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Influence of prostate volume in the detection of prostate cancer
ADULT UROLOGY
INFLUENCE OF PROSTATE VOLUME IN THE DETECTION OF PROSTATE CANCER JAY B. BASILLOTE, NOEL A. ARMENAKAS, DAVID A. HOCHBERG,
AND
JOHN A. FRACCHIA
ABSTRACT Objectives. To assess the influence of prostate volume on prostate cancer (CaP) detection in men who underwent repeated sextant transrectal ultrasound biopsy of the prostate. Methods. Between September 1991 and September 2000, 4376 men underwent sextant transrectal ultrasound-guided biopsy of the prostate. Of the 4376 men, 556 underwent repeat biopsy because of persistent prostate-specific antigen elevation (greater than 4 ng/mL) and/or an abnormal digital rectal examination or suspicious pathologic findings. The percentage of CaP missed on the initial biopsy and detected on the repeat biopsy between arbitrary prostate volumes of less than 50 and 50 cm3 or greater and between less than 37.5 and 37.5 cm3 or greater, the median prostate volumes of men with CaP, were compared. Patient age, prostate-specific antigen level, digital rectal examination findings, and Gleason score in each volumetric cutoff group were also compared. Results. CaP was detected in 22% of men who underwent a repeat biopsy. The percentage of CaP missed on the initial biopsy but subsequently detected on the repeat biopsy consistently increased as the volume increased. A statistically significant difference in the percentage of CaP not detected on the initial biopsy was found between prostate volumes of less than 50 and 50 cm3 or greater and between less than 37.5 and 37.5 cm3 or greater (P ⬍0.05). No statistically significant difference in prostate-specific antigen, age, digital rectal examination, or Gleason score was found between each volumetric cutoff group. Conclusions. A significant percentage of men are diagnosed with CaP after a repeat biopsy. We have demonstrated that the percentage of CaP missed on the initial biopsy and detected on the repeat biopsy increases as the prostate volume increases. The results of our study suggest that in men with large prostates, traditional sextant biopsies may not be adequate to detect CaP. UROLOGY 61: 167–171, 2003. © 2003, Elsevier Science Inc.
S
ince its introduction by Hodge et al.1 in 1989, the systematic sextant biopsy method has become a routine approach for the diagnosis of prostate cancer (CaP). Notwithstanding its widespread acceptance, several studies have suggested that sextant biopsy alone may not provide a reliable detection rate for CaP. Uzzo et al.2 and Karakiewicz et al.3 in their analyses of men who underwent a single biopsy of the prostate showed that the yield of a positive sextant biopsy decreased with increasing prostate volume. Several factors were proposed as the rationale for the differing incidence rates of CaP according to gland volume, including “better” From the Division of Urology, Lenox Hill Hospital, New York, New York; and Private Practice, Tampa, Florida Reprint requests: Jay B. Basillote, M.D., Lenox Hill Hospital, 100 East 77th Street, New York, NY 10021 Submitted: February 5, 2002, accepted (with revisions): August 26, 2002 © 2003, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
sampling of smaller glands relative to larger glands. To improve the inverse relation between prostate volume and sextant biopsy yield, the investigators of several studies have suggested increasing the number of biopsy cores in men with large glands.4,5 A common clinical situation arises in which a persistently elevated prostate-specific antigen (PSA) and/or an abnormal digital rectal examination (DRE) is found after an initial negative biopsy. The positive repeat biopsy rate in this group of patients is 20% to 40%.6,7 Fleshner et al.8 described this as the false-negative rate of sextant biopsy in their evaluation of men who underwent a repeat biopsy 1 year after the initial negative biopsy. In our study, we assessed the effect of prostate volume on the likelihood of CaP not detected on the initial sextant biopsy. Although others have examined the effect of prostate volume on the yield of CaP in a single sextant biopsy setting, to our knowledge, 0090-4295/03/$30.00 PII S0090-4295(02)02103-9 167
this is the first analysis of the relation between prostate volume and the percentage of CaP not detected on the initial biopsy in a subset of men who underwent a repeat biopsy. MATERIAL AND METHODS At our institution, 4376 men underwent transrectal ultrasound (TRUS)-guided sextant biopsy of the prostate between August 1991 and September 2000. Of these, 556 men underwent a repeat biopsy after an initial negative biopsy. The indications for the repeat biopsies were a persistently abnormal PSA level and/or abnormal DRE findings (palpation by the clinician of a firm prostate or nodules) or, less commonly, the finding of suspicious histologic features on the initial biopsy, such as severe atypia or high-grade prostatic intraepithelial neoplasia. A cleansing enema was performed the morning of the biopsy, and all patients received prophylactic antibiotics the night before and for 48 hours after the procedure. Prostate imaging was performed using the Bruel & Kjaer 