Magnetic Resonance Imaging Targeted Biopsy in Men with Previously Negative Prostate Biopsy Results

Abstract

Purpose:

To evaluate the efficacy of targeted prostate biopsy using magnetic resonance imaging (MRI) and to characterize clinicopathologic features of tumors detected with targeted prostate biopsy in men with previous negative prostate biopsy results.

Patients and Methods:

We prospectively studied 87 patients with a persistently increasing level of serum prostate-specific antigen (PSA), at least one previous set of negative 12-core prostate biopsies, and normal digital rectal examination. All patients were examined with combined T2-weighted and diffusion-weighted MRI before undergoing the prostate biopsy. Prostate biopsy was performed using transrectal ultrasonography-guided standard 12 cores plus targeted biopsy to suspicious region(s) as identified on T2 images on their MRI.

Results:

Of a total of 87 cases, 82 (94.2%) patients had suspicious lesion(s) on their MRI. Of these 82 patients, 46 (56.0%) patients had prostate cancer (PCA) as determined by the biopsy. The patients with PCA showed a significantly higher incidence of having suspicious lesion(s) (the anterior or apex) on MRI than the patients without PCA (P<0.05). On analysis by dividing all biopsy cores into the targeted cores and standard cores, PCA was found in 149/518 (28.8%) MRI-targeted cores and in 32/903 (3.6%) standard cores (P=0.012) Of 43 patients who underwent radical prostatectomy, 37 (86.0%) patients were detected with PCA located at the anterior or apex portion of the prostate. For tumor characteristics according to tumor locations, there was no significant correlation between tumor location and Gleason scores or pathologic stage.

Conclusions:

Our data suggest that a MRI-targeted prostate biopsy after prostate MRI might be considered for the identification of cancer foci and the detection of PCA, for patients with a previous negative standard prostate biopsy result despite a persistently elevated PSA value.

Introduction

E levated serum prostate-specific antigen (PSA) is a common finding in patients with prostate cancer (PCA), and patients with high marker levels undergo transrectal ultrasonography (TRUS)-guided biopsy to confirm the diagnosis.¹ A common dilemma for urologists, however, is the situation when the prostate biopsy is negative and there is still a clinical suspicion of PCA. Efforts to detect PCA have been focused on increasing the number of biopsy cores.^2,3 The location of the cores, however, may be a more significant factor for the detection of PCA. Currently, MRI is used not only for accurate staging of tumors but also for targeting biopsies.^4,5

Targeted biopsies have the advantage of detecting PCAs that are unlikely to be detected, particularly those outside the peripheral zone (PZ) or locations not biopsied in normal schemes.⁶ In men with palpably normal prostates, tumors that are detected by repeated biopsies seem to be detected at the anterior prostatic lesion, and probably arise from either the transition zone (TZ) or anterior lateral horn tissue.⁷ Many of these patients had had multiple sets of negative TRUS-guided biopsies or had been treated by an active surveillance protocol based on a PZ biopsy, suggesting a minimal risk for disease.⁴

We aimed to evaluate the efficacy of targeted prostate biopsy using MRI and to characterize clinicopathologic features of tumors detected with targeted prostate biopsy in men with previous negative prostate biopsy results.

Patients and Methods

Patients

From July 2008 to June 2010, we prospectively included 87 patients with a persistently increasing trend of serum PSA (higher than 4 ng/mL and PSA velocity 0.75 ng/mL/y), at least one previous set of negative 12-core TRUS-guided prostate biopsies, and normal digital rectal examination (DRE). All patients were examined with prostate MRI before undergoing repeated targeted biopsy. Exclusion criteria were patients who had received hormonal, surgical, or irradiation therapy. Informed consent for the MRI examinations was obtained from all patients, and the Institutional Review Board approved this study.

MRI and imaging analysis

All patients were imaged using a 3.0 T MRI system (Intera Achieva 3.0T, Phillips Medical System, Best, The Netherlands), equipped with a phased-array coil (six-channel). All patients underwent diffusion-weighted (DW) MRI in addition to the imaging sequences as part of a routine prostate MRI protocol. T2-weighted turbo spin-echo images were acquired in three orthogonal planes (axial, sagittal, and coronal). All images were reviewed by two uroradiologists who were blinded to the PSA and DRE data. The two radiologists conducted a consensus review of the MRIs obtained from all patients.

