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Prostatic Transrectal Ultrasound (TRUS) Guided Biopsy Schemes and TRUS Prostatic Lesion-Guided Biopsies

      Abstract

      Objectives: Recent data support the sextant TRUS guided biopsy scheme of the prostate and TRUS prostatic lesion-guided biopsies are inadequate to detect all clinically important cancers. Consequently, different types of schemes with more than six biopsies have recently been proposed. The type of scheme and the number of biopsies needed to optimize the detection rate of prostate cancer is still a somewhat controversial issue. In order to draw attention to the most interesting issues and controversies involving needle biopsies, we describe not only the most common methods used but also some of the new schemes proposed in literature.
      Methods: Literature on prostate biopsy was reviewed and a selection of articles made. Keywords used for the Medline search included: prostate cancer, biopsy, transrectal ultrasound and diagnosis.
      Results: Over the last few years, an increasing number of investigators have modified the standard sextant biopsy scheme, increasing the number and areas of the prostate sampled, especially biopsies taken more laterally or in the anterior horn or medially towards the apex of the prostate. Cancer yield does not appear to be related solely to the number of biopsies but also to the regions of the prostate sampled.
      Conclusions: In the current PSA era, prostatic biopsies only performed at lesions detected by TRUS are obsolete. Sextant and lesion-directed biopsies maximizes detection rate using the lowest possible number of biopsy cores if hypoechoic lesions are clearly visible. In the case of a negative TRUS and/or digital rectal examination, the ideal number of cores and prostate areas requiring sampling is still not defined, but the use of 10 or 12 multiple biopsies is becoming routine in many centers. In the future, biopsy techniques will probably be individualized for each patient according to TRUS findings, prostatic volume and PSA levels.

      Keywords

      1. Introduction

      In the prostate specific antigen (PSA) era, without the parallel development of transrectal ultrasound (TRUS) and TRUS guided prostate biopsy, the diagnosis of prostate cancer would not have undergone such a marked improvement. Since its introduction in the early 1980s, TRUS of the prostate has developed from a fixed probe attached to a chair to more modern, handheld high resolution probes with multi-axial planar imaging capabilities right up until the most recent powerful ultrasound machines encompassing new technological methods such as color Doppler, power Doppler and three-dimensional imaging [
      • Sedelaar M.
      • Vijverberg P.
      • De Reijke T.
      • de la Rosette J.
      • Kil P.
      • Braeckman J.
      • et al.
      Transrectal ultrasound in the diagnosis of prostate cancer: state of the art and perspectives.
      ]. The introduction of spring-loaded 18 gauge needles and the intrarectal injection of lidocaine gel now facilitates the taking of multiple core biopsies according to a rapid, pain-free method [
      • Issa M.M.
      • Bux S.
      • Chun T.
      • Petros J.A.
      • Labadia A.J.
      • Anastasia K.
      • et al.
      A randomized prospective trial of intrarectal lidocaine for pain control during transrectal prostate biopsy: the Emeroy University experience.
      ].
      Unfortunately, due to the lack of specificity and the variability in the ultrasonic appearance of tumors, TRUS alone performs poorly for prostate cancer identification [
      • Sedelaar M.
      • Vijverberg P.
      • De Reijke T.
      • de la Rosette J.
      • Kil P.
      • Braeckman J.
      • et al.
      Transrectal ultrasound in the diagnosis of prostate cancer: state of the art and perspectives.
      ]. Even though some prostatic tumors are able to be visualized as a hypoechoic area distinguishable from the normal homogenous isoechoic parenchyma, most hypoechoic lesions are not cancers [
      • Partin A.W.
      • Stutzman R.E.
      Elevated prostate-specific antigen, abnormal prostate evaluation on digital rectal examination and transrectal ultrasound and prostate biopsy.
      ]. Moreover, many early stage cancers are isoechoic and not distinguishable from surrounding benign tissue. More than 10 years ago, Hodge et al. were the first to report that six systematic spatially separated biopsies may improve diagnostic accuracy of prostate cancer rather than limiting the biopsy to hypoechoic lesions [
      • Hodge K.K.
      • McNeal J.E.
      • Terris M.K.
      • Stamey T.A.
      Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate.
      ]. Soon afterwards, TRUS using systematic sextant biopsies with targeted biopsies of the base, mid and apical portions of the gland, taken from each side in the parasaggital plane, became the standard biopsy scheme.
      The policy of using a systematic biopsy to sample all areas of the prostate regardless of the presence of hypoechoic lesions became strongly recommended and preferred by many urologists rather than the old method of searching for and biopsying each single lesions in addition to adding systematic biopsies [
      • Ellis W.J.
      • Brawer M.K.
      The significance of isoechoic prostatic carcinoma.
      ]. Over recent years, many reports have shown that sextant biopsies do not detect all clinically significant cancers and efforts have been made to improve the sextant protocol by adding other biopsies and/or changing biopsy positions [
      • Norberg M.
      • Egevad L.
      • Holmberg L.
      • Sparén P.
      • Norlén B.J.
      • Busch C.
      The sextant protocol for ultrasound-guided core biopsies of the prostate understimates the presence of cancer.
      ,
      • Keetch D.W.
      • Catalona W.J.
      • Smith D.S.
      Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values.
      ,
      • Ellis W.J.
      • Brawer M.K.
      Repeat prostate needle biopsy: who needs it?.
      ,
      • Chen M.E.
      • Troncoso P.
      • Johnston D.A.
      • Tang K.
      • Babaian R.J.
      Optimization of prostate biopsy strategy using computer based analysis.
      ]. The aim of this article is to present and comment upon different prostatic biopsy modes and schemes adopted by different urologists around the world in an attempt to propose an optimal biopsy strategy.

