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DOI:10.2214/AJR.07.2011
AJR 2007; 189:830-844
© American Roentgen Ray Society

Review

Imaging in Oncology from The University of Texas M. D. Anderson Cancer Center: Diagnosis, Staging, and Surveillance of Prostate Cancer

Vikas Kundra1,2, Paul M. Silverman1, Surena F. Matin3 and Haesun Choi1

1 Department of Radiology, The University of Texas M. D. Anderson Cancer Center, Box 57, 1515 Holcombe Blvd., Houston, TX 77030.
2 Department of Experimental Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
3 Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.

Received February 5, 2007; accepted after revision May 19, 2007.

 
CME

This article is available for CME credit. See www.arrs.org for more information.

Address correspondence to V. Kundra (vkundra{at}di.mdacc.tmc.edu).


Abstract
Top
 Abstract
Introduction
 Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
OBJECTIVE. The purpose of this article is to discuss the epidemiology, risk factors, and presentation of prostate cancer. After reviewing the prostate anatomy, the article will show how imaging plays an important role in establishing the diagnosis, staging, and monitoring the therapeutic response in prostate cancer, with a focus on adenocarcinomas.

CONCLUSION. Imaging studies, in the appropriate laboratory and clinical context, contribute essential information that enhances the capacity to provide individualized risk stratification, a suitable treatment strategy, and monitoring for the patient with prostate cancer.

Keywords: diagnosis • prostate cancer • staging • surveillance


Introduction
Top
 Abstract
 Introduction
Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
Imaging plays an important role in an integrative approach to a patient with prostate cancer. The contributions of imaging have expanded from characterizing locally advanced or metastatic disease to also include intra- and extraprostatic tumor delineation. After a discussion of epidemiology, risk factors, presentation, and anatomy, a description of the current role of imaging in diagnosing, staging, and monitoring prostate carcinoma will follow, focusing on adenocarcinomas.


Background
Top
 Abstract
 Introduction
 Background
Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
Epidemiology
Prostate carcinoma is the most frequently diagnosed visceral cancer and the second most common cause of cancer death among American men [1]. Geographically, the disease is more common in North America and north-western Europe than in Asia and South America [2]. In the United States, African American men have both a higher incidence of and more than twice the death rate from prostate cancer as whites. Fortunately, death rates from prostate cancer have been declining, particularly since the mid 1990s. Some of the decline may be attributed to earlier diagnosis and therapeutic intervention. The 5-year survival is effectively 100% when the disease is local or regional but drops to 34% with distant metastases. For all stages, survival is 99% at 5 years, 92% at 10 years, and 61% at 15 years [2].

Risk Factors and Presentation
Established risk factors include age, ethnicity, and family hist ory, the latter being a contributor in only 5–10% of cases [2]. Environmental factors, including diets high in saturated fat, may increase risk [3]; and obesity may increase the risk of dying from the disease. At presentation, early prostate cancer is commonly asymptomatic. When present, local symptoms include difficulty starting or stopping urine flow; painful, weak, or interrupted urine flow; increased frequency of urination; and hematuria. Back, pelvis, or thigh pain may indicate metastasis. Unfortunately, these symptoms are not specific to prostate cancer and can be mimicked by a variety of benign conditions [2].

Anatomy
In the model by McNeal et al. [4], the prostate gland is divided into four zones: the transition zone, the central zone, the peripheral zone, and the nonglandular anterior fibromuscular stroma (Fig. 1A, 1B). These zones contain 5%, 20%, 70–80%, and 0% of glandular tissue, and 25%, 5%, 70%, and 0% of prostate cancers, respectively. Cancers diagnosed at imaging are essentially in the peripheral zone. The transition zone cannot be separated from the central zone at imaging, and on images the two together are often referred to as the central gland or zone. The ejaculatory ducts traverse the central zone, providing a conduit for seminal fluid from the seminal vesicles to the urethra. The relative amount of peripheral zone to central zone increases from the base of the gland to the apex of the gland.


Figure 1
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  		Fig. 1A —Prostate anatomy. Drawing shows sagittal view of prostate anatomy.

 

Figure 2
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  		Fig. 1B —Prostate anatomy. Drawings show axial views of prostate near level of base (A), middle portion (B), and apex (C) of gland corresponding to lines labeled A, B, and C in A. Asterisks indicate urethra; short arrows indicate ejaculatory ducts.

 
The prostate gland is partially invested by a coalition of fibrous tissue, historically called the"capsule," that is most apparent posteriorly and posterolaterally. The capsule is an important landmark for assessing extraprostatic tumor extension. The neurovascular bundles course posterolateral to the prostate capsule bilaterally at the 5- and 7-o'clock positions (Fig. 1A, 1B). At the apex and the base, the bundles send penetrating branches through the capsule, providing a route for extraprostatic tumor extension.

Histology
Ninety-five percent of prostate cancers are adenocarcinomas that develop from the acini of the prostatic ducts. They are classified by Gleason score (see Diagnosis section). Other histologic types include small cell carcinoma, which is the most common variant; mucinous, ductal, squamous, sarcomatoid, and transitional cell carcinomas; adenoid basal cell tumors; and malignant mesenchymal tumors [5].


