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Imaging in Localized Prostate Cancer
C H A P T E R
11 Imaging in Localized Prostate Cancer Sandeep Sankineni, MD*, Peter L. Choyke, MD*, Peter Pinto, MD**, Baris Turkbey, MD* *Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA **Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
INTRODUCTION
left them with decades of decreased quality of life. As a result of these two studies and several other smaller studies that reached the same conclusion, the US Preventative Screening Task Force (USPSTF) in 2012 issued a grade of “D” for PSA screening using existing criteria. This has been widely interpreted to mean PSA screening is of no value to patients.6 However, there is still no suitable alternative and no better screening method currently available. In 2015, a 3221-patient study in Toronto, Canada looked at the impact of the new PSA screening guidelines set forth by the USPSTF. As a result of curtailment of PSA screening by family practitioners, there was a 42.8% decrease in per-month detection of clinically significant prostate cancer (Gleason >7) in the year following the release of the updated PSA screening recommendation.7 Thus, while reducing the use of PSA screening certainly reduces the overdiagnosis of lowgrade disease, it also reduces the potentially life-saving diagnosis of higher-grade disease. It is therefore important that a new balance be struck between the extremes of screening everyone and screening no one. There is some hope that imaging, particularly prostate MRI, might prove a useful adjunct to PSA screening. It is often lost in the discussion that PSA is only partly to blame for the current dilemma. Elevated PSA leads to a systematic but undirected prostate biopsy where it is quite likely that small incidental islands of low-grade disease could be discovered. Thus, this “random” biopsy is equally to blame for the unintended diagnosis of many low-grade tumor islets. Meanwhile, larger and more consequential lesions outside of the normal biopsy template are likely to be missed. Therefore, the addition of MRI could be helpful in detecting lesions within the prostate more likely to be clinically significant and directing biopsies into those lesions while avoiding biopsies of normalappearing tissue, which is nonetheless likely to contain
Prostate cancer affects one in seven men in the U nited States, and it is estimated that 12% of affected men will die from their disease.1 Prostate cancer represents a spectrum of disease ranging from indolent with a low risk of mortality to very aggressive with a high risk of metastases leading to death. For most patients, prostate cancer will not be the cause of death but may nonetheless be a source of great anxiety and may lead to treatment-related adverse events. The paradox of prostate cancer is that while it is mostly a slow-growing, nonlife-threatening diagnosis, it can also be an aggressive cancer in which metastases portend a median 5-year survival of only 28%.2 Motivated by the hope that early detection could lead to improved outcomes, population screening with prostate-specific antigen (PSA) was initiated beginning in the late 1980s.3 Now that over a quarter of a decade has elapsed, it is clear that PSA screening has also led to overdiagnosis and overtreatment of low-grade prostate cancer since PSA cannot discriminate between low- and high-risk cancers with reasonable specificity. Moreover, many men underwent workups for a variety of pathologies including prostatitis and benign prostatic hyperplasia (BPH), which cause false-positive increases in PSA.4 The results of two recently completed large trials of screening, including the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and the European Randomized Study of Screening for Prostate Cancer showed a high rate (17–50%) of overdiagnosis of low-grade prostate cancer based on routine PSA screening with no perceptible benefit to the patient.5 Up to the time of this report, many men with low-risk disease were being aggressively treated with surgery or radiation therapy for low-risk disease. While this treatment no doubt cured patients of their prostate cancer, it also Prostate Cancer. http://dx.doi.org/10.1016/B978-0-12-800077-9.00011-6 Copyright © 2016 Elsevier Ltd. All rights reserved.
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92 11. Imaging in Localized Prostate Cancer indolent islands of low-grade cancer. Over the past decade, there has been rapid improvement in image-guided biopsy technology.8 Most importantly, the acceptance and use of multiparametric prostate MRI in combination with transrectal ultrasound (TRUS) biopsy has increased clinicians’ ability to detect clinically significant disease while reducing the detection of low-grade disease, and is now directly impacting the clinical management of patients with prostate cancer. While it is still too early to definitively state that this approach will result in a more efficacious screening method for prostate cancer, it is nonetheless very promising and readily applied today whereas new biomarkers are still years away from the clinic. This chapter will discuss the current state of imaging in prostate cancer detection, including ultrasound, multiparametric MRI (mpMRI), and PET/CT.
ULTRASOUND TRUS is a widely available, portable, readily repeatable, and relatively inexpensive imaging technique. Ultrasound enables real-time visualization of the prostate, thus allowing the clinician to determine the gland volume and the distinction between the peripheral zone (PZ) and transition zone (TZ). Prostate cancers usually appear as hypoechoic regions on TRUS; however, this pattern can be mimicked by a variety of other pathologies such as BPH and inflammatory process. Moreover, not every prostate cancer is hypoechoic, and lesions commonly appear isoechoic, which reduces the diagnostic utility of TRUS. ECE (extracapsular extension) detection by TRUS is also limited except in very extensive cases. Color or power Doppler modes in TRUS can improve the tumor detection rate, but this is dependent upon the extent of angiogenesis. In smaller or less aggressive cancers, this affect may be minimal and lead to lower sensitivity rates. Today TRUS is mainly used for the purpose of guiding biopsies during systematic, blind sampling of the prostate. More recently, contrast-enhanced TRUS with microbubbles has been reported to improve the sensitivity for tumor detection. Microbubbles are 5–10 mm gas-filled bubbles that can be seen on ultrasound. However, microbubbles tend to act like blood pool agents because of their large size, and often, only the vessels themselves are visualized. A study on contrast-enhanced TRUS demonstrated recently the ability to differentiate prostate cancer from normal tissue. It reported a sensitivity of 100%, but a specificity of only 48% in patients having previous negative biopsies but rising PSA values.9 While the addition of contrast-enhancement ultrasound (CEUS) is a promising contribution to conventional TRUS biopsy, the value of CEUS is controversial, with experts achieving excellent results but several multicenter trials achieving mediocre results. As with all facets of ultra-
sound, the method is still highly operator-dependent and results will vary according to skill and experience. More research is warranted before this can be considered a routine option in clinical practice.
MAGNETIC RESONANCE IMAGING mpMRI is now considered to be the most powerful noninvasive diagnostic method for the detection of prostate cancer. While needle biopsy and histopathology remain the gold standard of diagnosis, mpMRI offers a high level of confidence in diagnosing clinically significant cancers.10 A study of 1003 men by the National Cancer Institute showed the significant improvement in prostate cancer detection with the use of mpMRI followed by targeted MRI-TRUS fusion-guided biopsy.11 Prostate MRI can be acquired at 1.5T or 3T, with or without the use of an endorectal coil (ERC). There is an understanding that while the lower field strength of 1.5T is sufficient for evaluation, imaging at 3T is likely to be of higher quality. This is because 3T scanners exhibit a higher signal-to-noise ratio (SNR). However, multiple studies have shown minimal difference in outcomes between prostate MRIs conducted at 1.5T with an ERC versus 3T using only phased-array surface coils.12,13 The routine use of the ERC is still debated, particularly at 3T. Newer MRI units are capable of performing excellent prostate MRIs without the ERC, thus reducing cost, time, and patient discomfort. Nonetheless, several studies have determined that there is benefit to using ERC at 3T. Heijmink et al. found mpMRI with ERC to have better accuracy for tumor localization when compared to mpMRI with body coil.14 Turkbey et al. recently showed increased positive predictive value of 80% versus 64% for mpMRI with and without an ERC, respectively, in 20 patients who underwent radical prostatectomy.15 However, the clinical consequence of this slightly increased sensitivity with the ERC has not yet been determined. Thus, in general, better-quality scans can be obtained with ERC, and this translates to higher sensitivity and specificity; however, it is unclear whether the use of ERC is justified in terms of better patient outcomes. Eventually, it is expected that routine use of ERC will no longer be used for the reasons just mentioned. With time and technological advancement in MR technology, mpMRI with ERC may be reserved for very specific purposes – such as in local staging after histopathological diagnosis and especially in the postprostatectomy follow-up after biochemical recurrence.
