Guerrera Francesco, Renaud Stéphane, Tabbó Fabrizio, Voegeli' Anne-Claire, Filosso Pier Luigi, Legrain Michèle, Boita Monica, Schaeffer Mickaël, Beau-Faller Michèle, Ruffini Enrico, Falcoz Pierre-Emmanuel, Inghirami Giorgio, Oliaro Alberto, Massard Gilbert
Department of Thoracic Surgery, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Department of Thoracic Surgery, Strasbourg University Hospital, Strasbourg, France.
Eur J Cardiothorac Surg. 2017 Apr 1;51(4):680-688. doi: 10.1093/ejcts/ezw362.
The impact of skip N2 metastases (i.e. N2 lymph node metastases without N1) on survival in surgically resected non-small lung cancer remains an intriguing and rarely investigated topic. The goal of our study was to elucidate (i) skip N2 influence on overall survival (OS) and time to recurrence (TTR) in patients with resected lung adenocarcinoma and (ii) its link with epidermal growth factor receptor ( EGFR ) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations.
A retrospective analysis of 279 consecutive patients with lung pN2 adenocarcinoma, operated in two institutions between 2003 and 2013, was conducted. OS and TTR were calculated using the Kaplan-Meier method. Crude and multivariable-adjusted comparisons by skip N2 for OS and TTR were performed using the Cox method with shared frailty (accounting for the within-centre correlation). Associations between skip N2 metastasis, clinicopathological characteristics and EGFR and KRAS mutations were investigated using the Fisher exact test and Cramér's V -test.
The mean age at the time of surgery was 63 years (±12), and the median follow-up time was 36 months (min 3; max 101). Skip N2 was observed in 54 patients (19%). EGFR mutations were observed in 38 patients (14%); KRAS mutations were seen in 86 patients (31%). Patients with skip N2 metastasis were predominantly non-smokers ( P = 0.001), underwent segmentectomy or limited resections ( P = 0.004) and were not submitted to adjuvant therapy ( P = 0.022). Moreover, there was a correlation between EGFR mutations and skip N2 (Cramér's V : 0.25, P < 0.001). Indeed, EGFR mutations were significantly more frequent in skip N2 tumours (33%) compared with non-skip tumours (10%), P < 0.001. No correlation between skip N2 and KRAS mutations was observed (Cramér's V : 0.05, P = 0.46). The multivariable-adjusted model showed a significant skip N2 protective effect on OS (hazard ratio, HR 0.503; P = 0.014; 95% confidence interval, CI: 0.291-0.8704) but not on TTR (HR 0.788; P = 0.446; 95% CI: 0.427-1.454).
In our series, lung adenocarcinoma skip N2 metastasis demonstrated a favourable prognosis. The presence of EGFR mutations could have significance in the better survival and in the specific anatomic pathway of lymphatic metastases exhibited by skip N2 tumours.
跳跃性N2转移（即无N1的N2淋巴结转移）对手术切除的非小细胞肺癌患者生存的影响仍是一个引人关注但很少被研究的课题。我们研究的目的是阐明（i）跳跃性N2对肺腺癌切除患者总生存期（OS）和复发时间（TTR）的影响，以及（ii）其与表皮生长因子受体（EGFR）和v-Ki-ras2 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变的关系。
对2003年至2013年在两家机构接受手术的279例连续性肺pN2腺癌患者进行回顾性分析。采用Kaplan-Meier法计算OS和TTR。使用具有共享脆弱性的Cox方法（考虑中心内相关性）对跳跃性N2的OS和TTR进行粗率和多变量调整比较。使用Fisher精确检验和Cramér's V检验研究跳跃性N2转移、临床病理特征与EGFR和KRAS突变之间的关联。
手术时的平均年龄为63岁（±12），中位随访时间为36个月（最小值3；最大值101）。54例患者（19%）观察到跳跃性N2。38例患者（占14%）检测到EGFR突变；86例患者（占31%）检测到KRAS突变。有跳跃性N2转移的患者主要为非吸烟者（P = 0.001），接受肺段切除术或局限性切除术（P = 0.004），未接受辅助治疗（P = 0.022）。此外，EGFR突变与跳跃性N2之间存在相关性（Cramér's V：0.25，P < 0.001）。实际上，跳跃性N2肿瘤中EGFR突变（33%）显著高于非跳跃性肿瘤（10%），P < 0.001。未观察到跳跃性N2与KRAS突变之间的相关性（Cramér's V：0.05，P = 0.46）。多变量调整模型显示跳跃性N2对OS有显著的保护作用（风险比，HR 0.503；P = 0.014；95%置信区间，CI：0.291 - 0.8704），但对TTR无保护作用（HR 0.788；P = 0.446；95% CI：0.427 - 1.454）。
在我们的研究系列中，肺腺癌跳跃性N2转移显示出较好的预后。EGFR突变的存在可能对更好的生存以及跳跃性N2肿瘤所表现出的特定淋巴转移解剖途径具有重要意义。
