Magnetic Resonance Imaging Guided Prostate Biopsy in Men With Repeat Negative Biopsies and Increased Prostate Specific Antigen

Oncology: Prostate/Testis/Penis/Urethra

Magnetic Resonance Imaging Guided Prostate Biopsy in Men With Repeat Negative Biopsies and Increased Prostate Specific Antigen Thomas Hambrock, Diederik M. Somford, Caroline Hoeks, Stefan A. W. Bouwense, Henkjan Huisman, Derya Yakar, Inge M. van Oort, J. Alfred Witjes, Jurgen J. Fütterer and Jelle O. Barentsz* From the Departments of Radiology and Urology (DMS, IMvO, JAW), University Medical Centre St. Radboud, Nijmegen, The Netherlands

Abbreviations and Acronyms CSD ⫽ clinically significant disease DCE-MRI ⫽ dynamic contrast enhanced MRI DR ⫽ detection rate GS ⫽ Gleason score M-M ⫽ multimodal MR ⫽ magnetic resonance MR-GB ⫽ MRI guided biopsy MRI ⫽ MR imaging PSA ⫽ prostate specific antigen PSAD ⫽ PSA density PZ ⫽ peripheral zone T2-w ⫽ T2-weighted TRUS ⫽ transrectal ultrasound TRUS-GB ⫽ TRUS guided biopsy TSR ⫽ tumor suspicious region TZ ⫽ transition zone Submitted for publication June 17, 2009. Study received institutional review board approval. Supported by the Dutch Cancer Society. * Correspondence: Department of Radiology, P. O. Box 9101, 6500HB Nijmegen, The Netherlands (telephone: ⫹ 31 24 3614011; FAX: ⫹ 31 24 3540866; e-mail: [email protected]).

Purpose: Undetected cancer in repeat transrectal ultrasound guided prostate biopsies in patients with increased prostate specific antigen greater than 4 ng/ml is a considerable concern. We investigated the tumor detection rate of tumor suspicious regions on multimodal 3 Tesla magnetic resonance imaging and subsequent magnetic resonance imaging guided biopsy in 68 men with repeat negative transrectal ultrasound guided prostate biopsies. We compared results to those in a matched transrectal ultrasound guided prostate biopsy population. Also, we determined the clinical significance of detected tumors. Materials and Methods: A total of 71 consecutive patients with prostate specific antigen greater than 4 ng/ml and 2 or greater negative transrectal ultrasound guided prostate biopsy sessions underwent multimodal 3 Tesla magnetic resonance imaging. In 68 patients this was followed by magnetic resonance imaging guided biopsy directed toward tumor suspicious regions. A matched multisession transrectal ultrasound guided prostate biopsy population from our institutional database was used for comparison. The clinical significance of detected tumors was established using accepted criteria, including prostate specific antigen, Gleason grade, stage and tumor volume. Results: The tumor detection rate of multimodal 3 Tesla magnetic resonance imaging guided biopsy was 59% (40 of 68 cases) using a median of 4 cores. The tumor detection rate was significantly higher than that of transrectal ultrasound guided prostate biopsy in all patient subgroups (p ⬍0.01) except in those with prostate specific antigen greater than 20 ng/ml, prostate volume greater than 65 cc and prostate specific antigen density greater than 0.5 ng/ml/cc, in which similar rates were achieved. Of the 40 patients with identified tumors 37 (93%) were considered highly likely to harbor clinically significant disease. Conclusions: Multimodal magnetic resonance imaging is an effective technique to localize prostate cancer. Magnetic resonance imaging guided biopsy of tumor suspicious regions is an accurate method to detect clinically significant prostate cancer in men with repeat negative biopsies and increased prostate specific antigen. Key Words: prostate, prostatic neoplasms, biopsy, magnetic resonance imaging, prostate-specific antigen

520

www.jurology.com

IN 2008 prostate cancer was the most commonly diagnosed cancer in men, accounting for 25% of all cancers. The

most widely used tests to screen for prostate cancer are digital rectal examination and the PSA blood serum

0022-5347/10/1832-0520/0 THE JOURNAL OF UROLOGY® Copyright © 2010 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 183, 520-528, February 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.10.022

