肺内多发磨玻璃影诊疗的最新进展
Progress on Diagnosis and Surgery Multiple Ground-Glass Nodules
DOI: 10.12677/ACM.2017.74037, PDF, HTML, XML, 下载: 2,209  浏览: 5,762  国家自然科学基金支持
作者: 董 林, 李钦传:上海市东方医院(同济大学附属东方医院),上海
关键词: 多发磨玻璃影肺癌诊断手术治疗 Multiple Ground-Grass Nodules Lung Cancer Diagnosis Surgery
摘要: 随着诊断技术的不断发展,肺部磨玻璃结节(Ground-Grass Opacity,GGO)检出率明显增高。其中肺内多发磨玻璃影发病率也呈上升趋势,其成分主要为纯磨玻璃结节(pure GGO, pGGO)。结合多发磨玻璃影的影像学特征以及一些血清学检验可以帮助我们预测其恶性程度,并制定合理的随访策略和治疗方法。针对多发磨玻璃影的治疗,目前以手术治疗为主,但并不是所有的结节都需要同期切除,手术切除范围可以行亚肺叶切除或肺叶切除。还可以运用其他治疗方法例如立体定向消融放射治疗(stereotactic ablative radiotherapy, SABR)等。对于多发磨玻璃影的患者要根据其病情个体化精准治疗,制定合理的随访策略和治疗方式。
Abstract: With the continuous development of diagnostic techniques, the detection rate of ground-grass opacity (GGO) was significantly higher. The incidence of multiple GGO in the lungs also showed an increasing trend, with the main components of pure glass ginger (pure GGO, pGGO). Combining the imaging features of multiple ground glass shadows and some serological tests can help us predict malignancy and develop appropriate follow-up strategies and treatments. For the treatment of multiple ground glass, the preferred surgical treatment, but not all of the nodules need to resection, surgical resection can be sub-lung lobectomy or lobectomy. Other treatment methods such as stereotactic ablation radiotherapy (SABR) and the like may also be used for patients with multiple GGO according to their individualized treatment of disease, to make a reasonable follow-up strat-egies and treatment.
文章引用:董林, 李钦传. 肺内多发磨玻璃影诊疗的最新进展 [J]. 临床医学进展, 2017, 7(4): 222-229. https://doi.org/10.12677/ACM.2017.74037

1. 引言

肺癌目前仍是世界上发病率和死亡率处于首位的肿瘤 [1] 。而早期肺癌术后平均五年生存率能达到80%以上,以磨玻璃影(Ground-Grass Opacity, GGO)为表现的早期肺癌患者术后五年生存率能达到 100%。近年来由于人们健康意识的提高与体检筛查 CT 的广泛使用,GGO 的检出率越来越高。肺部磨玻璃影指的是肺内局灶结节样密度增高影,但其密度又不能完全掩盖其中走行的细支气管及血管束 [2] [3] 。它的出现与恶性肿瘤密切相关,占据胸外科手术病人的一大部分。目前,对于肺内多发GGO 还没有最佳的判断标准及处理方式。加强对其的认识可以有效指导临床医师对患者的治疗及随访,从而改善以肺内多发GGO为表现的肺癌患者的预后。而对多发GGO的治疗方式目前主要以手术为主,但针对不同的情况,手术方式有所区别。其他的治疗方法还有SBRT等。在临床工作中,我们应针对不同的患者予以最合适个性化处理方式,使我们的治疗更精准,使患者获益最大化。

2. GGO及肺腺癌分类

GGO分为两大类,不含实性成分的纯磨玻璃影(pure GGO,pGGO)以及伴有实性成分的混合磨玻璃影(mixed GGO, mGGO) [4] 。通常认为GGO初期表现为pGGO,而mGGO为pGGO发展而来的。并不是所有的GGO都与恶性肿瘤有关系,肺炎、出血、局灶性的肺纤维化等也可以表现为GGO [5] [6] 。但需要我们重视的是恶性的GGO,根据2011年美国胸科学会、国际肺癌研究学会、欧洲呼吸医学会共同发布的标准 [7] ,将肺腺癌分为以下几类:浸润前病变、微浸润腺癌(minimally invasive adenocarcinoma, MIA)及浸润性腺癌(invasive adenocarcinoma, IA)。浸润前病变分为不典型腺瘤样增生(atypical adenomatous hyperplasia, AAH)和原位腺癌(adenocarcinoma in situ, AIS)。浸润性腺癌包括:附壁生长为主型(Lepidic predominant adenocarcinoma, LPA),微乳头型、乳头型、腺泡型以及实体型等。通过GGO的CT表现,临床医师可以大致判断出结节的恶性程度。以多发GGO为表现的肺癌通常被认为是一种多原发的肿瘤而不是肺内转移,且结节生长缓慢 [8] [9] 。Kishi等认为,当肺CT提示多发、界限清晰、大小均一的GGO 应考虑多发不典型腺瘤样增生(AAH)或细支气管肺泡癌(BAC)的可能 [10] 。对可能为恶性GGO的患者进行EGFRv III蛋白表达及EGFR突变基因的检测,有助于合理的制定治疗计划和手术方案 [11] 。

