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.