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Currently, six sextant systematic biopsy of the prostate is widely used in the detection of prostate cancer and has much improved the detection rate for the disease.1 However, the considerably higher number of positive biopsies for prostate cancer in repeat biopsies has suggested many cancer lesions are missed by this biopsy strategy.2–4
With the aim of improving the detection rate for prostate cancer, several protocols have been proposed, including sampling the transition zone,5–7 and extended fields of the prostate,8–11 or increasing the number of biopsy cores.12–14 Despite these trials, the optimum methodology of prostate biopsy for detecting cancer lesions remains unknown.
The present study was designed to assess the clinical value of transperineal 12-core systematic biopsy of the prostate guided by transrectal ultrasound in the detection of prostate cancer in the experience of Nagoya Urology Hospital, Japan.
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Between April 1994 and February 2000, a total of 679 patients underwent transperineal ultrasound-guided systematic biopsy of the prostate at Nagoya Urology Hospital in Nagoya, Japan, as a result of abnormal findings on digital rectal examination (DRE) and/or transrectal ultrasonography (TRUS) and/or an elevated serum level of prostate-specific antigen (PSA; Fig. 1). Their ages ranged from 41 to 92 years with an average of 69.8 ± 8.5 years. Of the total, 138 patients underwent six-core systematic biopsy in the period between April 1994 and February 1995 and the remaining 541 received 12-core biopsy after March 1995.
Figure 1. Reasons for transperineal prostate biopsy in 679 patients. DRE, digital rectal examination; TRUS, transrectal ultrasonography; PSA, prostate-specific antigen.
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Serum PSA levels were measured using an ACS-PSA assay before DRE and TRUS. The referenced normal level was lower than 4.0 ng/mL. Prostate volume was measured using elliptical volumetry with an ultrasound machine (SSD 650 or SSD 2000; Aloka, Tokyo, Japan) and PSA density (PSAD) was obtained by dividing the serum PSA value by the prostate volume.
Transperineal prostate biopsy guided by transrectal ultrasound was carried out under spinal anesthesia according to the procedure described previously by Saitoh et al.15 Briefly, a transrectal linear scanner with a needle-guide attachment was used for the procedure. Prostatic biopsy was performed transperineally using an 18-gauge biopsy needle driven by a spring-loaded device. In the procedure, the horizontal section of the prostate was divided into six (six-core biopsy) or 12 (12-core biopsy) areas numbered as shown in Fig. 2. In conventional sextant (six-core) biopsy areas numbered 1–4, 6 and 7 were sampled and in 12-core biopsy those numbered 5 and 8–12 were sampled in addition. Areas numbered 5 and 8 correspond to the lateral portion of the peripheral zone and areas numbered 9–12 correspond to the anterior portion.
Figure 2. Schematic drawings of the horizontal section of the prostate demonstrating transperineal biopsy sites in conventional six sextant biopsy (●) and additional cores (○) in the 12-core biopsy protocol. Areas were numbered 1–12, as shown in the figure.
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The cancer-detection rate was compared between the groups and correlated with DRE and TRUS findings, serum PSA levels and prostate volume. When only the extended cores, above the conventional six cores, were positive for cancer, it was concluded that six-core biopsy would have failed to make the diagnosis. Complications in association with biopsy were collected from clinical records and were also compared between the groups.
The variables were expressed as mean ± SD. An unpaired t-test or Mann–Whitney U-test was used to compare variables between groups. The χ2 for trend was also used. These statistical analyses were performed using commercially available software (StatView; Abacus Concepts, Berkeley, CA, USA). A P-value of less than 0.05 was considered statistically significant.
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In 156 (23.0%) out of 679 patients, prostate cancer was detected by transperineal systematic biopsy. Figure 3 demonstrates the detection rate for prostate cancer by the screening tests. The frequency of positive biopsy increased as serum PSA level and PSAD increased (Fig. 4).
Figure 3. Detection rate for prostate cancer by screening tests. DRE, digital rectal examination; TRUS, transrectal ultrasonography; PSA, prostate-specific antigen.
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Figure 4. Detection rate for prostate cancer by (a) serum prostate-specific antigen (PSA) level; and (b) PSA density.
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Table 1 demonstrates the frequency of positive biopsy and characteristics of patients undergoing six-core or 12-core biopsy. The detection rate for prostate cancer by 12-core biopsy was higher (24.0%vs 18.8%), although this was statistically not significant, than that by six-core biopsy. Comparing the characteristics of patients undergoing six- and 12-core biopsies, there were no differences in age, prostate volume or PSAD. There was, however, statistically significant difference in the frequency of patients who had abnormal DRE or TRUS. More importantly, significant difference was also noted in the distribution of serum PSA levels. The prevalence of patients with normal PSA levels was significantly higher in those undergoing six-core biopsy. In contrast, there was no difference in the percentage of patients with markedly elevated PSA levels such as 20 ng/mL or more.
