Computer simulated additional deep apical biopsy enhances cancer detection in palpably benign prostate gland

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1 Blackwell Publishing AsiaMelbourne, AustraliaIJUInternational Journal of Urology Blackwell Publishing Asia Pty Ltd? ? Original ArticleAdditional apical biopsy in prostatic gland K Matsumoto et al. International Journal of Urology (2006) 13, doi: /j x Original Article Computer simulated additional deep apical biopsy enhances cancer detection in palpably benign prostate gland KAZUMASA MATSUMOTO, 1 SHIN EGAWA, 1 * TAKEFUMI SATOH, 1 HIDETOSHI KURUMA, 1 NOBUYUKI YANAGISAWA 2 AND SHIRO BABA 1 Departments of 1 Urology and 2 Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan Objectives: The objective of this study was to use computer simulation to investigate the optimal biopsy scheme for enhancing the detection of cancer in palpably benign prostate glands. Methods: The predominant distribution of palpably benign prostate cancer is anterior apex to mid-prostate. We used computer simulation to optimize apical samplings and to simulate the biopsy procedure, including angle and length. A total of 254 consecutive patients with palpably benign prostate glands underwent sextant biopsy plus two additional deep apical biopsies. Results: Based on the computer simulation, lateral sextant and two additional medially located deep apical cores with a sagittal penetration angle of 80 had the maximum cancer detection. Of the 254 patients, 58 (22.8%) had prostate cancer: 28 (48.3%) were positive only at the standard sextant sites, 12 (20.7%) were positive exclusively at the deep apical sites, and the remaining 18 (31.0%) were positive at both sites. Patients with gray-zone prostate-specific antigen (PSA) ranges of ng/ml had increased cancer detection rates of 24% compared to sextant biopsy. Enhanced cancer detection by the deep apical biopsy was also evident in patients with a prostatic volume >40 cm 3 (by 36.4%) and PSA ng/ml (by 13.3%). Conclusions: Using a computer simulation-based biopsy scheme with deep apical sampling cores enhanced the detection of prostate cancer in palpably benign glands, especially in men with PSA ranges of ng/ml or a gland volume of >40 cm 3. Our approach with fewer sampling cores may have been more cost-effective than other extensive biopsy schemes, but further studies with larger samples are warranted. Key words early detection, prostate cancer, prostate specific antigen, sextant biopsy, transrectal ultrasonography. Introduction There remains controversy regarding the methods of appropriate samplings in the prostatic gland and the potential of overlooking clinically significant cancer in up to approximately 30% of cases. 1 4 To overcome this limitation, numerous studies have been conducted to investigate additional samplings or alternative site biopsy schemes, which have resulted in higher cancer detection rates than the standard sextant biopsy Several investigators observed that biopsies obtained over 12 core samplings had a better detection rate than the standard sextant biopsy. 6,8,9,11 Eskew et al. used a systematic five region biopsy method and reported a 35% increase in cancer detection that would have been missed by the standard sextant biopsy alone. 5 Recently, new sampling sites have been hypothesized using computer simulation. 7,12 Whether Correspondence: Kazumasa Matsumoto MD, Department of Urology, Kitasato University School of Medicine, Kitasato, Sagamihara, Kanagawa, , Japan. kazumasa@cd5.so-net.ne.jp Received 12 September 2005; accepted 19 April *Dr Egawa is currently at the Department of Urology, Jikei University, Tokyo, Japan. or not such extended field biopsies with increased pathology charges are cost-effective remains to be seen. 13 We have previously shown that palpably benign prostate cancer lies predominantly on the anterior apex to midprostate region. 