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© 1999 American Society for Clinical Oncology Declining Rates of Extracapsular Extension After Radical Prostatectomy: Evidence for Continued Stage MigrationFrom the Section of Urologic Oncology, Department of Urology, and Departments of Radiation Oncology and Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Eric A. Klein, MD, Department of Urology, Desk A100, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; email kleine{at}ccf.org
PURPOSE: Prostate-specific antigen (PSA)-based screening is responsible for a profound clinical stage migration in newly detected prostate cancers. Extracapsular extension (ECE) is an important predictor of outcome after radical prostatectomy (RP). We examined trends in the rate of ECE for cancers detected by PSA screening in 731 RP specimens between 1987 and 1997, when screening became routine urologic practice in the United States. METHODS: The rates of ECE were examined in 311 prostates with nonpalpable (stage T1c) disease and 420 with palpable but clinically localized (stage T2) disease. Specimens were step-sectioned and examined by a senior pathologist. Rates of ECE were compared with respect to time, and logistic regression was used to identify predictors of ECE. RESULTS: The rate of ECE decreased from 81% to 36% during the 10-year observation period. Multivariateanalysis involving clinical tumor stage, preoperative serum PSA level, and Gleason score demonstrated that year of treatment was an independent predictor of ECE, with a two-fold reduction of risk occurring during the study period (P < .001; odds ratio, 1.96; 95% confidence interval, 1.37 to 2.78). CONCLUSION: PSA screening has resulted in a downward trend in pathologic stage in clinically localized prostate cancer, independent of preoperative PSA level, tumor stage, and Gleason score. This time-dependent downward stage migration suggests the need for continuous updating of predictive nomograms and caution in interpreting differences in contemporarily treated patients compared with historical controls. Further study is needed to determine whether this trend will translate into improved disease-free survival.
PROSTATE-SPECIFIC antigen (PSA)-based screening has been responsible for a marked stage migration in newly diagnosed prostate cancers. In the pre-PSA era, when prostate cancer was diagnosed by digital rectal examination (DRE) or when prostatic symptoms were evident, the proportion of clinical organ-confined tumors found was one half that discovered in the PSA era.1-3 Multiple longitudinal and cross-sectional studies have confirmed that PSA testing results in the discovery of prostate cancer earlier in the natural history of the disease.3-8 Furthermore, since the start of the PSA era, there has been a profound increase in the number of nonpalpable (clinical stage T1c) tumors found, along with a decrease in the number of palpable (T2) tumors.9-12 Several recent studies have suggested that extracapsular extension (ECE), defined as tumor extending into extraprostatic tissue, is an important predictor of adverse outcome after radical prostatectomy (RP).13-15 ECE occurs in 25% to 48% of specimens in large RP series,16-20 and one study has suggested that ECE is more important than margin status in predicting outcome, especially in the case of tumors with Gleason scores of 5 to 7 that are common in this screening era.13 In this study, we examined rates of ECE in a large cohort of patients with clinically localized prostate cancer diagnosed by PSA screening during the 10-year interval (1987 to 1997) when screening for prostate cancer became a routine part of urologic practice in the United States.
Study Population Included in the study were all patients with clinically localized prostate cancer diagnosed by PSA screening (all had PSA levels of > 4.0 ng/mL) and treated with RP without neoadjuvant hormone therapy at our institution between 1987 and 1997. Serum PSA levels were determined using Abbott IMX (Abbott Laboratories, Abbott Park, IL) or Tosoh assays (Tosoh Medics, South San Francisco, CA). The study population consisted of 731 patients: 311 with nonpalpable (clinical stage T1c [1992 American Joint Committee on Cancer criteria21]) disease and 420 with palpable but clinical organ-confined (clinical stage T2a to T2c) disease. All patients underwent standard retropubic RP, as previously described.22,23
Pathologic Evaluation Of the 731 specimens, more than 98% were evaluated by a single pathologist (H.S.L.) to determine the absence or presence and extent of ECE and findings were entered into a computerized database. ECE was defined as histologic evidence of prostate cancer in extraprostatic tissue. For the purposes of this study, focal and established ECE were not distinguished.
Statistical Analysis
Data were grouped by 2-year intervals for ease of presentation. Trends in the presenting clinical and histologic characteristics for all 731 patients are included in Table 1. The number of patients eligible for study inclusion increased steadily. There was a statistically significant decrease in mean age at the time of diagnosis, from 64.8 years (in 1987 to 1989) to 62.7 years (in 1996 to 1997) (P = .02, r2 = .89, 95% confidence limits, -0.68, -0.14). A statistically significant increase in the proportion of nonpalpable tumors was also noted, from no cases (in 1987 to 1989) to the majority of cases (64%) (in 1995 to 1997) (P < .0001). Mean preoperative serum PSA levels decreased slightly during the study, but this decrease was not statistically significant (P = .07, r2 = .71, 95% confidence limits, -6.09, 0.43). Finally, although there was a statistically significant trend toward diagnosis of fewer high-grade (Gleason score  7) tumors on biopsy samples (P = .03), this was not reflected in assigned scores for the surgical specimens—the proportion with high-grade tumors remained constant over the 10-year period (P = .26).
