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The Influence of Prostate Volume on Prostate Cancer Detection

      Abstract

      Objectives: The influence of prostate volume on the positive yield of the systematic sector biopsy is logical and has been demonstrated in numerous reports.
      Methods: Literature on prostate biopsy was reviewed and a selection of articles made. Keywords used for the Medline search included: Prostate cancer, Biopsy, Diagnosis.
      Results: Sextant biopsies have the highest positive biopsy rate (≤40 g) in small prostates (<20 g), whereas in large prostate (80–90 cc) it drops to 10% only.
      Conclusions: The present paper reviews the influence of total and peripheral zone volumes of the prostate on prostate cancer detection rates.

      Keywords

      In the last two decades, there have been significant changes in the approaches to the diagnosis of prostatic carcinoma. This has arisen owing to three technological advances: first, the development of the spring-loaded biopsy device; second, transrectal ultrasound to guide biopsies; third, and most importantly, the widespread utilization of prostate specific antigen as an indication for biopsy. Indeed, these three changes have resulted in staggering differences in the presentation of prostate cancer today [
      • Newcomer L.M.
      • Stanford J.L.
      • Blumenstein B.A.
      • Brawer M.K.
      Temporal trends in rates of prostate cancer: declining incidence of advanced stage disease, 1974–1994.
      ].
      Associated with these developments has been a significant modification in the biopsy approach. Initially, an abnormality on digital rectal examination resulted in biopsies specifically directed either digitally or manually to the area of palpable abnormality was utilized.
      The development of transrectal prostate ultrasound resulted in a significant change. Initially it was felt that the most common presentation on most common sonographic appearance of prostate cancer was the hypoechoic peripheral zone legion [
      • Lee F.
      • Gray J.
      • McCleary R.
      Transrectal ultrasound in the diagnosis of prostate cancer: location, echogenicity, histopathology and staging.
      ,
      • Lee F.
      • Littrup P.J.
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      • Mettlin C.
      • McHugh T.A.
      • Gray J.M.
      Prostate cancer: comparison of TRUS and DRE for screening.
      ,
      • Lee F.
      • Torp-Pedersen S.T.
      • McLeary R.D.
      Diagnosis of prostate cancer by transrectal ultrasound.
      ,
      • Lee F.
      • Torp-Pedersen S.T.
      • Siders D.B.
      • et al.
      Transrectal ultrasonography in the diagnosis and staging of prostatic carcinoma.
      ,
      • Lee F.R.
      • Gray J.M.
      • McLeary R.D.
      • et al.
      Prostatic evaluation by transrectal sonography: criteria for diagnosis of early carcinoma.
      ,
      • Cooner W.H.
      • Mosley R.B.
      • Rutherford J.
      • et al.
      Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate-specific antigen.
      ,
      • Rifkin M.D.
      Endorectal sonography of the prostate: clinical implications.
      ,
      • Rifkin M.D.
      • Friedland G.W.
      • Shortliffe L.
      Prostatic evaluation by transrectal ultrasonography: detection of carcinoma.
      ,
      • Watanabe H.
      Transrectal sonography: a personal review and recent advances.
      ]. Later, a number of authors suggested that many cancers occur in sonographically normal peripheral zone [
      • Resnick M.I.
      • et al.
      Transrectal prostate ultrasonography-variability of interpretation.
      ,
      • Carter H.B.
      • Hamper U.M.
      • Sheth S.
      • Sanders R.C.
      • Epstein J.I.
      • Walsh P.C.
      Evaluation of transrectal ultrasound in the early detection of prostate cancer.
      ,
      • Dahnert W.F.
      • Hamper U.M.
      • Eggleston J.C.
      • Walsh P.C.
      • Sanders R.C.
      Prostatic evaluation by transrectal sonography with histopathologic correlation: the echopenic appearance of early carcinoma.
      ,
      • Salo J.O.
      • Rannikko S.
      • Makinen J.
      • Lehtonen T.
      Echogenic structure of prostatic cancer imaged on radical prostatectomy specimens.
      ,
      • Ellis W.J.
      • Brawer M.K.
      The significance of isoechoic prostatic carcinoma.
      ,
      • Ellis W.J.
      • Brawer M.K.
      Repeat prostate needle biopsy: who needs it?.
      ]. For example, we noted that in 2036 consecutive patients biopsied, cancer was detected in 25.5%. The cancer was found only in isoechoic sections in 14.4% of these men [

      Brawer MK, Chetner MP. Ultrasonography of the prostate and biopsy. In: Walsh PC, Retik AB, Vaughan Jr ED, Wein AJ, editors. Campbell’s urology, Vol. 3. 7th ed. Philadelphia: Saunders, 1998.

