Prostate Cancer and Prostatic Diseases (2000) 3, 100±106 ß 2000 Macmillan Publishers Ltd All rights reserved 1365±7852/00 $15.00 www.nature.com/pcan Ultrasound-guided seminal vesicle biopsies in prostate cancer
LFA Wymenga1*, FJ Duisterwinkel2, K Groenier3 & HJA Mensink4 1Department of Urology, Martini Hospital, Groningen, The Netherlands; 2Clinical Chemistry, Nij Smellinghe Hospital Drachten, The Netherlands; 3Department of General Practice, University Hospital, Groningen, The Netherlands; and 4Department of Urology, University Hospital, Groningen, The Netherlands
Invasion of prostatic adenocarcinoma into the seminal vesicles (SV) is generally accepted as an index of poor prognosis. The pre-operative identi®cation of SV invasion is an important element in staging since it may alter subsequent treatment decisions. We studied the possibility of diagnosing SV invasion with two biopsies from the junction between the prostate and seminal vesicles. Also we studied the correlation of several prognostic factors with the risk of clinical stage T1,2,3 prostate cancer patients of having cancer growth into the seminal vesicles. Consecutive patients referred for transrectal ultrasound (TRUS) and biopsy because of clinical suspicion of prostate cancer were examined. This staging procedure was evaluated in patients who underwent a pelvic lymphadenectomy and radical retropubic prostatectomy (RRP). In 83 out of 138 patients prostate cancer was detected whereas 55 patients had benign disease. In 44% of prostate cancer patients a positive SV biopsy was found. The accuracy of the biopsies adjacent to the junction of the SV and the prostate was 91%. The best predictors for SV invasion were tumor grade of the biopsy sample (P<0.001), serum prostate-speci®c antigen (PSA) (P<0.0005), PSA density (P<0.0005) and clinical stage (P<0.0005). No signi®cance was found in the relation to seminal vesicle involvement with free/total (f/t) PSA ratio (P 0.588) for the prostate cancer group (SV and SV 7 ). In a receiver operating characteristic curves analysis, PSA density was sig- ni®cantly more accurate for prediction of SV invasion than PSA or f/t PSA ratio. In ®ve prostatectomized patients (and negative SV biopsy) no SV invasion was found in the ®nal pathologic examination either. SV biopsy at the junction of the SV and prostate is accurate for staging with high ef®cacy and low morbidity. To predict SV invasion in prostate cancer patients, PSA density was more accurate than PSA or f/t PSA ratio. The determination of the f/t PSA ratio in patients with low and intermediate PSA levels (eg <15 mg/L) is not useful to estimation of the risk of seminal vesicle involvement. The combination of serum PSA concentration, PSA density, tumor grade from the biopsy specimens ad clinical stage provides the best prediction of SV invasion. These parameters are identical to the conventional predictors of pathology after RRP. SV biopsies may provide additional information; if one or both basal biopsies are positive, a clinical T1,2 disease is altered to T3. Hence SV biopsy is useful for selection of patients who might obtain good results from RRP for prostate cancer. Prostate Cancer and Prostatic Diseases (2000) 3, 100±106.
