Prostate cancer magnetic resonance imaging (MRI): multidisciplinary standpoint

Introduction

It was in 1853 that John Adams first described a case of prostate cancer (Pca) in a 59-year-old male patient, and this disease was considered rare because of the short life expectancy at the time. In 2012, there were expected to be about 239,000 new cases diagnosed with Pca and about 30,000 Pca deaths (1). Nowadays, it is the most common noncutaneous cancer and the second/third leading cause of cancer death in men in the United States and European Community (1-3). The management and imaging in Pca remains a big challenge.

The main diagnostic biomarker for Pca is prostate-specific antigen (PSA). PSA test was approved by the U.S. Food and Drug Administration (FDA) in 1986 to monitor the disease status (4). However, a PSA test has some drawbacks. It is not capable of differentiating between Pca, benign prostatic hyperplasia (BPH), and chronic prostatitis, particularly when serum PSA level is lower than 10 ng/mL. This method indeed produces over-diagnosis of clinically insignificant cancers. Thus, in 2012, the U.S. Preventive Services Task Force (USPSTF) recommended against PSA-based screening all men for Pca (5). Transrectal Ultrasound (TRUS)-guided prostate biopsy has become a standard method to obtain specimen for histopathological examination. Positive results of biopsy of the prostate confirm clinical suspicion of Pca, but they provide limited information on extent and differentiation of Pca. Furthermore, prostate biopsy without evidence of Pca does not rule out its presence (6).

To replace somewhat arbitrary combinations of individual variables, there is a need for instruments to aid patients and their physicians in treatment decision. Using algorithms that incorporate multiple variables, the nomograms have been developed to give a prediction of the pathologic stage, the probability of freedom from disease recurrence. The Partin staging nomogram (also called the “Partin tables”), which is based on serum PSA value, clinical stage, Gleason score, and was first published in 1993 and was updated in 1997 and again in 2001 to predict the pathological stage at radical prostatectomy. Other nomograms, such as Kattan’s nomograms, have been developed to predict stage, recurrence, or biologic potential (7). As an important advance in accurate prediction for clinical medicine, the nomograms allow calculation of the continuous probability of a particular trend and tend to outperform both expert clinicians and risk grouping. The nomograms are widely used for individual patient counseling and important decision-making. However, the nomograms are limited by the lack of results from imaging studies and digital rectal examination (DRE)-based clinical staging. Thus, despite the high predictive ability and the cost-effectiveness of the nomograms, there is still some room for improved accuracy of prediction.

MRI is a good imaging modality of choice in Pca detection, localization, and staging (8-10). The interpretation of Pca on T2-weighted MR imaging (T2WI) can be affected by false-positive findings such as prostatitis, postbiopsy hemorrhage, and fibrosis (11,12). To improve the diagnostic accuracy of Pca imaging, functional MR imaging (fMRI) techniques have been applied, such as diffusion-weighted MR imaging (DWI) (13-15), proton (1H) MR spectroscopic imaging (MRSI) (16-18), and dynamic contrast-enhanced MR imaging (DCE-MRI) (19-21).

DWI has quickly evolved to become one of the most relevant sequences for imaging Pca. In tumor, the increased cellularity and associated loss of ductal morphology result in a smaller extracellular space, the restriction of water diffusion and a corresponding reduction in ADC values (22). A recent meta-analysis demonstrated the sensitivity and specificity of DWI combined with T2WI to range from 65% to 84% and 77% to 87%, respectively (23). MRSI identifies Pca by an increased ratio of choline plus polyamines plus creatine to citrate (24). As a result of increased energy metabolism, the citrate level is reduced in tumor. Owing to a high phospholipid cell membrane turnover the choline level is elevated in proliferating malignant tissue (25). DCE-MR imaging relies on tumor neoangiogenesis for Pca detection. In malignant tumour, the number of vessels (microvascular density) is increased in comparison with the surrounding normal tissue, leading to greater relative tumoral enhancement (26).