Anatomic MR Imaging (T1W, T2W MRI) Anatomic MR imaging includes T1W and T2W MRI. T1W images are not used for diagnostic purposes because zonal anatomy is difficult to identify and tumors are
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Magnetic resonance imaging
typically not well seen. However, T1W images are helpful in determining if there is residual hemorrhage due to prior biopsy, which appears hyperintense on T1W images.16 It is important to identify hemorrhage prior to further sequence evaluation as hemorrhage can result in false- positive diagnoses on mpMRI. It is widely agreed that it is best to wait at least 8–10 weeks postbiopsy to reduce the chance of hemorrhagic artifact related to biopsy.17 T2W imaging offers high-resolution and excellent anatomical detail (Figure 11.1a, b). T2W imaging is acquired in axial, sagittal, and coronal views. The high clarity offered by T2W imaging allows the clinician to determine zonal anatomy. The normal PZ tends to have a higher signal, whereas the TZ has an intermediate-lower signal intensity pattern mainly due to benign hyperplasia. Cancers appear as hypointense foci within PZ and TZ, but may be more difficult to detect in the latter due to the heterogeneous background in the TZ. T2W MRI for detection of cancer is known to have a wide range of sensitivities and specificities, 27–100%, and 32–99%, respectively, but this reflects a broad range of experience, patient selection, MR quality, and diagnostic criteria.18–20 A major concern for clinicians and a motivation behind the acquisition of the T2W sequence in routine diagnosis of prostate cancer is to detect ECE (Figure 11.2). ECE is seen as a direct extension of the tumor into the periprostatic fat.21 This is important for preoperative staging since the presence of ECE would upstage a patient to Stage T3A. This could redirect a patient’s clinical management approach including altering the surgical approach or even ruling out the possibility of surgery. On MRI, indirect features of ECE include capsular bulge, broad capsular base, and border irregularity, obliteration of rectoprostatic angle, and/or capsular retraction.22 Despite the superior spatial resolution of T2W MRI, it is still limited for the evaluation of microscopic ECE with sensitivity and specificity ranges of 14.4–100% and 67–100%, respectively.23,24 Seminal vesicles, which are located superiorly at the base of the prostate, are another important structure to evaluate for accurate staging. On T2W MRI, they normally appear as hyperintense saccules due to their high fluid content. When there is seminal vesicle invasion, they often appear hypointense and may enhance after contrast media.25 MRI with an ERC has a high reported accuracy (91%) for detection of seminal vesicle invasion.26
Functional MR Imaging Diffusion Weighted MRI and Apparent Diffusion Coefficient Maps (DWI and ADC) DWI is based on the Brownian motion of free water within tissues. Cellular density increases in malignancies when compared with normal tissue. Due to the increased number of cell membranes, water diffusion is
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more restricted in the tumor site. This restriction or impedance can be noninvasively detected on DWI and can be quantified by calculating the apparent diffusion coefficient (ADC). DWI does not require contrast injection, and can be done readily in almost all clinical scanners along with T2W MRI. A meta-analysis of 5892 patients showed that DWI alone yielded higher sensitivity, specificity, and area under the ROC curve than T2W alone.27 On ADC maps, prostate cancer shows decreased signal intensity relative to normal tissue (Figure 11.1c). DWI and ADC maps demonstrate a wide range of sensitivities and specificities, 57–93.3% and 57–100%, respectively, for tumor detection.28–32 Additionally, it has been shown that the use of high b value imaging, (e.g., 1000–2000 s/mm2) also improves performance for lesion detection (Figure 11.1d).33,34 DWI is a major component of the mpMRI and has great utility for improving prostate cancer detection and management. However, it has some challenges to be addressed, as it has a lower spatial resolution and is highly susceptible to bulk motion.35 Also, air within the rectum may distort the DWI image and cause susceptibility artifacts if an ERC filled with a perfluorocarbon is not used. Improvements in technology (parallel imaging and field strength) may mitigate these technical shortcomings. Dynamic Contrast Enhanced (DCE) MRI DCE MRI uses a gadolinium-chelate-based agent injected as bolus and offers information on the vascularity of a lesion.36 Blood vessel proliferation increases in response to oxygen and nutrient deprivation as tumors surpass a few millimeters in diameter. These new vessels are tortuous and permeable in comparison to normal vessels. DCE MRI consists of a T1W gradient echo imaging prior to, during, and after intravenous bolus injection of a low molecular weight gadolinium chelate agent. The prostate imaging is acquired continuously for several minutes, and the interval between the beginning and end of each component scan is known as the temporal resolution, which typically varies from 5 s to 30 s. Shorter temporal resolution is preferred in order to image the enhancement peak after injection as early enhancement can be an indicator of a positive study. On DCE MRI, malignant lesions appear with early focal enhancement and rapid washout 37 (Figure 11.1e); however, BPH and prostatitis may also show early enhancement leading to false positives. Analysis of DCE MRI can be done qualitatively, semiquantitatively, or quantitatively. Qualitative evaluation simply includes visual assessment of serially acquired images in a video mode, and tumoral enhancement is usually characterized by rapid and early opacification (1–3 phases after the contrast arrives in the major arteries such as femoral artery) compared to its surrounding. Semiquantitative analysis mostly relies on evaluating the DCE by matching the time-signal curve to
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94 11. Imaging in Localized Prostate Cancer
FIGURE 11.1 An mpMRI was acquired at 3T with an ERC in a 58-year-old male with serum PSA = 4.46 ng/mL, DRE negative, with no prior prostate biopsy. (a, b) Axial and coronal T2W imaging shows a lesion in the right apical peripheral zone, (c) ADC maps of DWI identify the same right apical peripheral zone region with hypo-intense features, (d) b2000 shows a focal hyperenhancing region corresponding to the right apical PZ, and (e) DCE shows early focal enhancement of the right apical PZ. The lesion, located in the peripheral zone, is scored with PI-RADS Version 2.0 based on the diffusion imaging, and therefore receives a score of 4, with moderately-high level of suspicion for clinically significant prostate cancer; it is therefore recommended that the patient undergo a targeted biopsy. Following the targeted MRI/TRUS fusion-guided biopsy, histopathology confirms a Gleason 3 + 4 (60%) with perineural invasion.
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FIGURE 11.2 An mpMRI was acquired at 3T with an ERC in a 66-year-old male with serum PSA = 12.1 ng/mL, DRE negative, with one prior positive conventional prostate biopsy (Gleason 3 + 3 in the right mid peripheral zone), who was on active surveillance at the time of his mpMRI. (a) Axial T2W imaging shows a large lesion in the right midbase peripheral zone with possible ECE, (b) ADC maps of DWI show a larger hypointense area corresponding with the T2W imaging, (c) b2000 shows a focal enhancement of the suspicious region, (d) DCE shows early focal enhancement of the suspected lesion, (e) axial T2W imaging shows a possible ECE of the lesion. The lesion, located in the peripheral zone, is scored with PI-RADS Version 2.0 based on its diffusion imaging, and therefore receives a score of 5. There is a high level of suspicion for clinically significant prostate cancer and the patient requires a targeted biopsy for this reason. Following the targeted MRI/TRUS fusion-guided biopsy, histopathology confirms a Gleason 4 + 4, in 95% of the targeted core from the right midbase peripheral zone.
