Ruffato Alberto, Mattioli Sandro, Pileri Stefano, Daddi Niccolò, D'Ovidio Franco, Pilotti Vladimiro, Tazzari Pierluigi
Division of Esophageal and Pulmonary Surgery, Villa Maria Cecilia and San Pier Damiano Hospitals, University of Bologna, Bologna, Italy.
Eur J Cardiothorac Surg. 2009 Mar;35(3):463-8. doi: 10.1016/j.ejcts.2008.11.017. Epub 2009 Jan 15.
Inconsistent information on the prognostic significance of non-small cell lung cancer (NSCLC) isolated tumor cells (ITC) has been reported to date. We sought to evaluate the survival for NSCLC in a group of patients in which the presence of bone marrow isolated tumor cells and their DNA ploidy was assessed.
Seventy patients (58 males [83%]; median age 70 years, range 49-89) with T1-4, N0, M0 clinical staging entered the study; 68 who underwent complete resection, were included in the follow-up. Two patients with clinical stage T2 and T4, N0, M0 were excluded because of pleural carcinosis discovered at thoracotomy. Recruitment ended in 2002. None received neoadjuvant therapy. The rib bone marrow was extracted and assessed for ITC by hematoxylin and eosin (H&E) staining, immunohistochemistry and flow cytometry. The latter was regarded as positive when >10% of cells reacted to pan-cytokeratin antibody MNF116. DNA ploidy was studied by propidium iodide staining. Patient follow-up was with chest X-ray and abdominal US every 6 months, and CT-PET scan every 12 months for at least 5 years after surgery. Causes of death were assessed.
Rib bone marrow ITC were documented in 17 patients (25%), 6 with DNA euploidy (p stage: I 4; III 2), and 11 with DNA aneuploidy (p stage: I 5; II 4; III 2) while 51 (75%) patients were free of ITC (p stage: I 32; II 8; III 9; IV 2). The median follow-up was 61 months, 21 patients died from causes unrelated to NSCLC and 12 patients died from causes related to tumor relapse. Significant survival differences were observed according to stage, presence of ITC and DNA aneuploidy. In particular free from recurrence survival was significantly reduced in stage IA and IB patients presenting aneuploid ITC (Wilcoxon (Gehan) test p=0.031).
The prognostic role of bone marrow ITC seems to be corroborated by DNA ploidy studies. Patients with bone marrow ITC with abnormal DNA content showed a significantly reduced survival particularly in stage I NSCLC.
迄今为止，关于非小细胞肺癌（NSCLC）孤立肿瘤细胞（ITC）的预后意义的信息并不一致。我们试图评估一组评估了骨髓中孤立肿瘤细胞及其DNA倍性的NSCLC患者的生存率。
70例临床分期为T1-4、N0、M0的患者（58例男性[83%]；中位年龄70岁，范围49-89岁）进入本研究；68例接受了根治性切除的患者纳入随访。2例临床分期为T2和T4、N0、M0的患者因开胸手术时发现胸膜转移而被排除。招募工作于2002年结束。所有患者均未接受新辅助治疗。提取肋骨骨髓，通过苏木精和伊红（H&E）染色、免疫组织化学和流式细胞术评估ITC。当>10%的细胞对全细胞角蛋白抗体MNF116反应时，流式细胞术结果被视为阳性。通过碘化丙啶染色研究DNA倍性。术后至少5年，每6个月对患者进行胸部X线和腹部超声检查，每12个月进行CT-PET扫描。评估死亡原因。
17例患者（25%）的肋骨骨髓中发现ITC，6例为DNA整倍体（p分期：I期4例；III期2例），11例为DNA非整倍体（p分期：I期5例；II期4例；III期2例），而51例（75%）患者未发现ITC（p分期：I期32例；II期8例；III期9例；IV期2例）。中位随访时间为61个月，21例患者死于与NSCLC无关的原因，12例患者死于肿瘤复发相关的原因。根据分期、ITC的存在和DNA非整倍体情况观察到显著的生存差异。特别是，IA期和IB期出现非整倍体ITC的患者无复发生存率显著降低（Wilcoxon（Gehan）检验p=0.031）。
DNA倍性研究似乎证实了骨髓ITC的预后作用。骨髓ITC且DNA含量异常的患者生存率显著降低，尤其是在I期NSCLC患者中。