      ].
      It is now generally assumed that no sonographic appearance is definitive for cancer, and thus biopsy approaches have adopted random nature. Other than concentrating on the peripheral zone where the majority of cancers arise, there is no other sonographically identified target to aim for.
      This realization made the prostate volume an essential component in our diagnostic strategy. This stems from the fact that if we have nothing to aim for, we are more likely to identify cancer in a smaller gland with an equivalent number of biopsies than in a larger gland. The first observations in this regard actually stem from our initial inability to replicate the intriguing work suggesting the utility of prostate specific antigen density.
      PSA density refers to the quotient of the serum PSA divided by the volume of the prostate gland [
      • Benson M.C.
      • Whang I.S.
      • Pantuck A.
      • et al.
      Prostate-specific density: a means of distinguishing benign prostatic hypertrophy and prostate cancer.
      ]. Because of the fact that the largest component of prostate volume is benign prostatic hyperplasia, it makes intrinsic sense that normalization of total PSA by the gland volume may make PSA more specific. A number of investigators carried out early work in this regard [
      • Benson M.C.
      • Whang I.S.
      • Pantuck A.
      • et al.
      Prostate-specific density: a means of distinguishing benign prostatic hypertrophy and prostate cancer.
      ,
      • Benson M.C.
      • Whang I.S.
      • Olsson C.A.
      • McMahon D.J.
      • Cooner W.H.
      The use of PSA density to enhance the predictive value of intermediate levels of serum PSA.
      ,
      • Seaman E.
      • Whang M.
      • Olsson C.A.
      • Katz A.
      • Cooner W.H.
      • Benson M.C.
      PSA density (PSAD): role in patient evaluation and management.
      ,
      • Bazinet M.
      • Meshref A.W.
      • Trudel C.
      • et al.
      Prospective evaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma.
      ,
      • Rommel F.M.
      • Augusta V.E.
      • Breslin J.A.
      • et al.
      The use of PSA and PSAD in the diagnosis of prostate cancer in a community based urology practice.
      ,
      • Littrup P.J.
      • Kane R.A.
      • Mettlin C.J.
      • et al.
      Cost-effective prostate cancer detection: reduction of low-yield biopsies.
      ,
      • Bangma C.H.
      • Kranse R.
      • Blijenberg B.G.
      • Schroder F.H.
      The value of screening tests in the detection of prostate cancer. Part I. Results of a retrospective evaluation of 1726 men.
      ,
      • Brawer M.K.
      • Aramburu E.A.G.
      • Chen G.L.
      • Preston S.D.
      • Ellis W.J.
      The inability of PSA index to enhance the predictive value of PSA in the diagnosis of prostatic carcinoma.
      ,
      • Mettlin C.
      • Littrup P.J.
      • Kane R.A.
      • et al.
      Relative sensitivity and specificity of serum PSA level compared with age-referenced PSA, PSA density and PSA change.
      ,
      • Ohori M.
      • Dunn J.K.
      • Scardino P.T.
      Is prostate-specific antigen density more useful than prostate-specific antigen levels in the diagnosis of prostate cancer.
      ]. As shown in Table 1, initial investigations demonstrated enhanced specificity with a minimal reduction in test sensitivity when PSA density was utilized [
      • Benson M.C.
      • Whang I.S.
      • Pantuck A.
      • et al.
      Prostate-specific density: a means of distinguishing benign prostatic hypertrophy and prostate cancer.
      ,
      • Benson M.C.
      • Whang I.S.
      • Olsson C.A.
      • McMahon D.J.
      • Cooner W.H.
      The use of PSA density to enhance the predictive value of intermediate levels of serum PSA.
      ,
      • Bazinet M.
      • Meshref A.W.
      • Trudel C.