14 Although the optimal biopsy strategy usually includes a number of cores and more appropriate sites, an in-depth study to optimize sampling may also enhance prostate cancer detection. The objectives of this study were to use computer simulation based on radical prostatectomy specimens to investigate an optimal prostatic biopsy scheme, and then to verify if this scheme contributes to enhanced detection of prostate cancer in an actual biopsy setting. Methods Preparing a computer-simulated template of T1c prostate cancer and optimizing the prostatic biopsy The same dataset of 62 T1c tumors reported in a previous study was used in this study. 14 These patients underwent radical retropubic prostatectomies at the Kitasato University Hospital between April 1992 and April The predominant distribution of non-palpable T1c tumors has been shown to be anterior apex to mid-prostate. We used

2 Additional apical biopsy in prostatic gland 1291 the truespace3 version 3.0 three-dimensional software program (Caligari, Mountain View, CA, USA) and Adobe Photoshop 4.01 J graphic software program (Adobe System, San Jose, CA, USA) to simulate sagittal reconstruction of tumor distribution in a 40cc prostate for further investigation (Fig. 1). Four different biopsy schemes with fixed puncture sites were initially designed arbitrarily: (i) sextant biopsy alone from the lateral peripheral zone (PZ); (ii) lateral sextant biopsy and far lateral quadrant cores from the base and mid-prostate; (iii) lateral sextant biopsy and two additional deep apical cores; and (iv) basal and mid-prostate cores in the lateral sextant biopsy with four additional deep apical cores (Fig. 2). The apex was defined as the most inferior 5 mm of the prostate gland and the base as the most superior 1 cm. The mid-gland was defined as the region between the defined basal and apical regions. The standard angle of firing in sextant biopsy was assumed to be fixed to 30 at the prostatic margin in the axial and sagittal planes (Fig. 1). An appropriate combination of situations was tested in deep apical cores by changing axial (0 40 ) and sagittal (30 80 ) angles by every 10. The depth of the needle from the prostatic margin at the time of firing (0 5 mm) was also tested to optimize apical sampling. We used the computer program to simulate the ordinary biopsy procedure with an 18 gauge, 16 cm biopsy needle and a spring-loaded Biopty-gun (CR Bard, Murray Hill, NJ, USA). Specifically, the inner needle was supposed to advance 23 mm when fired and reveal a 17-mm biopsy slot for tissue sampling. The in-house computer program automatically determined the frequency of tumors in biopsy cores. 14 Patients and biopsy outcome We used this optimized computer simulation based biopsy strategy to study 536 consecutive patients who underwent biopsies at Kitasato University Hospital between June 2001 and December Seventy-nine patients with abnormal digital rectal examination, 69 patients with a history of prostate cancer, and 134 patients who had a different biopsy scheme because of clinical indication were excluded from further analysis. Of the remaining 254 patients with palpably benign glands, 198 (78%) had not previously undergone biopsy and 56 (22%) had previously undergone at least one biopsy with negative findings. Patients with suspicious digital rectal examination findings, hypoechoic lesions on transrectal ultrasonography or serum prostate-specific antigen (PSA) levels >2.0 ng/ml a) b) c) Fig. 1 (a) Standard angle of biopsy firing in sextant biopsy is axial and sagittal 30 at the prostatic margin (red line). The axial location of each biopsy relative was calculated symmetrically from the mid-line of the prostate gland to every 10. (b, c) The computer automatically determined the frequency of tumors in biopsy cores (lines A-C). Prostate cancer model was constructed using each pathological specimen taken form radical prostatectomy (P1 as apex to P10 as base). Color bar shows the frequency of tumors.

