Prostate Cancer: Detection using Multiparametric 1 H-MRI

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1 DOI: /mcpharmacol Molecular and Cellular Pharmacology Prostate Cancer: Detection using Multiparametric 1 H-MRI Nilesh Mistry 1, Andrew Rosenkrantz 2, Steven Roys 3, John Papadimtiriou 4, Khan Siddiqui 3, Michael Naslund 5, James Borin 5, Warren D Souza 1, and Rao P. Gullapalli 3 1 Department of Radiation Oncology, University of Maryland School of Medicine, 2 Department of Radiology, NYU Langone Medical Center, 3 Department of Diagnostic Radiology, 4 Department of Pathology, and 5 Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland Abstract Magnetic resonance imaging (MRI) offers the possibility to accurately detect, localize, and stage prostate cancer, thereby assisting in the selection of an individualized course of treatment. Conventional, anatomical MRI (T 2 -weighted MRI) lacks the required sensitivity and specificity, in identifying prostate cancer foci, especially in the transition zone, in areas of post-biopsy hemorrhage, and in the setting of post-treatment change. In addition, T 2 -weighted MRI is suboptimal in determining the presence of extracapsular extension (ECE), which can be the most important factor for selection of an individualized therapy and for predicting the risk of tumor recurrence. Advanced MRI techniques comprising of dynamic contrast enhanced -MRI (DCE-MRI) that provides vascular information, diffusion-weighted MRI (DWI) that provides biophysical information, and magnetic resonance spectroscopic imaging (MRSI) that provides metabolic information can assist in overcoming the limitations of conventional anatomical MRI. In this article, we provide a brief review of these advanced imaging techniques and how they correlate with pathologic findings in prostate cancer. Advanced MRI techniques may increase the specificity of conventional MRI by identifying functional, metabolic, and microstructural changes of the prostate that occur in areas of cancer. MRSI and DWI have added value in detecting tumor within the transitional zone of the prostate, while MRSI and DCE may assist in predicting the presence of ECE, as well as in evaluating for recurrent tumor following hormonal Received 03/15/12; accepted 12/25/12 Correspondence: Nilesh Mistry, M.D. Department of Radiation Oncology, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD, 21201, USA. Tel nmistry@som.umaryland.edu or radiation therapy. Using a combined multiparametric approach can provide a thorough evaluation for the presence and extent of prostate cancer using MRI. Keywords: Prostate cancer; Magnetic resonance imaging; transition zone; Radiation therapy Introduction Prostate cancer represents the most frequent cause of a new cancer diagnosis and the second most frequent cause of cancer death among United States men according to the 2012 American Cancer Society statistics (1). Since the 1980 s, there has been a drastic increase in the incidence of prostate cancer, reflecting increased implementation of prostate specific antigen (PSA) screening, improved techniques for establishing a prostate cancer diagnosis using transrectal ultrasound (TRUS)- guided biopsy, and an overall aging of the population (2-5). This improved screening and detection has been associated with a significant improvement in cancer stage at the time of diagnosis. As compared to the past, these patients are now often younger when first diagnosed and harbor foci of tumor that are smaller in size (2, 6). A report from 2004 from a national registry of over 10,000 men with prostate cancer found that there was an increase in low-risk clinical features at the time of diagnosis over a span of eight years (7). A separate analysis of 896 consecutive patients receiving radical prostatectomy from 1988 to 1996 found a significant increase in the percentage of tumors that were organ confined and had negative surgical margins (8). This downward shift in cancer stage at the time of diagnosis impacts the clinical management of newly detected cases. Specifically, the earlier detection of smaller and more localized tumors has allowed for increasing use of an emerging array of 5

2 6 Prostate Cancer: Detection using Proton MRI between the penis and the rectum. The urethra passes through the prostate from the bladder into the penis to allow urine to flow through. The seminal vesicles are paired bilaterally between the prostate and the bladder. The prostate can be divided into four main zones consisting of the peripheral zone (PZ), central zone (CZ), transition zone (TZ), and anterior fibro-muscular zone (AFS) as shown in Figure 1. Each of the prostate zones has unique architecture, histology, and predisposition to characteristic local disease processes. It is generally recognized that 70-80% of the cancers arise in the peripheral zone, 2.5% in the central zone and 20% in the transitional zone (15). Figure 1. Schematic of prostate gland in the sagittal plane targeted therapies that includes high-intensity focused ultrasound, cryo- or radiofrequency-ablation, photodynamic therapy, as well as injectable suicide gene therapy (2). More traditional therapies, such as radical prostatectomy and external beam radiation therapy, may also be refined and targeted based upon the local distribution of