      • et al.
      Prospective evaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma.
      ,
      • Rommel F.M.
      • Augusta V.E.
      • Breslin J.A.
      • et al.
      The use of PSA and PSAD in the diagnosis of prostate cancer in a community based urology practice.
      ,
      • Mettlin C.
      • Littrup P.J.
      • Kane R.A.
      • et al.
      Relative sensitivity and specificity of serum PSA level compared with age-referenced PSA, PSA density and PSA change.
      ,
      • Ohori M.
      • Dunn J.K.
      • Scardino P.T.
      Is prostate-specific antigen density more useful than prostate-specific antigen levels in the diagnosis of prostate cancer.
      ]. Our own investigations were unable to recapitulate these findings [
      • Brawer M.K.
      • Aramburu E.A.G.
      • Chen G.L.
      • Preston S.D.
      • Ellis W.J.
      The inability of PSA index to enhance the predictive value of PSA in the diagnosis of prostatic carcinoma.
      ].
      Table 1PSA results
      AuthorBiopsyNumber of patientsPSA (ng/ml)
      Data reported as mean (Standard Deviation).
      Prostate volume (cc)
      Data reported as mean (Standard Deviation).
      PSA density
      Data reported as mean (Standard Deviation).
      Benson et al.
      • Benson M.C.
      • Whang I.S.
      • Olsson C.A.
      • McMahon D.J.
      • Cooner W.H.
      The use of PSA density to enhance the predictive value of intermediate levels of serum PSA.
      Positive987.0 (1.7)
      <0.05.
      28.9 (14.6)
      <0.05.
      0.30 (0.15)
      <0.05.
      Negative1916.8 (1.8)40.1 (20.2)0.21 (0.11)
      Seaman et al.
      • Seaman E.
      • Whang M.
      • Olsson C.A.
      • Katz A.
      • Cooner W.H.
      • Benson M.C.
      PSA density (PSAD): role in patient evaluation and management.
      Positive1156.87 (1.70)29.2 (14.2)
      <0.05.
      0.285 (0.147)
      <0.05.
      Negative3116.77 (1.71)42.2(21.8)0.199 (0.108)
      Brawer et al.
      • Brawer M.K.
      • Aramburu E.A.G.
      • Chen G.L.
      • Preston S.D.
      • Ellis W.J.
      The inability of PSA index to enhance the predictive value of PSA in the diagnosis of prostatic carcinoma.
      Positive6810.7 (11.4)
      <0.05.
      40.5 (16.6)0.29 (0.41)
      Negative1595.2 (5.0)42.6 (25.6)0.14 (0.14)
      Bazinet et al.
      • Bazinet M.
      • Meshref A.W.
      • Trudel C.
      • et al.
      Prospective evaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma.
      Positive21721.4 (29.6)
      <0.05.
      37.6 (21.4)
      <0.05.
      0.63 (0.86)
      <0.05.
      Negative3179.1 (8.1)51.6 (27.3)0.21 (0.25)
      Rommel et al.
      • Rommel F.M.
      • Augusta V.E.
      • Breslin J.A.
      • et al.
      The use of PSA and PSAD in the diagnosis of prostate cancer in a community based urology practice.
      Positive61215.5 (21.6)
      <0.05.
      42.7 (27.2)
      <0.05.
      0.47 (0.11)
      <0.05.
      Negative13944.947.0 (31.6)0.105 (0.09)
      Mettlin et al.
      • Mettlin C.
      • Littrup P.J.
      • Kane R.A.
      • et al.
      Relative sensitivity and specificity of serum PSA level compared with age-referenced PSA, PSA density and PSA change.
      Positive17112.0 (16.0)
      <0.05.
      38.9 (16.4)0.35 (0.5)
      <0.05.
      Negative6502.1 (2.3),33.5 (14.2)0.08 (0.09)
      Ohori et al.
      • Ohori M.
      • Dunn J.K.
      • Scardino P.T.
      Is prostate-specific antigen density more useful than prostate-specific antigen levels in the diagnosis of prostate cancer.
      Positive1109.3 (0.3–1320)
      Data reported as median (range) p<0.05.
      <0.05.
      28.1 (15.1–228.7)
      Data reported as median (range) p<0.05.
      <0.05.
      0.21 (0.009–39.3)
      Data reported as median (range) p<0.05.
      <0.05.
      Negative1344.8 (0.2–64.1)
      Data reported as median (range) p<0.05.
