or more transrectal ultrasonography (TRUS)-guided ng/ml and 39% if it was 20.0 ng/ml. of >10 ng/ml have prostate cancer [3], many other

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1 BJU International (1999), 83, Elevated serum prostate specific antigen levels in conjunction with an initial prostatic biopsy negative for carcinoma: who should undergo a repeat biopsy? G.C. DURKAN and D.R. GREENE Department of Urology, Sunderland Royal Hospital, Kayll Road, Sunderland, UK Objective To determine the outcome of repeated pros- (31%) had carcinoma on repeat biopsy, 11 after the tatic biopsies in men attending with suspected prostate second and four after a third biopsy. The positive cancer but an initial negative biopsy. repeat biopsy rate was 24% where the PSA level Patients and methods Patients who had undergone two was ng/ml, 33% if the level was or more transrectal ultrasonography (TRUS)-guided ng/ml and 39% if it was 20.0 ng/ml. prostate biopsies were identified from the Hospital There was no significant dicerence in age or initial Information Support System database. Indications for PSA concentration between those men with positive TRUS were a raised prostate-specific antigen (PSA) and those with negative repeat biopsies. However, level (>4.0 ng/ml), with or without an abnormal patients with cancer had significantly higher PSA digital rectal examination (DRE). Sextant prostate levels before repeat biopsy than at first biopsy (P= biopsies plus biopsies of any suspicious hypoechoic ) and had greater PSA velocities than had area or area of DRE abnormality were obtained for patients with no diagnosis of cancer (P=0.0067). histology. Forty-eight patients underwent repeat Conclusion Where subcient clinical suspicion exists, TRUS-guided prostatic biopsies (mean age 67.5, sd despite an initial negative biopsy, repeat TRUS-guided 7.25, range years). prostate biopsies should be carried out to exclude Results The mean (sd, median, range) PSA level was carcinoma of the prostate (13.5, 11.6, ) ng/ml. Fifteen patients Keywords Prostate cancer, PSA, TRUS, biopsy, diagnosis While almost 60% of patients with a serum PSA value Introduction of >10 ng/ml have prostate cancer [3], many other Awareness of prostate cancer has increased among conditions, e.g. BPH, prostatitis, prostatic infarct and patients and GPs because of the increase in prostate prostatic intraepithelial neoplasia (PIN), cause an elevation cancer-related publications in the medical literature and of serum PSA. In contrast, only a quarter of general press in recent years. While the natural history patients with a serum PSA level of 4 10 ng/ml are of prostate cancer is not yet fully known, the availability found to have cancer [4] and many patients will undergo of PSA testing, combined with a greater awareness of unnecessary prostate biopsies as a result. In an attempt prostate cancer, has led to a significant increase in the to refine the sensitivity of PSA as a predictor of prostate referral of patients with an elevated PSA for evaluation. cancer, several PSA derivatives have been studied, Despite a recommendation against screening for the UK including PSA density, PSA velocity and free to total population [1] it is likely that more patients with LUTS PSA ratio. Despite these advances, considerable dibculties will have their PSA level measured, because of concerns may still arise in the detection of prostate cancer, by the patient and/or GP about underlying cancer. This especially in the PSA range of 4 10 ng/ml [5]. will lead to more patients being diagnosed with stage When evaluating a patient with suspected prostate T1c prostate cancer. This factor, combined with the cancer, the accepted diagnostic investigations include a increased incidence of prostate cancer, will provide a DRE, the estimation of serum PSA, and TRUS of the considerable challenge for urologists, although the scale prostate [4,6]. Candidates for such management must of the problem in the UK is unlikely to parallel that in stand to benefit significantly from the diagnosis and the USA where, as a result of screening, new subsequent treatment of their prostate cancer, whether cases of prostate cancer were predicted in 1996 [2]. in terms of improved quality of life, reduced morbidity or prolonged survival. However, many of these patients Accepted for publication 15 July 1998 have no discrete hypoechoic areas visible on TRUS. In BJU International