This review addresses the major role of MRI in the advanced management of Pca to improve cancer staging noninvasively, biologic potential, treatment planning, therapy response, local recurrence, and to guide target biopsy for clinically suspected cancer with previous negative biopsy, and discusses the future prospects of MRI in Pca management from a multidisciplinary standpoint.

Prostate cancer staging

The staging of Pca is based on tumor, node and metastasis (TNM) staging. The latest modification was made in 2010 by the American Joint Committee on Cancer (AJCC). The 2010 revised TNM system, shown in Table 1, is clinically useful and precisely stratifies newly diagnosed cancer (27). The most important advantage is distinguishing between patients with pathologically organ-confined Pca (pT2) from those with non-confined Pca (pT3-4). As is well known, once the tumor extends outside the prostate, the chances of cure are substantially diminished (28,29).

Table 1 Prostate tumor node metastasis (TNM) staging (American Joint Committee on Cancer, 7th ed. 2010)
Full Table

Detection of OCPC (pT2)

Clinicians must distinguish between patients with pathologically organ-confined prostate cancer (OCPC) (pT2) and those with non-organ-confined prostate cancer (pT3-4). T2 tumors are subclassified as T2a (less than one-half of one lobe involved) (Figure 1), T2b (more than one-half of one lobe involved), and T2c (bilateral involvement). After radical prostatectomy (RP), patients with OCPC have an excellent prognosis, as more than 90% of them are free from biochemical recurrence in the period of 5 years (30).

Figure 1 3T magnetic resonance (MR) images of organ-confined prostate cancer (OCPC) in a 59-year-old man with a Gleason score of 3+4 and a PSA level of 12.09 ng/mL. A. Transverse 3 mm-thick MR (4580/105) image shows a low-signal-intensity lesion in the right lobe of the prostate; B. Transverse 3 mm-thick DWI (3500/73, b-value of 1,000 s/mm²) clearly demonstrates a focal high intensity area, a fining indicative of increase diffusion

One study of Wang et al. demonstrated that MR findings contributed significant incremental value to the Partin tables in predicting OCPC. The contribution of MR findings was significant in all risk groups but was greatest in the intermediate- and high-risk groups. Overall, in the prediction of OCPC, the area under the ROC curve (AUC) for the staging nomograms was 0.80, while the AUC for the staging nomograms plus MR findings was 0.88. In the combined endorectal MRI-MRSI group, the AUC were 0.81 for the staging nomograms and 0.90 for the staging nomograms plus MR findings (31).

Detection of extracapsular extension (ECE) (pT3a)

ECE of Pca is associated with increased risk of a positive surgical margin, which in turn influences postoperative biochemical recurrence after radical prostatectomy (32). On T2-weighted MRI, criteria for detecting ECE include at least one of the following: irregular capsular bulge or edge retraction, disruption of the prostatic capsule, extension into the periprostatic fat, broad contact with the capsule (>12 mm), obliteration of the rectoprostatic angle, or asymmetry of the neurovascular bundles (Figures 2,3) (33).

Figure 2 3T magnetic resonance (MR) images of extracapsular extension (ECE) of prostate cancer in a 57-year-old man with a Gleason score of 4+4 and a PSA level of 13.85 ng/mL. A and B. Transverse 3 mm-thick MR (4580/105) image, and coronal 3 mm-thick MR (2990/86) image show a hypointense tumor with extraprostatic extension in the left peripheral zone of the prostate; C. Transverse 3 mm-thick DWI (3500/73, b-value of 1,000 s/mm²) shows intense, increased signal (restricted diffusion) throughout the mass; D. The disease was clinically staged as T4 prostate cancer and confirmed by pathology

Figure 3 3T magnetic resonance (MR) images of extracapsular extension (ECE) of prostate cancer in a 69-year-old man with a Gleason score of 4+3 and a PSA level of 40.64 ng/mL. A. Transverse 3 mm-thick MR (4580/105) image shows a hypointense tumor with extraprostatic extension in the left peripheral zone of the prostate; B. Transverse 3 mm-thick DWI (3500/73, b-value of 1,000 s/mm²) shows intense, increased signal (restricted diffusion) throughout the mass; C. A color-coded wash-out map shows a focal area of wash-out in the location of cancer; D. The disease was clinically staged as T4 prostate cancer and confirmed by pathology

