Makino Takashi, Mikami Tetuo, Hata Yoshinobu, Otsuka Hajime, Koezuka Satoshi, Isobe Kazutoshi, Tochigi Naobumi, Shibuya Kazutoshi, Homma Sakae, Iyoda Akira
Division of Chest Surgery, Toho University School of Medicine, Tokyo, Japan.
Department of Pathology, Toho University School of Medicine, Tokyo, Japan.
Ann Thorac Surg. 2016 Nov;102(5):1694-1701. doi: 10.1016/j.athoracsur.2016.04.100. Epub 2016 Jun 28.
The prognosis for patients with large cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor, and optimal treatment strategies have not yet been established. To improve prognoses in patients with LCNEC, this study analyzed immunohistochemical expression and gene mutations of several known molecular targets in LCNECs and compared the expression levels of these targets with those in lung adenocarcinomas.
Twenty-six patients with primary LCNEC and 40 patients with adenocarcinoma were analyzed. Excision repair cross-complementation group 1 (ERCC1), class III β-tubulin, topoisomerase I, topoisomerase II, epidermal growth factor receptor (EGFR)-L858R, and somatostatin receptor expression were evaluated by immunohistochemistry, and EGFR mutations were evaluated using direct DNA sequencing and the Scorpion-amplified refractory mutation system.
In patients with LCNEC and adenocarcinoma, positive rates of topoisomerase I, topoisomerase II, ERCC1, class III β-tubulin, EGFR-L858R, and somatostatin were 100.0% and 100.0%, 65.4% and 15.0% (p < 0.0001), 42.3% and 17.5% (p = 0.0462), 46.2% and 62.5%, 0.0% and 20.0% (p = 0.0182), and 50.0% and 5.0% (p < 0.0001), respectively. The frequencies of EGFR mutations were 0.0% and 37.5% in LCNEC and adenocarcinoma (p = 0.0002), respectively. Five-year overall survival rates were 64% in LCNEC and 91% in adenocarcinoma in stage I (p = 0.0132). Multivariate analysis showed that LCNEC histologic type was an independent prognostic factor in stage I.
LCNEC showed overexpression of topoisomerase II, somatostatin, and ERCC1. These findings suggested that it was possible to have good response to treatment with etoposide and octreotide and that LCNEC may be resistant to platinum-based therapy compared with adenocarcinoma. EGFR mutations were not observed in LCNEC. These results may indicate a favorable response to adjuvant treatments that are not typically prescribed for non-small cell lung cancer.
肺大细胞神经内分泌癌（LCNEC）患者的预后极差，尚未确立最佳治疗策略。为改善LCNEC患者的预后，本研究分析了LCNEC中几种已知分子靶点的免疫组化表达和基因突变情况，并将这些靶点的表达水平与肺腺癌中的表达水平进行比较。
分析了26例原发性LCNEC患者和40例腺癌患者。通过免疫组化评估切除修复交叉互补组1（ERCC1）、Ⅲ类β微管蛋白、拓扑异构酶I、拓扑异构酶II、表皮生长因子受体（EGFR）-L858R和生长抑素受体的表达，并使用直接DNA测序和蝎尾扩增难治性突变系统评估EGFR突变。
在LCNEC和腺癌患者中，拓扑异构酶I、拓扑异构酶II、ERCC1、Ⅲ类β微管蛋白、EGFR-L858R和生长抑素的阳性率分别为100.0%和100.0%、65.4%和15.0%（p<0.0001）、42.3%和17.5%（p=0.0462）、46.2%和62.5%、0.0%和20.0%（p=0.0182）以及50.0%和5.0%（p<0.0001）。LCNEC和腺癌中EGFR突变的频率分别为0.0%和37.5%（p=0.0002）。I期LCNEC和腺癌的5年总生存率分别为64%和91%（p=0.0132）。多因素分析显示，LCNEC组织学类型是I期的独立预后因素。
LCNEC显示拓扑异构酶II、生长抑素和ERCC1过表达。这些发现提示，依托泊苷和奥曲肽治疗可能有良好反应，并且与腺癌相比，LCNEC可能对铂类治疗耐药。LCNEC中未观察到EGFR突变。这些结果可能表明对非小细胞肺癌通常不开具的辅助治疗有良好反应。