      2. TRUS lesion-guided prostatic biopsies

      One of the controversial issues is whether it is necessary to take samples from a TRUS visible lesion area in addition to systematic biopsies or simply to add more biopsies to the standardized sextant biopsy scheme in order to increase the detection rate of prostate cancer. Hypoechoic prostatic lesions are more than twice as likely to have cancer on biopsy than isoechoic prostatic tissue [
      • Melchior S.W.
      • Brawer M.K.
      Role of transrectal ultrasound and prostate biopsy.
      ] and the average biopsy yield of a peripheral zone hypoechoic lesion is 30–50% [
      • Langer J.E.
      The current role of transrectal ultrasonography in the evaluation of prostate carcinoma.
      ]. On the contrary, hypoechoic lesions in the transition zone are less specific in terms of prostatic cancer owing to the fact that benign prostatic hyperplasia nodules may normally appear hypoechoic [
      • Stamey T.A.
      Making the most out of six systematic sextant biopsies.
      ] (Table 1).
      Table 1Positive predictive value (PPV) of biopsies directed to a hypoechoic area
      AuthorsNo. of patientsPSA levels (ng/ml)DRE
      DRE: digital rectal examination.
      PPV (%)
      Hodge et al.
      • Hodge K.K.
      • McNeal J.E.
      • Terris M.K.
      • Stamey T.A.
      Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate.
      57Not availablePositive5
      Spencer et al.
      • Spencer J.A.
      • Alexander A.A.
      • Gomella L.
      • Matteucci T.
      • Goldberg B.B.
      Ultrasound-guided four quadrant biopsy of the prostate: efficacy in the diagnosis of isoechoic cancer.
      403Not availableNot available22
      Melchior and Brawer
      • Melchior S.W.
      • Brawer M.K.
      Role of transrectal ultrasound and prostate biopsy.
      2231<4.0Negative13
      <4.0Positive14
      >4.0Negative27
      >4.0Positive45
      Fleshner et al.
      • Fleshner N.E.
      • O’Sullivan M.
      • Premdass C.
      • Fair W.R.
      Clinical significance of small (less than 0.2 cm3) hypoechoic lesions in men with normal digital rectal examinations and prostate-specific antigen levels of less than 10 ng/ml.
      81<10Negative17
      a DRE: digital rectal examination.
      Since only 60% of clinically diagnosed prostate cancer is hypoechoic [
      • Partin A.W.
      • Stutzman R.E.
      Elevated prostate-specific antigen, abnormal prostate evaluation on digital rectal examination and transrectal ultrasound and prostate biopsy.
      ,
      • 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?.
      ] and owing to the fact that transition zone cancers are generally concentrated in the farthest anterior areas of the prostate near the midline (a zone in which it is virtually impossible to detect prostate cancer based on TRUS alone). TRUS lesion-guided biopsies would detect only about 50% of all prostate cancers [
      • Chen M.E.
      • Troncoso P.
      • Johnston D.A.
      • Tang K.
      • Babaian R.J.
      Optimization of prostate biopsy strategy using computer based analysis.
      ]. Moreover, the identification of hypoechoic lesions in the peripheral zone is subjective.
      For these reasons, in all cases, most urologists perform the standard sextant biopsy protocol and do not take additional biopsy samples from visible lesions located outside the predetermined location for standardized biopsies [
      • Applewhite J.C.
      • Matlaga B.R.
      • McCullough D.L.
      • Hall C.M.
      Transrectal ultrasound and biopsy in the early diagnosis of prostate cancer.
      ]. They maintain that TRUS findings are clinically irrelevant because the sensitivity and specificity of a TRUS visible lesion is too low [
      • Applewhite J.C.
      • Matlaga B.R.
      • McCullough D.L.
      • Hall C.M.
      Transrectal ultrasound and biopsy in the early diagnosis of prostate cancer.
      ]. Many authors have reported that the exclusive use of TRUS lesion-guided biopsies has such a low sensitivity that up to 60% of the cancer would be missed if systematic biopsies [
      • Partin A.W.
      • Stutzman R.E.
      Elevated prostate-specific antigen, abnormal prostate evaluation on digital rectal examination and transrectal ultrasound and prostate biopsy.
      ,
      • Ellis W.J.
      • Brawer M.K.
      The significance of isoechoic prostatic carcinoma.
      ,
      • Melchior S.W.
      • Brawer M.K.
      Role of transrectal ultrasound and prostate biopsy.
      ] were not used. In a large series of 2231 consecutive patients who underwent six sextant biopsies, Melchior and Brawer reported that cancer was found in 31% of patients with a hypoechoic sector [
      • Melchior S.W.
      • Brawer M.K.
      Role of transrectal ultrasound and prostate biopsy.
      ]. Even if the positive predictive value of hypoechoic lesion was 90% in patients with a suspicious DRE, performing directed biopsies of hypoechoic lesions would only have resulted in misdiagnosing 25% of patients. Their results strongly suggested the need to obtain biopsy samples of the normal-appearing peripheral zone as opposed to directed biopsies which only sample areas showing abnormality with ultrasound [