disease within a specific patient, as demonstrated by nerve-sparing surgery and intensity-modulated radiation therapy respectively (9). The selection of which treatment to use for a given patient, the planning of surgery and radiation therapy, as well as the use of more focused therapies, all benefit from precise localization of tumor within the gland (10, 11). While conventional anatomical magnetic resonance imaging (MRI) offers the benefit for detection and localization of tumor within the prostate, it also faces numerous challenges and limitations related to low sensitivity and specificity (9, 11-14). Advanced MRI applications, including magnetic resonance spectroscopy (MRSI), dynamic contrast-enhanced MRI (DCE-MRI), and diffusionweighted imaging (DWI), have emerged to potentially address these limitations. In this article, we provide a brief overview of the current proton- MRI imaging findings of prostate cancer using each of these advanced techniques, and relate it to the histopathology of the tumor. We start with the description of the underlying anatomy and physiology that can help us understand the avenues that are used in some of the advanced diagnostic imaging techniques. Prostate Anatomy The prostate gland is a walnut sized organ situated deep in the male pelvis. It is nestled Prostate Physiology The prostate is an important reproductive organ supplying substances that facilitate fertilization, sperm transit, and survival. PSA is an enzyme that mixes with the sperm (produced in the testes) to help the transit of the sperm. PSA is present in small quantities in men with healthy prostate, but is often elevated in the presence of prostate cancer; although PSA-based screening for prostate cancer remains controversial (16). The prostatic secretion is also known to be rich in citrate. Typically, the metabolism of normal cells involves the oxidation of glucose and fat via the Krebs cycle, through the intermediate step involving the synthesis and oxidation of citrate (17). The intermediary synthesis and oxidation of citrate, coupled with phosphorylation, is essential in the generation of cellular energy through the production of ATP. While, these established pathways are essential to normal aerobic cellular metabolism, the normal human prostate does not go through the process of citrate oxidation thus resulting in large amounts of citrate accumulation and secretion (18). In the presence of cancer, the normal glandular epithelial cells are replaced by cancer leading to changes in the concentration of citrate and choline (17). Citrate levels decrease drastically in the presence of active cancer, along with an increase in levels of choline. Although the mechanism for the elevation of the choline peaks is less understood, it is associated with changes in cell membrane synthesis and degradation in the presence of cancer. Current Methodologies for Diagnosing Prostate Cancer The American Cancer Society currently recommends annual screening starting at age 50 using a prostate-specific antigen (PSA) test and

3 Prostate Cancer: Detection using Proton MRI 7 digital rectal exam (DRE) in average-risk patients (19). However, there is some controversy regarding the effectiveness of either of the techniques in controlling the mortality (16). Any patient with suspected prostate cancer based on the screening tests proceeds to get a transrectal ultrasound (TRUS)-guided biopsy. This procedure entails obtaining at least one random core biopsy of each sextant of the gland. Random biopsy is necessary because the ultrasound examination can often miss significant fraction of prostate cancers that are isoechoic or indistinguishable from the normal tissue (20, 21). Despite routinely obtaining multiple (6 to12 cores) random biopsies throughout the gland, TRUS-guided biopsy may miss a significant fraction of cancers due to the selective sampling of the prostate (13, 22). Due to the location of the TZ (away from the rectum), the conventional transrectal ultrasound guided biopsy fails to effectively sample the TZ. In fact, the TZ is not sampled during routine TRUS-guided biopsy (23, 24) and one study found that TZ cancers are usually diagnosed incidentally during transurethral resection of the prostate (6, 15). When TRUS-guided biopsy does accurately detect cancer, the origin of the location is uncertain and the localization of tumor within the gland remains imprecise (21). The sensitivity of standard TRUS guided biopsy for tumor localization was found to be 48% in a study of patients undergoing radical prostatectomy (25), and even a lower 38% in the apex of the prostate (13). In addition, TRUS-guided biopsy alone is limited in evaluating the presence and spread of extraprostatic extension of tumor, hindering accurate disease staging (2, 24). Finally, due to the imprecise nature of the biopsy procedure and its low sensitivity, a patient may need to undergo repeated biopsy sessions (as many as ten) due to persistently elevated DRE or PSA despite negative biopsy results (22). This has resulted in the use of other MRI based noninvasive imaging based techniques for cancer detection. Anatomical MRI accurately depicts internal prostatic zonal anatomy at high spatial resolution. Conventional anatomical MRI using integrated pelvic phased array and endorectal coils