1860 (Marlborough, Mass) ultrasound machine with a 7.0-MHz biplanar probe. The biopsies were performed in the sagittal plane using the method described by Hodge et al.1 Triaxial distances at the maximal length (L), height (H), and width (W) of the prostate were measured, and the prostate volume was calculated using the well-described prolate ellipse formula (volume ⫽ /6 ⫻ L ⫻ W ⫻ H). Using an 18-gauge needle driven by a springloaded biopsy gun, tissue cores were obtained bilaterally from the base, mid-gland, and apex of the prostate. A total of six cores was obtained at each biopsy session. All biopsy material was assessed and classified according to the Gleason system when CaP was identified. The repeat biopsies were performed within a median of 14.6 months (range 4.9 to 22.1) of the initial negative biopsy. All men diagnosed with CaP after the initial and repeat biopsies were combined and grouped into ascending deciles of prostate volume. The percentage of CaP not detected on the initial biopsy and subsequently diagnosed on the repeat biopsy was calculated for each volume decile. Chi-square analysis was used to compare the percentage of CaP missed on the initial biopsy and subsequently detected on the repeat biopsy in men with prostate volumes less than 50 and 50 cm3 or greater and prostate volumes less than 37.5 and 37.5 cm3 or greater. The prostate volume as measured by TRUS during the initial biopsy was used in the analysis. Although the use of the cutoff volume of 50 cm3 was somewhat arbitrary, it represents the generally accepted cutoff range of large and small glands clinically and has been previously evaluated by Uzzo et al.2 This 50-cm3 cutoff also approximated the mean gland volume of all the men in our study. In addition, the 37.5-cm3 cutoff volume was chosen because it represents the median prostate volume of all the men found to have CaP in our study. Student’s t test was used to analyze any differences in the clinical characteristics on the basis of PSA level, patient age, DRE findings, and Gleason score, which may affect the positive biopsy rate in men with CaP, divided into cutoff volumes of 50 cm3 and 37.5 cm3.
RESULTS Of the 4376 men biopsied, 1325 (30.3%) were found to have CaP on the initial biopsy (group 1). Of the 3051 men with an initial negative biopsy, 556 underwent a repeat biopsy, of whom 125 (22%) were diagnosed with CaP (group 2). The indications for repeat biopsy were elevated PSA 168
FIGURE 1. Percentage of CaP missed on initial biopsy and subsequently detected on repeat biopsy in each volume decile.
with or without abnormal DRE findings in 469 (84.5%), abnormal DRE findings only in 32 (5.8%), prostatic intraepithelial neoplasia in 28 (5%), and atypia in 26 (4.7%). The mean age, PSA level, percentage with abnormal DRE findings, and prostate volume for group 1 versus group 2 was 68.7 ⫾ 7.8 years versus 68.6 ⫾ 9.0 years, 14.6 ⫾ 15.9 ng/mL versus 12.0 ⫾ 10.9 ng/mL, 38% versus 32%, and 43.1 ⫾ 25 cm3 versus 52 ⫾ 28.5 cm3, respectively. No statistically significant difference in the clinical characteristics between the two groups was found (P ⬎0.05). The median prostate volume of all men in our study and all the men with CaP detected (groups 1 and 2) was 52 cm3 and 37.5 cm3, respectively. The percentage of men with CaP missed on the initial biopsy but detected on the repeat biopsy for each volume decile is illustrated in Figure 1. As the prostate volume increased, the percentage of CaP subsequently diagnosed on the repeat biopsy after a negative initial biopsy consistently increased. When a cutoff volume of 50 cm3 was used, the percentage of CaP not detected in the less than 50 and 50 cm3 or greater groups was 6.5% and 13.7%, respectively. When the median volume of 37.5 cm3 was used as the cutoff, the percentage of CaP missed was 6.2% and 12.5% in the less than 37.5 and 37.5 cm3 or greater groups, respectively. Using the cutoff volume of 50 cm3, a statistically significant difference was found in the percentage of CaP not detected between men with prostate volumes less than 50 cm3and those with volumes 50 cm3 or greater (chi-square analysis, P ⬍0.05). This statistically significant difference was maintained when the cutoff volume of 37.5 cm3 was used (chi-square analysis, P ⬍0.05). The clinical characteristics of the men in group 2 (repeat biopsy) separated into prostate volumes less than 50 and 50 cm3 or greater and less than 37.5 and 37.5 cm3 or greater are summarized in Table I. No statistically significant difference was found between the small and large glands using either cutoff points when PSA, patient age, DRE, and Gleason grade were compared (P ⬎0.05). UROLOGY 61 (1), 2003
TABLE I. Clinical characteristics of subjects with CaP detected on repeat biopsy by prostate volume Mean PSA (P >0.05)
Prostate Volume (cm3) ⬍50 (n ⫽ 65) ⱖ50 (n ⫽ 60) ⬍37.5 (n ⫽ 15) ⱖ37.5 (n ⫽ 110)
11.1 12 10.4 11.9
⫾ ⫾ ⫾ ⫾
10.5 10.1 10.4 10.2
Mean Age (P >0.05) 67.7 68 67.6 67.9
⫾ ⫾ ⫾ ⫾
8.9 9 8.8 9
DRE* (P >0.05) 33 30 29 33
Mean Gleason Score (P >0.05) 6.7 6.4 6.6 6.5
⫾ ⫾ ⫾ ⫾
0.98 0.99 0.98 0.99
KEY: CaP ⫽ prostate cancer; PSA ⫽ prostate-specific antigen; DRE ⫽ digital rectal examination. * Percentage of men with positive or abnormal DRE findings.