All MRI datasets were obtained at identical slice locations with a slice thickness of 3 mm and no intersection gap. MRI morphologic images were analyzed based on T2 signal intensity as normal, equivocal, or suspicious for PCA. An abnormal area was judged suspicious if it was discrete and homogenously low in signal, and if it did not correspond to hemorrhagic areas with a high signal on T1-weighted scans. An abnormal area was judged equivocal if the low signal on T2-weighted images was slightly heterogeneous. For the TZ, an ill-defined nodule that distorted the normal architecture and had concordant abnormalities on DW imaging was considered suspicious for malignancy.⁸

An anterior tumor was defined as a tumor located anterior to a horizontal line drawn at the midpoint of the prostatic urethra (tumor with ≥70% anterior to the urethra on MRI).^4,9 The extreme anterior apical tumor was regarded as an anterior tumor.³

Biopsy protocol

All biopsies were obtained under TRUS guidance using a Voluson 530D ultrasound scanner and an S-IC5–9 endfire endocavity probe (Kretz AG, Zipf, Austria). Biopsies were performed under the laryngeal mask anesthesia, using an 18-G biopsy gun (Bard, Murray Hill, NJ). Twelve systematic biopsies of the PZ were obtained in all patients (parasagittal and laterally directed biopsies at the apex, midgland, and base, on both sides. Targeted prostate biopsies were taken within 4 weeks of the MRI to identify a correlation between the biopsies and imaging findings. A targeted biopsy was defined as TRUS-guided needle biopsy for all the suspicious lesions being malignancy on MRI (as described above) interpreted by an experienced radiologist. In addition to the 12-core biopsy regime that was the standard biopsy protocol in a previous study,¹⁰ up to 14 cores were taken in addition from a suspicious lesion in proportion to the size of the suspicious lesion. The number of additional cores was determined by the distribution of the positive MRI lesion and the size of the prostate.

The MRIs appeared on the screen adjacent to the TRUS, allowing real-time comparison of the methods and zones of interest. When a suspicious lesion was present at MRI, the operator had access to the MRIs and tried to target the lesion area by using only anatomic landmarks (shape of the prostate, position of the verumontanum, distance from the apex or the prostate base, presence of a benign cyst or a calcification nearby, etc.) Of the 46 patients with PCA, 43 patients underwent radical prostatectomy (RP) at our institution.

Pathology

All prostate biopsies were reviewed by one uropathologist (BJL) who was blinded to the MRI results, PSA values, and DRE data, as were the 43 RP specimens. The prostatectomy specimens were fixed overnight in 10% neutral buffered formaldehyde and coated with India ink. Transverse whole mount step section specimens were obtained with 4 mm intervals on a plane parallel to that in which transverse T2-weighted sequences were performed. Matching of the findings between MRI and RP specimen was made by the fact that both MRI sequences and RP sections were oriented perpendicular to the rectal surface area.

The prostate was divided into eight regions of interest by the octant technique (top and bottom were divided into four quadrants [TZ, PZ, left, right]). Within each octant, TZ or PZ or anterior fibromuscular stroma boundaries were traced, and tumor was located according to these histologic zone boundaries. For a suspicious area on MRI to be confirmed as a true malignancy, it had to be located in the same octant and at the same distance from all anatomic boundaries as in the RP specimen and have roughly the same contours. If more than one tumor was present in an octant, we considered only the largest one. According to the Epstein criteria, insignificant PCA was defined as a PSA density of less than 0.15 ng/dL, a biopsy Gleason score 6, less than or equal to two positive cores in six-core biopsies, and a single core percentage under 50%.^11,12

Statistical analysis

All statistical analyses were conducted with SPSS program (version 15.0). Statistical analysis was performed with the Mann-Whitney U test. The Fisher exact test was used to compare categorical variables. P<0.05 was considered significant.

Results

Of a total of 87 cases, 82 (94.2%) patients had suspicious lesion(s) on their MRI. Of these 82 patients, 46 (56.0%) had PCA in at least one core by the biopsy.

The baseline characteristics of patients with and without confirmed PCA showed no significant difference in age, PSA value, prostate volume, number of previous biopsies, duration from previous biopsy, and number of cores. Thirty-two patients had suspicious anterior positive findings on MRI, and targeted biopsy detected PCA in 19 (59.4%) of them (Fig. 1). Among 30 patients with a suspicious apex lesion on MRI, 19 (63.3%) were found with PCA (Table 1). For prostate cores, 149/518 (28.8%) samples from targeted lesions and 32/903 (3.6%) from standard biopsies had PCA (P=0.012). Seven patients were detected with PCA both in the targeted and standard prostate biopsy cores, and two patients with normal finding on MRI were detected with PCA in the standard biopsy cores. The mean number of positive cores per patient was 4.7 cores and the percentage of positive cores per core was 59.2%. According to the Epstein criteria, five patients had insignificant PCA after prostate targeted biopsy.

FIG. 1.