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96 11. Imaging in Localized Prostate Cancer one of three different curve types. Type 1 curve refers to benign enhancement pattern where there is continuous gradual enhancement, whereas Type 2 curves, wherein the signal initially increases and then plateaus, can represent inflammatory processes. Finally, Type 3 includes a rapid wash in and out of contrast material and is highly predictive of a malignant lesion. However, almost all of the curve types can be identified in any given lesion within the prostate, regardless of whether they are benign or malignant. Thus, one typically selects the “worst” curve (i.e., Type 3) to represent the DCE of the malignant lesion. This can reduce the effectiveness of DCE in distinguishing prostate cancers from other benign conditions such as inflammation or BPH. Quantitative approaches to DCE utilize a T1 map and an arterial input function (either personalized or population-based), which are integrated into a two-compartment model to calculate several quantitative parameters, such as forward and reverse contrast flow rates (Ktrans and kep, respectively). Qualitative evaluation is the most commonly used technique because it does not require special software. Compared to T2W and DWI, DCE MRI plays a relatively modest role in prostate cancer diagnosis. However, it may be beneficial in identifying recurrences in the posttreatment setting. Despite its utility, some challenges exist for DCE MRI including standardization of image acquisition protocols and analysis techniques. Patients with severe renal failure cannot receive gadolinium contrast material; hence, the use of gadolinium-contrast agents should be carefully evaluated in such patients.
MR SPECTROSCOPIC IMAGING MR spectroscopy is another functional MRI technique that aims to display certain compounds inside the prostate, such as choline and citrate, by representing the amount of signal from particular proton resonance frequencies that correspond to those compounds. MR spectroscopic imaging (MRSI) thus produces a spectrum of peaks corresponding to relevant and nonrelevant molecules. While it truly provides molecular information about the chemicals within the prostate, this technique is largely limited due to its long acquisition times, necessity for expert personnel (e.g., MR physicist), and complex processing methods. Because it utilizes a much lower spatial resolution than the other sequences previously discussed, it has a lower sensitivity due to significant partial volume effects. Therefore, it is not recommended in routine clinical practice; however, it is still used for research purposes in a limited number of centers. mpMRI is therefore a powerful imaging technique for detection and staging of prostate cancer. The most underappreciated benefit of prostate mpMRI is its strong negative predictive value. Studies have typically reported
negative predictive values of mpMRI ranging from 70% to 80%.38 The ability to rule out clinically significant disease is one of its most important features. In patients with BPH or prostatitis, who often have an elevated PSA (>4.0), PSAD (>0.15), and/or abnormal DRE, the failure to identify a prostate lesion can be highly useful in eliminating significant cancers. Without an mpMRI and a targeted biopsy approach, a patient may go on to have numerous negative biopsies. Negative MRIs give physicians confidence to minimize the number of biopsy sessions a patient undergoes over several years. In a recent study by Gupta et al., the NPV of mpMRI in detecting prostate cancer has been reported as high as 73.1% for all prostate cancer and 89.7% for ECE.39 mpMRI is a precision imaging modality that has the future potential to be tailored for personalized imaging. In case of suspicion for prostate cancer, a patient-specific mpMRI may be performed. The individual mpMRI sequences can be acquired for screening, diagnosis, staging, and follow-up. Further trials and studies will need to be performed before guidelines are established for such a practice. One important aspect of mpMRI is the adoption of a standardized reporting system. mpMRI as defined by the 2014 American College of Radiology’s Prostate Imaging Reporting and Data System (PI-RADS version 2.0) consists of evaluation of numerous MR sequences to determine a reproducible scoring system which may be readily communicated among radiologists, urologists, and their patients.40 The sequences used are 1) T2-weighted (T2W) pulse sequence for anatomic assessment,41 2) DWI and ADC maps with high-b value imaging, and 3) dynamic contrast enhanced (DCE) imaging for functional assessment.42 In PI-RADS, DWI is used primarily for the scoring of the PZ, but T2W is primarily used in the TZ due to overlap between cancer lesions and BPH nodules. The use of PI-RADS is therefore expected to improve education and communication and thereafter improve the overall utility of mpMRI in patients with suspected cancer.
PET/CT Conventional CT and mpMRI are unable to detect changes in tissue at the molecular level. These changes can be imaged by using targeted radionuclides, which are highly sensitive for detecting malignancies. Imaging of nodal and bony metastatic spread may benefit from such studies, whereas they are likely too expensive for routine use in localized prostate cancer. The current standard of care for bone metastasis is the 99mTc methyldiphosphonate (MDP) bone scan. Radiolabeled MDP agent is taken up in osteoblastic lesions seen in metastatic prostate cancer.43 Unfortunately, because it
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Conclusions
is a single photon emitter, sensitivity is less than optimal, and false-positive findings in nonmalignant conditions such as benign neoplasms, trauma, and degenerative joint disease are commonplace. Because bone scans are typically not acquired with a CT scan, it can be difficult to resolve whether a particular focus of uptake is associated with a benign condition on CT. For this reason, there has been interest in the development of 18F-sodium fluoride (18F-NaF) PET/CT as a viable alternative for detection of bone metastases. A recent study evaluated the efficacy of 18F-NaF versus that of 99mTc-bone scintigraphy in detecting bone metastases in patients with lung, breast, and prostate cancer.44 18F-sodium fluoride outperformed the bone scan in all components and had a sensitivity and NPV of 100%. However, due to a high rate of false positives, these scans must be correlated with the coregistered CT. This can be a time-consuming process, but new automated methods of detecting and eliminating benign lesions from further consideration are under development. More recently, there has been a tremendous growth in research in radiotracers for PET/CT diagnostics in localized prostate cancer. Results of studies have been published on several of these agents. 18 F-DCFBC (PSMA target), developed at Johns H opkins University (Baltimore, MD), is one such promising radiotracer. A preliminary study in five patients identified 32 PET-positive suspected metastatic sites. Out of these, 21 (65%) of the sites were positive on both PET and conventional imaging suggestive of metastatic disease, while the remaining 11 PET positive-only lesions (34%) were indeterminant but were likely to be metastatic.45 A Phase 2 clinical trial, with an enrollment of 45 patients, is now underway at the National Institutes of Health (NIH, Bethesda, MD) to determine the efficacy of 18F-DCFBC. Another related agent is 68Ga-PSMA (gallium labeled PSMA ligand). In early 2014 a comparison study from Germany reported results on 68Ga-PSMA versus 18Fcholine PET/CTs. A total of 78 lesions were detected in 32 patients using 68Ga-PSMA, and 56 lesions were detected in 26 patients using 18F-choline. The higher detection rate in 68Ga-PSMA PET/CT was statistically significant (p = 0.04).46,47 Another radiotracer unrelated to PSMA was developed at Emory University (Atlanta, GA). This agent, 18F-FACBC (radiolabeled leucine analog targeting protein metabolism), has now also been studied at multiple sites. A sector-based comparison with histopathologic analysis performed at NCI revealed sensitivity and specificity of 67 and 66%, respectively, for 18F-FACBC in patients with localized prostate cancer although the performance was inferior to T2W MRI (sensitivity and specificity at 73 and 79%, respectively). Yet the combined positive predictive value (FACBC + T2W MRI) was shown to be higher, at 82%.48,49 18 F-FDHT, targeting the androgen receptor, was created in 2004 at Memorial Sloan Kettering (New York, NY).