Diagnosis
Top
 Abstract
 Introduction
 Background
 Diagnosis
Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
Prostate carcinoma is often suspected when an abnormal digital rectal examination (DRE) is noted at physical examination or the serum prostate-specific antigen (PSA) is elevated. Interobserver agreement among urologists is only fair for detecting malignancy [6] by DRE, and DRE is not accurate for staging [7]. For serum PSA, no specific cutoff point simultaneously provides optimal sensitivity and specificity; instead, it provides a spectrum of risk at all ranges [8]. Although a serum PSA level greater than 4 ng/mL has traditionally been considered abnormal, almost 27% of biopsy-proven prostate cancers present with "normal" PSA, and 70–80% of patients with "elevated" PSA levels (> 4 ng/mL) do not have prostate carcinoma [9, 10]. The chance of prostate carcinoma increases with increasing PSA level [11].

If used, the American Cancer Society guidelines for early detection of prostate cancer include annual screening by DRE and serum PSA of men 50 years or older who have a 10-year life expectancy. Evaluation may begin at 40–45 years for high-risk individuals such as African Americans and patients with a first-degree relative who was diagnosed with the disease at a young age [2]. Although the role of early detection with PSA has been questioned, recent findings suggest that early detection and active treatment were important in the recent lowering of death rates [1], having the greatest survival impact on younger (< 65 years old) men [12]. To improve on traditional serum PSA, tests based on PSA (PSA derivatives) have been and are being developed [13]—for example, PSA density, PSA velocity, age-specific reference range, PSA isoforms, and percentage of free PSA.

Once prostate carcinoma is suspected, the diagnosis is generally made by endorectal sonographically guided biopsy. Because of the limited sensitivity of sonography for visualizing prostate tumors, systematic biopsy is used, which traditionally used a sextant (six-site) approach. Three cores of each lobe (base, mid gland, and apex) along a parasagittal plane, yielded an approximately 25% cancer detection rate when serum PSA was between 4 and 20 ng/mL [14]. Repeat biopsy showed cancer in approximately 20% of men with a persistently elevated level of serum PSA and a negative initial biopsy [15, 16]. Presti et al. [17] achieved approximately 40% yield using a 10-core approach, and even more cores have been advocated [18] to minimize sampling errors.

In the United States, histologic evaluation of prostate tumor tissue is performed using the Gleason grading system. Tumors are assigned a primary grade on the basis of the predominant pattern of differentiation and a secondary grade on the basis of the second most common pattern. The two numbers are added to produce a Gleason score. For example, a tumor described as "Gleason grade 3 + 4 (or 4 + 3)" will have a Gleason score of 7 [19]. The biologic behavior of a Gleason score 4 + 3 is more aggressive than 3 + 4, regardless of the number of cores [20].

Cancers with Gleason scores lower than 6 are considered well differentiated and are associated with a good prognosis. Those with a Gleason score of 8–10 have the worst prognosis and the highest risk for recurrence [21]. Tumors with Gleason scores of 7 have a variable prognosis and intermediate risk of recurrence. In the rare high-grade tumors (e.g., Gleason scores of 9–10) that produce little or no PSA, this marker has little value [21].

Models combining DRE, serum PSA level, and Gleason score (such as the D'Amico, Partin, or Kattan nomograms) can significantly improve accuracy in predicting the risk of treatment failure compared with a single parameter alone [19, 22]. These models provide general probabilities, not the specific risk for an individual patient. Recently, the number of positive biopsy cores, the amount of cancer in each core, and the location of large-volume cores have been taken into consideration to improve the accuracy of local staging [23–25]. Imaging can aid individualization of risk and treatment [26]. Endorectal MRI contributes incrementally to the value of staging nomograms in predicting organ-confined prostate cancer [27].


Staging
Top
 Abstract
 Introduction
 Background
 Diagnosis
 Staging
Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
The primary goals of staging (Appendix 1) are to distinguish patients with organ-confined, locally invasive, or metastatic disease and to assess the risk of treatment failure. Risk stratification may integrate PSA, TNM clinical staging, and Gleason score (Table 1) and may guide therapy.


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  		TABLE 1: Risk Stratification for Patients with Clinically Localized Disease

 

Local Staging (T Stage)
Although local tumor staging is based on findings from DRE, imaging can be beneficial. Stages T1a and T1b describe the incidental detection of cancer, such as in specimens from transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH). When cancer is detected by elevated PSA level but is not palpable by DRE, it is considered stage T1c. Cancer palpable by DRE or imaged on endorectal sonography but confined in the prostatic capsule is considered stage T2 (Fig. 2A, 2B). Cancer extending beyond the capsule is considered T3. This latter group includes extraprostatic tumor extension (Fig. 3), periprostatic neurovascular involvement, and seminal vesicle involvement. Tumor extending to other adjacent structures is considered stage T4 [28] (Fig. 4).


Figure 3
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  		Fig. 2A —Organ-confined prostate cancer (TNM stage T2) in 73-year-old man. Axial T2-weighted MR image (A) shows prostate carcinoma presenting as focal low-signal area in peripheral zone on left (arrow) and having isointense signal on T1-weighted image (B). Peripheral zone (arrowheads) is normally high signal and central zone (diamond) is often heterogeneous because of benign prostatic hyperplasia on T2-weighted sequences. Note that the transition and central zones cannot be distinguished and are termed central zone or central gland on MR images. Central gland and peripheral zone are isointense on T1-weighted sequences.

