Dynamic contrast enhanced MRI in prostate cancer

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Abstract

Angiogenesis is an integral part of benign prostatic hyperplasia (BPH), is associated with prostatic intraepithelial neoplasia (PIN) and is key to the growth and for metastasis of prostate cancer. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) using small molecular weight gadolinium chelates enables non-invasive imaging characterization of tissue vascularity. Depending on the technique used, data reflecting tissue perfusion, microvessel permeability surface area product, and extracellular leakage space can be obtained. Two dynamic MRI techniques (T2*-weighted or susceptibility based and T1-weighted or relaxivity enhanced methods) for prostate gland evaluations are discussed in this review with reference to biological basis of observations, data acquisition and analysis methods, technical limitations and validation. Established clinical roles of T1-weighted imaging evaluations will be discussed including lesion detection and localisation, for tumour staging and for the detection of suspected tumour recurrence. Limitations include inadequate lesion characterisation particularly differentiating prostatitis from cancer, and in distinguishing between BPH and central gland tumours.

Introduction

Carcinoma of the prostate is the commonest form of human cancer, found at autopsy in 30% of men at the age of 50 and in over 80% of men in their 90s [1]. Worldwide, more than 650,000 men are diagnosed with the disease every year, accounting for a tenth of all new male cancers. In Europe the lifetime risk of being diagnosed with prostate cancer is approximately 1 in 13. There is a close association between recent increases in the incidence of prostate cancer, the use of trans-urethral resection (TURP) for treating lower-urinary tract symptoms due to presumed benign prostatic hyperplasia (BPH) and more recently with serum PSA testing. In the US, widespread serum PSA testing of asymptomatic men from around 1986 resulted in dramatic increases in prostate cancer rates (an 82% rise between 1986 and 1991). In Western Europe the widespread use of serum PSA tests began later, although the current level of population screening is still much lower than in the US. Whether there is a real increase in incidence or not, the number of cases of prostate cancer has risen and will rise further as the population at risk (older men) grows with the general lengthening of life expectancy.

Angiogenesis involves a cascade of events in which mature, resting host endothelial cells are stimulated to proliferate, degrade their basement membranes and to form new blood vessels. The angiogenic process is a complex multistep sequence involving many growth factors (cytokines) and interactions between varieties of cell types. Expression of angiogenic cytokines in prostate cancer can be induced as a response to hypoxic stress, by hormonal stimulation, but can also result from activation of oncogenes. The angiogenic process in prostate cancer is highly dependent on vascular endothelial growth factor (VEGF). It has been shown that VEGF is produced in abundance by the prostatic secretory epithelium of normal, hyperplastic, and tumour containing glands [2]. The physiological role(s) of VEGF in the prostate is poorly understood and targets may include cells other than the vascular endothelium. With respect to the vasculature, it is clear that VEGF is required for vascular homeostasis in BPH and maintains a high fraction of immature vessels (those without investing pericytes/smooth muscle cells) in prostate cancers. Androgens seem to regulate VEGF expression in prostate cancer cells and benign prostatic tissues [3]. VEGF expression in androgen-dependent cell lines is down regulated upon androgen withdrawal and prostate tumours from these cell lines undergo vascular regression prior to tumour cell death [4].

Increased microvessel density (MVD) counts are seen in BPH [5] and in high grade prostatic intraepithelial neoplasia (HGPIN) [6]. Higher MVD counts are also associated with prostate cancer with Gleason scores >7 [6]. Immuno-histochemical studies have found that MVD in prostate cancer and BPH are higher than in the peripheral zone [7] but there is an overlap in MVD counts between tumours and BPH. MVD is a potential prognostic factor that has been correlated with clinical and pathological stage, metastasis and histological grade in prostate cancer. MVD has also been correlated with disease-specific survival and progression after treatment [8], [9], [10]. MVD has not, however, been shown to correlate consistently with outcome after radical prostatectomy [11].

