Imaging microvascular structure with contrast enhanced MRI

Abstract

Over the past 10 years there has been increasing interest in the development of novel MRI techniques that enable researchers and clinicians to study the development and structure of vasculature in pathological tissues. Although the majority of this work has been performed in studies of human tumours the techniques are potentially widely applicable in other pathological states [1–4]. All tissues depend on their vasculature for an adequate supply of nutrients and removal of waste metabolic materials. As tissues develop, an adequate and appropriately structured vascular supply must develop at the same time. This process, known as angiogenesis, is also an essential component of the behaviour of many pathological tissues including tumours and inflammatory disease [1, 5]. More importantly, the angiogenic process appears to be largely independent of the developing tissue. This has given rise to the concept of antiangiogenic therapies which could be effective in a wide range of tumours independent of the tissue type. The angiogenic process is complex and can be stimulated by any one of several mechanisms. Typically, growth of tissue which has outstripped its local blood supply results in regional hypoxia and hypoglycaemia which stimulates the release of local chemical messengers from the cells of the tissue itself. The best known of these messengers is the cytokine, vascular endothelial growth factor (VEGF) [6–9]. VEGF is a common and potent angiogenic stimulator, which is found in many pathological tissues. It is released in response to local hypoglycaemia and/or hypoxia and has several effects each of which will improve metabolic supply. In the short term VEGF will act directly on local capillaries to increase endothelial permeability resulting in an immediate increase in the supply of nutrients [10]. This increase in permeability is also believed to form an important part of the metastatic mechanism allowing passage of tumour cells into the circulation. In the medium to long term, VEGF will stimulate mitosis in endothelial cells from local blood vessels so that they divide and develop a new vascular infrastructure to supply the tumour. The angiogenic mechanism also is responsible for breakdown of local connective tissues, which allows in-growth of new blood vessels. Where the angiogenic process fails tissue development cannot occur and novel antiangiogenic therapies are currently being developed which use this mechanism for the treatment of a wide range of cancers and other pathologies [11, 12]. The increasing understanding of the role of the angiogenic process in disease progression has led to interest in methods for documenting the presence and activity of angiogenesis [12–14]. In particular there has been considerable interest in the development of reliable quantitative methods which can provide independent indicators of the status of, and changes in, microvascular structure [13, 14]. In pathological tissues the angiogenic process is often abnormal, leading to the development of distorted vascular beds characterized by an excessive proportion of blood vessels and blood vessels with abnormal morphology and flow characteristics [15]. Central areas of a rapidly growing tumour will commonly exhibit inadequate blood flow due to reduce local perfusion pressure resulting from a combination of inadequate vascularization and increased interstitial tumour pressure. Finally, the angiogenic neovasculature will exhibit increase endothelial permeability to medium and large sized molecules [16, 17]. Initial studies of microvascular structure in tumours were undertaken using histological techniques, however these are essentially unsatisfactory for a number of reasons [18, 19]. Pathological assessment relies on the acquisition of tissue samples which is clearly invasive and which can be repeated only infrequently. Furthermore, many tumours and other pathological tissues demonstrate considerable heterogeneity in microvascular structure so that isolated regional biopsies may give misleading information. These limitations have led to the development of imaging based methods for quantification of microvascular structure. These methods are commonly based on dynamic contrast enhanced imaging techniques using MRI or CT data collection combined with analytic algorithms to calculate descriptive parameters related to microvascular structure. The availability of quantitative imaging based methods to describe the microvasculature in biological tissues is potentially of considerable importance. Such methods can provide important surrogate markers of therapeutic response in trials of novel antiangiogenic therapy and the majority of applications to date have been in this area. However, these techniques can also be seen to have directly clinical relevance providing information about diagnosis, tumour grade, therapeutic response, tumour recurrence and prognosis. At the present time the majority of technical development of these techniques has been centred around the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). This article will describe the development and range of DCE-MRI techniques and the range of image analysis approaches available. The article aims to provide insight into the benefits and disadvantages of specific approaches rather than to detail the actual analysis mechanisms in detail.