COMMENT Despite the somewhat arbitrary conception of its method, the TRUS-guided sextant biopsy of the prostate has become the standard method for the detection of CaP. Although widely used, concern exists regarding its accuracy. Several studies have reported that 20% to 40% of men with an initially negative biopsy will subsequently be found to have CaP on a repeat biopsy.6,7 It is also known that the positive yield of a single sextant TRUS-guided biopsy decreases as the prostate volume increases.2,3 We therefore undertook this study to determine the applicability and accuracy of TRUS-guided sextant biopsy in the detection of CaP with varying prostate sizes. Our finding that 22% of men who underwent a repeat biopsy were found to have CaP concurs with previous reports. Fleshner et al.8 in their evaluation of 130 men who underwent a repeat biopsy at a mean of 12.8 months from the initial benign biopsy, found that 30% of these men had CaP, which they described as the false-negative rate of TRUSguided biopsy. In our study, the median inter-biopsy interval was 14.6 months. Although it is conceivable that a de novo tumor may have developed during the intervening period, it is unlikely that a de novo tumor had reached sufficient volume to be clinically detectable on a subsequent biopsy; it is well known that CaP has a relatively slow growth rate.9 Therefore, it can be assumed that the CaP detected on the repeat biopsies was probably missed on the initial biopsy and corresponds to the false-negative group. The results indicate that the percentage of CaP not detected on the initial sextant TRUS-guided biopsy and subsequently diagnosed on the repeat biopsy consistently increased with increasing gland size. A statistically significant difference in the rate of undetected CaP was seen between volumes less than 50 cm3 and those 50 cm3 or greater and less than 37.5 cm3 and 37.5 cm3 or greater. Specifically, CaP was missed and subsequently diagnosed on the repeat biopsy in 13.7% and 6.5% of men with a prostate volume 50 cm3 or greater and less than 50 cm3, respectively. Consequently, the UROLOGY 61 (1), 2003
false-negative rate more than doubled as the prostate volume exceeded 50 cm3. This is a noteworthy finding even though most men with CaP in our study had a prostate volume of less than 50 cm3 (median 37.5), because more than one half of the men who were biopsied had a prostate volume greater than 50 cm3 (median 52). This indicates that more than one half of all men biopsied in our study were potentially exposed to a significantly higher risk of missing CaP. These results concur with the findings of Epstein et al.10 who, using radical prostatectomy specimens, found a 32.5% likelihood of a prior benign biopsy in prostate volumes of 75 cm3 or greater compared with 15.2% for prostate volumes less than 75 cm3. Our study, however, differs from theirs in that we assessed men diagnosed with CaP by prostate biopsy and they selected a subgroup of patients who subsequently underwent radical prostatectomy. The higher prostate volumes in their study can be attributed to the use of a more select group of patients and also to the more accurate measurement of the prostate volume with the surgical specimen. We also considered a possible difference in the clinical characteristics of men with prostate volumes between less than 50 and 50 cm3 or greater and between less than 37.5 and 37.5 cm3 or greater. Such a difference could explain the disparity in the detection of CaP between the groups. However, no statistically significant difference was found between these groups with regard to age, PSA, DRE, and Gleason scores. This suggests that both small and large glands are clinically similar. Consequently, the disparity in the false-negative rate between the groups can be explained only by the difference in prostate gland size. It has been suggested that there is relative undersampling of large prostate glands on sextant TRUSguided biopsy. Studies by Uzzo et al.,2 Karakiewicz et al.,3 and Letran et al.11 found that the positive yield of a single sextant TRUS-guided biopsy decreased as the prostate volume increased and seem to support this hypothesis. This has caused several investigators to increase the number of biopsy cores obtained in their subjects empirically in an 169
attempt to increase the detection rate of CaP. Norberg et al.,12 using a protocol performing 8 to 10 biopsy cores, showed a 15% increase in the positive biopsy rate. Eskew et al.,4, by adding two lateral biopsies to the sextant biopsy, increased the positive biopsy rate by 35%. Chen et al.,13 in a clinical trial comparing sextant biopsy to an 11-core multisite protocol in which each patient served as his own control, showed an increased positive biopsy rate when an additional 5 cores were added to the standard 6 cores. To our knowledge, our study is the first to illustrate the relationship between prostate volume and the percentage of CaP missed on the initial biopsy in men who underwent a repeat prostate biopsy. The increase in the false-negative rate with increasing prostate volume supports the suggestion that glands with large volumes are relatively undersampled. This undersampling of large glands is explained in that the volume of the sextant prostate biopsy specimen is fixed and therefore