗结合的综合治疗, 避免EPP或P/D过度治疗^[15]。UICC分期方法自发布以来逐渐得到认同, 但其临床应用价值仍需要进一步研究。

表 1 恶性胸膜间皮瘤(MPM) UICC分期 Tab 1 UICC staging system for MPM

UICC	Definition
Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor involves ipsilateral parietal pleura, with or without focal involvement of visceral pleura
T1a	Tumor involves ipsilateral parietal (mediastinal, diaphragmatic) pleura; no involvement of the visceral pleura
T1b	Tumor involves ipsilateral parietal (mediastinal, diaphragmatic) pleura with focal involvement of the visceral pleura
T2	Tumor involves any of the ipsilateral pleural surfaces with at least one of the following: Confluent visceral pleural tumor (including fissure); Invasion of diaphragmatic muscle; Invasion of lung parenchyma
T3	Describes locally advanced but potentially resectable tumor Tumor involves any of the ipsilateral pleural surfaces with at least one of the following: Invasion of the endothoracic fascia; Invasion into mediastinal fat; Solitary focus of tumor invading the soft tissues of the chest wall; Nontransmural involvement of the pericardium
T4	Describes locally advanced technically unresectable tumor Tumor involves any of the ipsilateral pleural surfaces with at least one of the following: Diffuse or multifocal invasion of soft tissues of the chest wall; Any involvement of rib; Invasion through the diaphragm to the peritoneum; Direct extension of any mediastinal organs; Direct extension to the contralateral pleura; Invasion into the spine; Extension to the internal surface of the pericardium; Pericardial effusion with positive cytology; Invasion of the myocardium; Invasion of the brachial plexus
Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastases
N1	Metastases in the ipsilateral bronchopulmonary and/or hilar lymph nodes
N2	Metastases in the subcarinal lymph nodes and/or the ipsilateral internal mammary or mediastinal lymph nodes
N3	Metastases in the contralateral mediastinal, contralateral internal mammary, or hilar lymph nodes and/or the ipsilateral or contralateral supraclavicular or scalene lymph nodes
Distant metastasis
MX	Distant metastases cannot be assessed
M0	No distant metastasis
M1	Distant metastasis present
Stage Ⅰ
Stage ⅠA	T1a N0 M0
Stage ⅠB	T1b N0 M0
Stage Ⅱ	T2 N0 M0
Stage Ⅲ	Any T3, any N1, any N2
Stage Ⅳ	Any T4, any N3, any M1

表选项

目前的TNM分期系统仍有很大局限性, 尤其是术前的准确临床分期和N分期类型存在很大争议。2016年, 国际肺癌研究协会(International Association for the Study of Lung Cancer, IASLC)发起了间皮瘤分期计划, 提供了胸膜间皮瘤数据库, 旨在为第8版UICC TNM分期系统提供参考。

IASLC搜集3 519例胸膜间皮瘤, 对于T分期, 509例患者只有术前临床(clinical, c) T分期, 836例患者只有病理(pathologic, p) T分期, 642例患者二者均有。根据目前的TNM分期, 术前临床T分期进展程度越严重, 患者的总体生存越差。但是临床T1a期与T1b期患者的生存无明显差异(HR=0.99, P=0.95);临床T3期与T4期患者的生存时间也无显著不同(HR=1.22, P=0.09)。术后病理T3期与T4期患者的生存具有显著差异, 而术后病理T分期与其他相邻类别的患者生存差异并不明显。值得注意的是, 胸膜厚度及肿瘤的大体形状(结节状增厚/环状增厚)与患者生存具有显著相关性。因此, IASLC建议将T1a期与T1b期合并为T1期^[17]。

该数据库详细分析了MPM患者N分期资料。Kaplan-Meier分析显示cN0期, cN1期与cN2期患者总体生存无显著差异(cN1 vs. cN0:HR=1.06, P=0.77;cN2 vs. cN1:HR=1.04, P=0.85)。根据pTNM分期系统, pN1和pN2患者的生存时间显著短于pN0患者(HR=1.51, P＜0.000 1), 但是pN1期与pN2期患者的生存时间并无明显差异(HR=0.99, P=0.99)。同时具有pN1及pN2淋巴结转移的患者比单纯pN2期(HR=1.60, P=0.007)及pN0期(HR=1.62, P＜0.000 1)患者的预后更差。因此, IASLC建议将原N1、N2归为一类(同侧淋巴结转移), 胸腔内淋巴结转移归为N1, 原N3重新分类为N2, 取消N3分类^[18]。

IASLC数据库cM1患者的中位总体生存时间是9.7个月, 局部进展期(cT4M0及cN3M0)患者的中位总体生存时间是13.4个月, 两者具有显著差异(P=0.001 3)。通过对患者的总体生存进行递归分析及进一步合并生成生存树, IASLC建立了优化TNM分期系统:Ⅰ A期(T1N0), Ⅰ B期(T2-3N0), Ⅱ期(T1-2N1), ⅢA期(T3N1), ⅢB期(T1-3N2或any T4), Ⅳ期(any M1) (表 2)^[19]。

