three after the most recent release in These modifications were based primarily on data from clinical, not pathological, staging [1].

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1 BJU INTERNATIONAL Urological Oncology PATHOLOGICAL T2 SUB-DIVISIONS AS A PROGNOSTIC FACTOR IN PROSTATE CANCER CASO ET AL. BJUI BJU INTERNATIONAL Pathological T2 sub-divisions as a prognostic factor in the biochemical recurrence of prostate cancer Jorge R. Caso, Matvey Tsivian, Vladimir Mouraviev, Thomas J. Polascik and Judd W. Moul Division of Urologic Surgery and Duke Prostate Center (DPC), Department of Surgery, Duke University Medical Center, Durham, NC, USA Accepted for publication 1 February 2010 Study Type Prognosis (case series) Level of Evidence 4 OBJECTIVE To determine the adequacy of T2 prostate cancer (PCa) sub-staging as an independent Predictor of biochemical disease-free survival (bdfs) after radical prostatectomy. MATERIALS AND METHODS The Duke Prostate Center database was queried for patients who underwent radical prostatectomy between 19 and 2007 and had 2 PCa, identifying 1990 cases. Prostate-specific antigen (PSA) recurrence was defined as a single value ng/ml. Kaplan Meier curves compared differences in bdfs between T2 sub-divisions. Multivariate analysis was performed, adjusting for age, pathological Gleason sum, surgical margin status, preoperative PSA, race, total tumour percentage and prostate weight on biochemical recurrence. RESULTS The mean age at surgery was 2 years, and 1% of patients were African-American. Median prostate weight was 40 g [interquartile range (IQR) 31 52] and median preoperative PSA was 5. (IQR ). Pathological Gleason score was in 57%, 7 in 3%, and in 5%; pathological T stage distribution was 1% T2a, % T2b, and 7% T2c; and percentage tumour involvement was 5% in 43%, between 5.1 and 10% in 24%, between 10.1 and 15% in 10%, and >15% in 19%. 3 (1.4%) patients had a biochemical recurrence after a median of 4. years (IQR 2.1.2) follow-up. bdfs was significantly (P = 0) higher for 2a disease than for 2b and 2c, which were comparable. Adjusting for demographic and other pathological variables, T2 sub-divisions lost statistical significance. CONCLUSIONS Pathological T2a prostate cancer has significantly higher bdfs than the 2b or 2c sub-groups in univariate but not multivariate analyses. Different pathological features should be explored to create more meaningfully predictive pathological T2 subdivisions. KEYWORDS prostate cancer, neoplasm staging, PSA, recurrence INTRODUCTION Although clinical prostate cancer (PCa) T2 sub-stage evaluation appears to be a useful independent predictor of biochemical disease-free survival (bdfs) [1], there is growing evidence that pathological T2 sub-staging does not have the same value [2 ]. After its introduction in 1992, the American Joint Committee on Cancer/ International Union Against Cancer (AJCC/ UICC) tumour, node, metastases system became the standard method in which PCa is clinically and pathologically staged [9]. The system has been modified over the years, changing from an original three T2 sub-divisions for pathological and clinical staging to two (1997 version), and again to three after the most recent release in These modifications were based primarily on data from clinical, not pathological, staging [1]. Biochemical recurrence (BCR) rates after radical prostatectomy can be as high as 30% [10]. Several risk factors have been identified, including surgical margin (SM) status [2,5,7,], pathological Gleason sum [2 5,], preoperative PSA [2 5,], prostate weight [11,12], and percentage tumour involvement (PTI) [13]. In the present study, we evaluate the contribution of pathological T2 substaging to the prediction of bdfs in a large cohort of men with pathologically localized disease and review the available literature. MATERIALS AND METHODS After approval from the Institutional Review Board, the Duke Prostate Center (DPC) database was analysed for patients who had undergone radical prostatectomy between 19 and 2007 for clinically localized disease. Only those patients who were found on subsequent pathological evaluation to have T2 PCa were included. We excluded patients with lymph node involvement and those who had previously been exposed to hormonal, chemotherapeutic or radiation therapy. A total of 1990 cases were identified for which demographic, clinical and pathological characteristics had been collected. Surgical procedures in the cohort included radical retropubic prostatectomy (n = 751, 37.%), 2010 BJU INTERNATIONAL 10, doi: /j x x 123

