Since the beginning of the prostate-specific antigen (PSA) era in the. Characteristics of Insignificant Clinical T1c Prostate Tumors

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1 2001 Characteristics of Insignificant Clinical T1c Prostate Tumors A Contemporary Analysis Patrick J. Bastian, M.D. 1 Leslie A. Mangold, B.A., M.S. 1 Jonathan I. Epstein, M.D. 2 Alan W. Partin, M.D., Ph.D. 1,2 1 The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 2 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. BACKGROUND. The authors examined the cases of men who had undergone radical prostatectomy for low-volume clinical T1c prostate carcinoma that was judged to be insignificant on the basis of previously established preoperative clinicopathologic parameters. Pathologic findings subsequently were analyzed for correlations with extent of disease in an attempt to validate the contemporary usefulness of existing parameters for predicting the significance of prostate tumors. METHODS. A series of 237 men who had undergone radical prostatectomy for T1c disease between December 2000 and August 2003 was evaluated. Insignificant prostate carcinoma as assessed on biopsy was defined according to the 1994 Epstein criteria, which were as follows: prostate-specific antigen density 0.15 ng/ml, Gleason score 6, fewer than 3 cores containing prostate carcinoma, and 50% involvement of any core with prostate carcinoma. Postsurgical pathologic findings were analyzed for potential correlations with the Epstein criteria. RESULTS. According to the Epstein needle biopsy criteria, organ-confined prostate carcinoma was detected in 91.6% of all patients, whereas the remaining 8.4% of patients were found to have non-organ-confined disease. Comparison of pathologic findings and Epstein biopsy criteria revealed that alteration of the original criteria did not improve the detection of non-organ-confined prostate carcinoma. CONCLUSIONS. The findings made in the current study suggest that the majority of patients with T1c prostate carcinoma have insignificant disease. Furthermore, it was found that the Epstein criteria for identifying insignificant prostate carcinoma remained a useful tool in the making of treatment-related decisions. Cancer 2004; 101: American Cancer Society. KEYWORDS: prostate carcinoma, insignificant cancer, prostatectomy, prostatespecific antigen density. See editorial on pages , this issue. Supported by National Institutes of Health Specialized Programs of Research Excellence Grant P50CA Address for reprints: Alan Partin, M.D., Ph.D., The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, 600 North Wolfe Street, Jefferson Bldg., Room 157, Baltimore, MD 21287; Fax: (410) ; apartin@jhmi.edu Received July 7, 2004; accepted July 13, Since the beginning of the prostate-specific antigen (PSA) era in the early 1990s, an increasing number of cases of prostate carcinoma have been diagnosed solely on the basis of elevated PSA levels (T1c disease), rather than on the basis of suspicious findings on a digital rectal examination (T2 disease). 1,2 Because the prevalence of prostate carcinoma increased dramatically during the PSA era, clinicians feared that widespread PSA screening was leading to the detection of an unreasonable number of so-called clinically insignificant tumors and, in turn, to a marked increase in potentially unnecessary treatment. 3,4 Epstein et al. 5 developed PSA- and needle biopsy related criteria (namely, PSA density 0.15 ng/ml, the absence of adverse pathologic findings on biopsy [i.e., biopsy Gleason score 6], the presence of prostate carcinoma in fewer than 3 cores [from a 6-core biopsy 2004 American Cancer Society DOI /cncr Published online 15 September 2004 in Wiley InterScience (

2 2002 CANCER November 1, 2004 / Volume 101 / Number 9 sample], and the finding of no more than 50% prostate carcinoma involvement in any of these cores) for identifying insignificant prostate carcinoma. According to these criteria, in 1994, 79% of tumors with volume 0.5 cm 3 were organ confined and did not qualify as high-grade lesions at the time of radical prostatectomy. Among men who had undergone surgery and who had PSA density 0.15 ng/ml or any adverse findings on needle biopsy, 83% had tumors that were larger than 0.5 cm 3 in volume and/or non-organ-confined disease. There are several treatment options for patients with insignificant, small-volume prostate tumors; among these options are radical surgery, radiotherapy, and expectant management. Radical prostatectomy has proven to be an effective definitive treatment method, yielding excellent long-term results. 