| Japanese Journal of Clinical Oncology | Pages |
Results of Transrectal Ultrasound-Guided Biopsies and Clinical Significance of Japanese Prostate Cancer
Introduction
Materials And Methods
Results
Results of Initial Biopsy
Results of Repeat Biopsy and TURP
Correlation between Calculated Cancer Volume and Measured Total Tumor Volume in Radical Prostatectomy Specimens
Clinical Significance of Detected Prostate Cancers
Discussion
Conclusion
Acknowledgments
References
Results of Transrectal Ultrasound-Guided Biopsies and Clinical Significance of Japanese Prostate Cancer
Background: We review the outcomes of ultrasound-guided biopsy in consecutive patients and assess clinical significance of Japanese prostate cancer.
Methods: Examination was made of 1469 patients subsequent to transrectal ultrasound-guided biopsy of the prostate gland. For 84 patients, two or more sets of ultrasound-guided biopsies were conducted following the initial negative results during this period. Two hundred and thirty-two patients with benign histology at the initial biopsy underwent transurethral resection of the prostate (TURP). The clinical significance of the cancers was assessed based on patient age and calculated tumor volume at diagnosis, assumed cancer volume doubling time and life-expectancy in the Japanese male population.
Results: Overall, 327 of the 1469 patients (22.3%) had prostate carcinoma. Positive biopsy rates in patients with PSA 2.0 ng/ml or lower, 2.1-4.0 ng/ml, 4.1-10.0 ng/ml and 10.1 ng/ml or greater were 4.6%, 8.6%, 15.8% and 59.5%, respectively. Of the 232 patients who underwent TURP, 15 (6.5%) had cancer. Of the 84 patients subjected to the multiple sets of biopsies, 19 (22.6%) cancers were detected. Of the 203 cancers without distant metastasis at initial biopsy, 13.3%, 25.1%, 32.5% and 40.4% of tumors for 2-, 3-, 4- and 6-year tumor doubling times gave no indication of clinical significance. Nearly half these patients (43-52%) had clinical stage T1c disease. The estimated proportion of clinically insignificant tumors in repeat biopsy was virtually the same as first set biopsies.
Conclusions: Low PSA was not necessarily an indication of indolent cancer and repeat biopsy did not often demonstrate clinically unimportant cancers. Many patients with stage T1c disease may eventually prove to require no treatment.
INTRODUCTION
The incidence of prostate cancer is on the rise and presently ranks as the 9th highest cause of male cancer death in Japan (1-3). There were 6482 cases in 1988 and the number is anticipated to increase to as many as 12 783 by 2000. The greater values of statistical data are due in part to the more sensitive detection possible through the use of the prostate-specific antigen (PSA) (4). Ultrasound-guided biopsy, particularly random sextant biopsy, also has facilitated the detection of prostate cancer (5). But how this will affect long-term patient survival is unknown, mainly due to the unpredictability of the clinical significance of tumors at diagnosis. For assessing clinical significance of prostate cancer, various factors should be considered (6-9). Dugan et al. propose a model to assess the clinical significance of prostate cancer based on cancer volume, grade, cancer volume doubling time and life expectancy (8). Using a modification of this model, the authors previously assessed the clinical significance of Japanese prostate cancer subsequent to radical prostatectomy (6). However, clinical applicability of this model is limited since it fails to accurately predict tumor volume prior to treatment. In 1996, D'Amico and Propert introduced a new method to estimate prostate cancer volume (10), which was used in this study to assess the clinical significance of Japanese prostate cancer detected by ultrasound-guided biopsy.
Table 1.
