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How and When to Take Prostate Biopsies

      Abstract

      Objectives: To investigate whether current literature gives the answer to the questions how biopsies of the prostate should be taken and when they should be taken in order to diagnose prostate cancer.
      Methods: Using Medline we searched for the latest articles using keywords like: prostate, cancer, PSA, DRE, ultrasound, biopsy, imaging, prophylaxis, PIN, repeat biopsy and number of biopsies.
      Results: In today’s urological practice the questions when and how to take prostate biopsies are serious concerns. This is reflected in the large amount of literature that is available. We selected from the latest 500 abstracts the most appealing articles and summarized the current opinion in this review article.
      Conclusions: Taking prostate biopsies has become a well-known and well-tolerated urological technique. The answer to the question how to take biopsies is answered satisfactorily, which does not exclude future improvements. The answer to the question when to take biopsies is not fully answered yet which results in a lot of negative biopsies. In the future a more predictive test for prostate cancer will ameliorate the answer to the question when it is needed to take biopsies. Hopefully the currently available large number of indicators will be replaced in the future by one very good predictive test in order to decrease the numbers of true negative biopsies.

      Keywords

      1. Introduction

      Since 1984, prostate specific antigen (PSA) is in use not only for follow-up of prostate cancer but also to detect early, and potentially curable, prostate cancers. If the PSA-level is elevated a biopsy of the prostate should give confirmation on the presence of cancer before further investigations are planned and a possible treatment plan is set up. But PSA may also rise in benign hyperplasia (BPH) and in prostatitis and this explains why many patients undergo unnecessary biopsies. This implies not only costs, and takes some time; it also causes in a significant number of cases morbidity and even mortality. Therefore, it is necessary to avoid taking biopsies in cases where another factor causes this elevation. Unfortunately until today there is no other means to diagnose, or to exclude, cancer but by biopsies. The criteria when to take biopsies are at his moment not completely defined yet.
      Then there is also the issue of the size-insignificant prostate tumor that can be detected on biopsies. The tumor can be very small. Finding a cancer will mostly induce further evaluation and treatment. The problem is that this tumor might be a latent and/or a very small tumor and would never cause problems of any kind. Until today there is no proper way to differentiate between a size-insignificant tumor and a size-significant one. In the extreme case no residual tumor can be found after a radical prostatectomy.
      When biopsies are taken a great effort should be undertaken to do it in optimal conditions to avoid morbidity and to provide good and representative biopsies to the pathologist.
      The purpose of this article is to give an overview on the current opinions on how to take biopsies and when to take them. The decision to take biopsies is often easy. The challenge, however, is to decide when NOT to take biopsies.

      2. Preparation

      The patient should first of all be informed on the fact that the reason for taking biopsies is to investigate the possibility of the presence of prostate cancer. To avoid infectious problems at least one dose of quinolones should be administered 1 h prior to the procedure to avoid urosepsis [
      • Isen K.
      • Kupeli B.
      • Sinik Z.
      • Sozen S.
      • Bozkirli I.
      Antibiotic prophylaxis for transrectal biopsy of the prostate: a prospective randomized study of the prophylactic use of single dose oral fluoroquinolone versus trimethoprim-sulfamethoxazole.
      ]. In case of allergy for quinolones prescription of trimethoprim-sulfamethoxazole is advised. Bowel preparation using an enema does not lower the rate of infectious complications [
      • Lindert K.A.
      • Kabalin J.N.
      • Terris M.K.
      Bacteremia and bacteriuria after transrectal ultrasound guided prostate biopsy.
      ,
      • Carey J.M.
      • Korman H.J.
      Transrectal ultrasound guided biopsy of the prostate. Do enemas decrease clinically significant complications?.
      ]. Oral anticoagulation therapy should be stopped. Patients should know it is normal to have a little haematuria, blood on the stool and that haematospermia may occur.
      In some centers injection of 1% lidocaine periprostatically has been introduced on a routine basis to lower the pain caused by the multiple stings. Vaidya describes good results with adequate pain relief with this method [
      • Vaidya A.
      • Soloway M.S.
      Periprostatic local anesthesia before ultrasound-guided prostate biopsy: an update of the Miami experience.
      ]. On the other side, Wu and Carter described that using lidocaine does diminish the pain associated with tissue sampling of the prostate [
      • Wu C.L.
      • Carter H.B.
      • Naqibuddin M.
      • Fleisher L.A.
      Effect of local anesthetics on patient recovery after transrectal biopsy.
      ]. As pain is a very subjective matter the need for analgesia will remain a point of controversy. Patients who indicate they have a low pain threshold or have had a painful experience in the past might benefit from local anesthesia.
      In some centers, general anesthesia is used routinely to perform biopsies transrectally; general anesthesia should, however, be reserved for very few selected cases.