A 64-year-old man with an elevated prostate-specific antigen level (6.2 ng/mL) and two previous negative transrectal ultrasonography (TRUS) biopsy sessions underwent magnetic resonance imaging (MRI) of the prostate: (A) TRUS did not show any abnormal lesion in the whole prostate; (B) the axial T2-weighted MRI shows a suspicious area of low signal intensity (arrow) in the anterior prostate; (C) apparent diffusion coefficients (ADC) map at the same level shows a significant reduction in ADC (arrow). A targeted biopsy of the suspicious area was taken under TRUS guidance and corresponded with prostate cancer (Gleason 7 [4+3]). This patient underwent robot-assisted laparoscopic radical prostatectomy; (D) The prostatectomy specimen shows the cancer lesion (arrow) as seen in the MRI.

Table 1.

The Baseline Characteristics of Patients With and Without Confirmed Prostate Cancer by Targeted Prostate Biopsy

	Patients without PCA (n=41)	Patients with PCA (n=46)
Median age, y (range)	68 (50–84)	66 (48–76)
Median (mean):
Prebiopsy total PSA (ng/ml)^a	7.90 (11.24)	9.48 (12.78)
PSA density	0.19 (0.49)	0.28 (0.57)
Prostate volume (cc)	40.8 (33.9)	35.4 (33.1)
No previous biopsy (range)	2 (1–3)	2 (1–4)
No. of cores/biopsy (range)	12 (10–12)	11 (10–12)
No. of targeted cores/biopsy (range)	9 (6–14)	8 (6–14)
Months from previous biopsy (range)	13.2 (6–19)	11.8 (7–21)
MRI finding (%)
Normal	3 (7.7)	2 (4.3)
Suspicious anterior^b	13 (30.8)	19 (41.3)
Suspicious apex^b	11 (26.9)	19 (41.3)
Other	14 (34.6)	6 (13.0)
Suspicious tumor size (cm)	1.68	1.47

P<0.05 by Mann–Whitney U test.

P<0.05 by Fisher exact test.

PCA=prostate cancer; PSA=prostate-specific antigen; MRI=magnetic resonance imaging.

Table 2 compares the location of PCA on MRI, prostate biopsy, and RP (n=43) specimens. After RP, 37 of 43 (86.0%) patients were detected with PCA located at the anterior or apex portion of the prostate. Eight cases of anterior PCA on biopsy were Gleason scores 7 or more. On pathology determination, 14 patients had Gleason scores 7 or more at the anterior prostatic lesion. There were seven patients whose Gleason scores were upgraded and one patient had a downgraded Gleason score. For anterior portion, there were four patients with an upgraded score and no patients with a downgraded score. For the apical portion, three patients had an upgraded score and one patient had a downgraded score. After RP, three patients with insignificant PCA after prostate biopsy had upgraded Gleason scores. Finally, two patients had insignificant PCA after surgery.

Table 2.

Comparison of Prostate Cancer Location Among Magnetic Resonance Imaging, Prostate Biopsy, and Radical Prostatectomy Specimens (n=43)

	Biopsy findings (positive/total cores)				Pathologic findings
	Patients	Anterior	Apex	Others	Anterior	Apex	Others
Positive sites (MRI)	43	15	19	9	19	18	6
Normal	1	0	0	1 (3/16)	0	0	1
Anterior	17	12 (50/264)	3 (9/56)	2 (3/37)	15	1	1
Apex	19	2 (3/38)	15 (73/287)	2 (4/41)	3	16	0
Other	6	1 (3/21)	1 (2/20)	4 (15/71)	1	1	4
Gleason scores
≤5	–	1	3	0	0	2	0
6	–	6	8	3	5	6	3
7 (3+4)		4	3	2	5	5	1
7 (4+3)		3	2	3	7	3	1
≥8		1	3	1	2	2	1
Stage
T_1c	–	0	1	1	–	–	–
T₂	–	13	15	8	15	13	5
T₃	–	2	3	0	3	4	1
T₄	–	0	0	0	1	1	0

MRI=magnetic resonance imaging.

For tumor characteristics according to tumor locations, there was no significant correlation between tumor location and Gleason scores or pathologic stage (Table 2).

Discussion

For patients with a persistently high level of serum PSA and previous negative biopsy, urologists often increase the number of systematically placed biopsy cores (eg, saturation biopsy) to decrease the false-negative rate that is associated with the conventional sextant prostate biopsy; however, the best way to care for these patients remains uncertain.¹³ Another strategy is placing these patients on an active surveillance after a negative biopsy. This strategy, however, might be advocated for patients whose negative biopsy result is absolutely reliable. An ideal workup of patients for whom a possible malignancy is suspected is to maximize the detection rate using a much more reliable method.