| Characteristics | Initial biopsy (n=1469) | Subsequent TUR and/or biopsy (n=316) | ||||
| Non-cancer (%) Median ± SE (range) |
Prostate cancer (%) Median ± SE (range) |
P value | Non-cancer (%) Median ± SE (range) |
Prostate cancer (%) Median ± SE (range) |
P value | |
| No. of patients | 1142(77.7) | 327(22.3) | 282(89.2) | 34(10.8) | ||
| Age (years) | 67.0 ± 0.3 | 70.0 ± 0.5 | <0.0001 | 66.0 ± 1.1 | 69.0 ± 1.6 | 0.6761 |
| (30-92) | (48-94) | (46-87) | (51-83) | |||
| Prostatic volume | 33.4 ± 0.7 | 27.8 ± 1.2 | <0.0001 | 43.4 ± 1.5 | 29.6 ± 2.6 | <0.0001 |
| (cm3) | (2.1-196.6) | (4.6-179.3) | (9.0-164.4) | (5.1-78.1) | ||
| PSA (ng/ml) | 3.8 ± 0.4 | 16.6 ± 67.3 | <0.0001 | 5.4 ± 0.7 | 6.3 ± 3.0 | 0.1532 |
| (0.0-350.0) | (0.0-20 100) | (0.0-161.0) | (0.5-79.7) | |||
| PSAD | 0.11 ± 0.01 | 0.58 ± 3.04 | <0.0001 | 0.11 ± 0.01 | 0.23 ± 0.10 | 0.0002 |
| (ng/ml.cm3) | (0.00-4.56) | (0.04-893.33) | (0.00-3.63) | (0.02-2.73) | ||
MATERIALS AND METHODS
Examination was carried out on 1469 consecutive patients subsequent to transrectal ultrasound guided biopsy of the prostate gland at Kitasato University Hospital between October 1991 and October 1997. No patients had previously been diagnosed with prostate cancer or had undergone endocrine manipulation. All patients whose digital rectal examination results appeared questionable and/or with serum PSA greater than 2.0 ng/ml by Eiken polyclonal radioimmunoassay (Eiken, Tokyo, up to March 1993) or 2.0 ng/ml by Dainapack IMx PSA assay (Dinabot, Tokyo, thereafter) underwent biopsy (11). Of these, 123 underwent biopsy in the PSA-based early detection program at this institution (12). A lower PSA cut-off value of 2.0 ng/ml in Eiken polyclonal radioimmunoassay and Dainapack IMx PSA assay has been used at this hospital as indication for biopsy instead of recommended values (0-3.0 and 0-4.0 ng/ml, respectively) by the manufacturers (11,13). For uniformity, Eiken PSA in 554 patients was inter-converted as recommended by Machida et al.: IMx PSA=1.39×Eiken PSA -1.02 (11). This conversion arbitrarily gave negative values in IMx PSA in the event of low Eiken PSA. These were taken as 0 for the purpose of statistical analysis and other calculations. Biopsy was indicated based in part on pre-prostatectomy evaluation in some patients regardless of clinical findings.
Most patients (n=1390) underwent ultrasound-guided systematic needle biopsy at six or more separate sites in such a way as to maximize sampling of the peripheral zone (14). Biopsy specimens from superior, middle and inferior regions were followed by additional needle biopsy of hypoechoic lesions appearing suspicious on ultrasound. A subgroup of 420 patients underwent transition zone sampling at the time of peripheral zone sampling (5). Seventy-nine patients underwent only biopsy directed at hypoechoic lesions and/or random non-systematic biopsy. Eighty-four patients underwent two or more sets of ultrasound-guided biopsy owing to initial negative results during this period. Indications for repeat biopsy included atypia or prostatic intraepithelial neoplasia on initial biopsy or strong clinical suggestion of carcinoma based on PSA or digital rectal examination. A total of 232 patients underwent TURP following the clinical diagnosis of benign prostatic hyperplasia (BPH) based on negative biopsy results.
Patients with prostate cancer were examined for staging by digital rectal examination, prostatic acid phosphatase, intravenous urography, computed tomography, magnetic resonance imaging and bone scanning, supplemented with radiographs of abnormal areas. Clinical stage was determined in accordance with the unified tumor node metastasis (TNM) system (15). In this study, data were stratified according to T- and M-stage since nodal status could not be accurately determined using methods currently available. All histology slides were examined and reviewed by a single pathologist (S.K.) and tumor grade was assigned based on the Gleason grading system. Digital rectal examination was conducted by several board-certified urologists who recorded abnormal findings. Prostate scanning and ultrasound-guided biopsy were conducted using the Bruel & Kjaer (Gentofte, Denmark) model 1846 scanner equipped with a 7 MHz multiplanar transducer. PSA density (PSAD) was derived by dividing serum PSA by prostatic volume, as in transrectal ultrasonography. Prostatic volume was determined as prostatic length×width×height×([pi]/6).
Prostate cancer volume was determined as described by D'Amico et al. (10,16). The clinical significance of cancer was assessed by this calculated volume and criteria of Dugan et al. (6,8).
The Mann-Whitney U or Kruskal-Wallis test was conducted for comparison of age, positive biopsy rate, PSA, PSAD and prostatic volume with P values <0.05 as significant. Logistic regression analysis was conducted to assess variables for usefulness to predict cancer in repeat biopsy with other variables controlled.
