判断多灶肺腺癌原发与转移性质的形态学特征及分子克隆性对比研究

Adenocarcinoma is the most common histologic subtype of multifocal lung cancer. According to TNM classification, patients with two malignant lung lesions with the same histology are graded into T3 (two lesions in the same lobe), T4 (two lesions in the same ipsilateral lobe) or M1 (heterolateral lobes or lungs). However in routine clinical practice some multifocal lung adenocarcinomas are multiple primaries, which are graded into T1 or T2 separately. It suggests that the present criterion is not well established for the discrimination of multiple primary lung cancers from intrapulmonary metastases. In 2011 international multidisciplinary classification of lung adenocarcinoma, a nonmucinous lepidic component is proposed as the most distinctive characteristic of adenocarcinoma in situ. Whether lepidic characteristic could be applied to assess primary lung cancer has not been well demonstrated. In our previous study, lepidic component could potentially improve the diagnosis of multiple primary lung adenocaricnomas. However molecular analysis should be performed to support this hypothesis. In this study, we plan to apply illumina exome sequencing analysis to evaluate the clonal relationships among multiple tumors in each case. The correlation of the molecular signature with the morphological characteristics (especially nonmucinous lepidic component) for the discrimination of multiple primaries and metastases will be determined. This study will provide molecular and morphological evidences in identification of multiple primaries and intrapulmonary metastases in lung adenocarcinoma.

多结节肺癌中以腺癌最常见。目前TNM分期将同侧肺内多肿瘤结节定义为T3(同叶)和T4（不同叶），对侧多结节则为M1a，但实际工作中常遇到多灶为单独多个T1或T2病灶，说明目前国际上对肺内多灶肺腺癌之间属多原发或转移性质的确立尚缺乏准确认知及有效判断，从而导致临床分期存在缺陷。尽管国际肺腺癌多学科新分类将单纯附壁归入原位腺癌，却仍无将此原位癌形态作为确定原发灶依据的学说。前期初步研究结果显示附壁结构对原发肺腺癌的诊断有很好的提示意义，而明确多灶腺癌间关系需依靠对其克隆性进行分析。本研究在前期研究基础上，利用illumina全基因组外显子测序技术对同一病例中的不同病灶石蜡包埋组织进行分析，判断各病灶间的克隆性关系并与组织形态比较，尤其是含有附壁成分的病灶，试图寻找能够确定多灶腺癌原发与转移的病理形态学鉴别诊断特征，为准确判断多灶肺腺癌性质提供分子病理及组织病理依据。

近年来多灶肺腺癌的发生率逐年攀升。临床实践中，如何判断多灶肺腺癌克隆性关系（即多灶原发或肺内转移）是影响临床分期和治疗策略的重要问题。本研究立足于临床实际情况，从病理形态学、拷贝数变异分析和基因突变等三个角度对多灶肺腺癌的特点进行全面的研究。首先，完善了判断多灶腺癌原发与转移的病理形态学方法，发现肿瘤内低级别的附壁成分是判断多灶肺腺癌原发和转移的重要形态学依据。其次，高通量测序在多灶肺腺癌克隆性分析的应用策略还需要进一步探索、完善。Array-CGH是判断多灶肺腺癌克隆性可靠方法，并与疾病的预后密切相关，Array-CGH在判断多灶肺腺癌克隆性方面较高通量测序更为可靠。