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Imaging Prostate Cancer: A Multidisciplinary Perspective¹

¹ From the Departments of Radiology (H.H.) and Urology (P.T.S.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, C-278, New York, NY 10021; Molecular Imaging Program, National Cancer Institutes Center for Cancer Research, Bethesda, Md (P.L.C.); Department of Radiology, University of New Mexico School of Medicine, Albuquerque, NM (S.C.E.); and Department of Radiation Oncology, Stanford University School of Medicine, Stanford, Calif (S.A.L.). Received April 11, 2003; revision requested May 29; revision received June 19, 2006; final version accepted August 9; final review and update by H.H. August 25. Address correspondence to H.H. (e-mail: hricakh{at}mskcc.org).

	ABSTRACT

TOP ABSTRACT CARE PATTERNS AND REVIEW... USE OF IMAGING IN... SUMMARY ESSENTIALS References

 
The major goal for prostate cancer imaging in the next decade is more accurate disease characterization through the synthesis of anatomic, functional, and molecular imaging information. No consensus exists regarding the use of imaging for evaluating primary prostate cancers. Ultrasonography is mainly used for biopsy guidance and brachytherapy seed placement. Endorectal magnetic resonance (MR) imaging is helpful for evaluating local tumor extent, and MR spectroscopic imaging can improve this evaluation while providing information about tumor aggressiveness. MR imaging with superparamagnetic nanoparticles has high sensitivity and specificity in depicting lymph node metastases, but guidelines have not yet been developed for its use, which remains restricted to the research setting. Computed tomography (CT) is reserved for the evaluation of advanced disease. The use of combined positron emission tomography/CT is limited in the assessment of primary disease but is gaining acceptance in prostate cancer treatment follow-up. Evidence-based guidelines for the use of imaging in assessing the risk of distant spread of prostate cancer are available. Radionuclide bone scanning and CT supplement clinical and biochemical evaluation (prostate-specific antigen [PSA], prostatic acid phosphate) for suspected metastasis to bones and lymph nodes. Guidelines for the use of bone scanning (in patients with PSA level > 10 ng/mL) and CT (in patients with PSA level > 20 ng/mL) have been published and are in clinical use. Nevertheless, changes in practice patterns have been slow. This review presents a multidisciplinary perspective on the optimal role of modern imaging in prostate cancer detection, staging, treatment planning, and follow-up.

© RSNA, 2007

Despite recent improvements in detection and treatment, prostate cancer continues to be the most common malignancy and the third leading cause of cancer-related mortality in American men. The American Cancer Society estimated that in 2007, 218 890 new cases of prostate cancer would be diagnosed and approximately 27 050 men would die of the disease in the United States (1). As the baby boomers age, it is anticipated that the rate of prostate cancer will increase. Thus, although the 5-year survival rate continues to improve, prostate cancer remains a compelling medical health problem.

	CARE PATTERNS AND REVIEW OF IMAGING TECHNOLOGIES

TOP ABSTRACT CARE PATTERNS AND REVIEW... USE OF IMAGING IN... SUMMARY ESSENTIALS References

 
The face of prostate cancer is changing. The widespread use of prostate-specific antigen (PSA) screening has led to a dramatic downstaging of prostate cancer at diagnosis (1,2). Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program demonstrate a remarkable decrease in the percentage of patients with distant metastatic disease at the time of diagnosis, from 20% for the period 1974–1985 to 5% for the period 1995–2000 (3,4). Similarly, in a single-institution study of patients with clinical stages T1 to T3NXM0 prostate cancer, the frequency of lymph node metastasis found at pelvic lymphadenectomy decreased from 23% in 1984 to 2% in 1995 (5). Earlier detection of prostate cancer has brought new challenges to clinical assessment and treatment selection—challenges that are compounded by the variability in natural history of the disease within the population at risk. The cancers detected today are smaller, lower stage, and lower grade than they were 20 years ago, but a wide range of aggressiveness remains. Our ability to predict biologic aggressiveness of tumors is still based on the histologic appearance of prostate cancer as assessed with the Gleason grading system, which has substantial limitations. A host of new biomarkers for prostate cancer are entering clinical practice and will undoubtedly alter treatment. Because men are being treated at a younger age, the long-term consequences of specific therapies merit increased consideration, since men may have to live with them for 20–30 years.

Prostate cancer is currently characterized by its clinical TNM stage, Gleason grade, and PSA serum level (1,6–8). PSA level is a strong indicator of stage and prognosis and is helpful in monitoring response to therapy. However, absolute PSA serum levels must be interpreted carefully with regard to the age of the patient, the size of the gland, and the presence of infection. Algorithms or nomograms that combine stage, grade, and PSA level to predict pathologic stage or prognosis (eg, progression-free probability after definitive local therapy) for the individual patient perform better than individual factors alone (9,10).

The thrust of cancer care in the new millennium is a risk-adjusted patient-specific therapy designed to maximize cancer control while minimizing the risks of complications. In the case of prostate cancer, such care requires accurate characterization of the tumor and selection of the optimal therapeutic approach from a bewildering array of alternatives: namely, deferred therapy (watchful waiting), androgen ablation, radical surgery (radical retropubic or laparoscopic prostatectomy), and various forms of radiation therapy (brachytherapy, external-beam irradiation, and combinations). Recently, focal ablative therapies (cryoablation, radiofrequency ablation, and focused ultrasound) have been added to the list of options (11,12). Imaging is becoming increasingly important in the assessment of prostate cancer because it can guide treatment selection, as well as treatment planning.