6,7 In the current study, we attempted to validate the 1994 Epstein criteria in a contemporary series ( ) by investigating whether these criteria (as assessed in pathologic specimens obtained from clinical T1c prostate tumors) continued to be indicative of small-volume, insignificant prostate carcinoma. MATERIALS AND METHODS The study population consisted of 237 men who had been diagnosed with clinical T1c prostate carcinoma. All participants had undergone anatomic radical retropubic prostatectomy with pelvic lymph node dissection at The Johns Hopkins Hospital (Baltimore, MD) between December 2000 and August Staging was performed according to the 1992 American Joint Committee on Cancer TNM system, with disease stages being based on tumor palpability. The initial PSA concentration was assessed before therapeutic intervention. Tissue samples obtained via transrectal ultrasound biopsy were graded according to the Gleason system. All patient data were reviewed retrospectively as part of an internal review board approved, Health Insurance Portability and Accountability Act compliant protocol, and informed consent was obtained prior to surgery. According to Epstein et al., 5 insignificant prostate carcinoma was defined by the following features: PSA density 0.15 ng/ml, biopsy Gleason score 6, the presence of disease in fewer than 3 biopsy cores, and 50% prostate carcinoma involvement in each of these cores. All prostate biopsy samples obtained at outside institutions were reviewed at The Johns Hopkins Hospital. PSA density was calculated by dividing the absolute PSA value by the prostatic weight, which was defined as the weight of the surgical specimen minus the weight of the seminal vesicles. Due to the large number of external referrals, data on prostatic volume as assessed by transrectal ultrasonography and on number of biopsies performed were not available for the entire study population. Surgical specimens were evaluated using the Gleason grading system. Extraprostatic extension, when present, was subclassified as being either focal or established. 8 In addition, using a previously described method, 9 surgical resection margins were designated as being positive or negative. Seminal vesicle involvement was considered to be present upon penetration of the tumor into the muscular coat of the seminal vesicle. RESULTS Table 1 summarizes the characteristics of the patient population, and Table 2 summarizes the pathologic findings made in these patients after radical retropubic prostatectomy. Organ-confined disease was found on radical prostatectomy in 217 patients (91.6%). In addition, 11 patients with non-organ-confined disease had PSA densities of ng/ml. Of these 11 patients, 6 had 1 positive biopsy core, and the remaining 5 had 2 positive biopsy cores. Overall, 10 patients with non-organ-confined disease had 1 biopsy core that was positive for malignancy, and another 10 had 2 cores that were positive for malignancy. Fifteen of the 20 patients with non-organ-confined disease had a maximum core involvement level of less than 30%, whereas 5 (25%) had a maximum involvement level of 30 50%. Alteration of any one of the original Epstein criteria did not change the accuracy with which nonorgan-confined disease could be predicted. Patients with extraprostatic extension, negative surgical margins, and no seminal vesicle or lymph node involvement (n 13) had a mean PSA density of 0.11 ng/ml (median, 0.12 ng/ml; standard deviation, 0.02 ng/ ml), a mean maximum of 19.6% involvement in positive biopsy cores (median, 15%; standard deviation, 12.33%), and a mean of 1.4 positive cores per patient (median, 1; standard deviation, 0.51). Among patients with extraprostatic extension, positive surgical margins, and no seminal vesicle or lymph node involvement (n 5), the mean PSA density was 0.13 ng/ml (median, 0.14 ng/ml; standard deviation, 0.02 ng/ ml), the mean maximum percentage of involvement in positive cores was 34% (median, 40%; standard deviation, 13.42%), and the mean number of positive cores per patient was 1.8 (median, 2; standard deviation, 0.45). In two specimens, involvement of the seminal vesicle was detected in the absence of lymph node involvement; the PSA densities recorded in these specimens were 0.07 ng/ml and 0.10 ng/ml, respectively. In one of these two cases, one core was found to be