2 REPEAT BIOPSY FOR SUSPECTED PROSTATE CANCER 35 such cases, the standard procedure has been to take Sunderland Royal Hospital, using the Hybritech sextant biopsies, sampling the base, mid-prostate and Tandem-E assay (Hybritech Inc, San Diego, CA, USA). apex on each side [6]. Unfortunately, despite an elevated Each patient s medical record was carefully reviewed PSA level, abnormal DRE or both, in a significant number and the patient s age, prebiopsy PSA values, PSA velocof cases no cancer is detected on TRUS-guided prostate ity, histopathological diagnosis of each biopsy, DRE biopsy [7 10]. As the volume of prostate sampled by the findings and outcome of each TRUS examination entered standard sextant biopsy technique is relatively small, the into a database and analysed statistically. Data are possibility remains that these individuals may harbour presented as mean (sd) and distributions compared using prostate cancer, despite an initial negative biopsy. As Student s t-test, with significance assumed at P<0.05. yet, no parameters have been agreed that would prevent a patient in this situation undergoing an unnecessary repeat biopsy. The urologist must weigh carefully the Results potential morbidity and associated anxiety of repeat Of the 48 men who underwent repeat TRUS-guided prostatic biopsy against the benefit to the patient of a prostatic biopsies, where their initial biopsy failed to confirmed diagnosis. This issue has been addressed by reveal carcinoma of the prostate, 12 underwent three several studies from the USA [7 10], but has not been and two underwent five biopsies. Overall, 15 (31%) widely discussed in urological literature from the UK. patients had carcinoma on repeat biopsy, 11 after a Thus, the aim of the present study was to investigate second and four after a third biopsy. Histologically, 12 the outcome of repeat prostatic biopsies in men referred of 15 tumours detected were Gleason grade 3+3, while with a clinical suspicion of prostate cancer and persistent the three remaining tumours were Gleason grades 3+2, elevation of PSA, but an initial negative prostate biopsy, 4+3 and 4+5, respectively. The positive biopsy rate and to evaluate which clinical variables are most helpful was 23% (11/48) at the second and four of 14 at the in predicting cancer on repeat biopsy in this group. third biopsy. All patients had an abnormal serum PSA value (>4.0 ng/ml). Their mean PSA was 16.9 (13.5) (median 11.6, range ) ng/ml at the time of Patients and methods their initial biopsy. Fourteen of the 48 men (29%) had Between May 1995 and November 1997, 1059 patients an abnormal DRE, 15 of 48 (31%) had an abnormal attended for TRUS at our institution. We reviewed the TRUS examination and in eight of 48 (17%) both the Hospital Information Support System database and identified DRE and TRUS were abnormal. Based on the outcome 48 men (mean age 67.5 years, sd 7.25, range of their repeat biopsies, seven of the 15 men with a 53 82) with suspected carcinoma of the prostate who positive (cancer detected) repeat biopsy had an abnormal had undergone two or more TRUS-guided prostatic DRE, 10 had an abnormal TRUS and seven had both, biopsies during this period. The indications for TRUS in whereas of the 33 with a negative (cancer not detected) this subgroup of patients were an elevated PSA repeat biopsy, seven (21%) had an abnormal DRE, five (>4.0 ng/ml) with or without an abnormal DRE. A (15%) had an abnormal TRUS and only one had both Bruel and Kjaer system 3535 diagnostic ultrasound unit abnormalities. with a 7 MHz biplanar transrectal probe (model 8551) The histological diagnoses at the first biopsy fell into was used in all examinations. Using the biplanar probe, five main categories, as shown in Table 1; BPH was by the prostate was scanned in both transverse and sagittal far the commonest diagnosis on first biopsy. In five of planes. Sextant biopsies were routinely obtained and a the original 1059 cases (0.5%), the initial biopsies were further two biopsies taken from any area of DRE abnormality reported as inadequate for diagnosis, necessitating or any suspicious hypoechoic area. Biopsies were repeat biopsies. The outcome of the second set of biopsies obtained using an automatic biopsy gun (BioptyA, Bard, in relation to the initial biopsies are also shown in Covington, USA) and 18 G biopsy needles. All TRUS Table 1. There was no significant dicerence in patient examinations were carried out by the same operator age between those with a negative or positive repeat (D.R.G.), either personally or in direct supervision of a biopsy, with mean (sd) age of 69.6 (8.6) and Higher Urological Trainee (7.1) years, respectively (P=0.3311, two-tailed All biopsy material was submitted to the Pathology t-test). Department at Sunderland Royal Hospital and graded The probability of a positive repeat biopsy was 24% by Consultant histopathologists. All patients were given where the serum PSA level was ng/ml, 33% a metronidazole (1 g) suppository after biopsy and were where it was ng/ml and 39% where it was treated for 3 days with amoxicillin/clavulinic acid, or 20.0 ng/ml. There was no significant dicerence ciprofloxacin if allergic to penicillin. PSA was measured between the PSA level at the time of first biopsy in those in all cases by the Department of Chemical Pathology, with a negative or a positive repeat biopsy, with mean

