Magnetic resonance imaging in prostate cancer

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1 (2004) 7, & 2004 Nature Publishing Group All rights reserved /04 $30.00 Review Magnetic resonance imaging in prostate cancer 1 * 1 Department of Clinical Radiology, St George s Hospital, London, UK With the recently published National Institute of Clinical Excellence guidelines, it is now generally accepted that magnetic resonance imaging (MRI) is the imaging method of choice for staging prostate cancer in patients for whom radical treatment is being considered. MRI offers the single most accurate assessment of local disease and regional metastatic spread. As well as detecting extraprostatic extension, this technique can locate the site of intraprostatic disease, which may prove useful in planning disease-targeting therapies currently being developed. However, numerous studies have reported widely varying accuracies indicating that MRI is not the perfect imaging modality; microscopic and early macroscopic invasion cannot be reliably shown using current technology. The role of MRI including advantages, limitations and future developments will be discussed. (2004) 7, doi: /sj.pcan Keywords: prostatic neoplasms; magnetic resonance imaging Introduction With an incidence at autopsy of nearly 90% by the age of 90 y, prostate cancer is one of the most common malignancies. Despite the high prevalence of occult disease, it is still the second leading cause of male cancer deaths in the USA and UK. 1,2 However, controversy persists regarding the best methods of detection and subsequent management of this disease. There is no reliable and accurate test or imaging modality that can confidently diagnose and stage prostate cancer. A combination of digital rectal examination (DRE), prostate-specific antigen (PSA) level and transrectal ultrasound (TRUS) with systematic core biopsy and assessment of Gleason grade are used to make the diagnosis. Nomograms, such as those developed by Partin, incorporate these factors and others such as patient age, and can provide important information with regard to risk assessment and local staging, but despite using these methods of predicting disease extent, nearly 47% of men undergoing radical prostatectomy in a population study of over 3800 had extraprostatic spread. 3,4 *Correspondence:, Department of Clinical Radiology, St George s Hospital, London SW17 0QT, UK. susan.heenan@stgeorges.nhs.uk Received 15 March 2004; revised 26 August 2004; accepted 8 September 2004 The development of magnetic resonance imaging (MRI) has been driven by the limitations of these modalities with the aim of improving staging accuracy prior to treatment, particularly in demonstrating the presence or absence of extracapsular spread. The mainstay of treatment for organ-confined prostate cancer is either radical prostatectomy or curative external beam radiotherapy, although there is now debate as to whether the presence of extracapsular disease alone is a contraindication to definitive therapy. The National Comprehensive Network guidelines, published in 2003, suggest that patients with T3a or T3b disease can be considered for either radical prostatectomy or curative radiotherapy as long as their life expectancy is over 5 y. 5 Initial expectations that TRUS would prove a useful tool in assessing capsular penetration were tempered when large multicentre trials failed to show consistent results. Similarly, studies in the late 1980s into the use of MRI concluded that prostate cancer could not be differentiated from benign prostatic hyperplasia (BPH) and that usefulness in staging was comparable to DRE. 6,7 However, the introduction of new coils (the pelvic phased array and endorectal coils), use of orthogonal planes and increasingly experienced observers have shown an improvement in accuracy. Although some reports have been encouraging, it is recognised that microscopic extracapsular extension will not be detected with existing technology and the use of MRI remains controversial with contradictory studies showing divergent accuracies ranging from 51 to 85%. 8 12

2 Currently MRI is not advocated for routine staging but it offers advantages over other imaging techniques in selected patients. Promising technological advances include MRI with dynamic contrast, MR spectroscopic imaging and specific lymph node contrast agents. These techniques may prove useful adjuncts to conventional imaging strategies in improving staging accuracy, localisation of disease and volume assessments, particularly with the development of lower morbidity treatment options, such as brachytherapy, cryotherapy and highintensity focused ultrasound prostate ablation. MRI technique Although MRI has advantages over other cross-sectional imaging modalities such as CT, which requires ionising radiation and nephrotoxic contrast media, MRI is not suitable for everyone. Contraindications include cardiac pacemakers, intracranial aneurysm clips and intraorbital metal fragments. The claustrophobic patient may require sedation and although open magnets may partially solve this problem, these generally have lower strength fields and are not ideal for imaging the pelvis. Formerly long imaging times have proved challenging when trying to produce good-quality images, but