      3. How to take biopsies

      3.1 Transrectally or transperineally?

      Before the era of ultrasound the transperineal way of taking a biopsy was performed routinely. Since ultrasound has made it possible to visualize the prostate while sampling the prostate, the transperineal method lost its popularity tremendously. Imaging the prostate while sampling seemed such a benefit that a possible minor increase in the adverse effects, compared to the transperineal method, did not jeopardize the growing popularity of taking ultrasound-guided biopsies of the prostate [
      • Chiari R.
      • Harzmann R.
      Perineal and transrectal needle biopsy of the prostate (author’s translation).
      ]. Today the new generation of urologists is trained to take biopsies transrectally using ultrasonography and it has become by now the standard procedure for sampling the prostate in most centers.
      It is recommended to look at the prostate after taking biopsies transrectally in order to trace an induced haematoma; upon visualization of a haematoma one can compress the site of bleeding with the ultrasound-transducer. To avoid serious bleedings from large hemorrhoids one should consider performing the biopsy transperineally, as the chance of perforating a large vein is smaller in this way [
      • Chiari R.
      • Harzmann R.
      Perineal and transrectal needle biopsy of the prostate (author’s translation).
      ].
      In some countries, however, ultrasound is not so widespread in use as in most western countries. And in some countries were ultrasonography is widely spread this examination is not always performed by the urologist. This means that not every urologist is able to perform on a routine basis ultrasound-guided prostate biopsy.
      In case there is no ultrasound available transperineal biopsies are still a good alternative. But if there is an ultrasound device available the urologist should establish either a good working relation with the radiologist or get acquainted with ultrasonography and perform biopsies himself.