 

Figure 4
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  		Fig. 2B —Organ-confined prostate cancer (TNM stage T2) in 73-year-old man. Axial T2-weighted MR image (A) shows prostate carcinoma presenting as focal low-signal area in peripheral zone on left (arrow) and having isointense signal on T1-weighted image (B). Peripheral zone (arrowheads) is normally high signal and central zone (diamond) is often heterogeneous because of benign prostatic hyperplasia on T2-weighted sequences. Note that the transition and central zones cannot be distinguished and are termed central zone or central gland on MR images. Central gland and peripheral zone are isointense on T1-weighted sequences.

 

Figure 5
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  		Fig. 3 —Extracapsular extension of prostate cancer (TNM stage T3) in 65-year-old man. Axial MR image shows extraprostatic extension of prostate carcinoma presenting as low-signal area in peripheral zone and extending beyond prostatic capsule at 7-o'clock position, resulting in irregular bulge (arrow). On this T2-weighted image, prominent periprostatic vessels (arrowheads) are also seen.

 

Figure 6
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  		Fig. 4 —Invasion into adjacent organs (TNM stage T4) in 72-year-old man. Axial CT scan shows invasion of prostate cancer into rectum (arrow). Foley catheter (black arrowhead) and rectal tube (white arrowhead) are also seen.

 
Metastatic Disease (N and M Stages)
Prostate cancer metastasis can be lymphatic or hematogenous. The incidence of metastatic disease is extremely low in patients with stage T1–T2 disease, serum PSA less than 20 ng/mL, and Gleason score less than 8 [29]. Therefore, metastatic workup is usually performed when the Gleason score is greater than 7, serum PSA is greater than 20 ng/mL, stage is greater than T2, or when symptoms suggest metastasis [29].

Metastasis to lymph nodes occurs primarily along the obturator, internal iliac, common iliac, and presacral chains. Although it has been suggested that lymph node metastasis occurs stepwise from the pelvis to the retroperitoneum [30], there have been reports that up to 50% of nodal metastases can be paraaortic (Fig. 5) with no concurrent pelvic nodal metastasis, suggesting hematogenous rather than lymphatic spread [31]. At staging, nodal disease in the pelvis is considered regional nodal metastasis (N1), whereas nodal disease in the common iliac chains and retroperitoneum is considered distant metastasis (M1a). This, and the propensity of prostate cancer to metastasize to the lumbar spine [32], suggest that including the abdomen may be helpful when performing prostate MRI.


Figure 7
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  		Fig. 5 —Retroperitoneal lymph node metastasis in 75-year-old man. Axial CT shows enlarged, round lymph node metastasis (arrow) from prostate cancer.

 
Hematogenous metastasis to bone (Fig. 6) occurs most frequently to the lumbar spine, pelvis, ribs, and femoral heads (M1b) [28, 29]. The liver, adrenal glands, and lungs can become involved in advanced disease (M1c). However, visceral metastases are quite rare with prostate cancer; and in such cases, in addition to considering less-differentiated forms of prostate cancer, consideration should also be given to a second primary cancer (Fig. 7).


Figure 8
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  		Fig. 6 —Bone metastases in 70-year-old man. Bone scintigraphy using 99mTc-MDP (methylene diphosphate) shows multiple focal areas of increased uptake throughout bones, consistent with multiple bone metastases from prostate cancer. Above-knee amputation is seen.

 

Figure 9
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  		Fig. 7 —Metastasis from carcinoid tumor. Axial CT scan shows low-attenuation lesion in liver in 67-year-old man with prostate cancer and carcinoid tumor (arrow).

 

Treatment
Top
 Abstract
 Introduction
 Background
 Diagnosis
 Staging
 Treatment
Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
Because prostate cancer is generally a disease of older men and has a relatively good prognosis, particularly for early disease, life expectancy is taken into account when making treatment decisions. In patients with T1 or T2 (low-risk) disease, local therapy with radical prostatectomy or radiation (brachytherapy or external beam radiation) is often indicated. Because the disease may be clinically insignificant, expectant management or watchful waiting may be considered, meaning reserving curative treatment for early disease until evidence of progression is seen or reserving palliative treatment in patients with competing risks of death until symptoms arise. Although biopsy evidence of perineural invasion does not appear to curtail survival, it may indicate extraprostatic tumor extension [33], and it remains important when planning for nerve-sparing prostatectomy.

In locally advanced disease—stage T3 or beyond—systemic combination therapy is used. Neoadjuvant hormone therapy does not improve survival compared with surgery alone [34]. Hormone therapy before, during, and after irradiation improves 5-year survival compared with external beam radiation alone [25].

For distant metastasis, hormonal therapy is used primarily. Metastatic prostate cancer tends to escape hormonal control at a median time of 13–21 months [35]. In patients with androgen-independent prostate cancer or a rising level of PSA or clinical progression in the setting of castration levels of testosterone, docetaxel-based regimens improve survival [36]. New therapies, such as angiogenesis inhibitors, are currently being assessed.


Disease Recurrence and Surveillance
Top
 Abstract
 Introduction
 Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
Risk of recurrence after radical prostatectomy correlates with preoperative level of serum PSA, pathologic tumor stage, Gleason score, and positive surgical margins [37, 38]. About 50% of patients with preoperative serum PSA greater than 10 ng/mL [39] and 70% of patients with a Gleason score of 8–10 [37] have recurrence within 7 years after radical prostatectomy. About 25% of patients with positive tumor margins have recurrence within 5 years [39]. Any detectable PSA level after radical prostatectomy suggests recurrence; whereas PSA remains detectable after radiation therapy. In general, biochemical failure or recurrent disease is suspected when three consecutive increases in PSA level are observed after the radiation therapy serum PSA nadir [39].