表 2 恶性胸膜间皮瘤(MPM) IASLC分期 Tab 2 IASLC staging system for MPM

IASLC	Definition
Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor limited to the ipsilateral parietal or visceral or mediastinal or diaphragmatic pleura
T2	Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features: involvement of diaphragmatic muscle; extension of tumor from visceral pleura into the underlying pulmonary parenchyma
T3	Describes locally advanced but potentially resectable tumor Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:involvement of the endothoracic fascia; extension into the mediastinal fat; solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall nontransmural involvement of the pericardium
T4	Describes locally advanced technically unresectable tumor Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction; direct transdiaphragmatic extension of tumor to the peritoneum; direct extension of tumor to the contralateral pleura; direct extension of tumor to mediastinal organs; direct extension of tumor into the spine; tumor extending through to the internal surface of the pericardium with or without a pericardial effusion; or tumor involving the myocardium
Regional lymph nodes
NX	Regional lymph nodes cannotbe assessed
N0	No regional lymph node metastases
N1	Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal lymph nodes) lymph nodes
N2	Metastases inthe contralateral bronchopulmonary, hilar, or mediastinal lymph nodes or ipsilateral or contralateral supraclavicular lymph nodes
Distant metastasis
MX	Distant metastases cannot be assessed
M0	No distant metastasis
M1	Presence of distant metastatic disease outside of the ipsilateral hemithorax or regional lymph node; hematogenous metastasis
Stage Ⅰ
Stage ⅠA	T1 N0 M0
Stage ⅠB	T2-3 N0 M0
Stage Ⅱ	T1-2 N1 M0
Stage Ⅲ
Stage ⅢA	T3 N1 M0
Stage ⅢB	T1-3 N2 M0 or any T4
Stage Ⅳ	any M1

表选项

IASLC分期系统并不是完美的, 比如没有深入分析不同转移部位的生存差异, 也没有探讨多点转移与寡转移的预后区别。但是该分期系统比UICC分期的患者预后相关性更强。而且IASLC的研究证明了胸膜厚度与肿瘤形态的预后价值。因此, IASLC分期系统具有重要的临床意义。更重要的是, 通过整合29个国际研究机构的前瞻性数据集(1 566例)及回顾性临床研究资料(1 953例), IASLC建立了大样本、多中心的MPM数据库。该数据库为MPM的分期提供循证医学证据, 将促进MPM临床研究的进一步发展。

MPM的分子生物学分期 MPM患者的生存时间受多种因素影响, 包括病理类型、石棉暴露、全身状态、年龄等。TNM分期单纯从临床病理学角度对肿瘤分期, 因而不能完全准确预测MPM患者的生存。对于所有肿瘤, 局部浸润和远处转移均是肿瘤生物学行为的具体表现, 而癌基因、抑癌基因的遗传学或表观遗传学改变才是肿瘤生物学行为的决定性因素。单纯从解剖病理学对肿瘤进行分期有很大局限性, 而研究肿瘤驱动基因的改变, 对肿瘤进行分子生物学分期才能更准确地预测肿瘤的生物学行为, 更早地判断患者预后。肿瘤分子学分期不仅可以判断肿瘤恶性程度, 更能预测化疗、放疗的敏感性, 从而实现肿瘤患者的个体化治疗。近年来, 肿瘤的基因组和蛋白组改变成为研究热点, 肿瘤的特异性驱动基因不断被鉴定, 肿瘤的治疗也进入个体化和特异化时代。

MPM分子生物学分期尚处于理论研究阶段。实现MPM分子生物学分期, 首先要鉴定它的特异性标志物。学者已经鉴定了多种MPM生物学指标, 例如Mesothelin^[20]、PDGFRB ^[21]、Midkine^[22]、CD26 ^[23]和EML4-ALK^[24]。这些生物学指标改变揭示了MPM的发生、发展机制, 为MPM的治疗提供新的靶点。利用特异性标志物可以判断MPM患者的放化疗敏感性, 也可以预测患者的生存时间, 但应用于分子生物学分期仍需进一步研究。

结语随着对MPM研究的不断深入, 分期方法从传统四分期发展至国际规范的TNM分期。最新的TNM分期为MPM的治疗提供了可靠信息, 但是预测患者生存的特异性和敏感性有待提高。近年来提出的肿瘤分子分期为MPM的研究指明了方向。目前无论是单一治疗或者综合治疗, MPM的治疗效果均不理想^[25-26]。MPM的分期、治疗相关的诸多问题需要更为深入地多学科探索。基于分子生物学技术的转化医学研究有望进一步完善MPM的分期, 并为MPM的治疗提供有价值信息。

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文章信息

王帅, 马可, 詹成, 蒋伟, 王群

WANG Shuai, MA Ke, ZHAN Cheng, JIANG Wei, WANG Qun

恶性胸膜间皮瘤(MPM)分期的研究进展

Research progress on staging of malignant pleural mesothelioma (MPM)

复旦学报医学版, 2019, 46(1): 108-113.

Fudan University Journal of Medical Sciences, 2019, 46(1): 108-113.

Corresponding author
ZHAN Cheng, E-mail: czhan10@fudan.edu.cn.

基金项目
上海市青年科技英才扬帆计划(17YF1402400);国家自然科学基金(81401875, 81472225)

Foundation item
This work was supported by Shanghai Sailing Program of Skilled Youth Personnel (17YF1402400) and the National Natural Science Foundation of China (81401875, 81472225)

文章信息

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