There are a number of features of tumour vascularity that are characteristic of malignancy which are amenable to study by imaging techniques. These include: (1) Spatial heterogeneity and chaotic structure. (2) Poorly formed, fragile vessels with high permeability to macromolecules. (3) Arteriovenous shunting, high vascular tortuosity and vasodilatation. (4) Intermittent or unstable flow due to transient rises in already raised interstitial pressure. These and other microenvironment characteristics can be reflected by currently available, clinical imaging techniques such as dynamic contrast enhanced MRI (DCE-MRI), perfusion CT, diffusion weighted MRI (DW-MRI), proton MR spectroscopy (1H-MRS) and ultrasound (US). In this review we focus on DCE-MRI as the biomarker of prostate cancer angiogenesis illustrating its use as a clinical tool but we also highlight its limitations.

Section snippets

Non-dynamic contrast enhancement of the prostate gland

Review of the older MRI literature shows that T1-weighted contrast enhanced MR images can depict prostatic zonal anatomy (not visible on unenhanced T1-weighted images) but in general, T2-weighted spin-echo images are better in this regard. The normal central gland enhances more than the peripheral prostate; both enhancing homogeneously. In the presence of BPH, enhancement of the central gland becomes heterogeneous [12]. Prostate cancer also enhances following contrast medium administration.

Dynamic contrast-enhanced MRI technique

When a paramagnetic, low-molecular weight contrast agent is injected intravenously, it enters tumour blood vessels and subsequently passes into the extra-vascular extra-cellular space (EES) (Fig. 1). A high first pass extraction occurs in most normal tissues (with the exception of the brain, testes and retina) as well as in hyperplastic prostatic tissues and prostate cancer. In tumours, typically 12–45% of the contrast media leaks into the EES during the first pass [16]. Once out of the blood

Data acquisition

Perfusion-weighted images can be obtained with “bolus-tracking techniques” that are sensitive to susceptibility effects caused by the passage of contrast material in a capillary bed. Bolus injection of contrast medium is essential to the success of this technique. The degree of signal intensity loss (Fig. 2) observed on susceptibility-weighted images is dependent on sequence types and parameters used, the vascular concentration of the contrast agent and microvessel size and density [17], [18].

Data acquisition

To monitor the tissue enhancing effects of contrast agents using T1-weighted sequences requires that confounding T2 and T2* signal intensity lowering effects must be minimised. T1-weighted gradient-echo, saturation recovery/inversion recovery snapshot sequences are often used for prostate imaging. The choice of sequence and parameters used is dependent on intrinsic advantages and disadvantages of the sequences taking into account T1 sensitivity, anatomical coverage, acquisition times,

Primary diagnosis of prostate cancer

Following the widespread availability of PSA testing many men are referred for ultrasound guided biopsy with a high clinical index of suspicion that malignancy will be detected. The pre-biopsy probability of histological confirmation of cancer is up to 70% if the PSA  10 ng/ml. However, a proportion of these men will have a negative biopsy, posing the clinical problem of whether this is a true-negative or false-negative result and the patient will usually be subjected to repeated biopsies. Some

Conclusions

DCE-MRI techniques utilising low molecular weight contrast media have become mainstream clinical tools with recognised indications in the imaging of prostate cancer. Current roles of T1-weighted techniques include tumour staging (depiction of capsular penetration and seminal vesicle invasion) and for the detection of suspected tumour recurrence following definitive treatment. Its exact role in monitoring tumour response to hormonal treatment and radiation remains to be defined although its

Acknowledgement

Parametric images produced using Magnetic Resonance Imaging Workbench (MRIW) software (Institute of Cancer Research, London, United Kingdom) [51].

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      Citation Excerpt :

      Tumours differ from normal tissue in many aspects, including having a higher proportion of leaking capillaries. DCE measures blood vessel wall leakage from intravascular to extravascular space continuously by imaging the inflow of the injected Gd in the tissue [11] and can be quantified and visualised as a kinetic parameter, Ktrans [11]. ADT affects the tumour and results in decreased prostate cancer conspicuity on MRI [1–3,12,13].

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