Japanese Journal of Clinical Oncology 32:172-176 (2002)
© 2002 Foundation for Promotion of Cancer Research
Preoperative Prediction of Extracapsular Tumor Extension at Radical Retropubic Prostatectomy in Taiwanese Patients with T1c Prostate Cancer
1 Division of Urology, Department of Surgery and 3 Department of Pathology, Taichung Veterans General Hospital, National Yang-Ming University School of Medicine and 2 Institute of Medicine, 4 Institute of Toxicology and 5 Institute of Biochemistry, Chung Shan Medical University, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Background: To find a predictor for extracapsular tumor extension at radical retropubic prostatectomy (RRP) in Taiwanese patients with stage T1c prostate cancer (PC), preoperative transrectal sonoguiding prostate biopsy outcomes and clinicopathological data obtained from these patients were reviewed.
Methods: Fifty-five consecutive men who underwent radical retropubic prostatectomy for stage T1c PC were included. Preoperative sextant needle biopsies of the prostate were performed and whole-mount prostatectomy specimens were processed. The pathological end point was tumor capsular perforation extending entirely through the prostate capsule. Preoperative prostate-specific antigen (PSA), free-to-total PSA ratio, prostate volume, PSA density, Gleason score, number of positive biopsy cores, percentage cancer of sextant biopsies, percentage cancer of one lobe and percentage cancer of one core were analyzed for their ability to predict extracapsular tumor extension at RRP.
Results: Eighteen of the 55 specimens showed evidence of tumor capsular perforation. Those with extracapsular tumor extension (ECE) had higher PSA than organ-confined disease (OCD) (18.4 vs 8.3 ng/ml, P < 0.01). The ECE had a higher PSA density than OCD (0.556 vs 0.226, P < 0.01). The percentage of cancer in biopsies, percentage cancer of one lobe and percentage cancer of one core were all higher in ECE than OCD (P < 0.05). The ECE had a higher biopsy Gleason score than OCD (5.6 vs 4.5, P < 0.01).
Conclusions: The four strongest predictors for extracapsular tumor extension of patients with T1c PC were PSA density 
0.35, biopsy Gleason score 6, 20% cancer in biopsies and PSA 10 ng/ml.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Since the use of prostate-specific antigen (PSA) has become widespread for the detection of prostate cancer, impalpable PSA-detected tumor (clinical stage T1c) are the most commonly diagnosed prostate cancers (1). The incidence of T1c prostate cancer (PC) has increased from 2.7% in 1989 to 47.2% in 1994 (2). In one screening study, 78% of PC detected were stage T1c (3). Since sextant biopsies of the prostate alone may miss half of existing cancers in men with a normal digital rectal examination and PSA >4 ng/ml, an extended biopsy technique (8–10 biopsies) was suggested in 2000 (4). The Stamey modification of the traditional sextant biopsy technique by directing needles more laterally to sample more of the anterior horn of the peripheral zone was widely adopted from 1995 to 2000 (5). This method detected 14.6% of cancers not discovered with traditional sextants (6).