MRI has benefited from rapid changes in technology: increasing magnet strength has improved signal-to-noise ratio leading to faster imaging times and resulting in less movement artifact, while superior coil technology has increased spatial resolution. Radiofrequency coils within the magnet are required both to transmit radiofrequency waves and to receive the released MRI signals necessary to construct representative images. The built-in body coil was the only coil available when MRI was first developed, but now surface coils, such as the pelvic phased array (PPA), are more commonly used and placed on the patient over the region of interest. The endorectal coil (ERC) is a specialised surface coil that is introduced rectally and held in place by a balloon. With a small field-of-view and position immediately adjacent to posterior prostate, higher spatial resolution is achieved, although patient discomfort can lead to possible motion artifact. When combined with the PPA to provide an integrated system (ER-PPA coil), the whole pelvis can be assessed. A smooth muscle relaxant, such as glucagon or hyoscine butylbromide, can be administered to reduce bowel motion artifact. Sequences acquired should include axial T1 weighted fast spin echo (FSE) images from the aortic bifurcation to the symphysis pubis to give an overview of the whole pelvis. High-resolution fine-section axial, sagittal and coronal T2 weighted FSE images show the seminal vesicles and zonal anatomy of the prostate down to apex. Large field of view T1 weighted coronal or sagittal images are helpful for assessing bone marrow for metastatic involvement. Fat suppressed sequences have no staging benefit over conventional T1 and T2 weighted FSE imaging. A gadolinium-based contrast medium can be administered intravenously. Gadolinium will usually increase signal intensity on T1 weighted images but the effect does depend on tissue perfusion. Dynamic enhancement can improve tumour detection in prostate cancer, but is not widely used at present. Using picture archive and communication systems (PACS) workstations, abnormal findings can be cross-referenced in multiple planes to enhance the accuracy of prostate cancer detection. Imaging features of prostate cancer T1 weighted images (WI) show that normal prostate, seminal vesicles and periprostatic veins have a uniform intermediate signal surrounded by high signal periprostatic fat. T1 weighted sequences also give an overview of the abdomen and pelvis for detection of lymph node and bone marrow involvement. The contrast between low signal prostate and immediately adjacent high signal fat can be helpful in the evaluation of the neurovascular bundles and delineation of extracapsular spread. With T2 weighting, the zonal anatomy of the normal prostate is seen well. The peripheral zone is homogeneously high in signal intensity and surrounded by a thin, lower signal rim representing capsule. The central gland, comprising transitional and central zones, is low signal. With increasing age, BPH causes the transitional zone to increase in size, to become more heterogeneous in signal and to compress the peripheral zone. The seminal vesicles are shown as high signal multilocular cystic structures with thin hypointense walls. In all, 71 79% of tumours arise from the peripheral zone and are of low signal on T2 weighted images but prostatitis, scars, infarction and calcification can mimic this appearance Postbiopsy haemorrhage can also show as low signal within the gland on T2 weighted images. This can be differentiated from tumour by accompanying high signal on T1 weighting. As these changes can result in overestimation of tumour extent, MR should probably be delayed for 3 weeks following TRUS biopsy. 16,17 Tumours arising from transitional zone are usually indistinguishable from normal tissue, given the variable signal found in the central gland with BPH on T2 weighted sequences. Extracapsular spread is demonstrated by a number of features, which include focal bulges, loss of well defined capsule or low signal soft tissue infiltrating through capsule into periprostatic fat, neurovascular bundle or superiorly into seminal vesicles (Figures 1 5). To complete the examination, the whole pelvis must be assessed for lymphadenopathy and bone marrow for the presence or absence of bony metastases. Staging accuracy and indications A meta-analysis by Engelbrecht et al 18 in 2002 indicated that it is impossible to quote an overall accuracy for MRI staging of prostate cancer or to account for the heterogeneity of performance but concluded that FSE, ERC and multiple imaging planes may improve performance. Although the combined ERC and PPA coils have been shown to improve accuracy, others have reported significant artifacts with the ERC that have degraded images resulting in nondiagnostic studies in 20% The latest scanners have software to overcome this nearfield artefact by using an analytical correction of the 283