demonstrates prostate cancer as areas of decreased T2 signal intensity (an MRI parameter indicating water content from low to high) within the peripheral zone and potentially offers much benefit in addressing the limitations of ultrasound. The direct anatomic depiction of tumor provided by MRI enables more precise localization of tumor foci and provides significantly increased accuracy in comparison with DRE and TRUS-guided biopsy (14, 25). In addition, MRI may identify extracapsular spread of disease to the peri-prostatic tissues, as well as distant spread to lymph nodes or bone. This improved localization allows for more accurate disease staging and selection of an individualized treatment regimen. Improved localization may also assist in surgical planning for patients undergoing radical prostatectomy, and is critical for the performance of emerging focused therapies that directly target the tumor site. MRI also increases sensitivity by detecting tumors missed by repeated TRUS-guided biopsy attempts, for instance within the transitional zone or apex, thereby identifying sites to target in future biopsy sessions (13, 26). However, conventional anatomical MR imaging using T2 weighted sequences has limitations as well. The low T2 signal used to identify the location of the tumor foci is often non-specific and can be seen in the setting of most prostate pathologies, including hyperplasia, prostatitis, fibrosis, and atrophy (11). One study with 50 patients noted a specificity of 37% for detecting cancer when using anatomical T2 weighted MRI (27). While MRI may detect tumors missed by TRUS-guided biopsy, it too has limited sensitivity under certain circumstances. For instance, with aging, the normal transitional zone undergoes benign prostatic hyperplasia (BPH) and contains less abundant glandular tissue, leading to overall decreased T2 signal that often overlaps the appearance of cancer. Also, hemorrhage following earlier TRUS-guided biopsy for attempted tumor detection alters the gland's T2 signal, thereby limiting detection of tumor in areas of biopsy. Further, while the sensitivity of tumor detection is 85% for foci > 1cm, the sensitivity decreases to 26% (tumors < 1 cm) for small tumor foci (28), limiting the use of standard anatomical T2 weighted MRI. Advanced MRI/MRSI Techniques Given the limitations of the anatomic assessment of the prostate offered by conventional anatomical imaging, there has been increasing use of advanced MRI techniques to provide additional functional information. Some of these techniques include Magnetic Resonance Spectroscopy Imaging, Diffusion-Weighted Imaging, and dynamic contrast enhanced-mri. These different techniques exploit varies aspects of the underlying tumor biochemistry and tumor physiology. Here we look at the techniques that are sometimes used to identify tumor foci using these advanced MRI/MRSI.

4 8 Prostate Cancer: Detection using Proton MRI (a) Biochemical information: Magnetic Resonance Spectroscopic Imaging (MRSI) MRSI aims to detect alterations in cellular metabolism that occur in prostate cancer and can provide useful biochemical information associated with many different metabolites (29-32). Normal prostate tissue is unique among tissues in the human body in its production and secretion of extremely high levels of citrate (17, 33). Cancer places a stress on prostate tissue that causes a metabolic shift from the production of citrate to the oxidation of citrate, yielding an overall decrease in the amount of citrate (25). This enhanced citrate oxidation allows for increased production of adenosine triphosphate (ATP), supplying more energy to the proliferative malignant tissue (33, 34). Furthermore, the increased synthesis and degradation of phospholipid cell membrane within areas of cancer is associated with increased levels of choline-containing metabolic intermediates. Spectroscopy is able to detect the relative concentration of these various chemical metabolites within small voxels throughout the gland. A parameter that combines both citrate and choline metabolites is desirable, as there is variability amongst the severity of metabolite alteration among prostate cancer patients (35). Given the closeness of the choline and creatine peaks, the height of these two peaks is often summed, and compared with the height of the citrate peak. This ratio of (choline+creatine)/citrate (CC/C), is 0.22 ± 0.13 [mean ± standard deviation] in healthy PZ and is expected to increase in prostate tumors (36, 37). CC/C value of 2 or 3 standard deviations higher than the mean CC/C value is typically used as a threshold to identify tumors (3, 12, 35, 38). More recently, an additional peak corresponding with various polyamine (PA) compounds, particularly spermine, has received closer attention. Similar to citrate, PAs are accumulated and secreted by well-differentiated benign prostate tissue (37). The PA peak is located between the choline and creatine peaks and typically cannot be clearly differentiated from these two compounds, thereby becoming incorporated into the choline+creatine sum contained within the CC/C ratio (12, 38). In the setting of cancer, the PA peak decreases (37), allowing for better visual separation of the choline and creatine peaks, as well as for calculation of a choline/creatine ratio. The