      • Melchior S.W.
      • Brawer M.K.
      Role of transrectal ultrasound and prostate biopsy.
      ].
      Nowadays, lesion-guided biopsies only play a role in the combination of systematic biopsies in prostates with visible lesions. There is some convincing data that the cancer yield is higher in those patients with some hypoechoic lesions seen at TRUS compared to those with no pathological ultrasound findings [
      • Melchior S.W.
      • Brawer M.K.
      Role of transrectal ultrasound and prostate biopsy.
      ].
      Norberg et al. reported that the combination of lesion-guided biopsies and systematic biopsy samples increases sensitivity by up to 15%, but only by a small percentage when more than six (8 or 10 biopsies depending on gland size) standardized biopsy samples are taken [
      • Norberg M.
      • Egevad L.
      • Holmberg L.
      • Sparén P.
      • Norlén B.J.
      • Busch C.
      The sextant protocol for ultrasound-guided core biopsies of the prostate understimates the presence of cancer.
      ]. On the contrary, six systematic biopsy samples, even when combined with target biopsy samples, underestimated the presence of prostate cancer.
      In a prospective trial of 483 consecutive patients, Presti et al. demonstrated that a 10-core biopsy scheme weighted more towards the lateral aspect of the peripheral zone, increased cancer detection rates by 14% thus almost eliminating the need for lesion-directed biopsies [
      • Presti J.C.J.
      • Chang J.J.
      • Bhargava V.
      • Shinohara K.
      The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial.
      ]. Recently, Reitburgen et al. performed an additional hypoechoic lesion biopsy in 1546 patients and concluded that 5% of the cancers identified would have been missed had the additional biopsy been eliminated [
      • Reitburgen J.B.W.
      • Kranse R.
      • Kirkels W.J.
      • Hoedemaeker F.
      • Schröder F.H.
      Prostate cancer screening: value of the “seventh” targeted to visible lesions.
      ].
      Fleshner et al. have also demonstrated the advantages of biopsying small hypoechoic lesions in patients with negative results following digital rectal examination and a PSA of less than 10 ng/ml [
      • Fleshner N.E.
      • O’Sullivan M.
      • Premdass C.
      • Fair W.R.
      Clinical significance of small (less than 0.2 cm3) hypoechoic lesions in men with normal digital rectal examinations and prostate-specific antigen levels of less than 10 ng/ml.
      ]. Although, they detected cancer in 17% of the patients with a small visible lesion at TRUS, the overall yield of a separate hypoechoic area biopsy was less than 4%. The authors recommended the identification and biopsying of small hypoechoic lesions in patients with suspected clinical stage T1c prostate cancer with minimal PSA elevations owing to the fact that a significant proportion of small hypoechoic lesions are positive for malignancy.
      It is surprising to note that the detection rate of suspect findings for cancer by TRUS may vary from one institution to another. Melchior and Brawer reported that 72% out of 2231 patients had a hypoechoic lesion [
      • Melchior S.W.
      • Brawer M.K.
      Role of transrectal ultrasound and prostate biopsy.
      ] and, in a series of 512 patients, Norberg et al. reported the presence of visible lesions in 64% of the population study [
      • Norberg M.
      • Egevad L.
      • Holmberg L.
      • Sparén P.
      • Norlén B.J.
      • Busch C.
      The sextant protocol for ultrasound-guided core biopsies of the prostate understimates the presence of cancer.
      ]. On the contrary, Gore et al. recently reported a positive TRUS in only 6% out of 396 patients who underwent extended multisite biopsies [
      • Gore J.L.
      • Shariat S.F.
      • Miles B.J.
      • Kadmon D.
      • Jiang N.
      • Wheeler T.M.
      • et al.
      Optimal combinations of systematic and laterally directed biopsies for the detection of prostate cancer.
      ]. In fact, an accurate imaging study showed that only 12% of men with non-palpable carcinoma of the prostate have no TRUS or endorectal coil magnetic resonance imaging abnormalities. Different cancer yields of the various studies may depend on the amount of the prostate following a positive TRUS or digital rectal examination [
      • Werner-Wasik M.
      • Whittington R.
      • Malkowicz S.B.
      • Corn B.W.
      • Arger P.
      • Reisinger S.
      • et al.
      Prostate imaging may not be necessary in nonpalpable carcinoma of the prostate.
      ].
      In conclusion, in the absence of any proof that an extensive biopsy protocol may eliminate the need for directed biopsy, it seems wise to add one single biopsy targeted at the peripheral hypoechoic lesions located outside the standard biopsy location. Moreover, the ultimate biopsy scheme (six or more cores) in patients with TRUS visible lesions is yet to be determined.