Table 1. Comparison of detection rate for prostate cancer and patient characteristics between patients who underwent six-core and 12-core biopsies
| ||Six-core biopsy||Twelve-core biopsy||P-value|
|Detection rate||18.8% (26/138)||24.0% (130/541)||NS*|
|Age (years)||69.1 ± 9.7||70.0 ± 8.2||NS†|
|Prostate volume (mL)||32.2 ± 21.1||33.3 ± 17.2||NS†|
|PSA (ng/mL)||50.7 ± 176.8||52.5 ± 366.2||NS†|
|(median, range)||8.1, 0.3–1640||11.0, 0.7–7960|| < 0.01‡|
|PSA density||1.79 ± 6.21||1.69 ± 10.08||NS†|
|(median, range)||0.351, 0.019–42.9||0.382, 0.020–211.4||NS‡|
|Abnormal DRE||42.8% (59/138)||31.2% (169/541)|| < 0.05*|
|Abnormal TRUS||49.3% (68/138)||35.7% (193/541)|| < 0.005*|
|PSA (ng/mL)|| || ||P < 0.0001*|
|< 4||22 (15.9%)||27 (5.0%)|
| 4–10||55 (39.9%)||221 (40.8%)|
| 10–20||25 (18.1%)||141 (26.1%)|
|> 20||36 (26.1%)||152 (28.1%)|
The frequency of positive biopsy was also compared between patients groups categorized by the results of screening tests or prostate volume as shown in Table 2. In patients with abnormal TRUS, the frequency of positive biopsy was significantly improved by 12-core biopsy compared to six-core biopsy from 29.4% up to 49.7% (P < 0.005). In patients with normal DRE or serum PSA levels less than 10 ng/mL, the frequency of positive biopsy also improved by 12-core biopsy, although statistically this was not significant.
Table 2. Comparison of detection rate for prostate cancer in patient groups categorized by screening tests and prostate volume
| ||Detection rate for prostate cancer (%)||Improvement in detection rate||P-value|
| ||Six-core biopsy||Twelve-core biopsy|
In Table 3, clinical and pathologic characteristics of prostate cancer are compared between patients who underwent six-core and 12-core biopsies. Among them, a significant difference was noted in the distribution of clinical stage. Out of 130 cases detected by 12-core biopsy, 68 (52.3%) were diagnosed as having prostate cancer of early stage (Stage B), compared to 26.9% (7/26) in those detected by six-core biopsy (P < 0.05).
Table 3. Comparison of clinical and pathologic characteristics of prostate cancer between patients who underwent six-core and 12-core biopsies
| ||No. patients (%)||P-value|
|Six-core biopsy (n = 26)||Twelve-core biopsy (n = 130)|
|Normal|| 6 (23.1%)||53 (40.8%)||NS|
|Abnormal||20 (76.9%)||77 (59.2%)|
|Normal|| 6 (23.1%)||34 (26.2%)||NS|
|Abnormal||20 (76.9%)||96 (73.8%)|
|<4|| 2 (7.7%)|| 2 (1.5%)|
| 4–10|| 5 (19.2%)||32 (24.6%)||NS|
| 10–20|| 6 (23.1%)||23 (17.7%)|
|>20||13 (50.0%)||73 (56.2%)|
|No of positive cores|
|1|| 7 (26.9%)||16 (13.1%)|
|2|| 2 (7.7%)||19 (14.6%)||NS|
|≥3||17 (65.4%)||94 (72.3%)|
|Well|| 6 (23.1%)||50 (38.5%)|
|Moderately||17 (57.7%)||61 (46.9%)||NS|
|Poorly|| 5 (19.2%)||19 (14.6%)|
|B|| 7 (26.9%)||68 (52.3%)|
|C||10 (38.5%)||30 (23.1%)||< 0.05|
|D|| 9 (34.6%)||32 (24.6%)|
The prevalence of complications in association with transperineal biopsy such as urinary retention (5.1%vs 7.2%), gross hematuria (0.7%vs 2.6%) and fever elevation over 38.0°C (3.6%vs 5.2%) were all higher in patients with 12-core biopsy than those with six-core biopsy. There were, however, no statistically significant differences noted between them.
Comparing the location of the positive biopsy cores in 130 patients in whom prostate cancer was detected by 12-core biopsy, 112 (86.2%) would have been detected also by conventional six-core biopsy. However, 18 (13.8%) of these were considered to be detectable only by additional biopsies. Interestingly, 17 (94%) out of these 18 patients were diagnosed as having prostate cancer of clinical Stage B, compared to only 51 (45%) out of 112 patients in whom prostate cancer could be detected by six-core biopsy.