A study of 32 patients demonstrated the mean sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for assessment of ECE with the combined DCE and T2WI 3 Tesla MRI system using an endorectal coil were 86%, 95%, 90%, and 93%, respectively (34). Bloch et al. (35) analysed the value of DCE combined with T2WI at 3 Tesla scanner for determining ECE of Pca, and found that the overall sensitivity, specificity, PPV and NPV for ECE were 75%, 92%, 79% and 91%, respectively. 3 Tesla MRI of the prostate combining DCE and T2WI is an accurate pretherapeutic staging tool for assessment of ECE in clinical practice. In a study using MRI with combining transaxial and coronal plane images using picture and communication systems (PACS) cross-referencing to facilitate the diagnosis of ECE, Wang and colleagues (36) showed that sensitivity and specificity for ECE with MRI alone and with cross-referencing were 43% and 94% and 57% and 100% for reviewer 1 and 40% and 93% and 59% and 98% for reviewer 2, respectively. The weighted Kappa was 0.56 with MRI alone and 0.76 with cross-referencing, indicating good interobserver agreement.

Detection of seminal vesicle invasion (SVI) (pT3b)

SVI is considered an important marker of tumor progression and connected with increased risk of lymph node invasion, local tumor recurrence. On MRI T2WI direct signs of SVI are contiguous low-signal intensity (SI) tumor extension from base of the gland to seminal vesicles, focal low-SI within the seminal vesicles disruption or loss of the normal structure of the seminal vesicles, non-visualization or enlarged of the ejaculatory ducts, obliteration of seminal vesicle angle and decreased conspicuity of seminal vesicles (Figure 4).

Figure 4 3T magnetic resonance (MR) images of seminal vesicle invasion (SVI) of prostate cancer in a 69-year-old man with a Gleason score of 4+4 and a PSA level of 49.7 ng/mL. A and B. Transverse 3 mm-thick MR (4580/105) image and sagittal 3 mm-thick MR (3088/70) image show a hypointense tumor with bilateral seminal vesicle invasion in the apex of the prostate; B. Transverse 3 mm-thick DWI (3500/73, b-value of 1,000 s/mm²) shows intense, increased signal (restricted diffusion) throughout the mass; D. The disease was clinically staged as T4 prostate cancer and confirmed by pathology

A study of 45 consecutive patients demonstrating the endorectal MRI following radiation therapy can help identify tumor sites and depict ECE and SVI with reasonable accuracy in patients with recurrent Pca (37). The AUC values for prediction of SVI were 0.76 (95% CI: 0.62, 0.90) for reader 1 and 0.70 (95% CI: 0.56, 0.85) for reader 2. The Kappa statistics used to assess interobserver agreement were fair (0.45, 0.47 for tumor location, SVI, respectively).

A study investigated 154 consecutive patients who underwent endorectal MRI before surgery. MRI sensitivity, specificity, PPV, NPV, overall accuracy resulted in respectively 0.88, 0.98, 0.82, 0.99 and 0.97 for SVI (38). Nepple et al. evaluated the accuracy of endorectal MRI compared with subsequent pathology specimen from prostatectomy. PPV, NPV, sensitivity, specificity of MRI were 93%, 75%, 94%, 38%, 99% for SVI. Endorectal MRI in the evaluation of high-risk Pca was moderately accurate for SVI (39).

A study of 1,161 consecutive patients demonstrated that endorectal coil MRI had limited clinical value in preoperatively detecting SVI (40). In evaluating SVI, sensitivity and specificity were 33% and 89%, respectively. The PPV of MRI to assess SVI was 50% in both, with a NPV of 63%.

The addition of DWI to MRI has been shown to significantly increase staging accuracy for the less inexperienced readers and thus reduce interobserver variability (41). A study of 30 patients demonstrated significant improvement in the prediction of SVI for the less experienced readers. Interobserver agreement showed a substantial agreement (Kappa =0.613) for T2WI, and a substantial agreement (Kappa =0.737) for T2WI with DWI (41). In 2009, a study of Ren et al. showed that T2WI combined with DWI demonstrated significantly higher accuracy than T2WI alone in the detection of SVI (42).