      3.2 Imaging

      3.2.1 Ultrasound (US)

      Ultrasonography is very suitable for imaging of the prostate. Mc Neal described three regions of the prostate: the central zone, the transition zone and the peripheral zone (see Fig. 1). Tumors of the prostate arise mostly in the peripheral zone of the prostate; therefore, biopsies should be taken from that region within the prostate. Adenocarcinoma’s can sometimes be recognized as hypo-echogenic lesions. Upon detection of such a zone an additional guided biopsy should be done. But some tumors can be hyperechogenic or iso-echogenic (up to 50%), which implies that US is not suited for accurate detection of prostate cancer zones [
      • Kuligowska E.
      • Barish M.A.
      • Fenlon H.M.
      • Blake M.
      Predictors of prostate carcinoma: accuracy of gray-scale and color Doppler US and serum markers.
      ].
      Figure thumbnail gr1
      Fig. 1Difference between echogenicity of the peripheral zone and the transition zone.
      For performing biopsies ultrasound is the ideal companion. The needle holder mounted on the ultrasound transducer targets, in combination with the guiding-line on the screen, the biopsy-needle right where it is wanted by the investigator. It is obvious that in this way one can sample tissue in any specific region of the prostate more accurate compared to finger-guided sampling. To measure the volume of the prostate the gray-scale US is a very useful, reliable and relatively cheap tool too.
      In this way grayscale ultrasound has been established as the first choice imaging technique that allows taking biopsies, to measure the volume and to have a general overview on the prostate.
      To improve, however, the detection rate of ultrasonography for prostate cancer improvements are introduced and continuously evaluated.
      One of the most interesting developments in ultrasonography has been the analysis of Doppler ultrasound signals. With this technique it is possible to visualize real time flow in the vessels within the prostate. Based on the fact that prostate cancer can induce an increase of blood vessels (bringing in nutrients and removing waste) one could try to differentiate between benign regions and suspect lesions (having a higher micro-vessel density) within the prostate [
      • Sedelaar J.P.
      • van Leenders G.J.
      • Hulsbergen-van de Kaa C.A.
      • van der Poel H.G.
      • van der Laak J.A.
      • Debruyne F.M.
      • et al.
      Microvessel density: correlation between contrast ultrasonography and histology of prostate cancer.
      ]. As these suspect lesions can be localized it is easy to guide the needle of the biopsy gun into this region. Until today a higher detection rate of prostate cancer, based on Doppler-ultrasound alone, has not been demonstrated yet [
      • Kuligowska E.
      • Barish M.A.
      • Fenlon H.M.
      • Blake M.
      Predictors of prostate carcinoma: accuracy of gray-scale and color Doppler US and serum markers.
      ].
      An evolution that rejuvenated interest in Doppler ultrasonography is the introduction of contrast enhancing products. These agents consist of small capsules filled with little air-bubbles; they disintegrate quite rapidly upon injection in the bloodstream but they are stable enough to enlighten the vessels during the first passage in the end organ. The small air-containing bubbles cause hyperechogenicity of the blood vessels. The micro-vessel density can be measured more accurate using this technique. One can also reconstruct a 3D-image of the prostate and localize zones of higher MVD within the prostate. Biopsies taken from these zones have a higher chance of containing malignant tissue [
      • Frauscher F.
      • Klauser A.
      • Halpern E.J.
      • Horninger W.
      • Bartsch G.
      Detection of prostate cancer with a microbubble ultrasound contrast agent.
      ,
      • Bogers H.A.
      • Sedelaar J.P.
      • Beerlage H.P.
      • de la Rosette J.J.
      • Debruyne F.M.
      • Wijkstra H.
      • et al.
      Contrast-enhanced three-dimensional power Doppler angiography of the human prostate: correlation with biopsy outcome.
      ]. This reconstruction is done with the help of a computer.
      This is another way of improving imaging of the internal structure of the prostate. Some might think that these improved ultrasound data are almost diagnostic. Sedelaar et al. demonstrated that for differentiation between cancer and BPH the contrast enhanced US is not appropriate, so biopsies are still needed to confirm the suspicion of cancer [
      • Sedelaar J.P.
      • van Roermund J.G.
      • van Leenders G.L.
      • Hulsbergen-van de Kaa C.A.
      • Wijkstra H.
      • de la Rosette J.J.
      Three-dimensional grayscale ultrasound: evaluation of prostate cancer compared with benign prostatic hyperplasia.
      ]. Sedelaar et al. also demonstrated that 3D-contrast-enhanced-ultrasonography is highly reproducible and not investigator-dependent [
      • Sedelaar J.P.
      • Goossen T.E.
      • Wijkstra H.
      • de la Rosette J.J.
      Reproducibility of contrast-enhanced transrectal ultrasound of the prostate.
      ]. This renders 3D-contrast enhanced prostate ultrasound very promising. On the other hand, the use of contrast enhancement is limited because specialized skills and equipment is needed.

      3.2.2 Computer aided tomography (CT) and magnetic resonance imaging (MRI)

      CT is not used to detect prostate cancer. It is used for screening regional lymph nodes once adenocarcinoma of the prostate has been demonstrated on biopsy. The purpose of performing a CT of the pelvis is to investigate whether the cancer is localized or already metastasized towards the lymph nodes in the fossa obturatorius.
      Whether or not MRI is useful in the management of prostate cancer is heavily debated. Whether there are benefits, compared to US, in guidance while taking biopsies of the prostate is not clear yet. MRI is more time-consuming and the need for navigation software to direct the needle limits its use in daily practice. MRI is not available in every hospital nowadays. But staging lymph nodes of a proven malignant prostate seems accurate using MRI [
      • Kuhn M.
      • Huttmann P.
      • Spielhaupter E.
      • Gross-Fengels W.
      • Schreiter F.
      Clinical value of native and contrast enhanced MRI in staging prostatic carcinoma before planned radical prostatectomy.
      ].

