Evaluation of pt2 subdivisions in the TNM staging system for prostate cancer

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1 . JOURNAL COMPILATION 2008 BJU INTERNATIONAL Urological Oncology HONG et al. BJUI BJU INTERNATIONAL Evaluation of pt2 subdivisions in the TNM staging system for prostate cancer Sung Kyu Hong, Byung Kyu Han, Jae Seung Chung, Dong-Soo Park, Seong Jin Jeong, Seok-Soo Byun, Gheeyoung Choe* and Sang Eun Lee Departments of Urology and *Pathology, Seoul National University Bundang Hospital, Seongnam, Korea Accepted for publication 5 March 2008 OBJECTIVE To evaluate the subclassifications of pt2 diseases in tumour-nodes-metastases (TNM) staging system for prostate cancer. PATIENTS AND METHODS We retrospectively analysed the data of 372 patients who underwent radical retropubic prostatectomy (RRP) for pathologically organ-confined prostate cancer at our institution. Pathological staging of all subjects were re-evaluated using the 1997 and the 2002 TNM staging system for prostate cancer. Various clinicopathological features along with biochemical recurrencefree survival (BRFS) of pt2 subgroups were assessed. RESULTS Using the 2002 TNM staging criteria, 87 of the tumours (23.4%) were pt2a, and 284 (76.3%) were pt2c. Of all subjects, there was only one (0.3%) pathological 2002 T2b tumour identified. When subjects were classified according to the 1997 versions of the T2 subclassification (pt2a vs pt2b), the 1997 pt2a and pt2b cases showed no significant difference regarding BRFS (logrank P = 0.645) among those who were followed-up for >2 years after RRP. Also, pathological stage (1997 pt2a vs pt2b) was not a significant predictor of BRFS in either uni- or multivariate analysis (P = and P = 0.241, respectively). Only preoperative serum PSA level and pathological Gleason score along with positive surgical margin were significant predictors of PSA outcome after RRP on multivariate analysis. CONCLUSION Our results suggest that two- or three-tiered subclassification of pt2 organ-confined prostate cancer via methods used in the previous or current TNM staging system may not be appropriate. Efforts should be made to upgrade the current TNM staging system for prostate cancer. KEYWORDS prostate cancer, prostatectomy, TNM staging, pathologic Stage INTRODUCTION For cancer of any origin, a well-established staging system would be crucial for appropriate prognostication and treatment. For prostate cancer, the TNM staging system was first adopted in 1975 by the American Joint Committee for Cancer Staging and End Result Reporting (AJCC) [1]. A new TNM classification system was adopted in 1992 by AJCC and the International Union Against Cancer (UICC) [2]. Under this system, T2 prostate cancer was subclassified into three categories: T2a (unilateral tumour involving one half of a lobe or less), T2b (unilateral tumour involving greater than one half of a lobe, but not both lobes), and T2c (tumour involving bilateral lobes). In 1997, the TNM staging system for prostate cancer was revised to combine unilateral diseases into one category (T2a) and to reclassify bilateral involvement of tumour as T2b [3]. Subsequently in 2002, a new version of the TNM staging system was again adopted, which reverted to the 1992 three-tiered subdivision of T2 disease [4]. Meanwhile, questions have been raised on the adequacy of the subclassification of the T2 stage in prostate cancer. Despite the fact that criteria for assessing clinical stage of prostate cancer are relatively clear-cut, the application of the same criteria for pathological staging, which requires histological analysis of tumour extent, may not be as simple. Also, defining pathological tumour stage according to unior bilateral lobe involvement may not be optimal for prostate cancer, which frequently present as a multifocal tumour. Moreover, some Western researchers have reported that pt2b prostate cancers (according to the 1992 and the 2002 TNM staging systems) actually do not exist [5,6]. Meanwhile, to our knowledge, the current TNM staging system for prostate cancer has not been evaluated formally in an Asian series of prostate cancer. Thus, we analysed the subclassifications of pt2 diseases in the TNM staging system for prostate cancer by reviewing pathological outcomes of surgical specimens in a series of Korean patients who underwent radical retropubic prostatectomy (RRP). PATIENTS AND METHODS Excluding those who had received preoperative radiation or androgen deprivation therapy, we reviewed the clinicopathological data of 372 patients who were diagnosed as having pt2 disease using the 2002 TNM staging system after undergoing RRP by a single surgeon from November 2003 to June 2007 at our institution. Before surgery, serum PSA levels (ng/ml) were measured before any prostate JOURNAL COMPILATION 2008 BJU INTERNATIONAL 102, doi: /j x x