3 36 G.C. DURKAN and D.R. GREENE Table 1 Outcome of first biopsy, and of the second biopsy in relation to histology Outcome of second biopsy* Initial No biopsy* (%) BPH LG PIN HG PIN Cancer Suspicious Prostatitis Inadequate BPH: 25 (52) LG-PIN: 8 (17) HG-PIN: 4 (8) Prostatitis: 6 (13) Inadequate: 5 (10) *LG/HG PIN, Low/high grade prostatic intra-epithelial neoplasia. levels of 15.7 (13.3) and 18.9 (15.1) ng/ml, respectively harbour cancer. Five patients had their second biopsy (P=0.505, two-tailed t-test). However, those men with reported as suspicious (but not diagnostic) of maligcancer on repeat biopsy had significantly higher mean nancy, and of those, two had cancer on their third (sd, range) PSA values before repeat biopsy than at the biopsy. Interestingly, two of eight patients with lowtime of their initial biopsy, at 24.7 (18.3, grade PIN (LGPIN) were found to have cancer on later ) ng/ml and 18.9 (15.1, ) ng/ml, biopsies, but no patient with high-grade PIN (HGPIN) respectively (P=0.0043, two-tailed t-test). Also, those was subsequently found to have cancer. patients with a positive repeat biopsy had significantly higher mean PSA velocities than those with a negative repeat biopsy, at 7.4 (8.9) ng/ml per year and Discussion 1.0 (6.7) ng/ml per year (P=0.0067, two-tailed t- At present, no set criteria exist to guide the urologist in test, Fig. 1). the management of patients with persistently elevated In the 25 men with BPH on first biopsy, nine (36%) serum PSA levels (with or without an abnormal DRE), had cancer on repeat biopsy. There was no dicerence where the initial set of prostate biopsies have been between the positive and negative repeat biopsy groups negative. In the present series, 31% of patients were in initial PSA values, at 16.8 (14.4) and found to harbour cancer on repeat biopsy. This value 17 (12.9) ng/ml, respectively (P=0.486). Of those compares with the series by Fleshner et al. [7], where patients initially in the inadequate for diagnosis cate- 30% of patients had positive repeat biopsies, but is higher gory, two of five had carcinoma on the second and one than the 19 23% quoted by other studies [8 10]. All had carcinoma on the third biopsy. Two patients had authors ultimately recommend repeat prostatic biopsy inadequate second biopsies and of these, one had carciwhere there is a high level of clinical suspicion, despite noma on his next biopsy. Overall, four of seven patients an initial negative biopsy, given the significant initial with inadequate biopsies were subsequently found to false-negative biopsy rate. Fleshner et al. defined a subgroup of patients deemed to be at lowest risk for 30 cancer (PSA<10 ng/ml, PSA density<0.15, PSA velocity<0.75 ng/ml per year, no PIN and a negative DRE, TRUS and no family history) and found that five of 21 (24%) patients in this group had carcinoma on 25 repeat biopsy [7]. Using these parameters, a subset of patients cannot, as yet, be identified for whom repeat biopsy is not required. 20 All the present patients underwent systematic parasagittal TRUS-guided sextant biopsies, as well as directed biopsies of any DRE abnormality or hypoechoic lesion. In view of the high false-negative biopsy rate, this may 15 not be the optimal approach. Eskew et al. [11] described a systematic five-biopsy technique and recommended Time (months) biopsies where the prostate volume was Fig. 1. Comparative PSA velocity (ng/ml per year) for those with <50 ml, and up to 18 biopsies where it was 50 ml; positive (green) and negative (red) repeat biopsies. P= this method increased their cancer detection rate by Mean serum PSA (ng/ml)