2 CASO ET AL. TABLE 1 Patient and tumour characteristics Median (interquartile Characteristic range) or % Age, years 2 (5 7) Race White 2 African-American 1 Other 2 Preoperative PSA 5. (4.2 7.) Prostate weight, g 40 (31 52) Pathological T2 stage T2a 1 T2b T2c 7 Gleason score PTI >15 20 Positive SM T2a 11.1 T2b 13. T2c 2.7 BCR 1.4 FU, years 4.5 (2.1.3) BCR, biochemical recurrence; FU, follow-up; PTI, percentage tumour involvement; SM, surgical margins. radical perineal prostatectomy (n = 93, 47%), and robot-assisted laparoscopic prostatectomy (n = 303, 15.2%). Prostatectomy samples were fixed in 10% neutral formalin. The apex and base were sectioned in the vertical parasagittal plane at 3-mm intervals. The seminal vesicles were sectioned parallel to the prostatic junction and submitted entirely for evaluation. The specimen was embedded in paraffin and sectioned at 5-μm thickness, with the remaining prostate serially sectioned perpendicular to the long axis of the gland. All specimens were initially evaluated by expert uropathologists at our institution, and were re-classified as the AJCC/UICC system evolved by reviewing pathology reports. Currently all records in the DPC database are staged according to the 2002 edition [9]. For pathological T2 organ-confined cancers, T2a corresponds to unilateral disease involving % of one lobe, T2b corresponds to unilateral disease involving >50% of one lobe, and T2c corresponds to bilateral disease. PSA recurrence was defined as a single value ng/ml after surgery. Univariate Kaplan Meier method and logrank comparison were used to assess the difference in bdfs between T2 sub-divisions. Proportional hazards regression was used to adjust for demographic, clinical and additional pathological variables. Race was classified as African-American and non- African-American. PSA values and prostate weights were log-transformed to approximate normal distribution. Percentage tumour involvement was classified as <5%, %, %, and >15%. Statistical analyses were performed using the SPSS v17 software (SPSS Inc, Chicago, IL, USA). P values <5 were considered significant. RESULTS Demographic and pathological characteristics of the entire cohort are shown in Table 1. At a median follow-up of 4.5 years, a total of 3 (1.4%) patients developed BCR. For 2a PCa, bdfs was 94.3, 9.4,.3 and 3.3% at 1, 3, 5, and 10 years, respectively; for 2b PCa it was 5.7, 0., 79.7 and 72%, and for 2c FIG. 1. Kaplan Meier biochemical disease-free survival curves for overall cohort. T2a N % T2b N % T2c N % PCa it was 9., 2., 79.3 and 72.7% (Fig. 1). bdfs was significantly (P = 0) higher for 2a disease than for either 2b or 2c, which were comparable. If sub-stratified by SM status, of the 490 patients with positive margins, 32.2% experienced a BCR compared with 13.9% who had negative margins (P < 01). With positive margins, 2a PCa bdfs rates were 7.5, 7.5, 71, and 71% at 1, 3, 5, and 10 years, respectively; for 2b PCa the rates were 79.4, 71.5, 71.5 and 71.5%, respectively, and for 2c PCa they were 1., 7.5, 2. and 52.3%, respectively. Conversely, if the margins were negative, 2a PCa bdfs rates were 95.2, 90.,.2, and 4.7% at 1, 3, 5, and 10 years, respectively; for 2b PCa they were., 2.1, 0.9 and 72.3%, respectively, and for 2c PCa they were 93,.7, 5. and 79.%, respectively (Fig. 2). Among patients with positive margins, there was no significant difference in bdfs between the T2 subgroups. However, in the margin-negative cohort, 2a showed significantly better bdfs than 2b (P = 04); 2b conferred the worst prognosis, as it was also significantly worse than 2c (P = 42). 2a bdfs was not statistically different from 2c. On multivariate analysis we adjusted for age, pathological Gleason sum, SM status, BJU INTERNATIONAL