3 Insignificant Prostate Carcinoma/Bastian et al TABLE 1 Patient Characteristics Characteristic No. of patients (%) a All patients 237 Age at surgery (yrs) Mean 56.8 Median 57 Range Preoperative PSA value (ng/ml) Mean 4.77 Median 4.5 Range PSA density (ng/ml) Mean 0.10 Median 0.09 Range Prostatic weight in surgical specimen (g) Mean 53 Median 45.5 Preoperative Gleason score (100) Postoperative Gleason score 5 1 (0.43) (89.87) 7 21 (8.86) 8 2 (0.84) Undergraded 23 (9.7) Overgraded 1 (0.43) Graded correctly 213 (89.87) No. of positive biopsy cores (67.09) 2 78 (32.91) Maximum percent involvement in positive cores 5% 24 (10.13) 10% 64 (27) 15% 17 (7.17) 20% 42 (17.72) 25% 8 (3.38) 30% 37 (15.61) 35 40% 25 (10.55) 45 50% 20 (8.44) PSA: prostate-specific antigen. a Unless otherwise indicated. TABLE 2 Pathologic Findings on Radical Prostatectomy Finding No. of patients (%) Organ-confined prostate carcinoma 217 (91.57) With positive SM 0 (0) Non-organ-confined prostate carcinoma 20 (8.43) With EPE, negative SM, no SV involvement, and negative LN 13 With EPE, positive SM, no SV involvement, and negative LN 5 With SV involvement and negative LN 2 With positive LN 0 Total 237 (100) EPE: extraprostatic extension; SM: surgical margins; SV: seminal vesicle; LN: lymph nodes. positive for malignancy, and in the other case, two cores were found to be positive; however, in both cases, the percent involvement per positive core was 30%. Of the 217 patients with organ-confined prostate carcinoma, 2 had Gleason Grade 8 tumors, and 16 had Gleason Grade 7 tumors. Five patients with findings of Gleason Grade 7 disease in their surgical specimens had non-organ-confined prostate carcinoma. With a maximum follow-up duration of less than 3 years, useful information regarding biochemical recurrence was not available for patients in the current cohort. DISCUSSION Patients diagnosed with clinical T1c disease can choose from a range of treatment options, including expectant management, radical retropubic prostatectomy, and various forms of radiotherapy. The established combination of independent predictors of prostate carcinoma significance may help to identify patients who are more likely to have non-organ-confined disease. Despite the commonly feared possibilities of overdetection and overtreatment, non-organconfined disease was detected in only 8.4% of the current cohort. Although the 1994 Epstein criteria were developed to identify potentially insignificant tumors at radical prostatectomy and thus to ascertain patients who are suited to undergo expectant therapy, these criteria also could be used to identify men for whom definitive therapy, with its excellent cure rate, would be appropriate. Using these criteria in the current series, 91.6% of tumors were correctly identified as organ-confined lesions, which can be cured with radical surgery. Although it might have been possible to manage many of these tumors with expectant therapy, some tumors, if left untreated over time, may have grown incurable before they became palpable, especially in younger men with relatively long life expectancies. In 17 patients with organ-confined prostate carcinoma, Gleason Grade 7 or 8 disease was detected in a surgical specimen. Due to complete prostate removal, such patients are likely to be cured; however, they continue to be at risk for biochemical recurrence and/or disease progression. 10,11 Despite the commonly used core method, it is possible for the dominant tumor to go undetected on needle biopsy. It has been demonstrated that the probability of detecting prostate carcinoma and the accuracy of pathologic grading both increase with increasing number of biopsy cores obtained. 12,13 The number of cores found to be positive for malignancy also varies according to the number of cores obtained, as does the probability of detecting an elevated level of involvement in a given positive core. When the Epstein criteria were developed, the standard technique