      <0.05.
      47.3 (13.3–332.6)
      Data reported as median (range) p<0.05.
      <0.05.
      0.09 (0.007–1.82)
      Data reported as median (range) p<0.05.
      <0.05.
      a Data reported as mean (Standard Deviation).
      b Data reported as median (range) p<0.05.
      * <0.05.
      We theorized that a number of possible reasons to explain this apparent discrepancy. These included differences in the accuracy in prostate ultrasound measurement, the size of the prostate in the study population, variability of the histologic makeup in the cohort of men being tested, as well as biopsy sampling error and PSA variability [
      • Brawer M.K.
      • Aramburu E.A.G.
      • Chen G.L.
      • Preston S.D.
      • Ellis W.J.
      The inability of PSA index to enhance the predictive value of PSA in the diagnosis of prostatic carcinoma.
      ]. Subsequently, it became apparent that in most of the papers in which PSA density appeared to provide enhancement of PSA specificity, the glands harboring carcinoma were significantly smaller than in men without malignancy [
      • Benson M.C.
      • Whang I.S.
      • Pantuck A.
      • et al.
      Prostate-specific density: a means of distinguishing benign prostatic hypertrophy and prostate cancer.
      ,
      • Benson M.C.
      • Whang I.S.
      • Olsson C.A.
      • McMahon D.J.
      • Cooner W.H.
      The use of PSA density to enhance the predictive value of intermediate levels of serum PSA.
      ,
      • Seaman E.
      • Whang M.
      • Olsson C.A.
      • Katz A.
      • Cooner W.H.
      • Benson M.C.
      PSA density (PSAD): role in patient evaluation and management.
      ,
      • Bazinet M.
      • Meshref A.W.
      • Trudel C.
      • et al.
      Prospective evaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma.
      ,
      • Rommel F.M.
      • Augusta V.E.
      • Breslin J.A.
      • et al.
      The use of PSA and PSAD in the diagnosis of prostate cancer in a community based urology practice.
      ,
      • Ohori M.
      • Dunn J.K.
      • Scardino P.T.
      Is prostate-specific antigen density more useful than prostate-specific antigen levels in the diagnosis of prostate cancer.
      ]. In our patients in which either there was no difference in the prostate volume between men without cancer. PSA specificity afforded no benefit [
      • Brawer M.K.
      • Aramburu E.A.G.
      • Chen G.L.
      • Preston S.D.
      • Ellis W.J.
      The inability of PSA index to enhance the predictive value of PSA in the diagnosis of prostatic carcinoma.
      ]. It made us ponder whether it was not the performance of PSA density calculation that made a difference, but rather the fact that given an equal number of biopsy cores obtained, a larger gland would be more likely to give a false negative test result of biopsy, i.e. more cancers would be missed in the larger gland—those with a lower PSA density (Fig. 1).
      Figure thumbnail gr1
      Fig. 1A schematic example of sampling error that could occur between larger and smaller prostate glands. Cancer in a larger gland is more likely to be missed by systematic sextant needle biopsy. (Taken from Nixon RG, Brawer MK, Refinements in serum prostate-specific antigen testing for the diagnosis of prostate cancer. Recent Advances in Urology. 7 ed. London: Churchill Livingstone; 1998.)
      In an effort to make density even more specific, a number of authors evaluated the transition zone density where the serum PSA divided by the volume of the transition zone. Reports in this regard again were positive and indicated enhancement of test specificity [
      • Djavan B.
      • Zlotta A.R.
      • Shariat S.
      • Omar M.
      • Schulman C.C.
      • Marberger M.
      Prostate specific antigen density of the transition zone for early detection of prostate cancer.
      ,