MAGNETIC RESONANCE IMAGING GUIDED PROSTATE BIOPSY

test. Increased PSA is not cancer specific since numerous benign prostate conditions can increase PSA. Urologists are increasingly faced with the dilemma of how best to treat a patient with increased PSA in whom repeat TRUS-GB reveals no cancer. Systematic prostate TRUS-GB is the standard procedure for prostate histological sampling. Prostate cancer is often multifocal and the volume sampled by systematic TRUS-GB is relatively small. The value of MRI to accurately localize prostate cancer is well established.1 The accuracy of cancer localization on anatomical T2-w imaging remains low.2 Thus, DCE-MRI and diffusion weighted imaging have been implemented to improve the accuracy of prostate cancer localization. A M-M approach using a combination of these techniques appears to be optimal.3 Imaging guided biopsies are advocated to improve tumor detection. However, grayscale TRUS, the most commonly used technique for biopsy guidance, has low sensitivity to localize prostate cancer.4 A combined approach that appears more useful is systematic and additional lesion directed biopsies of contrast enhanced suspicious areas.5,6 Our principal aim was to determine the tumor detection yield of M-M MRI followed by directed MR-GB in a large patient group clinically suspicious for cancer but with repeat negative systematic TRUS-GBs. We also determined whether detected tumors were clinically significant.

521

axial diffusion weighted imaging and DCE-MR images were obtained using 15 ml gadopentetate dimeglumine. MR data analysis. Prostate images were viewed on an in-house developed analytical software work station that projected calculated DCE-MRI parameters7 and apparent diffusion coefficient maps as color overlays over T2-w images. All patient images were read in consensus by 2 readers (TH, JF) with 2 and 5 years of experience, respectively, with prostate MRI. MR images were used to determine up to 3 TSRs per patient using features described in the literature.8,9

MR Guided Biopsy An average of 2 weeks (range 1 to 6) after initial MRI to localize possible tumors and identify TSR for MR-GB planning patients underwent 3 Tesla prostate MR-GB. Antibiotic prophylaxis was given with 500 mg ciprofloxacin orally. A previously described translation technique10 using a MR compatible biopsy device was used to obtain 18 gauge biopsy cores of re-identified TSRs with a MR compatible biopsy gun. Briefly, a needle guider attached to the arm of the biopsy device was inserted rectally and adjusted to aim toward the TSR in the prostate. Biopsies were obtained through the needle guider. Only TSR directed biopsies were obtained with no random biopsies. All biopsies were done by 1 radiologist (TH). Samples were processed by routine histopathological fixation and staining, and evaluated by a histopathologist.

Statistical Analysis

METHODS

The chi-square test was used to calculate significant differences between the MR-GB and TRUS-GB subgroups. The Mann-Whitney U test was done to compare mean age, PSA, prostate volume and PSAD between groups with significant differences considered at p ⬍0.05. Statistical analysis was performed with SPSS®, version 16.0.01.

Patients

Tumor Clinical Significance

Between August 2006 and March 2008, 71 consecutive patients with PSA greater than 4 ng/ml and 2 or greater negative TRUS-GB sessions (of which the last session included at least an extended scheme of 8, 9 or 10 cores, including TZ sampling) were referred from the departments of urology at our medical center and at Canisius Wilhelmina Hospital, Nijmegen, The Netherlands, for clinically routine prostate M-M MRI. The institutional review board approved this study. The histopathology database at our institution was searched for consecutive patients from January 2000 to December 2006 with 2 or more TRUS-GB sessions. Only patients who underwent at least 1 systematic biopsy protocol of 8 to 10 cores, including TZ biopsy, were included in analysis. At each TRUS-GB session the principal diagnosis, patient age, PSA and prostate volume were noted. To remove the bias effect of differences in PSA and prostate volume tumor detection rates were compared by subgroup analysis of PSA, prostate volume and PSAD.

The clinical significance of detected tumors was determined by currently accepted criteria.11–14 In patients in whom prostatectomy was done after positive biopsy a Gleason grade 4 or 5 component, stage pT3 or tumor volume greater than 0.5 cc was considered to represent CSD. In patients diagnosed with cancer in whom no prostatectomy was done cancer was considered significant when PSA at biopsy was greater than 10 ng/ml and PSAD greater than 0.15 ng/ml/cc or Gleason grade 4 or 5 was found at biopsy.

Localization MRI. To identify possible tumor site(s) MRI was done with a 3 Tesla Trio® Tim MR scanner with an endorectal coil (Medrad®) in 28 patients and with pelvic phased array coils only in 40. Axial, sagittal and coronal T2-w images,

RESULTS In 70 of 71 patients TSRs were identified on MRI. One patient refused biopsy and in another none was performed due to a high bleeding risk and no certain evidence of tumor on MRI. Thus, 68 patients underwent MR-GB. In the 68 patients mean age was 63 years (range 48 to 74) and median PSA was 13 ng/ml (range 4 to 243). They underwent a median of 3 previous negative TRUS-GB sessions (range 2 to 7). The median duration of prostate MR-GB was 30 minutes (range 14 to 75).

