Ultrasonographically Guided Biopsy of the Prostate Gland

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1 Review Article Ultrasonographically Guided Biopsy of the Prostate Gland Andrew L. Altman, MD, Martin I. Resnick, MD Abbreviations BPH, benign prostatic hyperplasia; PIN, prostatic intraepithelial neoplasia; PSA, prostate-specific antigen; TRUS, transrectal ultrasonography Received October 30, 2000, from the Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Revised manuscript accepted for publication November 27, We acknowledge Lippincott Williams & Wilkins for permitting us to reprint Dr. J. E. McNeal s original figure depicting the concept of prostate zonal anatomy. We also acknowledge Rhonda Knighton (Siemens Medical Systems, Issaquah, WA) and Carol Benson (Brigham and Women s Hospital, Boston, MA) for providing our prostate sonogram figures. Address correspondence and reprint requests to Martin I. Resnick, MD, Department of Urology, University Hospitals of Cleveland, Euclid Ave, Cleveland, OH Anatomy and Histopathology An understanding of the normal structure of the prostate gland is crucial as one approaches its sonographic evaluation. Historically, Lowsley described the lobar structure of the prostate in 1912, and he suggested that the gland was composed of 5 lobes: anterior, posterior, middle, and 2 lateral. In 1968 McNeal described the zonal anatomy of the prostate, which is used today in clinical practice. 1 He suggested that the prostate was composed of 4 zones: transition, central, peripheral, and anterior fibromuscular (Fig. 1). The transition zone constitutes 5% to 10% of the volume of the normal prostate. A discrete fibromuscular band of tissue separates the transition zone from the remaining glandular tissue of the prostate and can occasionally be visualized on transrectal ultrasonography (TRUS). 2 The transition zone is the site of development of benign prostatic hyperplasia (BPH) and as such can grow to represent up to 90% of organ volume. The growth of the transition zone in BPH displaces the anterior fibromuscular and peripheral zones radially and creates the surgical capsule encountered at enucleation during open simple prostatectomy. Finally, adenocarcinoma can originate in this zone approximately 20% of the time. The central zone represents 15% to 20% of the volume of the normal prostate. This zone is characterized by glandular tissue, whose ducts open circumferentially around the ejaculatory ducts as they exit at the verumontanum. These acinar units are structurally separate from those constituting the remainder of the prostate and give rise to only 1% to 5% of adenocarcinomas. The peripheral zone represents 70% to 75% of the volume of the normal prostate and wraps the organ posterolaterally to the apex. Its glands give rise to 70% of prostate adenocarcinomas and are not subject to the changes of BPH by the American Institute of Ultrasound in Medicine J Ultrasound Med 20: , /01/$3.50

2 Ultrasonographically Guided Biopsy of the Prostate Figure 1. Zonal anatomy of the prostate as described by J. E. McNeal. Reprinted from Am J Surg Pathol 1988; 12: , by permission from Lippincott Williams & Wilkins. Indications Ultrasonography of the prostate has revolutionized the diagnostic approach to the evaluation of this gland. One might consider it an extension of the physical examination, because it can be done in real time during an office visit. The most common indication for prostate ultrasonography is for the targeting of needle biopsy performed for either an elevated prostate-specific antigen (PSA) level or abnormal digital rectal examination findings, or both. Furthermore, ultrasonography of the prostate is used in pretreatment planning for brachytherapy as well as during actual radioactive seed implantation. Additionally, prostate volume derived from sonography is useful in calculating PSA density and in following prostate size in patients undergoing hormone therapy for the treatment of BPH. Finally, it is also used in the evaluation of infertile patients secondary to suspected ejaculatory duct obstruction and in cases of unusual lower urinary tract symptoms. The primary focus of this review will be on the utility of TRUS in the evaluation of the patient with a suspected prostate malignancy. TRUS provides excellent visualization of the prostate in step sections in both the transverse and sagittal planes. Because of these orientations, spatially directed biopsies can be obtained systematically throughout the gland. Furthermore, any questionable finding in either contour or echotexture can be sampled (see Sonographic Findings). The data comparing digitally versus ultrasonographically directed biopsies are few. In 1 early study, Resnick 4 looked at 45 patients with palpable prostate nodules and evaluated them with both digitally and