      3.3 Number of biopsies

      In most centers sextant biopsies are performed as Hodge et al. described this procedure. One should take biopsies at the apex, the middle and near the base of the prostate on the left and right side and perform additional biopsies of hypo-echogenic areas or palpable lesions not visible on ultrasound [
      • Hodge K.K.
      • McNeal J.E.
      • Terris M.K.
      • Stamey T.A.
      Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate.
      ]. The detection rate of sextant biopsies alone is 23% [
      • Aus G.
      • Bergdahl S.
      • Hugosson J.
      • Lodding P.
      • Pihl C.G.
      • Pileblad E.
      Outcome of laterally directed sextant biopsies of the prostate in screened males aged 50–66 years. Implications for sampling order.
      ]. These random biopsies will remain necessary until accurate imaging of suspect lesions will be possible. When using the sextant pattern a few considerations have to be made for optimal results.
      First of all it is necessary to direct the needle as lateral into the peripheral zone to sample in every biopsy the capsule of the prostate; since most prostate tumors are located right there see Fig. 2 [
      • Stamey T.A.
      Making the most out of six systematic sextant biopsies.
      ].
      Figure thumbnail gr2
      Fig. 2A large tumor can be missed if the biopsy-needle is not directed into the peripheral zone.
      Secondly, additional biopsies have to be taken from suspect lesions. This suspicion originates from DRE, hypo-echogenicity or high vessel density.
      Some urologists take only four biopsies in order to decrease the morbidity of the punctures. But an increasing number of urologists prefer taking more than six biopsies. Taking 10 instead of 6 biopsies did not affect complication rates in a recent study [
      • Manseck A.
      • Guhr K.
      • Froehner M.
      • Hakenberg O.W.
      • Wirth M.P.
      Morbidity and discomfort of ten-core biopsy of the prostate evaluated by questionnaire.
      ].
      Emiliozzi says that taking 12 biopsies, transperineally, results in a detection rate of cancer of up to 51% [
      • Emiliozzi P.
      • Longhi S.
      • Scarpone P.
      • Pansadoro A.
      • DePaula F.
      • Pansadoro V.
      The value of a single biopsy with 12 transperineal cores for detecting prostate cancer in patients with elevated prostate specific antigen.
      ].
      But it is not only the number of biopsies that matters in getting a higher detection rate; it is also the location of the puncture that matters. First of all Stamey states that biopsies should be taken as lateral as possible within the prostate (see Fig. 2) [
      • Stamey T.A.
      Making the most out of six systematic sextant biopsies.
      ]. As quite a lot tumors are located near the apex of the prostate one should, on repeat biopsy, also take this knowledge in account. A recent study of Mazal et al. showed that most tumors, missed on initial biopsy, are indeed located near the apex [
      • Mazal P.R.
      • Haitel A.
      • Windischberger C.
      • Djavan B.
      • Sedivy R.
      • Moser E.
      Spatial distribution of prostate cancers undetected on initial needle biopsies.
      ].
      Whether during the first occasion additional biopsies at the apex and the postero-basal region need to be taken is still under debate since it increases a lot the number of biopsies, which might increase discomfort for the patient. Manseck et al. indicated that increasing the amount of biopsies does not increase the problems. These findings will upon confirmation definitely lead to increasing numbers of biopsies per session in the future [
      • Manseck A.
      • Guhr K.
      • Froehner M.
      • Hakenberg O.W.
      • Wirth M.P.
      Morbidity and discomfort of ten-core biopsy of the prostate evaluated by questionnaire.
      ].
      Today, however, the sextant biopsy is still the method used in most clinics. But there is no objection to take more biopsies in one session except the patient’s who might consider it more uncomfortable.
      In patients with a very high level of PSA and suspicion of metastases it is not necessary to perform more than six biopsies since the exact localization is of minor importance when there is systemic disease. One could even take less biopsies.

      4. When to take biopsies

      Biopsies should only be taken when a strong suspicion of prostate cancer exists AND treatment is wishful. This means that biopsies should definitely not be taken in patients with low life expectancy due to other pathology than a possible prostate cancer. In fact it is debatable whether a PSA level should be measured in patients with low life expectancy.