Imaging has played a critical role in prostate cancer staging since the development of radiography of the axial skeleton, but precise indications for and sensitivity and specificity of conventional imaging methods such as radionuclide bone scanning, computed tomography (CT), magnetic resonance (MR) imaging, ultrasonography (US), and combined positron emission tomography (PET)/CT remain under debate. The literature is replete with controversy about the value of imaging, ranging from enthusiastic endorsement to serious skepticism. Data from the Cancer of the Prostate Strategic Urologic Research Endeavor show that from 1995 to 2002, there was a national shift toward fewer imaging studies in all risk categories; the proportion of patients receiving any staging imaging test decreased by 63% in low-risk patients, by 25.9% in intermediate-risk patients, and by 11.4% in high-risk patients (13). The most precipitous decreases occurred in bone scan utilization rates, which decreased by 68.2%, 24.6%, and 11.1% in the low-, intermediate-, and high-risk groups, respectively. To some degree, these changes reflect the more appropriate use of imaging in response to the downward stage migration caused by PSA screening, but it is clear that some high-risk patients are proceeding to treatment without appropriate imaging evaluation (ie, work-up for metastases) (13).

Optimal use of imaging is not easy to define. However, this review will provide a multidisciplinary perspective on the optimal role of imaging in prostate cancer detection, staging, treatment planning, and follow-up by incorporating supporting evidence-based data when available.

Imaging Guidelines, Patterns of Care, and Practical Points of Technology
The selection of an imaging modality for prostate cancer should be based on the questions that need to be answered for a particular patient. The menu of available imaging options is continuously evolving in response to changes in clinical care, scientific discoveries, and technologic innovations. Transrectal US, MR imaging, CT, radionuclide bone scanning, and PET each have advantages, disadvantages, and specific indications. The Table summarizes the recommendations for imaging test utilization published in reports supported by the American Urological Association, the American Joint Committee on Cancer, and the American College of Radiology (8,14,15). In the following sections, we will review each of the major modalities for their utility in the detection of prostate cancer, local and distant staging, and tumor monitoring. We will also consider future developments that may improve the utility of each method.

Cores are typically obtained from six areas, or sextants, of the peripheral zone: left and right apex, left and right midgland, and left and right base. In addition, cores should be obtained from any sonographically suspicious (eg, hypoechoic) areas. A single biopsy session has a sensitivity of 70%–80% for the detection of cancer (16). To minimize the need for repeat biopsy sessions, many physicians obtain more cores the first time (17). There is growing evidence that 10 or 12 cores obtained from the medial and lateral apex, middle and base peripheral zones (the medial aspect of the peripheral zone seems to yield the least) of each side increases the sensitivity (15%–30% more cancers detected) (17,18). Biopsies become increasingly painful after six to eight samples, so many urologists and radiologists inject a local anesthetic (1% lidocaine without epinephrine) (19) around the nerves laterally at the junction of the seminal vesicles and base of the prostate and wait 10 minutes before obtaining samples. Separate samples of the anterior prostate (or transition zone) are usually not obtained unless previous biopsy sessions have failed to find a suspected cancer (eg, in a patient with a high PSA level, abnormal findings at digital rectal examination [DRE], and multiple negative peripheral zone biopsy specimens), or imaging with transrectal US or MR suggests an anterior cancer.

Diagnostically, transrectal US is used to measure the volume of the prostate gland (20), an important factor in computing "PSA density" (serum PSA level in nanograms per milliliter divided by the volume of the prostate in cubic centimeters). Moreover, the volume as measured with transrectal US can be used in staging and in predictive nomograms (21). Cancer, depending on its size, grade, and location, usually appears hypoechoic relative to the normal peripheral zone of the prostate (only approximately 1% are hyperechoic) (22). As a diagnostic test for cancer, transrectal US without biopsy is as accurate as DRE and complements the physical examination. Some palpable cancers are not visible at US, and some visible cancers are not palpable (23–25). With the shift toward smaller, early-stage cancers, many cancers detected at biopsy are not visible at US (low sensitivity) and many hypoechoic areas do not prove to be malignant at biopsy (low specificity); therefore, transrectal US alone, without the addition of biopsy, has limited value in the detection of cancer.

Transrectal US has been used for local staging of prostate cancer in some studies but is generally considered insufficient (Fig 1). The criteria for identifying extracapsular extension (ECE) on transrectal US scans are bulging or irregularity of the capsule adjacent to a hypoechoic lesion (Fig 2). The length of the contact of a visible lesion with the capsule is also associated with the probability of ECE (26). Seminal vesicle invasion (SVI) is heralded by a visible extension of a hypoechoic lesion at the base of the prostate into a seminal vesicle or by echogenic cancer within the normally fluid-filled seminal vesicle (27). Asymmetry of the seminal vesicles or solid hypoechoic masses within the seminal vesicles are indirect indicators of disease extension. When extraprostatic extension into the seminal vesicles is suspected, additional transrectal US-guided biopsies of the seminal vesicles can be performed.

View larger version (107K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: (a) Transverse and (b) sagittal transrectal US scans in 65-year-old man with prostate cancer show possible tumor in right posterior prostatic peripheral zone as fairly well-defined hypoechoic region (arrows) abutting the capsule. Outer outline along the posterior capsule is smooth; evidence of cancer confined to the gland. Stage T2b organ-confined disease was confirmed at surgical pathologic examination.

View larger version (95K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: (a) Transverse and (b) sagittal transrectal US scans in 65-year-old man with prostate cancer show possible tumor in right posterior prostatic peripheral zone as fairly well-defined hypoechoic region (arrows) abutting the capsule. Outer outline along the posterior capsule is smooth; evidence of cancer confined to the gland. Stage T2b organ-confined disease was confirmed at surgical pathologic examination.

View larger version (178K): [in this window] [in a new window] [Download PPT slide]   Figure 2: Transverse transrectal US scan of prostate in 59-year-old man with prostate cancer shows hypoechoic lesion (arrow) in left posterior peripheral zone. Irregular or spiculated margin along the capsule is evidence of ECE of tumor. Focal ECE was confirmed at surgical pathologic examination.

