Novel imaging techniques for prostate cancer should improve staging and better evaluate treatment results.
Introduction
Imaging for prostate carcinoma can serve several clini-cal goals. First, it can assist in assessing the primary or recurrent tumor within the prostate gland, as well as tumor size, multifocality, extracapsular extension, seminal vesicle extension, neurovascular bundle in-volvement, and bladder involvement. Second, imag-ing can be used to assess metastatic disease such as spread to lymph nodes and bones. Third, imaging is used to guide interventions such as prostate biopsies or computed tomography (CT)-guided biopsy of sus-picious lymph nodes. Fourth, functional or metabolic imaging could potentially assess tumor aggressiveness
From the Department of Diagnostic Imaging at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Submitted January 24, 2012; accepted September 17, 2012. Address correspondence to Eric K. Outwater, MD, Department of Diagnostic Imaging, Moffitt Cancer Center, 12902 Magnolia Drive, WCB-RAD MD/OPI, Tampa, FL 33612. E-mail: Eric.Outwater@ Moffitt.org
No significant relationship exists between the authors and the companies/organizations whose products or services may be ref-erenced in this article.
The authors have disclosed that this article discusses unlabeled/ unapproved use of ferumoxytol, a contrast agent indicated for iron deficiency anemia, for lymph node imaging in prostate cancer.
Imaging of Prostate Carcinoma
Eric K. Outwater, MD, and Jaime L. Montilla-Soler, MDBackground: Imaging of prostate carcinoma is an important adjunct to clinical evaluation and prostate-specific antigen measurement for detecting metastases and tumor recurrence. In the past, the ability to assess intraprostatic tumor was limited.
Methods: Pertinent literature was reviewed to describe the capabilities and limitations of the currently available imaging techniques for assessing prostate carcinoma. Evaluation of primary tumor and metastatic disease by ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine techniques is discussed.
Results: Ultrasonography and MRI have limited usefulness for local staging of prostate cancer because of suboptimal sensitivity and specificity for identifying tumor extent and capsular penetration. Additional MRI techniques such as magnetic resonance-based perfusion imaging, diffusion imaging, and spectroscopy may provide incremental benefit. CT and bone scanning provide an assessment of metastatic disease but are also limited by the poor sensitivity of lymph node size as a criterion for detecting metastases. Novel imaging techniques such as hybrid imaging devices in the form of single-photon emission CT/CT gamma cameras, positron emission tomography/CT cameras, and, in the near future, positron emission tomography/MRI combined with tumor-specific imaging radiotracers may have a significant impact on tumor staging and treatment response. Conclusions: Cross-sectional imaging and scintigraphy have an important role in assessing prostate carcinoma metastases and treatment response. Increasingly, the incremental value of primary tumor imaging through MRI is being realized.
or other parameters that correlate with outcome, al-though such techniques have not yet entered routine clinical practice. It is hoped that these novel imag-ing methods will be superior to the current standard means in assessing mortality, tumor size, and thera-peutic response to targeted therapies. This review focuses on the main imaging methods and their use for these purposes.
The National Comprehensive Cancer Network clini-cal practice guidelines show a fairly limited role for imaging in patients with prostate carcinoma (Table 1).1 According to these guidelines, imaging is largely used to evaluate metastatic disease, with a limited role for endorectal magnetic resonance imaging (MRI) in pa-tients who have received radiation therapy but have evidence of failure by prostate-specific antigen (PSA) level. According to these recommendations, low-risk prostate cancer requires no imaging; however, actual adherence to these guidelines by urologists is highly variable.2 Many more applications and types of imag-ing have been explored, with a plethora of suggested imaging applications for the management of prostate carcinoma. Many of these, such as investigational
nuclear medicine agents, are exploratory, but others, such as endorectal MRI for initial staging, have been the focus of numerous studies.
Reports on the diagnostic performance of some of these techniques vary widely in the literature, particu-larly regarding MRI. In some respects, this resembles the decline effect3 or other statistical biases,4 but meth-odological aspects assess diagnostic performance in the prostate that may give rise to these varying results. To determine the accuracy of a diagnostic technique such as MRI in locating a tumor within the prostate, it is common to divide the prostate into multiple areas or segments and determine the presence or absence of the tumor in each segment. These results can be correlated with the absence or presence of tumor on MRI. If the prostate specimen is distorted during processing or if discordance exists between the orien-tation of the pathological specimen to MRI, then the diagnostic accuracy will be poor, not related to the actual performance of the technique.5,6 Different re-sults can be obtained, for example, when exact corre-spondence is required rather than when approximate correspondence is required.6 These methodological problems may lead to varying results and introduce bias in reported results for the diagnostic performance of MRI and for other diagnostic techniques. Turkbey et al7 found a 61% sensitivity rate for the detection of tumors larger than 3 mm in size on T2-weighted im-ages using a stringent correlation and 94% sensitivity rate for less stringent correlation. The magnitude of this discrepancy indicates that correlating imaging findings with histology is not as straightforward as one might think.
Evaluation of the Primary Tumor
Transrectal Ultrasonography
Ultrasonography is the most common method used for direct visualization of the prostate, primarily because it is indispensable to imaging-guided prostate biop-sies. Ultrasonography has the advantages of real-time imaging, portability, ease of use, and low cost. It can visualize intraprostatic zonal anatomy, with the pe-ripheral zone showing slightly increased echogenicity compared with the central gland. Prostate carcinoma typically presents as a hypoechoic area within the peripheral zone (Fig 1). However, transrectal ultra-sonography is not highly sensitive or specific for the detection of prostate carcinoma.8 Color Doppler and power Doppler imaging do not substantially add ac-curacy to the technique.9 However, vessel density as shown on color Doppler and power Doppler imaging may have prognostic importance, with high vessel densities predicting a slower rate of decline of PSA with radiation treatment.10 Similarly, transrectal ultra-sonography has limited accuracy for the detection of extraprostatic extent of tumor.11 In general, ultraso-Table 1. — Selected NCCN Clinical Practice Guidelines
for Prostate Cancer Clinical Group Indicated Imaging New diagnosis:
> 5-yr life expectancy
Bone scan if: T1 and PSA > 20 T2 and PSA > 10 Gleason score 8 T3, T4, or symptomatic Pelvic CT or MRI if:
T3, T4, or T1–T2 and nomogram indicate probability of lymph node involvement > 10%a
Rise in PSA following prostatectomy
± CT ± MRI ± Bone scan Rise in PSA following
radiation
± Abdomen/pelvis CT or MRI ± Endorectal MRI
± MR spectroscopy Bone scan
a Staging studies may not be cost effective until the likelihood of
lymph node positivity reaches 45%.