greater spectroscopic separation that occurs when imaging at 3T as compared to the 1.5T may allow for the routine differentiation of the PA peak in both benign and malignant tissue (39). (b) Vascular information: Dynamic Contrast Enhanced-MRI (DCE-MRI) It is generally recognized that dynamic contrast enhanced MRI can be used to characterize tumors and that the onset and rate of enhancement are valuable parameters for differentiating malignant from normal tissues (40-43). A consistent observation by many investigators has been that both BPH and normal peripheral zone enhance slowly compared to the tumor implying the induction of new vessels by malignant tissue. DCE- MRI aims to detect tumor based on patterns of altered tumor angiogenesis, including increased vascularity, increased vessel permeability, and expansion of the interstitial space (44). This pattern of vascularity is in contrast to the homogeneous low level of enhancement of healthy PZ tissue (45). There is ongoing debate as to different methods for quantifying enhancement characteristics. These methods fall into two general categories: a) a direct time-resolved evaluation of contrast kinetics, using such parameters as relative peak enhancement, time-to-peak, wash-in time, and wash-out time, and b) a two-compartmental pharmacokinetic model. The first technique relies on differences in the wash-in and wash-out times between the tumor and normal tissue (44). The second technique relies on a pharmacokinetic model to yield parameters that reflect differences in flow and endothelial permeability (46). One such parameter represented by KTrans, measures the volume-rate product of forward contrast flow from the blood plasma space to the extracellular extravascular space (EES) and is expected to increase in prostate cancer. While this is generally true, there is considerable variability in the vascular characteristics of tumor tissue, with overlap in the KTrans values of benign and malignant tissue. For instance, tumor foci that do not have adequate vascularity cannot be distinguished from normal PZ using DCE-MRI (27). Accordingly, there is no established threshold at which the KTrans is deemed suspicious for cancer, and this determination is often made subjectively based on a visual analysis (27, 47). (c) Biophysical information: Diffusion Imaging (DWI) Diffusion-weighted imaging (DWI) assesses the random molecular motion of water molecules in tissue. Due to the rapid growth of cells in the tumor microenvironment, most of the water is trapped within the cells that leads to lowered diffusion of

5 Prostate Cancer: Detection using Proton MRI 9 water compared to normal cells. Several investigators have shown a decrease in apparent diffusion coefficient (ADC) in malignant tissue in comparison to normal tissue, attributed to increased cellular density (48-51). This decrease in diffusion due to barriers from cell membranes can be exploited to delineate the margins of the tumor. Quantitative ADC measurements can often identify subtle tumors that are not apparent on the T2 weighted image (52). However, there is considerable individual variability in the diffusion characteristics of benign prostate tissue, with overlap in the ADC values of benign and malignant tissue (53, 54). Recent studies have analyzed receiver operating characteristic curves to propose threshold values for differentiating benign and malignant tissue using ADC. However, using such measurements alone can prove challenging due to the different values of thresholds suggested in 3 separate studies (55-57). Features of Normal Prostate Majority of the glandular tissue (~70%) of the prostate is found in the peripheral zone. Within this zone, the glandular tissue is arranged into a branching acinar network that secretes copious mucin-rich fluid with high citrate content. This fluid accounts for the increased T2 signal within the normal PZ (11, 19, 58). MRS of the normal PZ demonstrates a large citrate peak with choline and creatine peaks that are approximately 60% lower in height (35). DCE-MRI demonstrates a homogeneous low level of vascularity within the normal PZ. The ADC map by convention displays the normal PZ as bright. The remaining 30% of the glandular tissue of the prostate is contained within the central and transitional zones. With increasing age, the transitional zone enlarges due to the development of BPH causing the effacement of the central zone, making it virtually impossible to visualize. After age 40, changes of BPH within the TZ are virtually always present (35, 59). BPH constitutes a highly variable process that is heterogeneous within a single patient. Typically, BPH entails formation of nodules with varying degrees of glandular tissue and fibromuscular stroma. This process leads to overall less abundant glandular tissue within the TZ and overall lower T2 signal as compared with the PZ. In addition, the T2 signal within the TZ is heterogeneous, with depending on the relative degree of glandular and stromal components within areas of BPH (6, 35, 59, 60). In a similar manner, the appearance of the TZ using MRS depends greatly on the histologic nature of the BPH nodules. While the citrate level may be similar to the level within the PZ in the setting of predominantly glandular BPH, citrate will be decreased