Optimizing Prostate Biopsy Strategies for the Diagnosis of Prostate Cancer

Technique Review

TECHNIQUE REVIEW Optimizing Prostate Biopsy Strategies for the Diagnosis of Prostate Cancer Samir S. Taneja, MD Department of Urology, New York University School of Medicine, New York, NY The importance of prostate biopsy in urologic practice has been magnified by the routine use of serum prostate-specific antigen in prostate cancer screening. Given the potential impact of the procedure on both patient care and health care costs, an optimal strategy for accurate and judicious detection of early prostate cancer is imperative. Maintaining maximal sensitivity and negative predictive value are equally important to the patient. In this article, we review recent modifications in prostate biopsy indications and techniques that may allow for a systematic biopsy approach to the patient in whom prostate cancer is suspected. [Rev Urol. 2003;5(3):149–155] © 2003 MedReviews, LLC Key words: Prostate biopsy • Transrectal ultrasound • Prostate cancer • Prostate-specific antigen ince the first description of a sextant ultrasound-guided prostate biopsy,1,2 the technique has been modified many times. These modifications have enhanced our ability to sample the prostate effectively, both for detecting prostate cancer and for ruling it out. Given the popularity of serum prostate-specific antigen (PSA) testing in medicine today, biopsy strategy presents a challenge for the practicing urologist. Certain guidelines can be implemented to optimize early cancer detection by biopsy in the modern era. S VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY 149 Prostate Biopsy Strategies continued When to Biopsy In the past, the indications for prostate biopsy have been based on digital rectal examination (DRE) and serum PSA measurement. DRE has been relatively subjective, as it is heavily based on the experience level of the examiner and the threshold for biopsy. The contribution of DRE to a screening effort is strongly influenced by the PSA cutoff level employed. Lower PSA cutoff levels reported rates of detection much higher than those in historical controls in men with serum PSA levels in the range of 2.5 ng/mL to 4.0 ng/mL.13–16 With extended biopsy strategies, the rate of cancer detection among this group has varied from 22% to 27%.13–15,17 Cancers detected in this PSA range appear to be clinically significant and (in theory) more likely to be organ-confined than cancers diagnosed in men with The use of serum PSA has greatly improved our ability to predict prostate cancer risk in a reproducible fashion. will reduce the usefulness of DRE. Thus, defining a clear predictive value for abnormal DRE can be difficult, and investigators have reported differing results regarding the use of DRE in prostate cancer screening.3–7 Nevertheless, it remains a general consensus in the United States that in men with an abnormal DRE, regardless of serum PSA level, the possibility of prostate cancer should be aggressively investigated. The use of serum PSA has greatly improved our ability to predict prostate cancer risk in a reproducible fashion. Using standard sextant techniques, biopsy of men with PSA values in the range of 4.0 ng/mL to 10.0 ng/mL has generally resulted in a cancer detection rate of 20% to 30%.8–11 A relatively poor negative predictive value is observed, with cancer found in approximately 20% of those undergoing repeat biopsy.9,12 Historically, the designation of 4.0 ng/mL as the cutoff point for “abnormal" was based on a relatively low rate of detection (~2%) in men with PSA levels less than 4.0 ng/mL. This detection rate is influenced by many factors, including adequacy of sampling and biopsy technique. Recently, several authors have 150 VOL. 5 NO. 3 2003 higher PSA levels.14,15 Lowering the serum PSA cutoff value for biopsy offers the potential advantage of increased and earlier detection but, obviously, increases the number of unnecessary biopsies performed. Catalona and colleagues14 reported on 363 men with PSA levels of 2.6 ng/mL to 4.0 ng/mL who underwent prostate biopsy. A cancer detection rate of 22% was noted, and 81% of those undergoing surgery demonstrated organ-confined disease. Relatively few cancers (17%) were potentially clinically insignificant at the time of surgery. Controversy over the stipulation that cancers detected in the 2.6 ng/mL to 4.0 ng/mL range are more likely to be organ-confined has developed in subsequent studies. Validation of this concept may require the collective experience of additional investigators. One obvious shortcoming of using a strategy involving a lower PSA cutoff value is the necessary increase in negative biopsies. Catalona and colleagues14 suggested that specificity in the total PSA range of 2.6 ng/mL to 4.0 ng/mL could be improved by applying a