An initial trial by Larson and coworkers compared 18FFDHT with 18F-FDG PET. In the study, 59 lesions were found by conventional imaging. 18F-FDG PET was positive in 57 of 59 lesions (97%), while 18F-FDHT PET was positive in 46 of 59 lesions (78%).50 11 C-acetate (targeting fatty acid metabolism) for prostate cancer, first used in Japan, now also has published results from comparison studies. Mena et al. performed a sector-based comparison with histopathology, which determined a sensitivity and specificity of 61.6 and 80.0%, respectively, for 11C-acetate, and 82.3 and 95.1%, respectively, for MRI for localized disease.51,52 Finally, 18F-choline and 11C-choline (targeting increased membrane turnover) have been used in numerous studies of prostate cancer. Umbehr et al. reported a systematic meta-analysis of 10 studies for staging 637 patients with proven but untreated prostate cancer, and showed a pooled sensitivity and specificity of 84 and 79%, respectively.53 Thus, 18F-choline and 11C-choline are promising PET/CT agents for staging prostate cancer. It should be noted that 11C-choline and 11C-acetate have a half-life of only 20 min so they must be produced on site, whereas, the 18F labeled compounds have the potential to be centrally produced and shipped to various medical sites for injection. While nearly all of the aforementioned agents have shown promising early results, the question currently remains regarding which one is the best and even what metric should be utilized to better assess these agents against one another. There are numerous clinical trials currently underway to better understand the capabilities of these agents, the results of which are awaited with much anticipation.54
CONCLUSIONS The development and acceptance of precise and powerful MRI techniques has altered the diagnosis and management of localized prostate cancer. MRI is currently the most valuable imaging modality available for localized disease. mpMRI employs a combination of T2W, DWI, and DCE. T2W provides the most detailed anatomic information while DWI is the most effective functional technique and has good specificity. DCE MRI is sensitive for prostate cancer but plays a secondary role in diagnosis and characterization. Using these sequences in combination may improve initial detection and staging of clinically significant disease, and also improve targeted biopsy techniques. These advances will continue to improve both the decision-making and utility of active surveillance and focal therapies. Novel imaging techniques such as PET/CT radiotracer agents are emerging to improve the detection and staging of prostate cancer.
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References 1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29. 2. The American Cancer Society. Cancer Facts & Figures 2015. http:// www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/; 2015[accessed 10.01.15]. 3. Stamey TA, Yang N, Hay AR, et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909. 4. Schröder FH, Carter HB, Wolters T, et al. Early detection of prostate cancer in 2007. Part 1: PSA and PSA kinetics. Eur Urol 2008;53: 468–77. 5. Miller AB. New data on prostate cancer mortality after PSA screening. N Engl J Med 2012;366:1047–8. 6. Moyer VA, LeFevre ML, Siu AL, et al. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157(2):120–34. 7. Bhindi B, Mamdani M, Kulkarni GS, et al. Impact of the U.S. Preventive Services Task Force recommendations against PSA screening on prostate biopsy and cancer detection rates. J Urol 2014. 8. Turkbey B, Choyke PL. Decade in review-imaging: a decade in image-guided prostate biopsy. Nat Rev Urol 2014;11(11):611–2. 9. Taymoorian K, Thomas A, Slowinski T, et al. Transrectal broadband-Doppler sonography with intravenous contrast medium administration for prostate imaging and biopsy in men with an elevated PSA value and previous negative biopsies. Anticancer Res 2007;27:4315–20. 10. Muller BG, Shih J, Sankineni S, et al. Prostate Cancer: Interobserver Agreement and Accuracy with the Revised Prostate Imaging Reporting and Data System at Multiparametric MR Imaging. Radiology 2015;142818 [Epub ahead of print]. 11. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 2015;313(4): 390–7. 12. Sosna J, Pedrosa I, Dewolf WC, et al. MR imaging of the prostate at 3 Tesla: comparison of an external phased-array coil to imaging with an endorectal coil at 1.5 Tesla. Acad Radiol 2004;11:857–862; Beyersdorff D, Taymoorian K, Knösel T, et al. MRI of prostate cancer at 1.5 and 3.0 T: comparison of image quality in tumor detection and staging. Am J Roentgenol 2005;185:1214–1220. 13. Park BK, Kim B, Kim CK, et al. Comparison of phased-array 3.0-T and endorectal 1.5-T magnetic resonance imaging in the evaluation of local staging accuracy for prostate cancer. J Comput Assist Tomogr 2007;31:534–8. 14. Heijmink SWTPJ, Futterer JJ, Hambrock T, et al. Prostate cancer: body-array versus endorectal coil MR imaging at 3 T – comparison of image quality, localization, and staging performance. Radiology 2007;244:184–95. 15. Turkbey B, Merino MJ, Gallardo EC, et al. Comparison of endorectal coil and nonendorectal coil T2W and diffusion-weighted MRI at 3 Tesla for localizing prostate cancer: correlation with wholemount histopathology. J Magn Reson Imaging 2014;39:1443–8. 16. Barrett T, Vargas HA, Akin O, et al. Value of the hemorrhage exclusion sign on T1-weighted prostate MR images for the detection of prostate cancer. Radiology 2012;263:751–7. 17. Qayyam A, Coakley FV, Lu Y, et al. Organ-confined prostate cancer: effect of prior transrectal biopsy on endorectal MRI and MR spectroscopic imaging. Am J Roentgenol 2004;183:1079–83. 18. Aydin H, Kizilgoz V, Tatar IG, et al. Detection of prostate cancer with magnetic resonance imaging: optimization of T1-weighted, T2-weighted, dynamic-enhanced T1-weighted, diffusion-weighted imaging apparent diffusion coefficient mapping sequences and MR spectroscopy, correlated with biopsy and histopathological findings. J Comput Assist Tomogr 2012;36(1):30–45.