Transrectal US continues to play an important role in therapy. Worldwide, transrectal US is the modality of choice for directing brachytherapy seeds into the prostate (34). Cryotherapy of the prostate also requires US guidance as does high-intensity focused ultrasound, which, coupled with US targeting, is used for focal ablation of prostate cancers (36,36). New treatment approaches such as hyperthermia, photodynamic therapy, direct injection of oncolytic viruses, tumor vaccines, and gene therapy also depend on transrectal US for easy access to cancers of the prostate (37). While guidance techniques using MR imaging and other modalities are being developed, transrectal US will continue to play a major role in the management of prostate cancer, not least because of its wide availability and relatively low cost. Of course, the advantages of transrectal US (flexibility and relatively low cost) are balanced by its limited ability to define the prostate cancer in situ. The latter makes evaluation of US-guided therapies difficult, because recurrence could result either from the tumor being missed during treatment or from the inability of the treatment modality to kill the tumor.

Future developments in transrectal US include the use of microbubble contrast agents and targeted imaging. Microbubbles are relatively large, micrometer-sized, gas-filled bubbles that can be seen with exquisite sensitivity with real-time US. Indeed, by using harmonic imaging and encoded phased imaging, single microbubbles can be detected (38). Moreover, microbubbles can be coated with surface ligands, which preferentially target tumor neovascularity. Because of their large size (>1 µm), these agents are mostly confined to the vascular space and hence provide information primarily about large-vessel microvascularity but nonetheless could play a major role in improving cancer detection in the future.

CT Imaging
Although CT continues to be widely used in patients with newly diagnosed prostate cancer, it has virtually no role in prostate cancer detection or primary tumor staging. On CT scans, the separation between the prostate and the levator ani muscle is poorly defined, and intraprostatic anatomy is not well demonstrated. However, because of increased temporal resolution, multidetector CT, when properly performed, can more clearly depict intraprostatic anatomy. The major role of CT is in the nodal staging of prostate cancer, for which it is limited. Nomograms based on clinical data (PSA level, Gleason grade, DRE findings) provide risk stratification estimates that guide the appropriate ordering of imaging tests, including CT. For instance, it is recommended that CT should be performed only in patients with a PSA level grater than 20 ng/mL, Gleason score greater than 7, and/or clinical tumor stage T3 or higher (39). This is because the criterion for detection of positive nodal disease at CT is based on node size (> 1 cm diameter), and nodal enlargement due to metastases occurs relatively late in the progression of prostate cancer (Fig 3). Since nodal metastases are often microscopic, neither CT nor standard MR imaging can be used to reliably rule them out. Reported CT sensitivity for the detection of lymph node metastases varies, but it is typically in the range of 36% (40). One study published in 1980 reported an 85% sensitivity and 67% specificity (41), while another published in 1988 reported specificity of as low as 25% (42), which reflects the changes in the presentation of prostate cancer. Oyen et al (43) found a sensitivity of 78% and a specificity of 97% by using a size criterion of 0.6 cm or larger. The same study also reported a specificity of 100% for CT combined with CT-guided fine-needle aspiration biopsy. The smaller size criterion (0.6 cm) and use of fine-needle aspiration have not been widely adopted. It should be noted that the reported sensitivity and specificity of CT are highly dependent on the proportions of high-, medium-, and low-risk patients in the population studied.

View larger version (166K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Transverse contrast material–enhanced CT scan of pelvis in a patient with prostate cancer and PSA level of 45 ng/mL shows enlarged left external iliac lymph node (arrow) 1.3 cm in short-axis diameter, suggestive of nodal metastatic disease.

CT can be useful as a baseline examination in high-risk patients with clinically apparent, grossly advanced local disease (gross extracapsular disease, gross SVI, or invasion of the surrounding structures, including bladder, rectum, levator ani muscles, or pelvic floor). These patients will almost always fall above the cutoff recommendations for the appropriate use of CT imaging on the basis of DRE findings, PSA level, and Gleason grade; they will also be at risk for lymph node metastases, which may be assessed concurrently (Fig 4).

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 4: Unenhanced CT scan in 78-year-old man with prostate cancer, Gleason score of 3 + 4 at biopsy, PSA level of 21 ng/mL, and palpable tumor shows enlarged prostate with evidence of gross tumor ECE (arrow) along left posterolateral margin of the gland.

CT has been used to monitor bone metastases, but bone scanning and MR imaging are superior to CT in the diagnosis of bone metastases (52,53). Lytic and blastic bone metastases will commonly be visible at CT, however, and should not be overlooked. CT scans may be normal in cases of metastatic disease detected at radionuclide bone scanning, but CT allows more accurate distinction of malignant from benign causes of increased radioisotope uptake at bone scanning (54). Individual osseous metastases are more accurately defined as individual lesions on a CT scan than on a bone scan and, therefore, clear changes in osseous lesions seen at CT can be used to monitor responses to systemic therapy. Caution should be exercised in interpreting all osteoblastic lesions as metastases, as CT typically depicts the effects of tumor cells on normal osteoblasts rather than directly reflecting metastases, and bone changes in response to therapy may lag behind therapeutic effects.

MR Imaging
MR imaging can be used for prostate cancer detection, although it is recommended only if cancer is suspected despite negative transrectal US and biopsy findings. MR imaging can also aid in local and distant staging. Although it is a highly versatile technique, MR imaging has gone through several phases of popularity. Overall, its use has not shown a marked increase in recent years, but at centers that offer the technique the number of prostate MR examinations performed per month ranges from one to 150, which reflects a lack of consensus about the still-evolving role of this modality.