ultrasonographically guided perineal approaches. Of 14 patients with adenocarcinoma, tumors were found by both methods in 11. Of the 3 remaining patients, 2 had disease identified by the digital technique, and 1 had disease identified by the sonographic technique. He concluded that ultrasonographically guided biopsy is not necessary in the patient with palpable disease. In contrast, Rifkin et al 5 looked at 112 patients with palpable disease and previously negative digitally directed biopsy results and then proceeded with ultrasonographically directed biopsy using either the transperineal approach (n = 51) or the transrectal approach (n = 61). They detected adenocarcinoma in 39.3% of these men and concluded that ultrasonographically guided biopsy is in fact a useful adjunct that should be a part of the biopsy procedure. There was no difference in accuracy between the transperineal and transrectal approaches. Finally, Renfer et al 6 assessed 200 consecutive transrectal prostate biopsies done with both the digitally and sonographically directed techniques. They found that biopsy sensitivity was superior for ultrasonographic guidance in all categories of tumors studied, with an overall sensitivity of 88% compared with 74% for digital guidance. They also noted that only 12% of the cancers were found by the use of digital guidance alone. They concluded that ultrasonographic guidance is necessary for optimal cancer detection. We now think that ultrasonographic guidance is an important adjunct to the biopsy procedure, even in the presence of palpable disease, because it facilitates spatially symmetric tissue sampling in addition to identifying questionable areas that may not be evident on the digital examination. Patient Preparation and Instrumentation Preparation Prophylactic antibiotics are essential and usually consist of an oral fluoroquinolone administered 2 hours before the procedure and continued for 24 to 48 hours after the procedure. Lindert et al 7 found that of 50 consecutive patients undergoing TRUS-guided biopsy, 44% had bacteriuria and 16% had bacteremia documented on postprocedure culture. Sieber et al 8 reviewed 4439 patients 160 J Ultrasound Med 20: , 2001

3 Altman and Resnick pretreated with ciprofloxacin, 500 mg twice a day starting on the day before the procedure and continuing for 48 hours after the procedure, and found only 5 urinary tract infections, of which only 2 were febrile. Additionally, a cleansing enema is often administered on the morning of the procedure to evacuate gas and feces, which might impair visibility. The ability of an enema to reduce the risk of bacteremia is unclear; however, Lindert et al 7 did show that of their patients who had postbiopsy bacteremia (16% of the total group), 87% had not had an enema. Patient positioning is a matter of surgeon preference, because all positions are equally efficacious. We favor the lateral decubitus position, because it does not require stirrups, allows the patient to facilitate visibility of the gland by drawing his knees to his chest, and is generally well tolerated. Although an anesthetic is not required, some patients may request that certain comfort measures be provided. Soloway and Obek 9 looked at 50 consecutive patients who underwent prebiopsy ultrasonographically directed anesthetic infiltration of the periprostatic neurovascular plexus. They encountered no morbidity, and only 1 patient had discomfort during biopsy. Furthermore, 10 patients who had undergone biopsy without an anesthetic in the past commented very favorably on the difference. In another study assessing ultrasonographically directed periprostatic blocks, Nash et al 10 looked at the difference in mean pain scores for patients receiving periprostatic lidocaine versus placebo and found a significant difference in favor of using the anesthetic block (mean pain score, 1.6 versus 2.4 for the lidocaine- versus placebotreated group, respectively; P <.0001). Instrumentation The transrectal probes used today have the ability to provide biplanar images of the prostate most commonly by using an end fire transducer that can be rotated 90 to display either a transverse or sagittal image. Alternative methods of achieving single-probe biplanar capability are to have a single transducer that can rotate or 2 transducers oriented at 90 to each other. 