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Keywords:

  • biopsy;
  • diagnosis;
  • morbidity;
  • prostate-specific antigen;
  • prostatic neoplasms

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Purpose: Previous studies have indicated that 6-core transrectal prostate biopsy misses a considerable number of cancers. We performed an extensive biopsy protocol of 12-core sampling using both transperineal and transrectal approaches to determine the impact on the cancer detection rate.

Materials and methods: We prospectively evaluated 402 men who underwent 6-core transperineal and 6-core transrectal biopsies simultaneously due to abnormal digital rectal examination (DRE) and/or elevated prostate-specific antigen (PSA) levels of 4.0 ng/mL or greater. Using the transperineal approach we obtained four cores from the bilateral peripheral zone targeting the lateral and parasagittal areas and two cores from the bilateral transition zone. The following transrectal biopsy was performed traditionally. We compared cancer detection rate between the extended 12-core procedure and conventional 6-core transperineal and transrectal groups in terms of total PSA and DRE findings.

Results: Using the extensive combined method, prostate cancer was detected in 195 cases (48.5%) and the detection rate significantly increased 7.2% and 8.5% compared to the transperineal and transrectal groups, respectively. According to PSA levels and DRE findings, the cancer detection rate by the combined method was significantly improved in patients with PSA levels of 4–10 ng/mL and negative DRE: 10.3% and 11.6% compared to the transperineal and transrectal groups, respectively.

Conclusions: The extensive 12-core method significantly improved the overall cancer detection rate and was especially efficient for men with PSA levels of 4–10 ng/mL accompanied by a negative DRE finding.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Ultrasound-guided transrectal sextant prostate biopsy has become a common procedure for most urologists in the detection of prostate cancer since Hodge et al. reported it in 1989.1 The transrectal sextant method attempts to obtain adequate samples from the peripheral zone by directing the needle to the parasagittal area at the base, middle, and apical regions of the prostate. In the era of prostate-specific antigen (PSA) screening, as the number of men undergoing this routine sextant biopsy has increased, so has the percentage of prostate cancer detection. Positive rates in men undergoing repeated biopsy have been reported to be nearly 30%, suggesting that the sextant biopsy misses a considerable number of prostate cancers.2–5 The number of biopsy cores needed or the area in which the biopsy should be performed to optimize the detection of prostate cancer is still controversial. Some have recommended an increase in the number of biopsies.4,6,7 Others have reported that including the lateral, apico-dorsal peripheral and transition zones in the routine biopsy may increase rates of prostate cancer detection.8–11

On the basis of these reported data, we have performed a transrectal and transperineal combination biopsy to improve the detection rate. The transperineal biopsy is targeted to the lateral, apico-dorsal peripheral zones and transition zones, which traditional transrectal biopsy does not approach. To our knowledge there has been no previous study of such a combination with this targeting. We prospectively investigated the diagnostic efficacy of this new systematic 12-core biopsy.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Between January 1995 and December 2001, 487 patients with clinically suspicious prostatic irregularities detected on digital rectal examination and/or elevated PSA (Tandem-R) levels of 4.0 ng/mL or greater underwent prostate biopsy. Of the patients, 402 agreed to undergo transperineal and transrectal combined biopsy during a two-day hospitalization. We explained to all the patients both expected advantages of this combined procedure, such as improvement of cancer detection, and disadvantages such as invasiveness of spinal anesthesia. None of the patients had previously undergone prostate biopsy, and men with an active urinary tract infection were excluded from the study. A total of 12 biopsy samples were obtained from each patient. All procedures were performed using commercially available ultrasound equipment with 7.5 MHz probes; biopsy samples were obtained using an automatic spring-loaded biopsy gun with an 18-gauge needle. A cleansing enema was administered in the morning and fluoroquinolone was begun for a 3-day course from the procedure day.

