European Urology

1. Introduction

Since its introduction by Hodge et al [1], random, systematic, ultrasound-guided transrectal needle biopsy of prostate has significantly improved the diagnosis and treatment of prostate cancer. This sextant method attempts to sample adequately the cancer-rich peripheral zone by directing the needle along the parasagittal plane, and the basal, median, and apical regions on both sides of the prostate. Studies [2], [3], and [4] have demonstrated that a traditional sextant technique may miss substantial numbers of cancers and that additional sampling of the lateral peripheral zone may increase the diagnostic yield. Despite such modifications and strategies using 10 to 14 cores, the false-negative rate remains substantial [4]. As a result, saturation biopsy has been adopted in several centers, resulting in cancer detection rates approaching a third when extended biopsy schemes with up to 45 cores were used, even following multiple negative biopsies [5]. The application of local anesthesia has greatly decreased the pain and discomfort associated with transrectal prostate biopsy [6]. It is also possible to perform saturation biopsy with only mild discomfort for the patient. Our group demonstrated that saturation biopsy can be performed safely and effectively in the office using local anesthesia; our initial experience reported an increase of prostate cancer detection using 21 biopsies including the peripheral, middle peripheral, and transition zones [6]. Here we report the cancer detection rate in 1000 consecutive patients who had 21 biopsies at the first procedure.

2. Patients and methods

Between December 2001 and October 2005, 1000 consecutive men prospectively underwent 21-core biopsies of the prostate, because of suspected localized prostate cancer based on abnormal digital rectal examination (DRE) and/or elevated serum prostate-specific antigen (PSA) (>4 ng/ml of 3 ng/ml for patients younger than 60 yr). For all patients it was the first prostate biopsy procedure. Clinical and pathologic data, including patient age, PSA, DRE, prostate volume measured by transrectal ultrasound, Gleason score, and number and location of positive cores were abstracted from the computerized database in our institution. Patient's characteristics are shown in Table 1. All men were instructed to discontinue anticoagulants 5 d before biopsy, but biopsy ensued if they were taking aspirin or nonsteroidal anti-inflammatory drugs. Patients were prescribed enemas 1 d and 3 h before the procedure. A fluoroquinolone antibiotic was prescribed for 7 d after the procedure. All patients were adequately informed of mode of execution of the procedure and its potential complications. All procedures were performed by three senior urologists. All patients received local anesthesia by means of a 22-G spinal needle that was passed through the biopsy guide channel, followed by injection of 5 cc 2% lidocaine into each neurovascular bundle. Ultrasound examination and volume calculations were then performed. A total of 21 biopsies were taken with the use of 18-G biopsy needles and a spring-loaded biopsy gun, which provided tissue cores of 17-mm length. The patients were allowed to leave the hospital 2 h after the procedure. The biopsies were performed in the following order. First, 6 sextant biopsies (standard 45° angle) were taken, followed by 3 biopsies in each peripheral zone from base to apex at an 80° angle from base to apex. Next, 3 biopsies were taken in each TZ from base to apex. Finally, 3 biopsies were taken in the midline peripheral zone (Fig. 1). Each prostate core was given a specific number according to the biopsy protocol and was analyzed separately. For each patient with abnormal rectal examination or hypoechoic lesions, our 21-biopsy protocol included these areas, and we did not specifically biopsy these anomalies. Each biopsy was placed in separate pots according to its location. Two senior uropathologists performed the analysis.

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Fig. 1 Location of biopsies in the 21-sample procedure. Lat = far lateral biopsy; TZ = transition zone biopsy; sext = sextant biopsy; mid = peripheral zone (PZ) midline biopsy.

The patients were divided into subgroups according to the results of DRE, serum PSA, and prostate volume. We evaluated the cancer detection rate overall and in each subgroup.

To compare the results of our biopsy protocol with those from 6-, 12-, and 18-core biopsy protocols, we then analyzed only those cores from our protocol that would correspond to a routine sextant biopsy, a sextant biopsy plus 3 additional posterolateral cores from each lobe (12 biopsies), and an additional 3 cores from each TZ (18 biopsies), ignoring the results from the other cores as if they had not been done. We determined the percent of improvement in cancer detection rate resulting from our 21-core biopsy protocol versus 6-, 12-, and 18-biopsy cores overall and in each subgroup. Statistical analysis was performed with the use of the Statistical Package for Social Sciences software (SPSS Inc, Chicago, IL, USA). The diagnostic performance of the 21-sample procedure was assessed relative to that of the sextant biopsy alone. The Mantel-Haentzel test was used to analyze the increase in the prostate cancer detection rate, with a correction coefficient used because of the multiple tests of significance performed.

