Wang Xiaohui, Gong Yuan, Yao Jianfei, Chen Yan, Li Yuemin, Zeng Zhen, Lu Yinying, Song Lele
Department of Oncology, The Fifth Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.
The Medical Division, HaploX Biotechnology, Shenzhen, China.
Front Oncol. 2021 Jan 21;10:614430. doi: 10.3389/fonc.2020.614430. eCollection 2020.
Differential diagnosis of multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) is one difficulty in lung cancer diagnosis, and crucial for establishment of treatment strategies and prognosis prediction. This study aims to establish the criteria for molecular differential diagnosis of synchronous MPLC and IPM by the next-generation sequencing (NGS) method.
Training cohort included 30 synchronous MPLC (67 samples) patients and 5 synchronous IPM (13 samples) patients with adenocarcinoma. Criteria of MPLC/IPM differential diagnosis were established by results from a NGS-based 605-gene panel test. Subsequently, 16 patients (36 samples) were recruited as the validation cohort to verify the criteria.
IPM lesions showed a high degree of mutation overlap with an average concordance rate of 60.2% (range: 15.8%-91.7%). IPM lesions had at least three common alterations, including both high-frequency driver gene alterations and low-frequency gene alterations. In contrast, the average concordance rate of MPLC was 11.0% (range: 0.0%-100.0%), among which 66.7% (20/30) of patients had no common alterations (concordance rate: 0%). In the remaining 10 patients, 9 had only one overlapping alteration while 1 had two overlapping alterations, in which 6 patients had EGFR L858R overlapping mutation. Alterations were classified into trunk, shared, and branch subtypes. Branch alterations accounted for 94.4% of mutations in MPLC, while accounted for only 45.0% in IMP. In contrast, the ratio of trunk (38.3%) and shared (16.7%) alterations in IPM was significantly higher. The criteria for differentiating MPLC from IPM using 605-gene panel was established: 1) MPLC can be interpreted if no overlapping alterations is found; 2) MPLC is recommended if one overlapping high-frequency drive gene alteration and/or one overlapping low-frequency gene alteration are/is found; 3) IPM can be interpreted if more than three common alterations are found. Subsequently, 16 patients were recruited as the validation cohort in the single-blind manner to verify the criteria, and 14 MPLC and 2 IPM were identified, which was 100% consistent with the results from independent imaging and pathological diagnosis.
NGS detection can distinguish synchronous MPLC from IPM and is a useful tool to assist differential diagnosis.
多原发性肺癌（MPLC）与肺内转移（IPM）的鉴别诊断是肺癌诊断中的一个难点，对于治疗策略的制定和预后预测至关重要。本研究旨在通过下一代测序（NGS）方法建立同步性MPLC和IPM分子鉴别诊断的标准。
训练队列包括30例同步性MPLC（67个样本）患者和5例同步性IPM（13个样本）腺癌患者。基于NGS的605基因panel检测结果建立MPLC/IPM鉴别诊断标准。随后，招募16例患者（36个样本）作为验证队列以验证该标准。
IPM病灶显示出高度的突变重叠，平均一致性率为60.2%（范围：15.8%-91.7%）。IPM病灶至少有三种常见改变，包括高频驱动基因改变和低频基因改变。相比之下，MPLC的平均一致性率为11.0%（范围：0.0%-100.0%），其中66.7%（20/30）的患者没有共同改变（一致性率：0%）。在其余10例患者中，9例只有一个重叠改变，1例有两个重叠改变，其中6例有EGFR L858R重叠突变。改变分为主干型、共享型和分支型。分支改变在MPLC的突变中占94.4%，而在IPM中仅占45.0%。相比之下，IPM中主干型（38.3%）和共享型（16.7%）改变的比例明显更高。建立了使用605基因panel区分MPLC和IPM的标准：1）如果未发现重叠改变，则可诊断为MPLC；2）如果发现一个重叠的高频驱动基因改变和/或一个重叠的低频基因改变，则推荐诊断为MPLC；3）如果发现三个以上的共同改变，则可诊断为IPM。随后，以单盲方式招募16例患者作为验证队列以验证该标准，共鉴定出14例MPLC和2例IPM，与独立影像和病理诊断结果100%一致。
NGS检测可区分同步性MPLC和IPM，是辅助鉴别诊断的有用工具。