free/total PSA ratio (f/t PSA) cutoff value of 27%. In doing so, a 90% sensitivity could be REVIEWS IN UROLOGY achieved with an 18% reduction in unnecessary biopsies. The experience of other investigators has suggested that f/t PSA measurement may not improve specificity greatly in the low total PSA range. Okihara and colleagues16 reported a cancer detection rate of 24.5% in men with PSA values between 2.5 ng/mL and 4.0 ng/mL. At 95% sensitivity for cancer detection, the specificity of complexed PSA (cPSA) was 38%, compared with 11% for f/t PSA. Follow-up studies have additionally suggested that the specificity of f/t PSA in the total PSA range of 2.5 ng/mL to 4.0 ng/mL is relatively poor compared with the specificity of cPSA. Application of these findings to cost analyses will allow determination of the optimal PSA cutoff level to be implemented in clinical practice. How to Biopsy The increased likelihood of cancer detection at the time of biopsy reported in many recent series can be attributed to improved biopsy techniques. Several investigators have demonstrated the importance of adequate sampling to improve not only sensitivity but also negative predictive value. Thus, current biopsy techniques focus on optimizing the number and location of cores at the time of biopsy. Number of Cores Ever since sextant biopsy in men with PSA elevation became routine, it has been recognized that the negative predictive value of a 6-core biopsy alone is relatively poor.9,11,12,18,19 Catalona and colleagues10 reported on the results of serial sextant biopsies in a prostate cancer screening population. Among 962 men with cancer diagnoses based on biopsy performed because of elevated PSA levels, 73% of the cancers were detected after the first biopsy, 91% after the second, 97% after the third, Prostate Biopsy Strategies B A X X X X X X X X X X C X X Figure 1. The New York University biopsy strategy. (A) A total of 12 cores are taken. (B) Cores are taken from traditional mid-lobar locations along with additional far lateral locations. (C) Far lateral sampling is carried out in the longitudinal ultrasound plane with care to include an anterior far lateral core. and 99% after the fourth. The likelihood of cancer declined with each serial biopsy. This experience is consistent with older reports that up to 96% of cancers are diagnosed within the first 2 sets of sextant biopsies.12 Based on the relatively poor negative predictive value of a sextant biopsy alone, investigators have employed various techniques of increased sampling at the time of first biopsy. Levine and colleagues11 evaluated the use of a 12-core biopsy, employing 2 consecutive sets of sextant biopsy at one sitting. They demonstrated an increase in cancer detection of 31% overall, with only 21% being detected on the first sextant alone. These findings are consistent with the sextant data: based on previous sextant biopsy series, one could conclude that the negative predictive value of a 12-core biopsy would be high. Other authors have subsequently demonstrated that increased core biopsy is well tolerated,20 causes no increase in complications relative to a sextant biopsy,20 and appears to identify clinically significant cancers. Pathologic analysis demonstrates that cancers diagnosed on increased core biopsy are smaller, on average, than those diagnosed on sextant biopsy. Thus, earlier detection of cancer may be facilitated by increased sampling of the gland.21,22 The necessary number of cores may vary with the size of the prostate. Uzzo and colleagues23 previously demonstrated a 38% cancer detection rate in glands greater than 50 cc, compared with 23% in glands less than 50 cc, at the time of sextant biopsy. Thus, one could argue that a strategy of increasing core number relative to increasing prostate size may be a means of optimizing cancer detection. Chen and associates,24 however, through simulated biopsy of prostatectomy specimen, have demonstrated that increasing the number of biopsies in larger glands is likely to increase the detection of clinically insignificant tumors. Clearly, a balance between detection and overdetection must be achieved, and avoidance of saturation biopsy techniques at first presentation of the patient may be advisable. Location of Cores In addition to increased sampling of the prostate, improved cancer detection may be achieved through sampling of additional locations in the prostate.19,22,25–29 The original description of the ultrasound-guided biopsy technique included sextant core sampling in the parasagittal location.1,2 Terris and colleagues8 postulated that the high rate of false negatives after sextant biopsy might be reduced by sampling more laterally in order to achieve better sampling of the peripheral zone. Laterally directed biopsies identified additional cancers in 14.6% of patients; however, if