      3. TRUS guided biopsy schemes

      3.1 Sextant biopsies

      Over the last 10 years, the most frequently used biopsy protocol was the sextant protocol described by Hodge et al. [
      • Hodge K.K.
      • McNeal J.E.
      • Terris M.K.
      • Stamey T.A.
      Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate.
      ] (Fig. 1). In 1995 Stamey proposed shifting the sextant biopsies more laterally in order to sample better the peripheral zone where most of the cancers are located [
      • Stamey T.A.
      Making the most out of six systematic sextant biopsies.
      ]; however, recent reports have shown that a single set of sextant biopsies may miss clinically detectable prostate cancer in 15–34% of men [
      • Partin A.W.
      • Stutzman R.E.
      Elevated prostate-specific antigen, abnormal prostate evaluation on digital rectal examination and transrectal ultrasound and prostate biopsy.
      ,
      • Hodge K.K.
      • McNeal J.E.
      • Terris M.K.
      • Stamey T.A.
      Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate.
      ,
      • Ellis W.J.
      • Brawer M.K.
      The significance of isoechoic prostatic carcinoma.
      ,
      • Norberg M.
      • Egevad L.
      • Holmberg L.
      • Sparén P.
      • Norlén B.J.
      • Busch C.
      The sextant protocol for ultrasound-guided core biopsies of the prostate understimates the presence of cancer.
      ,
      • Keetch D.W.
      • Catalona W.J.
      • Smith D.S.
      Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values.
      ,
      • Ellis W.J.
      • Brawer M.K.
      Repeat prostate needle biopsy: who needs it?.
      ].
      Figure thumbnail gr1
      Fig. 1Prostatic biopsy schemes according to different authors.
      Based on the studies of Chen et al., we now know that approximately 70% of prostate cancer arises in the peripheral zone and that most of these cancers are located in the posterolateral peripheral zone (especially in the so called “anterior horn” at the prostatic base) and near the midline at the apex [
      • Chen M.E.
      • Troncoso P.
      • Johnston D.A.
      • Tang K.
      • Babaian R.J.
      Optimization of prostate biopsy strategy using computer based analysis.
      ,
      • Chen M.E.
      • Johnston D.A.
      • Tang K.
      • Babaian R.J.
      • Troncoso P.
      Detailed mapping of prostate carcinoma foci. Biopsy strategy implications.
      ]. The authors had also reported that transition zone cancers, often small in volume (<0.5 cm3), are concentrated in the farthest anterior areas of the prostate near the midline. Thanks to computer modeling, they were also able to demonstrate that traditional mid-lobe parasaggital sextant biopsies routinely fail to sample the anterior transition zone, midline peripheral zone and inferior portion of the anterior horn of the peripheral zone [
      • Chen M.E.
      • Troncoso P.
      • Johnston D.A.
      • Tang K.
      • Babaian R.J.
      Optimization of prostate biopsy strategy using computer based analysis.
      ,
      • Chen M.E.
      • Johnston D.A.
      • Tang K.
      • Babaian R.J.
      • Troncoso P.
      Detailed mapping of prostate carcinoma foci. Biopsy strategy implications.
      ].
      Keetch et al. interestingly reported that a positive biopsy rate following a subsequent second set of sextant biopsies is about 20% in patients with initially negative sextant biopsies [
      • Keetch D.W.
      • Catalona W.J.
      • Smith D.S.
      Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values.
      ]. Other authors have reported that a 20–40% positive rate is commonly found on re-biopsy in patients with elevated PSA levels [
      • Ellis W.J.
      • Brawer M.K.
      Repeat prostate needle biopsy: who needs it?.
      ], demonstrating that standard sextant biopsies provide a limited sampling of the peripheral zone especially in patients with large prostates (>45 cm3) [
      • Djavan B.
      • Zlotta A.R.
      • Ekane S.