522

MAGNETIC RESONANCE IMAGING GUIDED PROSTATE BIOPSY

The tumor DR of MR-GB was 59% (40 of 68 cases). A total of 260 prostate cores (directed cores only with no random cores) were obtained from 114 TSRs with a TSR tumor DR of 40% (46 of 114). The median number of biopsies per patient was 4 (range 2 to 7). Table 1 lists patient and pathological findings. A total of 28 patients had no tumor. Radical prostatectomy was done in 20 of the 40 patients with tumor. GS 7 or greater was found in 10 of these 20 patients (50%) with extracapsular disease evident in 6 of 20 (30%). In 10 of 20 cases tumor volume was greater than 0.5 cc with GS 6. Thus, all patients with prostatectomy harbored CSD. The remaining 20 patients underwent external beam raTable 1. Patient, radiological and pathological features

Mean age (range) Median ng/ml PSA (range) No. pos prostate Ca family history (%) No. suspicious digital rectal examination (%) Median No. previous TRUS-GBs (range) No. TSRs/pt (range) Median No. biopsy cores (range) Median mins MR-GB (range) No. principal histological diagnosis: Tumor Chronic prostatitis Prostatitis ⫹ reactive atypia Acute prostatitis Atypia suspicious for malignancy Atypical adenomatous hyperplasia Fibromuscular nodule Necrosis No abnormality No. highest GS (%): 5 6 7 8 9 No. disease clinical significance: GS 7 or greater Radical prostatectomy GS 7 or greater MR-GB GS 7 or greater ⫹ no radical prostatectomy Tumor greater than 0.5 cc in radical prostatectomy ⫹ GS 6 or less M⫹, GS 6 or less ⫹ noradical prostatectomy M⫹ & GS 7 or greater Stage pT3 in radical prostatectomy PSA greater than 10 ng/ml ⫹ PSAD greater than 0.15 ng/ml/cc, GS 6 or less ⫹ no radical prostatectomy Insignificant disease not ruled out No. advanced disease: M⫹/N⫹ Stage T3 in radical prostatectomy

All Pts

Tumor

No Tumor

63 (48–76) 13 (4–243) 4 (6) 2 (3)

65 (48–76) 13 (5–243) 2 (50) 1 (50)

62 (54–70) 12 (4–58) 2 (50) 1 (50)

3

(2–8)

1 (1–3) 4 (2–7) 30 (14–75)

3

(2–7)

1 (1–3) 3 (2–6) 29 (14–75)

3

2 (2–3) 4 (2–7) 33 (15–55)

40 15 2 1 2 2 2 1 3 40 3 19 10 5 3 40 18 10

(7) (48) (25) (12) (8)

9 8 1 2 5 10

3 8 (20%) 3 5

(2–8)

diotherapy (11), brachytherapy (3), hormonal ablation (3) or active surveillance (3). In these patients biopsy GS, prostate volume and PSA were used to assess CSD with biopsy GS 7 or greater in 9 and PSA greater than 10 ng/ml plus PSAD greater than 0.15 ng/ml/cc in 10. One patient had skeletal metastasis. Thus, CSD was considered present in 17 of the 20 patients (85%) and in 37 of all 40 (93%) with tumor. Aggressive cancer was evident in at least 19 of the 40 patients (48%) with tumor (GS 7 or greater/ pT3/N⫹/M⫹). Table 2 lists tumor characteristics. The principal tumor site was the most ventral aspect of the TZ in 26 of 46 cases (57%), followed by the PZ paramedian region in 9 (20%) and the PZ anterior horns in 5 (11%) (fig. 1). Figure 2 shows MRI in a patient in whom tumor was detected by MR-GB. In our reference database we identified 248 patients with at least 2 TRUS-GB sessions and 65 with 3 sessions. No MRI was done before biopsy in these men and biopsies were performed on a systematic basis only. Overall tumor DR at biopsy sessions 2 and 3 was 22% (55 of 248 cases) and 15% (10 of 65), respectively. Table 2 shows tumor DR in the TRUS-GB and MR-GB subgroups according to PSA, prostate volume and PSAD. MR-GB achieved a significantly higher tumor DR in all PSA subgroups (p ⬍0.01), and for prostate volume (p ⬍0.01) and PSAD (p ⬍0.05). However, in patients with PSA greater than 20 ng/l, prostate volume greater than 65 cc, and PSAD less than 0.15 and greater than 0.5 ng/ml/cc superior results were evident but not significant (p ⬎0.05, figs. 3 to 5). Self-limiting transurethral hemorrhage and uncomplicated urinary tract infection in 1 case each were the only procedure related complications.