2 Variable Value No. patients 372 Mean (SD; range): Age, years 64.2 (6.7; 37 78) BMI, kg/m (3.7; ) Preoperative serum PSA, ng/ml 8.7 (8.1; ) Prostate weight, g 41.5 (15.4; ) Tumour volume, ml 4.1 (4.3; ) N (%): 2002 AJCC pathologic classification: pt2a 87 (23.4) pt2b 1 (0.3) pt2c 284 (76.3) Pathological Gleason score (39.8) (57.3) 8 11 (3.0) Tumour multifocality ( 2 foci) Negative 85 (22.8) Positive 287 (77.2) Surgical margin Negative 326 (87.6) Positive 46 (12.4) FIG. 1. Kaplan Meier curve showing BRFS among patients with pt2 tumour according to the 1997 pt2 subclassification (log-rank P = 0.645). Cumulative survival pathologic T2a pathologic T2b Time to biochemical failure, months manipulation, and samples were processed without delay via immunoradiometric assay using the 125 I-PSA IRMA kit (Institute of Isotopes, Budapest, Hungary). At our institution, indications for performing prostate biopsy ( 12 cores) included a high serum PSA level ( 3.0 ng/ml), a suspicious DRE, and/or hypoechoic lesion on TRUS. Our Institutional Review Board approved the present study. The specimens from RRP were weighed, measured, and fixed in 10% neutral formalin. Subsequently, the apex and base were amputated and serially sectioned at 3 5 mm TABLE 1 The patients characteristics intervals in the vertical parasagittal plane. The seminal vesicles were sectioned parallel to their junction with the prostate and entirely submitted for evaluation. The remaining specimen was serially sectioned at 3 5 mm interval perpendicular to the long axis of the gland from the apex to the base. Sections were subdivided into halves or quadrants according to the prostate size, labelled to allow reconstruction as whole-mount sections, and stained with haematoxylin and eosin for histological evaluation. Tumours were graded according to the Gleason system. Surgical margins were considered positive when carcinoma cells contacted with the inked margin. Tumour volume, defined as the sum of the volumes of individual tumour foci, was determined using the grid method as previously described [7 9]. One pathologist did all the histopathological analyses. Using the 1997 and the 2002 TNM staging system, all cases were retrospectively analysed. Clinicopathological variables that are known prognostic factors for prostate cancer were compared between men with unilateral and bilateral tumours using rank-sum analysis for continuous variables and chi-square analysis for categorical variables. The serum PSA level along with prostate volume and patient age were evaluated as continuous variables, whereas body mass index (BMI) (<18.5, 18.5 to <23, 23 to <27.5, and 27.5 kg/m 2 ), clinical stage (T1 vs T2), Gleason score (2 6, 7, 8 10), and surgical margin status were evaluated as categorical variables. To assess the BMI data, patients were categorized according to the classification proposed for Asian populations [10]. Among the subjects who were followedup for >2 years after RRP, biochemical recurrence was indicated by a PSA level of >0.2 ng/ml. For multivariate analysis, a Cox proportional-hazards model was used. Time to PSA recurrence was compared between the groups using a log-rank survivorship analysis and a Cox proportional-hazards model. The actuarial risk of PSA recurrence was calculated using the Kaplan Meier survivor curve. RESULTS The patients characteristics are shown in Table 1. The median (range) age at the time of surgery was 62 (37 78) years. The median (range) weight of the prostate specimens was 42 ( ) g. Using the 2002 TNM staging criteria, most of the patients had pathological T2c disease. Notably, only one patient was identified as having a pathological T2b tumour. In all, 77.2% had tumour multifocality, and 12.4% had positive surgical margins on final pathological analysis of the RRP specimens. With only one 2002 pt2b case among our patients, we re-subdivided pt2 cases into two categories: the 1997 version of pt2a (unilateral lobe) and pt2b (bilateral lobe) diseases (Table 2). And, there were no differences between the two groups in age at surgery, BMI, preoperative PSA level, prostate weight, and clinical stage. Meanwhile, the two groups had significant differences in tumour volume, pathological Gleason score, and positive margin rate. Among those who were followed-up for >2 years after RRP (pt2a, 54; pt2b, 168), the 1997 pt2a and pt2b cases showed no significant difference regarding biochemical recurrence-free survival (BRFS; log-rank analysis, P = 0.645) (Fig. 1). We performed a multivariate analysis to identify significant independent predictors of time to biochemical recurrence (Table 3). The variables entered into the multivariate model included age, BMI, serum PSA level, clinical stage, tumour volume, pathological Gleason score, pathological stage (pt2a vs pt2b), and marginal status. On multivariate analysis, preoperative serum PSA level and pathological Gleason score along with JOURNAL COMPILATION 2008 BJU INTERNATIONAL 1 093