RESULTS
Results of Initial Biopsy
The median subject age of the 1469 patients was 67.0 years (range 30-94, Table 1), for cancer patients 70.0 years and 67.0 years for men with benign histology (P<0.0001). Pre-operative PSA was available for 1446 of these patients, prostatic volume for 1427, ultrasound findings for all and PSAD for 1404 patients. Patients with benign histology had significantly larger prostatic glands compared to those with prostate cancer (33.4 versus 27.8 cm3, P<0.0001). Patients with prostate cancer had significantly higher median PSA compared to those with benign histology (16.6 versus 3.8 ng/ml, P<0.0001). Men with prostate cancer had significantly higher PSA density (PSAD) than those with benign histology (P<0.0001). Median values for patients with prostate cancer versus non-cancer were 0.58 versus 0.11 ng/ml.cm3.
Overall, 327 of the 1469 patients (22.3%) had prostate carcinoma (Table 1 and 2). Stage T1c was applicable to 70 cases, T2a to 24, T2b to 77, T2c to 32, T3a to 4, T3b to 17, T3c to 84 and T4 to 19 (Table 2). Distant metastasis was found in 30.9% (101/327). Tumor grade distribution was as follows: Gleason score 2-4 in 14.9%, 5 and 6 in 29.7%, 7 in 36.7% and 8-10 in 18.7%. Positive biopsy rates in patients with PSA 2.0 ng/ml or lower, 2.1-4.0 ng/ml, 4.1-10.0 ng/ml and 10.1 ng/ml or greater were 4.6%, 8.6%, 15.8% and 59.5%, respectively. The incidence of extraglandular disease (>T3) and poorly differentiated histology of Gleason scores 7 or greater in these PSA ranges were 25.0%, 15.6%, 11.0%, 51.4% and 58.3%, 34.4%, 42.5%, 62.9%, respectively.
Calculated tumor volume ranged from 0.0 to 14 356.0 cm3 (median 3.9). Graded increase in median values of calculated tumor volume according to PSA was noted: 0.10 cm3 for 2.0 ng/ml or lower, 0.19 cm3 for 2.1-4.0 ng/ml, 1.22 cm3 for 4.1-10.0 ng/ml and 12.19 cm3 for 10.1 ng/ml or more (P<0.0001, Table 2).
Rectal findings were significant for predicting prostate cancer and positive results were in proportion to PSA: 8.7% for 2.0 ng/ml or lower, 22.5% for 2.1-4.0 ng/ml, 42.0% for 4.1-10.0 ng/ml and 87.8% for 10.1 ng/ml or more (P<0.0001, Table 3). Graded increase in detection was also noted for patients with normal rectal findings (P=0.028), as also for patients with negative and positive ultrasound findings or PSAD>0.15 (P<0.0001). Cancer was found 1.3 times more often for glandular volume of 40.0 cm3 or less (P=0.008).
Table 2.
| Initial biopsy | Subsequent TUR and biopsy | |||||||||||
| PSA range (ng/ml) | PSA range (ng/ml) | |||||||||||
| -2.0 | 2.1-4.0 | 4.1-10.0 | 10.1- | ND | Total | -2.0 | 2.1-4.0 | 4.1-10.0 | 10.1- | ND | Total | |
| Biopsy results | ||||||||||||
| Pos. No. (%) | 12(4.6) | 32(8.6) | 73(15.8) | 210(59.5) | 0(0.0) | 327(22.3) | 5(9.8) | 7(8.9) | 7(6.0) | 14(22.6) | 1(12.5) | 34(10.8) |
| Neg. No. (%) | 248(95.4) | 339(91.4) | 389(84.2) | 143(40.5) | 23(100.0) | 1142(77.7) | 46(90.2) | 72(91.1) | 109(94.0) | 48(77.4) | 7(87.5) | 282(89.2) |
| T-stage, No. (%) | ||||||||||||
| T1a | - | - | - | - | - | - | 3(60.0) | 4(57.1) | - | 2(14.3) | 1(100.0) | 10(29.4) |