would represent a proportionally smaller percentage of tissue in large compared with small glands. In addition, in a standard sextant biopsy pattern, more areas of prostatic tissue will be unsampled between each biopsy site, thereby increasing the likelihood of missing an area or CaP. Another possible explanation for the decreased CaP detection rate in large glands was proposed by Chen et al.14 They observed that the proportion of low tumor volume is higher in large glands. In examining radical prostatectomy specimens, they found that 33% of prostates greater than 50 cm3 had small-volume CaP (0.5 cm3 or less) compared with 16% of glands less than 30 cm3 and 14% of glands between 30 and 50 cm3. This would make the detection of CaP more difficult in the larger glands using the standard sextant biopsy. The impact of missing small-volume CaP, however, is unknown, because it is believed that tumors with a volume less than 0.5 cm3 may be clinically insignificant.15 Although the evidence strongly suggests an inverse relation between prostate volume and the ability of sextant TRUS-guided biopsy to detect CaP, no consensus has been reached on how to best sample the prostates to detect CaP better. Increasing the number of biopsy cores may not be necessary in all patients. In a recent study by Naughton et al.,16 no improvement occurred in the detection rate when the number of biopsy cores was increased from 6 to 12. They suggested that a higher threshold number of biopsy cores might be needed to improve the detection rate and that the ideal number of biopsy cores may depend on prostate size and/or CaP volume. By sampling the transition zone in prostates greater than 50 cm3, Chang et al.17 increased the CaP detection rate by 13% 170
compared with peripheral zone biopsies alone. Terris,18 in her review of extended field biopsy, recommended taking additional cores only in certain situations, including prostate volumes greater than 30 cm3 and abnormal DRE findings and in men who continue to have a clinical indication for a repeat biopsy. By narrowing down the indications for a more extensive biopsy protocol, the number of men undergoing this relatively uncomfortable procedure and its associated morbidity would be limited. Although it is generally accepted that the amount of pain during TRUS-guided biopsy of the prostate is associated with the number of biopsy cores obtained,19 a recent prospective trial comparing 6 versus 12-core biopsies did not reveal a significant difference in the pain experienced between both groups.20 However, the rate of hematochezia and hematospermia was significantly increased in the extended biopsy group. Therefore, the gain in the detection rate of CaP must be measured against the clinical significance of this finding and the resulting morbidity associated with the procedure. Additional studies are needed to better determine the appropriate number of prostate biopsies for each individual patient. Our results suggest that prostate volume is a key factor in choosing patients for a more extensive biopsy protocol. CONCLUSIONS We found a statistically significant inverse relationship between prostate volume and the ability of sextant TRUS-guided biopsy to detect CaP. These findings illustrate the inadequacy of TRUSguided sextant biopsy in detecting CaP in men with large prostates and that more extensive biopsy strategies may need to be selectively used. REFERENCES 1. Hodge KK, McNeal JE, Terris MK, et al: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 142: 71–74, 1989. 2. Uzzo RG, Wei JE, Waldbaum RS, et al: The influence of prostate size on cancer detection. Urology 46: 831–836, 1995. 3. Karakiewicz PI, Bazinet M, Aprikian AG, et al: Outcome of sextant biopsy according to gland volume. Urology 49: 55– 59, 1997. 4. Eskew LA, Bare RL, and McCullough DL: Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 157: 199 –202, 1997. 5. Levine MA, Ittman M, Melamed J, et al: Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 159: 471–475, 1997. 6. Keetch DW, Catalona WJ, and Smith DS: Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol 151: 1571–1574, 1994. 7. Lui PD, Terris MK, McNeal JE, et al: Indications for ultrasound guided transition zone biopsies in the detection of prostate cancer. J Urol 153 (3 Pt 2): 1000 –1003, 1995. UROLOGY 61 (1), 2003
8. Fleshner NE, O’Sullivan M, and Fair WR: Prevalence and predictors of a positive repeat transrectal ultrasound guided needle biopsy of the prostate. J Urol 158: 505–508, 1997. 9. Schmid HP, McNeal JE, and Stamey TA: Observations on the doubling time of prostate cancer: the use of serial prostate specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 71: 2031–2040, 1993. 10. Epstein JI, Walsh PC, Akingba G, et al: The significance of prior benign needle biopsies in men subsequently diagnosed with prostate cancer. J Urol 162: 1649 –1652, 1999. 11. Letran JL, Meyer GE, Loberiza FR, et al: The effect of prostate volume on the yield of needle biopsy. J Urol 160: 1718 –1721, 1998. 12. Norberg M, Egevad L, Holmberg L, et al: The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. Urology 50: 562–566, 1997. 13. Chen ME, Kamoi K, Troncoso PT, et al: New biopsy strategy detects prostate cancers missed by conventional sextant biopsies (abstract). J Urol 161: 322, 1999.