3. 肺内多发GGO的影像学特点与肺癌的相关性

在临床工作中,当我们预估一个GGO的性质时候,更多的是通过仔细观察其影像学特征来判断。有助于我们良恶性鉴别的CT特征包括病灶大小、边缘、内部结构及邻近结构,如圆形/类圆形、分叶、毛刺,空泡征、充气支气管征、胸膜凹陷征、血管集束征、血管扩张等 [12] ,这些征象是现阶段胸外科医师对肺结节性质诊断的主要依据。对多发GGO的患者,需要医师对每个结节都要仔细观察,尤其是形态较为明显的突出结节。

3.1. GGO的大小与肺癌

2017年更新的Fleischner指南明确了结节的大小的定义是同一最大层面的长径和短径的平均值 [13] 。Cho等 [14] 的研究发现,恶性GGO (20.3 + 11.0) mm的直径明显大于良性GGO (15.1 + 9.3) mm,且较大的直径是恶性的独立危险因素(OR = 1.086; 95% CI: 1.001~1.178; P = 0.047)。多项研究表明,GGO的大小(包括mGGO和pGGO)与其是否存在侵袭性有一定关系。Jin等 [15] 发现当pGGO最大径超过10.5 mm时,其为侵袭性的概率为88.73%;Liu等 [16] 的研究发现当pGGO大小超过12.5 mm时,其很有可能为侵袭性肿瘤。因此就pGGO来讲,当其直径 > 10 mm时,就应当考虑其是否具有侵袭性的。而含实性成分的mGGO比pGGO更具有恶性倾向 [17] 。在Lee等 [18] 的研究中,关于pGGO,可通过病灶直径判断是否为浸润性病变;对mGGO,他指出病灶的直径、实性部分比例、分叶征及毛刺征可作为预测因素。也有国内学者认为mGGO的直径对于良恶性鉴别无统计学意义 [19] 。

3.2. GGO的实性成分比例与肺癌

Maeyashiki等 [20] 对398例IA期的肺癌病人调查发现,实性成分的最大径是一个独立的危险因素。有国外学者根据结节中的实性成分比例将GGO分为5度,分别为I度(0%)、II度(1%~25%)、III度(26%~50%)、IV度(51%~75%)、V度(76%~100%),而与之对应的出现淋巴结转移的情形为0/18、0/18、2/18、4/18、12/18,以此证明结节所含实性成分越多,肿瘤的侵袭力越强 [21] 。与孤立GGO不同的是,多发GGO相对更小,而且其磨玻璃成分比例更大,这可能与多发GGO中AAH较多有关 [10] 。

3.3. GGO的边缘及内部结构与肺癌

CT中磨玻璃影周围出现的分叶征和毛刺征是因为肿瘤细胞向周围正常肺组织浸润程度的不同所导致;同时,肿瘤细胞对周围组织的侵犯以及肺泡壁的坍塌又会牵拉胸膜,从而引起血管移位,这就形成胸膜凹陷征和血管聚集 [22] 。在肿瘤细胞生长的过程中,有些含气的肺泡组织未被破坏或者肿瘤局部的坏死组织排出会在CT上表现为点状透亮影,即为支气管空泡征 [23] 。这些征象均提示恶性病变。在一项103例GGO患者的调查中发现,与孤立GGO相比,光滑边缘在多发GGO中更常见,提示我们病灶属于低侵袭性甚至非侵袭性 [24] 。

