Zlobec Inti, Minoo Parham, Baumhoer Daniel, Baker Kristi, Terracciano Luigi, Jass Jeremy R, Lugli Alessandro
Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
Cancer. 2008 Feb 1;112(3):495-502. doi: 10.1002/cncr.23208.
The heterogeneity of stage II colon cancer underlines the need for identifying high-risk, lymph node-negative patients. The objective of this study was to define a multimarker prognostic model of 5-year survival in patients with lymph node-negative, mismatch repair (MMR)-proficient colorectal cancer (CRC).
Immunohistochemistry for 13 tumor markers was performed on 587 lymph node-negative, MMR-proficient CRC samples by using a tissue microarray. Immunoreactivity was evaluated semiquantitatively. A receiver-operating characteristic-based approach was used to detect clinically relevant tumor markers and to determine cutoff scores for tumor positivity. Univariate and multivariate analyses stratified by pathologic T3 (pT3) or pT4 tumor classification were performed.
In univariate analysis, the absence of CD8+ tumor infiltrating lymphocytes (TILs) (P < .001), loss of p27 (P = .006), positive urokinase-type plasminogen activator (uPA) expression (P = .002), and positive uPA receptor (uPAR) expression (P = .037) were associated with an adverse prognosis. In multivariate analysis, CD8 (P = .001), p27 (P = .031), and uPA (P = .014) were independent prognostic factors. The multimarker phenotype of negative CD8, loss of p27, and positive uPA expression led to significantly worse survival compared with all other combinations of these features. Stratified by pT3 or pT4 stage, CD8 (P = .006) and uPA (P = .011) had independent prognostic value. Combined CD8 negativity and uPA positivity led to a more adverse prognosis in both patients with pT3 tumors and patients with pT4 tumors (P < .001). No difference was observed in the length of survival between patients with pT3 tumors who had CD8 negativity and uPA positivity and patients with pT4 tumors (P = .267).
The multimarker phenotype of the absence of CD8+ TILs, loss of p27, and positive uPA expression was predictive of an adverse prognosis in patients with lymph node-negative, MMR-proficient CRC. The current findings suggested that a subgroup of patients with high-risk, lymph node-negative pT3 tumors should be considered for adjuvant therapy.
II期结肠癌的异质性凸显了识别高危、淋巴结阴性患者的必要性。本研究的目的是确定淋巴结阴性、错配修复（MMR）功能正常的结直肠癌（CRC）患者5年生存的多标志物预后模型。
通过组织芯片对587例淋巴结阴性、MMR功能正常的CRC样本进行13种肿瘤标志物的免疫组织化学检测。免疫反应性进行半定量评估。采用基于受试者工作特征曲线的方法检测临床相关肿瘤标志物并确定肿瘤阳性的临界值。按病理T3（pT3）或pT4肿瘤分类进行单因素和多因素分析。
在单因素分析中，CD8 +肿瘤浸润淋巴细胞（TILs）缺失（P <.001）、p27缺失（P =.006）、尿激酶型纤溶酶原激活剂（uPA）表达阳性（P =.002）和uPA受体（uPAR）表达阳性（P =.037）与不良预后相关。在多因素分析中，CD8（P =.001）、p27（P =.031）和uPA（P =.014）是独立的预后因素。与这些特征的所有其他组合相比，CD8阴性、p27缺失和uPA表达阳性的多标志物表型导致生存率显著更差。按pT3或pT4分期分层，CD8（P =.006）和uPA（P =.011）具有独立的预后价值。CD8阴性和uPA阳性在pT3肿瘤患者和pT4肿瘤患者中均导致更差的预后（P <.001）。CD8阴性和uPA阳性的pT3肿瘤患者与pT4肿瘤患者的生存时长无差异（P =.267）。
CD8 + TILs缺失、p27缺失和uPA表达阳性的多标志物表型可预测淋巴结阴性、MMR功能正常的CRC患者的不良预后。当前研究结果表明，高危、淋巴结阴性pT3肿瘤患者亚组应考虑辅助治疗。
