Zlobec I, Terracciano L, Tornillo L, Günthert U, Vuong T, Jass J R, Lugli A
Institute of Pathology, University Hospital of Basel, Schönbeinstrasse 40, Basel, CH-4031, Switzerland.
Gut. 2008 Oct;57(10):1413-9. doi: 10.1136/gut.2007.141192. Epub 2008 Apr 24.
To compare the independent prognostic effect of a panel of immunohistochemical protein markers in colorectal cancer (CRC) and determine their ranking among the established prognostic factors T stage, N stage, vascular invasion, tumour budding and tumour grade.
A tissue microarray of 1420 CRCs was immunostained for 23 markers and mismatch repair (MMR) proteins. Immunoreactivity was assessed semi-quantitatively. Receiver operating characteristic (ROC) curves were used to determine cut-off scores for tumour marker positivity. Survival time was investigated for each marker in multivariable analysis with T stage, N stage, vascular invasion, tumour budding and tumour grade. The hazard ratio (HR) was used to compare the prognostic effect of each marker on 5 year survival.
To the standard prognostic features, only six markers added independent prognostic information including receptor for hyaluronic acid mediated motility (RHAMM) (HR = 2.39 (1.88 to 3.05)), epidermal growth factor receptor (HR = 1.65 (1.31 to 2.09)), tumour infiltrating lymphocytes (HR = 0.7 (0.54 to 0.92)), urokinase plasminogen activator (HR = 1.38 (1.09 to 1.75)), Raf-1 kinase inhibitor protein (HR = 0.75 (0.58 to 0.96)) and mammalian sterile 20-like kinase 1 (MST1) (HR = 0.75 (0.58 to 0.95). Diffuse (>90% staining) expression of RHAMM ranked above T stage, vascular invasion, tumour budding and tumour grade in terms of adverse prognostic significance and was associated with distant metastasis (p = 0.012) and with worse outcome in patients with metastatic disease (p = 0.031).
The strong adverse effect of RHAMM on outcome in addition to its position within the hierarchy of well-established prognostic factors suggest that RHAMM should be considered a more important prognosticator than tumour grade, tumour budding and vascular invasion in patients with CRC.
比较一组免疫组化蛋白标志物在结直肠癌（CRC）中的独立预后作用，并确定它们在既定预后因素T分期、N分期、血管侵犯、肿瘤芽生和肿瘤分级中的排名。
对1420例CRC的组织芯片进行23种标志物和错配修复（MMR）蛋白的免疫染色。免疫反应性进行半定量评估。采用受试者工作特征（ROC）曲线确定肿瘤标志物阳性的临界值。在多变量分析中，将每个标志物与T分期、N分期、血管侵犯、肿瘤芽生和肿瘤分级一起研究生存时间。采用风险比（HR）比较每个标志物对5年生存率的预后作用。
对于标准预后特征，只有六种标志物增加了独立的预后信息，包括透明质酸介导运动受体（RHAMM）（HR = 2.39（1.88至3.05））、表皮生长因子受体（HR = 1.65（1.31至2.09））、肿瘤浸润淋巴细胞（HR = 0.7（0.54至0.92））、尿激酶型纤溶酶原激活剂（HR = 1.38（1.09至1.75））、Raf-1激酶抑制蛋白（HR = 0.75（0.58至0.96））和哺乳动物 sterile 20样激酶1（MST1）（HR = 0.75（0.58至0.95））。就不良预后意义而言，RHAMM的弥漫性（>90%染色）表达在T分期、血管侵犯、肿瘤芽生和肿瘤分级之上，并且与远处转移相关（p = 0.012），在转移性疾病患者中与更差的预后相关（p = 0.031）。
RHAMM对预后的强烈不良影响以及它在既定预后因素层次中的位置表明，在CRC患者中，RHAMM应被视为比肿瘤分级、肿瘤芽生和血管侵犯更重要的预后指标。