11 Earlier probes used transducers in the 2- to 4-MHz range 12 and accordingly sacrificed image resolution in favor of depth penetration. As more experience with the transrectal approach to prostate sonography was gained, transducers in the 5- to 8-MHz range were used that provided clearer resolution of the gland periphery, for the purpose of biopsy targeting, and less resolution of the anterior fibromuscular zone, which is of less clinical interest. To eliminate rectal air artifact and to provide patient comfort, sonographic gel is used liberally over an investing latex condom. In the last decade several enhancements of TRUS have been evaluated for their ability to increase the accuracy of detecting adenocarcinoma. In 1993 Kelly et al 13 looked at 158 patients who underwent TRUS with and without color Doppler imaging and found only a small improvement in the positive predictive value when Doppler imaging was added. In 1994 Sehgal et al 14 described the computer generation of three-dimensional prostate images for use in volume determination. Some have suggested that cancer detection may be improved with this three-dimensional technology 15 ; however, its utility in clinical practice remains to be clearly demonstrated. Sonographic Findings In the most cephalad transverse plane the first structures encountered in the normal TRUS examination are the paired seminal vesicles. These structures are symmetric in shape and contour and are isoechoic (compared with the peripheral zone). Moving in a caudal direction the prostate base is seen as a semilunar ellipsoid isoechoic structure. At this level the anteriormost aspect of the gland may appear hypoechoic and is most commonly due to an artifact of poor depth penetration with the 8-MHz transducer. As the apex is approached the diameter of the gland symmetrically tapers and remains isoechoic. To fully appreciate the apical tissue, a sagittal view is best. In BPH the transition zone volume expands, compressing the other anatomic zones of the prostate and creating a surgical capsule. Often corpora amylacea or prostatic calculi, which appear hyperechoic with posterior shadowing (Fig. 2), will demarcate this capsule. The ellipsoid shape of the gland is often transformed into a more circular configuration or into an asymmetric contour. The echotexture of the transition zone in BPH is hypoechoic and rarely hyperechoic or isoechoic. 3 J Ultrasound Med 20: ,

4 Ultrasonographically Guided Biopsy of the Prostate A B Figure 2. Benign prostatic hyperplasia. A, Transverse view; note the hypoechoic transition zone. B, Sagittal view; note calcification. The echotexture of prostate cancer is inconsistent (Table 1); however, the sonographic feature most often associated with adenocarcinoma is a hypoechoic lesion found in the peripheral zone 16 (Fig. 3). The reason for this finding is unclear. One possibility is that it represents the reflection from the acoustic interface between normal prostate tissue and the cancerous focus. The fact that some have observed a correlation between grade and hypoechogenicity supports this theory. 17 Because of the difficulty in sonographically identifying adenocarcinoma with certainty, TRUS is not routinely used in the staging of prostate cancer, nor does it have a role in screening for this disease. The primary role of TRUS is in directing the systematic biopsy of the patient with a suspected malignancy. Additionally, TRUS can be used to determine prostate volume at the time of biopsy. Biopsy Technique After the transrectal probe is inserted and the console is set to provide a uniform midgray image of the peripheral zone, we proceed with volume determination. A transverse section of the midgland, at the level of the verumontanum, is captured. A cursor is then used to label the anteroposterior and transverse diameters (Fig. 4). A second midplane sagittal image is captured, and the cephalocaudal diameter is similarly labeled. Prostate volume is then calculated using the prolate ellipse formula 0.523(transverse diameter)(anteroposterior diameter)(cephalocaudal diameter). Although this calculation is not as accurate as planimetry, 18 which requires multiple 2- to 5-mm step sections, it is more practical in the clinical setting. A spring-loaded biopsy gun is placed in a stabilizing cradle alongside the ultrasonic probe. Biopsies are then obtained in a systematic, spatially oriented fashion, usually under surveillance in the sagittal plane (Fig 3). Additionally, questionable areas are sampled after the biopsy template is complete. The goal of biopsy is to maximize the diagnostic yield. The most effective biopsy template to achieve this goal is presently the subject of much investigation and debate. In 1989 Hodge et al 19 compared a template biopsy approach with biopsy directed by sonographically questionable areas and found that 9% of cancers were missed by the latter technique. Accordingly, they recommended a sextant biopsy scheme that included base, mid, and apical samples bilaterally. In 1993 Stricker et al 20 intuitively postulated that by increasing the number of biopsy cores taken, the cancer detection rate would concurrently become elevated, particularly in larger glands where the area sampled might not contain the tissue from an existing cancer. They showed this to be true using a mathematical model that took into account prostate volume. Taking this concept further, Naughton et al 21 retrospectively Table 1. Variability in Echotexture of Prostate Cancer Echotexture Prostate Adenocarcinoma,% Hypoechoic Isoechoic Hyperechoic J Ultrasound Med 20: , 2001