19. Chen M, Dang HD, Wang JY, et al. Prostate cancer detection: comparison of T2-weighted imaging, diffusion-weighted imaging, proton magnetic resonance spectroscopic imaging, and the three techniques combined. Acta Radiol 2008;49(5):602–10. 20. Tan CH, Wei W, Johnson V, et al. Diffusion-weighted MRI in the detection of prostate cancer: meta-analysis. Am J Roentgenol 2012;199(4):822–9. 21. Wang L, Mullerad M, Chen HN, et al. Prostate cancer: incremental value of endorectal MR imaging findings for prediction of extracapsular extension. Radiology 2004;232:133–9. 22. Claus FG, Hricak H, Hattery RR. Pretreatment evaluation of prostate cancer: role of MR imaging and H-1 MR spectroscopy. Radiographics 2004;232:133–9. 23. Nakashima J, Tanimoto A, Imai Y, et al. Endorectal MRI for prediction of tumor site, tumor size, and local extension of prostate cancer. Urology 2004;64:101–5. 24. Bloch BN, Furman-Haran E, Helbich TH, et al. Prostate cancer: accurate determination of extracapsular extension with high- spatial-resolution dynamic contrast-enhanced and T2-weighted MR imaging – initial results. Radiology 2007;245:176–85. 25. Raskolnikov D, George AK, Rais-Bahrami S, et al. Multiparametric magnetic resonance imaging and image-guided biopsy to detect seminal vesicle invasion by prostate cancer. J Endourol 2014;28(11):1283–9. 26. Sala E, Akin O, Moskowitz CS, et al. Endorectal MR imaging in the evaluation of seminal vesicle invasion: diagnostic accuracy and multivariate feature analysis. Radiology 2006;238(3):929–37. 27. Tan CH, Wei W, Johnson V, et al. Diffusion-weighted MRI in the detection of prostate cancer: meta-analysis. Am J Roentgenol 2012;199:822–9. 28. Kim CK, Park BK, Lee HM, et al. Value of diffusion-weighted imaging for the prediction of prostate cancer location at 3T using a phased-array coil: preliminary results. Invest Radiol 2007;42:842–7. 29. Miao H, Fukatsu H, Ishigaki T. Prostate cancer detection with 3-T MRI: comparison of diffusion-weighted and T2-weighted imaging. Eur J Radiol 2007;61:297–302. 30. Haider MA, van der Kwast TH, Tanguay J, et al. Combined T2weighted and diffusion-weighted MRI for localization of prostate cancer. Am J Roentgenol 2007;189:323–8. 31. Kozlowski P, Chang SD, Jones EC, et al. Combined diffusionweighted and dynamic contrast-enhanced MRI for prostate cancer diagnosis – correlation with biopsy and histopathology. J Magn Reson Imaging 2006;24:108–13. 32. Woodfield CA, Tung GA, Grand DJ, et al. Diffusion-weighted MRI of peripheral zone prostate cancer: comparison of tumor apparent diffusion coefficient with Gleason score and percentage of tumor on core biopsy. Am J Roentgenol 2010;194:316–22. 33. Tamada T, Kanomata N, Sone T, et al. High b value (2000 s/mm2) diffusion-weighted magnetic resonance imaging in prostate cancer at 3 Tesla: comparison with 1000 s/mm2 for tumor conspicuity and discrimination of aggressiveness. PLoS ONE 2014;9:e96619. 34. Grant KB, Agarwal HK, Shih JH, et al. Comparison of calculated and acquired high b value diffusion-weighted imaging in prostate cancer. Abdom Imaging 2015;40:578–86. 35. Hoeks CMA, Berentsz JO, Hambrock T, et al. Prostate cancer: multiparametric MR imaging for detection, localization, and staging. Radiology 2011;261:46–66. 36. Alonzi R, Padhani AR, Allen C. Dynamic contrast enhanced MRI in prostate cancer. Eur J Radiol 2007;63:335–50. 37. Bonekamp D, Macura KJ. Dynamic contrast-enhanced magnetic resonance imaging in the evaluation of the prostate. Top Magn Reson Imaging 2008;19:273–84. 38. Panebianco V, Barchetti F, Sciarra A. Multiparametric magnetic resonance imaging vs. standard care in men being evaluated for prostate cancer: a randomized study. Urol Oncol 2015;33(1):17. e1–e7.
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39. Gupta RT, Faridi KF, Singh AA, et al. Comparing 3-T multiparametric MRI and the Partin Tables to predict organ-confined prostate cancer after radical prostatectomy. Urol Oncol 2014;32(8): 1292–9. 40. American College of Radiology. PI-RADS v2 - Prostate Imaging and Reporting and Data System: Version 2. http://www.acr.org/Quality-Safety/Resources/PIRADS/; 2015[accessed 10.01.15]. 41. Bhavsar A, Verma S. Anatomic imaging of the prostate. Biomed Res Int 2014;2014:728539. 42. Sankineni S, Osman M, Choyke PL. Functional MRI in prostate cancer detection. Biomed Res Int 2014;2014:590638. 43. Bouchelouche K, Tagawa ST, Goldsmith SJ, et al. PET/CT imaging and radioimmunotherapy of prostate cancer. Semin Nucl Med 2011;41:29–44. 44. Damle NA, Bal C, Bandopadhyaya GP, et al. The role of 18Ffluoride PET-CT in the detection of bone metastases in patients with breast, lung and prostate carcinoma: a comparison with FDG PET/CT and 99mTc-MDP bone scan. Jpn J Radiol 2013;31:262–9. 45. Cho SY, Gage KL, Mease RC, et al. Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecularweight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J Nucl Med 2012;53(12):1883–91. 46. Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2014;41(1):11–20.
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47. Afshar-Oromieh A, Malcher A, Eder M, et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging 2013;40(4):486–95. 48. Turkbey B, Mena E, Shih J, et al. Localized prostate cancer detection with 18F-FACBC PET/CT: comparison with MR imaging and histopathologic analysis. Radiology 2014;270(3):849–56. 49. Schuster DM, Votaw JR, Nieh PT, et al. Initial experience with the radiotracer anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid with PET/CT in prostate carcinoma. J Nucl Med 2007;48(1): 56–63. 50. Larson SM, Morris M, Gunther I, et al. Tumor localization of 16beta-18F-fluoro-5alpha-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med 2004;45(3):366–73. 51. Mena E, Turkbey B, Mani H, et al. 11C-acetate PET/CT in localized prostate cancer: a study with MRI and histopathologic correlation. J Nucl Med 2012;53(4):538–45. 52. Oyama N, Akino H, Kanamaru H, et al. 11C-acetate PET imaging of prostate cancer. J Nucl Med 2002;43(2):181–6. 53. Umbehr MH, Müntener M, Hany T, et al. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. Eur Urol 2013;64(1):106–17. 54. US National Institutes of Health. Prostate PET/CT. https://ClinicalTrials.gov; 2015[accessed 5.02.15].
I. Etiology, Pathology, and Tumor Biology
11 Imaging in Localized Prostate Cancer Sandeep Sankineni, MD*, Peter L. Choyke, MD*, Peter Pinto, MD**, Baris Turkbey, MD* *Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA **Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
INTRODUCTION
left them with decades of decreased quality of life. As a result of these two studies and several other smaller studies that reached the same conclusion, the US Preventative Screening Task Force (USPSTF) in 2012 issued a grade of “D” for PSA screening using existing criteria. This has been widely interpreted to mean PSA screening is of no value to patients.6 However, there is still no suitable alternative and no better screening method currently available. In 2015, a 3221-patient study in Toronto, Canada looked at the impact of the new PSA screening guidelines set forth by the USPSTF. As a result of curtailment of PSA screening by family practitioners, there was a 42.8% decrease in per-month detection of clinically significant prostate cancer (Gleason >7) in the year following the release of the updated PSA screening recommendation.7 Thus, while reducing the use of PSA screening certainly reduces the overdiagnosis of lowgrade disease, it also reduces the potentially life-saving diagnosis of higher-grade disease. It is therefore important that a new balance be struck between the extremes of screening everyone and screening no one. There is some hope that imaging, particularly prostate MRI, might prove a useful adjunct to PSA screening. It is often lost in the discussion that PSA is only partly to blame for the current dilemma. Elevated PSA leads to a systematic but undirected prostate biopsy where it is quite likely that small incidental islands of low-grade disease could be discovered. Thus, this “random” biopsy is equally to blame for the unintended diagnosis of many low-grade tumor islets. Meanwhile, larger and more consequential lesions outside of the normal biopsy template are likely to be missed. Therefore, the addition of MRI could be helpful in detecting lesions within the prostate more likely to be clinically significant and directing biopsies into those lesions while avoiding biopsies of normalappearing tissue, which is nonetheless likely to contain
Prostate cancer affects one in seven men in the U nited States, and it is estimated that 12% of affected men will die from their disease.1 Prostate cancer represents a spectrum of disease ranging from indolent with a low risk of mortality to very aggressive with a high risk of metastases leading to death. For most patients, prostate cancer will not be the cause of death but may nonetheless be a source of great anxiety and may lead to treatment-related adverse events. The paradox of prostate cancer is that while it is mostly a slow-growing, nonlife-threatening diagnosis, it can also be an aggressive cancer in which metastases portend a median 5-year survival of only 28%.2 Motivated by the hope that early detection could lead to improved outcomes, population screening with prostate-specific antigen (PSA) was initiated beginning in the late 1980s.3 Now that over a quarter of a decade has elapsed, it is clear that PSA screening has also led to overdiagnosis and overtreatment of low-grade prostate cancer since PSA cannot discriminate between low- and high-risk cancers with reasonable specificity. Moreover, many men underwent workups for a variety of pathologies including prostatitis and benign prostatic hyperplasia (BPH), which cause false-positive increases in PSA.4 The results of two recently completed large trials of screening, including the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and the European Randomized Study of Screening for Prostate Cancer showed a high rate (17–50%) of overdiagnosis of low-grade prostate cancer based on routine PSA screening with no perceptible benefit to the patient.5 Up to the time of this report, many men with low-risk disease were being aggressively treated with surgery or radiation therapy for low-risk disease. While this treatment no doubt cured patients of their prostate cancer, it also Prostate Cancer. http://dx.doi.org/10.1016/B978-0-12-800077-9.00011-6 Copyright © 2016 Elsevier Ltd. All rights reserved.