At present, optimal MR imaging of prostate cancer for detection and local staging requires the use of an endorectal coil in conjunction with a pelvic phased-array coil on a mid- to high-field-strength magnet. Thin (3-mm) sections and a small (14-cm) field of view are required to obtain submillimeter-resolution T2-weighted images necessary for local staging (55). The use of an endorectal coil at 3 T is more controversial, as the improved signal-to-noise ratio of the high-field-strength systems can compensate for the lack of signal from an endorectal coil, providing images of a similar quality to those obtained with 1.5-T endorectal MR imaging. However, it is expected, though not yet proven, that the use of an endorectal coil at 3 T will allow better prostate cancer detection. The detection of prostate cancer depends on the type of imaging sequence used. On T1-weighted images, the prostate demonstrates homogeneous medium signal intensity and tumors are impossible to discern. On T2-weighted images, cancer most commonly demonstrates decreased signal intensity relative to the high-signal-intensity normal peripheral zone (56) (Fig 5).

View larger version (154K): [in this window] [in a new window] [Download PPT slide]   Figure 5a: Images in 45-year-old man with prostate cancer stage pT2b and presurgical PSA level of 5.1 ng/mL. (a) Transverse, (b) coronal, and (c) sagittal unenhanced T2-weighted fast spin-echo (repetition time msec/echo time msec of 5000/96[effective]) MR images demonstrate a low-signal-intensity area (arrow) in the peripheral zone of right posterolateral midgland and apex. Tumor appears confined to the gland, as outer margin in all planes is smooth.

View larger version (150K): [in this window] [in a new window] [Download PPT slide]   Figure 5b: Images in 45-year-old man with prostate cancer stage pT2b and presurgical PSA level of 5.1 ng/mL. (a) Transverse, (b) coronal, and (c) sagittal unenhanced T2-weighted fast spin-echo (repetition time msec/echo time msec of 5000/96[effective]) MR images demonstrate a low-signal-intensity area (arrow) in the peripheral zone of right posterolateral midgland and apex. Tumor appears confined to the gland, as outer margin in all planes is smooth.

View larger version (159K): [in this window] [in a new window] [Download PPT slide]   Figure 5c: Images in 45-year-old man with prostate cancer stage pT2b and presurgical PSA level of 5.1 ng/mL. (a) Transverse, (b) coronal, and (c) sagittal unenhanced T2-weighted fast spin-echo (repetition time msec/echo time msec of 5000/96[effective]) MR images demonstrate a low-signal-intensity area (arrow) in the peripheral zone of right posterolateral midgland and apex. Tumor appears confined to the gland, as outer margin in all planes is smooth.

View larger version (161K): [in this window] [in a new window] [Download PPT slide]   Figure 6a: Images in 54-year-old man with preoperative PSA level of 12.6 ng/mL and biopsy Gleason score of 3 + 3. Prostate was normal (stage T1c) at clinical examination. Unenhanced (a) transverse and (b) sagittal T2-weighted fast spin-echo (5000/96 [effective]) MR images show large tumor (t) in the transition zone and tumor bulging with interruption of very low-signal-intensity anterior fibromuscular stroma by slightly higher signal intensity tumor, suggestive of anterior ECE (arrow). (c) Transverse gross pathologic whole-mount specimen. Outer linear margin defines border of tumor predominantly Gleason grade 3 with established anterior ECE (arrows), stage pT3a. Internal smaller marked regions define Gleason grade 4 components. (Hematoxylin-eosin stain.)

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 6b: Images in 54-year-old man with preoperative PSA level of 12.6 ng/mL and biopsy Gleason score of 3 + 3. Prostate was normal (stage T1c) at clinical examination. Unenhanced (a) transverse and (b) sagittal T2-weighted fast spin-echo (5000/96 [effective]) MR images show large tumor (t) in the transition zone and tumor bulging with interruption of very low-signal-intensity anterior fibromuscular stroma by slightly higher signal intensity tumor, suggestive of anterior ECE (arrow). (c) Transverse gross pathologic whole-mount specimen. Outer linear margin defines border of tumor predominantly Gleason grade 3 with established anterior ECE (arrows), stage pT3a. Internal smaller marked regions define Gleason grade 4 components. (Hematoxylin-eosin stain.)

View larger version (89K): [in this window] [in a new window] [Download PPT slide]   Figure 6c: Images in 54-year-old man with preoperative PSA level of 12.6 ng/mL and biopsy Gleason score of 3 + 3. Prostate was normal (stage T1c) at clinical examination. Unenhanced (a) transverse and (b) sagittal T2-weighted fast spin-echo (5000/96 [effective]) MR images show large tumor (t) in the transition zone and tumor bulging with interruption of very low-signal-intensity anterior fibromuscular stroma by slightly higher signal intensity tumor, suggestive of anterior ECE (arrow). (c) Transverse gross pathologic whole-mount specimen. Outer linear margin defines border of tumor predominantly Gleason grade 3 with established anterior ECE (arrows), stage pT3a. Internal smaller marked regions define Gleason grade 4 components. (Hematoxylin-eosin stain.)

MR imaging also permits detection of the presence and location of ECE and SVI, and its use in staging prostate cancer is gaining acceptance at select centers around the world (64–66). On endorectal MR images, criteria for ECE include asymmetry of the neurovascular bundle, tumor envelopment of the neurovascular bundle, an angulated prostate gland contour, an irregular or spiculated margin, obliteration of the rectoprostatic angle, capsular retraction, a tumor-capsule interface greater than 1 cm, and a breech of the capsule with evidence of direct tumor extension (65,67,68) (Fig 7). In the evaluation of extracapsular invasion, transverse sections are essential and a combination of transverse and coronal images is ideal. The addition of sagittal images facilitates evaluation of tumor located at the apex and base.