      Maeda H, Ishitoya S, Maekawa S, et al. Prostate specific antigen density of the transition zone in the detection of prostate cancer. J Urol 1997;(Suppl):58A.

      ]. We, too, were unable to reproduce these results [
      • Lin D.W.
      • Gold M.H.
      • Ransom S.
      • Ellis W.J.
      • Brawer M.K.
      Transition zone PSA density: lack of utility in prediction of prostatic carcinoma.
      ] and again concluded that this was an artifact of missing cancer in the larger glands.
      In order to further evaluate this observation, we carried out an investigation studying the effect of prostate volume on the yield of needle biopsy [
      • Letran J.
      • Meyer G.
      • Loberiza F.
      • Brawer M.
      The effect of prostate volume on the yield of needle biopsy.
      ]. In this study, we evaluated the cancer detection of six systematic sector biopsies performed because of either an abnormality on digital rectal examination or an elevation on serum PSA in 1057 men (Table 2). 326 were diagnosed with prostate cancer (30.8%). We observed a trend of decreasing cancer yield in men with larger glands (Fig. 2). Statistical tests utilizing an odds ratio analysis by yield was used to determine the cancer detection rate by quartile increase in total gland volume was utilized. No statistical relationship was observed between gland size and cancer yield when comparing the first quartile to the second or third quartile. However, when comparing the smallest quartile to the largest quartile of patients, a significantly lower cancer detection rate was noted (odds ratio 1.5).
      Table 2Patient age, serum PSA, and total gland and peripheral zone volumes according to presence or absence of cancer on transrectal ultrasound guided prostate needle biopsy
      Mean ± S.D. (range)p-value
      Positive biopsy (326 pts.)Negative biopsy (731 pts.)
      Age67.6 ± 7.6 (46–92)66.2 ± 7.9 (31–73)0.0079
      Serum PSA (ng/ml)15.5 ± 34.2 (0.6–386.0)6.0 ± 6.6 (0.1–20.4)0.0001
      Gland volume (cm3)40.2 ± 19.3 (10.5–139.4)48.2 ± 31.2 (4.5–311.5)0.0001
      Peripheral zone volume (cm3)24.2 ± 12.5 (1.4–93.2)29.3 ± 21.4 (1.8–204.6)0.0001
      Taken from
      • Letran J.
      • Meyer G.
      • Loberiza F.
      • Brawer M.
      The effect of prostate volume on the yield of needle biopsy.
      .
      Figure thumbnail gr2
      Fig. 2Cancer detection rate as function of total gland volume. (Taken from Letran J, Meyer G, Loberiza F, Brawer M: The effect of prostate volume on the yield of needle biopsy. J Urol 160(5):1718–1721, 1998.)
      We concluded that the positive yield of the systematic sector biopsy decreases significantly when total gland volume is greater than 55.6 cc (Table 3). These findings were reproduced by the work of Karakiewicz et al. [
      • Karakiewicz P.L.
      • Bazinet M.
      • Aprikian A.G.
      • et al.
      Outcome of sextant biopsy according to gland volume.
      ] as well as Uzzo et al. [
      • Uzzo R.G.
      • Wei J.T.
      • Waldbaum R.S.
      • Perlmutter A.P.
      • Byrne J.C.
      • Vaughan E.D.
      The influence of prostatic size on cancer detection.
      ]. In the Karakiewicz investigation, 1974 men who had systematic sextant biopsies had decreasing yield of biopsy with increasing gland volume (p<0.001). The highest positive biopsy rate (39.6%) was recorded among prostates that were smaller than 20 cc. The lowest biopsy rate in his study (10.1%) was noted in those glands between 80 and 90 cc. Uzzo et al. [
      • Uzzo R.G.
      • Wei J.T.
      • Waldbaum R.S.
      • Perlmutter A.P.
      • Byrne J.C.
      • Vaughan E.D.
      The influence of prostatic size on cancer detection.
      ] noted similar results.
      Table 3Biopsy yield as a function of the total gland and peripheral zone volumes using odds ratio analysis
      Quartile 1 (265 pts.)Quartile 2 (264 pts.)Quartile 3 (264 pts.)Quartile 4 (264 pts.)
      GlandPeripheral zoneGlandPeripheral zoneGlandPeripheral zoneGlandPeripheral zone
      Cut-off volume (cm3)27.91 or less15.98 or less38.42 or less23.06 or less55.60 or less33.61 or less237.1 or less204.6 or less
      Yield (%)32.9532.8334.8532.5833.7134.4721.9723.11
      Odds ratio0.9461.0120.9780.9561.51.421
      95% CI0.745–1.20.79–1.290.75–1.220.75–1.221.128–1.9951.08–1.88
      p-valueNot significantNot significantNot significantNot significantSignificantSignificant
      Taken from
      • Letran J.
      • Meyer G.
      • Loberiza F.
      • Brawer M.
      The effect of prostate volume on the yield of needle biopsy.
      .
      It has been widely reported that the absence of detection of cancer on the initial systematic six biopsy sector approach does not eliminate the possibility of missed cancer. Indeed, the literature is replete with articles indicating cancer detection in 20–40% of men with an initial negative biopsy [
      • Ellis W.J.
      • Brawer M.K.
      Repeat prostate needle biopsy: who needs it?.
      ,
      • Keetch D.W.
      • Catalona W.J.
      • Smith D.S.
      Serial prostatic biopsies in men with persistently elevated serum prostate-specific antigen levels.
      ,
      • Roehrborn C.G.
      • Pickens G.J.
      • Sanders J.S.
      Diagnostic yield of repeated transrectal ultrasound-guided biopsies stratified by specific histopathologic diagnoses and prostate-specific antigen levels.
      ]. This has resulted in a variety of strategies to enhance the yield of cancer by both increasing the number and the trajectory utilized and obtained in the biopsy. A number of authors have carried out investigations where they used a variety of number of needle biopsies and compared cancer yield detection. As shown in Table 4, all of these studies demonstrate increased cancer detection with increased number of cores obtained.
      Table 4Prostate cancer detection rate with corresponding number of biopsy cores
      ReferencesNumber of pts.Number of cores% Ca detection
      Eskew et al.
      • Eskew L.A.
      • Bare R.L.
      • McCullough D.L.
      Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate.
      119626.1
      1191140.3
      Reitbergen et al.
      • Reitbergen J.B.W.
      • Kruger A.E.B.
      • Kranse R.
      • Schroder F.H.
      Complications of transrectal ultrasound-guided systematic sextant biopsies of the prostate: evaluation of complication rates and risk factors within a population-based screening program.
      617624.5
      725.4
      Nava et al.
      • Nava L.
      • Montorsi F.
      • Consonni P.
      • Scattoni V.
      • Guazonni G.
      • Rigatti P.
      Results of a prospective randomized study comparing 6,12, and 18 transrectal ultrasound-guided sextant biopsies in patients with elevated PSA normal DRE and normal prostate ultrasound.
      40622.0
      401225.0
      401831.0
      Levine et al.
      • Levine M.A.
      • Melamed J.
      • Ittmann M.
      • Lepor H.
      Two consecutive sets of transrectal ultrasound (TRUS) guided sextant biopsies of the prostate for the diagnosis of prostate cancer.
      124633.0
      1241245.0
      Brown et al.