DISCUSSION Using state-of-the-art 3 Tesla M-M MRI to localize tumors we noted that a definite diagnosis of prostate cancer could be made in 40 of 68 patients (59%) in whom repeat prostate biopsies remained negative but continuous concern regarding cancer was evident. Of the 40 patients diagnosed with prostate cancer 37 (93%) were considered to harbor CSD. Therefore, it is justifiable to deduce that prostate MRI accurately portrays tumor sites and, thus, offers urologists a method to improve biopsy outcomes. Since MR-GB is limited by restricted general availability, other methods of MRI targeted biopsy techniques could be considered, such as MR-TRUS fusion15 during TRUS biopsy. Nevertheless, MR-GB is probably the most accurate technique because translating TSR to another imaging modality is not required.

MAGNETIC RESONANCE IMAGING GUIDED PROSTATE BIOPSY

523

Table 2. TRUS-GB vs MR-GB populations TRUS-GB2 No. pts: Tumor (%) No tumor Mean age (range): All pts Tumor No tumor Median ng/ml PSA (range): All pts Tumor No tumor No. previous biopsy atypia (%): All pts Tumor No tumor No. previous biopsy HGPIN in (%): All pts Tumor No tumor No. PSA less than 4 ng/ml: All pts Tumor (%) No. PSA 4–10 ng/ml: All pts Tumor (%) No. PSA 10.1–15.0 ng/ml: All pts Tumor (%) No. PSA 15.1–20.0 ng/ml All pts Tumor (%) No. PSA ⬎20.1 ng/ml All pts Tumor (%) Median cc prostate vol (range): All pts Tumor No. prostate vol less than 30 cc: All pts Tumor (%) No. prostate vol 30.1–50 cc: All pts Tumor (%) No. prostate vol 50.1–65 cc: All pts Tumor (%) No. prostate vol greater than 65.1 cc: Total All pts Tumor (%) Median ng/ml/cc PSAD (range): All pts Tumor No. PSAD less than 0.15 ng/ml/cc: All pts Tumor (%) No. PSAD 0.15–0.30 ng/ml/cc: All pts Tumor (%) No. PSAD 0.30–0.50 ng/ml/cc: All pts Tumor (%) No. PSAD greater than 0.50 ng/ml/cc: All pts Tumor (%)

TRUS-GB3

MR-GB

p Value vs TRUS-GB2

p Value vs TRUS-GB3

⬍0.001

⬍0.001

248 55 193

(22)

65 10 55

(15)

68 40 28

(59)

64 66 64

(74–80) (52–78) (52–78)

65 64 65

(48–76) (57–75) (48–76)

63 65 62

(48–76) (48–76) (54–70)

0.39 0.22

0.24 0.61

8 9 8

(0.1–63) (2–60) (0.1–63)

10 13 10

(2–36) (6–29) (2–36)

13 13 12

(4–243) (5–243) (4–58)

⬍0.01 ⬍0.01

0.01 0.80

34 10 24

(14) (29) (71)

14 4 10

(22) (29) (71)

14 6 8

(21) (43) (57)

0.19 0.38

0.93 0.45

12 4 8

(5) (33) (66)

7 2 5

(11) (29) (71)

3 2 1

(4) (67) (33)

0.88 0.33

0.18 0.31

22 4

4 0

Not applicable

Not applicable

(18)

142 29

(20)

28 4

(11)

21 10

(48)

45 8

(18)

20 1

(5)

17 11

(65)

16 4

(25)

6 2

(33)

14 11

(79)

23 10

(43)

7 3

(43)

16 8

(50)

58 42

* (15–201) (15–160)

61 30

† (17–212) (17–94)

48 42

(12–152) (12–83)

31 9

(29)

7 5

(71)

14 14

(100)

67 21

(31)

14 1

(7)

21 15

(71)

50 10

(20)

15 1

(7)

14 7

(50)

96 14

(14)

27 2

(7)

19 5

(26)

* 0.14 (0.01–1.14) 0.21 (0.04–1.14)

0 0

† 0.15 (0.03–1.69) 0.48 (0.1–1.69)

0.29 (0.06–4.5) 0.33 (0.09–4.5)

138 19

(14)

32 2

(6)

12 2

(17)

68 17

(25)

20 2

(20)

23 13

(57)

28 11

(39)

6 1

(17)

17 12

(71)

10 7

(70)

5 4

(80)

16 13

(81)

* No prostate volume available in 4 patients. † No prostate volume available in 2 patients.