| T1b | - | - | - | - | - | - | 1(20.0) | - | 2(28.6) | 2(14.3) | - | 5(14.7) |
| T1c | 4(33.3) | 16(50.0) | 22(30.1) | 28(13.3) | - | 70(21.4) | 1(20.0) | 3(42.9) | 2(28.6) | 6(42.9) | - | 12(35.5) |
| T2a | 1(8.3) | 4(12.5) | 9(12.3) | 10(4.8) | - | 24(7.3) | - | - | 1(14.2) | 1(7.1) | - | 2(5.9) |
| T2b | 3(25.0) | 5(15.6) | 25(34.3) | 44(21.0) | - | 77(23.5) | - | - | 2(28.6) | 3(21.4) | - | 5(14.7) |
| T2c | 1(8.3) | 2(6.3) | 9(12.3) | 20(9.5) | - | 32(9.8) | - | - | - | - | - | - |
| T3a | - | - | - | 4(1.9) | - | 4(1.2) | - | - | - | - | - | - |
| T3b | - | 2(6.3) | 2(2.7) | 13(6.2) | - | 17(5.2) | - | - | - | - | - | - |
| T3c | 3(25.0) | 3(9.3) | 6(8.2) | 72(34.3) | - | 84(25.7) | - | - | - | - | - | - |
| T4 | - | - | - | 19(9.0) | - | 19(5.8) | - | - | - | - | - | - |
| M-stage, No. (%) | ||||||||||||
| M0 | 8(66.7) | 29(90.6) | 60(82.2) | 106(50.4) | - | 203(62.1) | 4(80.0) | 6(85.7) | 7(100.0) | 11(78.6) | 1(100.0) | 29(85.3) |
| M1 | 4(33.3) | 2(6.3) | 5(6.8) | 90(42.9) | - | 101(30.9) | - | - | - | 1(7.1) | - | 1(2.9) |
| Mx | - | 1(3.1) | 8(11.0) | 14(6.7) | - | 23(7.0) | 1(20.0) | 1(14.3) | - | 2(14.3) | - | 4(11.8) |
| Gleason score, No. (%) | ||||||||||||
| 2-4 | 4(33.3) | 12(37.5) | 13(17.8) | 20(90.5) | - | 49(14.9) | 4(80.0) | 7(100.0) | 1(14.3) | 4(28.6) | 1(100.0) | 17(50.0) |
| 5,6 | 1(8.3) | 9(28.1) | 29(39.7) | 58(29.6) | - | 97(29.7) | - | - | 4(57.1) | 4(28.6) | - | 8(23.5) |
| 7 | 5(41.7) | 6(18.8) | 21(28.8) | 88(41.9) | - | 120(36.7) | - | - | 2(28.6) | 4(28.6) | - | 6(17.6) |
| 8-10 | 2(16.7) | 5(15.6) | 10(13.7) | 44(21.0) | - | 61(18.7) | 1(20.0) | - | - | 2(14.2) | - | 3(8.8) |
| Calculated TV (cm3) | ||||||||||||
| median±SE | 0.10±0.05 | 0.19±0.09 | 1.22±0.11 | 12.19±67.70 | - | 3.90±42.61 | 0.10 | 0.16±0.02 | 0.63±0.27 | 5.87±1.98 | - | 2.04±1.33 |
| range | 0.00-0.37 | 0.00-2.29 | 0.00-4.85 | 0.35-14 356.00 | - | 0.00-14 356.00 | - | 0.10-0.17 | 0.35-1.85 | 2.04-19.20 | - | 0.10-19.20 |
Table 3.
| Initial biopsy | Subsequent TUR or biopsy | |||||||||||
| PSA (ng/ml) | PSA (ng/ml) | |||||||||||
| -2.0 % Pos. (No.) |
2.1-4.0 % Pos. (No.) |
4.1-10.0 % Pos. (No.) |
10.1- % Pos. (No.) |
ND % Pos. (No.) |
Total % Pos. (No.) |
-2.0 % Pos. (No.) |
2.1-4.0 % Pos. (No.) |
4.1-10.0 % Pos. (No.) |
10.1- % Pos. (No.) |
ND % Pos. (No.) |
Total % Pos. (No.) |
|
| DRE | ||||||||||||
| Normal | 2.4 | 5.3 | 6.7 | 20.3 | 0.0 | 7.5 | 10.2 | 9.3 | 2.8 | 18.2 | 12.5 | 8.8 |
| (4/168) | (16/300) | (23/343) | (30/148) | (0/20) | (73/979) | (5/49) | (7/75) | (3/109) | (10/55) | (1/8) | (26/296) | |
| Abnormal | 8.7 | 22.5 | 42.0 | 87.8 | 0.0 | 51.8 | 0.0 | 0.0 | 57.1 | 57.1 | - | 40.0 |
| (8/92) | (16/71) | (50/119) | (180/205) | (0/3) | (254/490) | (0/2) | (0/4) | (4/7) | (4/7) | - | (8/20) | |
| US findings | ||||||||||||
| Negative | 2.5 | 6.2 | 11.3 | 44.3 | 0.0 | 15.2 | 8.1 | 12.1 | 4.3 | 21.2 | 14.3 | 10.6 |
| (4/160) | (18/290) | (42/372) | (97/219) | (0/18) | (161/1059) | (3/37) | (7/58) | (4/92) | (11/52) | (1/7) | (26/246) | |
| Positive | 8.0 | 17.3 | 34.4 | 84.3 | 0.0 | 40.5 | 14.3 | 0.0 | 12.5 | 30.0 | 0.0 | 11.4 |