      • Remzi M.
      • Kramer G.
      • Roumeguère T.
      • et al.
      Is one set of sextant biopsies enough to rule out prostate cancer? Influence of transition and total prostate volumes on prostate cancer yield.
      ].
      The reliability of systematic biopsy for cancer detection relates to the number of cores as well as to their placement. It is probable that six biopsies may be enough to sample most of the prostate even if the standard sextant biopsy scheme does not appear to be the best method of sampling the peripheral zone of the prostate and does not sample the transitional and anterior zone. By means of the use of computer generated distribution plots, a new six biopsy protocol could be feasible and could be targeted at areas of higher tumor concentration within the prostate (Table 2).
      Table 2Positive predictive value (PPV) of systematic biopsies according to number and position of cores
      AuthorsNo. of patientsNo. of biopsiesTRUSDRE
      DRE: digital rectal examination.
      PSA levels (ng/ml)PPV (%)
      Spencer
      • Spencer J.A.
      • Alexander A.A.
      • Gomella L.
      • Matteucci T.
      • Goldberg B.B.
      Ultrasound-guided four quadrant biopsy of the prostate: efficacy in the diagnosis of isoechoic cancer.
      1774Data not available<1011
      >2032
      Overall18
      Melchior and Brawer
      • Melchior S.W.
      • Brawer M.K.
      Role of transrectal ultrasound and prostate biopsy.
      2231Sextant (6)NegativeNegative<411
      Positive<48
      Negative>423
      Positive>421
      Overall27
      Norberg et al.
      • Norberg M.
      • Egevad L.
      • Holmberg L.
      • Sparén P.
      • Norlén B.J.
      • Busch C.
      The sextant protocol for ultrasound-guided core biopsies of the prostate understimates the presence of cancer.
      5128–10Positive in 23% (117)Data not available>454
      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.
      11913–18 (5 region)Data not availablePositive<429
      Positive<1048
      Positive>1062
      Negative<1028
      Negative>1041
      Nava et al.
      • Nava L.
      • Montorsi F.
      • Consonni P.
      • Scattoni V.
      • Guazzoni G.
      • Rigatti P.
      Results of a prospective randomized study comparing 6, 12, 18 transrectal ultrasound guided sextant biopsies in patients with elevated PSA, normal DRE and normal prostatic ultrasound.
      1206NegativeNegative<1015
      12NegativeNegative<1018
      18NegativeNegative<1032
      Ravery et al.
      • Ravery V.
      • Goldblatt L.
      • Royer B.
      • Blanc E.
      • Toublanc M.
      • Boccon-Gibod L.
      Extensive biopsy protocol improves the detection rate of prostate cancer.
      30310–12Data not availablePositive in 34%<433
      <1029
      >1058
      Babaian et al.
      • Bauer J.J.
      • Zeng J.
      • Weir J.
      • Zhang W.
      • Sesterhenn I.A.
      • Connelly R.R.
      • et al.
      Three-dimensional computer-simulated prostate models: lateral prostate biopsies increase the detection rate of prostate cancer.
      36211Positive in 29%Positive in 18%<417
      <1030
      >1039
      Presti et al.
      • Presti J.C.J.
      • Chang J.J.
      • Bhargava V.
      • Shinohara K.
      The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial.
      48310Data not availablePositive<419
      Negative>434
      Positive>462
      Naughton et al.
      • Naughton C.K.
      • Miller D.C.
      • Mager D.E.
      • Ornstein D.K.
      • Catalona W.J.
      A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection.
      24412Data not availablePositive in 17%<1029
      >1036
      Gore et al.
      • Gore J.L.
      • Shariat S.F.
      • Miles B.J.
      • Kadmon D.
      • Jiang N.
      • Wheeler T.M.
      • et al.
      Optimal combinations of systematic and laterally directed biopsies for the detection of prostate cancer.
      396 (264)10–16Positive in 6% (23)Positive<1035
      Negative>1048
      a DRE: digital rectal examination.