in the setting of predominantly stromal BPH. This correlation between the citrate level and the relative glandular and stromal content of BPH nodules has been confirmed on histologic analysis of resected prostate specimens (35). On DCE-MRI, the TZ is heterogeneous and demonstrates areas of increased vascularity corresponding with nodules of BPH (45). Using DWI, the TZ demonstrates overall lower ADC compared with the PZ (56), perhaps attributable to stromal proliferation and associated increased cellularity occurring in BPH. Figure 2, shows a normal prostate imaged using T2W-MRI, MRSI, DCE-MRI, and DWI. Features of Prostate Cancer (a) Peripheral Zone Approximately 95% of prostate cancers are adenocarcinomas, of which ~70-80% occur within the PZ. These tumors start as small foci of intraductal dysplasia that can remain slow growing for many years, only to eventually differentiate and develop a propensity to invade other structures (59). These tumor foci disrupt and replace the normal architecture of the gland, with associated decreased glandular activity and less mucinous fluid production (11, 59, 61). These changes result in the decreased T2 signal that characterizes prostate cancer. MRSI helps to further define areas of tumor by demonstrating an elevated choline peak and decreased citrate peak. In a study of 85 prostate cancer patients undergoing MRSI (35), no overlap was found in the CC/C ration between the tumor and normal PZ. A high specificity of approximately 90% for sextant localization of tumor was obtained in two separate studies when MRSI was combined with conventional MRI (12, 62). One study used a standardized scoring system to differentiate individual voxels as benign or malignant with an accuracy of 74-85% (38). In a study of 94 patients, there was a trend toward an increasing CC/C ratio with increasing Gleason score (a grading scale based on microscopic appearance of the biopsy), suggesting that findings on MRSI correlate with tumor aggressiveness (63).

6 10 Prostate Cancer: Detection using Proton MRI Figure 2. Multiparametric images acquired using T 2-weighted MRI (T2W), DWI (ADC), DCE-MRI (ktrans), and MRSI (MRS). Figure 3. Multiparametric Imaging of Prostate Cancer DCE-MRI, by demonstrating tumors as areas of hypervascularity, has been demonstrated to significantly increase overall accuracy for prostate cancer localization compared with conventional MRI (47). In a study of 50 patients, combined T2-weighted MRI and DCE-MRI had a specificity of 88%, significantly higher than a specificity of 37% for conventional MRI alone (27). An additional study found strong statistical differences in the enhancement characteristics of benign and malignant PZ, although the enhancement parameters did not correlate with PSA or Gleason score (43). DWI identifies tumor as foci of restricted diffusion and has been found to increase the accuracy for prostate cancer detection in multiple studies (52, 64). For instance, in one study of 49 patients, the sensitivity for detection was 81% for conventional MRI combined with DWI, significantly higher than 54% for T2-weighted images alone (52). Another study noted an increase in specificity from 54% for conventional MRI alone to 85% for T2- weighted images combined with DWI (64). DWI at 3 Tesla has shown extremely high sensitivity and specificity of 94% and 91% respectively for detecting cancer, based solely on ADC values (56). Finally, a

7 Prostate Cancer: Detection using Proton MRI 11 Figure 4. Multiparametric Imaging of Prostate Cancer study that measured the mean ADC value of the entire peripheral zone prior to biopsy found an inverse correlation with PSA (57). As pre-operative PSA has a significant correlation with likelihood of disease recurrence following radical prostatectomy (65), this relationship suggests a possible role for DWI in predicting disease aggressiveness and prognosis. Figure 3, shows multiparametric MRI images along with the histology in a tumor in the PZ. (b) Transition Zone About 20-30% of prostate cancers occur within the TZ, with the central zone being relatively resistant to pathology (60, 61, 66). A pseudocapsule separating the PZ and the central gland may pose a barrier to the spread of TZ tumors, and when detected, TZ tumors are generally smaller in size, more often confined to the prostate, and have a better prognosis in comparison with PZ tumors (6, 66). One feature of these tumors is their difficulty in detection. In addition to being frequently missed on TRUS-guided biopsy, TZ tumors are often missed on conventional MRI given their overlap with the appearance of BPH (59). One study suggests using the homogeneity of the reduced T2 signal compared to the remaining TZ as a marker for TZ tumors (11). Advanced MRI techniques have been applied within the TZ to address the limitations of conventional MRI. While these techniques have been found to add benefit, they too are challenged by the heterogeneous nature of the TZ that can hide or mimic cancer using conventional sequences. MRSI shows elevated choline peak and decreased citrate peak within TZ tumors. However, unlike the PZ tumors, the range of measured CC/C ratios between normal and cancerous TZ tissue overlap (12, 60, 66). One study used a more stringent CC/C ratio cut-off of 4 standard deviations above the mean