Under spinal anesthesia all patients first underwent transrectal longitudinal ultrasound imaging followed by ultrasound-guided transperineal sextant biopsy (Fig. 1), by which we were able to obtain enough tissue from both the lateral area of the peripheral zone (PZ) and from the transition zone (TZ). We performed an additional two apico-dorsal transperineal biopsies at the bilateral peripheral space between the parasagittal planes of the transrectal biopsy. After the ultrasound probe was removed, ultrasound-guided transrectal biopsy was performed traditionally (Fig. 1). If hypoechoic lesions or palpable nodules by digital rectal examination were noted, biopsy of the area was targeted to the lesion and finally 12 cores were obtained. In each biopsy we sent three cores each from the right and left prostatic lobes in separate specimen containers. In this series, histopathological diagnosis was made by the same pathologist. The cancer was clinically staged according to the TNM 1997 classification.12 Histological grading of biopsy specimens was done using Gleason's system.13

image

Figure 1. Locations of transperineal and transrectal biopsies.

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Cancer detection rates were compared among the extended 12-core procedure, 6-core transperineal and 6-core transrectal procedure; the analysis was conducted in terms of digital rectal examination (DRE) findings, total PSA, clinical stage and biopsy Gleason score. Statistical significance of any differences between the two groups was analysed by Fisher's exact test. All calculated P-values were considered significant to less than 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

A total of 402 patients underwent transperineal and transrectal combined biopsy. Table 1 shows patient characteristics in the groups. Patient age ranged from 41 to 98 years (mean, 72.5 years). The distribution was as follows: less than 60 years, 4.3%; 60–69 years, 22.5%; 70–79 years, 60.3%; and greater than 79 years, 12.9%. The number with positive DRE findings was 130 (32.3%) and median total PSA was 10.3 ng/mL. Using the combined method, prostate cancer was detected in 195 cases (48.5%). The cancer detection rate in each site was as follows: 13.2% (TZ), 25.6% (lateral PZ), 23.9% (apico-dorsal PZ) in transperineal biopsy, and 22.8% (apical), 17.3% (middle), 16.9% (basal) in transrectal biopsy.

Table 1.  Patient characteristics
 Combined biopsy
PositiveNegative
  1. DRE, digital rectal examination; PSA, prostate-specific antigen.

Number Patients195207
Mean age (range) 73.9 (42–98) 71.4 (41–96)
Number with positive DRE (%)107 (54.9%) 23 (11.1%)
Median ng/mL PSA (range) 15.2 (1.5–460.0)  8.1 (0.6–42.1)

Table 2 lists the detection rate in each group. The patients were divided according to DRE findings. The overall detection rate achieved by the combined biopsy significantly increased by 7.2% compared to the transperineal (P < 0.05), and 8.5% compared to the transrectal group (P < 0.05). The difference in detection rate between the transperineal and transrectal groups was not significant. Among 29 patients in the transperineal and 34 in the transrectal group, prostate cancer went undiagnosed. Positive detection in patients with cancer increased 14.9% (29/195) in the transperineal and 17.4% (34/195) in the transrectal group. When considered according to DRE findings, only in the patients with negative DRE was the cancer detection rate in combined biopsy significantly improved, 8.1% compared to the transperineal (P < 0.05) and 10.0% compared to the transrectal group (P < 0.05).

Table 2.  Cancer detection rates according to DRE findings
 Number with Positive Biopsy (%)
Number PatientsCombinedTransperinealP ValueTransrectalP Value
  1. Fisher's exact test. DRE, digital rectal examination.

Overall Patients402195 (48.5)166 (41.3)0.047161 (40.0)0.019
DRE:
 Positive130107 (82.3)100 (76.9)0.36100 (76.9)0.36
 Negative272 88 (32.4) 66 (24.3)0.046 61 (22.4)0.012

Table 3 lists the detection rate, divided according to PSA level and/or DRE findings for each group. When considered according to PSA level, only in the range of 4–10 ng/mL was the cancer detection rate in combined biopsy significantly improved, 10.6% compared to the transperineal (P < 0.05) and 11.7% compared to the transrectal group (P < 0.05). According to both PSA level and DRE findings, a range of 4–10 ng/mL accompanied by negative DRE demonstrated significantly improved detection rates, 10.3% compared to the transperineal (P < 0.05) and 11.6% compared to the transrectal group (P < 0.05).