The clinical and pathologic characteristics of the patients with and those without ECE are listed in Table 2. The overall rate of ECE for the whole study group decreased substantially, from 81% in 1987 to 36% in 1997 (P < .0001, Fig 1). Furthermore, the rate of ECE decreased in each period across tumor stage categories (Fig 2), PSA levels (Fig 3), and Gleason scores (Figs 4 and 5), although the rate remained high for tumors with surgical Gleason scores of 8 to 10. For nonpalpable (stage T1c) tumors, the rate of ECE decreased from 62% to 28% (P = .027), and for palpable (T2) tumors from 81% to 51% (P = .003) during the study period (Fig 2). Similar decreases in ECE rate were noted for groups defined by preoperative serum PSA levels (Fig 3): from 77% to 32% for the group with preoperative PSA levels of 4.1 to 10.0 ng/mL (P < .0001), from 83% to 55% for the group with PSA levels between 10.1 and 20.0 ng/mL (P = .014), and from 87% to 72% for those with PSA levels of more than 20 ng/mL (P = .15). The decrease in rates of ECE did not reach statistical significance in those with preoperative PSA levels of more than 20 ng/mL, because of the small number of patients in this group (n = 73).
Similar decreases in ECE rate were noted for all biopsy Gleason scores (Fig 4). For biopsy Gleason scores of 2 to 6, the rate decreased from 70% to 35% (P < .0001) during the study period; for a biopsy Gleason score of 7, from 100% to 42% (P < .0001), and for biopsy Gleason scores of 8 to 10, from 100% to 50% (P = .13). The decrease in ECE rate for biopsy Gleason scores of 8 to 10 did not reach statistical significance, because of the small number of patients in this group (n = 47). Decreases in ECE rates for groups defined by surgical Gleason scores (except for surgical Gleason scores of 8 to 10) (Fig 5) paralleled those for groups defined by biopsy Gleason scores. Logistic regression analysis involving age, race, family history, clinical stage, pretreatment PSA level, and biopsy Gleason score revealed year of treatment to be an independent predictor of ECE (P < .001; odds ratio [OR], 1.96; 95% confidence interval [CI], 1.37 to 2.78) (Table 3). When year of treatment was defined as a continuous variable, it remained an independent predictor of ECE, with an OR of 1.17 (P < .0001, 95% CI, 1.09 to 1.25).
In this study, we examined rates of ECE in RP specimens over a 10-year period from men with localized prostate cancer detected by PSA screening. Using standardized pathologic analysis, with interpretation by a single experienced pathologist in more than 98% of cases, we found a statistically significant, two-fold decrease in the rate of ECE during the study period (P < .001, OR 1.96, 95% CI, 1.37 to 2.78 (Table 3 and Fig 1). The observed decrease in ECE rate occurred despite a slight but statistically nonsignificant decrease in mean levels of preoperative serum PSA and a stable proportion of patients with high-grade (Gleason score 7) tumors on surgical specimens (Table 1). Furthermore, when grouping by known preoperative risk factors was performed, the decrease in ECE rate was seen for all clinical tumor stages, preoperative serum PSA levels, biopsy Gleason scores, and all but the highest surgical Gleason scores (Figs 2 through 5). The results suggest that in addition to previously reported effects on migration to earlier clinical stage disease, PSA screening also causes an important downward pathologic stage migration, resulting in more favorable pathologic parameters for each clinical stage. This observation has important implications for predicting the likelihood of adverse pathologic factors on the basis of pretreatment clinical characteristics, counseling patients on their likelihood of cure with definitive therapy, and comparing results of more recently treated patients with historical controls. That PSA-based screening has induced a profound downward migration in clinical stage among newly diagnosed prostate cancers has been amply demonstrated during the last several years. The National Prostate Cancer Detection Project demonstrated a reduction in the proportion of locally advanced (clinical stage T3) and metastatic (stage T1-4N0-1M1) tumors to less than 5% of all newly diagnosed cancers in 2,999 men who underwent serial screening (PSA screening, DRE, and transrectal ultrasonography) during a 5-year period,25 compared with a combined incidence of 41% for these stages determined in the 1982 American College of Surgeons' survey.26 Other studies in which changes in both clinical and pathologic staging in the pre-PSA era were compared with those in the PSA era have demonstrated a doubling of the proportion of organ-confined tumors found during the PSA era.1-3 For example, Thompson et al27 reported that