Hawighorst H, Weikel W, Knapstein P G, Knopp M V, Zuna I, Schönberg S O, Vaupel P, van Kaick G
Department of Radiological Diagnostics, German Cancer Research Center, Heidelberg.
Clin Cancer Res. 1998 Oct;4(10):2305-12.
Angiogenesis plays a fundamental role in tumor growth and metastasis. What is needed is a quantitative, noninvasive, and repeatable assay to estimate functional angiogenic activity of the entire tumor. The aims of the present study were to: (a) examine the relationship between functional magnetic resonance imaging (MRI)-based parameters with established histomorphological markers of tumor angiogenesis [histological microvessel density (HMVD) and vascular endothelial growth factor expression (VEGF)]; and (b) determine the ultimate value of both approaches to assess functional angiogenic active hotspots as markers of disease outcome in patients with cancer of the uterine cervix. Pharmacokinetic parameters (amplitude A, tissue exchange rate constant k21) were calculated from contrast-enhanced dynamic MRI series in 57 patients (mean age, 49 +/- 14 years) with biopsy proven uterine cervical cancer. Both pharmacokinetic parameters were correlated to histomorphologically determined areas of high HMVD and VEGF expression obtained from the operative specimens after radical surgery. In addition, the functional MRI and histomorphological data were used to assess disease outcome. A significant association was found between HMVD and the amplitude A (P < 0.001) and a less pronounced association with k21, (P < 0.05), respectively. No significant associations were found between the pharmacokinetic parameters (A, k21) and VEGF expression. When stratified into high and low median k21 groups, median k21 values >5.4 min(-1) were the only significant (P < 0.05) factors in predicting poor patient survival. None of the histomorphological markers of angiogenesis (HMVD or VEGF expression) showed any predictive power. We have found that: (a) focal hotspots of HMVD are the pathophysiological basis for differences in functional MRI; (b) areas of high microvessel density and microvessel permeability do not necessarily coincide, as demonstrated by the histomorphological and functional MRI findings; (c) the functional angiogenic activity of a tumor may not be sufficiently characterized by a histomorphological approach but rather by a functional MRI-based approach; and (d) functional MRI-based analysis may assess tumor angiogenic activity in terms of disease outcome more comprehensively than the histomorphological approach.
血管生成在肿瘤生长和转移中起着根本性作用。需要一种定量、无创且可重复的检测方法来评估整个肿瘤的功能性血管生成活性。本研究的目的是：(a) 研究基于功能磁共振成像（MRI）的参数与已确立的肿瘤血管生成组织形态学标志物[组织学微血管密度（HMVD）和血管内皮生长因子表达（VEGF）]之间的关系；(b) 确定这两种方法评估功能性血管生成活性热点作为子宫颈癌患者疾病预后标志物的最终价值。从57例（平均年龄49±14岁）经活检证实为子宫颈癌的患者的对比增强动态MRI序列中计算药代动力学参数（幅度A、组织交换率常数k21）。这两个药代动力学参数均与根治性手术后手术标本中组织形态学确定的高HMVD和VEGF表达区域相关。此外，功能MRI和组织形态学数据用于评估疾病预后。分别发现HMVD与幅度A之间存在显著关联（P<0.001），与k21之间存在不太明显的关联（P<0.05）。在药代动力学参数（A、k21）与VEGF表达之间未发现显著关联。当分为高和低中位数k21组时，中位数k21值>5.4分钟-1是预测患者生存不良的唯一显著（P<0.05）因素。血管生成的组织形态学标志物（HMVD或VEGF表达）均未显示出任何预测能力。我们发现：(a) HMVD的局灶性热点是功能MRI差异的病理生理基础；(b) 高微血管密度和微血管通透性区域不一定重合，组织形态学和功能MRI结果证明了这一点；(c) 肿瘤的功能性血管生成活性可能无法通过组织形态学方法充分表征，而更适合通过基于功能MRI的方法表征；(d) 基于功能MRI的分析在评估疾病预后方面可能比组织形态学方法更全面地评估肿瘤血管生成活性。