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14. Chen ME, Troncoso P, Johnston D, et al: Prostate cancer detection: relationship to prostate size. Urology 53: 764 – 768, 1999. 15. Stamey TA, Freiha FS, McNeal JE, et al: Localized prostate cancer: relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 71: 933–938, 1993. 16. Naughton CK, Miller DC, Mager DE, et al: A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. J Urol 164: 388 –392, 2000. 17. Chang JJ, Shinohara K, Hovey RM, et al: Prospective evaluation of systematic sextant transition zone biopsies in large prostate for cancer detection. Urology 52: 89 –93, 1998. 18. Terris MK: Extended field prostate biopsies: too much of a good thing? Urology 55: 457–460, 2000. 19. Soloway MS, and Obek C: Periprostatic local anesthesia before ultrasound guided prostate biopsy. J Urol 163: 172– 173, 2000. 20. Naughton CK, Ornstein DK, Smith DS, et al: Pain and morbidity of transrectal ultrasound guided prostate biopsy: a prospective randomized trial of 6 versus 12 cores. J Urol 163: 168 –171, 2000.
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INFLUENCE OF PROSTATE VOLUME IN THE DETECTION OF PROSTATE CANCER JAY B. BASILLOTE, NOEL A. ARMENAKAS, DAVID A. HOCHBERG,
AND
JOHN A. FRACCHIA
ABSTRACT Objectives. To assess the influence of prostate volume on prostate cancer (CaP) detection in men who underwent repeated sextant transrectal ultrasound biopsy of the prostate. Methods. Between September 1991 and September 2000, 4376 men underwent sextant transrectal ultrasound-guided biopsy of the prostate. Of the 4376 men, 556 underwent repeat biopsy because of persistent prostate-specific antigen elevation (greater than 4 ng/mL) and/or an abnormal digital rectal examination or suspicious pathologic findings. The percentage of CaP missed on the initial biopsy and detected on the repeat biopsy between arbitrary prostate volumes of less than 50 and 50 cm3 or greater and between less than 37.5 and 37.5 cm3 or greater, the median prostate volumes of men with CaP, were compared. Patient age, prostate-specific antigen level, digital rectal examination findings, and Gleason score in each volumetric cutoff group were also compared. Results. CaP was detected in 22% of men who underwent a repeat biopsy. The percentage of CaP missed on the initial biopsy but subsequently detected on the repeat biopsy consistently increased as the volume increased. A statistically significant difference in the percentage of CaP not detected on the initial biopsy was found between prostate volumes of less than 50 and 50 cm3 or greater and between less than 37.5 and 37.5 cm3 or greater (P ⬍0.05). No statistically significant difference in prostate-specific antigen, age, digital rectal examination, or Gleason score was found between each volumetric cutoff group. Conclusions. A significant percentage of men are diagnosed with CaP after a repeat biopsy. We have demonstrated that the percentage of CaP missed on the initial biopsy and detected on the repeat biopsy increases as the prostate volume increases. The results of our study suggest that in men with large prostates, traditional sextant biopsies may not be adequate to detect CaP. UROLOGY 61: 167–171, 2003. © 2003, Elsevier Science Inc.
S
ince its introduction by Hodge et al.1 in 1989, the systematic sextant biopsy method has become a routine approach for the diagnosis of prostate cancer (CaP). Notwithstanding its widespread acceptance, several studies have suggested that sextant biopsy alone may not provide a reliable detection rate for CaP. Uzzo et al.2 and Karakiewicz et al.3 in their analyses of men who underwent a single biopsy of the prostate showed that the yield of a positive sextant biopsy decreased with increasing prostate volume. Several factors were proposed as the rationale for the differing incidence rates of CaP according to gland volume, including “better” From the Division of Urology, Lenox Hill Hospital, New York, New York; and Private Practice, Tampa, Florida Reprint requests: Jay B. Basillote, M.D., Lenox Hill Hospital, 100 East 77th Street, New York, NY 10021 Submitted: February 5, 2002, accepted (with revisions): August 26, 2002 © 2003, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
sampling of smaller glands relative to larger glands. To improve the inverse relation between prostate volume and sextant biopsy yield, the investigators of several studies have suggested increasing the number of biopsy cores in men with large glands.4,5 A common clinical situation arises in which a persistently elevated prostate-specific antigen (PSA) and/or an abnormal digital rectal examination (DRE) is found after an initial negative biopsy. The positive repeat biopsy rate in this group of patients is 20% to 40%.6,7 Fleshner et al.8 described this as the false-negative rate of sextant biopsy in their evaluation of men who underwent a repeat biopsy 1 year after the initial negative biopsy. In our study, we assessed the effect of prostate volume on the likelihood of CaP not detected on the initial sextant biopsy. Although others have examined the effect of prostate volume on the yield of CaP in a single sextant biopsy setting, to our knowledge, 0090-4295/03/$30.00 PII S0090-4295(02)02103-9 167
