Colpaert Cecile G, Vermeulen Peter B, Fox Stephen B, Harris Adrian L, Dirix Luc Y, Van Marck Eric A
Department of Pathology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium.
Breast Cancer Res Treat. 2003 Sep;81(2):137-47. doi: 10.1023/A:1025702330207.
The value of the fibrotic focus (FF) as a marker of intra-tumoral hypoxia in invasive breast carcinoma was assessed by studying its relationship with the expression of the hypoxia-induced carbonic anhydrase IX (CA IX), angiogenesis indices and prognosis. CA IX expression was immunohistochemically detected in 2 independent study groups, totaling 184 patients, and correlated with tumor characteristics, angiogenesis related parameters and patient outcome by univariate analysis. CA IX immunostaining scores in carcinoma cells and in tumoral fibroblasts were significantly higher in expansively growing tumors (p = 0.0001 and p < 10(-4), respectively), containing an FF (p = 0.0004 and p < 10(-4)) and showing high histological grade (p = 0.016 and p = 0.0006). Microvessel density, quantified by Chalkley counting, was correlated with CA IX expression both in the carcinoma cells and in the fibroblasts (p = 0.0076 and p = 0.0025) and with the presence and relative size of an FF (p = 0.006). The fraction of proliferating endothelial cells was positively correlated with CA IX scores in the fibroblasts (r = 0.4, p = 0.02) and with the presence of an FF (p = 0.02). CA IX scores in the fibroblasts--and to a lesser extent in the carcinoma cells--were associated with a higher relapse rate (p = 0.006) and a worse overall survival (p = 0.003). The highest CA IX immunostaining scores were found in the fibroblasts of large FF occupying more than one-third of the tumor. A large FF was associated with worse overall survival in a consecutive patient group (p = 0.01) and with shorter disease-free (p = 0.02) and overall survival (p = 0.0005) in T1-2N0 breast cancer patients. The strong association of CA IX expression with the presence of an FF shows that the latter is a marker of intra-tumoral hypoxia. FF is useful as a surrogate marker of hypoxia-driven ongoing angiogenesis and is associated with a higher relapse rate and a worse overall survival.
通过研究纤维化灶（FF）与缺氧诱导的碳酸酐酶IX（CA IX）表达、血管生成指标及预后的关系，评估其作为浸润性乳腺癌瘤内缺氧标志物的价值。在2个独立研究组共184例患者中，通过免疫组织化学检测CA IX表达，并通过单因素分析将其与肿瘤特征、血管生成相关参数及患者预后相关联。在呈膨胀性生长的肿瘤（分别为p = 0.0001和p < 10⁻⁴）、含有FF的肿瘤（p = 0.0004和p < 10⁻⁴）以及组织学分级高的肿瘤（p = 0.016和p = 0.0006）中，癌细胞和肿瘤成纤维细胞中的CA IX免疫染色评分显著更高。通过Chalkley计数定量的微血管密度与癌细胞和成纤维细胞中的CA IX表达均相关（p = 0.0076和p = 0.0025），并与FF的存在及相对大小相关（p = 0.006）。增殖内皮细胞分数与成纤维细胞中的CA IX评分呈正相关（r = 0.4，p = 0.02），并与FF的存在相关（p = 0.02）。成纤维细胞中的CA IX评分——以及在较小程度上癌细胞中的评分——与较高的复发率（p = 0.006）和较差的总生存率（p = 0.003）相关。在占据肿瘤三分之一以上的大FF的成纤维细胞中发现最高的CA IX免疫染色评分。在连续的患者组中，大FF与较差的总生存率相关（p = 0.01），在T1-2N0乳腺癌患者中与较短的无病生存期（p = 0.02）和总生存期（p = 0.0005）相关。CA IX表达与FF的存在之间的强关联表明FF是瘤内缺氧的标志物。FF可作为缺氧驱动的正在进行的血管生成的替代标志物，并且与较高的复发率和较差的总生存率相关。
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