| (8/100) | (14/81) | (31/90) | (113/134) | (0/5) | (166/410) | (2/14) | (0/21) | (3/24) | (3/10) | (0/1) | (8/70) | |
| PSAD | ||||||||||||
| <0.15 | 3.6 | 6.8 | 4.8 | 0.0 | - | 5.1 | 8.2 | 6.0 | 6.7 | 0.0 | - | 6.5 |
| (9/253) | (21/310) | (9/186) | (0/18) | (39/767) | (4/49) | (4/67) | (4/60) | (0/9) | (12/185) | |||
| [ge]0.15 | 33.3 | 22.4 | 24.3 | 62.7 | - | 43.6 | 50.0 | 27.3 | 5.7 | 27.5 | - | 17.9 |
| (1/3) | (11/49) | (64/263) | (202/322) | (278/637) | (1/2) | (3/11) | (3/53) | (14/51) | (21/117) | |||
| Prostatic volume (cm3) | ||||||||||||
| [le]40.0 | 4.6 | 9.4 | 22.7 | 75.1 | 0.0 | 24.3 | 9.5 | 10.0 | 11.4 | 54.5 | 0.0 | 16.4 |
| (11/237) | (25/266) | (58/256) | (139/185) | (0/14) | (233/958) | (4/42) | (4/40) | (5/44) | (12/22) | (0/4) | (25/152) | |
| >40.0 | 0.0 | 7.5 | 7.8 | 40.6 | 0.0 | 18.1 | 11.1 | 7.9 | 2.9 | 5.1 | 25.0 | 5.7 |
| (0/20) | (7/93) | (15/193) | (63/155) | (0/8) | (85/469) | (1/9) | (3/38) | (2/68) | (2/39) | (1/4) | (9/158) | |
Results of Repeat Biopsy and TURP
Two hundred and thirty-two of the 1142 patients with benign histology at initial biopsy underwent TURP after a median period of 2.0 months (mean 5.0, range 0.2-63.0 months) from the last negative biopsy. Indication of surgery was made at the discretion of the attending physicians. Fifteen (6.5%) cancers were diagnosed as stages T1a in 10 and T1b in 5 patients (Table 2). No patient had distant metastasis. Of the 84 patients who underwent multiple sets of ultrasound-guided biopsy (mean 2.2, median 2.0, range 2-5) following initial negative biopsy 19 (22.6%) cancers were detected. Fifteen cancers were detected at the second and four at the third biopsy. Median period to cancer diagnosis from the first biopsy was 13.4 months (mean 17.6, range 1.6-62.6 months). Stage T1c was applicable to 12 patients, T2a to two and T2b to five. One patient with stage T1c disease had distant metastasis. Tumor grade distribution in these 34 patients with cancer was as follows: Gleason score 2-4 in 50.0%, 5 and 6 in 23.5%, 7 in 17.6% and 8-10 in 8.8%. Multiple logistic regression analysis including age, PSA prior to repeat biopsy or surgery, rectal and ultrasound findings, gland volume and the presence or absence of atypia or prostatic intraepithelial neoplasia in initial biopsy cores indicated not any one of these variables by itself to be useful for predicting positive biopsy(P>0.05, unpublished data).
Correlation between Calculated Cancer Volume and Measured Total Tumor Volume in Radical Prostatectomy Specimens
Linear regression analysis indicated calculated cancer volume to be fairly well correlated with measured total tumor volume (5,6) determined in a Japanese patient subset following sextant biopsy and radical prostatectomy at this hospital (n=94, r=0.590, P<0.0001). Median (±standard error, range) tumor volumes were 1.9 cm3 (±0.8, 0.004-44.91) and 3.1 cm3 (±0.9, 0.07-44.01), respectively. Stage T1c was noted in 34 patients, T2a in 10, T2b in 26, T2c in 10, T3a in 2, T3b in 3 and T3c in 9. Underestimation of actual volume by more than 0.5 cm3 occurred more frequently (n= 56) than overestimation (n=22).