this is the first analysis of the relation between prostate volume and the percentage of CaP not detected on the initial biopsy in a subset of men who underwent a repeat biopsy. MATERIAL AND METHODS At our institution, 4376 men underwent transrectal ultrasound (TRUS)-guided sextant biopsy of the prostate between August 1991 and September 2000. Of these, 556 men underwent a repeat biopsy after an initial negative biopsy. The indications for the repeat biopsies were a persistently abnormal PSA level and/or abnormal DRE findings (palpation by the clinician of a firm prostate or nodules) or, less commonly, the finding of suspicious histologic features on the initial biopsy, such as severe atypia or high-grade prostatic intraepithelial neoplasia. A cleansing enema was performed the morning of the biopsy, and all patients received prophylactic antibiotics the night before and for 48 hours after the procedure. Prostate imaging was performed using the Bruel & Kjaer 1860 (Marlborough, Mass) ultrasound machine with a 7.0-MHz biplanar probe. The biopsies were performed in the sagittal plane using the method described by Hodge et al.1 Triaxial distances at the maximal length (L), height (H), and width (W) of the prostate were measured, and the prostate volume was calculated using the well-described prolate ellipse formula (volume ⫽ /6 ⫻ L ⫻ W ⫻ H). Using an 18-gauge needle driven by a springloaded biopsy gun, tissue cores were obtained bilaterally from the base, mid-gland, and apex of the prostate. A total of six cores was obtained at each biopsy session. All biopsy material was assessed and classified according to the Gleason system when CaP was identified. The repeat biopsies were performed within a median of 14.6 months (range 4.9 to 22.1) of the initial negative biopsy. All men diagnosed with CaP after the initial and repeat biopsies were combined and grouped into ascending deciles of prostate volume. The percentage of CaP not detected on the initial biopsy and subsequently diagnosed on the repeat biopsy was calculated for each volume decile. Chi-square analysis was used to compare the percentage of CaP missed on the initial biopsy and subsequently detected on the repeat biopsy in men with prostate volumes less than 50 and 50 cm3 or greater and prostate volumes less than 37.5 and 37.5 cm3 or greater. The prostate volume as measured by TRUS during the initial biopsy was used in the analysis. Although the use of the cutoff volume of 50 cm3 was somewhat arbitrary, it represents the generally accepted cutoff range of large and small glands clinically and has been previously evaluated by Uzzo et al.2 This 50-cm3 cutoff also approximated the mean gland volume of all the men in our study. In addition, the 37.5-cm3 cutoff volume was chosen because it represents the median prostate volume of all the men found to have CaP in our study. Student’s t test was used to analyze any differences in the clinical characteristics on the basis of PSA level, patient age, DRE findings, and Gleason score, which may affect the positive biopsy rate in men with CaP, divided into cutoff volumes of 50 cm3 and 37.5 cm3.
RESULTS Of the 4376 men biopsied, 1325 (30.3%) were found to have CaP on the initial biopsy (group 1). Of the 3051 men with an initial negative biopsy, 556 underwent a repeat biopsy, of whom 125 (22%) were diagnosed with CaP (group 2). The indications for repeat biopsy were elevated PSA 168
FIGURE 1. Percentage of CaP missed on initial biopsy and subsequently detected on repeat biopsy in each volume decile.
with or without abnormal DRE findings in 469 (84.5%), abnormal DRE findings only in 32 (5.8%), prostatic intraepithelial neoplasia in 28 (5%), and atypia in 26 (4.7%). The mean age, PSA level, percentage with abnormal DRE findings, and prostate volume for group 1 versus group 2 was 68.7 ⫾ 7.8 years versus 68.6 ⫾ 9.0 years, 14.6 ⫾ 15.9 ng/mL versus 12.0 ⫾ 10.9 ng/mL, 38% versus 32%, and 43.1 ⫾ 25 cm3 versus 52 ⫾ 28.5 cm3, respectively. No statistically significant difference in the clinical characteristics between the two groups was found (P ⬎0.05). The median prostate volume of all men in our study and all the men with CaP detected (groups 1 and 2) was 52 cm3 and 37.5 cm3, respectively. The percentage of men with CaP missed on the initial biopsy but detected on the repeat biopsy for each volume decile is illustrated in Figure 1. As the prostate volume increased, the percentage of CaP subsequently diagnosed on the repeat biopsy after a negative initial biopsy consistently increased. When a cutoff volume of 50 cm3 was used, the percentage of CaP not detected in the less than 50 and 50 cm3 or greater groups was 6.5% and 13.7%, respectively. When the median volume of 37.5 cm3 was used as the cutoff, the percentage of CaP missed was 6.2% and 12.5% in the less than 37.5 and 37.5 cm3 or greater groups, respectively. Using the cutoff volume of 50 cm3, a statistically significant difference was found in the percentage of CaP not detected between men with prostate volumes less than 50 cm3and those with volumes 50 cm3 or greater (chi-square analysis, P ⬍0.05). This statistically significant difference was maintained when the cutoff volume of 37.5 cm3 was used (chi-square analysis, P ⬍0.05). The clinical characteristics of the men in group 2 (repeat biopsy) separated into prostate volumes less than 50 and 50 cm3 or greater and less than 37.5 and 37.5 cm3 or greater are summarized in Table I. No statistically significant difference was found between the small and large glands using either cutoff points when PSA, patient age, DRE, and Gleason grade were compared (P ⬎0.05). UROLOGY 61 (1), 2003
TABLE I. Clinical characteristics of subjects with CaP detected on repeat biopsy by prostate volume Mean PSA (P >0.05)
Prostate Volume (cm3) ⬍50 (n ⫽ 65) ⱖ50 (n ⫽ 60) ⬍37.5 (n ⫽ 15) ⱖ37.5 (n ⫽ 110)
11.1 12 10.4 11.9
⫾ ⫾ ⫾ ⫾
10.5 10.1 10.4 10.2
Mean Age (P >0.05) 67.7 68 67.6 67.9
⫾ ⫾ ⫾ ⫾
8.9 9 8.8 9
DRE* (P >0.05) 33 30 29 33
Mean Gleason Score (P >0.05) 6.7 6.4 6.6 6.5
⫾ ⫾ ⫾ ⫾
0.98 0.99 0.98 0.99
KEY: CaP ⫽ prostate cancer; PSA ⫽ prostate-specific antigen; DRE ⫽ digital rectal examination. * Percentage of men with positive or abnormal DRE findings.