3 PATHOLOGICAL T2 SUB-DIVISIONS AS A PROGNOSTIC FACTOR IN PROSTATE CANCER FIG. 2. (a) Kaplan Meier biochemical disease-free survival curves adjusted for positive surgical margin. (b) Kaplan Meier biochemical disease-free survival curves adjusted for negative surgical margin. preoperative PSA, race, PTI and prostate weight on BCR (Table 2). We found that higher pathological Gleason sum (P = 09), positive SM (P = <01) and lower prostate weight (P = 12) were significantly associated with PSA recurrence. African- a b American race had a trend towards significance (P = ) in conferring increased risk of recurrence. Pathological T2 stage sub-division lost significance in this multivariate model after adjusting for these factors. T2a N % T2b N % T2c N % T2a N % T2b N % T2c N % DISCUSSION The present study to our knowledge, the largest to date confirms that when adjusted for other risk factors, the 2a, 2b and 2c sub-groups confer no additional prognostic value. Staging of clinically localized prostate cancer evolved from the Whitmore Jewett system favoured in the 190s and early 1990s into the currently accepted AJCC/UICC system, most recently released in 2002 [9]. In the original 1992 version, there were three sub-divisions of T2 cancer corresponding to a unilaterally palpable nodule involving 50% (T2a) or >50% (T2b) of a lobe or bilaterally palpable nodules (T2c). This was simplified in 1997 to two sub-divisions, indicating palpable unilateral vs bilateral disease (T2a or T2b). It was subsequently found, however, that clinical staging of T2 disease into the T2a and T2b sub-groups as defined in the 1992 version was useful in stratifying risk for bdfs when performed by an expert surgeon [1]. The 2002 AJCC/UICC system restored the original three sub-classifications for T2 disease. These divisions persist in pathological staging, substituting the presence of cancer on microscopic evaluation for palpable nodularity. Evaluating prostatectomy specimens that straddle the time period before 1992 through the current era requires careful categorization with attention to potential pitfalls. Specimens taken before 1992 must be sub-categorized as T2a through T2c, and the samples from require re-classification. Additionally, tumours attached to and invading, but not penetrating, the capsule are reported as 2 in the present system but may have been classified as 3 in the former TNM classification from 197 [14]. Our database was updated to reflect current staging criteria. The presence of true 2b tumours has been questioned, as a mass occupying one-quarter of the prostate is unlikely to remain within a single lobe, and there is a high prevalence of prostate cancer multi-focality [15]. However, although at a lower proportion to 2a and 2c tumours, our study confirms the presence of 2b tumours in similar numbers to those reported by other groups analysing specimens obtained over a similar time period [3,]. An earlier report using the DPC database has demonstrated a trend towards a greater proportion of pathologically unilateral disease after PSA screening was introduced [1] BJU INTERNATIONAL 125

4 CASO ET AL. The usefulness of pathological T2 stage subdivision in predicting BCR in prostate cancer has been questioned previously [2,15]. Table 3 summarizes data from studies evaluating bdfs and pathological T2 stage sub-groups. On univariate analysis we found a significant difference in bdfs comparing 2a tumours with 2b and 2c tumours at 5 and 10 years; a trend towards significance has been noted elsewhere [3,7]. Other researchers previously found that tumour laterality, essentially a comparison between 2a and 2b vs 2c tumours, did not have independent prognostic significance [4,17]. A significant difference between these specific sub-groups was found in a large European study on univariate analysis; although it persisted in multivariate analysis for 2a vs 2c tumours there was nonsignificance when the 2 sub-groups were analysed as a whole [2]. Indeed, a multivariate model