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92 11. Imaging in Localized Prostate Cancer indolent islands of low-grade cancer. Over the past decade, there has been rapid improvement in image-guided biopsy technology.8 Most importantly, the acceptance and use of multiparametric prostate MRI in combination with transrectal ultrasound (TRUS) biopsy has increased clinicians’ ability to detect clinically significant disease while reducing the detection of low-grade disease, and is now directly impacting the clinical management of patients with prostate cancer. While it is still too early to definitively state that this approach will result in a more efficacious screening method for prostate cancer, it is nonetheless very promising and readily applied today whereas new biomarkers are still years away from the clinic. This chapter will discuss the current state of imaging in prostate cancer detection, including ultrasound, multiparametric MRI (mpMRI), and PET/CT.
ULTRASOUND TRUS is a widely available, portable, readily repeatable, and relatively inexpensive imaging technique. Ultrasound enables real-time visualization of the prostate, thus allowing the clinician to determine the gland volume and the distinction between the peripheral zone (PZ) and transition zone (TZ). Prostate cancers usually appear as hypoechoic regions on TRUS; however, this pattern can be mimicked by a variety of other pathologies such as BPH and inflammatory process. Moreover, not every prostate cancer is hypoechoic, and lesions commonly appear isoechoic, which reduces the diagnostic utility of TRUS. ECE (extracapsular extension) detection by TRUS is also limited except in very extensive cases. Color or power Doppler modes in TRUS can improve the tumor detection rate, but this is dependent upon the extent of angiogenesis. In smaller or less aggressive cancers, this affect may be minimal and lead to lower sensitivity rates. Today TRUS is mainly used for the purpose of guiding biopsies during systematic, blind sampling of the prostate. More recently, contrast-enhanced TRUS with microbubbles has been reported to improve the sensitivity for tumor detection. Microbubbles are 5–10 mm gas-filled bubbles that can be seen on ultrasound. However, microbubbles tend to act like blood pool agents because of their large size, and often, only the vessels themselves are visualized. A study on contrast-enhanced TRUS demonstrated recently the ability to differentiate prostate cancer from normal tissue. It reported a sensitivity of 100%, but a specificity of only 48% in patients having previous negative biopsies but rising PSA values.9 While the addition of contrast-enhancement ultrasound (CEUS) is a promising contribution to conventional TRUS biopsy, the value of CEUS is controversial, with experts achieving excellent results but several multicenter trials achieving mediocre results. As with all facets of ultra-
sound, the method is still highly operator-dependent and results will vary according to skill and experience. More research is warranted before this can be considered a routine option in clinical practice.
MAGNETIC RESONANCE IMAGING mpMRI is now considered to be the most powerful noninvasive diagnostic method for the detection of prostate cancer. While needle biopsy and histopathology remain the gold standard of diagnosis, mpMRI offers a high level of confidence in diagnosing clinically significant cancers.10 A study of 1003 men by the National Cancer Institute showed the significant improvement in prostate cancer detection with the use of mpMRI followed by targeted MRI-TRUS fusion-guided biopsy.11 Prostate MRI can be acquired at 1.5T or 3T, with or without the use of an endorectal coil (ERC). There is an understanding that while the lower field strength of 1.5T is sufficient for evaluation, imaging at 3T is likely to be of higher quality. This is because 3T scanners exhibit a higher signal-to-noise ratio (SNR). However, multiple studies have shown minimal difference in outcomes between prostate MRIs conducted at 1.5T with an ERC versus 3T using only phased-array surface coils.12,13 The routine use of the ERC is still debated, particularly at 3T. Newer MRI units are capable of performing excellent prostate MRIs without the ERC, thus reducing cost, time, and patient discomfort. Nonetheless, several studies have determined that there is benefit to using ERC at 3T. Heijmink et al. found mpMRI with ERC to have better accuracy for tumor localization when compared to mpMRI with body coil.14 Turkbey et al. recently showed increased positive predictive value of 80% versus 64% for mpMRI with and without an ERC, respectively, in 20 patients who underwent radical prostatectomy.15 However, the clinical consequence of this slightly increased sensitivity with the ERC has not yet been determined. Thus, in general, better-quality scans can be obtained with ERC, and this translates to higher sensitivity and specificity; however, it is unclear whether the use of ERC is justified in terms of better patient outcomes. Eventually, it is expected that routine use of ERC will no longer be used for the reasons just mentioned. With time and technological advancement in MR technology, mpMRI with ERC may be reserved for very specific purposes – such as in local staging after histopathological diagnosis and especially in the postprostatectomy follow-up after biochemical recurrence.