0.006

⬍0.001

⬍0.001

⬍0.001

⬍0.001

⬍0.001

0.69

0.75

0.09 0.08

0.02 0.99

0.02

0.04

0.001

⬍0.001

0.03

⬍0.009

0.21

⬍0.08

⬍0.01 0.02

0.01 0.69

0.96

0.37

0.03

0.001

0.04

0.02

0.51

0.95

524

MAGNETIC RESONANCE IMAGING GUIDED PROSTATE BIOPSY

Figure 1. Prevalence of 46 tumor positive TSRs (for 9 biopsies 2 adjacent regions were positive for total of 55 tumor maps) in prostate on MR-GB. Prostate was divided into 5 craniocaudal segments equal to apex (A), mid apex (B), mid (C), mid base (D) and basal (E) levels. Red areas indicate 5 or greater positive TSRs. Orange areas indicate 4 positive TSRs. Yellow areas indicate 3 positive TSRs. Green areas indicate 2 positive TSRs. Blue areas indicate 1 positive TSRs. R, right. L, left. VT, ventral TZ. MT, middle TZ. DT, dorsal TZ. AH, PZ anterior horn. DL, dorsolateral PZ. D, dorsal PZ.

For comparison we selected a TRUS-GB population from our institution that was clinically matched for age, atypia prevalence on previous biopsy, PSA, prostate volume and PSAD. We also determined tumor DR in each subgroup. In most studies of 8 to 12-core extended schemes cancer was detected in around 10% to 17% of patients on the second biopsy.16–18 Thus, the overall 22% and 15% tumor DRs at TRUS-GB sessions 2 and 3, respectively, at our institution are in agreement with reported data. Since different PSA values can predict the likelihood of finding tumor and represent a bias for comparison, cases were substratified according to different PSA levels. MR-GB DR was superior to repeat TRUS-GB sessions in all PSA subgroups (p ⬍0.01) except in the group with a high PSA of greater than 20 ng/ml, in which a similar DR was achieved (50% vs 43%). Prostate volume is another important factor that has a role in the tumor DR achieved by different biopsy protocols. In a previous series 8 cores were appropriate in patients with less than 30 cc prostates, 10 to 12 were needed in 30 to 50 cc prostates and greater than 12 were needed in prostates greater than 50 cc.19 In all prostate volume groups MR-GB significantly outperformed TRUS-GB for tumor detection (p ⬍0.05) except in excessively large prostates greater than 65 cc, in which similar rates were achieved.

In patients with tumor PSAD less than 0.15 ng/ ml/cc is considered a good prognostic feature with a low progression rate.13 MR-GB did not achieve significant detection improvements over TRUS-GB in this patient subset with probably insignificant disease. In contrast, in the greater than 0.50 ng/ml/cc PSAD group tumors were likely to have larger volume and, therefore, they were more easily diagnosed by TRUS-GB. In cases of negative TRUS-GB radical measures involving 24 to 64-core saturation biopsy were advocated with a reported DR of 18% to 34% at session 2.20,21 No widespread application and acceptance of this technique by urologists exist with conflicting published results.22,23 Saturation biopsy appears to increase tumor detection in high risk cases but the additional use of analgesia/anesthesia, the higher incidence of side effects and the high cost of processing the large amount of pathological material are its greatest drawbacks. Since our study shows that MR-GB has a high tumor detection yield and requires a low number of cores (median 4), this method could be an appealing alternative to patient, urologist and pathologist alike. Whether prostate MR-GB detects a substantial proportion of potentially insignificant tumors is a legitimate question. Higher sensitivity to detect tumor implies a higher chance of finding tumors that do not need treatment, so-called clinically insignifi-

MAGNETIC RESONANCE IMAGING GUIDED PROSTATE BIOPSY

525

Figure 2. Endorectal coil 3 Tesla MRI in 64-year-old male with 4 previous negative TRUS-GBs, including 2 ⫻ 8, 10 and 12 cores, and PSA 18 ng/ml. T2-w axial (a) and coronal (b) images show low signal intensity lesions (arrow) in ventral portion of apex. This area showed restriction on apparent diffusion coefficient map (c) and high Ktrans on DCE-MRI (d). Axial T2-w true fast imaging with steady state precession during MR-GB demonstrates needle guider (dashed red line) directed toward TSR (dashed yellow oval) (e). Histopathological analysis of biopsy cores revealed GS 4 ⫹ 3 ⫽ 7 adenocarcinoma and pelvic lymph node dissection showed metastatic disease.