using pre-treatment PSA, SM status and Gleason score had slightly better accuracy than models that additionally used information from the 1997 or 1992/ staging systems [2]. It is notable that there was a much higher proportion of 2b tumours (%) [2] in their cohort than has been reported elsewhere when examining this association (0 19%) [1,3 7]. The factors noted on our multivariate analysis to be significantly correlated with bdfs are in agreement with other reports: SM status [2,5,7,], pathological Gleason sum [2 5,] and preoperative PSA [2 5,]. We also found prostate weight to be significant; to our knowledge this variable has not been analysed in the other articles reporting on differences in pathological T2 sub-stages, although higher prostate weights appear to be protective against BCR [11,12,1]. Our rate of positive SM is consistent with that found in similar series, which ranged from to 3% [4,5,7]. The prognostic impact of 2b was heightened in patients with a negative margin. This may be due to the size necessary to qualify as a 2b cancer, whereas 2c does not necessarily imply large tumour volume. Overall BCR rates for 2 tumours have been reported from 4 to 11% [2 4,], which is slightly lower than the 1.4% noted in the present study. This may, in part, be due to our more robust numbers at longer follow-up, as many cancers may recur after 5 years [10]. Interestingly, in the present study, percentage tumour involvement was not found to be an independent risk factor, although it has been noted to be so elsewhere [13,19]. This may be due to different stratifications in our study [13], as well as the highest group encompassing >15% tumour involvement, HR 95% CI P value Age at surgery African-American race PSA <01 PTI <5% (reference) % % >15% Prostate weight Positive SM <01 Pathological T stage T2a (reference) T2b T2c rather than the >20% used by others [19]. Likewise, race did not reach statistical significance on multivariate analysis, although a trend was noted. Race has been found to be an independent predictor of BCR elsewhere [1]. The present study has limitations inherent in its retrospective nature. Additionally, we did not calculate exact tumour volume, in part because assessment of this variable is quite laborious and is not routinely reported by our pathologists. There has also been a shift in pathological Gleason grading, which has evolved over time into a higher likelihood of more aggressive cancer being reported, which may have introduced a bias in this cohort [20]. Percentage tumour involvement is calculated in an imperfect manner, as has been previously reported [13]. Also, our statistics reflect BCR rates which, while suggestive, are not an adequate surrogate for cancer-specific TABLE 2 Multivariate analysis for prediction of biochemical recurrence (BCR) HR, hazard ratio; PTI, percentage tumour involvement; SM, surgical margins. TABLE 3 Association of sub-divisions of pathological organ-confined prostate cancer with biochemical recurrence-free survival (brfs) Study Years Number of patients FU (months) % of 2a-c 5-year brfs 10-year brfs T2a T2b T2c T2a T2b T2c T2a T2b T2c May et al. [] Mn Freedland et al. [4] Md Chun et al. [2] Md NA* van Oort et al. [7] Md DeCastro et al. [3] Md Hong et al. [5] NA NA* Kordan et al. [] Md NA 7.5 Present study Md *Results reported as Kaplan Meier curve. Mn, mean; Md, median; NA, not available BJU INTERNATIONAL

5 PATHOLOGICAL T2 SUB-DIVISIONS AS A PROGNOSTIC FACTOR IN PROSTATE CANCER survival, which may be a more appropriate endpoint. The present study offers the additional insight that pathological staging of localized PCa, as currently defined, is inadequate as an independent predictor of biochemical recurrence. 