      3.2 Extended multisite directed biopsies

      Over the last few years, there has been an increasing interest in defining a more efficient biopsy scheme for prostate cancer detection. Several schemes have been suggested with the number of systematic biopsies ranging from 6 to 18 [
      • Hodge K.K.
      • McNeal J.E.
      • Terris M.K.
      • Stamey T.A.
      Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate.
      ,
      • Applewhite J.C.
      • Matlaga B.R.
      • McCullough D.L.
      • Hall C.M.
      Transrectal ultrasound and biopsy in the early diagnosis of prostate cancer.
      ,
      • Presti J.C.J.
      • Chang J.J.
      • Bhargava V.
      • Shinohara K.
      The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial.
      ,
      • Reitburgen J.B.W.
      • Kranse R.
      • Kirkels W.J.
      • Hoedemaeker F.
      • Schröder F.H.
      Prostate cancer screening: value of the “seventh” targeted to visible lesions.
      ,
      • Fleshner N.E.
      • O’Sullivan M.
      • Premdass C.
      • Fair W.R.
      Clinical significance of small (less than 0.2 cm3) hypoechoic lesions in men with normal digital rectal examinations and prostate-specific antigen levels of less than 10 ng/ml.
      ,
      • Gore J.L.
      • Shariat S.F.
      • Miles B.J.
      • Kadmon D.
      • Jiang N.
      • Wheeler T.M.
      • et al.
      Optimal combinations of systematic and laterally directed biopsies for the detection of prostate cancer.
      ,
      • Werner-Wasik M.
      • Whittington R.
      • Malkowicz S.B.
      • Corn B.W.
      • Arger P.
      • Reisinger S.
      • et al.
      Prostate imaging may not be necessary in nonpalpable carcinoma of the prostate.
      ,
      • Chen M.E.
      • Johnston D.A.
      • Tang K.
      • Babaian R.J.
      • Troncoso P.
      Detailed mapping of prostate carcinoma foci. Biopsy strategy implications.
      ,
      • Djavan B.
      • Zlotta A.R.
      • Ekane S.
      • Remzi M.
      • Kramer G.
      • Roumeguère T.
      • et al.
      Is one set of sextant biopsies enough to rule out prostate cancer? Influence of transition and total prostate volumes on prostate cancer yield.
      ]. While biopsy of the transitional zone has been reported as adding little to detection [
      • Terris M.K.
      • Pham T.Q.
      • Issa M.M.
      • Kabalin J.N.
      Routine transition zone and seminal vesicle biopsies in all patients undergoing transrectal ultrasound guided prostate biopsies are not indicated.
      ,
      • Fleshner N.E.
      • Fair W.R.
      Indications for transition zone biopsy in the detection of prostatic carcinoma.
      ], it would appear that the addition of far lateral biopsy improves the detection rate of adenocarcinoma [
      • Chang J.J.
      • Shinohara K.
      • Bhargava V.
      • Presti J.C.J.
      Prospective evaluation of lateral biopsies of the peripheral zone for prostate cancer detection.
      ,
      • Terris M.K.
      • Wallen E.M.
      • Stamey T.A.
      Comparison of mid-lobe versus lateral systematic sextant biopsies in the detection of prostate cancer.
      ,
      • Aus G.
      • Bergdahl S.
      • Hugosson J.
      • Lodding P.
      • Pihl C.G.
      • Pileblad E.
      Outcome of the laterally directed sextant biopsies of the prostate in screened males aged 50–66 years.
      ,
      • Bauer J.J.
      • Zeng J.
      • Weir J.
      • Zhang W.
      • Sesterhenn I.A.
      • Connelly R.R.
      • et al.
      Three-dimensional computer-simulated prostate models: lateral prostate biopsies increase the detection rate of prostate cancer.
      ]. Evidently, different schemes have different abilities in terms of prostate cancer detection. Comparing different protocols in different patients in order to discover which is the most accurate is almost impossible since, in order to obtain a precise comparison, these biopsies schemes should be used in the same patients. Moreover, the false negative biopsy rate in each single technique is never known. The increase in cancer detection of a new extended biopsy scheme, generally constituted by the sextant standard protocol and additional biopsies, is conventionally defined as the number of tumors detected only in additional cores.
      Adding more biopsies to prostatic areas not sampled by standard sextant schemes should intuitively increase the detection rate for prostate cancer. However, it is not clear whether the increased detection rate is simply a function of the added biopsies or whether the location from which the cores are taken play an equal or greater role [
      • Babaian R.J.
      • Toi A.
      • Kamoi K.
      • Troncoso P.
      • Sweet J.
      • Evans R.
      • et al.
      A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy.
      ,
      • Babaian R.J.
      Extended field prostate biopsy enhances cancer detection.
      ,
      • Toi A.
      • Chen M.E.
      • Kamoi K.
      • Troncoso P.T.
      • Babaian J.
      New biopsy strategy detects prostate cancers missed by conventional sextant biopsies.
      ].
      A few years ago, during a prospective randomized study on 120 patients with elevated PSA levels but normal DRE and TRUS, we demonstrated that the prostate cancer detection rate increases when more biopsies are used and more prostate areas sampled [
      • Nava L.
      • Montorsi F.
      • Consonni P.
      • Scattoni V.
      • Guazzoni G.
      • Rigatti P.
      Results of a prospective randomized study comparing 6, 12, 18 transrectal ultrasound guided sextant biopsies in patients with elevated PSA, normal DRE and normal prostatic ultrasound.