View larger version (52K): [in this window] [in a new window] [Download PPT slide]   Figure 7a: Images in 58-year-old man with prostate cancer clinical stage T2a. (a, b) Transverse unenhanced T2-weighted fast spin-echo (5000/96 [effective]) MR images with corresponding spectroscopic data show large low-signal-intensity lesion in the right side of peripheral zone with a focal bulge (arrowhead) and obliteration of the rectoprostatic angle (arrow) in addition to broad (>1 cm) capsular contact. Findings are indicative of ECE, which was proved at surgery (stage pT3a). Abnormal spectra (elevated choline and decreased citrate level) suspicious (SC) or very suspicious (VC) for prostate cancer are seen in voxels containing tumor (*). A = artifact, ED = ejaculatory duct, H = healthy prostate tissue, ND = nondiagnostic. (c) Corresponding pathology step section shows tumor (outlined) and site of established ECE (arrow). (Hematoxylin-eosin stain.)

View larger version (50K): [in this window] [in a new window] [Download PPT slide]   Figure 7b: Images in 58-year-old man with prostate cancer clinical stage T2a. (a, b) Transverse unenhanced T2-weighted fast spin-echo (5000/96 [effective]) MR images with corresponding spectroscopic data show large low-signal-intensity lesion in the right side of peripheral zone with a focal bulge (arrowhead) and obliteration of the rectoprostatic angle (arrow) in addition to broad (>1 cm) capsular contact. Findings are indicative of ECE, which was proved at surgery (stage pT3a). Abnormal spectra (elevated choline and decreased citrate level) suspicious (SC) or very suspicious (VC) for prostate cancer are seen in voxels containing tumor (*). A = artifact, ED = ejaculatory duct, H = healthy prostate tissue, ND = nondiagnostic. (c) Corresponding pathology step section shows tumor (outlined) and site of established ECE (arrow). (Hematoxylin-eosin stain.)

View larger version (100K): [in this window] [in a new window] [Download PPT slide]   Figure 7c: Images in 58-year-old man with prostate cancer clinical stage T2a. (a, b) Transverse unenhanced T2-weighted fast spin-echo (5000/96 [effective]) MR images with corresponding spectroscopic data show large low-signal-intensity lesion in the right side of peripheral zone with a focal bulge (arrowhead) and obliteration of the rectoprostatic angle (arrow) in addition to broad (>1 cm) capsular contact. Findings are indicative of ECE, which was proved at surgery (stage pT3a). Abnormal spectra (elevated choline and decreased citrate level) suspicious (SC) or very suspicious (VC) for prostate cancer are seen in voxels containing tumor (*). A = artifact, ED = ejaculatory duct, H = healthy prostate tissue, ND = nondiagnostic. (c) Corresponding pathology step section shows tumor (outlined) and site of established ECE (arrow). (Hematoxylin-eosin stain.)

View larger version (159K): [in this window] [in a new window] [Download PPT slide]   Figure 8a: Unenhanced T2-weighted fast spin-echo (5000/96 [effective]) endorectal coil pelvic MR images in 61-year-old man with clinical stage T2a prostate cancer. (a) Transverse image shows a dominant tumor (arrow) at the right base; loss of normal contour and irregular bulging are evidence of extracapsular disease. There is direct tumor extension into both seminal vesicles (arrowheads) on (b) transverse and (c) corresponding coronal images, seen as mild enlargement of the involved seminal vesicles and low-signal-intensity tissue replacing normal thin walls and obliterating the lumen (compare to preserved vesicle architecture laterally). Note prominent apical veins (*). (d) Sagittal image shows SVI (arrow) and adjacent tumor extending into extracapsular space between urinary bladder and seminal vesicle.

View larger version (171K): [in this window] [in a new window] [Download PPT slide]   Figure 8b: Unenhanced T2-weighted fast spin-echo (5000/96 [effective]) endorectal coil pelvic MR images in 61-year-old man with clinical stage T2a prostate cancer. (a) Transverse image shows a dominant tumor (arrow) at the right base; loss of normal contour and irregular bulging are evidence of extracapsular disease. There is direct tumor extension into both seminal vesicles (arrowheads) on (b) transverse and (c) corresponding coronal images, seen as mild enlargement of the involved seminal vesicles and low-signal-intensity tissue replacing normal thin walls and obliterating the lumen (compare to preserved vesicle architecture laterally). Note prominent apical veins (*). (d) Sagittal image shows SVI (arrow) and adjacent tumor extending into extracapsular space between urinary bladder and seminal vesicle.

View larger version (166K): [in this window] [in a new window] [Download PPT slide]   Figure 8c: Unenhanced T2-weighted fast spin-echo (5000/96 [effective]) endorectal coil pelvic MR images in 61-year-old man with clinical stage T2a prostate cancer. (a) Transverse image shows a dominant tumor (arrow) at the right base; loss of normal contour and irregular bulging are evidence of extracapsular disease. There is direct tumor extension into both seminal vesicles (arrowheads) on (b) transverse and (c) corresponding coronal images, seen as mild enlargement of the involved seminal vesicles and low-signal-intensity tissue replacing normal thin walls and obliterating the lumen (compare to preserved vesicle architecture laterally). Note prominent apical veins (*). (d) Sagittal image shows SVI (arrow) and adjacent tumor extending into extracapsular space between urinary bladder and seminal vesicle.