5 Altman and Resnick A B Figure 3. Ultrasonographically guided prostate biopsy. A, Transverse view; note the peripheral hypoechoic lesion at 5 o clock. B, Sagittal view showing the biopsy needle passing through the lesion. reviewed 185 radical prostatectomy specimens and found that men with a prostate volume of greater that 30 g required a mean of 11 cores to detect cancer compared with 8 cores for men with glands of 30 g or less (P =.01). Other authors have retrospectively found a 35% to 37% increase in cancer detection when either 12 cores are obtained or a 5-region technique is used. 22,23 Five prospective studies have been reported detailing cancer detection rates with increasing numbers of biopsy cores (Table 2). Nava et al 24 reported no increase in the cancer detection rate until 18 cores had been obtained, at which point a detection improvement of 17% was observed. Horninger et al 25 noted no significant difference in the detection rate between 10 and 14 biopsy cores. More recently, Naughton et al 26 randomized 244 men into 6- and 12-core groups and found the cancer detection rates to be 26% and 27% (P =.09), respectively. Interestingly, of the tumors detected in the 12-core group, 21% were diagnosed exclusively on the basis of the second sextant. These data support the idea that more than 12 biopsies are needed to improve detection rates significantly. In contrast, Ravery et al 27 found a 7% increase in detection when the number of cores was increased from 6 to 10. And similarly, Presti et al 28 found a 7% increase in detection when they increased the number of cores from 6 to 10. Figure 4. Prostate volume calculation. A, Transverse view, transverse diameter. B, Sagittal view, anteroposterior and cephalocaudal dimensions. A B J Ultrasound Med 20: ,

6 Ultrasonographically Guided Biopsy of the Prostate Table 2. Number of Cores and Cancer Detection Cancer Detection Rate by No. of Biopsy Cores, % Study n Nava et al Horninger et al Naughton et al Ravery et al Presti et al We favor a 12-core biopsy template containing the standard sextant with the addition of 2 laterally placed biopsies on each side and 2 centrally located urethral biopsies (Fig. 5). The lateral biopsies are very important, because the peripheral zone, which contains the majority of adenocarcinomas, has a horseshoe configuration that wraps the gland laterally (Fig. 1). The urethral biopsies are important because nearly 20% of prostate cancers are found exclusively within the transition zone that invests the prostatic urethra. Morbidity and Complications No procedure is without risk and morbidity, and TRUS-guided prostate biopsy is no exception. Sixty-five percent to 90% of men undergoing biopsy will report significant discomfort during the procedure. 29,30 Irani et al 31 found that 19% of their patients would not agree to repeated biopsy unless anesthesia were provided. Hematuria, Figure 5. Twelve-core biopsy template. hematospermia, and hematochezia are the most common findings immediately after biopsy (seen in 39% 58%, 28% 45%, and 21% 37% of patients, respectively). 30,32,33 These are minor and represent the majority of conditions. However, 0.7% to 2.0% of postbiopsy morbidity can be considered major. 34 These procedurespecific complications include sepsis, urinary tract infection, and urinary retention (seen in 0.2% 0.6%, %, and % of patients, respectively). 34 For the most part, TRUS-guided prostate biopsy is safe and well tolerated. However, given the above-mentioned morbidity and the 15% 40% detection rate, great effort has been put forth to increase the specificity of PSA screening. The full history of this effort is beyond the scope of this review. Presently, however, the percent free PSA, antichymotrypsin-bound PSA, and human kallikrein 2 (hk2) screening assays hold great promise in our attempt to avoid unnecessary biopsies while maintaining the ability to diagnose prostate cancer. Pathologic Reporting and Repeated Biopsies There is no standard protocol for the submission of biopsy material or the dictated components of the pathologic report. Iczkowski and Bostwick 35 recently surveyed both urologists and pathologists on perceived practice standards. They found that 58% of urologists submit their biopsy material in 6 separate containers compared with 39% who use only right- and left-designated containers (3% admitted variance in their practice). Furthermore, of the urologists surveyed, 61% preferred a separate Gleason score for each sextant compared with 34% who did not (5% unsure), and 68% preferred reporting the percentage of each sextant occupied by tumor compared with 21% who did not (11% unsure). Seventy-two percent of urologists thought that the format and content of the pathologic report influenced patient treatment compared with 57% of pathologists. There was closer agreement between the groups on the need to report highgrade prostatic intraepithelial neoplasia (PIN) and its location (56% and 64%, respectively); however, more than 35% of each group thought that such reporting was not necessary. Many practitioners cite cost as the main reason for limiting specimen submission to 2 contain- 164 J Ultrasound Med 20: , 2001