There is a difference in the age-specific prevalence of clinical prostate cancers between Asians and Whites (7). However, from our previous study, latent PC in patients with transitional cell carcinoma of the urinary bladder receiving radical cystoprostatectomy was 33%, similar to Japan and the USA (8–10). The clinicopathological features of T1c PC in Japanese patients were similar to those of Whites reported elsewhere (11). In this study, clinicopathological features of stage T1c PC Taiwanese patients were evaluated. To predict the likelihood of extracapsular tumor extension at radical retropubic prostatectomy (RRP), outcomes of preoperative transrectal ultrasound-guided sextant biopsy of prostate along with clinicopathological data obtained from these patients were reviewed.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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From January 1996 to December 2000, 385 patients with PC received treatment in this hospital. Among them were 58 patients (15.1%) with stage T1c PC who received RRP. Three patients with T1c prostate cancer received neoadjuvant hormonal therapy and were excluded owing to the influence of pathological interpretation. Fifty-five patients were enrolled in this study. Clinical data, including patient age, initial PSA and free-to-total PSA ratio, were collected. The serum total PSA and free PSA concentration were measured with TPSA-RIACT and FPSA-RIACT kits (Cis Bio International, France). Sextant biopsies of the prostate using the Stamey modified technique (5) were performed using an 18-gauge biopsy gun (Bard, USA) under transrectal urological ultrasound (TRUS) guidance (Bruel and Kjer 3535, Denmark). The PSA density (PSAD) was calculated by dividing the serum PSA by the prostate volume measured by TRUS. In each needle biopsy certain variables were assessed, including Gleason score, number of cancer positive cores, maximum percentage of cancer in one core, percentage of cancer in one prostate lobe and percentage of cancer in all sextant biopsies. The total percentage of cancer in all sextant biopsies (% cancer of biopsies) was calculated using the formula [(area of cancer at site 1 + area of cancer at site 2 + ...)/total area in all sextant biopsies] x 100%. The percentage of cancer of the right or left lobe was calculated using (sum of area of cancer in the right or left lobe/area in three cores of right or left lobe) x 100%. The higher percentage cancer in either the right or left lobe was reported as the percentage cancer in the more affected lobe (% cancer of one lobe). The percentage cancer of each core was calculated using (area of cancer in each positive core/area of each core) x 100%. The highest percentage cancer in any core was reported as maximum percentage of cancer in one core (% cancer of one core). For example, one sextant biopsy demonstrated three positive cores of cancer, including two positive cores of cancer in the right lobe and one positive core in the left lobe. Two positive cores of cancer in the right lobe estimated that the percentage of cancer in one positive core was 50% and the other positive core was 30%. The percentage of cancer in the right lobe was calculated using the formula as 30%. One positive core in the left lobe estimated that the percentage of cancer in one positive core was 25%. The percentage of cancer in the left lobe of prostate was calculated using the formula as 10%. The percentage of cancer in these sextant biopsies was calculated using the formula as 20%. Hence the maximum percentage of cancer in one core was 50%, the percentage of cancer in one prostate lobe was 30% and the percentage of cancer in sextant biopsies was 20%.
RRP and bilateral pelvic lymphadenectomy were performed. Prostatectomy specimens were fixed, coated with India ink and cut in systemic stepwise sections at 3 mm intervals. The tumors were evaluated for Gleason score and tumor location. Tumor volume was calculated by multiplying the resulting tumor areas by section thickness (3 mm) and correcting for tissue shrinkage factor (1.5) following fixation (12). Radical prostatectomy stage was classified as either extracapsular tumor extension (ECE) or organ-confined disease (OCD). The ECE was defined as tumor involved capsular perforation extending entirely through the prostate capsule. The OCD was defined as tumor limited within the prostate capsule, with no seminal vesicle or lymph node involvement. All pathological findings were reviewed by a pathologist (J. T. Chen) to assign Gleason score, percentage of cancer in biopsies, tumor volume and ECE/OCD.
All data were expressed as mean ± standard deviation. The statistical analysis was performed using Student’s t-test, Fisher’s exact test and Pearson’s chi-squared test. Receiver-operating characteristic (ROC) curves were generated for various factors, plotting sensitivity versus 1 – specificity. Areas under the ROC curves (AUC) were calculated for various factors. The cutoffs of various factors were determined from the points that would provide the greatest sensitivity and specificity. Stepwise multivariate logistic regression analysis was performed to developed a model for predicting extracapsular tumor extension (ECE). A P value <0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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The whole-mount of RRP specimens revealed 37 cases of OCD and 18 cases of ECE. Among 18 cases of ECE there were 14 cases of positive surgical margin, three cases of seminal vesicle invasion and two cases of combined lymph node and seminal vesicle involvement. Clinical characteristics of the 55 patients with stage T1c PC are shown in Table 1. The ECE group had a significantly higher PSA level than the OCD group (P < 0.01). The ECE group had a higher PSAD than the OCD group (P < 0.001). The ECE group had a higher percentage of cancer in six biopsies, percentage cancer in one lobe and percentage cancer in one core than the OCD group, all statistically significant. The ECE group had a higher Gleason score than OCD group in needle biopsies (P < 0.01).