to be able to identify TZ tumors (12). DCE-MRI has not been supported within the TZ, as BPH nodules can demonstrate hypervascularity that mimics the appearance of cancer (27). Indeed, one study found no significant difference in the enhancement patterns of benign and malignant TZ tissue (43). Similarly, a reduction in the ADC value measured with DWI has been noted within TZ tumors when compared to normal TZ tissue. However, considerable overlap between healthy and cancerous TZ tissue exists with this technique as well (67). One study that applied DWI at 3T was able to obtain a sensitivity and specificity of 90% and 84% respectively for identifying cancer within the TZ, using a more stringent threshold for ADC than is applied within the PZ (56). Figure 4, shows multiparametric MRI images along with the histology in a tumor in the TZ. Evaluation for Extracapsular Extension The prostatic capsule comprises a thin rim of loose connective tissue that surrounds the PZ. After penetration through the capsule, prostate cancer may spread to peri-prostatic tissues such as the neurovascular bundles, seminal vesicles, bladder, and rectum. The determination of whether tumor extends beyond the capsule (extracapsular extension [ECE]) is one of the most important factors in predicting tumor recurrence following radical prostatectomy. ECE plays a central role in disease

8 12 Prostate Cancer: Detection using Proton MRI staging, constituting T3 disease using the TNM system and stage C disease using the Jewitt- Whittmore system (11, 68). In a study of 1,623 men with organ-confined disease, radical prostatectomy was associated with increased disease-free survival at 10 years compared with conservative therapy, supporting this surgery as the treatment of choice for otherwise healthy patients with localized disease (65). On the other hand, those with ECE are traditionally not considered candidates for radical prostatectomy, given an increased likelihood for positive surgical margins and disease recurrence in these patients (11, 69). Alternate therapies, such as radiation, may then be pursued, depending on the individual clinical context. Some urologists will not perform radical prostatectomy in patients who they deem to be at high risk for ECE, regardless of imaging findings (7, 11, 69). There have been studies challenging this central role for ECE by showing acceptable survival rates following radical prostatectomy in patients with ECE. Accordingly, some urologists may take an alternative approach and attempt curative surgery in the face of MRI findings suspicious for ECE (70, 71). ECE may appear as gross visualization of extension of tumor into the peri-prostatic tissues (11) on a conventional anatomical MRI. However, such direct extensions are often not visualized easily on an MRI, but rather inferred due to the asymmetry of the neurovascular bundle, capsular thickening or retraction, irregular capsular bulge, or a broad area of contact between the capsule and a suspected focus of tumor. However, alterations in the appearance of the capsule may represent normal variation (72), and these changes are suboptimal as a marker of ECE. One study found all signs other than gross visualization of tumor outside of the capsule to be unreliable, with poor positive predictive value (73). The sensitivity of conventional MRI for ECE was found to be 57% in a separate study (28). Advanced MRI techniques may therefore play an important role in increasing the reliability for determining whether ECE is present. MRSI is limited by inability to directly evaluate the periprostatic tissues. However, the number of intraprostatic voxels involved by tumor on MRSI correlates with overall tumor volume, which in turn correlates with the likelihood of ECE (8, 74). One study combined the number of voxels in a given lobe of the prostate having spectroscopic evidence of cancer with strict T2 criteria to obtain improved accuracy for predicting ECE using MRS (3). There have been recent attempts to use DCE-MRI to directly visualize ECE as clustered areas of hypervascularity external to the capsule that do not represent vessels. Applying this technique in combination with conventional MRI produced positive and negative predicted values for ECE of 90% and 93% respectively, both higher than values that have been obtained when using T2-weighed images alone (75). Another study of 30 patients using diffusion tensor imaging, an extension of DWI, found that fiber tractography was able to delineate the prostatic capsule, as well as possible capsular involvement and extension, with good correlation with histopathologic findings (76). It is important to note that MRI is only able to detect macroscopic extracapsular extension, even when advanced techniques such as MRSI and DCE- MRI are applied. Involvement of the capsule without penetration and extension into the surrounding tissues also occurs. Such microscopic involvement remains undetected by any imaging modality, including MRI (11, 59). However, microscopic involvement has been found to not carry the prognostic significance associated with macroscopic ECE (77) and traditionally will not alter therapy as is the case for gross ECE (11). Post-Biopsy Hemorrhage Prostate MRI is often difficult to interpret in patients that have received TRUS-guided