Table 3.  Cancer detection rates according to DRE findings and total PSA
 Number with positive biopsy (%)
Number PatientsCombinedTransperinealP ValueTransrectalP Value
  1. Fisher's exact test. DRE, digital rectal examination; PSA, prostate-specific antigen.

PSA (ng/mL)
<4 15 3 (20.0) 3 (20.0)>0.999 2 (13.3)>0.999
DRE: positive 15 3 (20.0) 3 (20.0)>0.999 2 (13.3)>0.999
Negative 0 0 (0) 0 (0)>0.999 0 (0)>0.999
4–1018061 (33.9)42 (23.3) 0.03640 (22.2) 0.019
Positive 2519 (76.0)16 (64.0) 0.5416 (64.0) 0.54
Negative15542 (27.1)26 (16.8) 0.03924 (15.5) 0.018
10.1–2011951 (42.9)44 (37.0) 0.4343 (36.1) 0.35
Positive 2722 (81.5)20 (74.1) 0.7420 (74.1) 0.74
Negative 9229 (31.5)24 (26.1) 0.5223 (25.0) 0.41
>20 8880 (90.9)77 (87.5) 0.6376 (86.4) 0.48
Positive 6360 (95.2)59 (93.7)>0.99960 (95.2)>0.999
Negative 2520 (80.0)18 (72.0)  0.7416 (64.0) 0.35

Table 4 shows the cancer detection rates in the groups according to clinical stage and biopsy Gleason score. We compared with regard to the number of men diagnosed with prostate cancer. In patients diagnosed with T1c and T2 cancers, positive detection significantly increased by 25.6% (P < 0.001) and 17.4% (P < 0.001) compared with the transperineal, and 35.9% (P < 0.001) and 18.6% (P < 0.001) compared with the transrectal group. In the advanced stages (T3 or T4) there was no significant improvement. As to Gleason score (average, 5.9), in cases with scores of 2–4, 5–6, and 7, cancer detection rates significantly increased by 32.4% (P < 0.001), 15.7% (P < 0.001), and 9.6% (P < 0.05), respectively, compared with the transperineal, and 29.7% (P < 0.001), 21.4% (P < 0.001), and 13.5% (P < 0.01), respectively, compared with the transrectal group.

Table 4.  Cancer detection according to clinical stage and biopsy Gleason score
 Number with positive biopsy (%)
CombinedTransperinealP ValueTransrectalP Value
  1. Fisher's exact test.

Clinical stage
 T1c3929 (74.4)<0.00125 (64.1)<0.001
 T28671 (82.6)<0.00170 (81.4)<0.001
 T3–T47066 (94.3)0.1266 (94.3)  0.12
Biopsy Gleason score
 2–43725 (67.6)<0.00126 (70.3)<0.001
 5–67059 (84.3)<0.00155 (78.6)<0.001
 75247 (90.4)0.02845 (86.5) 0.0063
 8–93635 (97.2)0.5035 (97.2) 0.50

Of our 402 patients, 5 had an adverse event (1.2%). Significant hematuria requiring transurethral coagulation of prostatic bleeding was noted in one patient. Urinary retention requiring urethral catheterization occurred in two patients, in whom the catheter was removed within 72 h. An additional antibiotic therapy due to fever greater than 38.5°C was needed in two patients. There was no obvious adverse event of spinal anesthesia, such as spinal headache and need to prolong the hospital stay.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Repeated biopsies after the initial sextant ultrasound-guided transrectal biopsy are necessary in a considerable number of patients with clinically significant prostate cancer. Some recent reports show the false negative rate of the routine transrectal biopsy is as high as 15–31%.2,5,14 Based on these reports the interest in defining a more efficient biopsy procedure for prostate cancer detection has been increasing. Since the 6-core biopsy may not be enough to screen the whole prostate, various approaches that add biopsy cores have been evaluated recently.4,6,7,9,15,16 Several groups indicated additional sampling of the lateral aspects of the peripheral zone to improve cancer detection rate.6,7 Another reported that cancer in the transition zone was often undersampled by conventional transrectal sextant biopsy and that selective biopsy of this area improved cancer detection.16