Keywords: prostate cancer; prostate-speci®c antigen; prostate-speci®c antigen density; free-to-total PSA ratio; seminal vesicle invasion; prostatectomy
*Correspondence: LFA Wymenga, Department of Urology, Martini Hospital, loc. v. Ketwich, PO Box 30.033, NL-9700 RM Groningen, The Netherlands. Received 22 March 2000; revised 10 May 2000; accepted 18 May 2000 Ultrasound-guided biopsies LFA Wymenga et al 101 Introduction Patients and methods There has been an increase in the referral of men for A total of 138 consecutive patients referred for prostate diagnosis or exclusion of prostate cancer to urological evaluation (range 48 ± 94 y old, mean age 71.4, median services. This is due to the growing awareness of pro- 70.5) were investigated. The following criteria were used static disease and the prevalence of prostate cancer in to trigger prostate biopsies: (1) DRE suggestive of cancer; men. Simultaneously, prostate-speci®c antigen (PSA) (2) elevated PSA level ( > 4.0 mg/l); (3) TRUS abnormal- assays have become widely available and are used ities; (4) abnormal PSAD (a value of > 0.15 was judged increasingly in primary care for the purpose of early abnormal); (5) f/t PSA ratio <25%. detection. As a result, prostate cancer is the most fre- The population in this study does not represent a quently diagnosed malignancy among men in the USA,1 screening population. None of the patients received any and it is second in frequency in Europe.2 Consequently hormonal therapy prior to the sampling of blood speci- more clinically localized tumors, with the greatest poten- mens. Serum PSA, free PSA and the proportion of free-to- tial for cure, are being identi®ed.3 Radical prostatectomy total PSA (DPC-IMMULTE assay) were measured in all is an effective therapy for patients with organ-con®ned patients before any prostate manipulation (DRE, TRUS). disease. However, despite the enhanced detection of The volume of the prostate was estimated by transrectal these potentially organ-con®ned tumors, many patients ultrasound by measuring the maximal height (H) and width have extracapsular disease Ð 27 ± 63%, at the time of (W) obtained from the transverse images. Maximal length radical prostatectomy. This major problem of clinical (L) was obtained from the longitudinal image. The volume understaging is documented in several reports4±13 (not was calculated as follows: H 6 W 6 L 6 p/6. PSAD, a all studies are cited). The high percentage of patients parameter introduced by Benson et al to enhance early with extracapsular extension and positive margins has detection of prostate cancer, is de®ned as the serum PSA generated efforts to enhance early detection, improve value divided by the volume of the entire gland.28 The staging and, as a consequence, improve selection for PSAD was calculated during ultrasound. Transrectal ultra- therapy and hence improve prognosis for prostate cancer sound-guided biopsies were performed in the sagittal plane patients. with a 7.5 MHz sector scanner ®tted with a biopsy guide Capsular perforation and seminal vesicle (SV) invasion using an 18 gauge needle driven by a spring-loaded biopsy are unfavorable prognostic factors in prostate cancer.7,14 ± 17 gun. All the TRUS-guided biopsies were performed by one Both of these pathological ®ndings are associated with urologist using a Kretz 360 machine with a 7.5 ± 10 MHz a high likelihood of local recurrence and increased sector scanner. A suspicious lesion was one that appeared mortality compared with organ-con®ned cancer.16,18,19 hypoechoic relative to the echogenic pattern of the periph- Studies have shown SV invasion in 20 ± 26% of radical eral zone of the normal prostate. When a suspicious lesion prostatectomy specimens.15,18,19 Unfortunately, this evi- was seen, guided biopsies were taken; when no speci®c dence is only available after pathological examination of lesion was detected, the gland was biopsied systematically the radical prostatectomy specimen. according to the method of Stamey.29 In the longitudinal In 1990 Villers et al reported the mechanism of tumor plane an additional SV biopsy was obtained from each side spread into the seminal vesicles: in 46 of 47 cases of SV at the junction of the seminal vesicle and the prostate.30 invasion, the tumor spread directly from the mid base of Figure 1 shows in a diagram the correct placement of the the prostate along and between the ejaculatory ducts.18 needle just cephalad of the base of the prostate. The exact Transrectal ultrasound-guided biopsies of the seminal placement of the needle for biopsy is necessary in order to vesicles may provide important diagnostic and staging avoid the