3 284 Figure 2 Endorectal coil T2 WI demonstrating T3a disease. There is loss of definition of capsule on the left with low signal tumour tissue extending into adjacent periprostatic fat (arrows). As in this instance, extracapsular spread is most commonly seen posteriorly and laterally, particularly in the region of the neurovascular bundle. (Courtesy of the MRI Department, Royal Marsden Hospital, Sutton, UK). Figure 1 Axial T2 WI showing an elliptical region of low signal intensity in the right peripheral zone with an associated focal bulge (arrows). The capsule remains intact despite the bulge and this was shown to be stage T2c prostate cancer histologically, demonstrating that bulges alone do not necessarily indicate T3a disease. (Courtesy of the MRI Department, Royal Marsden Hospital, Sutton, UK). reception profile of the ERC. 22 Other examples illustrating the controversy include a study from 1996, which showed a reduction in understaging from 42 to 22% and a specificity for extracapsular invasion of 96% using the ERC. 23 Another group in the same year suggested that staging with ERC MRI overstaged 21% of the study group, denying them a potentially curative procedure and advised against routine use of MRI in staging. 9 While the controversy continues, accuracy for demonstrating seminal vesicle invasion, particularly with combined ER-PPA coil, appears to be consistently high, up to 94%. 24 The technique is not without pitfalls as haemorrhage, scarring, stones and amyloid can mimic cancer spread. Decision analysis studies suggest that MRI should be used in staging prostate cancer in a subgroup of patients at intermediate risk of having stage T3 disease (clinically localised at DRE, PSA level ng/ml, Gleason score 5 7) This approach has also been shown to be a costeffective both for those at intermediate and at high risk of having extracapsular spread. 27 Other indications include patient selection for brachytherapy, where disease must be organ-confined and tumour volume accurately assessed. 28 MRI has also been used to guide and assess seed implantation Radiotherapy planning may be facilitated by accurate demonstration of extraprostatic Figure 3 Axial T2 WI. There is invasion of the right seminal vesicle by low signal tumour (white arrows) compared to normal left seminal vesicle (thin white arrow) representing T3b prostate cancer. disease and involvement of adjacent organs. New developments including fusing MRI with other imaging modalities may help direct radiotherapy planning More accurate targeting may decrease morbidity by reducing dose to erectile tissue and rectum. 37,38 MRI can also be helpful in the post-treatment follow-up of

4 Future developments 285 Dynamic contrast-enhanced MRI Figure 4 Coronal and sagittal T2 WI. A rare finding of a large cystic adenocarcinoma of the prostate lifting bladder base (short white arrows). The capsule is seen as a fine black line (thin white arrow), which has been breached by tumour on the right (long white arrow). patients and in those with suspected local recurrence and a rising PSA who may be considered for treatment with salvage radiotherapy The superior soft tissue characterisation of MRI results in increased sensitivity and specificity over bone scintigraphy for detection of bone metastases but is not widely used partly due to lack of availability and significantly higher costs Faster imaging times now allow for whole-body MRI using rolling or automated table platforms. 45,46 It is possible that this technique may be added to the staging MRI scan of the pelvis in the future and may replace bone scintigraphy altogether. Meanwhile, bone scans are still advocated as the first screening method until resource issues can be addressed and this technology becomes more widely available. In early reports, delayed postcontrast images of the prostate showed no benefit in depiction of prostate cancer when compared to unenhanced images except for seminal vesicle invasion in equivocal cases. 47,48 Further technological developments with faster imaging techniques and improved spatial resolution have allowed rapid dynamic contrast-enhanced image acquisition following a bolus of intravenous gadolinium. This technique can improve tumour detection and visualisation of capsular penetration. 49 Preliminary studies have shown that early intense enhancement followed by more rapid washout of contrast compared to normal tissue indicates malignant angiogenesis. The changes are best appreciated by plotting time-enhancement curves during the first-pass phase to achieve best accuracy; the optimal parameter for discrimination of prostate cancer from normal tissue in the peripheral zone is relative peak enhancement. 50 These appearances may be affected by many different factors and the use of this technique remains controversial Ogura et al 54 demonstrated that dynamic contrast-enhanced MRI with ERC for staging local prostate cancer has an overall accuracy rate of 72% for tumour localisation in the prostate, 84% for extracapsular extension and 97% for seminal vesicle invasion. These results are not dissimilar to some studies assessing accuracy of MRI without contrast and it remains to be seen whether this technique confers additional benefit when compared to unenhanced scans alone. Further research is ongoing to determine the degree of overlap between prostate cancer and BPH. As technology improves, this technique may help confirm the hypointensities seen on conventional high-resolution T2 weighted images as malignancy, although there is still uncertainty regarding enhancement patterns of other pathologies such as prostatitis. 