View larger version (157K): [in this window] [in a new window] [Download PPT slide]   Figure 8d: Unenhanced T2-weighted fast spin-echo (5000/96 [effective]) endorectal coil pelvic MR images in 61-year-old man with clinical stage T2a prostate cancer. (a) Transverse image shows a dominant tumor (arrow) at the right base; loss of normal contour and irregular bulging are evidence of extracapsular disease. There is direct tumor extension into both seminal vesicles (arrowheads) on (b) transverse and (c) corresponding coronal images, seen as mild enlargement of the involved seminal vesicles and low-signal-intensity tissue replacing normal thin walls and obliterating the lumen (compare to preserved vesicle architecture laterally). Note prominent apical veins (*). (d) Sagittal image shows SVI (arrow) and adjacent tumor extending into extracapsular space between urinary bladder and seminal vesicle.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 9a: Graphs show receiver operating characteristic (ROC) curves in detection of ECE for base model with and without endorectal MR imaging findings in (a) patients whose MR imaging studies were evaluated by genitourinary radiologists and (b) patients whose MR imaging studies were evaluated by general body radiologists. Base model included PSA level, Gleason score, greatest percentage of cancer in all core biopsy specimens, percentage of cancer-positive core specimens in all core biopsy specimens, presence of perineural invasion, and tumor clinical stage. Base model with endorectal MR findings included MR findings with all other variables. Predicted probability was calculated with jackknife method. Diagonal line indicates area under ROC curve of 0.500. (Graphs courtesy of Michael Mullerad, MD, Department of Urology, Bnai-Zion Medical Center, Haifa, Israel.)

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 9b: Graphs show receiver operating characteristic (ROC) curves in detection of ECE for base model with and without endorectal MR imaging findings in (a) patients whose MR imaging studies were evaluated by genitourinary radiologists and (b) patients whose MR imaging studies were evaluated by general body radiologists. Base model included PSA level, Gleason score, greatest percentage of cancer in all core biopsy specimens, percentage of cancer-positive core specimens in all core biopsy specimens, presence of perineural invasion, and tumor clinical stage. Base model with endorectal MR findings included MR findings with all other variables. Predicted probability was calculated with jackknife method. Diagonal line indicates area under ROC curve of 0.500. (Graphs courtesy of Michael Mullerad, MD, Department of Urology, Bnai-Zion Medical Center, Haifa, Israel.)

In the evaluation of lymph node metastases, unenhanced MR imaging has no advantage over CT. However, promising results have been reported for the use of ultrasmall superparamagnetic iron oxide particles as an aid to diagnosing lymph node metastasis at MR imaging. This technique is discussed later in the Future Prospects for MR Imaging section.

MR Spectroscopic Imaging
Prostate MR spectroscopic imaging adds specificity to MR imaging in the detection of prostate cancer and allows assessment of tumor metabolism. MR spectroscopic imaging displays the relative concentrations of chemical metabolites within a small volume of interest or voxel. In vivo proton spectroscopy of the prostate in cancer detection is aimed at determining the levels or concentrations of the metabolites citrate, creatine, and choline, making use of the differences between the normal prostate gland tissue, which contains (secretes) citrate, and prostate cancer, which shows high levels of choline and often diminished citrate levels (Figs 7, 10). The differences in the concentrations of metabolites are believed to be due to enhancement of the phospholipid cell membrane turnover associated with tumor cell proliferation, increased cellularity, and growth.

View larger version (52K): [in this window] [in a new window] [Download PPT slide]   Figure 10a: Transverse unenhanced T2-weighted fast spin-echo (5000/96 [effective]) MR image and corresponding proton MR spectroscopic imaging voxels. (a) Section in midgland shows healthy (H, also in b) prostate tissue throughout peripheral zone as evidenced by high signal intensity on T2-weighted image with corresponding spectra demonstrating normal high citrate peaks (eg, arrow) and low or absent choline peaks (eg, arrowhead). (b) Adjacent inferior section shows a tumor focus in left peripheral zone, seen as low-signal-intensity area (arrow) within the surrounding high-signal intensity peripheral zone. * = Tumor-containing voxels. There is corresponding increased choline peak (Ch) and decreased citrate peak (Cit), evidence of cancerous tumor. SC = suspicious for cancer, VC = very suspicious for cancer.

View larger version (52K): [in this window] [in a new window] [Download PPT slide]   Figure 10b: Transverse unenhanced T2-weighted fast spin-echo (5000/96 [effective]) MR image and corresponding proton MR spectroscopic imaging voxels. (a) Section in midgland shows healthy (H, also in b) prostate tissue throughout peripheral zone as evidenced by high signal intensity on T2-weighted image with corresponding spectra demonstrating normal high citrate peaks (eg, arrow) and low or absent choline peaks (eg, arrowhead). (b) Adjacent inferior section shows a tumor focus in left peripheral zone, seen as low-signal-intensity area (arrow) within the surrounding high-signal intensity peripheral zone. * = Tumor-containing voxels. There is corresponding increased choline peak (Ch) and decreased citrate peak (Cit), evidence of cancerous tumor. SC = suspicious for cancer, VC = very suspicious for cancer.

While combined use of MR imaging and MR spectroscopic imaging is typically used to evaluate clinically high-risk cancers, it may also prove useful for evaluating clinically low-risk cancers to assess suitability for deferred therapy. An initial retrospective study of 220 patients with prostate cancer (82) found that in the prediction of insignificant cancer (pathologically defined as organ-confined tumor 0.5 cm³ or less in volume with no element of Gleason grade 4 or 5 cancer), a nomogram model incorporating MR imaging and MR spectroscopic imaging findings with clinical variables yielded an area under the receiver operating characterisitc curve of 0.854 and was significantly more accurate than previously published nomogram models that incorporated only clinical variables (P < .001). New nomograms incorporating MR imaging and MR spectroscopic imaging data with clinical variables for the prediction of very low-risk cancer are being designed.

Findings from proton high-resolution magic-angle spinning nuclear MR spectroscopy and histopathologic examination can be correlated with preoperative MR imaging and three-dimensional (3D) MR spectroscopic imaging to reveal spectral patterns associated with mixtures of different prostate tissue types and cancer grades, as well as molecular markers (83). Preliminary evidence obtained from prostate cancer tissue profiles supports the role of key molecular markers as a way to improve histologic prediction of prostate cancer aggressiveness. Examples include cellular proliferation markers, apoptosis markers, a variety of serum biomarkers, and molecules associated with key signal transduction pathways (35–37,40,84). For example, the tumor cell proliferation marker Ki-67 has shown utility in the prediction of tumor progression, treatment outcome, and biochemical recurrence (41,42,85). Research is underway in which MR imaging and MR spectroscopic imaging findings will be correlated with a variety of molecular markers identified at high-resolution magic-angle spinning spectroscopy and immunohistochemistry, including Ki-67, p27/Kip1, PTEN, phosphorylated AKT (an activated oncogene downstream of PTEN), Bax, and Bcl-2.

