Dunsmuir W D, Gillett C E, Meyer L C, Young M P, Corbishley C, Eeles R A, Kirby R S
Department of Urology, St. George's Hospital NHS Trust, London, UK.
BJU Int. 2000 Nov;86(7):869-78. doi: 10.1046/j.1464-410x.2000.00916.x.
To assess several molecular markers (detected by immunohistochemistry, IHC) to determine whether they can be used to improve the prognostic value of histological grade alone in predicting the behaviour of prostate cancer.
Tumour tissue was retrieved from 156 men in whom tumour grade, stage and survival were known. The outcome measures were: (i) local stage (T-stage, organ-confined vs extraprostatic); (ii) metastatic status (M-stage, bone metastasis vs no bone metastasis); and (iii) survival. The IHC markers used were chosen to provide a broad representation of various aspects of tumour biology, i.e. the androgen receptor (AR) and oestrogen receptor (ER), adhesion molecules (E-cadherin), proliferation markers (MIB-1), tumour-suppressor genes (TP53 and the retinoblastoma gene product, Rb) and other novel cancer-related proteins (cyclin D1 and the breast cancer susceptibility gene product, BRCA2). All factors were assessed using logistic regression and Cox proportional-hazards survival models for predictive value, after adjusting for effects.
MIB-1, ER, cyclin D1 and E-cadherin all showed close statistically significant univariate associations with histological grade. Univariate analysis also identified close statistically significant associations between T-stage and both MIB-1 and E-cadherin. Likewise, there were close univariate associations for both M-stage and survival, and MIB-1, cyclin D1 and ER. Logistic regression modelling identified MIB-1, cyclin D1 and ER as statistically significant predictors of M-stage and, once MIB-1 was entered into the model, the effects of grade no longer made a significant contribution. MIB-1 was a significant predictor for T-stage, but the effects of grade remained significant in this model. Cox proportional-hazards modelling identified MIB-1, cyclin D1 and ER as being statistically significant predictors of survival, after adjusting for grade. After adjusting for both grade and MIB-1, the effects of cyclin D1 and ER were no longer statistically significant. Excess MIB-1, cyclin D1 or ER expression tended to be present within the most poorly differentiated and advanced-stage lesions; this provides an inherent instability to the models described. TP53, Rb, AR and BRCA2 were of limited prognostic value.
MIB-1, ER and cyclin D1 provide prognostic information that is clearly independent of grade. However, their true clinical value is probably limited because they are expressed mainly in the most advanced lesions. Nevertheless, MIB-1 expression is of sufficient value to warrant inclusion in future prognostic models. Furthermore, the expression of cyclin D1 and ER may reflect aspects of tumour biology that individually are worthy of further investigation. However, none of the IHC markers used in this study can be recommended for use in routine histological preparations.
评估几种分子标志物（通过免疫组织化学法检测），以确定它们是否可用于提高仅根据组织学分级预测前列腺癌行为的预后价值。
从156名已知肿瘤分级、分期和生存情况的男性患者中获取肿瘤组织。观察指标包括：（i）局部分期（T分期，器官局限性与前列腺外侵犯）；（ii）转移状态（M分期，骨转移与无骨转移）；（iii）生存情况。所使用的免疫组织化学标志物旨在广泛代表肿瘤生物学的各个方面，即雄激素受体（AR）、雌激素受体（ER）、黏附分子（E-钙黏蛋白）、增殖标志物（MIB-1）、肿瘤抑制基因（TP53和视网膜母细胞瘤基因产物Rb）以及其他新型癌症相关蛋白（细胞周期蛋白D1和乳腺癌易感基因产物BRCA2）。在调整各种影响因素后，使用逻辑回归和Cox比例风险生存模型评估所有因素的预测价值。
MIB-1、ER、细胞周期蛋白D1和E-钙黏蛋白在单因素分析中均显示出与组织学分级有密切的统计学显著相关性。单因素分析还发现T分期与MIB-1和E-钙黏蛋白之间存在密切的统计学显著相关性。同样，M分期和生存情况与MIB-1、细胞周期蛋白D1和ER之间也存在密切的单因素相关性。逻辑回归模型确定MIB-1、细胞周期蛋白D1和ER是M分期的统计学显著预测因子，一旦将MIB-1纳入模型，分级的影响就不再具有显著贡献。MIB-1是T分期的显著预测因子，但在该模型中分级的影响仍然显著。Cox比例风险模型确定，在调整分级后，MIB-1、细胞周期蛋白D1和ER是生存情况的统计学显著预测因子。在同时调整分级和MIB-1后，细胞周期蛋白D1和ER的影响不再具有统计学显著性。MIB-1、细胞周期蛋白D1或ER表达过量往往出现在分化最差和分期最晚的病变中；这给所描述的模型带来了内在的不稳定性。TP53、Rb、AR和BRCA2的预后价值有限。
MIB-1、ER和细胞周期蛋白D1提供的预后信息明显独立于分级。然而，它们真正的临床价值可能有限，因为它们主要在最晚期的病变中表达。尽管如此，MIB-1的表达具有足够的价值，值得纳入未来的预后模型。此外，细胞周期蛋白D1和ER的表达可能反映了肿瘤生物学的某些方面，这些方面各自值得进一步研究。然而，本研究中使用的免疫组织化学标志物均不推荐用于常规组织学检查。