4 REPEAT BIOPSY FOR SUSPECTED PROSTATE CANCER 37 35%. Similarly, Levine et al. found that by performing closely in our clinic and will be re-biopsied if there is two consecutive sets of TRUS-guided sextant biopsies at any further significant increase in their serum PSA a single visit, an additional 30% of cancers were levels. detected in the second set of biopsies [12]. In both In an attempt to reduce the number of unnecessary cases, the procedures were well tolerated, with accept- repeat biopsies, several investigators have studied various able complication rates. Using a stochastic computer PSA derivatives as a means of refining PSA sensitivity. simulation of ultrasound-guided biopsies, using math- PSA density was not calculated in the present series, nor ematically reconstructed radical prostatectomy specimens, was free PSA measured, hence their potential impact on Chen et al. [13] found that sextant biopsies only the outcome of repeat biopsies cannot be assessed. There detected cancer in 73% of cases where the total tumour was a significant correlation between PSA velocity and volume was>0.5 ml. Mapping the tumour foci not a positive repeat biopsy (P=0.0067), but as this was detected by the sextant method revealed that these foci calculated by subtracting the PSA level at repeat biopsy were in areas not biopsied by the sextant technique from that at initial biopsy, and adjusting the result to (transition zone, mid-peripheral zone and anterior horn the rate of change over 12 months, rather than recording of peripheral zone). They found that a 10-core biopsy serial measurements of PSA over 18 months to calculate scheme incorporating these additional areas detected velocity, this conclusion may be unreliable. Keetch et al. 96% of cancers. On this evidence, taking more biopsies [18] found that although the combination of PSA density and from more areas of the prostate may reduce the (threshold>0.15) and PSA velocity (>0.75 ng/ml per number of repeat biopsies required in the future. year) could be useful in reducing the number of In the present series, routine transition zone biopsies unnecessary biopsies, they were not subciently sensitive were not taken; there would appear to be some for routine use in cancer detection. justification for this approach in patients with an initial Free PSA has been evaluated recently as a predictor negative biopsy, although this issue remains contro- of prostate cancer in several studies. In a multicentre versial. Lui et al. [14] found that nine of 17 patients trial, Thiel et al. [19] found that a free PSA value of with a positive repeat biopsy had cancer confined to <7% was highly suspicious of prostate cancer, whereas the transition zone. This finding conflicts with the a level of >25% suggested benign disease. In patients results of several other studies that question the with persistently elevated PSA levels, a normal DRE and usefulness of routine transition zone biopsy. Epstein two prior negative biopsies, Morgan et al. [20] found et al. [15] found that the transition zone biopsy alone that a free PSA value of <10% was 91% sensitive and was positive in only 2% of cases, while Bazinet et al. 86% specific in predicting the presence of cancer, and [16] concluded that the low additional yield of transition could help distinguish between BPH and malignancy in zone biopsies precludes their routine use in the detection such patients. Similarly, Catalona et al. [21] found that of prostate cancer. Keetch et al. [17] took transition free PSA thresholds of 28% and 30% detected 90% and zone biopsies in addition to repeat peripheral zone 95% of cancers, respectively, in men with PSA values of biopsies in men who had one or two sets of previous ng/ml, a normal DRE and a prior negative negative biopsies and found that transition zone biopsy biopsy. These studies show that measurement of free detected few additional tumours in this group of PSA provides predictive information about the presence patients. They suggested that cancers located in the of prostate cancer in men with initial negative biopsies transition zone do not usually cause persistently elev- and helps dicerentiate between benign and malignant ated PSA levels in the setting of negative prostate disease. It may prove to be a useful tool in reducing the biopsies. A large randomized prospective trial should number of unnecessary repeat biopsies in such patients resolve this issue. in the future. Of interest in the present series was the lack of In conclusion, the false-negative initial biopsy rate of association between HGPIN and carcinoma on repeat 31% in this selected series is cause for concern and in biopsy. Four of 48 (8%) patients had HGPIN initially, agreement with other authors, as current clinical practice but none were subsequently found to have cancer. stands, we recommend that all patients with persistbut However, two of eight patients with LGPIN had cancer ent elevation of PSA and prior negative biopsies should on repeat biopsy. These findings are similar to those of undergo repeat biopsy, to exclude carcinoma of the Roehrborn et al. [8], who found that no patient with prostate. In view of concerns raised about cancer detection PIN yielded cancer on second biopsy, but contradict by sextant biopsy it would seem appropriate to Ellis and Brawer [9], who found that all five patients in recommend a more extensive biopsy regimen for repeat their series with grade II/III PIN (but none of nine with TRUS-guided biopsies. There are several variables that grade I PIN) had cancer on repeat biopsy. In any event, warrant further evaluation and that may prove useful the present patients with HGPIN are being followed in reducing the need for repeat biopsies; of these, free