3 1292 K Matsumoto et al. Fig. 2 Variety of prostate biopsy methods. Comparison of prostate cancer detection rate among the biopsy placements using computer simulation. (a) Standard sextant biopsy; (b) standard sextant with lateral quadrant biopsy; (c) standard sextant with two deep apical biopsies; (d) standard quadrant with quadrant deep apical biopsy. ( ) 30 sampling; ( ) 80 sampling. by Dainapack AxSYM PSA assay (Dinabot, Tokyo, Japan) underwent biopsy. The Bruel and Kjaer 1846 console (Gentofte, Denmark) equipped with a 7 MHz multiplanar transducer was used for all ultrasound examinations and biopsies, as previously described. 14 Based on the simulation results, the following biopsy scheme was adopted in these patients. Transrectal systematic sextant biopsy was taken from lateral PZ. Two additional deep apical biopsies with a sagittal penetration angle of 80 were then directed to sufficiently cover the PZ anteriorly. All needles were fired at the prostatic margin. One patient required an additional core from a hypoechoic lesion that appeared suspicious on ultrasound. Patients received the standard antibiotic prophylaxis consisting of 100 mg ciprofloxacin on the morning of the biopsy and three times per day for the next 2 days. Assessed patients with prostate cancer All histology slides were examined and reviewed by a single pathologist (NY) and tumor grades were assigned based on the Gleason grading system. 15 Clinical stages were assigned in accordance with the unified tumor node metastasis (TNM) system. 16 PSA density (PSAD) was derived by dividing serum PSA by prostate volume (prostate length width height π/6), as determined by transrectal ultrasonography. Statistical analysis We used the Mann Whitney U-test and χ 2 test (P < 0.05 significant) to assess differences between clinical characteristics and biopsy outcomes. All analyses were performed using the StatView statistical package (StatView version 5.0 for Windows, SAS Institute, Cary, NC, USA). Results Computer simulation The probability of cancer in any of the sextant and apical cores is shown in Table 1. The maximum cancer detection rate in the computer simulation was estimated to be 47% in the lateral sextant biopsy scheme and 57% in the lateral sextant plus the additional far lateral PZ quadrant biopsy. The sextant biopsy with two additional deep apical cores appeared to be at least comparable to the four additional apical biopsy schemes (70% and 67%, respectively). Cancer detection was enhanced with more perpendicular penetration angles of additional apical cores. Depth of apical penetration before firing needles did not affect these findings (data not shown). Thus, lateral sextant biopsy with two additional deep apical cores with an 80 penetration angle

4 Additional apical biopsy in prostatic gland 1293 fired at the prostatic margin was found to have possibly the highest cancer detection rate in patients with palpably benign glands. Table 1 Probability of identifying prostate cancer in any cores of sextant and additional deep apical biopsy scheme using computer simulation according to variable sagittal angles Sagittal angle ( ) Additional deep apical biopsy Two cores (%) Four cores (%) Patient characteristics and biopsy results based on computer simulation The median age of the 254 eligible patients was 68 years (range years; mean 66.8 years) and median PSA was 5.6 ng/ml (range ; mean 7.6; Table 2). Median prostatic volume was 36.7 cm 3 (range ; mean 42.6) and median transition zone volume was 17.1 cm 3 (range ; mean 22.5). Patients with prostate cancer had significantly higher PSAD than those with benign lesions (0.23 vs ng/ml/cm 3, P < ). Patients with benign lesions had significantly larger prostate glands (40.2 vs cm 3, P < ) and transition zones (19.1 vs cm 3, P < ) than those with prostate cancer. There were no significant differences in age and PSA (5.4 vs. 6.1 ng/ml) between patients with benign histology and prostate cancer (P > 0.05). Cancer detection and characteristics Overall, 58 of the 254 patients with palpable benign glands (22.8%) had prostate cancer (Table 3). All were classified as T1cN0M0 disease. Prostate cancer was detected in 49 of 198 (24.7%) patients with no history of biopsy, and in nine of 56 (16.1%) with at least one