lateral biopsies were performed alone, cancer would have been missed in 7.3% of patients. Eskew and colleagues27 reported on the incorporation of far lateral biopsy cores when sampling the gland with a 5-region technique. Forty percent of patients were found to have cancer, and approximately 33% of these patients were found to have cancer in the additional regions only. The additional cancers were predominantly located in the far lateral regions. This experience has been confirmed by several authors who demonstrated increased cancer detection in the far lateral region of the peripheral zone.19,30–33 Our own experience demonstrates an increase in cancer detection from 30.9%, when using 2 sets of sextants, to 50% when using far lateral sampling in the second sextant (Figure 1). Cancer in the far lateral region only has been found in 24% of our patients (S.S. Taneja, unpublished data). Although it has been demonstrated that T1c cancers are more frequently VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY 151 Prostate Biopsy Strategies continued present in the transition zone than T2 cancers, the yield of routine biopsy remains low,34–38 probably because of the relative size of the transition zone and the difficulty of sampling adequately through a transrectal approach (Figure 2). In the setting of a primary biopsy, cancer detection rates with transition zone sampling have ranged from 1.8% to 4.3%, suggesting a limited role for routine use of transition zone biopsy.34,36,37 Because others have reported higher rates of detection with transition zone sampling at the time of repeat biopsy, this may be a reasonable approach.39 A B Figure 2. Transrectal transition zone sampling. (A) The number of cores desired depends on gland size and level of cancer suspicion. Cores are taken by visually advancing the needle tip through the peripheral zone prior to releasing the needle gun. (B) A radial technique is utilized to maximize sampling. reduce the discomfort associated with multiple-core biopsy.41 It has now been collectively demonstrated that: 1) lidocaine injection is more effective than placebo or intrarectal lidocaine jelly in reducing pain, 2) multiple-core biopsies are well tolerated with local anesthetic alone, and 3) the incidence of complications associated with the technique is low.20,40–48 Tolerability of Increased Sampling Increasing the number of cores has clearly resulted in increased patient discomfort during the biopsy procedure. Several investigators have anecdotally reported on the use of intravenous sedation to make multiple biopsy cores feasible. More recently, a technique using local prostatic anesthesia has been described40: 1% lidocaine is injected at the base of the gland adjacent to the seminal vesical and neurovascular bundle. Injection at this location leads to infiltration of the medication along the neurovascular bundle and retroprostatic space (Figure 3). The technique is associated with little or no morbidity and appears to history. Many have postulated that HGPIN represents a premalignant lesion based on the following: its strong association with cancer in both needle biopsy and radical prostatectomy specimens,50–53 its increased ploidy compared with normal controls,54 and an anecdotal risk of malignancy at a prolonged interval following diagnosis. Clearly, the tasks of the clinician diagnosing HGPIN are to rule out occult cancer at baseline as well as progression to cancer at a delayed interval. The risk of prostate cancer on repeat biopsy, following the diagnosis of HGPIN on sextant biopsy, has been consistently observed to be approximately 50% (30%–57%).50–52 The recommendation of most investigators Managing High-Grade PIN High-grade prostatic intraepithelial neoplasia (HGPIN) is diagnosed as an isolated lesion in 4.4% to 25% of prostate needle biopsies.49 Although HGPIN is established as a lesion strongly associated with occult malignancy, little is known of its natural Figure 3. Local anesthetic technique for prostate biopsy. (A) A soft tissue triangle posterolateral to the prostate base (P) is identified adjacent to the seminal vesical (SV). (B) 7–10 mL of 1% lidocaine is infiltrated in this location and a wheal is observed. (C) By rolling the ultrasound probe laterally, anesthetic can be seen infiltrating along the neurovascular bundle. B A 152 VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY C Prostate Biopsy Strategies has been to perform an immediate repeat biopsy in this setting. The location of repeat biopsy has been evaluated, and many have suggested that increased sampling of the area of HGPIN may improve the likelihood of cancer diagnosis on repeat biopsy. However, it has been demonstrated that cancer can occur well away from the site of HGPIN55; thus, most would advocate sampling of the whole gland at repeat