3.4. GGO的边缘及内部结构与肺癌

鉴于GGO是一种惰性结节,因此对于首次发现多发GGO的患者,除非其影像学提示指证很明确,目前的临床指南不建议采取过于积极的治疗。这样一来,随访并动态的观察GGO的变化就显得尤为重要。Fleischner学会 [13] 认为肺癌根据形态和组织学不同,生长率的差异很大,制定随访间隔需要考虑结节潜在生长的可能性。而目前所知实性结节倍增时间已确定,在100至400天;而mGGO呈惰性生长,平均倍增时间约为3至5年。因此2017年更新的指南比较重要的一点就是将GGO的随访时间延长至5年,并延长每次复查的时间间隔。对于多发GGO来说,若结节直径 < 6 mm,则推荐3~6月后复查CT观察结节是否存在,然后在2年后、4年后分别随访CT观察结节变化;若结节直径 > 6 mm,推荐3~6月后复查CT观察结节是否存在,对其中可疑的突出病灶进行治疗。对于其他结节的动态变化及随访计划在此不再赘述。

4. 肺内多发磨玻璃结节的外科治疗

4.1. 是否有必要切除全部结节

对于GGO应避免过度治疗,我们知道不是所有的GGO都需要外科手术干预。而另一个问题是,是否应当将一个多发GGO的患者的所有结节都分期甚至同期切除。GGO的良恶性确定较为困难,手术切除同时具有诊断和治疗的双重意义,对于不是突出病灶的多发GGO,是否要将其切除?Shimada等 [25] 统计了67例至少有2个GGO的肺部多发结节的患者,他们仅接受了对可疑恶性病灶的手术切除,而对剩余的结节或出现新的结节都未予以处理,随访结果显示这些患者与那些行肺叶切除术根治多发结节的患者生存率无明显差异。Kim等 [26] 回顾分析了73例接受了手术切除的细支气管肺泡癌患者,其中23例患者表现为多发GGO,在这23例患者中有18例未将多发GGO全部切除,术后平均随访40.3个月,发现其中有15例剩余的结节没有变化,有3例剩余的结节消失。因此我们认为没有必要切除所有结节。

4.2. 手术切除范围

目前对肺部多发GGO的手术方式、手术范围没有明确的标准。近年来,NCCN指南以及国内外部分学者对亚肺叶切除的地位有非常高的评价。Cardinale和Smith [27] 统计分析了在文献中报道的15,180例IA期非小细胞肺癌患者的疾病治疗及预后情况,其中有1200例(8%)患者接受了肺段切除。结果发现肺叶切除术与肺段切除术的生存率并无明显差异。基于此结论,我们认为亚肺叶切除应用于肺部多发磨玻璃结节的患者是可行的。有文献报道 [26] [28] [29] [30] [31] [32] ,多发GGO患者接受手术治疗的预后令人满意,尤其是亚肺叶切除的预后结果令人鼓舞。当然,不能一味地追求亚肺叶切除病灶。业内倾向于对直径为20 mm以下的病灶进行亚肺叶切除,此时亚肺叶切除与肺叶切除得到的治疗结果相似 [33] ,而且可以更多的保留患者的肺功能,使患者临床获益最大化 [34] 。但是若病灶中实变比例大于25%,肺叶切除依然为首选 [33] 。并且在临床实践中我们发现,当病灶处于肺段之间或者支气管根部等比较尴尬的位置时,需行肺叶切除。

对于肺内多发GGO来说,有同侧胸腔同肺叶内多发GGO、同侧胸腔不同肺叶多发GGO、双侧胸腔肺叶多发GGO。基于上面的结论同时结合我们的经验,对于同肺叶内多发GGO,可予以VATS下多处肺楔形切除、肺段切除或肺叶切除,尽量一期全部切除。或者,楔形切除突出病灶送术中冰冻,若是AIS、AAH或良性病变,手术结束;若为浸润性腺癌则行肺叶切除术联合淋巴结清扫。对于同侧胸腔不同肺叶多发GGO,根据结节位置,在不违反肿瘤外科切除原则的基础上个体化手术切除方式,予以多处肺部楔形切除或者肺段切除,尽可能保留患者肺功能。若是双侧肺叶多发GGO,有可疑病灶者建议分期处理,即首先处理有可疑病灶侧肺叶,处理方法同一侧多发GGO,对侧随访或者行二期切除;两侧均有突出病灶者,可考虑同期手术切除,但双侧肺叶切除需谨慎对待。肺总的切除范围应少于10个肺段;清扫淋巴结时务必注意保护迷走神经和膈神经。少数患者双侧肺多发GGO无法予以常规手术切除时,若明确同时没有发生远处转移或者纵膈转移,可考虑双肺移植。