      ]. We demonstrated that following the use of 6 and 12 biopsies, 16 and 17% of the carcinomas were found, respectively; however, with 18 biopsies performed on an outpatient basis without sedation nor anesthesia 32% of prostate cancers were detected. Complications rate was not significant different among the three groups of patients. We recommended performing 12 biopsies in smaller prostates (<50 g) and 18 biopsies in larger prostates (>50 g) since cancer detection was significantly associated with prostate weight (Table 2).
      Similarly Eskew et al. have demonstrated that a systematic 5 region biopsy protocol with 13–18 biopsies is capable of detecting cancer in 40% of patients and that 35% of cancers detected would have been missed through use of standard sextant biopsy alone [
      • 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.
      ]. The additional biopsy cores were most beneficial among patients with PSA levels of less than 10 ng/ml since those with increased PSA levels were more likely to be cancer positive and diagnosed by standard protocol. However, the major disadvantage of this procedure was the necessity of intravenous sedation and the impossibility of performing the biopsy on an outpatient basis. Since only few cancers were detected with midline biopsies and, owing to an increased risk of bleeding and pain, the authors suggested eliminating this region from routine biopsy.
      In a recent prospective study on 483 consecutive patients, Presti et al. reported an overall detection rate of 42% following the adoption of a 10 systematic biopsy scheme involving four lateral biopsies of the peripheral zone at the base and mid gland in addition to the routine sextant biopsy regimen plus additional transition zone biopsies in cases of prostate with a volume of more than 50 g [
      • Presti J.C.J.
      • Chang J.J.
      • Bhargava V.
      • Shinohara K.
      The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial.
      ]. This scheme is similar to the one proposed by Eskew et al. without adopting midline region biopsies. In conclusion, Presti et al. recommended an eight-core biopsy scheme owing to the fact that they were able to demonstrate that a minimal reduction in the cancer detection rate was obtained by eliminating the mid lobar base biopsies.
      Many authors have reported that merely increasing the number of cores sampled does not have any marked effect on the cancer detection rate. In a prospective randomized study on 244 patients subjected to 6 or 12 peripheral zone biopsies, i.e. double that of the sextant biopsy scheme (adding a more laterally parasaggital placed sextant set), Naughton et al. showed that this does not materially improve the overall cancer detection rate [
      • Naughton C.K.
      • Miller D.C.
      • Mager D.E.
      • Ornstein D.K.
      • Catalona W.J.
      A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection.
      ]. Levine et al. have shown that an immediate repeat set of sextant biopsies performed in a single office visit increased cancer detection by 30% and was most apparent in men with a non-palpable disease [
      • Levine M.A.
      • Ittman M.
      • Melamed J.
      • Lepor H.
      Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer.
      ]. Despite the increased detection rate of this approach, merely doubling the number of similarly directed biopsies in the standard mid parasagittal plane seems not to be the best strategy. In fact, Ravery et al. have shown that an extensive biopsy protocol with 10 biopsies in 303 patients is able to increase the detection rate by about 7% being more efficient in patients with a PSA level of lower than 10 ng/ml, a negative DRE and prostate with a volume of more than 50 cc [
      • Ravery V.
      • Goldblatt L.
      • Royer B.
      • Blanc E.
      • Toublanc M.
      • Boccon-Gibod L.
      Extensive biopsy protocol improves the detection rate of prostate cancer.
      ]. They believe that the most crucial factor vis-a-vis enhancement of the cancer detection rate is not increasing the number of cores but rather changing the zone sampled or changing the angle of the biopsy.
      Recently Gore et al. have reported that a 10 core protocol that includes laterally directed biopsies obtained from the base, mid gland and apex of the prostate with cores obtained from the mid lobar base and apex achieved an optimal detection rate in all patient subgroups regardless of prostate volume or PSA levels [
      • Gore J.L.
      • Shariat S.F.
      • Miles B.J.
      • Kadmon D.
      • Jiang N.
      • Wheeler T.M.
      • et al.
      Optimal combinations of systematic and laterally directed biopsies for the detection of prostate cancer.
      ]. In patients with a smaller prostate, an eight core regimen including two biopsies from the base and apex (sextant and lateral) for each lobe, was considered adequate. Again the apex and the base of the peripheral gland (including the anterior horn) are the sites at which prostate cancer is most likely to be located and at which the biopsies should be directed.
      All data presented demonstrates that the direction and number of biopsies performed determines procedure sensitivity; furthermore, the above also demonstrated that prostate sampling gives the best results in the diagnosis of prostate cancer using a 10 or 12 biopsy scheme. Nowadays, the optimal protocol should include six standard sextant biopsies with additional biopsies weighted more laterally at the base (anterior horn) and medially to the apex (possibly more distal to the anterior part of the transitional zone where transition zone cancers are more likely to be located). In the future, biopsy technique will most likely be individualized for each patient according to TRUS findings, prostatic volume and PSA levels.