Detection of LNM

Regarding the lymph node metastasis (LNM), 70% of them are too small (<8 mm) to be evaluated using MRI, so conventional size criteria may underestimate the extent of nodal disease. A meta-analysis reported that MRI demonstrated equally poor performance in the detection of LNM from Pca with a sensitivity of around 30% (43). For this reason, recently two other MR techniques have been developed: MR lymphography (MRL) [which uses a lymph node-specific contrast agent called ultrasmall superparamagnetic particles of iron oxide (USPIO)] and DWI-MRI (Figure 5).

Figure 5 3T MR images of prostate cancer in a 72-year-old man with a Gleason score of 4+5 and a PSA level of 23.89 ng/mL. A and B. Transverse 3 mm-thick T2WI (4580/105) and transverse 3 mm-thick T2 weighted fat-saturated MR imaging (4580/105) show a hypointense tumor with extraprostatic extension in the left transitional and peripheral zone of the prostate, and intermediate SI bulky adenopathy with short-axis dimensions of >8 mm is present in left external iliac and obturator distributions; C. Transverse 3 mm-thick DWI (3500/73, b-value of 1,000 s/mm²) shows intense, increased signal (restricted diffusion) throughout the mass; D. The disease was clinically staged as T3M1 prostate cancer and confirmed by pathology

In 1998, Bellin et al. reported on the initial clinical experience with MRL and found a perfect sensitivity of 100% at 80% specificity (44). In another prospective study with 334 lymph nodes in 80 patients, sensitivity and specificity were 90.5% and 97.8%, respectively (45). More recently, it has been shown that MRL is significantly more accurate than multidetector-row CT (46), and that in 41% of PCa patients MRL can detect LNM outside the surgical area of routine pelvic lymph node dissection (46). Although these results are very promising, MRL has not yet become available for clinical use due to the lack of an U.S. Food and Drug Administration (FDA) -approved lymph node-specific contrast agent.

The added value of DWI compared to USPIO-MRL did not improve diagnostic accuracy, but rather reduced significantly reading time for detecting pelvic LNM (47). However, one study also reported a good accuracy based on ADC value alone, with a sensitivity of 86.0% and a specificity of 85.3% (48).

A study of 411 consecutive patients demonstrated that MRI was an independent statistically significant predictor of LNM (P=0.002), with PPV and NPV value of 50% and 96.36%, respectively. On multivariate analysis, prediction of lymph node status using the model that included all MRI variables (ECE, SVI, and LNM) along with the Partin table results had also a significantly greater AUC than the univariate model that included only MRI LNM findings (AUC =0.892 vs. 0.633, respectively, P<0.01) (49).

Prostate cancer biologic potential

The Gleason scoring system remained one of the most powerful prognostic predictors in Pca for nearly 50 years after its initial description (50). It was endorsed as the primary staging system for Pca by the College of American Pathologists, the Armed Forces Institute of Pathology Fascicle on Prostate Cancer, the Association of Directors of Anatomic and Surgical Pathology, and the World Health Organization (WHO) (51).

Gleason grade has been associated with biochemical failure, local recurrences, and distant metastases such as skeletal and LNM after prostatectomy or radiation therapy (52-54). Since Gleason scores of 3+4, or lower, are associated with lower disease progression rates, and Gleason scores of 4+3, or higher, are associated with higher disease progression rates (55), a differentiating between both is meaningful.

Several studies reporting an association of Gleason staging with MRI are a great quantity, especially with DWI a significant negative correlation between Gleason score and ADC values been found (56,57). Furthermore, choline plus creatine-to-citrate ratios determined by using MRSI have also been correlated with Gleason grade (58,59). Wang et al. even reported the correlation of SI of Pca on T2WI with Gleason grade and found that SI evaluation on T2WI may facilitate noninvasive assessment of Pca aggressiveness (60).