Table 4.
| No. pts with insignificant cancer | |||||||||||
| Initial biopsy | Subsequent biopsies | ||||||||||
| No. pts | Doubling time (years) | No. pts | Doubling time (years) | ||||||||
| No. (%) | 2 | 3 | 4 | 6 | No. (%) | 2 | 3 | 4 | 6 | ||
| Age at diagnosis (years) | 45-49 | 1(0.5) | 0 | 0 | 0 | 0 | 1(7.1) | 0 | 0 | 0 | 0 |
| 50-59 | 26(12.8) | 1 | 5 | 9 | 9 | 2(14.3) | 0 | 0 | 0 | 0 | |
| 60-69 | 81(39.9) | 5 | 14 | 18 | 28 | 9(64.3) | 0 | 3 | 3 | 3 | |
| 70-79 | 72(35.5) | 12 | 20 | 24 | 30 | 2(14.3) | 2 | 2 | 2 | 2 | |
| 80-89 | 22(10.8) | 8 | 11 | 14 | 14 | 0(0.0) | 0 | 0 | 0 | 0 | |
| 90- | 1(0.5) | 1 | 1 | 1 | 1 | 0(0.0) | 0 | 0 | 0 | 0 | |
| PSA (ng/ml) | -2.0 | 8(3.9) | 3 | 4 | 4 | 4 | 0(0.0) | 0 | 0 | 0 | 0 |
| 2.0-4.0 | 29(14.3) | 9 | 17 | 18 | 18 | 2(14.3) | 1 | 2 | 2 | 2 | |
| 4.1-10.0 | 60(29.6) | 9 | 19 | 26 | 31 | 5(35.7) | 1 | 3 | 3 | 3 | |
| 10.1- | 106(52.2) | 6 | 11 | 18 | 29 | 7(50.0) | 0 | 0 | 0 | 0 | |
| Clinical stage | T1c | 57(28.1) | 14 | 22 | 30 | 36 | 8(57.1) | 1 | 4 | 4 | 4 |
| T2a | 22(10.8) | 3 | 5 | 9 | 11 | 1(7.1) | 0 | 0 | 0 | 0 | |
| T2b | 56(27.6) | 8 | 19 | 20 | 24 | 5(35.7) | 1 | 1 | 1 | 1 | |
| T2c | 23(11.3) | 1 | 4 | 5 | 6 | 0(0.0) | 0 | 0 | 0 | 0 | |
| T3a | 3(1.5) | 0 | 0 | 0 | 0 | 0(0.0) | 0 | 0 | 0 | 0 | |
| T3b | 6(3.0) | 0 | 0 | 0 | 1 | 0(0.0) | 0 | 0 | 0 | 0 | |
| T3c | 31(15.3) | 1 | 1 | 2 | 4 | 0(0.0) | 0 | 0 | 0 | 0 | |
| T4 | 5(2.4) | 0 | 0 | 0 | 0 | 0(0.0) | 0 | 0 | 0 | 0 | |
| Biopsy Gleason score | 2-4 | 39(19.2) | 15 | 24 | 32 | 37 | 3(21.4) | 1 | 3 | 3 | 3 |
| 5 | 38(18.7) | 6 | 17 | 19 | 29 | 1(7.1) | 1 | 0 | 0 | 0 | |
| 6 | 28(13.8) | 5 | 6 | 9 | 10 | 5(35.7) | 0 | 2 | 2 | 2 | |
| 7 | 64(31.5) | 1 | 4 | 6 | 6 | 2(14.3) | 0 | 0 | 0 | 0 | |
| 8-10 | 34(16.7) | 0 | 0 | 0 | 0 | 3(21.4) | 0 | 0 | 0 | 0 | |
| Total (%) | 203(100.0) | 27(13.3) | 51(25.1) | 66(32.5) | 82(40.4) | 14(100.0) | 2(14.3) | 5(35.7) | 5(35.7) | 5(35.7) | |
Clinical Significance of Detected Prostate Cancers
The criteria of Dugan et al. (6,8) indicated that 27 (13.3%) of the 203 prostate cancers at initial biopsy and without distant metastasis (M0) to be clinically insignificant for an assumed tumor doubling time of 2 years (Figure 1, Table 4). For 3-, 4- and 6-year doubling times, 51 (25.1%), 66 (32.5%) and 82 (40.4%) of the 203 cases had clinically insignificant cancers, respectively. The clinical stages of 82 patients with insignificant tumors for an assumed 6-year doubling time were T1c in 36 (43.9%), T2a in 11 (13.4%), T2b in 24 (29.3%), T2c in 6 (7.3%), T3b in 1 (1.2%) and T3c in 4 (4.9%). Clinically insignificant cancers were present in 9 of 27 (33.3%) patients less than 60 years old, in 28 of 81 (34.6%) patients aged 60-69 years and in 30 of 72 (41.7%) patients aged 70-79 patients, 15 of 23 (65.2%) patients over 80 years. Serum PSA was inversely correlated with insignificant cancers, 22 of 37 (59.5%) patients for 4.0 ng/ml or lower, 31 of 60 (51.7%) patients for 4.1-10.0 ng/ml and 29 of 106 (27.4%) for 10.1 ng/ml or more (P=0.0008). Of the 14 T1-2M0 cancers detected by repeat biopsy 2 (14.3%) were clinically insignificant for an assumed tumor doubling time of 2 years. For 3-, 4- and 6-year doubling times, 5 (35.7%), 5 (35.7%) and 5 (35.7%) cases had clinically insignificant cancers, respectively. These findings are consistent with those of initial biopsy findings.