55 Dynamic contrastenhancement may be useful in the identification of further tumour foci not currently seen on conventional T2 weighted images as they are iso-intense with normal peripheral zone. MR spectroscopic imaging MR spectroscopic imaging (MRSI) uses similar technology to conventional MRI but, rather than anatomical images, provides functional information by showing both the relative and absolute concentrations of various metabolites contained within organs. A description of absolute quantification is beyond the scope of this text but relative concentrations are depicted as spectra showing peaks and troughs, the area under the curve corresponding to concentration. In prostate cancer, three metabolites, citrate, creatine and choline, are measured. Tumours have significantly higher choline and lower citrate levels compared to normal tissue and BPH. Consequently, malignant tissue can be identified by demonstrating an increased choline and creatine to citrate ratio and located by correlation with conventional T2 FSE images (Figure 6). Creatine is included with choline as the spectral peaks often overlap, and it has a relatively constant level in both normal and malignant

5 286 Figure 5 Axial T2 WI. Stage T4 N1 M1b prostate cancer with invasion of rectal wall (white arrows), right external iliac lymph node involvement (open arrow) and bony metastases in left acetabulum (thin arrows). prostate tissue. One of the advantages of MRSI is the ability to interrogate smaller volumes of tissue (down to 0.34 ml) compared to conventional MRI enabling more accurate location of intraprostatic tumours but as yet is of limited accuracy for localisation of tumours less than 0.5 ml. 56,57 The addition of MRSI improves the accuracy of endorectal coil MRI in preoperative staging (specificity of 91% when both indicate cancer) and localisation of prostate cancer but may also prove useful in posttreatment follow-up Currently, no imaging modality can confidently demonstrate transitional zone cancers but as these have a different metabolic profile from benign tissue, MRSI has the potential to localise these tumours. 62 Work is underway to determine whether the metabolic ratios reflect histological grade of disease and whether early, possibly incidental cancer can be distinguished from aggressive, potentially life-threatening disease. MRSI may be helpful in directing intensity modulated radiation therapy and has already been used successfully to guide brachytherapy in localised prostate cancer. 57,63 As the technique evolves, novel metabolites such as spermine are under investigation, which may contribute to further advances in accuracy. Figure 6 MR spectroscopic imaging superimposed on conventional T2 FSE image through the prostate confirming cancer in left mid peripheral zone with raised choline peak on left (short white arrows) relative to citrate peak on right (long white arrows) compared to spectra elsewhere, which do not show a raised choline peak (thick white arrow). This corresponds to a region of low signal in the left peripheral zone on the conventional T2 images (rectangular boxes). (Courtesy of Dr A Qayyum, Department of Radiology, University of California San Francisco, USA.) the macrophages of the reticuloendothelial system. When the particles accumulate within normally functioning lymph nodes, there is loss of signal intensity on T2 FSE and T2* gradient echo images. Metastatic nodes, in which normal macrophages are replaced, will not take up the USPIO and therefore there will not decrease in signal. Early clinical experience suggests that USPIOenhanced MR lymphangiography improves sensitivity and specificity for detection of nodal metastases. 64,65 MR lymphangiography Lymph node involvement significantly alters tumour staging and thus treatment options and prognosis. Crosssectional imaging techniques rely on morphology, mainly size, to suggest metastatic involvement. There is no agreement in the literature regarding normal upper limits for pelvic lymph nodes, partly because studies have been performed on such a wide mix of patient groups, but 10 mm maximum short axis diameter is probably the most frequently used measurement. Shape, clustering and signal characteristics can also raise the possibility of malignant infiltration. To improve accuracy, lymph node-specific contrast agents are being developed. Ultra-small super-paramagnetic iron oxide (US- PIO) particles are injected intravenously and taken up by Conclusion It is well recognised that preoperative clinical staging of prostate cancer is inaccurate. Despite varying reports, conventional MRI probably offers the single most accurate imaging assessment of local and regional metastatic disease. It has the advantage of being able to evaluate local disease, lymph nodes and bone marrow in one session. The role of MRI in patients at low risk of having T3 disease is controversial and more work in this area is needed. Dynamic contrast imaging and use of spectroscopy may improve detection of extracapsular spread and accuracy of tumour volume assessments whilst whole-body MRI may replace bone scintigraphy for the detection of skeletal metastases. In the future, image fusion with other modalities, such as contrast

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