random biopsy before the imaging. The citrate produced by healthy prostate tissue is an anticoagulant and lengthens the amount of time that the blood products of biopsy persist (11), with one study observing the presence of fresh blood products on MRI obtained a full month following biopsy (78). The degree of hemorrhage is extensive, as the blood products can travel through the ductal system of the PZ and occupy a greater territory than expected from the biopsy needle tract itself (78). The hemorrhage may also be more extensive than previously encountered, as it is becoming routine to obtain a larger number of core biopsies at the time of initial sextant biopsy in order to obtain maximal sensitivity (79). These blood products cause areas of decreased T2 signal within the PZ that may mimic or mask foci of cancer. In general, hemorrhage is expected to persist for a shorter duration following biopsy within areas of cancer, given the decreased production of citrate associated with tumor cells. The presence of post-biopsy hemorrhage creates difficulty for all of the advanced MRI techniques. MRSI relies on precise determination of the chemical shift of different metabolites, which

9 Prostate Cancer: Detection using Proton MRI 13 requires a homogeneous magnetic field. Increased susceptibility (in-homogeneity of the magnetic field) from blood products distorts the field and interferes with the acquisition of reliable spectra (72). In spite of this difficulty, increased reliability has been observed for cancer detection in the setting of postbiopsy hemorrhage when combining MRSI and conventional MRI (80). A more recent study observed hypervascularity within benign areas of post-biopsy hemorrhage, attributable to inflammation and granulation tissue resulting from the biopsy procedure (27). These benign changes simulate the hypervascularity found in prostate cancer, rendering evaluation for tumor using DCE- MRI difficult. DWI imaging often relies on an imaging technique that is prone to susceptibility artifact, such as occurs in areas of post-biopsy hemorrhage, and currently is not specifically applied for this purpose. Diffuse Prostate Pathology A challenging scenario may occur when the PZ demonstrates a diffuse pathology. While this may occur in the setting of diffuse involvement by prostate cancer, other pathologies such as prostatitis, atrophy, or hemorrhage, may also impact the PZ in a diffuse manner (81). Post-treatment change is a cause of diffuse disease that deserves particular attention, as early detection of localized tumor recurrence following therapy may allow for treatment with salvage prostatectomy (25). Both external-beam radiation therapy and hormonal therapy are associated with diffuse glandular atrophy and fibrosis (25). These changes can render imaging evaluation difficult, and an integrated approach using all of the advanced techniques may be useful. Following therapy, there is an overall loss of metabolic activity and glandular secretion, producing diffusely decreased T2 signal (13, 25). This widespread reduced T2 signal may cause overestimation of recurrent tumor. For instance, one study of 22 patients following hormonal therapy found a positive predictive value of 57% using conventional sequences alone in identifying recurrent cancer (82). The use of MRSI to detect recurrence may be suboptimal as well, as the posttreatment change may lead to a decrease in all of the metabolic peaks. The citrate peak may be most severely impacted, yielding an increased CC/C ratio that overlaps with the ratios found in malignancy falsely suggesting tumor recurrence (25). Despite these difficulties, studies have found benefit in using MRSI to monitor response to therapy and to identify tumor recurrence, although the criteria for identifying tumor were modified from those typically used for healthy prostate tissue. In particular, a total loss of all metabolic peaks, termed metabolic atrophy, was associated with benign tissue, while in the setting of loss of only the citrate peak, the choline peak alone could be used to predict areas of tumor (83). DCE-MRI has also been used successfully in this context. The treated prostate gland demonstrates diminished vascularity as a result of glandular atrophy. When three independent readers examined findings in 22 patients with rising PSA following external-beam radiation therapy, 19 of whom proved to have cancer on biopsy, all readers correctly classified all of the patients when using DCE-MRI, yet had accuracies of 59%-68% for identifying cancer when using T2- weighted images alone (84). Another study suggested that DCE-MRI could be used to monitor treatment response after hormonal therapy (85). DWI may also offer a method of identifying recurrent tumor when the T2 signal becomes unreliable because of prior treatment. One study found an absence of correlation between quantitative T2 relaxation rates and ADC values within the prostate, suggesting that ADC reflects underlying aspects of prostate tissue not measured by T2-weighted images (50). Using a prostate cancer xenograft in mice, the ADC of tumor was found to increase following chemotherapy (86). This observation suggests that the reduction in ADC (an indicator of recurrence) may be used to differentiate the remainder of the PZ that is impacted solely