previous negative biopsy. In patients with the following PSA levels, positive biopsy rates were: <2.0 ng/ml, 50.0%; ng/ml, 22.6%; ng/ml, 18.2%; ng/ml, 29.3%; and >20.1 ng/ml, 50.0% (P = 0.07). Poorly differentiated cancer (Gleason score >7) in these PSA ranges were 100%, 28.6%, 48.0%, 75.0% and 50.0%, respectively. Cancer locations found by sextant biopsy plus two additional deep apical samplings Twenty-eight cancers (48.3%) were positive exclusively in cores from the lateral sextant sites, 12 (20.7%) were identified only in cores from the deep apical sites, and the remaining 18 (31.0%) were positive in cores from both sites (Table 4). Of the 12 men who had cancer only in deep Table 2 Clinical characteristics of patients No. patients Age (years) PSA (ng/ml) Median (range) PSAD (ng/ml/cm 3 ) TZ volume (cm 3 ) Prostate volume (cm 3 ) Overall (47 83) 5.6 (1.2 72) 0.16 ( ) 17.1 ( ) 36.7 ( ) Cancer (47 88) 6.1 (1.2 72) 0.23 ( ) 10.4 ( ) 29.2 ( ) No cancer (51 88) 5.4 ( ) 0.14 ( ) 19.1 ( ) 40.2 ( ) P-value < < < PSA, prostate-specific antigen; PSAD, prostate specific antigen density; TZ, transition zone. Table 3 biopsy Association of clinical findings and biopsy results detected by transrectal ultrasound-guided sextant plus deep apical No. patients (%) PSA (ng/ml) < >20.1 Total Biopsy results Positive 1 (50.0) 14 (22.6) 25 (18.2) 12 (29.3) 6 (50.0) 58 (22.8) Negative 1 (50.0) 48 (77.4) 112 (81.8) 29 (70.7) 6 (50.0) 196 (77.2) Gleason score (14.3) 1 (4.0) 1 (8.3) 4 (6.9) 5, 6 8 (57.1) 12 (48.0) 2 (16.7) 3 (50.0) 25 (43.1) 7 4 (28.6) 6 (24.0) 5 (41.7) 1 (16.7) 16 (27.6) (100) 6 (24.0) 4 (33.3) 2 (33.3) 13 (22.4) PSA, prostate-specific antigen.

5 1294 K Matsumoto et al. Table 4 Distribution of cancer detection sites Biopsy site No. patients (%) PSA (ng/ml) < >20.1 Total Sextant site only 1 (100) 8 (57.1) 10 (40.0) 8 (66.7) 1 (16.7) 28 (48.3) Apical site only 2 (14.3) 7 (28.0) 1 (8.3) 2 (33.3) 12 (20.7) Both sites 4 (28.6) 8 (32.0) 3 (25.0) 3 (50.0) 18 (31.0) Total 1 (100) 14 (100) 25 (100) 12 (100) 6 (100) 58 (100) PSA, prostate-specific antigen. Table 5 Association of clinical findings with unique cancer core Clinical findings No. ca. pts. No. ca. pts. detected by unique core (%) Sextant biopsy sites Deep biopsy site Apex Mid Base Apex PSA (ng/ml) < (26.7) 1 (6.7) 2 (13.3) 2 (13.3) (8.0) 1 (4.0) 2 (8.0) 6 (24.0) > (11.1) 2 (11.1) 1 (5.6) 3 (16.7) Age (years) < (17.9) 2 (7.1) 1 (3.6) 4 (17.9) > (10.0) 2 (6.7) 4 (13.3) 7 (23.3) Prostatic volume (cm 3 ) < (12.8) 3 (6.4) 4 (8.5) 7 (14.9) > (18.1) 1 (9.1) 1 (9.1) 4 (36.4) Total 58 8 (13.8) 4 (6.9) 5 (8.6) 11 (19.0) ca, prostate cancer; pts, patients; PSA, prostate-specific antigen. apical sites, seven (58.3%) had gray-zone PSA ranges of ng/ml. Twenty-eight (48.3%) patients had only a single positive core. Distribution of unique cancer core was more frequent in the deep apical region across all groups except for PSA < 4.0 ng/ml, but was not statistically significant (P > 0.05; Table 5). Eleven of the 12 men with cancer exclusively in deep apical sites had only one positive core. The remaining patient had bilaterally positive apical cores. Unique cancer detection by deep apical cores was most frequently seen in those with a prostatic volume of >40 cm 3 (36.4%) and PSA ng/ml (24.0%). Adverse events Three patients (1.2%) experienced transient fever >38 C but recovered without hospitalization. Microscopic hematuria after biopsy occurred in 205 patients (80.7%). However, no significant gross hematuria was reported in this series. Although 14 patients complained of perineal discomfort at the time of biopsy, none experienced serious adverse events. Discussion The widespread use of PSA and transrectal ultrasoundguided prostatic biopsy, particularly systematic sextant biopsy, 17 facilitates an earlier detection of prostate cancer, including that in palpably benign glands. 