Anatomic MR Imaging (T1W, T2W MRI) Anatomic MR imaging includes T1W and T2W MRI. T1W images are not used for diagnostic purposes because zonal anatomy is difficult to identify and tumors are
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Magnetic resonance imaging
typically not well seen. However, T1W images are helpful in determining if there is residual hemorrhage due to prior biopsy, which appears hyperintense on T1W images.16 It is important to identify hemorrhage prior to further sequence evaluation as hemorrhage can result in false- positive diagnoses on mpMRI. It is widely agreed that it is best to wait at least 8–10 weeks postbiopsy to reduce the chance of hemorrhagic artifact related to biopsy.17 T2W imaging offers high-resolution and excellent anatomical detail (Figure 11.1a, b). T2W imaging is acquired in axial, sagittal, and coronal views. The high clarity offered by T2W imaging allows the clinician to determine zonal anatomy. The normal PZ tends to have a higher signal, whereas the TZ has an intermediate-lower signal intensity pattern mainly due to benign hyperplasia. Cancers appear as hypointense foci within PZ and TZ, but may be more difficult to detect in the latter due to the heterogeneous background in the TZ. T2W MRI for detection of cancer is known to have a wide range of sensitivities and specificities, 27–100%, and 32–99%, respectively, but this reflects a broad range of experience, patient selection, MR quality, and diagnostic criteria.18–20 A major concern for clinicians and a motivation behind the acquisition of the T2W sequence in routine diagnosis of prostate cancer is to detect ECE (Figure 11.2). ECE is seen as a direct extension of the tumor into the periprostatic fat.21 This is important for preoperative staging since the presence of ECE would upstage a patient to Stage T3A. This could redirect a patient’s clinical management approach including altering the surgical approach or even ruling out the possibility of surgery. On MRI, indirect features of ECE include capsular bulge, broad capsular base, and border irregularity, obliteration of rectoprostatic angle, and/or capsular retraction.22 Despite the superior spatial resolution of T2W MRI, it is still limited for the evaluation of microscopic ECE with sensitivity and specificity ranges of 14.4–100% and 67–100%, respectively.23,24 Seminal vesicles, which are located superiorly at the base of the prostate, are another important structure to evaluate for accurate staging. On T2W MRI, they normally appear as hyperintense saccules due to their high fluid content. When there is seminal vesicle invasion, they often appear hypointense and may enhance after contrast media.25 MRI with an ERC has a high reported accuracy (91%) for detection of seminal vesicle invasion.26
Functional MR Imaging Diffusion Weighted MRI and Apparent Diffusion Coefficient Maps (DWI and ADC) DWI is based on the Brownian motion of free water within tissues. Cellular density increases in malignancies when compared with normal tissue. Due to the increased number of cell membranes, water diffusion is
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more restricted in the tumor site. This restriction or impedance can be noninvasively detected on DWI and can be quantified by calculating the apparent diffusion coefficient (ADC). DWI does not require contrast injection, and can be done readily in almost all clinical scanners along with T2W MRI. A meta-analysis of 5892 patients showed that DWI alone yielded higher sensitivity, specificity, and area under the ROC curve than T2W alone.27 On ADC maps, prostate cancer shows decreased signal intensity relative to normal tissue (Figure 11.1c). DWI and ADC maps demonstrate a wide range of sensitivities and specificities, 57–93.3% and 57–100%, respectively, for tumor detection.28–32 Additionally, it has been shown that the use of high b value imaging, (e.g., 1000–2000 s/mm2) also improves performance for lesion detection (Figure 11.1d).33,34 DWI is a major component of the mpMRI and has great utility for improving prostate cancer detection and management. However, it has some challenges to be addressed, as it has a lower spatial resolution and is highly susceptible to bulk motion.35 Also, air within the rectum may distort the DWI image and cause susceptibility artifacts if an ERC filled with a perfluorocarbon is not used. Improvements in technology (parallel imaging and field strength) may mitigate these technical shortcomings. Dynamic Contrast Enhanced (DCE) MRI DCE MRI uses a gadolinium-chelate-based agent injected as bolus and offers information on the vascularity of a lesion.36 Blood vessel proliferation increases in response to oxygen and nutrient deprivation as tumors surpass a few millimeters in diameter. These new vessels are tortuous and permeable in comparison to normal vessels. DCE MRI consists of a T1W gradient echo imaging prior to, during, and after intravenous bolus injection of a low molecular weight gadolinium chelate agent. The prostate imaging is acquired continuously for several minutes, and the interval between the beginning and end of each component scan is known as the temporal resolution, which typically varies from 5 s to 30 s. Shorter temporal resolution is preferred in order to image the enhancement peak after injection as early enhancement can be an indicator of a positive study. On DCE MRI, malignant lesions appear with early focal enhancement and rapid washout 37 (Figure 11.1e); however, BPH and prostatitis may also show early enhancement leading to false positives. Analysis of DCE MRI can be done qualitatively, semiquantitatively, or quantitatively. Qualitative evaluation simply includes visual assessment of serially acquired images in a video mode, and tumoral enhancement is usually characterized by rapid and early opacification (1–3 phases after the contrast arrives in the major arteries such as femoral artery) compared to its surrounding. Semiquantitative analysis mostly relies on evaluating the DCE by matching the time-signal curve to
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94 11. Imaging in Localized Prostate Cancer
FIGURE 11.1 An mpMRI was acquired at 3T with an ERC in a 58-year-old male with serum PSA = 4.46 ng/mL, DRE negative, with no prior prostate biopsy. (a, b) Axial and coronal T2W imaging shows a lesion in the right apical peripheral zone, (c) ADC maps of DWI identify the same right apical peripheral zone region with hypo-intense features, (d) b2000 shows a focal hyperenhancing region corresponding to the right apical PZ, and (e) DCE shows early focal enhancement of the right apical PZ. The lesion, located in the peripheral zone, is scored with PI-RADS Version 2.0 based on the diffusion imaging, and therefore receives a score of 4, with moderately-high level of suspicion for clinically significant prostate cancer; it is therefore recommended that the patient undergo a targeted biopsy. Following the targeted MRI/TRUS fusion-guided biopsy, histopathology confirms a Gleason 3 + 4 (60%) with perineural invasion.
I. Etiology, Pathology, and Tumor Biology
FIGURE 11.2 An mpMRI was acquired at 3T with an ERC in a 66-year-old male with serum PSA = 12.1 ng/mL, DRE negative, with one prior positive conventional prostate biopsy (Gleason 3 + 3 in the right mid peripheral zone), who was on active surveillance at the time of his mpMRI. (a) Axial T2W imaging shows a large lesion in the right midbase peripheral zone with possible ECE, (b) ADC maps of DWI show a larger hypointense area corresponding with the T2W imaging, (c) b2000 shows a focal enhancement of the suspicious region, (d) DCE shows early focal enhancement of the suspected lesion, (e) axial T2W imaging shows a possible ECE of the lesion. The lesion, located in the peripheral zone, is scored with PI-RADS Version 2.0 based on its diffusion imaging, and therefore receives a score of 5. There is a high level of suspicion for clinically significant prostate cancer and the patient requires a targeted biopsy for this reason. Following the targeted MRI/TRUS fusion-guided biopsy, histopathology confirms a Gleason 4 + 4, in 95% of the targeted core from the right midbase peripheral zone.
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96 11. Imaging in Localized Prostate Cancer one of three different curve types. Type 1 curve refers to benign enhancement pattern where there is continuous gradual enhancement, whereas Type 2 curves, wherein the signal initially increases and then plateaus, can represent inflammatory processes. Finally, Type 3 includes a rapid wash in and out of contrast material and is highly predictive of a malignant lesion. However, almost all of the curve types can be identified in any given lesion within the prostate, regardless of whether they are benign or malignant. Thus, one typically selects the “worst” curve (i.e., Type 3) to represent the DCE of the malignant lesion. This can reduce the effectiveness of DCE in distinguishing prostate cancers from other benign conditions such as inflammation or BPH. Quantitative approaches to DCE utilize a T1 map and an arterial input function (either personalized or population-based), which are integrated into a two-compartment model to calculate several quantitative parameters, such as forward and reverse contrast flow rates (Ktrans and kep, respectively). Qualitative evaluation is the most commonly used technique because it does not require special software. Compared to T2W and DWI, DCE MRI plays a relatively modest role in prostate cancer diagnosis. However, it may be beneficial in identifying recurrences in the posttreatment setting. Despite its utility, some challenges exist for DCE MRI including standardization of image acquisition protocols and analysis techniques. Patients with severe renal failure cannot receive gadolinium contrast material; hence, the use of gadolinium-contrast agents should be carefully evaluated in such patients.