cant cancer. For prostate cancer overtreatment of these tumors remains controversial.24 In the 1990s the concept of insignificant prostate cancer based on tumor size and favorable pathological characteristics was proposed.25 Clinical criteria to predict such tumors were later defined as PSA 10 ng/ml or less, GS 6 or less, clinical stage pT2 or less and tumor volume 0.5 cc or less.11,12,26 In prostatectomy series the predominant tumor site is the PZ in almost 70% of cases.27 Therefore, current

systematic biopsy schemes extensively sample the PZ and, thus, the prostate dorsal region. In contrast, 31 of the 46 tumors (68%) in our series were anterior, 26 (57%) were in the ventral TZ and 5 (11%) were in the PZ anterior horns. This may explain the previous negative biopsies in our patient group. The current literature on prostate MR-GB is sparse. The few currently available reports included a small number of patients, had excessively long imaging and biopsy times, and described only con-

Figure 3. Tumor detection rate in PSA subgroups at TRUS-GB sessions 2 (blue bars) and 3 (red bars), and MR-GB session (green bars)

Figure 4. Tumor detection rate in prostate volume subgroups at TRUS-GB sessions 2 (blue bars) and 3 (red bars), and MR-GB session (green bars).

526

MAGNETIC RESONANCE IMAGING GUIDED PROSTATE BIOPSY

highest number of cores per biopsy session was 8 to 10, 12 and 18, and even saturation biopsy was done. Patients selected for study inclusion based on PSA greater than 10 ng/ml may represent a selection bias in relation to determining the clinical significance of detected tumors.

CONCLUSIONS

Figure 5. Tumor detection rate in subgroups by prostate PSAD in ng/ml/cc at TRUS-GB sessions 2 (blue bars) and 3 (red bars), and MR-GB session (green bars).

ventional T2-w MRI to determine TSRs for MR-GB after 1 previous negative TRUS biopsy.28 –30 Limitations of the current study relate principally to the fact that a direct comparison of our results to other literature could not be made. This was because of differences in PSA, prostate volume, the number of previous biopsies and the biopsy schemes used at the initial sessions. A prospective, randomized trial would be superior. To determine the potential benefit we compared our study cohort with our institutional database, selecting similar patients but with TRUS guided multiple biopsies and subgrouped by PSA, prostate volume and PSAD. Since our institution is a referral hospital, patients with MR-GB underwent heterogeneous previous biopsy protocols. The

Results indicate that MRI is highly effective to detect and localize clinically significant prostate cancer. Since guided biopsies toward TSRs on MRI detect clinically significant tumor in a substantial proportion of patients, MRI should be considered essential in any evaluation protocol in patients suspected of harboring malignancy but who have had successive negative biopsies. Also, MR-GB directed toward TSRs on M-M MRI is useful to accurately validate the correct sampling of suspicious prostate tissue. Because of the low number of cores needed, MR-GB appears to be an appealing alternative to procedures such as saturation biopsy. Finally, detected tumors were mostly located in areas not explicitly sampled by routine schemes. Future studies of tumor DR using MR-TRUS fusion during TRUSGB, including saturation targeting of suspicious areas, transperineal sampling of the anterior prostate or changing sampling sites on TRUS-GB in patients with repeat sessions, are needed and ideally should be compared to a MRI directed MR-GB technique.

ACKNOWLEDGMENTS Ninki Minderhoud, Willem Vreuls and Jean-Paul van Basten provided assistance.

REFERENCES 1. Umbehr M, Bachmann LM, Held U et al: Combined magnetic resonance imaging and magnetic resonance spectroscopy imaging in the diagnosis of prostate cancer: a systematic review and meta-analysis. Eur Urol 2008; 55: 591. 2. Heijmink SW, Futterer JJ, Hambrock T et al: Prostate cancer: body-array versus endorectal coil MR imaging at 3 T– comparison of image quality, localization, and staging performance. Radiology 2007; 244: 184. 3. Tanimoto A, Nakashima J, Kohno H et al: Prostate cancer screening: the clinical value of diffusion-weighted imaging and dynamic MR imaging in combination with T2-weighted imaging. J Magn Reson Imaging 2007; 25: 146. 4. Halpern EJ and Strup SE: Using gray-scale and color and power Doppler sonography to detect prostatic cancer. AJR Am J Roentgenol 2000; 174: 623.