4 2004 CANCER November 1, 2004 / Volume 101 / Number 9 in use at The Johns Hopkins Hospital was a sextant (i.e., six-core) biopsy procedure. In contrast, the protocol currently favored at our institution (and increasingly throughout the United States) involves the acquisition of cores per patient. In the current study, when a tumor was detected by needle biopsy and fewer than 3 cores were found to be positive for malignancy, with each core exhibiting 50% tumor involvement, the number of cores obtained and the number of positive cores (1 or 2) did not affect the identification of insignificant tumors. Another parameter that plays a role in the prediction of tumor significance using the Epstein criteria is the maximum percent involvement in positive cores. A hypothetic reduction in this figure from 50% to 30% would have caused the number of patients identified as having organ-confined disease to decrease by 2.1% (n 5); however, alteration of the Epstein criteria with respect to this parameter alone did not lead to an increase in the rate of detection of non-organ-confined disease. Originally, the finding of a moderate prostate tumor was considered to be biologically significant. 5 Only 15% of all patients with such tumors, which typically are curable, were found to carry a risk of disease progression 10 years after radical prostatectomy. In the original model for identifying insignificant tumors, age, reason for evaluation, method of detection, and transrectal ultrasonography findings were not predictive of the extent of nonpalpable prostate carcinoma; instead, the best model for ascertaining insignificant tumors included PSA density, needle biopsy findings, and serum PSA level. 5 In the current study, no difference was noted when these parameters were altered; however, insignificant tumors were documented in 16% of the 157 patients in the original series examined by Epstein et al., 5 who concluded that a watchful waiting approach consisting of serial PSA measurements and repeated biopsies may be appropriate in such cases. It is noteworthy that even in the current series of insignificant tumors (as identified using the Epstein criteria), 8.4% of all cases were classified as nonorgan-confined disease. Due to complete tumor removal and the subsequent presence of negative surgical margins, 15 of the 20 patients with non-organconfined disease in the current study were likely to have been cured, with the probability of biochemical recurrence, especially in cases without seminal vesicle involvement, being low. 10 In patients with positive surgical margins, the likelihood of biochemical recurrence also is relatively low, but such recurrences nonetheless remain a possibility. To date, no patient in the current cohort has developed a biochemical or clinical recurrence; thus, the true biologic significance of the tumors encountered in this contemporary series remains unknown at present. The mechanisms by which prostate carcinoma develops and progresses involve multiple genetic and epigenetic factors, all of which contribute to the heterogeneity of this malignancy. Taking advantage of recent rapid advances in our understanding of the molecular carcinogenesis of prostate carcinoma, new tests may provide information that is useful for screening, detection of disease, staging, and prognosis and that draws further distinction between patients who may benefit from immediate treatment and those who will not. 14,15 In the current analysis, it was found that the 1994 Epstein criteria continued to be useful in the recommendation of treatment options to patients and that these criteria were predictive of extent of disease. In combination with existing nomograms (e.g., Partin tables), these criteria will allow urologists to assess the benefits of treatment on a patient-bypatient basis. In conclusion, the results of the current study of men who underwent radical surgery for clinical T1c disease indicate that insignificant tumors can be found in the majority of patients with prostate carcinoma. In this setting, the 1994 Epstein criteria were found to remain a useful tool in the making of treatment-related decisions. REFERENCES 1. Soh S, Kattan MW, Berkman S, Wheeler M, Sciardino PT. Has there been a recent shift in the pathological features and prognosis of patients treated with radical prostatectomy? J Urol. 1997;157: Lerner SE, Seay TM, Blute ML, Bergstralh EJ, Barrett D, Zincke H. Prostate specific antigen detected prostate cancer (clinical Stage T1c): an interim analysis. J Urol. 1996;155: Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003;95: Etzioni R, Penson DF, Legler JM, et al. Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends. J Natl Cancer Inst. 2002;94: Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (Stage T1c) prostate cancer. JAMA. 1994;271: Khan MA, Han M, Partin AW, Epstein JI, Walsh PC. Longterm cancer control of radical prostatectomy in men younger than 50 years of age: update Urology. 2003; 62:86 92.

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