To date, combined use of MR imaging and MR spectroscopic imaging has been limited to relatively few centers, but robust commercial MR spectroscopic imaging acquisition and display systems are now available. A multicenter American College of Radiology Imaging Network trial for tumor detection using MR imaging alone and MR imaging plus MR spectroscopic imaging with pathologic correlation has been completed, and the data are soon to be analyzed.

Dynamic Contrast-enhanced MR Imaging
Like other tumors, prostate cancers induce angiogenesis, which can be used as a diagnostic marker of disease. The normal prostate is a vascular organ, and so rapid injections with rapid scanning are needed to detect angiogenesis in a lesion. Typically, a full dose (0.1 mmol/kg) of gadolinium chelate is injected at 3 mL/sec, and serial 3D acquisitions are obtained every 2–5 seconds through the prostate. Cancers often demonstrate early nodular enhancement before the rest of the parenchyma and early washout of signal intensity. This pattern is highly predictive of prostate cancer but is not pathognomonic. Some prostate cancers are mildly or moderately hypervascular and thus are not detectable with this method. Dynamic contrast-enhanced MR imaging has been shown to have sensitivity of 73% and specificity of 81% in defining prostate cancers (86). A recent study found that dynamic contrast-enhanced MR imaging at 3 T had comparable sensitivity (73%) and specificity (77%) in prostate cancer localization (87). Combining dynamic contrast-enhanced MR imaging and 3D proton spectroscopy may prove helpful in tumor localization when T2-weighted images are inconclusive for a tumor focus (Fig 11). The analysis of dynamic contrast-enhanced MR imaging remains controversial. Relatively simple techniques such as measuring the relative peak enhancement (88) appear to work equally well with more complex methods such as two compartment models (89). For the field to move forward, however, some standardized analytic tools are required so that studies from different institutions can be directly compared.

View larger version (165K): [in this window] [in a new window] [Download PPT slide]   Figure 11a: (a) T2-weighted 3-T endorectal MR image demonstrates diffuse low signal intensity within peripheral zone. Finding is nonspecific. (b) Color map (Ktrans map) from dynamic contrast-enhanced MR imaging and (c) spectroscopic map (choline-to-citrate ratio) demonstrate abnormality in the left side of the gland. Surgically confirmed Gleason score 8 adenocarcinoma.

View larger version (88K): [in this window] [in a new window] [Download PPT slide]   Figure 11b: (a) T2-weighted 3-T endorectal MR image demonstrates diffuse low signal intensity within peripheral zone. Finding is nonspecific. (b) Color map (Ktrans map) from dynamic contrast-enhanced MR imaging and (c) spectroscopic map (choline-to-citrate ratio) demonstrate abnormality in the left side of the gland. Surgically confirmed Gleason score 8 adenocarcinoma.

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   Figure 11c: (a) T2-weighted 3-T endorectal MR image demonstrates diffuse low signal intensity within peripheral zone. Finding is nonspecific. (b) Color map (Ktrans map) from dynamic contrast-enhanced MR imaging and (c) spectroscopic map (choline-to-citrate ratio) demonstrate abnormality in the left side of the gland. Surgically confirmed Gleason score 8 adenocarcinoma.

Another prospect for the future is improved detection of nodal disease with the use of lymphotropic superparamagnetic nanoparticles as a contrast agent at MR imaging. The nanoparticles are taken up by circulating macrophages, which then traffic to the normal nodal tissue. The inability of malignant nodes to take up the agent provides tissue contrast within the lymph node and allows detection of metastases, even in nodes that do not meet the standard size criteria for metastasis (91). In a study in which 71.4% of nodes with histopathologically detected metastases were of normal size, sensitivity and specificity for the detection of metastasis on a node-by-node basis were 35.4% and 90.4%, respectively, for conventional MR imaging and 90.5% and 97.8%, respectively, for MR imaging with lymphotropic superparamagnetic nanoparticles; on a patient-by-patient basis, MR imaging with lymphotropic superparamagnetic nanoparticles had a sensitivity of 100% and a specificity of 95.7% (92). Since the incidence of lymph node metastasis in patients with newly diagnosed prostate cancer appears to be only 5% or less, it has been suggested that a combination of conventional MR imaging, which offers high negative predictive value for lymph node metastasis and anatomic information useful for treatment planning, and the standard staging nomogram, which has high accuracy in predicting lymph node metastasis, might be used to select patients for MR with lymphotropic superparamagnetic nanoparticles (30,93).

Radionuclide Bone Scanning
Radionuclide bone scanning has no role in prostate cancer detection or local staging; however, bone metastases are a common complication of prostate cancer, and bone scanning continues to be the mainstay of diagnosis of initial spread of cancer to bone. Evidence-based guidelines on the use of imaging in assessing the risk of distant spread of prostate cancer have been available since 1993, when it was proposed that routine bone scans should not be used for patients with PSA below 10 ng/mL (94). In 1997, O'Dowd et al (39) reconfirmed the recommendation that bone scans should be obtained routinely only for patients with PSA level greater than 10 ng/mL. Use of the bone scan has been modified in recent years by the measurement of PSA level. If the PSA level is less than 10 ng/mL (95), chances of a positive bone scan are less than 1%. When the PSA level is 10–50 ng/mL, the incidence of a positive bone scan increases to about 10%, and with PSA level above 50 ng/mL, it increases to about 50%. In our practice, we generally reserve bone scanning for patients with PSA level greater than 10 ng/mL.