2a does have some prognostic value on univariate analysis compared with 2b and 2c, and consideration could be given to simplifying the scheme. In the future, different pathological features should be explored to create more meaningfully predictive pathological T2 sub-divisions. CONFLICT OF INTEREST None declared. Source of Funding: Supported by research funds from the Committee for Urologic Research, Education, and Development (CURED) of Duke University (to J.R.C., V.M. and J.W.M.). REFERENCES 1 Han M, Walsh PC, Partin AW, Rodriguez R. Ability of the 1992 and 1997 American Joint Committee on Cancer staging systems for prostate cancer to predict progression-free survival after radical prostatectomy for stage T2 disease. J Urol 2000; 14: Chun FK, Briganti A, Lebeau T et al. The 2002 AJCC 2 substages confer no prognostic information on the rate of biochemical recurrence after radical prostatectomy. Eur Urol 200; 49: 273 ; discussion DeCastro GJ, McCann T, Benson MC, McKiernan JM. Pathologic T2 stage subgroups and recurrence-free survival after radical prostatectomy. Urology 200; 72: Freedland SJ, Partin AW, Epstein JI, Walsh PC. Biochemical failure after radical prostatectomy in men with pathologic organ-confined disease: 2a versus 2b. Cancer 2004; 100: Hong SK, Han BK, Chung JS et al. Evaluation of 2 subdivisions in the TNM staging system for prostate cancer. BJU Int 200; 102: 1092 May F, Hartung R, Breul J. The ability of the American Joint Committee on Cancer Staging system to predict progressionfree survival after radical prostatectomy. BJU Int 2001; : van Oort IM, Witjes JA, Kok DE, Kiemeney LA, Hulsbergen-Van De Kaa CA. The prognostic role of the pathological T2 subclassification for prostate cancer in the 2002 Tumour- Nodes-Metastasis staging system. BJU Int 200; 102: Kordan Y, Chang SS, Salem S et al. Pathological stage T2 subgroups to predict biochemical recurrence after prostatectomy. J Urol 2009; 12: Prostate. In Green et al. eds. American Joint Committee on Cancer: AJCC Cancer Staging Manual, th edn. New York, NY: Springer, 2002: Ward JF, Blute ML, Slezak J, Bergstralh EJ, Zincke H. The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol 2003; 170: D Amico AV, Whittington R, Malkowicz SB, Schultz D, Tomaszewski JE, Wein A. A prostate gland volume of more than 75 cm 3 predicts for a favorable outcome after radical prostatectomy for localized prostate cancer. Urology 199; 52: Freedland SJ, Isaacs WB, Platz EA et al. Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: a search database study. J Clin Oncol 2005; 23: Rampersaud EN, Sun L, Moul JW, Madden J, Freedland SJ. Percent tumor involvement and risk of biochemical progression after radical prostatectomy. J Urol 200; 10: 571 ; discussion Tanaka M, Suzuki N, Nakatsu H, Murakami S, Matsuzaki O, Shimazaki J. Significance of capsular attachment and invasion of cancer tissues in prostate cancer. Int J Urol 2003; 10: Eichelberger LE, Cheng L. Does 2b prostate carcinoma exist? Critical appraisal of the 2002 TNM classification of prostate carcinoma. Cancer 2004; 100: Polascik TJ, Mayes JM, Sun L, Madden JF, Moul JW, Mouraviev V. Pathologic stage T2a and T2b prostate cancer in the recent prostate-specific antigen era: implications for unilateral ablative therapy. Prostate 200; : Mouraviev V, Sun L, Madden JF, Mayes JM, Moul JW, Polascik TJ. Prostate cancer laterality does not predict prostate-specific antigen recurrence after radical prostatectomy. Urology 2007; 70: Schroeck FR, Sun L, Freedland SJ, Jayachandran J, Robertson CN, Moul JW. Race and prostate weight as independent predictors for biochemical recurrence after radical prostatectomy. Prostate Cancer Prostatic Dis 200; 11: Ramos CG, Roehl KA, Antenor JA, Humphrey PA, Catalona WJ. Percent carcinoma in prostatectomy specimen is associated with risk of recurrence after radical prostatectomy in patients with pathologically organ confined prostate cancer. J Urol 2004; 172: Tsivian M, Sun L, Mouraviev V et al. Changes in Gleason Score grading and their effect in predicting outcome after radical prostatectomy. Urology 2009; 74: Correspondence: Judd W Moul, MD, Division of Urologic Surgery, Duke University Medical Center, Box 3707, Room 1573, Duke South- White Zone, Durham, NC 27710, USA. judd.moul@duke.edu Abbreviations: PCa, prostate cancer; BCR, biochemical recurrence; bdfs, biochemical disease-free survival; brfs, biochemical recurrence-free survival; SM, surgical margin; PTI, percentage tumour involvement BJU INTERNATIONAL 127