only 33% of men in the pre-PSA era with DRE-detected cancers had pathologic organ-confined disease. Furthermore, Catalona et al2 found more pathologic organ-confined tumors in men who underwent initial and serial PSA-based screening compared with those with detection by DRE alone. A similar high rate of organ-confined disease was observed in the Hybritech study of 6,630 men who underwent RP for PSA-detected cancers.1 Other studies have shown that serum PSA level correlates directly with advancing clinical and pathologic stages.28-32 Prognosis after RP is closely linked to pathologic findings including Gleason score, margin status, and the presence of ECE. PSA screening has resulted in a decrease in the number of tumors with Gleason scores of 8 to 10, an increase in the number of tumors with Gleason scores of 5 to 7, and a marked reduction in rates of positive margins, the traditional pathologic end point for predicting surgical success or failure.12,14,23,33 The use of margin status after RP as a predictive end point is confounded by many factors, however, including the experience of the surgeon and the specifics of surgical technique, the experience of the pathologist, the thoroughness of pathologic analysis, and the fact that many patients with positive margins appear to be cured.23,32,34 Furthermore, the rate of positive surgical margins in contemporary series of RP patients has decreased to less than 15%, making margin status less important as a prognosticator.9,14,23,33 Because ECE is less likely to be influenced by variations in surgical experience or technique, it may be a better measure of biologic potential for tumor progression. Several observations support this proposition, including the observation that ECE is the strongest predictor of failure at 5 years in multivariate analysis of data from patients with negative margins after RP35 and the observation that ECE is more important than margin status in predicting outcome for the tumors with Gleason scores of 5 to 7 that are commonly seen in the screening era.13 These observations suggest that the observed decrease in rates of ECE during our study period are likely to translate into improved disease-free survival. They also suggest that reported improvements in outcome with other therapies for localized disease such as external beam radiation and interstitial brachytherapy may be related as much to downward pathologic stage migration as to improvements in specific therapeutic techniques. The decreasing rate of ECE in our study parallel that recently reported by Stamey et al.9 During a similar period (1988 to 1996), they observed a reduction in ECE rate from 60% to 25% (OR, 0.95; 95% CI, 0.94 to 1.98) in 896 men treated with RP, despite similar mean PSA levels before treatment and a stable percentage of high-grade tumors during the study. In another study, Soh et al11 found no significant reduction in the rate of ECE in 754 patients who underwent RP between 1983 and 1995. However, this study included a substantial proportion of men whose disease was diagnosed by transurethral prostatectomy and who had clinical stage T3 tumors, and the maximal observed rate of ECE was 45% in 1988, suggesting a substantial selection bias in favor of low-volume tumors even at the start of the PSA era. These investigators' reported rates of ECE during the last 3 years of observation (22% to 31%) are similar to the most recent rates in our series and those reported by Stamey et al.9 These observations have one other important implication. Nomograms based on the preoperative parameters of PSA level, clinical tumor stage, and Gleason score of the prostate biopsy specimen are frequently used in counseling men with newly diagnosed prostate cancer about treatment options and the probability of tumor eradication.32,36-38 These nomograms have been constructed from the pathologic analysis of RP specimens and represent historical probabilities on the likelihood of finding organ-confined disease. Our study suggests an ongoing downward pathologic stage migration for a given PSA level, clinical stage, and Gleason score, suggesting that such tables need to be updated continually to reflect time-related trends in pathologic stage. In conclusion, we have observed a significant downward trend in pathologic stage independent of other tumor characteristics in men with clinically localized prostate cancer treated with RP in the PSA era. These observations have important implications for predicting the likelihood of cure after definitive therapy and for the interpretation of results of historical and current treatment regimens. Additional study will be required to determine whether this pathologic stage migration will translate into improved disease-free survival.