COMMENT Despite the somewhat arbitrary conception of its method, the TRUS-guided sextant biopsy of the prostate has become the standard method for the detection of CaP. Although widely used, concern exists regarding its accuracy. Several studies have reported that 20% to 40% of men with an initially negative biopsy will subsequently be found to have CaP on a repeat biopsy.6,7 It is also known that the positive yield of a single sextant TRUS-guided biopsy decreases as the prostate volume increases.2,3 We therefore undertook this study to determine the applicability and accuracy of TRUS-guided sextant biopsy in the detection of CaP with varying prostate sizes. Our finding that 22% of men who underwent a repeat biopsy were found to have CaP concurs with previous reports. Fleshner et al.8 in their evaluation of 130 men who underwent a repeat biopsy at a mean of 12.8 months from the initial benign biopsy, found that 30% of these men had CaP, which they described as the false-negative rate of TRUSguided biopsy. In our study, the median inter-biopsy interval was 14.6 months. Although it is conceivable that a de novo tumor may have developed during the intervening period, it is unlikely that a de novo tumor had reached sufficient volume to be clinically detectable on a subsequent biopsy; it is well known that CaP has a relatively slow growth rate.9 Therefore, it can be assumed that the CaP detected on the repeat biopsies was probably missed on the initial biopsy and corresponds to the false-negative group. The results indicate that the percentage of CaP not detected on the initial sextant TRUS-guided biopsy and subsequently diagnosed on the repeat biopsy consistently increased with increasing gland size. A statistically significant difference in the rate of undetected CaP was seen between volumes less than 50 cm3 and those 50 cm3 or greater and less than 37.5 cm3 and 37.5 cm3 or greater. Specifically, CaP was missed and subsequently diagnosed on the repeat biopsy in 13.7% and 6.5% of men with a prostate volume 50 cm3 or greater and less than 50 cm3, respectively. Consequently, the UROLOGY 61 (1), 2003
false-negative rate more than doubled as the prostate volume exceeded 50 cm3. This is a noteworthy finding even though most men with CaP in our study had a prostate volume of less than 50 cm3 (median 37.5), because more than one half of the men who were biopsied had a prostate volume greater than 50 cm3 (median 52). This indicates that more than one half of all men biopsied in our study were potentially exposed to a significantly higher risk of missing CaP. These results concur with the findings of Epstein et al.10 who, using radical prostatectomy specimens, found a 32.5% likelihood of a prior benign biopsy in prostate volumes of 75 cm3 or greater compared with 15.2% for prostate volumes less than 75 cm3. Our study, however, differs from theirs in that we assessed men diagnosed with CaP by prostate biopsy and they selected a subgroup of patients who subsequently underwent radical prostatectomy. The higher prostate volumes in their study can be attributed to the use of a more select group of patients and also to the more accurate measurement of the prostate volume with the surgical specimen. We also considered a possible difference in the clinical characteristics of men with prostate volumes between less than 50 and 50 cm3 or greater and between less than 37.5 and 37.5 cm3 or greater. Such a difference could explain the disparity in the detection of CaP between the groups. However, no statistically significant difference was found between these groups with regard to age, PSA, DRE, and Gleason scores. This suggests that both small and large glands are clinically similar. Consequently, the disparity in the false-negative rate between the groups can be explained only by the difference in prostate gland size. It has been suggested that there is relative undersampling of large prostate glands on sextant TRUSguided biopsy. Studies by Uzzo et al.,2 Karakiewicz et al.,3 and Letran et al.11 found that the positive yield of a single sextant TRUS-guided biopsy decreased as the prostate volume increased and seem to support this hypothesis. This has caused several investigators to increase the number of biopsy cores obtained in their subjects empirically in an 169
attempt to increase the detection rate of CaP. Norberg et al.,12 using a protocol performing 8 to 10 biopsy cores, showed a 15% increase in the positive biopsy rate. Eskew et al.,4, by adding two lateral biopsies to the sextant biopsy, increased the positive biopsy rate by 35%. Chen et al.,13 in a clinical trial comparing sextant biopsy to an 11-core multisite protocol in which each patient served as his own control, showed an increased positive biopsy rate when an additional 5 cores were added to the standard 6 cores. To our knowledge, our study is the first to illustrate the relationship between prostate volume and the percentage of CaP missed on the initial biopsy in men who underwent a repeat prostate biopsy. The increase in the false-negative rate with increasing prostate volume supports the suggestion that glands with large volumes are relatively undersampled. This undersampling of large glands is explained in that the volume of the sextant prostate biopsy specimen is fixed and therefore would represent a