CT = computed tomography; MR = magnetic resonance;
MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen; T = tumor.
Reproduced/adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer.
V.2.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may
not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and com-plete version of the NCCN Guidelines, go online to www.NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN
GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
nography has no role in the evaluation of metastatic disease. However, ultrasonographic-guided needle biopsy of suspicious nodes found on CT or MRI is useful for confirming metastatic disease.
Ultrasonographic contrast agents can show hy-pervascularity, such as that caused by tumor angio-genesis, and can be used in transrectal ultrasonogra-phy of the prostate. However, the interpretation of the literature on contrast-enhanced ultrasonography for carcinoma detection is difficult for several rea-sons.12 Multiple contrast agents have been studied, and results may not be comparable across all contrast agents. The contrast effect on the ultrasonographic images is fleeting, and expertise is required. Further-more, studies generally compare positivity rates of directed biopsies with random biopsies rather than whole mount sections after prostatectomy. However, it seems clear that contrast-enhanced ultrasonography can improve the positivity of directed biopsies vs random biopsies. Furthermore, the additional benefit of contrast-enhanced ultrasonography is fairly mod-est.13,14 Because contrast-enhanced ultrasonography detects hypervascularity, the detected tumors tend to have higher Gleason grades and therefore are more
likely to be clinically significant.15,16 The vast majority of targeted biopsies are negative, and many tumors detected by blind biopsies are not targeted using contrast-enhanced ultrasonography.13
Elastography is a relatively new technique that measures tissue stiffness using ultrasonographic waves. Cancer tissue is generally stiffer than non-cancerous tissue and therefore is more resistant to mechanically induced vibration. Initial results have not shown high sensitivity and specificity.17,18
Magnetic Resonance Imaging
Although generally more involved and expensive than ultrasonography, MRI has the potential to provide significantly more information. Tissue properties such as diffusion, enhancement, and specific metabolites can be imaged with high resolution. In addition, a high-resolution study of the prostate can be easily combined with an examination of the abdominal and pelvic lymph node chains for comprehensive evalua-tion. A glossary of selected MRI terms are provided in Table 2.
Performing the Examination
Clinical interest in staging prostate carcinoma with MRI arose largely after the invention of the endorectal
Fig 1A-B. — Transrectal ultrasonographic imaging of prostate carcinoma (prostate-specific antigen level = 1.8 ng/mL). Biopsy showed a Gleason score of 3 + 3. (A) Transverse image reveals a slightly more echogenic peripheral zone (pz) and the carcinoma nodule (n) as a more hypoechoic focus. cg = central gland. (B) Sagittal image reveals a hypoechoic nodule (arrow). sv = seminal vesicle.
A
B
Table 2. — Glossary of Selected Terms Used in Magnetic Resonance Imaging Term Definition
Diffusion-weighted imaging
Images or a series of images that show rela-tive loss of signal intensity in tissues or fluid that has unrestricted diffusion. Frequently, an image map of the apparent diffusion coef-ficient is calculated from a set of diffusion-weighted images with increasing strengths of the diffusion encoding gradients, or b value. Dynamic
contrast-enhanced imaging
A set of fast images obtained during the injection of a contrast agent, showing uptake of the contrast agent in the prostate and tumor. Rapid arterial enhancement of tumors is typical because of angiogenesis.
Superparamagnetic Having magnet-like properties, usually due to complexes of iron, which causes dephasing (loss of coherence) and, thus, loss of signal intensity on the images. Superparamagnetic iron oxide agents reveal loss of signal on the images due to this effect.
Endorectal coil A receiver coil covered with a latex inflat-able balloon and placed in the rectum to lie adjacent to the prostate to optimize the signal from the prostate, allowing higher-resolution images of the prostate.
Phased-array coils (multicoils)
A set of receiver coils that detects the magnetic resonance signal. These are placed in a rigid or flexible platform set directly on the patient anterior and posterior to the pelvis used in combination with the endorectal coil (or as a substitute for it).
coil, which permitted high-resolution images of the prostate.19 Higher signal-to-noise images, high resolu-tion images, or both can be obtained with the use of the endorectal coil, phased-array coils, or high-field imaging with 3 Tesla magnets, or any combination of these (Fig 2). Imaging without the endorectal coil will not provide the best possible examination for staging purposes, but it may be suitable for certain clinical situations.
To perform a standard examination, the patient is placed on his side on the MRI table, and the en-dorectal coil is slid into place in the rectum. The coil is anteriorly oriented to receive a signal from the prostate. The patient is turned on his back, and an antiperistaltic agent such as glucagon is often intra-venously administered. Phased-array coils are placed against the skin anterior and posterior to the patient, and the table is slid into the MRI magnet.
Multiple images of different types, or series, are obtained on multiple planes. These typically include
T1-weighted images of the abdomen and pelvis for lymph node disease. Smaller field-of-view (higher res-olution) T1-weighted images, and T2-weighted images on multiple planes (coronal, axial, and sagittal) are also obtained. Additional sequences can include diffusion-weighted imaging, dynamic contrast-enhanced (DCE) imaging, and magnetic resonance spectroscopy.