MR SPECTROSCOPIC IMAGING MR spectroscopy is another functional MRI technique that aims to display certain compounds inside the prostate, such as choline and citrate, by representing the amount of signal from particular proton resonance frequencies that correspond to those compounds. MR spectroscopic imaging (MRSI) thus produces a spectrum of peaks corresponding to relevant and nonrelevant molecules. While it truly provides molecular information about the chemicals within the prostate, this technique is largely limited due to its long acquisition times, necessity for expert personnel (e.g., MR physicist), and complex processing methods. Because it utilizes a much lower spatial resolution than the other sequences previously discussed, it has a lower sensitivity due to significant partial volume effects. Therefore, it is not recommended in routine clinical practice; however, it is still used for research purposes in a limited number of centers. mpMRI is therefore a powerful imaging technique for detection and staging of prostate cancer. The most underappreciated benefit of prostate mpMRI is its strong negative predictive value. Studies have typically reported
negative predictive values of mpMRI ranging from 70% to 80%.38 The ability to rule out clinically significant disease is one of its most important features. In patients with BPH or prostatitis, who often have an elevated PSA (>4.0), PSAD (>0.15), and/or abnormal DRE, the failure to identify a prostate lesion can be highly useful in eliminating significant cancers. Without an mpMRI and a targeted biopsy approach, a patient may go on to have numerous negative biopsies. Negative MRIs give physicians confidence to minimize the number of biopsy sessions a patient undergoes over several years. In a recent study by Gupta et al., the NPV of mpMRI in detecting prostate cancer has been reported as high as 73.1% for all prostate cancer and 89.7% for ECE.39 mpMRI is a precision imaging modality that has the future potential to be tailored for personalized imaging. In case of suspicion for prostate cancer, a patient-specific mpMRI may be performed. The individual mpMRI sequences can be acquired for screening, diagnosis, staging, and follow-up. Further trials and studies will need to be performed before guidelines are established for such a practice. One important aspect of mpMRI is the adoption of a standardized reporting system. mpMRI as defined by the 2014 American College of Radiology’s Prostate Imaging Reporting and Data System (PI-RADS version 2.0) consists of evaluation of numerous MR sequences to determine a reproducible scoring system which may be readily communicated among radiologists, urologists, and their patients.40 The sequences used are 1) T2-weighted (T2W) pulse sequence for anatomic assessment,41 2) DWI and ADC maps with high-b value imaging, and 3) dynamic contrast enhanced (DCE) imaging for functional assessment.42 In PI-RADS, DWI is used primarily for the scoring of the PZ, but T2W is primarily used in the TZ due to overlap between cancer lesions and BPH nodules. The use of PI-RADS is therefore expected to improve education and communication and thereafter improve the overall utility of mpMRI in patients with suspected cancer.
PET/CT Conventional CT and mpMRI are unable to detect changes in tissue at the molecular level. These changes can be imaged by using targeted radionuclides, which are highly sensitive for detecting malignancies. Imaging of nodal and bony metastatic spread may benefit from such studies, whereas they are likely too expensive for routine use in localized prostate cancer. The current standard of care for bone metastasis is the 99mTc methyldiphosphonate (MDP) bone scan. Radiolabeled MDP agent is taken up in osteoblastic lesions seen in metastatic prostate cancer.43 Unfortunately, because it
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Conclusions
is a single photon emitter, sensitivity is less than optimal, and false-positive findings in nonmalignant conditions such as benign neoplasms, trauma, and degenerative joint disease are commonplace. Because bone scans are typically not acquired with a CT scan, it can be difficult to resolve whether a particular focus of uptake is associated with a benign condition on CT. For this reason, there has been interest in the development of 18F-sodium fluoride (18F-NaF) PET/CT as a viable alternative for detection of bone metastases. A recent study evaluated the efficacy of 18F-NaF versus that of 99mTc-bone scintigraphy in detecting bone metastases in patients with lung, breast, and prostate cancer.44 18F-sodium fluoride outperformed the bone scan in all components and had a sensitivity and NPV of 100%. However, due to a high rate of false positives, these scans must be correlated with the coregistered CT. This can be a time-consuming process, but new automated methods of detecting and eliminating benign lesions from further consideration are under development. More recently, there has been a tremendous growth in research in radiotracers for PET/CT diagnostics in localized prostate cancer. Results of studies have been published on several of these agents. 18 F-DCFBC (PSMA target), developed at Johns H opkins University (Baltimore, MD), is one such promising radiotracer. A preliminary study in five patients identified 32 PET-positive suspected metastatic sites. Out of these, 21 (65%) of the sites were positive on both PET and conventional imaging suggestive of metastatic disease, while the remaining 11 PET positive-only lesions (34%) were indeterminant but were likely to be metastatic.45 A Phase 2 clinical trial, with an enrollment of 45 patients, is now underway at the National Institutes of Health (NIH, Bethesda, MD) to determine the efficacy of 18F-DCFBC. Another related agent is 68Ga-PSMA (gallium labeled PSMA ligand). In early 2014 a comparison study from Germany reported results on 68Ga-PSMA versus 18Fcholine PET/CTs. A total of 78 lesions were detected in 32 patients using 68Ga-PSMA, and 56 lesions were detected in 26 patients using 18F-choline. The higher detection rate in 68Ga-PSMA PET/CT was statistically significant (p = 0.04).46,47 Another radiotracer unrelated to PSMA was developed at Emory University (Atlanta, GA). This agent, 18F-FACBC (radiolabeled leucine analog targeting protein metabolism), has now also been studied at multiple sites. A sector-based comparison with histopathologic analysis performed at NCI revealed sensitivity and specificity of 67 and 66%, respectively, for 18F-FACBC in patients with localized prostate cancer although the performance was inferior to T2W MRI (sensitivity and specificity at 73 and 79%, respectively). Yet the combined positive predictive value (FACBC + T2W MRI) was shown to be higher, at 82%.48,49 18 F-FDHT, targeting the androgen receptor, was created in 2004 at Memorial Sloan Kettering (New York, NY).
An initial trial by Larson and coworkers compared 18FFDHT with 18F-FDG PET. In the study, 59 lesions were found by conventional imaging. 18F-FDG PET was positive in 57 of 59 lesions (97%), while 18F-FDHT PET was positive in 46 of 59 lesions (78%).50 11 C-acetate (targeting fatty acid metabolism) for prostate cancer, first used in Japan, now also has published results from comparison studies. Mena et al. performed a sector-based comparison with histopathology, which determined a sensitivity and specificity of 61.6 and 80.0%, respectively, for 11C-acetate, and 82.3 and 95.1%, respectively, for MRI for localized disease.51,52 Finally, 18F-choline and 11C-choline (targeting increased membrane turnover) have been used in numerous studies of prostate cancer. Umbehr et al. reported a systematic meta-analysis of 10 studies for staging 637 patients with proven but untreated prostate cancer, and showed a pooled sensitivity and specificity of 84 and 79%, respectively.53 Thus, 18F-choline and 11C-choline are promising PET/CT agents for staging prostate cancer. It should be noted that 11C-choline and 11C-acetate have a half-life of only 20 min so they must be produced on site, whereas, the 18F labeled compounds have the potential to be centrally produced and shipped to various medical sites for injection. While nearly all of the aforementioned agents have shown promising early results, the question currently remains regarding which one is the best and even what metric should be utilized to better assess these agents against one another. There are numerous clinical trials currently underway to better understand the capabilities of these agents, the results of which are awaited with much anticipation.54
CONCLUSIONS The development and acceptance of precise and powerful MRI techniques has altered the diagnosis and management of localized prostate cancer. MRI is currently the most valuable imaging modality available for localized disease. mpMRI employs a combination of T2W, DWI, and DCE. T2W provides the most detailed anatomic information while DWI is the most effective functional technique and has good specificity. DCE MRI is sensitive for prostate cancer but plays a secondary role in diagnosis and characterization. Using these sequences in combination may improve initial detection and staging of clinically significant disease, and also improve targeted biopsy techniques. These advances will continue to improve both the decision-making and utility of active surveillance and focal therapies. Novel imaging techniques such as PET/CT radiotracer agents are emerging to improve the detection and staging of prostate cancer.
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98 11. Imaging in Localized Prostate Cancer
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