by post-treatment change and exhibits an elevated ADC. Comparison of Advanced MRI Techniques Each of the advanced MRI techniques offers its own set of advantages and disadvantages, and no individual technique can be concluded to be superior. Findings that are of improved sensitivity and specificity for cancer detection, compared with reliance on T2 signal intensity alone, have been shown for each technique within separate studies (10, 12, 35, 47, 52, 64). Furthermore, studies of multiple advanced applications have found incremental increases in accuracy when the various techniques are used in combination. For instance, in a study of the receiver-operator curve for detection of prostate cancer in 83 patients, the area-under-the curve using T2W images alone, T2W images with DWI, and T2W images with DWI and DCE-MRI,

10 14 Prostate Cancer: Detection using Proton MRI increased from to to respectively (64). In a separate study of 14 patients, the sensitivity for tumor detection when DWI and DCE- MRI were combined was 87%, higher than for either alone (54% for DWI, 59% for DCE-MRI) (87). In a study of 42 patients, a combination of MRS and DWI resulted in significantly increased specificity than either technique alone (10). DWI and MRSI were also found to be complimentary to each other in evaluating for recurrent tumor following hormonal or radiation therapy, particularly in areas with complete metabolic atrophy (88). In a study of 23 patients, DCE-MRI and MRSI parameters were both significantly correlated with areas of cancer, but poorly correlated with each other in these same regions, suggesting that these two techniques are of complimentary value (89). The combined use of these two techniques for increasing the staging accuracy of MRI was supported in a separate study (41). Application to Radiotherapy Treatment Currently, radiotherapy treatment options vary due to the stage of the prostate cancer and patient history. Typically, radiation is delivered in three different ways: by using a machine to deliver radiation (external beam radiation therapy), by placing radioactive beads at the site (brachytherapy), or by systemic delivery of radiation (use of radiopharmaceuticals). The goal of all of these treatment options is to irradiate the targeted cancer foci, while minimizing dose to the surrounding healthy tissue and organs. With the predominant use of external beam radiation therapy and brachytherapy, it is important to identify the tumor foci accurately. External beam radiation therapy uses one of many available techniques such as: 3D-conformal radiation therapy (3D-CRT), Intensity modulated radiation therapy (IMRT), or Proton beam radiation therapy (PBRT). Typically, an anatomical CT scan is used to guide the delivery of treatment. While each technique has its advantages and disadvantages, the underlying assumption is that the image used to guide the treatment can precisely identify the tumor foci. With the effective use of multi-modality and multi-parametric imaging techniques such as T2-W MRI, DCE-MRI, DWI-MRI and MRSI, it is possible to improve the sensitivity and specificity of the detection of tumor foci. With further development of such multi-parametric methods, and with the development of tools to combine information from disparate imaging sources, we may be able to assist physicians in identifying regions that need biopsies to confirm the aggressiveness of the tumor. This may help identify aggressive from indolent tumors, and spare unnecessary treatment of indolent tumors, sparing the patients from potential side effects of radiation. Conclusion We reviewed the imaging findings on conventional MRI, MRS, DCE-MRI, and DWI in a spectrum of prostate cancer patients, using pathologic correlation. We focused on the role of the advanced sequences in those contexts in which conventional sequences are most limited. Each of these techniques serves its own role in prostate imaging, and it is important to view these techniques as complimentary rather than as alternatives to one another. By integrating the advanced techniques with conventional sequences, MRI may achieve a comprehensive evaluation that impacts disease detection and localization, as well as treatment selection and administration. We suggest that T1-weighted and T2-weighted images initially be evaluated in conjunction to identify findings suspicious for tumor as well as possible associated ECE, with consideration for areas of post-biopsy hemorrhage. The advanced techniques may then be used to improve the accuracy of tumor detection and localization. There should be particular attention for TZ tumors with MRSI and DWI. ECE may be directly visualized using DCE-MRI and indirectly evaluated using MRS. MRSI and DWI, by correlating with Gleason score and PSA respectively, may provide markers of tumor aggressiveness (65). Continued research is expected to further refine the application of each of the individual MRI techniques, given the lack of standardization and high degree of variability in methodology. Acknowledgements Supported in part by DOD Grant W81XWH Conflicts of interest The authors declare no conflict of interest. References 1. American Cancer Society. Cancer facts and figures Atlanta: American Cancer Society; 2012.

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