      4.1 PSA-ratio PSA/fPSA?

      The main reason that raises suspicion of PCA is elevation of PSA >4 ng/ml. But as prostatitis and benign hyperplasia also causes PSA-elevation a lot of negative biopsies are taken based on this simple principle. Therefore, a lot of additional criteria were evaluated in an effort to increase specificity. Especially to cover the gray zone when PSA is between 4 and 10 ng/ml.
      Today the preferred additional test is the calculation of the ratio free PSA over total PSA when total PSA is between 4 and 10 ng/ml. In benign prostates, the ratio is >20% [
      • Djavan B.
      • Zlotta A.
      • Remzi M.
      • Ghawidel K.
      • Basharkhah A.
      • Schulman C.C.
      • et al.
      Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1051 men.
      ]. The difficulty with this criterion is to define the cut-off value. The consensus is to use 20% as cut-off value for patients younger than 70 years when PSA is between 4 and 10 [
      • Luboldt H.J.
      • Swoboda A.
      • Borgermann C.
      • Fornara P.
      • Rubben H.
      Clinical usefulness of free PSA in early detection of prostate cancer.
      ]. Applying strictly these criteria is not always rational. A person with a PSA of 3.9 and a ratio of 3% will probably have a higher risk than a patient with PSA 4.1 and a ratio of 19%, … or not? The only way to find out is to perform a biopsy. A person with a prostate of 100 g, a PSA of 8 and a ratio of 30% also has but a small chance, to have a tumor. But if he has a tumor it probably will be a curable one so it is pleasant to find it in an early stage.
      That these criteria are only indicators is shown clearly in recent study where it was demonstrated that even patients with a PSA between 3 and 4 had prostate cancer in 21.5% upon biopsy, and in 14% when PSA is between 2 and 3 [
      • Schroder F.H.
      Diagnosis, characterization and potential clinical relevance of prostate cancer detected at low PSA ranges.
      ]

      4.2 Abnormal DRE

      Excluding the possibility of prostate cancer using only DRE is not correct. PSA is much more sensitive. Some authors conclude to abandon DRE when examining the patient on prostate cancer and propose to perform only PSA. If one encounters a patient with a small prostate of about 20 g, a PSA of 3.5 but with a firm and, therefore, suspect node a biopsy is indicated. Although when combined with a PSA-ratio of 30% one could argue it is not needed.
      Another useful possibility with DRE is the possibility to measure more or less the weight of the prostate. A patient with a prostate weighing >50 g and a PSA of 5.5 could be interpreted as normal. But when encountered with a ratio <20% it is again suspect.
      Therefore, performing DRE and determining PSA in patients at risk for prostate cancer is very useful [
      • Potter S.R.
      • Horniger W.
      • Tinzl M.
      • Bartsch G.
      • Partin A.W.
      Age, prostate-specific antigen, and digital rectal examination as determinants of the probability of having prostate cancer.
      ].

      4.3 Abnormal ultrasound

      PSA and DRE should give the indication for sampling the prostate. If these two parameters are normal an ultrasound of the prostate is indicated only to measure the weight of the prostate when in doubt about how to operate on a patient with LUTS and BPH since TURP cannot safely be done with high prostate volumes.

      4.4 PIN lesions

      If a high-grade prostatic intraepithelial neoplasia (PIN) lesion has been detected on biopsies a new series of biopsies is indicated. This is because upon presence of a PIN-lesion in the biopsy there is a high chance the prostate harbors an adenocarcinoma as well [
      • Boccon-Gibod L.
      Rising PSA with a negative biopsy.
      ].