PSA kinetics can suggest the site of recurrence. In general, biochemical failure (> 24 months after local treatment), low PSA velocity (change in serum PSA over time), and long PSA doubling time (> 6 months) suggest local recurrence. In contrast, rapid biochemical failure, high PSA velocity, and short PSA doubling time suggest recurrence at a distant site [40, 41].

If local recurrence is suspected, a biopsy is usually required for confirmation. Sonographically guided biopsy is unlikely to be of value unless the PSA level is greater than 0.5 ng/mL, there is a palpable abnormality on DRE, or a target lesion is seen near the site of anastomosis after prostatectomy [42]. After irradiation, posttreatment changes can make histologic confirmation of recurrence difficult.

After systemic therapy, recurrent lymph node metastasis may be pelvic, retroperitoneal, retrocrural, or, rarely, mediastinal; but after pelvic irradiation [43] or lymph node dissection, metastasis to pelvic lymph nodes is less common. Radiographic surveillance plays an even more important role for the rare patient with a tumor that is a poor producer of PSA.


Imaging in Local Staging of Prostate Carcinoma
Top
 Abstract
 Introduction
 Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
Endorectal Sonography
The first imaging technique used for clinically suspected prostate carcinomas is often endorectal sonography for directing biopsies. Using a high-frequency transducer (7–10 MHz), endorectal sonography can delineate zonal anatomy but cannot reliably differentiate between benign and malignant prostate tissue. Tumors have varying appearances on endorectal sonography: approximately 40–50% are hypoechoic (Fig. 8), 40% are isoechoic, and others are hyperechoic [44]. Confounding lesions such as prostatitis, atrophy, prostatic epithelial neoplasia, and ductal ectasia can also present as hypoechoic lesions [45]. Lee et al. [44] noted that the positive predictive value for cancer of a hypoechoic area in the peripheral zone alone was 41%, 52% if PSA was greater than 4 ng/mL, and more than 71% if DRE findings were abnormal [44].


Figure 10
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  		Fig. 8 —Endorectal sonogram shows hypoechoic carcinoma (arrow) in prostate in 62-year-old man.

 
Color or power Doppler sonography may show lesions not visualized by conventional gray-scale sonography; however, such lesions are not specific, and the new techniques do not perform as well as a systematic biopsy in diagnosing prostate cancer [46]. New IV sonographic contrast agents can improve sensitivity for prostate cancer compared with gray-scale imaging from 38% to 69% [47]. The role of contrast-enhanced sonography has yet to be determined. Endorectal sonography can detect extraprostatic tumor extension, but its accuracy remains suboptimal [26].

MRI
The diagnosis of extraprostatic tumor extension (Fig. 3) is more accurate by endorectal sonography or endorectal MRI than by DRE [26]. Most studies have shown that high-resolution endorectal MRI provides higher accuracy in staging local disease than does endorectal sonography [48–50]. Recently, Wang et al. [27] found that adding data from endorectal MRI to Partin nomograms improves the prediction of organ-confined prostate cancer versus extraprostatic disease at radical prostatectomy (area under the receiver operating characteristic [ROC] curve, 0.81 vs 0.90 for nomogram vs nomogram plus MRI) in all risk groups, with the greatest impact on intermediate- and high-risk groups. In that study, extraprostatic disease was defined on MRI as extracapsular extension, seminal vesicle invasion, or lymph node metastasis, and no statistically significant improvement was noted with the addition of spectroscopy. MRI also allows simultaneous screening of the regional lymph nodes and pelvic bones.

Compared with conventional MRI of the pelvis, which uses only a phased-array coil, addition of an endorectal coil significantly improves signal quality and allows thinner slices for improved spatial resolution. Often, T1-weighted axial and T2-weighted (TR range/TE range, 3,500–4,000/130–140) axial, coronal, and sagittal images of the prostate are obtained. The efficacy of gadolinium-enhanced or dynamic imaging is controversial, and these techniques are not routinely used.

T1-weighted axial images are used to screen the pelvic nodes and bones for metastasis and to identify hemorrhage in the prostate gland. The zonal anatomy is best seen on T2weighted images (Fig. 2A, 2B) but cannot be distinguished on T1-weighted images. The central gland is typically heterogeneous on T2weighted images due to BPH and isointense on T1-weighted images. It is difficult to separate cancer in the central zone from BPH that invariably occurs in this age group. Normally, the peripheral zone is relatively homogeneous and hyperintense on T2-weighted images and isointense on T1-weighted images. The neurovascular bundles are recognized as oval in axial and linear in long-axis, hypointense structures surrounded by hyperintense fat on T1-weighted images (Fig. 9).


Figure 11
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  		Fig. 9 —Neurovascular bundle invasion in 65-year-old man. Axial T2-weighted MR image shows left-sided extraprostatic extension and neurovascular bundle invasion (long arrow). Fat plane (short arrow) is seen between prostate and uninvolved neurovascular bundle (arrowhead) on right.