Figure 1. Clinical significance of prostate cancer detected by transrectal ultrasound guided biopsy. Each case is represented by a single symbol according to patient age, calculated tumor volume and biopsy Gleason score. Solid data points represent clinically insignificant cancers as determined based on patient life expectancy, calculated tumor volume, biopsy Gleason score and tumor doubling times. The insignificant cases lie below the curve of each individual tumor doubling time. Data points with tick marks represent cases detected by repeat biopsy. The PSA test is now widely conducted in Japan for making early diagnosis of prostate cancer and this malignancy has thus been detected more frequently (1-4,12,17). The incidence of prostate cancer and advanced disease has been shown proportional to PSA, as also noted in this study (16-21). The cut-off for this test is determined by a balance between detecting all cancers as early as possible and avoidance of biopsy for cases of slight cancer possibility. It is known that age specific reference ranges of PSA differ significantly according to race (17,22). Selection of an ideal serum PSA cut-off value for early detection of prostate cancer is thus difficult and should be determined for each race. An arbitrarily chosen lower PSA cut-off value of 2.0 ng/ml in Eiken polyclonal radioimmunoassay and Dainapack IMx PSA assay is generally used at this hospital as an indication for biopsy (5,16). Of the 1469 consecutive patients, 631 (43.0%) had a PSA of 4.0 ng/ml or lower. Cancer was detected in 7% (44/631) of men in this low range (11,13), 4.6% in patients with a PSA of 2.0 ng/ml or lower and 8.6% in patients with a PSA between 2.1 and 4.0 ng/ml. Approximately half these patients had stage T1c disease. This low rate of detection may not necessarily justify routine use of the lower cut-off value of PSA, but 40.9% (18/44) of tumors had poorly differentiated histology of Gleason scores 7 or greater. Moreover, 18.2% and 13.6% had locally advanced disease and distant metastasis, respectively. Catalona et al. (23) recently reported that prostate cancer could be appreciably detected in men with a PSA of 2.6-4.0 ng/ml. Prostate cancer was detected in 22% of 332 screening volunteers aged 50 years or older who had a benign prostate examination. All cancers were clinically localized and for 8.2%, biopsy Gleason score was 7 or greater. Low PSA itself thus would not necessarily indicate indolent cancer. Though direct comparison of both studies may not be possible, disparity in the incidence of aggressive cancer may reflect differences in clinical significance of a given serum PSA in Japanese and Caucasian males of the same age (16,17). Lowering the recommended PSA for biopsy may be beneficial for certain Japanese patients. Approximately 20-30% of men with a PSA higher than 4.0 ng/ml whose initial biopsy showed no prostate cancer are diagnosed as cancer based on subsequent biopsy conducted within a year on average (24,25). This study is the first to report results of repeat ultrasound guided biopsy in the Asian male population. The outcomes were similar to previous studies of western countries. Of 84 patients who underwent multiple sets of biopsy due to initial negative results, 19 (22.6%) cancers were detected. Error in sampling using current biopsy methods rather than racial difference may significantly influence the detection rate in patient groups undergoing repeat biopsy. A single set of biopsies may not make sampling of the prostate sufficiently possible. Better biopsy methods should be established. Fifteen more cancers (6.5%) were diagnosed by TURP. All but one of these 34 patients had clinically localized cancer. One fourth had poorly differentiated tumors of Gleason score 7 or greater. Though Fleshner et al. (25) found PSA at more than 20 ng/ml to be a significant independent risk factor, by multivariate analysis in this study, it was not possible to identify variables useful for predicting the need for repeat biopsies. The assignment of any cancer to an unimportant category must be based on age, health and life expectancy and features of the cancer itself (6,8). Based on a modified model of Dugan et al. (8), clinical significance of Japanese prostate cancer subsequent to radical prostatectomy was assessed