      4. Conclusions

      This review provides some rational arguments for the decision of an optimal prostatic scheme. Nowadays, in prostates with visible lesions, lesion-guided biopsies only play a role in combination with systematic biopsies. TRUS lesion-guided prostatic biopsies are recommended owing to the fact that a hypoechoic lesion is the prostatic area where prostatic cancer is most likely to be located even though the PPV of a hypoechoic area may be less than 35% [
      • Stamey T.A.
      Making the most out of six systematic sextant biopsies.
      ]. Indeed, the combination of sextant and lesion-directed biopsies maximizes the detection rate using the lowest possible number of biopsy cores. In the case of a TRUS visible lesion, the optimal number and placement of added systematic biopsies is yet to be defined. Due to the multifocality of prostate cancer, in the future it is probable that, by adding more biopsies to the sextant standard scheme, the necessity of biopsying single small hypoechoic lesions will no longer be necessary. This topic will remain a subject for discussion in forthcoming papers on TRUS prostatic biopsies.
      The systematic prostatic scheme (currently tending to be the method most frequently adopted) should include 10 or 12 cores according to prostatic weight. In fact, in order to reduce patient discomfort, it is advisable to reduce the number of systematic biopsies to a minimum. Most protocols presented in this review and including 10–12 biopsies appear to be safe and well tolerated with an acceptable discomfort rate which can be further improved through use of local anesthesia. While midline biopsy cores have been shown to be the least frequently affected by prostate tumor, lateral biopsies, directed towards the apex and base (anterior horn) combined with standard sextant biopsies, are increasingly performed by numerous centers.

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