5 38 G.C. DURKAN and D.R. GREENE PSA shows greatest promise. However, until large ransets 12 Levine MA, Ittman M, Melamed J, Lepor H. Two consecutive domized clinical trials are conducted to answer these of transrectal ultrasound guided sextant biopsies of the questions, clinicians have no choice but to continue to prostate for the detection of prostate cancer. J Urol 1998; re-biopsy all patients where a high clinical suspicion of 159: Chen ME, Trancoso P, Johnston DA, Tang K, Babaian cancer exists, despite a negative initial biopsy, particu- RJ. Optimisation of prostate biopsy strategy using computer larly in the case of rising PSA velocity. based analysis. J Urol 1997; 158: Lui PD, Terris MK, McNeal JE, Stamey TA. Indications for References ultrasound guided transition zone biopsy in the detection of prostate cancer. J Urol 1995; 153: ECectiveness matters: screening for prostate cancer. NHS 15 Epstein JI, Walsh PC, Sauvageot J, Carter HB. Use of repeat centre for reviews and dissemination, Vol. 2, Issue 2, sextant and transition zone biopsies for assessing extent of Feb prostate cancer. J Urol 1997; 158: CA-Cancer Statistics Atlanta, Georgia. Am Cancer 16 Bazinet M, Karakiewicz PI, Aprikian AG et al. Value of Soc 1996; 46: 5 27 systematic transition zone biopsies in the early detection of 3 Cooner WH, Mosley BR, Rutherford CL Jr et al. Prostate prostate cancer. J Urol 1996; 155: cancer detection in a clinical urological practice by 17 Keetch DW, Catalona WJ. Prostatic transition zone biopsies ultrasonography, digital rectal examination and prostate in men with previous negative biopsies and persistently specific antigen. J Urol 1990; 143: elevated serum prostate specific antigen values. J Urol 4 Catalona WJ, Richie JP, Ahmann FR et al. Comparison of 1995; 154: digital rectal examination and serum prostate specific 18 Keetch DW, McMurtry JM, Smith DS, Andriole GL, Catalona antigen in the early detection of prostate cancer: results of WJ. Prostate specific antigen density versus prostate specific a multicenter clinical trial of 6630 men. J Urol 1994; antigen slope as predictors of prostate cancer in men with 151: initially negative prostate biopsies. J Urol 1996; 156: 5 Masters JG, Keegan PE, Hildreth AJ, Greene DR. Free/total serum prostate specific antigen ratio: how helpful is it in 19 Thiel RP, Oesterling JE, Wojno KJ et al. Multicenter detecting prostate cancer? Br J Urol 1998; 81: comparison of the diagnostic performance of free prostate 6 Selzman AA, Resnick MI. Transrectal ultrasound and specific antigen. Urology 1996; 48: prostate biopsy. Semin Urol 1994; 12: Morgan TO, McLeod DG, Leifer ES, Murphy GP, Moul JW. 7 Fleshner NE, O Sullivan M, Fair WF. Prevalence and Prospective use of free prostate specific antigen to avoid predictors of a positive repeat transrectal ultrasound-guided repeat prostate biopsies in men with elevated total prostate needle biopsy of the prostate. J Urol 1997; 158: specific antigen. Urology 1996; 48: Roehrborn CG, Pickens GJ, Sanders JS. Diagnostic yield of 21 Catalona WJ, Beiser JA, Smith DS. Serum prostate specific repeated transrectal ultrasound-guided biopsies stratified antigen and prostate specific antigen density measurements by specific histopathological diagnoses and prostate specific for predicting cancer in men with prior negative prostatic antigen levels. Urology 1996; 47: biopsies. J Urol 1997; 158: Ellis JW, Brawer MK. Repeat prostate needle biopsy: who needs it? J Urol 1995; 153: Keetch DW, Catalona WJ, Smith DS. Serial prostate biopsies Authors in men with persistently elevated serum prostate specific G.C. Durkan, FRCSI, SHO in Urology. antigen values. J Urol 1994; 151: D.R. Greene, MCh, FRCS(Urol), Consultant Urologist. 11 Eskew AL, Bare RL, McCullough DL. Systematic 5 region Correspondence: Mr D. Greene, Department of Urology, prostate biopsy is superior to sextant method for diagnosing Sunderland Royal Hospital, Kayll Road, Sunderland SR4 carcinoma of the prostate. J Urol 1997; 157: TP, UK.