Treatment planning

There are several therapeutic options including pelvic lymph node dissection (PLND), external beam radiotherapy (EBRT), radical prostatectomy (RP), androgen deprivation therapy (ADT), brachytherapy, cryosurgery, hyperthermia, and chemotherapy. Monotherapy or combination therapy is performed based on the TNM staging and clinical symptoms of the cancer. Good treatment strategies require a very careful evaluation of an individual prognosis to avoid inappropriate therapy induced morbidity or treatment failure. It is imperative that all tools available are used for different patients so that cancer is controlled.

RP is well established as a definitive treatment option in the management of localized Pca. The goal of this procedure is to achieve excellent oncologic control with negative surgical margins while preserving urinary continence and erectile function. A nerve-sparing radical prostatectomy preserves the neurovascular bundle (NVB) running along the posterior-lateral aspect of the prostate. This procedure is the standard of care for men with a low preoperative risk of extraprostatic diseases who wish to retain erectile function, and is also associated with improved urinary continence (61-64). The primary risk of nerve sparing is a positive surgical margin in a patient with organ-confined or extraprostatic extension (65,66). As such, accurate preoperative staging is very important for guiding treatment, and imaging techniques could provide a significant contribution.

Therapy response

Early selection of patients who are most likely to benefit from chemotherapy or radiotherapy may prevent the risk of toxicity in non-responding patients with prostate tumor. Early response to chemotherapy is monitored with DWI especially in bone metastases, as well as significant changes in perfusion due to tumor vascularity and extraction coefficient derived from DCE-MRI (Figure 6).

Figure 6 3T magnetic resonance (MR) images of extracapsular extension (ECE) of prostate cancer in a 56-year-old man with a Gleason score of 4+5 and a PSA level of 40.64 ng/mL. A and B. Transverse 3 mm-thick MR (4580/105) image and coronal 3 mm-thick MR (2990/86) image show a hypointense tumor with extraprostatic extension in the left transitional and peripheral zone of the prostate; C. Transverse 3 mm-thick DWI (3500/73, b-value of 1,000 s/mm²) shows intense, increased signal (restricted diffusion) throughout the mass; D. An ADC map shows a focal hypointense lesion extending outside the capsule; E. A color-coded wash-out map shows a focal area of wash-out in the location of cancer and left pulic bone metastases; F. The disease was clinically staged as T3 prostate cancer and confirmed by pathology

Foltz et al. found regional and temporal changes in ADC and T2 relaxation during radiation therapy (RT) in patients with low and intermediate risk localized Pca (67). A study of Franiel et al. showed statistically significant changes in perfusion and extraction coefficient parameters derived from DCE-MRI in monitoring the tissue changes to percutaneous intensity-modulated radiotherapy of Pca (68).

A study also demonstrated that after ADT, there was a significant reduction in all DCE-MRI parameters measured in tumor regions of interest (K^trans, K_ep, V_p). ADC values significantly decreased in areas of normal-appearing peripheral zone. As MRI provided dynamic information that was helpful in therapy response, their findings suggested that DCE as a marker of angiogenesis may help demonstrate ADT resistance and DWI may be more accurate in determining presence of tumor cell death versus residual tumor (69).

Tumor recurrence

Approximately 25% to 30% of patients who underwent RP will develop local or systemic recurrent diseases (70,71). Biochemical failure (i.e., a rising serum PSA in the absence of demonstrable metastases) is widely accepted as an appropriate end point for defining treatment failure in men with localized Pca. The serum PSA is routinely used to monitor disease recurrence after definitive therapy because biochemical recurrence antedates metastatic disease progression and Pca-specific mortality by an average of 10 years, respectively (72-74). Biochemical recurrence-free probability after salvage radical prostatectomy at 5 years ranged from 37% to 55% and the estimated cancer-specific survival at 10 years ranged from 70% to 83% (75).

Diagnosis of recurrence of Pca remains challenging by imaging, especially in the early stage. At present, serial serum PSA test plays the important role in the assessment of recurrence and progression of Pca after initial radical treatment (76).