Diffusion-weighted imaging is typically performed using echoplanar fast imaging with diffusion-encoding gradients in three directions. These gradients degrade the signal intensity of water moving in the direction of the gradient, and using gradients in three directions diminishes the signal in any direction. Therefore, the tissue has a lower signal from water motion due to perfusion and diffusion. Acquiring two or more sets of images with increasing gradient strength allows a calculated apparent diffusion coefficient (ADC) map; by necessity, these images are low resolution.
DCE images are fast, fat-saturated, T1-weighted images obtained during and after the administration of an intravenous contrast agent (eg, gadopentetate). These rapid images reveal the arrival of the contrast to the vessels and tissues as increased signal inten-sity, which will sequentially reflect the arterial arrival of the contrast, venous perfusion, uptake in the tis-sue interstitium, and the subsequent washout from these compartments. Such images may be acquired at several time points for qualitative assessment and at many time points for quantitative analysis. Addi-tional acquisitions may also include magnetic reso-nance spectroscopy. A complete examination usually takes 45 minutes.
Anatomy of the Prostate
The most important anatomical features of the pros-tate are shown in T2-weighted images (Fig 3). The central gland of the prostate includes the periurethral and transitional zones, generally with lower signal intensity than the peripheral zone.20 The signal in-tensity of the peripheral zone is generally high on T2-weighted images largely due to glandular fluid; by contrast, the signal intensity of the central gland is variable and highly dependent on the amount and characteristics of any present benign prostatic hyper-trophy.20 The anterior central gland appears as low signal intensity, the anterior fibromuscular stroma. A low signal intensity line, the prostatic capsule, limits the peripheral zone. Neurovascular bundles can be identified as a group of vessels posterolateral to the prostatic capsule on either side.
Seminal vesicles appear as high-signal-intensity, grape-like clusters of tubules that reveal low-signal intensity smooth muscle walls (Fig 3).20 This appear-ance is due to the high-signal-intensity folded mucosa filling the lumen with pockets of fluid. The ampullae of the vas deferens can be identified as well as the Fig 2A-B. — Imaging of the prostate with and without endorectal coil. (A)
Transverse image of the prostate performed with phased-array coils with-out an endorectal coil reveals adequate differentiation of the central gland (cg), peripheral zone (pz), and the tumor nodule (n). However, visualization of the prostatic capsule near the tumor is poor (arrow). (B) Transverse image of the prostate with the endorectal coil shows the central gland (cg), peripheral zone (pz), and tumor nodule (n), with better visualization of the prostatic capsule near the tumor (arrow).
A
ejaculatory ducts.20,21 The low-signal intensity bladder wall can also be seen. Periprostatic structures such as veins, puborectalis and pubococcygeal muscles, and lymph nodes will also be visible.21
Prostate Cancer Imaging
Prostate carcinoma appears on MRI as intermediate-signal intensity (gray) on T2-weighted images (Fig 2). Because the peripheral zone normally has high-signal
intensity (bright), carcinomas are generally clearly visible in the peripheral zone. Conversely, because the signal intensity of the central gland is variable and generally low or intermediate, tumors are not well visualized in this area. On diffusion-weighted images, prostate carcinoma has low-signal intensity, which reflects restricted diffusion (Fig 4) that often correlates with the degree of cellularity, macromolecular density, or fibrous tissue. Diffusion imaging may also assist
Fig 3A-D. — Prostate anatomy on endorectal coil magnetic resonance imaging. (A) Transverse image at the midprostate reveals high-signal intensity (brighter) in the peripheral zone (pz), low-signal intensity (darker) in the central gland (cg) with several scattered benign prostatic hyperplasia (BPH) nodules, and prostatic capsule (arrowhead), the neurovascular bundles (thick black arrows), urethra (thin black arrow) and the rectal wall (white arrow). (B) Coronal image of the prostate shows a high-signal intensity peripheral zone and a low-signal intensity central gland with the prostatic capsule (thick white arrows). The irregular ampulla of the vas deferens are visible (thin white arrows), as well as the prostatic urethra and verumontanum (black arrow). (C) Sagittal view of the prostate reveals the central gland (cg) with BPH producing a prominent subtrigonal nodule (stn) that protrudes into the bladder, a variant appearance of BPH. The peripheral zone (pz) has a higher signal intensity. The seminal vesicles and vas deferens lie superiorly (black arrow). White arrows denote the membranous urethra. (D) Transverse image of the seminal vesicles (black arrows) shows high-signal intensity lumens surrounded by the low-signal intensity walls. The ampullae of the vas deferens (white arrowheads) are visible as well as the low-signal intensity bladder wall (black arrowhead). The central subtrigonal nodule of the prostate is noted (stn).
A B
in differentiating between hemorrhage and tumor in the peripheral zone.22 The enhancement of prostatic tumors is somewhat variable; however, tumors typi-cally enhance more rapidly and to a greater degree than the peripheral zone normal tissue. Therefore, they may be best displayed on an early arterial phase image (Fig 5). Increased or more rapid contrast en-hancement correlates with microvascular density in the prostate tumor.23
Extracapsular extension, when gross, is mani-fested by protrusion of the intermediate-signal in-tensity tumors through the prostate capsule. More subtle capsular penetration may be manifested by a tumor that abuts the capsule over a wide area, capsu-lar thickening, noducapsu-larity or bulging of the capsule, or irregularity (Fig 6).24 Seminal vesicle invasion is
manifested by a low-signal intensity tumor, replacing the high-signal intensity seminal vesicle lumens, the mucosa, or both.25 Similarly, bladder wall invasion will be manifested by intermediate-signal intensity on T2-weighted images or enhancing tissue interrupting the low-signal intensity bladder wall.
Magnetic Resonance Spectroscopy
Spectroscopy is a magnetic resonance technique to assess the presence of metabolites in tissue. Proton spectroscopy can detect certain hydrogen-containing metabolites in the prostate such as choline, creatinine, and citrate. The normal prostate gland produces high levels of citrate and low levels of choline. Because of phospholipid metabolism and higher cell membrane turnover, prostate cancer has higher levels of choline.