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The pathological findings for RRP specimens from patients with stage T1c PC are shown in Table 2. The ECE group had higher Gleason scores than the OCD group (P < 0.05). There was a higher frequency of bilateral lobe cancer in the ECE group than the OCD group (P < 0.05). The ECE group had a larger tumor volume than the OCD group (P < 0.0001).
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From the ROC characteristic curves, the AUC was 0.63 for PSA, 0.35 for free/total PSA, 0.74 for PSAD, 0.69 for percentage cancer of biopsies, 0.67 for percentage cancer of one core, 0.66 for percentage cancer of one lobe and 0.68 for biopsy Gleason score. Cutoffs of preoperative clinical factors for relative risks of ECE in stage T1c PC are shown in Table 3. PSAD
0.35 is the best predictor of ECE in stage T1c PC. Biopsy Gleason score 6 is the second strongest predictor. PSA level 10 ng/ml and 20% cancer in biopsies are also good predictors of ECE in stage T1c PC. Multivariate logistic regression analysis showed that PSAD 0.35 and percentage cancer in biopsies 20% were the strongest predictors of ECE in stage T1c PC (Table 4). The best model for predicting ECE included the four most significant parameters: PSAD 0.35, biopsy Gleason score 6, percentage cancer in biopsies 20% and PSA level 10 ng/ml (Table 5).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Radical retropubic prostatectomy with neurovascular bundle preservation has been used for clinically localized PC since Walsh et al. introduced this surgical procedure (13). However, whenever tumor extracapsular extension or surgical margin positive is noted at RRP, neurovascular bundle preservation may not be safe for cancer control. Hence preoperative prediction of ECE at RRP is important for the selection of patients receiving nerve-sparing RRP (14).
Stage T1c PC is a unique group which may include insignificant cancer, localized PC, locally advanced PC or metastatic PC. Epstein and co-workers (15,16) defined four categories from 240 patients with T1c PC: (1) insignificant (confined tumor <0.2 ml with Gleason score <7); (2) minimal (confined tumor 0.2 to <0.5 ml with Gleason score <7); (3) moderate (>0.5 ml or capsular penetration with a Gleason score <7); and (4) advanced (capsular penetration with a Gleason score of 7 or positive margins, seminal vesicle or lymph node involvement). In our series, the incidences of insignificant, minimal, moderate and advanced disease were 3.6, 12.7, 40 and 43.6%, respectively. In Epstein and co-workers’ series from 1994 to 1996, the incidences of insignificant, minimal, moderate and advanced disease were 17, 12, 52 and 19%, respectively (16). Epstein and co-workers suggested that an increase in the detection of early cancers was manifested by an increase in the prevalence of organ-confined disease and a decrease in the positive margin rate (16,17). Our series had more cases of advanced disease than Epstein and co-workers’ series, because our patients were from a non-screened population and most men are unaware of prostate cancer. Our further perspectives for detecting more early cases (insignificant, minimal and moderate disease) were established. An awareness week for screening for prostate cancer in 10 medical centers of the Taiwan Cooperative Oncology Group (TCOG) has been performed since 1998. In our institute, serum PSA has been applied as a routine test in male check-ups since 1997 and at present we encourage serum PSA as a routine test for males aged >50 years in all outpatient departments. To increase the probability of cancer detection, we have adopted an extended biopsy technique with 10–14 biopsies since January 2001.
In Ogawa et al.’s series of T1c in Japanese (11), the incidence of organ-confined disease was 59% and the incidence of tumor volume <0.5 ml, 0.5–3.9 ml and 4.0 ml were 22, 49 and 29%, respectively. In our series among Taiwanese, the incidence of organ-confined disease was 67.2% and the incidence of tumor volume <0.5 ml, 0.5–3.9 ml and 4.0 ml were 20, 50.9 and 29.1%, respectively. The pathological features of stage T1c PC are very similar between the two Asian groups. Although the age-specific prevalence of clinical prostate cancers is higher in Whites than Asians (7), the incidence of latent PC was similar in Taiwan, Japan and the USA (8–10). Likewise, stage T1c PC in Asians (Taiwan and Japan) share similar pathological features: about one-third show extracapsular tumor extension and 20% of tumors are <0.5 ml as with Whites.