In addition, it has been reported that transperineal 6-core biopsy targeted to the peripheral zone detected more prostate cancer in 40 radical prostatectomy specimens than the transrectal 6-core procedure.17 In fact, the transperineal detection rates in lateral and apico-dorsal peripheral zone were higher than those of the other sites in transrectal biopsy. The present transperineal procedure using four samples from the peripheral zone showed a higher detection rate of prostate cancer compared to the transrectal 6-core biopsy, indicating that the efficient sampling of the peripheral zone by transperineal biopsy is reasonable because prostate cancer tends to localize in this zone.18 A recent study also indicated that the transperineal approach seemed superior to the transrectal approach for prostate cancer detection for the same reason.19

Consequently, the most important point of the present combination is to get an adequate sample from the peripheral zone by obtaining four cores via the transperineal approach. Using this sampling we were able to examine the lateral and apico-dorsal peripheral zones, where cancer foci are reported to be missed by conventional transrectal biopsy.8 Furthermore, to decrease the spatial area not sampled, additional transperineal biopsy targeted to the transition zone was performed. As a result, the cancer detection rate significantly increased 7.2% and 8.5% compared to the transperineal and transrectal groups, respectively.

Based on current data, among patients with negative DRE or with PSA levels of 4–10 ng/mL, the cancer detection rate of combined biopsy was significantly improved compared to 6-core procedures. Improvement was also observed in the other groups, although the differences were not statistically significant. The combined method seems especially efficient for men either with negative DRE findings or with PSA levels of 4–10 ng/mL. Our next interest is in clarifying for which group extended biopsy should be recommended. Analysed by both PSA level and DRE findings, we believe that men in the range of 4–10 ng/mL with negative DRE were the most appropriate candidates to be examined by the combined method.

The combined biopsy yielded a significantly higher percentage of cancer detection in patients designated as clinical stages of both T1c and T2, but not of T3 and T4. Stage T3 to T4 tumors are larger than those present in T1c to T2, and thus can be detected more easily by 6-core transrectal biopsy. In our preliminary unpublished analysis using specimens of radical prostatectomy, the percent volume of prostate cancer/prostate is significantly low in men whose cancer was missed by 6-core transrectal biopsy compared to those whose cancer was detected. In particular, 30 of 39 cases (76.9%) of T1c were within PSA levels of 4–10 ng/mL and current data implied that our protocol could be more useful in men with suspected early stage prostate cancer.

The anxiety that such a vigorous biopsy design may lead to the diagnosis of clinically non-significant cancers should be addressed. Previously published studies indicate no significant difference in the pathological features of prostate cancer in men detected by the standard versus the more extensive biopsy.11 In our unpublished data analysing specimens of radical prostatectomy, we found no significant disparity in either Gleason score or confinement of the disease by an organ between the cancers detected by 6-core transrectal biopsy and those disclosed only by 12-core combined biopsy. As in the present study, patients with a Gleason score of 7, indicating possibly serious prostate cancer, were significantly overlooked in both transperineal and transrectal 6-core procedures. One of the reasons could be that 22 of 52 patients (42.3%) with Gleason scores of 7 were within PSA levels of 4–10 ng/mL, indicating possible early prostate cancer.

Although we have not prospectively compared complication rates between 6-core and 12-core biopsy, others have reported no significant increase in pain or severe morbidity when men who underwent 12-core biopsy were compared with those who underwent the routine procedure.20 The incidence of major morbidity in our present study was 1.2% and this is generally in accordance with other studies examining the incidence of complication after extended biopsy.7,15 In this study the patients were investigated under spinal anesthesia, since transperineal biopsy may cause more pain and discomfort than routine transrectal biopsy. We believe that application of local perineal anesthesia and slight sedation will allow patients to tolerate combined biopsy in an outpatient clinical setting.

Combined transperineal and transrectal 12-core biopsy achieved an overall cancer detection rate of 48.5%, a significant improvement compared 6-core biopsy procedures. The advantage of the combined method is to sample efficiently from the peripheral zone by the transperineal approach, in addition to standard transrectal sampling. We conclude that the method is advisable for routine screening of prostate cancer in men with PSA levels of 4–10 ng/mL whose digital rectal examination is not abnormal.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References