 
Prostate tumors in the peripheral zone are hypointense on T2-weighted images and isointense on T1-weighted images (Figs. 2A, 2B and 9). However, low T2-weighted signal is not specific for cancer. Underlying hemorrhage resulting from biopsy (Fig. 10A, 10B), prostatitis, atrophy, or posttreatment change can present with low signal intensity. In general, MRI is performed at least 6 weeks after prostate biopsy to allow resolution of hemorrhage, which has become more problematic with the extended numbers of core biopsies. Fortunately, hemorrhage can be identified as an area of high signal on T1-weighted images. Unfortunately, areas of high T1 signal compromise detection of tumor in the prostate on T2-weighted images. Performing axial T1- and T2-weighted imaging with the same slice thickness and field of view allows alignment of the two sequences that can aid in distinguishing tumor from hemorrhage. MRI can reduce the number of false-negative biopsies in patients with a previous negative biopsy (negative predictive value of 84–91% and accuracy of 77–78%) [51].


Figure 12
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  		Fig. 10A —Hemorrhage in 70-year-old man.

 

Figure 13
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  		Fig. 10B —Hemorrhage in 70-year-old man. Hemorrhage (arrows) is seen as increased signal in peripheral zone on T1-weighted (A) and as decreased signal on T2-weighted (B) axial MR images. Biopsy of prostate was performed 5 weeks before MRI. In general, it is preferable to perform MRI at least 6 weeks after prostate biopsy to allow resolution of hemorrhage.

 


Figure 14
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  		Fig. 11 —MR spectroscopy in 65-year-old man. Axial T2-weighted MR image shows prostate cancer presenting as low signal in peripheral zone on left (single arrow). Grid over prostate marks location where spectra were acquired. Increased choline (long arrows) and decreased citrate (short arrows) peaks are noted in boxes corresponding to region of decreased T2 signal. Spectrum suggesting prostate cancer is magnified on right. Normal spectrum with low choline and high citrate is magnified on left. Choline and creatine peaks are close and are usually difficult to separate on spectra.

 
MR spectroscopic imaging (MRSI) with an endorectal coil has been used to improve tumor detection. MRSI is a metabolic imaging technique. The most commonly studied markers for prostate cancer include choline, creatine, and citrate; others include polyamines, lipids, and lysine [52]. Most commonly, prostate cancer is identified by increased choline, a by-product of increased cell membrane metabolism, and decreased citrate, a normal product of prostate metabolism (Fig. 11). In conjunction with endorectal MRI, MRSI has been reported to provide sensitivity and specificity for prostate cancer as high as 95% and 91%, respectively [53], and to provide accuracy similar to that of sextant biopsy for intraprostatic tumor localization, except at the apex, where MRI with MRSI was more accurate than biopsy [54]. MRSI may also predict tumor aggressiveness [55]. However, obtaining optimal spectral resolution and interpreting MRSI remain challenging. Drawbacks of MRSI include relatively poor spatial resolution (» 4 mm), technical-demand, artifacts, inability to directly depict the periprostatic area, and requirement of specialized software and expertise in acquiring and interpreting the data.


Figure 15
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  		Fig. 12A —Hemorrhage in 60-year-old man.

 


Figure 16
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  		Fig. 12B —Hemorrhage in 60-year-old man. Hemorrhage (arrows) is seen as increased signal in seminal vesicles on T1-weighted (A) and as increased signal on T2-weighted (B) axial MR images. Biopsy of prostate was performed 5 weeks before MRI.

 


Figure 17
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  		Fig. 13 —Locally advanced disease in 67-year-old man. Axial T1-weighted MR image shows prostate cancer invading bladder (white arrow) and rectum (black arrow).

 
Currently, the main roles of MRI of the prostate are local staging of tumors in patients with an intermediate risk of treatment failure [21] and assessing prostate size. The formula for a prolate ellipse is commonly used (anteroposterior x transverse x cephalocaudal x 0.52) to calculate prostate volume. Jager et al. [56] suggested that MRI is cost-effective when used for the patients with a prior probability of extraprostatic tumor extension of at least 30% (PSA > 10 ng/mL or Gleason score > 7). Extraprostatic tumor extension or seminal vesicle invasion is associated with a higher risk of recurrence after resection [57]. Depending on the criteria and techniques used, the accuracy of endorectal MRI in detecting extraprostatic tumor extension can vary between 58% and 90% [58]. For patients at intermediate risk, MRI has shown approximately 80% accuracy in predicting the pathologic stage [49, 50].

To prevent patients from being excluded from potentially curative treatment, specificity is more important than sensitivity for determining extraprostatic tumor extension [59]. The most specific findings for extraprostatic tumor extension include asymmetry of the neurovascular bundle, blunting of the rectoprostatic angle, and direct tumor extension outside the capsule (Fig. 9); these provide a specificity of greater than 90% [58]. Focal bulging is frequently used but is less specific [58]. Because microscopic extracapsular tumor extension does not affect patient survival, subtle findings suggesting capsular penetration, such as irregular bulge, irregular gland contour, focal capsular thickening, or retraction, may not influence management [60]. Neurovascular bundle invasion often is better assessed on T1-weighted images and may appear as asymmetric enlargement with loss of the intervening periprostatic fat plane or as gross tumor extension [61]. Tumor in the seminal vesicles appears as a low-signal area in the high-signal fluid on T2-weighted images and as a low-signal area on T1-weighted images. In contrast, postbiopsy hemorrhage usually has high T1 signal and either a low or a high T2 signal (Fig. 12A, 12B). Asymmetry, loss of the fat plane between the base of the bladder and the inferior aspect of the seminal vesicle as noted on coronal images, focal or diffuse wall thickening, or nonvisualization of the ejaculatory ducts or seminal vesicle wall may imply seminal vesicle involvement [62].