The radionuclide bone scan is simple to obtain and is a sensitive method for detecting osseous metastases, especially osteoblastic metastases. The most common appearance is of a focal area of increased tracer uptake, usually in the axial skeleton, related to host osteoblastic bone response to tumor invasion (Fig 12). Less commonly, an area of reduced uptake may be present, which reflects extensive damage to bone with little osteoblastic response. Bone scans are more reliable than symptoms alone in the evaluation of bone metastatic disease, and in one series, 34% of asymptomatic patients had abnormal scans (96). In the evaluation of 1403 patients with prostate cancer, bone scans were 28% more sensitive than conventional radiographs in detecting metastatic skeletal lesions (96).

View larger version (90K): [in this window] [in a new window] [Download PPT slide]   Figure 12: 99mTc methylene diphosphonate bone scans in patient with prostate cancer and markedly elevated PSA level (>100 ng/mL). Anterior and posterior projections show numerous foci of increased uptake in the axial skeleton, indicating widespread osseous metastatic disease.

View larger version (174K): [in this window] [in a new window] [Download PPT slide]   Figure 13a: Images in 56-year-old man after radical retropubic prostatectomy with rising PSA level at 10 ng/mL. (a) Transverse unenhanced T2-weighted fast spin-echo (5000/96 [effective]) MR image shows ovoid low-signal-intensity lesion (arrow) suspicious for bone metastasis in left inferior pubic ramus. Bone scan at that time was normal (not shown). (b) Anterior coronal image from a bone scan 3 months later shows focal increased tumor activity (arrow) as confirmatory evidence of metastasis.

View larger version (160K): [in this window] [in a new window] [Download PPT slide]   Figure 13b: Images in 56-year-old man after radical retropubic prostatectomy with rising PSA level at 10 ng/mL. (a) Transverse unenhanced T2-weighted fast spin-echo (5000/96 [effective]) MR image shows ovoid low-signal-intensity lesion (arrow) suspicious for bone metastasis in left inferior pubic ramus. Bone scan at that time was normal (not shown). (b) Anterior coronal image from a bone scan 3 months later shows focal increased tumor activity (arrow) as confirmatory evidence of metastasis.

Single photon emission computed tomographic (SPECT) studies of the skeleton have been shown to be more sensitive in the detection of metastatic disease than planar images alone and are usually performed when symptoms or clinical suspicion for disease are present, particularly bone pain. This technique has particular utility in the evaluation of the spine in patients with low back pain who present for evaluation of possible metastatic disease. Sites of abnormal uptake may be localized to the vertebral body or posterior elements, leading to other radiologic techniques for confirmation. Uptake in facet joints, in the absence of signs of metastatic disease on radiographs, may indicate active arthritis as the cause of a patient's back pain (100,101). Combined SPECT/CT, a recent development, adds anatomic information to SPECT, and its incremental value to SPECT is yet to be evaluated (Fig 14).

View larger version (49K): [in this window] [in a new window] [Download PPT slide]   Figure 14a: Images in 67-year-old man with Gleason score 8 prostate cancer. At diagnosis, the local tumor had spread outside the gland and only medical treatment (finasteride) was given. After treatment, when PSA level was 2.6 ng/mL, (a) transverse, (b) sagittal, and (c) coronal SPECT 99mTc methylene diphosphonate bone scans demonstrated uptake in fourth lumbar vertebra suggestive of metastasis. After fusion of a and (d) CT scans, (e) resulting SPECT/CT image shows uptake confined to region of L4-5 vertebrae facet joint, indicating degenerative changes rather than metastasis. Subsequent MR images were negative for metastasis.

View larger version (66K): [in this window] [in a new window] [Download PPT slide]   Figure 14b: Images in 67-year-old man with Gleason score 8 prostate cancer. At diagnosis, the local tumor had spread outside the gland and only medical treatment (finasteride) was given. After treatment, when PSA level was 2.6 ng/mL, (a) transverse, (b) sagittal, and (c) coronal SPECT 99mTc methylene diphosphonate bone scans demonstrated uptake in fourth lumbar vertebra suggestive of metastasis. After fusion of a and (d) CT scans, (e) resulting SPECT/CT image shows uptake confined to region of L4-5 vertebrae facet joint, indicating degenerative changes rather than metastasis. Subsequent MR images were negative for metastasis.

View larger version (71K): [in this window] [in a new window] [Download PPT slide]   Figure 14c: Images in 67-year-old man with Gleason score 8 prostate cancer. At diagnosis, the local tumor had spread outside the gland and only medical treatment (finasteride) was given. After treatment, when PSA level was 2.6 ng/mL, (a) transverse, (b) sagittal, and (c) coronal SPECT 99mTc methylene diphosphonate bone scans demonstrated uptake in fourth lumbar vertebra suggestive of metastasis. After fusion of a and (d) CT scans, (e) resulting SPECT/CT image shows uptake confined to region of L4-5 vertebrae facet joint, indicating degenerative changes rather than metastasis. Subsequent MR images were negative for metastasis.

View larger version (94K): [in this window] [in a new window] [Download PPT slide]   Figure 14d: Images in 67-year-old man with Gleason score 8 prostate cancer. At diagnosis, the local tumor had spread outside the gland and only medical treatment (finasteride) was given. After treatment, when PSA level was 2.6 ng/mL, (a) transverse, (b) sagittal, and (c) coronal SPECT 99mTc methylene diphosphonate bone scans demonstrated uptake in fourth lumbar vertebra suggestive of metastasis. After fusion of a and (d) CT scans, (e) resulting SPECT/CT image shows uptake confined to region of L4-5 vertebrae facet joint, indicating degenerative changes rather than metastasis. Subsequent MR images were negative for metastasis.

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