base of the prostate and the distal seminal vesicle. information in select clinical situations.14,20 ± 23 Using tra- Any SV biopsy judged grossly to be less than one-third of ditional investigational tools (PSA, digital rectal exam the needle channel was considered of insuf®cient length (DRE), transrectal ultrasound (TRUS), systematic prostate and was followed by a second SV sample out of that area. biopsies or pre-operative histological grading), the ability All patients received prophylactic antibiotics (O¯oxacine, of the urologist to predict organ-con®ned disease appears 400 mg) orally 1 h before biopsy and 24 h afterwards. Biopsy to be not much better than a ¯ip of the coin.24 Hence there specimens from each site in addition to the usual prostatic is a considerable risk of understaging and hence over- biopsies were processed separately. Each core was ®xed in treatment. The adverse effects such as postoperative 10% formalin embedded in paraf®n, sectioned longitudin- morbidity, the mortality of radical prostatectomy, albeit ally, stained with hematoxylin and eosin, and examined by low, and the costs must be considered. the pathologist for SV involvement at the base. SV invasion To decrease the risk of overtreatment, a comparison was de®ned as invasion of the muscular wall of the seminal was made between these traditional parameters and the vesicle as described by Epstein et al.16 Patients with SV performance of PSA density (PSAD the ratio of serum involvement were considered to have extracapsular exten- PSA to the size of the prostate), SV biopsies and the sion by de®nition. measurement in serum of the free-to-total (f/t) PSA ratio. The biopsy ®ndings were reported by the pathologist The latter, the f/t PSA ratio, is currently being evaluated using WHO grading as either well differentiated (G1), as a means to improve the speci®city of PSA.25,26 It was moderately differentiated (G2), or poorly differentiated demonstrated that a lower f/t PSA ratio is associated (G3).31 Preoperative clinical stages were assigned based with more adverse pathologic features.27 We investigated upon the biopsy results according to the TNM classi®ca- whether the f/t PSA ratio could enhance prediction of tion.32 The SV biopsy was well tolerated and there were extraprostatic spread of prostate cancer, particularly in no prostatic or SV infections or long-term complications. the seminal vesicles. In case of stage migration, because of a positive SV biopsy
Prostate Cancer and Prostatic Diseases Ultrasound-guided biopsies LFA Wymenga et al 102 Table 1 Pre-treatment PSA level and seminal vesicle biopsy results in prostate cancer patients
Prostate cancer in vesicula seminalis
No invasion Invasion PSA (mg/l) n (%) n (%) Total
0 ± 4.0 4 (100) Ð 4 4.1 ± 10.0 19 (90.5) 2 (9.5) 21 10.1 ± 20 15 (65.2) 8 (34.8) 23 > 20 8 (22.9) 27 (77.1) 35
Figure 1 Longitudinal sonographic appearance of prostate gland and Total 46 (55.4) 37 (44.6) 83 seminal vesicle.
the PSA densities between patients with (mean radical prostatectomy was no longer advocated. Five PSAD 2.7, median 0.83) and without (mean patients who underwent a pelvic lymphadenectomy fol- PSAD 0.6, median 0.3) SV in®ltration (P<0.0005; lowed by a radical retropubic prostatectomy served as Figure 2a). Patients with SV in®ltration demonstrated control patients. The rest of the patients with negative signi®cantly greater PSA values (mean PSA 128, seminal vesicle biopsies did not undergo a radical retro- median 32) than those with seminal vesicles free of pubic prostatectomy for several reasons (age, comorbidity tumor (mean PSA 25, median 9.8; P<0.0005; Figure etc). 2b). PSA and PSAD were more speci®c and had a higher positive predictive value than each of the other tests for the whole population of 138 patients. Statistical methods Table 2 shows f/t PSA ratios for 55 of the 83 patients with prostate carcinoma, in four categories (<10%, 10 ± Statistical analysis was performed using computer soft- 15%, 15 ± 20%, > 20%). The f/t PSA ratios were not ware and applying Student's t-test to the natural data measured in the other 28 patients. There was no signi®- and the chi-square test to the categorical data. A P-value cant correlation (P 0.588) of the percentage of f/t PSA <0.05 was considered statistically signi®cant. The relative with SV invasion in the whole group (negative SV: mean effectiveness of the diagnostic tests was illustrated by f/t ratio 10.4, median 9.0; and positive SV: mean f/t plotting the true positive (sensitivity) vs false positive ratio 9.1, median 9.0; see also Figure 2c). (1-speci®city) ratios in receiver operating characteristic The difference between