proportionally smaller percentage of tissue in large compared with small glands. In addition, in a standard sextant biopsy pattern, more areas of prostatic tissue will be unsampled between each biopsy site, thereby increasing the likelihood of missing an area or CaP. Another possible explanation for the decreased CaP detection rate in large glands was proposed by Chen et al.14 They observed that the proportion of low tumor volume is higher in large glands. In examining radical prostatectomy specimens, they found that 33% of prostates greater than 50 cm3 had small-volume CaP (0.5 cm3 or less) compared with 16% of glands less than 30 cm3 and 14% of glands between 30 and 50 cm3. This would make the detection of CaP more difficult in the larger glands using the standard sextant biopsy. The impact of missing small-volume CaP, however, is unknown, because it is believed that tumors with a volume less than 0.5 cm3 may be clinically insignificant.15 Although the evidence strongly suggests an inverse relation between prostate volume and the ability of sextant TRUS-guided biopsy to detect CaP, no consensus has been reached on how to best sample the prostates to detect CaP better. Increasing the number of biopsy cores may not be necessary in all patients. In a recent study by Naughton et al.,16 no improvement occurred in the detection rate when the number of biopsy cores was increased from 6 to 12. They suggested that a higher threshold number of biopsy cores might be needed to improve the detection rate and that the ideal number of biopsy cores may depend on prostate size and/or CaP volume. By sampling the transition zone in prostates greater than 50 cm3, Chang et al.17 increased the CaP detection rate by 13% 170
compared with peripheral zone biopsies alone. Terris,18 in her review of extended field biopsy, recommended taking additional cores only in certain situations, including prostate volumes greater than 30 cm3 and abnormal DRE findings and in men who continue to have a clinical indication for a repeat biopsy. By narrowing down the indications for a more extensive biopsy protocol, the number of men undergoing this relatively uncomfortable procedure and its associated morbidity would be limited. Although it is generally accepted that the amount of pain during TRUS-guided biopsy of the prostate is associated with the number of biopsy cores obtained,19 a recent prospective trial comparing 6 versus 12-core biopsies did not reveal a significant difference in the pain experienced between both groups.20 However, the rate of hematochezia and hematospermia was significantly increased in the extended biopsy group. Therefore, the gain in the detection rate of CaP must be measured against the clinical significance of this finding and the resulting morbidity associated with the procedure. Additional studies are needed to better determine the appropriate number of prostate biopsies for each individual patient. Our results suggest that prostate volume is a key factor in choosing patients for a more extensive biopsy protocol. CONCLUSIONS We found a statistically significant inverse relationship between prostate volume and the ability of sextant TRUS-guided biopsy to detect CaP. These findings illustrate the inadequacy of TRUSguided sextant biopsy in detecting CaP in men with large prostates and that more extensive biopsy strategies may need to be selectively used. REFERENCES 1. Hodge KK, McNeal JE, Terris MK, et al: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 142: 71–74, 1989. 2. Uzzo RG, Wei JE, Waldbaum RS, et al: The influence of prostate size on cancer detection. Urology 46: 831–836, 1995. 3. Karakiewicz PI, Bazinet M, Aprikian AG, et al: Outcome of sextant biopsy according to gland volume. Urology 49: 55– 59, 1997. 4. Eskew LA, Bare RL, and McCullough DL: Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 157: 199 –202, 1997. 5. Levine MA, Ittman M, Melamed J, et al: Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 159: 471–475, 1997. 6. Keetch DW, Catalona WJ, and Smith DS: Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol 151: 1571–1574, 1994. 7. Lui PD, Terris MK, McNeal JE, et al: Indications for ultrasound guided transition zone biopsies in the detection of prostate cancer. J Urol 153 (3 Pt 2): 1000 –1003, 1995. UROLOGY 61 (1), 2003
8. Fleshner NE, O’Sullivan M, and Fair WR: Prevalence and predictors of a positive repeat transrectal ultrasound guided needle biopsy of the prostate. J Urol 158: 505–508, 1997. 9. Schmid HP, McNeal JE, and Stamey TA: Observations on the doubling time of prostate cancer: the use of serial prostate specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 71: 2031–2040, 1993. 10. Epstein JI, Walsh PC, Akingba G, et al: The significance of prior benign needle biopsies in men subsequently diagnosed with prostate cancer. J Urol 162: 1649 –1652, 1999. 11. Letran JL, Meyer GE, Loberiza FR, et al: The effect of prostate volume on the yield of needle biopsy. J Urol 160: 1718 –1721, 1998. 12. Norberg M, Egevad L, Holmberg L, et al: The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. Urology 50: 562–566, 1997. 13. Chen ME, Kamoi K, Troncoso PT, et al: New biopsy strategy detects prostate cancers missed by conventional sextant biopsies (abstract). J Urol 161: 322, 1999.
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