The incidence of ECE in T1c PC in other series has been approximately 30–45%, which was similar to that in our series (32.8%) (2,7,11–18). It is helpful to predict the likelihood of ECE when we perform RRP, since these patients might not be cured by an RRP, especially if the bilateral neuromuscular bundle was preserved. Catalona and Bigg observed extracapsular tumor extension in 38% of patients who had undergone bilateral nerve-sparing procedures for presumed organ-confined disease (19). Bigg et al. observed organ-confined diseases and negative margins in only 33% of clinical stage B2 patients undergoing either unilateral or bilateral neurovascular preservation (20). Patients suspected of capsular perforation may benefit most from a cancer control standpoint from wide excision of the neurovascular bundle (14,20). Cookson et al. reported that stage T1c PC are pathologically similar to stage T2 PC (21).
It is critical to predict the possibility of ECE using preoperative clinical and pathological data. From our data, ROC curve analysis showed that PSAD and biopsy Gleason score were the two best predictors, with the best cut-off values being PSAD 0.35 and biopsy Gleason score 6. The relative risk of ECE is 4.6 with a PSAD cut-off 0.35 and AUC was 0.74. The relative risk of ECE is 3.5 with a biopsy Gleason cut-off 6 and AUC was 0.68. Ogawa et al. reported PSAD <0.3 as a good predictor for organ-confined diseases in T1c PC (11). Carter and Epstein also reported that the best pretreatment predictors of significant tumor in 157 T1c PC receiving RRP were PSAD combined with needle biopsy findings (22). Wills et al. reported that in biopsies with a Gleason score of 7 and more than one positive core in sextant biopsies only 10% were organ confined (23).
The PSA test has been studied as a predictor of ECE (11,14,22,24). As PSA increased, the incidence of ECE increased (24). In our results, the relative risk of ECE was 2.7 with a PSA cut-off 10 ng/ml and the AUC was 0.63. Cookson et al. reported that significantly higher rates of organ- and specimen-confined disease were seen in patients with PSA levels <10.0 ng/ml (21). In Ogawa et al.’s series, using a PSA cut-off of 17 ng/ml can predict 90% of organ-confined disease in stage T1c PC (11). Several authors have demonstrated that the free-to total PSA ratio provides useful information for the prediction of pathological features of patients with T1c PC (19,24,25). It seemed not to be a good predictor in this study, because different total PSA and free PSA assays caused different cut-off values and interpretation.
Preoperative sextant needle biopsy has been evaluated by several authors to compare and predict pathological features (14,23,26,27). Our results revealed the relative risks of ECE were 2.7, 2.0 and 2.3 with 20% cancer in biopsies, 30% cancer in one lobe and 50% cancer in one core, respectively. The AUCs were 0.69, 0.66 and 0.67, respectively. Wills et al. reported that the numbers of cores involved with cancer is the most important predictor of stage in sextant needle biopsy (23). Sebo et al. reported that the percentage of cores positive for cancer and percentage involvement in all cores are the strongest predictors of pathological stage and tumor volume (27).
This is the first report related to preoperative prediction of extracapsular tumor extension among 55 Taiwanese patients with stage T1c prostate cancer in an area with low age-specific prevalence of clinical prostate cancers. The four strongest predictors for extracapsular tumor extension of patients with T1c PC were PSAD 0.35, biopsy Gleason score 6, 20% cancer in biopsies and PSA 10 ng/ml.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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The authors thank Miss Hui-Ching Ho for her assistance with biostatistical analysis.
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FOOTNOTES |
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+ For reprints and all correspondence: Chi-Rei Yang, 160, Sec. 3, Taichung-Kang Road, Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan. E-mail: ycou@vghtc.vghtc.gov.tw
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Received December 17, 2001; accepted February 19, 2002
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