7 Altman and Resnick ers, right and left. This reduces the technical cost of additional paraffin block preparation. Epstein et al 36 have demonstrated, however, that the number of positive sextant biopsy cores can predict margin status at prostatectomy. Because of tissue fragmentation, submitting all cores from 1 side of the prostate in a single container would eliminate this opportunity for predicting margin positivity. To overcome this, some have suggested inking representative cores within each container. The validity of this approach remains to be proved. Most agree that high-grade PIN should be included in the pathologic report. Between 40% and 60% of men in whom high-grade PIN in the absence of adenocarcinoma is found on an initial biopsy will have malignancy detected on a subsequent biopsy. 37,38 In contrast, Ellis and Brawer 39 have shown that low-grade PIN (formerly called PIN I and II) has no impact on the risk of a positive second biopsy result. Accordingly, we think that low-grade PIN should not be a part of the pathologic report and that such reporting should be discouraged, because it may lead to bias toward unnecessary repeated biopsies. Repeated biopsy may also be needed in a patient with an entirely negative biopsy result and a persistently elevated PSA level. Between 20% and 36% of TRUS-guided prostate biopsies will yield positive results in this situation. Lui et al 40 looked at 47 men with negative biopsy results and elevated PSA levels and found that 36.1% had cancer detected on repeated biopsy, 19.1% of whom had isolated transition zone malignancies. This finding demonstrates the benefit of urethral, or transition zone, sampling as a routine part of TRUS-guided prostate biopsy, especially repeated biopsy. We advocate making use of percent free PSA screening in a patient with an elevated PSA level and negative initial biopsy results. If this value is less than 25% (this reference value varies significantly among assays), we think that repeated biopsy is needed. Furthermore, if a postbiopsy rise in the PSA level is greater than 0.75 ng/ml per year, we think that repeated biopsy is also indicated. However, it is our practice to present the patient with the statistical information provided by these tests and to allow him to make a decision based on his desire to not have a diagnosis missed or delayed. Conclusion Ultrasonography has had a profound impact on the way prostatic diseases, most notably adenocarcinoma, are evaluated and treated. The addition of TRUS to our armamentarium has enabled us to make the most of prostate biopsy in terms of diagnostic yield. This, combined with our ongoing attempt to avoid unnecessary biopsies and to ease the discomfort of required ones, will ensure that our patients receive the best possible care. References 1. Muldoon LD, Resnick MI. Normal anatomy of the prostate. In: Resnick MI (ed). Prostate Ultrasonography. Philadelphia, PA: BC Decker; 1990: Brooks JD. Anatomy of the lower urinary tract and male genitalia. In: Walsh PC (ed). Campbell s Urology. Philadelphia, PA: WB Saunders; 1998: Scheckowitz EM, Resnick MI. Imaging of the prostate: benign prostate hyperplasia. Urol Clin North Am 1995; 22: Resnick MI. Transrectal ultrasound guided versus digitally directed prostate biopsy: a comparative study. J Urol 1988; 139: Rifkin MD, Alexander AA, Pisarchick J, et al. Palpable masses in the prostate: superior accuracy of US-guided biopsy compared with accuracy of digitally guided biopsy. Radiology 1991; 179: Renfer LG, Schow D, Thompson IM, et al. Is ultrasound guidance necessary for transrectal prostate biopsy? J Urol 1995; 154: Lindert KA, Kabalin JN, Terris MK. Bacteremia and bacteriuria after transrectal ultrasound guided prostate biopsy. J Urol 2000; 164: Sieber PR, Rommel FM, Agusta VE, et al. Antibiotic prophylaxis in ultrasound guided transrectal prostate biopsy. J Urol 1997; 157: Soloway MS, Obek C. Periprostatic local anesthesia before ultrasound guided prostate biopsy. J Urol 2000; 163: Nash PA, Bruce JE, Indudhara R, et al. Transrectal ultrasound guided prostatic nerve blockade eases systematic needle biopsy of the prostate. J Urol 1996; 155: J Ultrasound Med 20: ,

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