Invasion into structures other than the seminal vesicles signifies stage T4 disease and is indicated by loss of the fat plane between the tumor and the adjacent structure or by direct visualization of tumor in the adjacent structure (Fig. 13).


Figure 18
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  		Fig. 14 —Adrenal metastasis in 60-year-old man. Axial CT scan shows prostate cancer metastasis (arrow) to left adrenal gland. Rarely, prostate cancer metastases involve solid organs such as lung, liver, pleura, and adrenal glands.

 

Imaging of Advanced Disease
Top
 Abstract
 Introduction
 Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 
CT
CT scans of the abdomen and pelvis are obtained primarily in patients with suspected metastatic disease to lymph nodes (Fig. 5) or bone. Lymph nodes greater than 1 cm in the short axis are considered suspicious for metastasis. CT may also be used for rare metastases to other solid organs, such as the lung, liver [31], pleura, and adrenal glands [32] (Fig. 14). Chest CT may be performed when a suspicious lesion is noted on chest radiographs.

Bone Scan, Radiography, and MRI
Bone scan, radiography, and MRI are used for detecting bone metastasis. Bone scan using 99mTc-methylene diphosphate (MDP) is performed on patients with an elevated level of PSA or clinically suspected (e.g., due to pain) bone metastasis. Because of the low likelihood of skeletal metastasis, a bone scan has been considered unnecessary in patients with newly diagnosed, untreated prostate cancer having a PSA level of less than 10 ng/mL and no clinical signs of bone abnormalities [63]. Patients with a PSA greater than 20 ng/mL have a high likelihood of bone metastasis.


Figure 19
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  		Fig. 15A —Focal bone metastasis in 72-year-old man.

 


Figure 20
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  		Fig. 15B —Focal bone metastasis in 72-year-old man. Prostate cancer metastasis to sacrum results in increased uptake (arrow, A) of 99mTc MDP (methylene diphosphate) on bone scan (A) and appears as sclerosis (arrows, B) on CT scan (B). Radiopharmaceutical injection site is seen on bone scan (arrowhead, A).

 
Metastases from prostate cancer usually present as focal areas of increased uptake on bone scans (Fig. 15A, 15B). With more advanced disease, the radiopharmaceutical may become incorporated into multiple metastases with no apparent focal uptake or apparent excretion of the radiopharmaceutical. Nonvisualization of the kidneys is the classic finding of such a "superscan" (Fig. 16A, 16B). Very rarely, an aggressive prostate cancer bone metastasis may appear as normal bone or as a cold spot on the bone scan. A flair reaction of increased uptake can be seen when therapy has decreased the size of a metastasis and healing results. Technetium-99m MDP mimics calcium phosphate and is incorporated into the bone matrix; thus, it assesses mineralized bone turnover, not the soft-tissue tumor itself.


Figure 21
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  		Fig. 16A —Diffuse bone metastases in 75-year-old man. Prostate cancer metastases throughout skeleton result in "superscan" with relatively normal-appearing bones but poor visualization of kidneys (arrows) on 99mTc MDP (methylene diphosphate) bone scintigraphy. Right renal pelvis (arrowhead) is seen because of obstruction of ureter.

 

Figure 22
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  		Fig. 16B —Diffuse bone metastases in 75-year-old man. CT image shows diffuse sclerosis (arrows) in pelvis due to diffuse prostate cancer metastases.

 
The bone scan is a functional technique that is more sensitive for bone metastases than is anatomic CT or conventional radiography. However, the latter two can aid in distinguishing increased uptake on the bone scan due to metastasis from other causes, such as degenerative disease, healing fractures, or metabolic disorders and their complications. Prostate cancer metastases are most often sclerotic on radiographs (Fig. 17A, 17B). CT can separate bone from overlying tissue. Bone scan, radiography, and CT primarily visualize the mineralized component of bone. Although CT is more sensitive than conventional radiography for detecting cortical invasion, it is less sensitive than MRI for medullary bone or marrow involvement [64], where metastasis begins. On MRI, bone metastases show low T1 signal and high T2 signal and enhance. MRI can delineate the soft-tissue component of the tumor and is more sensitive than the bone scan for detecting bone metastasis [65]. An advantage of the bone scan is its ability to visualize the entire skeleton. Newer MRI techniques for evaluating the entire skeleton are being studied. Major indications for MRI are to evaluate for epidural disease (Fig. 18A, 18B, 18C) and to resolve ambiguity or discrepancy among other techniques.


Figure 23
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  		Fig. 17A —Diffuse bone metastases in 68-year-old man. On frontal (A) and lateral (B) radiographs, prostate cancer metastases throughout skeleton appear as focal and diffuse areas of sclerosis (arrows indicate some examples). Sternotomy wires are present.

 

Figure 24
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  		Fig. 17B —Diffuse bone metastases in 68-year-old man. On frontal (A) and lateral (B) radiographs, prostate cancer metastases throughout skeleton appear as focal and diffuse areas of sclerosis (arrows indicate some examples). Sternotomy wires are present.