      Brown M, True LD, Ellis WJ, Brawer MK. Does increased number of ultrasound-guided prostate needle biopsies enhance the yield of the chance of finding carcinoma. Urol J 1997;157(4):144A.

      254633.9
      254835.0
      Taken from
      • Letran J.
      • Meyer G.
      • Loberiza F.
      • Brawer M.
      The effect of prostate volume on the yield of needle biopsy.
      .
      We are unaware of any study which prospectively used prostate volume as a determinant of the number of cores obtained. This would provide the definitive answer to the question whether the increased yield with more cores is a function of better sampling but this seems obvious. Our current biopsy methodology is to utilize ten cores with five obtained from each side. We performed systematic sector biopsy as originally described by Hodge in the parasaggital plane between the lateral and middle third of each half of the prostate [
      • Hodge K.K.
      • McNeal S.E.
      • Terris M.K.
      • Stamey T.A.
      Random systematic versus directed ultrasound-guided transrectal core biopsies of the prostate.
      ]. Two additional cores obtained from each side in an extreme lateral position to increase sampling of peripheral zone tissue extending into the anterior horn as suggested by Stamey [
      • Stamey T.A.
      Making the most out of six systematic sextant biopsies.
      ]. It would seem prudent to utilize prostate volume as a factor in determining the need for repeat biopsy in a man with an initial negative prostate biopsy.

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