Fig 4A-D. — Typical appearance of prostate carcinoma on magnetic resonance imaging. Subsequent biopsy revealed a Gleason score of 4 + 4. (A) T1-weighted image shows homogeneous low signal of the prostate (p), with no discrimination of the central and peripheral gland. The tumor nodule is not seen because no tissue contrast is present between the tumor and peripheral zone. The neurovascular bundles (black arrows) are seen laterally. (B) T2-weighted image shows the lower-signal intensity tumor (n) compared to the curve from zone on either side. (C) Coronal image shows the tumor nodule (n) with the adjoining apical prostatic capsule shown (arrow). (D) Early-phase gadolinium chelate-enhanced sections from a fast 3-dimensional gradient echo sequence show rapid intense enhancement of the tumor nodule (n), manifested by brighter signal intensity in the rest of the prostate, with tumor extending laterally to greater extent than is apparent on the T2-weighted image.
A B
Fig 5A-C. — Prostatic carcinoma on magnetic resonance imaging with dif-fusion-weighted imaging of a patient with a prostate-specific antigen level of 3.1 ng/mL. Subsequent biopsy revealed a Gleason score of 3 + 4 with extracapsular extension. (A) T2-weighted and rectal coil image reveals a tumor nodule (n) contrasted with a higher-signal intensity peripheral zone. The central gland (cg) is expanded by benign prostatis hyperplasia, which has a lower signal intensity. (B) Apparent diffusion coefficient (ADC) map of the prostate reveals that the tumor nodule (n) has a lower signal intensity than the peripheral zone or the central gland (cg). Low signal intensity indi-cates that the ADC is lower than that of water and the water diffusion within the tumor is restricted. The ADC map is calculated from a set of three images at the same level (not shown) and performed with three different magnitudes of strength of diffusion-encoding gradients. (C) Early-phase gadolinium chelate-enhanced slice from a fast 3-dimensional gradient-echo sequence reveals rapid, intense enhancement of the tumor nodule (n). Portions of the central gland (cg) also reveal rapid enhancement. Note: Multiparametric imaging refers to the characteristics of abnormalities on all three sets of images.
A
B
C
Fig 6A-C. — Typical enhancement characteristics of a tumor on dynamic contrast-enhanced images in a patient with a prostate-specific antigen level of 15 ng/mL. Biopsy showed a Gleason score of 4 + 4. (A) Transverse T2-weighted image reveals a tumor nodule (n) involving both the central gland and the peripheral zone on the right side of the prostate. The arrow points to the capsular involvement on the right. (B) Early-phase gadolinium chelate-enhanced slice from a fast 3-dimensional gradient-echo sequence reveals a rapid, intense enhancement of the tumor nodule (n) on the right side of the prostate. (C) Late-phase enhanced T1-weighted image reveals the tumor nodule (n) with a lower signal intensity, indicating washout of the contrast compared with the rest of the prostate. Typically, a tumor dem-onstrates early enhancement and early washout (as shown in this case).
A
B
The ratio of choline to citrate is increased in patients with cancer. At 1.5 Tesla, the spectroscopic peaks of choline overlap with creatinine; however, these can be resolved at 3 Tesla.
Magnetic resonance spectroscopy of the prostate can be performed with a 3-dimensional (3D) water and lipid suppressed, double-spin-echo point-resolved spectroscopy sequence; however, 3D magnetic reso-nance spectroscopy is time consuming and technically challenging. Adequate water and lipids suppression is necessary to exclude contamination from tissue outside the prostate. Data sets are typically acquired with 16 × 8 × 8 phase-encoded spectral arrays. The magnetic resonance spectra can be displayed as an rectangular array from the individual voxels.
Multiple studies have suggested improved detec-tion, localizadetec-tion, and staging with magnetic resonance spectroscopy.6,26-28 However, a multisite prospective trial showed no benefit of magnetic resonance spec-troscopy compared with MRI alone for tumor identifi-cation and compared with sextant localization on the prostatectomy specimens.29 It is not clear whether the results of this study represent inherent limitations of magnetic resonance spectroscopy for the localiza-tion of prostate cancer or difficulties in a technically demanding technique with a multicenter trial design. Accuracy of Staging
The reported sensitivity and specificity for prostate carcinoma staging vary from high to low, and it is difficult to determine the most appropriate figures to use.30-32 Studies commonly vary in patient population, particularly regarding the Gleason grading spectrum of patients or PSA levels, as well as in techniques or pulse sequences used (eg, diffusion imaging, dynamic-enhanced imaging), without standardization for coils (eg, endorectal or body coils), or field strength. Fur-thermore, the vast majority are single institutional and retrospective studies, which are prone to bias and can be insufficiently powered. Finally, methodological problems exist with mapping tumors or sites of cap-sular penetration to precise sites on any prostatectomy specimens to determine imaging accuracy.5
Results from a multicenter prospective trial dem-onstrated limited accuracy of MRI in locating the pros-tate tumor.29 One would expect that the accuracy for staging would be even lower. Several generalities can be stated regarding the accuracy of MR staging. First, the accuracy for extracapsular extension is prob-ably between 70% and 80%, while the identification of seminal vesicle invasion is more accurate.24,30,33-36 Second, MRI at 3 Tesla is probably superior to MRI at 1.5 Tesla.33,37 Third, diffusion-weighted and DCE imaging may provide small incremental increases in accuracy.6,7,33 Fourth, MRI probably provides a small incremental increase in accuracy over clinical
nomo-grams based on PSA, digital rectal examination, and Gleason grade, among others.38 Fifth, MRI is more accurate in patients at intermediate or high risk, but it is less accurate in patients with low-volume tumors and low Gleason grades.39 The detection rate of tu-mors is also dependent on size, with tutu-mors smaller than 2 cm unlikely to be detected.40
Multiparametric imaging, or the integration of various sequences such as diffusion, DCE, and T2-weighted imaging, may provide higher accuracy.6,33 However, how these varying data are combined for optimal accuracy is not clear.