 

Figure 25
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  		Fig. 18A —Bone metastasis with epidural extension in 78-year-old man Prostate cancer metatasis to thoracic vertebral body (short arrow) has low signal admixed with mild increased signal on T2-weighted image (A), low signal on T1-weighted image (B), and mild enhancement on fat-suppressed T1-weighted image with IV contrast material (C). Metatasis has epidural component (long arrow) that compresses spinal cord and appears isointense on T2-weighted image (A), hypointense on T1-weighted image (B), and enhances (C).

 

Figure 26
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  		Fig. 18B —Bone metastasis with epidural extension in 78-year-old man Prostate cancer metatasis to thoracic vertebral body (short arrow) has low signal admixed with mild increased signal on T2-weighted image (A), low signal on T1-weighted image (B), and mild enhancement on fat-suppressed T1-weighted image with IV contrast material (C). Metatasis has epidural component (long arrow) that compresses spinal cord and appears isointense on T2-weighted image (A), hypointense on T1-weighted image (B), and enhances (C).

 

Figure 27
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  		Fig. 18C —Bone metastasis with epidural extension in 78-year-old man Prostate cancer metatasis to thoracic vertebral body (short arrow) has low signal admixed with mild increased signal on T2-weighted image (A), low signal on T1-weighted image (B), and mild enhancement on fat-suppressed T1-weighted image with IV contrast material (C). Metatasis has epidural component (long arrow) that compresses spinal cord and appears isointense on T2-weighted image (A), hypointense on T1-weighted image (B), and enhances (C).

 

Immunoscintigraphy with ProstaScint (111In-capromab pendetide, Cytogen) has been used for detecting lymph node metastasis and recurrence. ProstaScint scanning, which uses an 111In-labeled murine monoclonal antibody to a transmembrane glycoprotein, prostate-specific membrane antigen (PSMA), may be used when other imaging tests are negative for metastasis but suspicion remains high. PSMA expression is up-regulated in prostate cancer. A sensitivity of 17–62% and specificity of 72% for detecting lymph node metastasis has been reported for ProstaScint [66, 67]. Compared with ProstaScint studies alone, a study with a small series of patients suggests that fusion of SPECT with CT may improve sensitivity and specificity [68]. Newer antibody-based imaging methods are being investigated that target the extracellular domain of PSMA instead of the less-available intracellular domain targeted by ProstaScint [69].


Local Recurrence
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 Abstract
 Introduction
 Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
Future Imaging of Prostate...
 Summary
 References
 
Recurrent tumor after therapy may present as a distant metastasis or as a new mass in the prostatectomy bed. For the latter, MRI is superior to CT. Endorectal sonography, CT, 18F-FDG PET, and DRE are limited in detecting local recurrence. ProstaScint imaging and MRI have shown encouraging initial results; however, they require further investigation [70]. On MRI, the recurrent lesion may be hyperintense on T2-weighted imaging (instead of hypointense on T2 when the tumor is in the context of the prostate), isointense on T1-weighted imaging, and may enhance [71, 72] (Fig. 19A, 19B, 19C).


Figure 28
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  		Fig. 19A —Local recurrence in 61-year-old man. Local prostate cancer recurrence (arrows) shows increased signal on T2-weighted image (A), isointense signal on T1-weighted image (B), and enhancement on contrast-enhanced T1-weighted image (C).

 

Figure 29
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  		Fig. 19B —Local recurrence in 61-year-old man. Local prostate cancer recurrence (arrows) shows increased signal on T2-weighted image (A), isointense signal on T1-weighted image (B), and enhancement on contrast-enhanced T1-weighted image (C).

 

Figure 30
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  		Fig. 19C —Local recurrence in 61-year-old man. Local prostate cancer recurrence (arrows) shows increased signal on T2-weighted image (A), isointense signal on T1-weighted image (B), and enhancement on contrast-enhanced T1-weighted image (C).

 


Future Imaging of Prostate Cancer
Top
 Abstract
 Introduction
 Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
Summary
 References
 
For intraprostatic cancer, endorectal MRI at 1.5 T has limitations such as less than ideal accuracy and, in particular, specificity; inability to distinguish tumors in the central gland, where 30% of prostate cancers arise [4]; inability to distinguish cancer in the presence of hemorrhage; and limited evaluation after hormone or radiation therapy because of gland shrinkage and a diffusely decreased T2 signal. Additional MR methods are being evaluated. As discussed previously, adding spectroscopy has shown promise in improving accuracy for localizing prostate cancer, particularly in improving specificity compared with traditional T1- and T2-weighted imaging alone. But in other studies, no significant improvement in accuracy was seen, especially by experienced reviewers. For example, Costouros et al. [73] found no significant difference between endorectal MR and endorectal MR plus spectroscopy in diagnosing prostate cancer in 40 patients with elevated PSA levels and noted that MRI may supplement but not replace biopsy for the diagnosis of prostate cancer. Wetter et al. [74] found no significant improvement in staging endorectal MR by adding spectroscopy. However, a preliminary study found MR spectroscopy can detect prostate tumors in the transition zone [75]; although there was overlap with BPH, the presence of choline implied cancer.