The current consensus considers a PSA increase over a threshold of 0.2 ng/mL as the cutoff that necessitates further evaluation (77). The main role of imaging would be to identify the patients with local recurrence who would potentially benefit from salvage radiotherapy. Detecting the site of recurrence is difficult, mainly because of the absence of any signs or symptoms in the early stage (78). A critical diagnostic dilemma for the evaluation of patients with biochemical failure is to differentiate between patients who only have local recurrence and those who have metastatic spread. At this point, diagnostic imaging strategies are able to provide crucial information toward differentiating local recurrence versus metastatic spread and in helping plan further therapeutic interventions.

To guide target biopsy for clinically suspected cancer in patients with negative biopsy Cancer suspicious regions (CSRs) seen on multiparametric MRI can be targeted for biopsy. This can be done by either performing a TRUS-guided biopsy or a MR-guided biopsy.

TRUS-guided prostate biopsy is the gold standard for the diagnosis of Pca. When applied as a sextant biopsy in patients with a total PSA value ranging from 4-10 ng/mL, this approach has a sensitivity of 39-52% and a specificity of 81-82% (79). Yet, about 20% of Pca are not detected at the first biopsy. When the first biopsy is negative, a repeat biopsy may be recommended, which has a cancer detection rate between 20% to 35% (80-82).

MRI-guided prostate biopsy is a diagnostic option for patients with CSRs, this technology has gained growing importance in the diagnosis of Pca. The capability of combining MR imaging with techniques to simultaneously perform a targeted biopsy of the prostate is of particular interest to urologists.

Several studies have already demonstrated this technology improved cancerous detection rate in subjects with an elevated PSA and repetitive negative TRUS-guided biopsies (11,83,84). In a study of 54 patients with elevated PSA and negative biopsies, MRI had a sensitivity of 83% and a PPV of 50% for detection of Pca. A study of 92 patients concluded that for patients with elevated PSA and 2 previous negative biopsies, a negative MRI can rule out cancer and avoid subsequent biopsies (85).

In a study of 68 patients with repeat negative TRUS-guided prostate biopsies, the tumor detection rate of 3 Tesla MRI-guided biopsy was 59% (40 of 68 cases) using a median of 4 cores (86). In a study of 96 patients with TRUS-negative results, the sensitivity, specificity, PPV and NPV of MRI-guided core biopsies for Pca detection were 95.8%, 95.5%, 95.8% and 99.5% to 95.5% (87).

MR-compatible robots for transrectal prostate biopsy are being developed. Preliminary results found in phantom and patient feasibility studies are promising (88-90). In future studies, robotics could also play an important role in guiding focal treatment of PCa. But before robot-assisted MRI guided focal therapy can be realized, further extensive research needs to be done.

Future prospects

Although functional MR system for staging Pca on 1.5 Tesla is commercially available and is becoming more widely used, 3 Tesla MR scanners offer improvements in both spatial and temporal resolution and in speed. Increasing static magnetic field strength, B₀, from 1.5 Tesla to 3 Tesla will result in a theoretical doubling of the signal-to-noise ratio (SNR). The increase in SNR results in an increase in spatial and temporal resolution and a decrease in the acquisition time (91). However, a disadvantage of 3 Tesla is the increased susceptibility effect in comparison with 1.5 Tesla due to the higher field inhomogeneity as well as the chemical shift effect, which are directly related to magnetic field strength (92).

Conclusions

The increasing incidence of Pca, which is the most frequently diagnosed malignancy in the Western male population (1), poses an increasing burden on health care. MRI is able to provide detailed anatomical images due to high spatial resolution, superior contrast resolution and multiplanar capability (93). MRI noninvasively improves cancer staging, biologic potential and treatment planning, monitors antitumor therapy and local recurrence, and guides target biopsy for clinically suspected cancer with previous negative biopsy. State-of-the-art techniques, such as DWI, MRSI, DCE-MRI, high-field strength scanner, image postprocessing and PACS improved interpretation of Pca images. To interpret these studies accurately, there is still a need for multi-institutional studies to standardize functional MRI techniques and interpretation criteria.

Acknowledgements

The work described in this paper was supported by a grant from the National Natural Science Foundation of China (Project No. 81171307).

Disclosure: The authors declare no conflict of interest.

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