5. Mitterberger M, Pinggera GM, Horninger W et al: Comparison of contrast enhanced color Doppler targeted biopsy to conventional systematic biopsy: impact on Gleason score. J Urol 2007; 178: 464. 6. Pelzer A, Bektic J, Berger AP et al: Prostate cancer detection in men with prostate specific antigen 4 to 10 ng/ml using a combined approach of contrast enhanced color Doppler targeted and systematic biopsy. J Urol 2005; 173: 1926. 7. Huisman HJ, Engelbrecht MR and Barentsz JO: Accurate estimation of pharmacokinetic contrastenhanced dynamic MRI parameters of the prostate. J Magn Reson Imaging 2001; 13: 607. 8. Akin O, Sala E, Moskowitz CS et al: Transition zone prostate cancers: features, detection, localization, and staging at endorectal MR imaging. Radiology 2006; 239: 784. 9. Futterer JJ, Heijmink SW, Scheenen TW et al: Prostate cancer localization with dynamic con-

trast-enhanced MR imaging and proton MR spectroscopic imaging. Radiology 2006; 241: 449. 10. Hambrock T, Futterer JJ, Huisman HJ et al: Thirtytwo-channel coil 3T magnetic resonance-guided biopsies of prostate tumor suspicious regions identified on multimodality 3T magnetic resonance imaging: technique and feasibility. Invest Radiol 2008; 43: 686. 11. Augustin H, Hammerer PG, Graefen M et al: Insignificant prostate cancer in radical prostatectomy specimen: time trends and preoperative prediction. Eur Urol 2003; 43: 455. 12. Bastian PJ, Mangold LA, Epstein JI et al: Characteristics of insignificant clinical T1c prostate tumors. A contemporary analysis. Cancer 2004; 101: 2001. 13. Nakanishi H, Wang X, Ochiai A et al: A nomogram for predicting low-volume/low-grade pros-

MAGNETIC RESONANCE IMAGING GUIDED PROSTATE BIOPSY

tate cancer: a tool in selecting patients for active surveillance. Cancer 2007; 110: 2441. 14. Ochiai A, Troncoso P and Babaian RJ: The relationship between serum prostate specific antigen level and tumor volume persists in the current era. J Urol 2007; 177: 903. 15. Xu S, Kruecker J, Turkbey B et al: Real-time MRI-TRUS fusion for guidance of targeted prostate biopsies. Comput Aided Surg 2008; 13: 255. 16. Mian BM, Naya Y, Okihara K et al: Predictors of cancer in repeat extended multisite prostate biopsy in men with previous negative extended multisite biopsy. Urology 2002; 60: 836. 17. Philip J, Hanchanale V, Foster CS et al: Importance of peripheral biopsies in maximising the detection of early prostate cancer in repeat 12core biopsy protocols. BJU Int 2006; 98: 559.

20. Campos-Fernandes JL, Bastien L, Nicolaiew N et al: Prostate cancer detection rate in patients with repeated extended 21-sample needle biopsy. Eur Urol 2008; 55: 600. 21. Pepe P and Aragona F: Saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. Urology 2007; 70: 1131. 22. Stav K, Leibovici D, Sandbank J et al: Saturation prostate biopsy in high risk patients after multiple previous negative biopsies. Urology 2008; 71: 399. 23. Walz J, Graefen M, Chun FK et al: High incidence of prostate cancer detected by saturation biopsy after previous negative biopsy series. Eur Urol 2006; 50: 498.

18. Roehl KA, Antenor JA and Catalona WJ: Serial biopsy results in prostate cancer screening study. J Urol 2002; 167: 2435.

24. Taylor JA III, Gancarczyk KJ, Fant GV et al: Increasing the number of core samples taken at prostate needle biopsy enhances the detection of clinically significant prostate cancer. Urology 2002; 60: 841.

19. Eskicorapci SY, Guliyev F, Akdogan B et al: Individualization of the biopsy protocol according to the prostate gland volume for prostate cancer detection. J Urol 2005; 173: 1536.

25. Dugan JA, Bostwick DG, Myers RP et al: The definition and preoperative prediction of clinically insignificant prostate cancer. JAMA 1996; 275: 288.