17,18 Anatomically, PZ extends anteriorly and occupies the whole apex. A target-stage specific biopsy scheme, including sampling sites and number of cores, is more logical because dominant foci of T1c prostate cancer are known to locate anteriorly in the apical PZ. 19 Our computer simulation study supports a potential benefit of obtaining two additional deep apical cores with the lateral sextant biopsy in patients with palpably benign glands. This biopsy scheme covers the entire PZ, that is, lateral sextant cores for posterolateral PZ and apical cores for more anteriorly located PZ. A steeper angle was needed to fully sample the anterior apex. The apex appeared to be the only and unique cancer detection site in 12 (20.7%) of 58 patients. Deep apical biopsy enhanced cancer detection in patient cohorts with PSA ranges of ng/ml by 24.0%, prostatic volume >40 cm 3 by 36.4% and PSA ng/ml by 13.3%. Other investigators have applied computer simulation technology to create optimal biopsy strategies. Chen et al. used a systematic stochastic computer simulation model to assess various types of biopsy. 20 They reported an 11- core biopsy strategy that includes standard sextant, transition zone, midline PZ, and anterior horn of the PZ. A 33% increase in cancer detection was reported with this biopsy scheme. 7 The alternate site biopsy was greatest at the anterior horn region in the 11-core biopsy. Bauer et al. also used a 10-core biopsy technique that includes a standard sextant and four lateral placements in bilateral apex and mid-gland. 12 Approximately 46% of the patients were diagnosed in only lateral portions. However, apical anterior glands were not intentionally sampled in these regimens. Some investigators suggest that anterior region sampling is useful. Bott et al. found that 21% of cancers lie

6 Additional apical biopsy in prostatic gland 1295 predominantly in the anterior regions of 547 radical prostatectomy specimens. They often require multiple sets of sextant biopsies for diagnosis and yield smaller areas of cancer on core biopsies than posterior tumors in glands of similar weight and tumor volume. 21 Ellis and Wright suggested a role of anterior apical biopsies to increase overall cancer detection, with a high unique cancer detection rate of 17%. 22 Meng et al. clinically tested apical anterior horn biopsies. 10 Overall, cancer detection of the apical anterior biopsies was only 2%, but it had greater utility in patients with lower PSA and normal digital rectal examination. All these studies indicated biopsy in patients with an elevated or rising PSA or abnormal rectal findings who were not target-stage specific. The procedure was tolerated well without local anesthesia. Most patients experienced microscopic hematuria afterwards but none required intensive treatment. This is presumably owing to the fewer sampling cores and urethral sparing in this biopsy protocol contrary to other schemes such as the midline cores by Eskew et al. 20 The whole incidence of adverse events did not differ substantially between the current eight-core biopsy strategy and more extensive samplings 11,23 Increasing pathology charges in an extended biopsy scheme are also of concern. 13 More costeffective prostatic sampling with comparable efficacy and without increased morbidity is desirable. The small number of patients in this study is also of concern and excludes definitive conclusions. An investigation with larger numbers and an independent prospective validation study are thus needed to appraise the efficacy of this biopsy scheme. Conclusions The lateral sextant plus deep apical biopsy scheme seemed to effectively detect T1c prostate cancer. The addition of two deep apical cores enhanced cancer detection by approximately 20%. Our approach with fewer sample cores may be more cost-effective than other extensive biopsy schemes that were once thought to be comparable. Further work is warranted with larger numbers of patients who have palpable benign prostate glands. Acknowledgments Supported in part by a grant from the Japanese Society for the Promotion of Science Grant-in-Aid for Science Research, and grants , and References 1 Keetch DW, Catalona WJ, Smith DS. Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J. Urol. 1994; 151: Ellis WJ, Brawer MK. Repeat prostate needle biopsy: who needs it? J. Urol. 1995; 153: Fleshner NE, O Sullivan M, Fair WR. Prevalence and predictors of a positive repeat transrectal ultrasound guided needle biopsy of the prostate. J. Urol. 1997; 158: 505 8; Discussion Matsumoto K, Egawa S, Suyama K et al. Indication of repeat prostatic biopsy following previous negative findings. 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