MR spectroscopy has shown potential in evaluating for metabolic atrophy after treatment and for distinguishing recurrence after radiation therapy [76]. When combined with endorectal MRI, MR spectroscopy improved detection of recurrence within 4 months of hormone therapy compared with endorectal MRI alone for a less experienced reviewer [77]. Improved spatial, temporal, and spectral resolution and potentially new markers should improve spectroscopy.

Combining MR spectroscopy and diffusion-weighted imaging (DWI) is superior to MR spectroscopy alone when tumor fills 70% of the voxel (AUC [area under the ROC], 0.98 vs 0.92) but not if tumor fills 30% of the voxel (AUC, 0.81 vs 0.79) [78]. This study also points out the importance of spatial resolution. DWI measures the restriction of diffusion in biologic tissues and can be acquired rapidly. It may be applied to both the central gland and the peripheral zone. Although DWI alone shows promise, there is not yet a standard acquisition protocol, and intersubject variability may limit its usefulness; further, a precise apparent diffusion coefficient (ADC) cutoff value is as yet uncertain both at 1.5 and 3 T [79]. Yet DWI can identify prostate cancer. Tanimoto et al. [80] noted that, compared with T2-weighted imaging alone, T2-weighted imaging with DWI improves prostate cancer detection, and there is a trend to even better test characteristics with the addition of dynamic contrast-enhanced imaging assessing early enhancement and late washout (AUC, 0.71, 0.91, and 0.97, respectively). In addition, ADC values appear to be lower in prostate cancer than in the central gland [80].

Dynamic contrast-enhanced MRI depicts tumor vascularity. The terminology for dynamic contrast-enhanced MRI is a bit unclear; it may represent a time-resolved enhancement pattern or quantitative pharmacologic model-based assessment. Both benefit from rapid temporal resolution and thus take advantage of fast gradient-echo sequences. Using time-resolved enhancement analysis, some have espoused early enhancement and either early contrast wash-in or delayed contrast washout to suggest tumor [80], with reported sensitivity and specificity as high as 96% and 97% [81], whereas others prefer peak or relative peak enhancement [82]. Overlap of enhancement patterns of cancer and the central gland may be seen [81, 83]. In a quantitative pharmacologic model-based assessment, pharmacodynamic parameters such as Ktrans (volume transfer constant between plasma and extravascular–extracellular space [EES]), kep (rate constant between EES and plasma), and ve (volume of EES per unit volume of tissue) may be extracted, depending on the model used. Some have advocated that Ktrans better than ve distinguishes prostate cancer from the peripheral zone and central gland [84], whereas others have found ve to be better [85]. Time-resolved dynamic contrast-enhanced MRI does not appear to correlate with tumor stage [83], and although it does not assist experienced reviewers in staging, it may benefit less experienced reviewers [86]. Exact timing and parameters for dynamic imaging have not yet been standardized.

Three-tesla magnets provide better signal- to-noise ratios (SNR) and thus better spatial, temporal, and spectroscopic resolution than 1.5-T systems [87] and can be used with combined endorectal coils and phased-array coils [88]. Susceptibility artifacts can increase at higher field strengths; yet, 3-T imaging should be a boon because spatial resolution is important for all MRI of the prostate. SNR is important for diffusion imaging to improve signal and to reduce scanning time. Temporal resolution is important for dynamic contrast-enhanced MRI, and spectral resolution is important for MR spectroscopy. Miao et al. [89] found that 3 T provides higher SNR and reduces scanning time and thus motion artifacts, when combined with parallel imaging. This results in decreased distortion on DWI compared with images on 1.5-T systems that have poorer SNR [89].

For lymph node evaluation, MR lymphography using ultrasmall superparamagnetic iron oxide (USPIO) contrast material has shown potential in detecting malignant nodes in prostate carcinomas, with 90% sensitivity and 98% specificity reported in an early experience [90].

The effectiveness of FDG PET in detecting prostate cancer has been discouraging, primarily because of the inherently low level of glucose metabolism by prostatic tumor cells and the physiologic excretion of FDG into the urinary bladder, which can mask tumor in or adjacent to the prostate [91]. Newer radiopharmaceuticals, such as those based on choline, [92] methionine [4, 93], acetate, or L-leucine [94], have shown some promising preliminary results.


Summary
Top
 Abstract
 Introduction
 Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
References
 
The range of radiologic techniques—endorectal sonography, MRI, CT, and nuclear medicine studies—allows an integrative approach to prostate cancer. The results of imaging studies performed in the appropriate laboratory and clinical context can contribute essential information that enhances the capacity to provide individualized risk stratification, a suitable treatment strategy, and monitoring of the patient with prostate cancer.

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  		APPENDIX 1: TNM Staging of Prostate Cancer

 


Acknowledgments
 
We thank Lea Newland, librarian, for her help in preparing this manuscript. We also thank David L. Bier, imaging specialist, for his artful rendition of prostate anatomy.


References
Top
 Abstract
 Introduction
 Background
 Diagnosis
 Staging
 Treatment
 Disease Recurrence and...
 Imaging in Local Staging...
 Imaging of Advanced Disease
 Local Recurrence
 Future Imaging of Prostate...
 Summary
 References
 

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G. J. Kelloff, P. Choyke, D. S. Coffey, and for The Prostate Cancer Imaging Working Group
Challenges in Clinical Prostate Cancer: Role of Imaging
Am. J. Roentgenol., June 1, 2009; 192(6): 1455 - 1470.
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