      4.5 When to repeat biopsies after a first negative result?

      Every urologist is confronted with patients he is sure about that they have prostate cancer although the biopsies were negative. This feeling being confronted with a suspect false negative result is very uncomfortable for the doctor as for the patient. Around 10% of the patients who have a first negative result do have a cancer on the second series of biopsies [
      • Djavan B.
      • Zlotta A.R.
      • Ekane S.
      • Remzi M.
      • Kramer G.
      • Roumeguere 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.
      ]. A first reason why a first set of biopsies has a serious chance being false negative is that the volume of the biopsies is very small compared to the volume of the prostate. The question is whether it is necessary to re-perform biopsies or to wait and follow the evolution of the PSA. Taking a second set of biopsies after a first negative result can safely be done after 6 weeks [
      • Djavan B.
      • Waldert M.
      • Zlotta A.
      • Dobronski P.
      • Seitz C.
      • Remzi M.
      • et al.
      Safety and morbidity of first and repeat transrectal ultrasound guided prostate needle biopsies: results of a prospective European prostate cancer detection study.
      ].
      As a first series of biopsies are performed on suspicion of cancer, and knowing there is an important chance the tumor might have been missed by the needle, there is no reason to delay a new series of biopsies.
      When repeating biopsies it is recommended to sample the apex and the apico-dorsal region zone as well as these zones often harbor tumors [
      • Mazal P.R.
      • Haitel A.
      • Windischberger C.
      • Djavan B.
      • Sedivy R.
      • Moser E.
      Spatial distribution of prostate cancers undetected on initial needle biopsies.
      ]. This is a second important reason to repeat biopsies after a first negative result.
      Some urologist are reluctant to perform a second series of biopsies; actually there is no objective reason to postpone a second set of biopsies.
      If a prostate is very suspect to harbor a tumor it is even recommended to perform up to three sets of sextant biopsies. Circumstances like a positive family history or a very low PSA-ratio do justify a third set. A fourth set is not recommended, however. The incidence of complications does rise in patients undergoing three of four series of biopsies. A tumor found on the fourth series could be a size-insignificant tumor [
      • Djavan B.
      • Ravery V.
      • Zlotta A.
      • Dobronski P.
      • Dobrovits M.
      • Fakhari M.
      • et al.
      Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop?.
      ].
      Increasing the number of biopsies will increase the risk of risk finding a size-insignificant tumor. Unfortunately there is no means to visualize the tumor appropriately on beforehand so there is no means of excluding this sub-group of patient today.
      When to re-perform PSA after a first series of negative biopsies is another question. Traditionally the interval for re-testing PSA is set at one year. If it rises significantly one has to repeat biopsies, if it has not risen significantly it is not considered a necessity to re-perform biopsies; but if another parameter (DRE, TRUS, free PSA) changes for the worse it is recommended to repeat biopsies.

      5. Conclusion

      The question how to take prostate biopsies is not so difficult to answer. Transrectal ultrasound guidance enables excellent visualization of the prostate. Sometimes a suspect lesion can be seen. This visualization enables the urologist to perform nice at random biopsies as directed ones. As sextant biopsies near the capsule of the prostate might miss tumors near the apex and those located postero-basal it is recommended to take biopsies of these regions on repeated sessions as well. Hypo-echogenic or hypervascular zones seen on ultrasound should always be sampled separately.
      In what region of the prostate the biopsy should be taken is a question not fully answered yet. It would be nice if we could see the tumor in the future before sampling. This would reduce the amount of biopsies substantially and would avoid repeat sessions.
      Antibiotic prophylaxis with quinolones is necessary as well as stopping anticoagulation therapy. Informing patients on the procedure, why it is done as the eventual consequences is also a necessity.
      The question when to take biopsies is not fully answered yet today. Therefore, another predictive test is needed that has a higher predictive value than PSA, DRE or ultrasound. The ideal predictive test will tell whether the prostate harbors a tumor or not and, therefore, would almost be diagnostic. Today we do not have such a test and only by further research the dilemma to take or not to take biopsies of the prostate will be solved. In Table 1, today’s decisive factors are set out.
      Table 1Decisive factors in taking prostate biopsies
      Strong suspicionFactors lowering suspicionDo not take biopsies
      PSA elevated related to agePSA elevated not related to ageIn the absence of clinical implications
      Ratio <20% and PSA 3–10PSA does not increase in timeAfter three negative series of biopsies based upon the same reasons
      Abnormal DREHistory of prostatitis
      Hypo-echogenic lesion on TRUSPSA 4–10 and a high prostatic volume
      High micro-vessel density on Doppler or contrast-enhanced DopplerNormal DRE
      Positive family historyNormal TRUS
      PIN lesionSecond negative series of prostate biopsies including apex and apico-dorsal region
      First negative series of prostate biopsiesEventual negative third series of prostate biopsies

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