Evaluation of Prostate Cancer Metastases
Patients with prostate carcinoma are evaluated for possible metastatic disease if they fall into a high-risk group with a new diagnosis or after biochemical failure following prostatectomy, radiation treatment, or local therapy.
Computed Tomography
CT is an important part of the management of prostate carcinoma. CT scanning provides a quick evalua-tion for metastases in the chest, abdomen, or pelvis. It is efficient at identifying enlarged lymph nodes, although lymph node enlargement is not highly sen-sitive and not entirely specific for lymph node me-tastases.41,42 Since CT provides poor tissue contrast within the prostate itself, evaluation of the intrapros-tatic tumor is limited.
CT scanning can detect bone metastases, particu-larly those that are osteoblastic; therefore, it is useful in patients at high risk of metastatic spread on initial evaluation or with suspected progression after pros-tatectomy or radiation treatment. It is also useful in patients with identified metastases to monitor the effectiveness of therapy.
Because lymph node size is not sensitive or spe-cific for metastasis in patients with prostate carci-noma, there is no one size criterion that is highly ac-curate. A commonly used criterion is a pelvic lymph node smaller than 10 mm but 8 mm or larger in size (if round in shape) or 10 mm or larger in size (if oval in shape). Using this criterion with contemporary scan-ners, one study found a sensitivity rate of 34% and a specificity rate of 97% for the detection of lymph node metastases.43 If CT is used to evaluate for lymph node metastases, suspicious nodes are generally subjected to fine-needle aspiration for confirmation, which can produce false-negative results. For these reasons, CT is recommended with a very high pretest probability of metastatic disease (Table 1).1
Magnetic Resonance Imaging
MRI can survey for metastatic disease similar to CT of the lymph nodes and skeletal structures. MRI of the
abdomen and pelvis is used to evaluate for lymphade-nopathy, bone metastases, and metastases elsewhere, but it is generally more time consuming and more expensive than CT scanning while providing similar diagnostic information.
Recent developments exist to provide a more spe-cific evaluation of lymph node metastases than an assessment based solely on size. Diffusion-weighted imaging of lymph nodes may be a more specific as-sessment than size criteria.44 Metastatic lymph nodes demonstrate a lower apparent ADC than benign lymph nodes,14,15 presumably reflecting greater cell density in lymph nodes with metastatic tumor. DCE properties of lymph nodes differ between normal and metastatic lymph nodes in that lymph nodes with metastases show stronger and more rapid enhancement.45
Another innovation in lymph node imaging us-ing MRI has been the development of superparamag-netic contrast agents with preferential lymph node uptake. These agents accumulate in normal lymph nodes, causing losses of signal intensity within these lymph nodes on imaging. Conversely, lymph nodes with metastases within them do not accumulate the agents in the metastatic portion and do not lose signal intensity, or, conversely, they will lose signal intensity in the normal part of the lymph node. A large trial of men with intermediate or high risk of having nodal metastases compared this MR contrast agent with CT showed 82% sensitivity for lymph node metastases vs 34% for CT.38 This could obviate the need for lymph node dissection in patients with a negative MRI.43
Because an MRI examination using a lympho-tropic agent reveals all the lymph nodes in the pelvis, it can reveal metastatic lymph nodes outside the nor-mal range of the pelvic lymph node dissection chains. For example, in a study of 296 men with prostate
cancer, MRI with a superparamagnetic agent revealed lymph nodes outside of the pelvic lymph node dis-section in 18 of the 44 patients (44%) with positive lymph node metastases.46 Currently, no approved superparamagnetic contrast agent exists in the United States for lymph node imaging. An off-label use of ferumoxytol, an agent indicated for iron deficiency anemia, is being investigated for lymph node imaging in prostate cancer, as it has similar properties to pre-viously investigated contrast agents (NCT01296139). MRI is sensitive for bone metastases (Fig 7). An MRI technique for skeletal imaging, as well as other organs to some extent, is termed whole-body MRI and most of the skeleton is revealed, comparable with bone scintigraphy or positron emission tomog-raphy (PET)/CT. Methods of evaluating for bone metastases by MRI include T1-weighted sequences, short TI inversion recovery imaging, and diffusion-weighted imaging. Large field-of-view coronal images can quickly image the chest, abdomen, and pelvis for bone metastases and lymph node metastases with short TI inversion recovery imaging or diffusion-weighted images. These survey examinations may be more sensitive than PET/CT or scintigraphy in identifying metastases.47,48 Diffusion-weighted im-ages using weak diffusion gradient strength are simi-lar in performance.49
Nuclear Medicine
The use of scintigraphic (nuclear medicine) exami-nations for the evaluation of prostate cancer is usu-ally reserved for patients with suspected osteoblastic skeletal metastatic disease or those with a rising PSA assay level without demonstrable bulky distant metastatic disease or skeletal metastatic disease fol-lowing prostatectomy.
Fig 7A-E. — Nuclear medicine evaluation of prostate carcinoma metastases. (A) Technetium 99m hydroxymethylene diphosphonate bone scan shows skeletal uptake of the tracer but no evidence of metastases. (B) 18F-sodium fluoride positron emission tomography scan performed 18 months later reveals
uptake in numerous sites, including the L4 and L5 vertebral bodies. (C) Sagittal reformatted image from the 18F-sodium fluoride PET scan reveals uptake
in the vertebral bodies (arrows). (D) 111In-capromab pendetide scan (sagittal reformatted image) shows no discernible uptake in the metastases. (E)
T1-weighted sagittal magnetic resonance imaging reveals bone marrow metastases in L4 and L5 (arrows).