vesicula seminalis invasion and curves (ROC). ROC analysis is particularly useful for histological tumor differentiation grade was statistically comparing two diagnostic tests when the cut-off point signi®cant (P 0.001). Table 3 shows the interrelationship for a positive or negative test has not been clearly de®ned. between seminal vesicle invasion and tumor grade, sug- Areas under the receiver operating characteristic curves gesting a higher invasion rate with de-differentiation. (AUC) were compared by a non-parametric method as Table 4 gives the distribution of the clinical estimation described by Hanley and McNeil.33 of tumor stage and seminal vesicle biopsy results and shows a higher invasion rate with advancing clinical stage (P 0.0005). Overall PSAD and PSA appeared to be the most Results important predictors of seminal vesicle involvement, The overall accuracy rate for obtaining SV tissue in the whereas the relationship between seminal vesicle involve- biopsies from 138 patients was 91% : 92% for the left SV ment and f/t PSA ratio was not signi®cant (P 0.588). and 89% for the right SV. Of the 138 patients on whom The areas under the ROC curve for the PSAD and for the biopsies were performed, 83 (60%) had carcinoma of the PSA were alike (0.85; Figure 3). prostate and 55 (40%) were negative for malignancy. In the ®ve patients who underwent radical prostatectomy, investigation of the prostatectomy specimens showed no Discussion extraprostatic involvement of the seminal vesicles. With the limitations of current pre-operative staging studies there is a suboptimal prediction of pathologic 34 ± 38 Seminal vesicle biopsies stage for the individual patient. It is therefore essen- tial to make a distinction between patients with organ- In the biopsies of the 83 patients with prostate cancer a con®ned vs margin-positive disease to plan subsequent positive SV biopsy was found in 37 patients (44.6%). PSA therapy. values of 0.0 ± 4.0 mg/l, 4.1 ± 10.0 mg/l, 10.1 ± 20 mg/l and Unfortunately, digital rectal examination (DRE) and more than 20 mg/l were used to assess the risk of a classical imaging techniques such as transrectal ultra- positive SV biopsy. Table 1 shows pre-treatment PSA sonography (TRUS), computed tomography (CT) and level and SV biopsy results. magnetic resonance imaging (MRI) cannot accurately PSAD was measured in 76 of the 83 patients with stage prostate cancer Ð 12 ± 30% of clinical T1 cancers 34,39,40 cancer. Statistically signi®cant differences were found in and 30 ± 60% of clinical T2 cancers are in fact pT3.
Prostate Cancer and Prostatic Diseases Ultrasound-guided biopsies LFA Wymenga et al 103 Table 2 Free-to-total PSA ratio and seminal vesicle results in 55 of 83 prostate cancer patients
Prostate cancer in vesicula seminalis
F/t PSA ratio No invasion Invasion (%) n (%) n (%) Total
<10 17 (56.7) 13 (43.3) 30 11 ± 15 11 (52.4) 10 (47.6) 21 16 ± 20 1 (50) 1 (50) 2 > 20 2 (100) Ð 2
Total 31 (56.4) 24 (43.6) 55
Table 3 Seminal vesicle invasion and tumor grade in prostate cancer
Prostate cancer in vesicula seminalis
No invasion Invasion Tumor grade n (%) n (%) Total
Grade 1 20 (80.0) 5 (20.0) 25 Grade 2 22 (53.7) 19 (46.3) 41 Grade 3 4 (23.5) 13 (76.5) 17 Total (%) 46 (55.4) 37 (44.6) 83
Table 4 Distribution of clinical estimation of tumor stage and seminal vesicle biopsy results in patients with prostate cancer
Vesicula seminalis
No invasion Invasion Clinical stage n (%) n (%) Total
T1 16 (88.9) 2 (11.1) 18 T2 14 (100.0) Ð 14 T3 16 (31.4) 35 (68.6) 51
Total 46 (55.4%) 37 (44.6%) 83
are mainly due to a higher stage disease. Seminal vesicle invasion has been regarded as an index of poor prog- nosis.7,17,19,41 ± 43 Several studies have presented evidence that this prognostic association relates to a strong correla- tion between seminal vesicle involvement and the pre- sence of lymph node metastases.44 ± 46 To improve clinical assessment before a therapy decision is made, a less Figure 2 Box plots of the relation between vesicula seminalis status and: invasive method was needed to detect seminal vesicle (a) PSA density; (b) PSA; (c) free-to-total PSA ratio. The box includes 50% involvement by the use of transrectal ultrasound-guided of results: median values for each group of patients are denoted by dark biopsies.47 horizontal lines. In this study a comparison was made between the traditional parameters (PSA, TRUS, histological grading The detection of seminal vesicle involvement has been from the biopsy specimen) and PSAD, the f/t PSA ratio demonstrated in several studies that examined retrospec- and seminal vesicle biopsy. TRUS and biopsies were tively the results of