527

26. Miyake H, Sakai I, Harada K et al: Prediction of potentially insignificant prostate cancer in men undergoing radical prostatectomy for clinically organ-confined disease. Int J Urol 2005; 12: 270. 27. Sakai I, Harada K, Hara I et al: A comparison of the biological features between prostate cancers arising in the transition and peripheral zones. BJU Int 2005; 96: 528. 28. Anastasiadis AG, Lichy MP, Nagele U et al: MRIguided biopsy of the prostate increases diagnostic performance in men with increased or increasing PSA levels after previous negative TRUS biopsies. Eur Urol 2006; 50: 738. 29. Beyersdorff D, Winkel A, Hamm B et al: MR imaging-guided prostate biopsy with a closed MR unit at 1.5 T: initial results. Radiology 2005; 234: 576. 30. Engelhard K, Hollenbach HP, Kiefer B et al: Prostate biopsy in the supine position in a standard 1.5-T scanner under real time MR-imaging control using a MR-compatible endorectal biopsy device. Eur Radiol 2006; 16: 1237.

EDITORIAL COMMENT These authors present the largest prostate MR-GB series to date. Results are promising. Unfortunately the current study has several limitations. Statistical comparison with a retrospective TRUS-GB series is not appropriate, although it is from the same institution and matched by serum PSA, prostate volume and PSAD. Also, an important selection bias must be kept in mind. Since the prerequisite for biopsy was the verification of TSRs on M-M MRI, the statements apply only in this particular patient subgroup. Consequently the key conclusion to be drawn from the data is that 41% of patients with TSRs harbored clinically significant prostate cancer, including 59% with positive biopsy findings, of which 70% were significant. The feasibility and diagnostic performance of MRI guided biopsy were already shown in previous studies. However, additional expenses in cost and time compared to those of conventional TRUS-GB do not justify its routine application to detect prostate cancer. TRUS-GB in the hands of an experienced urologist yields a 22% detection rate in the PSA gray zone of between 4 and 10 ng/ml at first biopsy and 10% at rebiopsy after a negative previous biopsy.1

For this reason MR-GB should be reserved for the specific subgroup persistently suspicious for prostate cancer after preceding negative biopsies. A potential future application of MRI may be monitoring patients with proven low risk prostate cancer who elect active surveillance.2 A prerequisite for an adequate modality to survey these cases is high sensitivity and specificity. The TSR DR in the current study is high (70 of 71 patients), which may be explained by the use of M-M rather than conventional T2-w MRI.3 However, other imaging modalities, such as elastography or contrast enhanced ultrasound, can be used more easily in an office setting and offer real-time imaging controlled biopsy of suspicious lesions. Image fusion of MRI and dynamic ultrasound may be the most promising way to evaluate cancerous prostate lesions, biopsy and possibly surveillance strategies (reference 15 in article). David Schilling and Arnulf Stenzl Department of Urology University Hospital Tuebingen Tuebingen, Germany

528

MAGNETIC RESONANCE IMAGING GUIDED PROSTATE BIOPSY

REFERENCES 1. Djavan B, Mazal P, Zlotta A et al: Pathological features of prostate cancer detected on initial and repeat prostate biopsy: results of the prospective European Prostate Cancer Detection study. Prostate 2001; 47: 111.

2. van As NJ, de Souza NM, Riches SF et al: A study of diffusion-weighted magnetic resonance imaging in men with untreated localised prostate cancer on active surveillance. Eur Urol, Epub ahead of print December 6, 2008.

3. Ahmed HU, Kirkham A, Arya M et al: Is it time to consider a role for MRI before prostate biopsy? Nat Rev Clin Oncol 2009; 6: 197.

REPLY BY AUTHORS The statistical approach we used is considered valid for our particular clinical question. Furthermore, we regard our subdivision of patients according to PSA, prostate volume and PSAD a strength in the comparison, which actually decreased potential bias. The prerequisite for biopsy in our study was verification of TSRs on M-M MRI, which were present in 98% of the patients. Of all TSRs 40% were biopsy positive, resulting in 59% of patients having a tumor diagnosis, 93% of whom (54% of patients) most likely had clinically significant cancer.

We agree that the additional expenses in cost and time compared to conventional TRUS-GB do not justify its routine application to detect prostate cancer, which is the reason we perform this procedure only in patients at high risk but with repeat negative biopsies. We agree that a potential future application of MRI may be for monitoring patients with proven low risk prostate cancer who elect active surveillance. Despite being easier to perform, other imaging modalities such as elastography or contrast enhanced ultrasound have not been proven to increase the detection of prostate cancer.