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The clinical utility of prostate biopsy has to be evaluated from several viewpoints, among which the sensitivity for clinically significant but not insignificant prostate cancer is of most importance. Despite the introduction of six sextant biopsy, positive biopsy rates in men undergoing repeated biopsy have previously been reported to be nearly 30%.2–4 These data suggest strongly that six sextant biopsy would miss a considerable number of prostate cancers. In our clinic, we changed the biopsy strategy from six-core to 12-core systematic biopsy in March 1995, supposing that increasing the number of biopsy cores would also increase the detection rate for prostate cancer.
Originally, transperineal sextant prostatic biopsy used in the present study sampled four cores from the peripheral zone and two from the transition zone.15 In the 12-core biopsy strategy, additional two cores were taken from the far lateral portions of the peripheral zone and four cores from the anterior portion of the transition zone. The importance of sampling a lateral portion of the peripheral zone was described by Stamey.16 In addition, Chen et al. optimized prostate biopsy strategies based on a computer simulation model of ultrasound guided biopsies using mathematically reconstructed radical prostatectomy specimens.17 As a result, they recommended the sampling of the anterior portion of the anterior horn and the anterior transition zone in addition to conventional sextant sites. Our 12-core biopsy protocol consequently seems to cover these areas in which significant prostate cancer is likely to exist.
In the present study, the detection rate for prostate cancer increased 5.2% from 18.8% to 24.0% by incorporating the 12-core biopsy protocol. There was, however, no statistically significant difference proved between them. In contrast, many authors in Western countries reported statistically significant improvement in detection rate by increasing the number of biopsy cores. With a 10-core biopsy scheme, the detection rate for prostate cancer was reported to increase from 33% to 40% (P < 0.05) by Presti et al.18 Similarly, Beurton et al. reported the detection rate for prostate cancer by 12-core biopsy to be significantly higher than that by six-core biopsy (36%vs 12%, P < 0.01).12 The reason why we failed to demonstrate a statistically significant improvement in the detection rate remains unknown. It may, however, be related to the inherently lower incidence of clinical prostate cancer in Japan compared with these countries.19 In 12-core biopsy employed in this study, two biopsy-sites in the peripheral zone and four in the transition zone were added to the conventional six-core biopsy. More biopsy-sites in the peripheral zone might improve the detection rate for prostate cancer. Further studies are needed to develop an optimal way of biopsy for prostate cancer in terms of numbers of biopsy cores and sites.
The possible disadvantage of increasing the number of biopsy cores is to increase the chance of detecting clinically insignificant cancer in the prostate. Eskew et al., who took 13 cores and increased the cancer detection rate by 35%, showed no significant difference not only in tumor volume but also in DNA ploidy status, Gleason score or final pathologic stage.20 Broessner et al. also compared pathologic parameters between prostate cancers detected by the sextant and 12-core methods. There was a significant difference noted in tumor volume (5.7 mL vs 1.99 mL) but not in Gleason score or final pathologic stage.21 In our series of patients, the comparison of clinical stage between prostate cancers detectable by conventional sextant biopsy and those by only additional biopsy suggested the possible use of 12-core biopsy to detect early stage cancer. Taken together, there might be some differences in pathologic features between prostate cancer lesions detected by sextant and extended biopsies. Further studies are necessary to assess the value of extended biopsy strategy in terms of oncological points of view.
Increasing the number of biopsy cores may also increase the complications and morbidity associated with the biopsy procedure. Naughton et al. compared pain and morbidity between six-core and 12-core transrectal biopsies using a self-administered questionnaire addressing pain and other morbidity, resulting in no difference for pain measures between them.22 In their 12-core group, however, there was a statistically significant increase in hematochezia and hematospermia but no significant difference between them reporting morbidity as a moderate or major problem. Thus, as for the transrectal procedure, the sampling of 12-cores is likely to be tolerated well and can be performed safely with no significant difference in pain or morbidity compared to the six-core procedure.
Although transperineal prostate biopsies appear to have a significantly lower incidence of complications such as hematuria, hematochezia, hematospermia and sepsis compared with transrectal biopsies,23 the possible increase in complications associated with the increase of biopsy cores remains unknown. In the present study, complications examined increased in the 12-core group compared to the six-core group. However, no statistically significant difference was found between them. It is therefore supposed that 12-core biopsy could also be performed as safely as conventional sextant biopsy.
In conclusion, transperineal 12-core biopsy detected a higher number of prostate cancers, although this was not statistically significant, compared to six sextant biopsy. This biopsy protocol might be promising in detecting early stage cancer.