5. 手术预后及其他治疗

本肺内多发GGO的术后病理多为AAH、AIS和微浸润腺癌,国内外学者对多发结节行基因测序后发现其基因突变类型不同,即表达了不同的EGFR 和KARS 基因突变位点,这说明多发GGO不是转移病灶而是多原发病灶 [35] [36] [37] [38] 。而且表现为GGO的肺癌是一种发展缓慢的肿瘤,淋巴结转移普遍较少,因此推测患者手术预后较好。Gu等 [36] 回顾了39例接受手术的多发GGO的患者,在平均随访时间为30.7个月,患者的总生存率为100%。Tanvetyanon等 [39] 回顾了467例多原发肺癌的患者,发现患者术后中位生存期为52个月。影响肺内多发GGO患者手术预后的主要是多发病灶中的可疑病灶,其实性成分越高提示恶性几率越大,侵袭性越强,预后越差 [31] [40] 。对于有可疑病灶的患者来说,及早发现并行外科手术治疗,在术中切除突出病灶,对患者的预后是有极大意义的 [27] 。除此以外,也有研究报道肺内多发GGO的患者较其他人来说更易产生新的GGO,这也是影响患者预后的一个因素 [41] 。

大多数多发GGO患者无需化疗。但对于有可疑病灶的患者来说,进行基因测序可能会发现其具有肿瘤基因突变,那此时是否予以靶向治疗或其他辅助治疗目前尚无定论。

部分患者由于肺功能因素或其他全身相关因素无法根治性切除病灶时,立体定向放疗(stereotactic body radiotherapy, SBRT)是国际上公认的的标准治疗方式 [42] - [48] 。2014年美国放射肿瘤治疗小组(Radiation Therapy Oncology Group, RTOG)发布报告,其0236试验发现无法手术的早期NSCLC患者使用SBRT/SABR治疗后的2年和5年局部控制率分别为97.6%和93%,3年生存率为55%,5年生存率为40% [42] [45] 。临床医师通过个体化评估患者的复发风险,来制定合理的术后辅助治疗方案或术前新辅助治疗方案是今后发展的趋势。2015年Chang等 [49] 汇总了ROSEL和STARS两项研究数据,手术组与SBRT/SABR组的患者的基本情况在统计学上无差别。手术组采用的术式为肺叶切除术联合纵隔淋巴结清扫;SBRT/SABR组采用分割方式为外周病灶54 Gy/3次,中央病灶50 Gy/4次(STARS研究)和60 Gy/5次(ROSEL研究)。手术组与SBRT/SABR组的中位随访时间分别为40.2个月和35.4个月,3年生存率分别为95%和79%,3年无复发生存率分别为86%和80%。这项研究结果首次证明对于可手术的早期NSCLC来说,SABR要优于手术治疗。2017年Chang等 [50] 发布了II期前瞻性随机对照试验的7年随访研究结果,是目前关于对手术与SABR相对照的前瞻性临床实验随访时间最长的临床研究。研究结果依然得出积极结论,支持对I期NSCLC的患者首选SABR治疗,而治疗失败的主原因是局部复发(3年和5年的局部复发率分别为12.3%和17.4%),但仍小于手术组的局部复发率。但目前国际上对SBRT治疗的真正实用价值还在探索中,尚不明确,希望正在进行的几个前瞻性临床试验可以给出结论。

6. 总结与展望

由于磨玻璃结节的特质,围绕其展开的相关诊疗还存在大量的问题亟待解决。除了上文介绍的以外,在对患者的评估诊疗中还要充分考虑患者本身的肺癌危险因素,例如性别、年龄、吸烟史、家族史、职业暴露等。HRCT是GGO的首选检查方法,但也不能忽略MRI、PET/CT对全身评估的重要性。对那些诊断较困难的多发结节,随访就显得极其重要。随访的策略可遵循亚洲结节随访指南或者Fleischner学会的随访指南。除此以外,良恶性GGO的鉴别;可以转化为临床应用的相关分子生物学机制;如何提高个体化治疗的准确性,开展术后辅助治疗,减少患者不必要的创伤;对于术后剩余的GGO是否要长期随访等一系列问题仍是目前普通胸外科研究的热点和方向。为制定完善的诊疗流程,实现最终的个体化精准治疗,我们需要在循证医学理论的指导下开展大规模、多中心的前瞻性临床研究。

基金项目

国家自然科学基金(No. 81372299)。

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