3. Results

Pathologic examination revealed adenocarcinomas in 425 (42.5%) of the patients. Ten atypical small acinar proliferations (1%) and 25 prostatic intraepithelial neoplasias were diagnosed. Overall, the 21-sample biopsy procedure yielded a diagnosis of prostate cancer in 42.5% of the patients compared with 31.7%, 38.7%, and 41.5% of patients on the basis of 6 biopsies (sextant biopsies only), 12 biopsies (sextant + 6 lateral biopsies), and 18 biopsies (sextant + 6 lateral + 6 TZ biopsies), respectively (Table 2). The 21-sample procedure improved the diagnosis yield by 34%, 9.8%, and 2.4% compared with sextant biopsies, 12 biopsies, and 18 biopsies, respectively. The midline and TZ biopsies added to detection of cancer in 10 (1%) and 28 (2.8%) patients, respectively.

Table 2 Number of prostate cancer and detection rate using 6-, 12-, 18-, and 21-biopsy schemes according to prostate volume, DRE, and serum PSA

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Lat = far lateral biopsy; TZ = transition zone biopsy; midline = peripheral zone (PZ) midline biopsy; PSA = prostate-specific antigen; DRE = digital rectal examination.p values calculated with Mantel-Haentzel test.

The DRE results influenced the detection rate: 312 (38.2%) of the 816 patients with normal DRE had prostate cancer compared with 113 (61.3%) of the 184 patients with abnormal DRE. For patients with normal DRE, the 21-sample biopsy procedure yielded a diagnosis of prostate cancer in 38.2% of the patients compared with 26.7%, 33.8%, and 36.9% of patients on the basis of 6, 12, and 18 biopsies (Table 2). Thus, the 21-sample procedure improved the diagnosis yield by 9.8%, relative to the 12-biopsy procedure. For patients with abnormal DRE, the 21-sample biopsy procedure yielded a diagnosis of prostate cancer in 61.4% of the patients compared with 53.8%, 60.3%, and 60.8% of patients on the basis of 6, 12, and 18 biopsies (Table 2). The 21-sample procedure improved the diagnosis yield by 1.8% compared with the 12-biopsy procedure. In the subgroup of patients with abnormal DRE, adding TZ biopsies to the 12 biopsy-scheme improved the diagnostic yield only by 0.9%.

PSA level also influenced the detection rate of cancer. For any given biopsy scheme, the detection rate increased as the PSA increased. In the subgroup of patients with PSA < 4 ng/ml, cancer was detected in 24.7% of the patients compared with 37.2%, 54.2%, and 78.7% of patients with PSA 4–10 ng/ml, 10–20 ng/ml, and >20 ng/ml, respectively. Comparing 12 versus 21 biopsies, the improvement in diagnostic yield was 13.6%, 12.6%, and 7.3% in the subgroups of patients with PSA < 4 ng/ml, PSA 4–10 ng/ml, and PSA 10–20 ng/ml, respectively. In the subgroup of patients with PSA > 20 ng/ml, 12 biopsies seemed to be sufficient because the 21 biopsies improved the diagnostic yield only by 3.2%.

The diagnostic rate was clearly influenced by the prostate volume, because for any given number of biopsies, the detection rate decreased as the prostate volume increased (Table 2).

Concerning morbidity, macroscopic hematuria occurred in 84% of patients and lasted an average of 3 d (range: 1–18); hematospermia occurred in 60% of patients and lasted an average of 12 d (range: 1–30). Minor rectal bleeding, lasting an average of 1.07 d (range: 0–15), was reported by 45% of patients. Prostatic infection (fever and required hospitalization) occurred in 4 of 1000 patients.

4. Discussion

Several studies in recent years have looked at the use of saturation needle biopsies. Most of these studies have dealt with the use of saturation needle biopsies in patients with prior negative biopsies, yet clinical findings suspicious for carcinoma [7], [8], [9], [10], [11], and [12]. Most of these studies documented that saturation needle biopsy of the prostate is a useful diagnostic technique in men at risk of prostate cancer with prior negative needle biopsies. The detection rates for cancer in these saturation biopsies ranged from 13.5% to 34%. Chen et al [13] showed that traditional sextant biopsy routinely fails to sample the anterior TZ, the midline peripheral zone, and the lower portion of the anterior horn of the peripheral zone. Eskew et al [7], and [14] observed that a five-region biopsy method that incorporates lateral and midline biopsy with traditional sextant cores improves the detection of clinically significant tumours. Others [15], and [16] have agreed that adding far lateral biopsy improves the detection of adenocarcinoma. The TZ zone is an area that is not sampled by sextant biopsy, and selective biopsy of this area has been advocated to improve cancer detection with mixed results [17], [18], and [19]. We chose a method of biopsy that samples the whole prostate to minimize the underdetection of cancer at any location. We performed saturation biopsy using local anesthesia in the office as the initial biopsy strategy in 1000 consecutive patients, with overall diagnostic yield of 42.5%.

