Zlobec Inti, Baker Kristi, Minoo Parham, Jass Jeremy R, Terracciano Luigi, Lugli Alessandro
Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
Clin Cancer Res. 2008 Jan 1;14(1):143-8. doi: 10.1158/1078-0432.CCR-07-1380.
To identify independent clinicopathologic factors and protein markers leading to the identification of colorectal cancer (CRC) patients with mismatch repair proficiency at risk of developing metastasis and, consequently, more likely to benefit from combined modality therapy.
Immunohistochemistry for 22 tumor markers was done using a tissue microarray. A subset of 387 CRC patients with complete clinicopathologic data and TNM stage was analyzed. Univariate and multivariate analyses were done to identify independent predictive markers of metastasis. The results were validated on 810 CRC patients.
In univariate analysis, T stage (P < 0.001), N stage (P < 0.001), tumor grade (P = 0.005), vascular invasion (P < 0.001), tumor budding (P < 0.001), positive expression of beta-catenin (P = 0.015), overexpression of RHAMM (P = 0.008), negative expression of Raf-1 kinase inhibitor protein (RKIP; P = 0.001), and absence of intraepithelial lymphocytes (P = 0.017) were significantly associated with the presence of distant metastasis. In multivariate analysis, higher N stage (P < 0.001), presence of vascular invasion (P = 0.009), and RKIP loss (P = 0.003) independently predicted distant metastatic disease. A subgroup of node-negative patients was identified as high risk for distant metastasis and showed a similar probability of metastatic risk and nearly identical survival times as node-positive patients with absence of vascular invasion and positive RKIP expression (metastatic risk, 24% and 22%; median survival time, 45.0 and 47.0 months, respectively).
The combined analysis of N stage, vascular invasion, and RKIP expression is highly predictive of distant metastasis in patients with mismatch repair--proficient CRC. Additionally, a subgroup of more aggressive N(0) tumors can be identified by evaluating vascular invasion and RKIP expression.
确定独立的临床病理因素和蛋白质标志物，以识别错配修复功能正常但有发生转移风险、因而更可能从联合治疗中获益的结直肠癌（CRC）患者。
使用组织芯片对22种肿瘤标志物进行免疫组织化学检测。分析了387例具有完整临床病理数据和TNM分期的CRC患者亚组。进行单因素和多因素分析以确定转移的独立预测标志物。结果在810例CRC患者中得到验证。
单因素分析中，T分期（P < 0.001）、N分期（P < 0.001）、肿瘤分级（P = 0.005）、血管侵犯（P < 0.001）、肿瘤芽生（P < 0.001）、β-连环蛋白阳性表达（P = 0.015）、RHAMM过表达（P = 0.008）、Raf-1激酶抑制蛋白（RKIP）阴性表达（P = 0.001）及上皮内淋巴细胞缺失（P = 0.017）与远处转移的存在显著相关。多因素分析中，更高的N分期（P < 0.001）、血管侵犯的存在（P = 0.009）和RKIP缺失（P = 0.003）独立预测远处转移性疾病。一组淋巴结阴性患者被确定为远处转移的高危人群，其转移风险概率与无血管侵犯且RKIP表达阳性的淋巴结阳性患者相似，生存时间也几乎相同（转移风险分别为24%和22%；中位生存时间分别为45.0和47.0个月）。
N分期、血管侵犯和RKIP表达的联合分析对错配修复功能正常的CRC患者远处转移具有高度预测性。此外，通过评估血管侵犯和RKIP表达可识别一组侵袭性更强的N(0)肿瘤。