In patients with suspected osteoblastic skeletal metastatic disease, nuclear medicine currently offers the option of gamma emitters, such as technetium-99m (99mTc) linked to a radioligand — in this case, a “bone-seeking” agent, such as methylene diphospho-nate or hydroxymethylene diphosphodiphospho-nate. Imaging of such radiotracers is performed using gamma cameras in the single detector (head), dual-head, or triple-head configuration. In the last 10 years, hybrid nuclear medicine–CT camera systems have become available that combine a diagnostic quality CT gantry with a dual-headed gamma camera system. These systems provide the option of obtaining a nuclear medicine tomographic examination (single-photon emission computed tomography [SPECT]) registered to a co-acquired low (nondiagnostic) or high radiographic dose (diagnostic) CT for localization purposes.
The major drawback of the radiotracers used for skeletal scintigraphy (bone scan) is low specificity. Inflammatory processes such as degenerative joint disease and osteoarthritis can demonstrate signifi-cant uptake. Certainly other active inflammatory pro-cesses, such as autoimmune propro-cesses, can also have increased uptake. Infectious or reparative processes involving the bone can also have increased uptake.
The above-discussed radiotracer primarily depos-its within the cortical bone through chemoabsorption. This radiotracer deposits in areas of bone deposition; therefore, these examinations demonstrate areas of osteoblastic response to tumoral deposits in bone, not deposition within the tumor tissue. Sensitivity for detection of osteoblastic activity related to metastatic prostate cancer can reach a rate of 95% in patients with PSA levels above 20 ng/mL.50-52 In cases where a rising PSA level is present following prostatectomy and negative skeletal scintigraphic findings, the likeli-hood of soft-tissue metastatic disease increases.
Skeletal scintigraphy is mainly reserved for pa-tients with high-risk cancer, elevated serum alkaline phosphatase levels, bone pain, or equivocal osseous lesions on other imaging modalities.53,54
Prior studies have demonstrated the relationship of increased incidence of skeletal metastatic disease with elevated PSA levels.50-52 The flare phenomenon, which refers to evidence of increasing osteoblastic metastatic disease (worsening of bone scan appear-ance) following therapy, with decreasing symptom-atology has been previously described.54-58 It is vis-ible in patients with prostate carcinoma metastatic to the skeleton, observable in 20% to 25% of scans if obtained soon after therapy has been instituted.56-58 Because of this paradoxical worsening of scintigraph-ic appearance in patients with favorably responding metastatic disease, skeletal scintigraphy is not the only test for the evaluation of such patients. Bone scans are useful for the evaluation of patients with
diagnosed prostate cancer with a rising or elevated PSA level, patients with normal PSA levels following hormonal therapy, or patients who have a normal PSA level but are symptomatic.
Bone scans using planar and tomographic tech-niques have adequate sensitivity and specificity rates and have been the main tool utilized for many years. However, tumor detection using novel radiotracers and newer imaging techniques may prove advantageous in the future. Novel radiotracers such as positron emit-ters (eg, 18F-fluoride [NaF]), as well as PET or PET/CT and PET/MRI techniques, may prove indispensable in the evaluation of metastatic skeletal disease. In malig-nant bone lesions, NaF reflects the increase in regional blood flow and skeletal turnover associated with meta-static osteoblastic deposits (Fig 7). NaF PET/CT has been shown to be more sensitive for the detection of metastases than 99mTc methylene diphosphonate bone scans. The use of hybrid imaging techniques such as PET/CT reduces the risk of false-positive findings and improves specificity of abnormalities detected by virtue of the imaging capabilities for lesion-by-lesion characterization using CT (Fig 7).59
In a recent study that reviewed the use of 99mTc methylene diphosphonate and NaF, a direct compari-son was made using whole-body planar images and tomographic (SPECT) bone scans as well as PET alone and PET/CT NaF for the detection and characterization of skeletal metastases in 44 patients with high-risk prostate cancer.59 In this study, whole-body planar imaging had sensitivity and specificity rates of 57%. Conversely, whole-body planar plus SPECT was 78% sensitive and 67% specific. 18F PET was 100% sensi-tive and 62% specific, whereas 18F PET/CT was 100% sensitive and 100% specific. Conversely, fludeoxyglu-cose 18F PET for the detection of prostate carcinoma skeletal metastases had a low yield with a sensitivity of less than 20% compared with skeletal scintigraphy.60 Soft-Tissue/Lymph Node Metastatic Disease Evaluation Molecular imaging techniques, such as the use of 111In capromab pendetide, allow for the evaluation of suspected metastatic prostatic carcinoma outside of the prostate bed, particularly the pelvic sidewall and retroperitoneal lymph nodes. 111In capromab pendetide consists of a murine monoclonal antibody (7D11-C5.3) covalently jointed to a liner-chelator mol-ecule. It is directed against the intracellular domain of prostate-specific membrane antigen (PSMA) expressed on the surface of prostate cancer metastases as well as the normal prostatic tissue. It is also expressed in other tissue types, such as the kidney, liver, bowel, and brain. PSMA is upregulated in hormone-resistant states and in metastatic disease, which is why it is used for the detection of extraprostatic, bone-scan- negative metastatic disease.
These molecular imaging techniques involve mul-tiday examinations, and time is allowed for the ra-diopharmaceutical to circulate in the blood pool and migrate to the targeted metastatic foci. Usual imaging protocols call for dosing on day 0, with imaging per-formed on day 4, day 5, or both (96 and/or 120 hours after injection). Imaging techniques available include the use of planar gamma camera images, evaluating the whole body from an anterior and posterior projection, as well as tomographic images obtained using SPECT or SPECT/CT camera systems. However, with all the advanced imaging systems used, the sensitivity rate ranges from 62% to 75% (Fig 7).61-63 This technique is also limited by nonspecific uptake in bowel, vas-culature, bone marrow, and normal prostatic tissues, and it has a low sensitivity rate for low-tumor-burden prostate fossa disease as well as small metastases. Novel Radiotracer
Novel radiotracers in different stages of research eval-uation include positron emitters such as 11C-acetate and 11C-choline.