1. 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 Urol151:1283-1290, 1994[Medline]
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Catalona WJ, Smith DS, Ratliff TL, et al: Detection of organ-confined prostate cancer is increased through prostate-specific antigen based screening. JAMA270:948-954, 1993 3. Mettlin C, Murphy GP, Lee F, et al: Characteristics of prostate cancers detected in a multimodality early detection program. Cancer72:1701-1708, 1993[Medline]
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Carter HB, Pearson JD, Metter JE, et al: Longitudinal evaluation of prostate specific antigen levels in men with and without prostate disease. JAMA267:2215-2220, 1992
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Helzlsouer KJ, Newby J, Comstock GW: Prostate-specific antigen levels and subsequent prostate cancer: Potential for screening. Cancer Epidemiol Biomarkers Prev1:537-540, 1992 6. Stenman UH, Hakama M, Knekt P, et al: Serum concentrations of prostate specific antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate cancer. Lancet344:1594-1598, 1994[Medline]
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Gann PH, Hennekens CH, Stampher MJ: A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer. JAMA273:289-294, 1995 8. Tibblin G, Welin L, Bergstrom R, et al: The value of prostate specific antigen in early diagnosis of prostate cancer: The study of men born in 1913. J Urol154:1386-1389, 1995[Medline] 9. Stamey TA, Donaldson AN, Yemoto CE, et al: Histological and clinical findings in 896 consecutive prostates treated only with radical retropubic prostatectomy: Epidemiologic significance of annual changes. J Urol 160:2412-2417, 1-24, 1998 10. Stephenson RA, Smart CR, James BC, et al: The fall in incidence of prostate carcinoma: On the down side of a prostate specific antigen induced peak in incidence—Data from the Utah Cancer Registry. Cancer77:1342-1348, 1995 11. Soh S, Kattan MW, Berkman S, et al: Has there been a recent shift in the pathological features and prognosis of patients treated with radical prostatectomy? J Urol157:2212-2218, 1997[Medline] 12. Stephenson RA: Population-based prostate cancer trends in the PSA era: Data from the SEER program. Monogr Urol19:1-24, 1998 13. Epstein JI, Partin AW, Sanregeot J, et al: Prediction of progression following radical prostatectomy: A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol20:286-292, 1996[Medline] 14. Pound CR, Partin AW, Epstein JI, et al: Prostate-specific antigen after anatomic radical retropubic prostatectomy: Patterns of recurrence and cancer control. Urol Clin North Am24:395-406, 1997[Medline] 15. Kupelian P, Katcher J, Levin H, et al: Correlation of clinical and pathologic factors with rising PSA profiles after radical prostatectomy alone for clinically localized prostate cancer. Urology48:249-260, 1996[Medline] 16. Partin AW, Pound CR, Clemens JQ, et al: Prostate-specific antigen after anatomic radical prostatectomy: The John Hopkins experience after ten years. Urol Clin North Am20:713-725, 1993[Medline] 17. Catalona WJ, Smith DS: 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol152:1837-1842, 1994[Medline] 18. Ohori M, Goad JR, Wheeler TM, et al: Can radical prostatectomy alter the progression of poorly differentiated prostate cancer? J Urol153:1160-1163, 1994 19. Zinke H, Oesterling JE, Blute ML, et al: Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J Urol152:1850-1857, 1994[Medline] 20. Hall GS, Kramer CE, Epstein JI: Evaluation of radical prostatectomy specimens: A comparative analysis of various sampling methods. Am J Surg Pathol16:315-324, 1992[Medline] 21. Fleming ID, Cooper JS, Hensen DE, et al (eds): AJCC Cancer Staging Handbook (ed 4). Philadelphia, PA, Lippincott-Raven, 1992 22. Klein EA: Early continence after radical prostatectomy. J Urol148:92-94, 1992[Medline] 23. Klein E, Kupelian P, Tuason L, et al: Initial dissection of the lateral fascia reduces the positive margin rate in radical prostatectomy. Urology51:766-773, 1998[Medline] 24. Hollander M, Wolfe DA: The one-way layout, in Nonparametric Statistical Methods. New York, NY, Wiley, 1973, pp 120-123 25. Mettlin C, Murphy GP, Babaian RJ, et al: The results of a five-year early prostate cancer detection intervention. Investigators of the American Cancer Society National Prostate Cancer Detection Project. Cancer77:150-159, 1996[Medline] 26. Murphy GP, Natarajan N, Pontes JE, et al: The national survey of prostate cancer in the United States by the American College of Surgeons. J Urol127:928-934, 1982[Medline] 27. Thompson IM, Ernst JJ, Gangai MP, et al: Adenocarcinoma of the prostate: Results of routine urological screening. J Urol32:690-694, 1984 28. Ercole CJ, Lange PH, Mathiesen M, et al: Prostate-specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostate cancer. J Urol138:1181-1184, 1987[Medline] 29. Stamey TA, Yang N, Hay AR, et al: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med317:909-916, 1987[Abstract] 30. Oesterling JE, Chan DW, Epstein JI, et al: Prostate-specific antigen in the preoperative and postoperative evaluation of localized prostate cancer treated with radical prostatectomy. J Urol139:766-772, 1988[Medline] 31. 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 Med324:1156-1161, 1991[Abstract] 32. Partin AW, Yoo JK, Carter HB, et al: The use of prostate-specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol150:110-114, 1993[Medline] 33. 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Partin AW, Kattan MW, Subong EN, et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: A multi-institutional update. JAMA277:1445-1451, 1997 Submitted January 15, 1999; accepted June 14, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 v > 10 ng/mL), clinical stage (T1 versus T2), biopsy Gleason score (
, T1c; 
, T2.
, PSA > 20.