radical prostatectomy in patients with performed in patients in whom there was a suspicion of clinically con®ned disease. In a study by Terris et al the prostate cancer on the basis of PSA level, abnormal PSAD, seminal vesicle positive rate was 13.8%.22 Villers et al a low f/t PSA ratio or DRE ®ndings. The overall accuracy reported pathological seminal vesicle involvement after rate to obtain seminal vesicle tissue in the biopsies was radical prostatectomy in 19% of 241 patients with clinical 91%, which is comparable to the 90 ± 92% rate reported by 18 22,30,48 stage T1/T2. Furthermore, he showed that the frequency others. of seminal vesicle invasion increased with tumor volume, Partin et al used digital rectal examination, pre-opera- in line with our ®ndings (Table 4). The present study had tive Gleason score and serum PSA level to predict organ a 44% rate of positive seminal vesicle biopsies. The con®nement status and ranked them in a series of prob- differences between our study and the previous studies ability nomograms.12 Among 667 men with clinically
Prostate Cancer and Prostatic Diseases Ultrasound-guided biopsies LFA Wymenga et al 104
Figure 3 Receiver operating characteristic curve analysis for PSA density, PSA and free-to-total PSA ratio in prostate cancer with seminal vesicle invasion. In a comparison between the area under the curve of PSA density (PSAD) (0.85), PSA (0.85) and free-to-total PSA ratio (0.66), PSAD and serum PSA levels are signi®cantly better predictors for the presence of prostate cancer invasion in the seminal vesicles than serum free-to-total PSA ratio (P<0.0005).
localized disease, 56% had pathologically organ-con®ned of the disease. Despite technical improvement in imag- disease. We followed this regime and added for the ing techniques and the use of molecular biology, the subgroup clinical stage T1±3 prostate cancer the following exact determination of the extracapsular extent of the items: PSAD, the f/t PSA ratio and the results of seminal tumor before surgery is not yet possible. The value of a vesicle biopsies to study the possible improvement in single factor can only clearly be assessed in multivariate staging prostate cancer. For this part of the study six analysis. patients with T4 disease were excluded and patients with In prostate cancer serum PSA, PSAD, clinical stage and clinical estimated tumor, stage T1,2 and T3 M0 tumors histological grading system are useful to select patients were included. Including patients with extraprostatic for systemic seminal vesicle biopsies. The free-to-total extension (and high PSA values) will skew the data and PSA ratio did not predict whether adenocarcinoma had as a consequence statistically signi®cant differences will spread into the seminal vesicles. Involvement of the arise in the variables tested. However, in this study seminal vesicle is of prognostic signi®cance52 and in statistically signi®cant differences were found between men with T1 or T2 prostate cancer it is the most signi®cant the cancer patients with and without seminal vesicle predictor of pelvic lymph node metastasis.46 Biopsies of in®ltration with respect to PSA (P<0.0005) and PSAD the seminal vesicle just cephalad to the junction of the (P<0.0005). For histological grade (P<0.001) there was a seminal vesicle and the prostate is an adjunct to staging less signi®cant correlation. Figure 3 shows an ROC curve with high ef®cacy and low morbidity. Our study showed for these parameters with the AUC respectively. Some that the predictors of seminal vesicle invasion as (biopsy) investigators recently showed that the f/t PSA ratio could tumor grade, PSAD, PSA and clinical stage are the same not predict extraprostatic spread of prostatic cancer.49 ± 51 as the conventional predictors of pathology at radical We have shown that the f/t PSA ratio did not predict prostatectomy. Given the considerable economic impact whether adenocarcinoma had spread into the seminal of the evaluation and management on the health care vesicles in the whole group of prostate cancer patients system for patients with prostate cancer, cost-effectiveness (P 0.588). This has not been reported by others to date. studies are needed. Our study showed that additional information can be gained about the extent of cancer in the seminal vesicles using systemic needle SV biopsy and the correlation with Acknowledgement the usual parameters, including PSAD and PSA. The goal of this combination is to stage patients more accurately Dr Paul EC Sibley is thanked for his technical assistance. when apparently localized disease is suspected.
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