Malignant transformation within the prostate cells leads to a change in intracellular metabolic processes, which result in a change from citrate-producing nor-mal cells to citrate-oxidizing neoplastic cells, thereby leading to an increased acetate turnover with increased expression of fatty acid synthase. Hence, increased anabolic metabolism is associated with cytoplasmic lipid synthesis. Imaging with acetate-linked radiotrac-ers benefits from this process.
Early studies using dedicated PET imaging sys-tems comparing the use of fludeoxyglucose 18F and 11C-acetate for the evaluation of recurrent prostate carcinoma showed promise when used to detect metastatic disease over the use of fludeoxyglucose 18F alone, which had limited sensitivity and specific-ity rates (Fig 8). However, a study by Oyama et al64 showed a statistical difference in the detection of re-current disease in patients with elevated PSA levels above 3 ng/mL but limited results in patients with PSA levels of 3 ng/mL or below. 11C-acetate PET was shown to have a sensitivity rate of 59% compared with a sensitivity rate of 17% for fludeoxyglucose 18F PET.
Fig 8A-B. — Comparison of fludeoxyglucose 18F and 18F-acetate positron emission tomography scans. (A) Normal scan. (B) 18F-acetate examination of the
same patient reveals prostate carcinoma metastases within the pelvic nodal stations. From Yu EY, Muzi M, Hackenbracht JA, et al. C11-acetate and F-18 FDG PET for men with prostate cancer bone metastases: relative findings and response to therapy. Clin Nucl Med. 2011;36(3):192-198. Reprinted with permission by Wolters Kluwer Health.
A Pre-RX PSA 432 B Post-RX PSA < 1
FDG PET Acetate PET
Of note, this study used stand-alone PET imaging systems. In one report, Fricke et al65 noted a higher rate of overall lesion detection with acetate (83%) compared with fludeoxyglucose 18F (75%).
In a recent pilot study by Yu et al66 involving 8 participants, conventional skeletal scintigraphy was compared with 99mTc methydiphosphonate, fludeoxy-glucose 18F, and 11C-acetate in the detection of skel-etal metastases and follow-up after therapy. Acetate PET generally detected more metastases and had a higher ratio of tumor-to-normal uptake. These results indicate that acetate PET holds promise for response assessment of prostate cancer skeletal metastases; it
was also complementary to fludeoxyglucose 18F in the detection of bone metastasis.
11C- and 18F-labeled choline derivatives have been used to detect primary or relapsing prostate carci-noma based on increased levels of phosphorylcholine, upregulated enzymes of choline metabolism, choline kinase with increased phosphatidylcholine turn-over, and the metabolic flux of radiolabeled choline through phospholipid biosynthesis and degradation in prostate carcinoma.67 This uptake is unrelated to proliferation (Ki67). Several authors68-70 have shown that 11C-choline is taken up by prostate carcinoma and its nodal and distant metastases (Fig 9).
In a recent study using hybrid imaging (PET/CT), Reske et al71 investigated the ability of 11C-choline contrast-enhanced PET/CT for the evaluation of pros-tatic carcinoma and differentiation of prospros-tatic cancer tissue from normal prostate tissue, benign prostate hyperplasia, and focal chronic prostatitis. The authors concluded that 11C-choline PET/CT accurately located and detected major areas of prostate carcinoma within the prostate gland and differentiated segments with prostate cancer from those with chronic prostatitis, benign hyperplasia, or normal prostatic tissue (Fig 10).
A study that compared 11C-choline and 11C-acetate PET in 10 patients with residual or recurrent prostate cancer showed similar detection rates for local tumor, lymph node, and skeletal metastases, but only in pa-tients with high PSA levels.70 In those with low PSA levels, studies performed thus far have shown low to moderate sensitivity in detection of local residual or Fig 9. — Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid image of a
patient with extensive prostate carcinoma (arrowheads) with involved bilater-al obturator (open arrows) and left iliac lymph nodes (solid straight arrows). Urinary activity is minimal and not present on the image (curved arrow at bladder location). From Schuster DM, Votaw JR, Nieh PT, et al. Initial experi-ence 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. Re-printed by permission of the Society of Nuclear Medicine.
Fig 10A-B. — Focal (A) and multifocal (B) distribution of prostate carcinoma within the prostate gland (arrows). Scatter plots of the segmental 11C-choline
maximal standardized uptake value reveal higher 11C-choline maximal standardized uptake values in most segments with prostate carcinoma compared with
segments with benign histopathological lesions. From Reske SN, Blumstein NM, Neumaier B, et al. Imaging prostate cancer with 11C-choline PET/CT.
J Nucl Med. 2006;47(8):1249-1254. Reprinted by permission of the Society of Nuclear Medicine.
7.5 5.0 0.0 Benign SUV max PCa 2.5 7.5 5.0 0.0 Benign SUV max PCa 2.5 A B
recurrent tumor. Similarly, these studies have shown moderate sensitivity in the detection of distant meta-static disease.72,73 In a recent study, Vees et al74 evalu-ated 20 patients with early-stage prostate carcinoma staging after prostatectomy with low PSA levels (< 1 ng/mL) for the presence of local or metastatic prostate carcinoma with 18F-choline, 11C-acetate, or both. Two of the 20 patients were evaluated with both radiotrac-ers. Both radiopharmaceuticals detected the presence of neoplastic disease in 50% of the participants.