Serum PSA tests are still the most important biomarker for detection of PCA. PSA-based screening can reduce disease specific mortality.¹⁴ Despite recent advances in our understanding of PSA indexes for discriminating between benign and malignant disease, it is noteworthy that they assess risk alone and have no tumor localizing potential, underscoring the need for improved tumor localizing modalities. Another possibility is to use imaging methods such as MRI to improve the chances of detecting significant cancers.

We would like to be careful, however, not to overstate our current findings. In our study, it is our firm belief that such imaging might be useful in patients with two or more previous negative prostate biopsies and persistent risk of harboring PCA based on PSA indexes. Therefore, future study should be focused on how best such MRI could be incorporated in suspicious patient care algorithms and on cost to benefit ratios.

Recently, more specific biomarkers have been developed. Many studies of both serum and urine-based PCA biomarker candidates have been presented within the last 10 years. Recently discovered biomarkers, such as PCA3, GSTP1, and AMACR, show favorable performance in several clinical settings.^14,15 To best use these markers, however, additional study is needed to define the appropriate context and optimal parameters for their use. In addition, the combination of MRI with these new biomarkers will provide more information on avoiding overuse of repeated biopsies.

In the present study, a cancer detection rate was 52.9% using a combination of a standard 12-core biopsy scheme with an oversampling strategy in sites targeted by combined T2-weighted and DW MRI, which is higher than the previously reported rates.^6,16,17 At the apex portion of the prostate gland, the PZ extends anteriorly to the distal prostatic urethra. It may be difficult to palpate by DRE cancers that arise in this apicoanterior PZ.¹⁸ Furthermore, an apical biopsy was not performed in the initial biopsy because it is widely recognized as being more painful than a biopsy of the remainder of the prostate.¹⁹ Because anterior prostate cancers are distant from the rectal surface, it could be challenging to visualize them by TRUS.²⁰ In addition, the anterior prostate is routinely undersampled by standard TRUS-guided biopsy because anterior biopsies are excluded from standard biopsy templates.

Similar to our results, Lawrentschuk and associates⁴ reported that MRI can help to direct biopsies to the anterior prostate with a high degree of accuracy. Furthermore, they observed that patients with anterior predominant prostatic tumors on MRI that were confirmed with a biopsy appear to have more aggressive tumors than expected. Al-Ahmadie and colleagues⁹ recently reported that the pathologic outcomes of anterior and posterior tumors were similar, and it appeared that anterior and posterior tumors have similar biologic potential. We could not find the relationship of the anterior prostate cancer with the aggressiveness, however, probably because of the small number of cases. Further large-scale studies are needed to compare long-term outcomes and molecular characteristics of these tumor groups to better define their true clinical and biologic behaviors.

We observed that the number of PCA cores was significantly higher in targeted cores (28.8%) than in standard biopsy cores (3.6%). In addition, of seven patients who were detected with PCA both in the targeted and standard prostate biopsy cores, six patients were detected with apex or anterior lesion and one patient with PZ. Interestingly, all positive cores from standard biopsy were similarly located with the positive cores from targeted biopsy. This result means the cancer foci were not different by standard or targeted biopsy method even though multiple positive cores were detected. Furthermore, if the patients undertook another standard biopsy without a targeted biopsy, only 8 (17.4%) of 46 PCA patients would have been detected with PCA. Considering the decreasing detection rate of cancer at each biopsy round (round 1: 23%, round 2: 17.6%, round 3: 11.7%, round 4: 8.7%, and round 5: 0%),¹³ a more intense prebiopsy study will be needed at least for the patients with a high suspicion of having PCA. It may also be more useful to perform other laboratory tests as well as MRI before conducting a repeated biopsy.

There are several limitations to our study. First, the present study consists of a relatively small number of patients; therefore, statistical results should be cautiously interpreted. Another limitation is the difficulty in matching TRUS biopsy sites to the suspicious combined T2-weighted and DW MRI areas intended for biopsy. Nevertheless, to our knowledge, there has been no prospective study that focuses on the tumor characteristics according to its location in the prostate. Finally, our data presented that only two patients were detected with PCA by the standard biopsy. One should cautiously interpret our data, however, because we were unable to record the natural course of the negative biopsy cases in further long-term follow up. Nevertheless, our study is important because it shows benefits of MRI in examining patients with persistently increasing PSA and one to four rounds of previous negative prostate biopsies.

Conclusions

In our study, patients with a previous negative prostatic biopsy were found to have PCAs in hard-to-detect lesions such as in the apex or anterior portion of the prostate. In these patients, a targeted prostate biopsy after combined T2-weighted and DW MRI might be considered for the identification of cancer foci and the detection of PCA.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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