previously (6). However, the results may not necessarily be representative for all prostate cancer patients. The clinical applicability of this model is significantly limited owing to the inability to accurately predict tumor volume prior to treatment. The tumor volume assessment model proposed by D'Amico and Propert (10) was used to investigate clinical significance of Japanese prostate cancer. Of 203 cancers detected by initial biopsy and without distant metastasis (M0), 13.3%, 25.1%, 32.5% and 40.4% of tumors would have been clinically insignificant for assumed 2-, 3-, 4- and 6-year tumor doubling times, respectively. These percentages exceed those estimated for patients subsequent to radical prostatectomy (6). Nearly half of these patients (43-52%) had clinical stage T1c disease. There is theoretical concern that repeat biopsy may identify clinically insignificant cancers more often owing to length time bias involved. Tumor grade tends to be more differentiated in cancers detected by repeat biopsy, but the estimated proportion of clinically insignificant tumors was virtually the same as first set biopsies. The present study has limited scope of application owing to the use of converted PSA data. Estimated tumor volume (calculated tumor volume) and biopsy Gleason score may also give rise to problems. Only modest correlation was found between calculated and measured tumor volumes in patients following radical prostatectomy (r=0.590). Similar findings were recently noted by Chan et al. (26). The overall correlation between calculated and measured tumor volumes was much less than that found by D'Amico et al. (0.537 versus 0.98) (10,16). Calculated tumor volume may have been less than actual volume. This parameter for 10 tumors was estimated as 0 cm3 in our study. Thus, with consideration to trend of undergrading by biopsy cores (18,19), some tumors may eventually prove clinically significant. The definition of clinical significance of prostate cancer based only on assumptions on fixed tumor doubling time, life expectancy and other estimates may also be problematic. Current findings and the definition for the clinical significance of prostate cancer should thus be evaluated further for confirmation of validity. In particular, comparative analysis with long-term follow-up data is essential before drawing any meaningful conclusions. Nevertheless, this estimation helped to provide an overview of clinically insignificant cancers detected by ultrasound guided biopsy. More precise estimation will be essential for future study. Earlier detection of prostate cancer in Japan is possible through PSA testing. Low PSA does not necessarily indicate indolent cancer. Reduction in PSA as the indication for biopsy may be beneficial for certain Japanese patients. Many patients with stage T1c disease may eventually prove to require no treatment. Supported in part by a Grant from the Ministry of Health and Welfare of Japan (7-42) and Foundation for Promotion of Cancer Research in Japan.
DISCUSSION
CONCLUSION
Acknowledgments
References
This article has been cited by other articles:
This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 24 Nov 1998
Copyright©Japanese Journal of Clinical Oncology, 1998.
CiteULike 
Connotea 
Del.icio.us What's this?
H. B. Shim, S. E. Lee, H. K. Park, and J. H. Ku
Histological Diagnosis of Prostate Cancer in Korean Men Aged 70 79 Years
Jpn. J. Clin. Oncol.,
October 3, 2007;
(2007)
hym093v1.
[Abstract]
[Full Text]
[PDF]
K. Hashine, K. Numata, K. Azuma, Y. Sumiyoshi, and M. Kataoka
Long-term Outcomes of 60 Gy Conventional Radiotherapy Combined with Androgen Deprivation for Localized or Locally Advanced Prostate Cancer
Jpn. J. Clin. Oncol.,
November 1, 2005;
35(11):
655 - 659.
[Abstract]
[Full Text]
[PDF]
S. Egawa, R. Takashima, K. Matsumoto, H. Mizoguchi, S. Kuwao, and S. Baba
A Pilot Study of Intermittent Androgen Ablation in Advanced Prostate Cancer in Japanese Men
Jpn. J. Clin. Oncol.,
January 1, 2000;
30(1):
21 - 26.
[Abstract]
[Full Text]
[PDF]
This Article 
Abstract
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (11)
Request Permissions
Google Scholar
Articles by Egawa, S
Articles by Koshiba, K
Search for Related Content
PubMed
PubMed Citation
Articles by Egawa, S
Articles by Koshiba, K
Social Bookmarking
What's this?