Other radiopharmaceuticals being evaluated in-clude 11C-methionine, 18F-fluoro-5-dihydrotestosterone, and anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (Fig 9).75
Evaluation of the Prostate or Surgical Site Following Therapy
MRI and sonography are two methods used to evalu-ate for local recurrence following local therapy or prostatectomy. PET and CT scanning are not accurate methods for identifying recurrent tumor.76,77
Ultrasonography
Following prostatectomy in the surgical bed, transrec-tal ultrasonography may detect recurrence of pros-tate carcinoma.78 Recurrences appear as ill-defined hypoechoic lesions in the bladder neck or at the anastomosis.79 Power Doppler imaging and contrast enhancement may improve the sensitivity of
ultraso-Fig 11A-D. — Recurrent tumor following radical prostatectomy (prostate-specific antigen level = 4.8 ng/mL). (A) Sagittal T2-weighted image reveals low-signal intensity soft tissue (thick arrow) posterior to the urethrovesical anastomosis (thin arrow). b = bladder. (B) Transverse T2-weighted image of the bladder lumen reveals the low-signal intensity soft tissue (thick arrow) involving the rectum muscularis posterior kidney urethrovesical anastomosis (thin arrow). (C) Early-phase gadolinium chelate-enhanced image shows a rapidly enhancing tumor nodule (arrow) that appears as a higher signal intensity plaquelike lesion involving the rectum muscularis propria. The other structures, which are low in signal intensity, including the urethrovesical anastomosis, on the T2-weighted image are not rapidly enhancing. (D) Early-phase gadolinium chelate-enhanced image at a higher level through the retained seminal vesicles reveals the right-retained seminal vesicle with diffuse enhancement (arrow), which was subsequently proven to be a recurrent tumor. By contrast, the left seminal vesicle (sv) does not contain a recurrent tumor.
A B
nography in identifying recurrent tumor.80 However, biopsies of the surgical site are still more sensitive than ultrasonographic imaging.81
Ultrasonography and Doppler imaging of the prostate following local therapy (eg, cryosurgery,
Fig 12A-C. — Recurrent tumor with magnetic resonance imaging follow-ing brachytherapy with radiation seed implants (prostate-specific antigen level = 1.2 ng/mL). (A) T1-weighted image with a rectal coil through the prostate that has numerous low-signal intensity foci representing an artifact arising from the individual radiation seeds. (B) T2-weighted image reveals diffuse low-signal intensity throughout the prostate with poor discrimina-tion between the central gland and peripheral zone. No definite tumor can be identified, although the central gland is slightly higher in signal intensity. The radiation seeds identified are less apparent because fewer artifacts are visible on the image. (C) An early dynamic contrast-enhanced study reveals focal enhancement within the central gland (between arrows) that was sub-sequently demonstrated to represent recurrent tumor.
A
B
C
brachytherapy) may have little role in identifying re-sidual tumor. Contrast-enhanced ultrasonography may have increased sensitivity and specificity and may help in evaluating the degree of ablation in local therapies by distinguishing between vascularized and nonvascularized (ie, ablated) tissue.82
Magnetic Resonance Imaging
Following total prostatectomy, MRI can detect recur-rence in the prostatic bed. The usual appearance after radical prostatectomy includes a descended bladder neck in the prostatectomy space with a small amount of fibrotic tissue around the urethrovesical anastomosis. Linear scarring may be present at the expected former site of the seminal vesicles.83 T2-weighted images can detect recurrence as a higher signal intensity nodule compared with the surround-ing fibrosis and smooth muscle of the bladder neck, urethra, and urethrovesical anastomosis.84 Sensitivity rates of 95% and specificity rates of 100% have been reported for MRI.84 DCE images may increase sen-sitivity and identify enhancing nodules of recurrent tumor (Fig 11).85,86
Following hormonal deprivation therapy, the prostate becomes smaller in size with diminished signal intensity of the peripheral zone, so tumors are more difficult to localize on T2-weighted images.87 As a result of apoptosis, androgen-deprivation therapies may cause atrophy of the prostatic epithelium.26
The histologic changes in the prostate caused by external beam irradiation include glandular atrophy, inflammation, prostate shrinkage, and fibrosis.88 After external beam radiation therapy, the peripheral zone generally loses signal intensity on T2-weighted imag-ing,89 which can effectively render most carcinomas difficult or impossible to identify on standard MRI following radiation therapy. Similar effects are vis-ible using brachytherapy with radiation seeds. Diffu-sion-weighted imaging or DCE imaging may increase sensitivity in the irradiated prostate for the presence of cancer.90 On diffusion-weighted or ADC imaging, carcinoma generally appears as a more restricted dif-fusion than the remainder of the prostate gland. MRI may detect residual or recurrent tumor in patients treated with high-intensity focused ultrasonography.91 DCE images are more sensitive than T2-weighted im-ages to tumor recurrence (Fig 12).91,92
Similar to the effects on T2-weighted images with external beam therapy, spectroscopic results also change with radiation. The citrate levels tend to decrease after radiation in nontumorous prostate and choline levels increase, causing confusion with a tumor. Nonetheless, spectroscopy can identify some patients with residual tumor after radiation, although reported accuracies are not as high as those seen in patients with untreated prostate cancer.27,93
Conclusions
Local staging of the prostate tumor is limited in ultra-sonography and magnetic resonance imaging; both techniques provide suboptimal sensitivity and speci-ficity for tumor identification and capsular penetra-tion. Additional magnetic resonance imaging tech-niques such as dynamic contrast-enhanced imaging, diffusion imaging, and spectroscopy may provide in-cremental benefit; however, none of these are highly sensitive. Computed tomography and bone scans are used to assess metastatic disease, but both techniques are limited by the poor sensitivity of lymph node size as a criterion for detecting metastases.
Accepted methodologies for evaluating metastatic prostate carcinoma to the skeletal system and soft tissues include skeletal scintigraphy (bone scan) and monoclonal antibody imaging that targets prostate-specific membrane antigen. However, novel imaging techniques such as hybrid imaging devices in the form of single-photon emission computed tomogra-phy/computed tomographic gamma cameras, posi-tron emission/computed tomographic cameras, and, in the near future, positron emission tomography/ magnetic resonance imaging combined with tumor-specific imaging radiotracers may significantly and favorably affect tumor staging, the accuracy of therapy response, and patient care.
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