biopsy. In a recent study, Borboroglu and associates18 demonstrated that extensive repeat biopsy (mean of 22 cores) detected cancer in 47% of men who had HGPIN noted on original sextant biopsy. This is not markedly greater than in historical series evaluating repeat sextant biopsy for HGPIN, implying that a 12-core biopsy probably provides adequate sampling to rule out occult cancer in men with HGPIN, rather than a repeat 6-core biopsy following HGPIN diagnosis. At our institution, we have evaluated the cancer detection rate among 43 men who underwent repeat biopsy within 1 year of the diagnosis of HGPIN on 12-core biopsy.56 Cancer was found in 1 man (2.4%) only, suggesting that, indeed, routine immediate repeat biopsy after the diagnosis of HGPIN on 12-core biopsy is unnecessary. In a follow-up study to assess the risk of delayed cancer progression in men with HGPIN, we performed repeat biopsy in 31 men who had been diagnosed with HGPIN on 12-core biopsy 3 years previously.57 Delayed repeat biopsy identified cancer in 25.8% of patients. This is markedly higher than the 2.4% incidence among men who were rebiopsied within 1 year following the diagnosis of HGPIN on 12-core biopsy, suggesting that a progression to clinically evident cancer occurs in this interval. Interestingly, no correlation between change in PSA level over time and the likelihood of cancer was noted. Men with stable PSA levels were no less likely to have cancer. Thus, routine delayed interval biopsy 3 years after the diagnosis of HGPIN is now recommended at our institution. Further follow-up will allow better delineation of the natural history of prostate cancer associated with HGPIN. When to Repeat the Biopsy A clear advantage of multiple-core biopsy is a presumed improvement in the negative predictive value of the test compared with 6-core biopsy. Even so, sampling error is a risk of any biopsy, and it is important to have a good algorithm for repeat biopsy. The use of PSA level to guide detection rate on repeat biopsy using the 11-core multisite biopsy technique. A 33% increase in the cancer detection rate was found after incorporation of lateral or transition zone sites. The number of cores required at repeat biopsy is not well defined. Using the 5-region technique, Applewhite and associates30 reported a 38.6% cancer detection rate with a mean of 17.6 cores. Saturation biopsies have likewise resulted in detection rates of 30% to 34% with a mean of 22 to 23 cores.18,63 Clearly, increased core number and sampling of additional locations are key to successful identification of cancer in men with a previous negative biopsy. In men with previously noted atypical small acinar proliferation, The biologic variability of PSA levels has been reported to approach 25%, and laboratory variation may account for an additional 10% variability. repeat biopsy is controversial. A longitudinal PSA survey is limited by the absence of clear guidelines regarding normal rate of increase and biologic variability. The biologic variability of PSA levels has been reported to approach 25%.58,59 Laboratory variation may account for an additional 10% variability among measurements. Thus, in following PSA levels, several measurements need to be obtained in order to establish trends depicting the rate of rise in PSA. The use of transition zone and laterally directed core biopsies appears to be essential on repeat biopsy.19,30,31,35,39,60–62 In fact, when cancers are diagnosed on repeat biopsy, they are more likely to be found in a lateral or transition zone than in the traditional sextant location. The rate of cancer detection in the transition zone at repeat biopsy has varied from 5.4% to 13%.35,39,62 Babaian and colleagues19 reported a 29% cancer biopsies should be clustered in the region in which the atypia was noted, whereas in men with HGPIN, sampling of the entire gland appears to be essential.55,64 We have employed an algorithm involving 3 PSA measurements during the year after a negative biopsy. For men with PSA levels in the range of 4.0 ng/mL to 10.0 ng/mL, we employ a strategy utilizing 3 PSA measurements spaced over the year following a negative biopsy. A trend is established, and if an increase of more than 20% is noted by the end of the year, a repeat biopsy is offered. Based on existing evidence that cancer at repeat biopsy is more likely identified in an anterior location, we routinely sample the transition zone in these patients. A 20-core biopsy is used, with 4 cores taken from the right and left transition zones. Consistent with the findings of others, cancer is rarely detected VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY 153 Prostate Biopsy Strategies continued in the transition zone cores. The use of transurethral biopsy is controversial; it has a higher morbidity than transrectal biopsy, with a relatively low yield of cancer. For effectiveness, the surgeon must perform a complete transurethral resection of the prostate, with a wide resection of anterior tissue. Given the relative risk, the procedure should be reserved for patients with consistently rising PSA levels and multiple negative transrectal biopsies that have included transition zone sampling. serum PSA levels. At the time of repeat biopsy, the urologist must be aggressive in obtaining not only a standard systematic sampling but also additional cores from the lateral and anterior gland. Through use of these simple guidelines, maximal cancer diagnosis and the necessary confidence in negative biopsy results can be achieved. 