In the routine sextant biopsy scheme, the posterolateral aspects of the prostate are not sampled. Epstein et al [3] demonstrated the importance of posterolateral guided biopsies in detection of prostate cancer, showing that combining both routine sextant and posterolateral needle biopsies maximizes the detection of significant cancers. Canto et al [25] also showed that the 12-biopsy scheme detects a greater number of biologically significant tumors than the sextant biopsy. Presti et al [20] investigated a 12-core biopsy strategy, including sextant biopsies and laterally directed sextant biopsies in a multipractice community study involving 2299 men. The laterally directed sextant biopsies detected 83% of the cancers and were superior to the sextant biopsies, which detected 78%. Our study also demonstrates the importance of adding far lateral biopsies to the standard 6-biopsy protocol, because the sampling of this area increased the cancer detection rate by 22%. This increase in diagnostic yield was evident across all subgroups.

Recently, Jones et al [12] compared 10-core with 24-core biopsies. The detection rates did not differ between each group. In our study each patient served as his own control because each core was analyzed separately; also a larger group of patients showed a significant increase of prostate cancer detection rates between standard protocol and extended protocol.

The addition of midline peripheral zone needle biopsies in the initial biopsy protocol is not supported by most of the studies [14], and [21]. The only study [13] that suggested adding the midline needle biopsy was based on computer modeling, not actual needle biopsies of the prostate. Our results support these studies, because only 10 of 425 patients (2.3%) were diagnosed on the sole basis of midline biopsies.

According to the literature, prostate cancer is diagnosed on the sole basis of TZ biopsies in 1.8–8% of cases [17], [18], [19], and [22]. In these studies TZ biopsies were indicated in patients with prior negative biopsy procedures and with risk factors for prostate cancer, such as elevated PSA and abnormal DRE. In the present study 28 of 425 patients (6.6%) were diagnosed on the sole basis of TZ biopsies. The addition of TZ biopsies to a 12-biopsy scheme increases the diagnostic yield by 7.2% overall. It is important to notice that, as the volume of the prostate increases, the improvement in the detection rate given by adding the TZ biopsies decreases. This improvement was 8.5% in patients with prostate volume <35 ml and 3.4% in patient with prostate volume ≥50 ml. A possible explanation for this observation would be that, as the volume of TZ increases, the sampling error also increases. The improvement added by TZ sampling was more evident in patients with normal DRE and PSA < 20 ng/ml, possibly because these patients had smaller tumors not detected by the 12-biopsy scheme.

The influence of prostate volume on the positive yield of the systematic biopsy has been proved in more than one study. Brawer [23] recently concluded that positive yield of the systematic biopsy decreases significantly when gland volume is >55 cc. In another study [24], there was a significant decreased yield of sextant biopsy with increasing gland volume. The highest positive biopsy rate (39.6%) was among prostates ≤20 cc, and the lowest positive biopsy rate (10.1%) was obtained in glands between 80 to 90 cc. In both studies, the range of prostate volumes was very wide (4.5–311.5 cc in the Brawer series), and a significant difference in cancer detection was found between extremes of volumes. In our study using the 12-biopsy scheme, the diagnostic rate was 45% in patients with prostate volumes <35 and 28.6% in prostate volumes ≥55. This observation suggests that even more than 12 biopsies from the peripheral zone are needed in larger prostates. Adding 6 more lateral biopsies to the sextant protocol improved the diagnostic yield by 20.4% in patients with a prostate <35 g. One can conclude that even patients with a small prostate should be offered a more extensive biopsy scheme.

5. Conclusions

In our experience, a 21-biopsy scheme improved significantly the diagnostic yield compared with the 6- or 12-biopsy scheme. Patients with suspected localized prostate cancer should be offered at least 12 biopsies in the peripheral zone and far lateral peripheral zone (statistically significant). TZ biopsies have to be considered, because these biopsies improve the diagnostic yield. For patients with abnormal DRE and/or PSA ≥ 20 ng/ml, the 6-biopsy scheme seems sufficient (statistically), but 6 far lateral peripheral zone biopsies as well as the TZ biopsies add little incremental value (not significant). Evidence does not support the use of routine midline peripheral zone needle biopsies in the initial biopsy to enhance the detection of prostate cancer.

Conflicts of interest

The authors have nothing to disclose.