9. 10. 11. References 1. 2. Summary The technique of transrectal prostate biopsy has evolved enormously in recent years. The optimal number of biopsies, locations, and number of cores to be taken remain controversial, but it is clear that the false-negative rate of standard sextant biopsy in unacceptably high. Contemporary biopsy strategies should incorporate a minimum of 10 to 12 cores, with concentrations in the lateral region of the gland. Routine transition zone sampling appears to be unnecessary for initial biopsy but should be considered at the time of repeat biopsy. In patients with HGPIN or atypia, delayed interval biopsy should be employed, regardless of the change in 8. 3. 4. 5. 6. 7. Hodge KK, McNeal JE, Stamey TA. Ultrasound guided transrectal core biopsies of the palpably abnormal prostate. J Urol. 1989;142:66–70. Hodge KK, McNeal JE, Terris MK, Stamey TA. Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol. 1989;142:71–75. Schroder FH, van der Maas P, Beemsterboer P, et al. Evaluation of the digital rectal examination as a screening test for prostate cancer. Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 1998;90:1817–1823. Richie JP, Catalona WJ, Ahmann FR, et al. Effect of patient age on early detection of prostate cancer with serum prostate-specific antigen and digital rectal examination. Urology. 1993;42:365–374. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol. 1994;151:1283–1290. Flanigan RC, Catalona WJ, Richie JP, et al. Accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. J Urol. 1994;152:1506–1509. Carvalhal GF, Smith DS, Mager DE, et al. Digital rectal examination for detecting prostate cancer 12. 13. 14. 15. 16. 17. 18. at prostate specific antigen levels of 4 ng./ml. or less. J Urol. 1999;161:835–839. Terris MK, Wallen EM, Stamey TA. Comparison of mid-lobe versus lateral systematic sextant biopsies in the detection of prostate cancer. Urol Int. 1997;59:239–242. Roehl KA, Antenor JA, Catalona WJ. Serial biopsy results in prostate cancer screening study. J Urol. 2002;167:2435–2439. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991;324:1156–1161. Levine MA, Ittman M, Melamed J, Lepor H. Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol. 1998;159:471–476. Keetch DW, Catalona WJ, Smith DS. Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol. 1994;151:1571–1574. Babaian RJ, Johnston DA, Naccarato W, et al. The incidence of prostate cancer in a screening population with a serum prostate specific antigen between 2.5 and 4.0 ng/ml: relation to biopsy strategy. J Urol. 2001;165:757–760. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination: enhancement of specificity with free PSA measurements. JAMA. 1997;277:1452–1455. Krumholtz JS, Carvalhal GF, Ramos CG, et al. 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Borboroglu PG, Comer SW, Riffenburgh RH, Main Points • Biopsy strategy presents a challenge for the practicing urologist; certain guidelines can be implemented to optimize early cancer detection. • An abnormal digital rectal examination is an indication for biopsy, regardless of prostate-specific antigen (PSA) level. • Use of a lower PSA level (2.5–4.0 ng/mL) as a biopsy indication may increase detection rates, but cost/benefit ratios must be considered. • Rates of early prostate cancer detection have been enhanced through the use of increased core numbers (10-12) and sampling of additional regions of the prostate (far lateral and anterior). • High-grade prostatic intraepithelial neoplasia calls for special management techniques; delayed interval biopsy (3 years after the initial screening), regardless of change in serum PSA level, has resulted in increased cancer detection, although more follow-up studies are needed. • As a guideline for repeat biopsy after a negative initial screening, 3 PSA measurements may be taken over the course of a year; an increase of more than 20% in PSA level would indicate the need for a second biopsy. 154 VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY Prostate Biopsy Strategies 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 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