3 HONG ET AL. positive surgical margin were significant predictors of PSA outcome after RRP. Pathological (pt2a vs pt2b) stage was not a significant predictor of PSA outcome in either uni- or multivariate analysis (P = and P = 0.241, respectively). DISCUSSION For prostate cancer, clinical stage is determined by pretreatment parameters such as DRE, PSA level, needle-biopsy results, and radiological imaging. On the other hand, pathological stage is determined after prostate removal and involves careful histological analysis of the removed specimen. Thus, pathological stage is generally considered a more accurate assessment of true disease status and is more useful for prognosis. The limitations of clinical staging have been well recognized. Several researchers have reported that clinical and pathological stages do not correspond in significant proportions of prostate cancers [11 13]. Also, the lack of a defined pathological equivalent based on the AJCC TNM clinical staging categories has been identified as a problem by others [14]. For the three-tiered T2 stage defined under the 2002 AJCC TNM staging system, which was first used in the 1992 version, controversy continues regarding its defined criteria. Stamey et al. [15] reported after examining clinically localized prostate cancer, stratified according to the 1992 AJCC TNM staging system, that T2a tumours were significantly different from T2b and T2c tumours in pathological features and BRFS rates. Also, Han et al. [16] reported that patients with 1992 T2a and 1992 T2b tumours had significantly different BRFS rates after RRP, whereas those with 1992 T2b and 1992 T2c tumours had similar rates. Also, Cagiannos et al. [17] reported similar data and mentioned that the 1992 T2 subclassification was better than the 1997 version. These reported data uniformly indicated that 1992 T2a and 1992 T2b tumours should not be combined as a single staging category as was done in the 1997 TNM staging system. Moreover, they also suggested that T2b prostate cancer indeed exists. However, all aforementioned studies actually analysed the significance of subdivisions of the clinical T2 stage rather than those of the pathological T2 stage. Meanwhile, Eichelberger and Cheng [5] reported after evaluating T2 tumours based TABLE 2 Patients reclassified according to the 1997 TNM staging system Variable 1997 pt2a 1997 pt2b P N (%) patients 88 (23.7) 284 (76.3) Mean (SD): Age, years 64.2 (6.8) 64.3 (6.7) BMI, kg/m (3.8) 23.6 (3.6) Serum PSA, ng/ml 8.6 (7.7) 8.7 (8.2) Prostate weight, g 43.3 (15.5) 40.9 (15.3) Tumour volume, ml 2.5 (2.4) 4.5 (4.6) <0.001 N (%): 1997 TNM clinical stage T1c 52 (59.1) 173 (60.9) T2a 31 (35.2) 86 (30.3) T2b 1 (1.1) 7 (2.5) T3 4 (4.5) 18 (6.3) Pathological Gleason score (53.4) 101 (35.6) 7 38 (43.2) 175 (61.6) 8 3 (3.4) 8 (2.8) Surgical margin positivity 7 (7.9) 39 (13.7) TABLE 3 Multivariate analysis of predictors for time to biochemical recurrence after RRP among the patients who were followed-up for 2 years Variable Hazard ratio (95% CI) P Age ( ) BMI ( ) Serum PSA level ( ) TNM clinical stage (T1c vs T2) ( ) Tumour volume ( ) Pathological Gleason score ( 6 vs 7) ( ) TNM pathological stage (T2a vs T2b) ( ) Surgical margin positivity ( ) on histological assessment of RRP specimens rather than on clinical staging criteria that they could not find any pt2b prostate cancers using the 1992 or the 2002 TNM staging criteria. They concluded that the three-tiered T2 classification system for staging organconfined prostate cancer is not necessary. In the present study, we obtained similar data to that of the Eichelberger and Cheng study. After thorough evaluation of all sections, we could find only one case that could be classified in the subcategory of 2002 pt2b disease in the present series of 372 pt2 tumours. Assessing the present raw data, we often observed that even a prostate cancer with a small index tumour size had accompanying smaller satellite tumour foci in contralateral lobe. Thus, as Eichelberger and Cheng [5] previously mentioned, we think that it would be unusual to identify organconfined prostate cancer histologically involving more than one half of a prostatic lobe without involving the other lobe, and that tumour staging would not be optimal when using such criteria for organ-confined prostate cancer. With regards to implementing the two-tiered classification for T2 organ-confined prostate cancer as done in the 1997 AJCC TNM staging system, controversy also exists regarding its appropriateness [3]. From comparing the 1992 and the 1997 AJCC TNM staging system in a series of men with clinically organconfined prostate cancer who underwent surgery, Han et al. [16] reported that the actuarial recurrence-free rate was significantly different for tumours with clinical stage of 1997 T2a vs 1997 T2b. Similarly, others have reported a worse JOURNAL COMPILATION 2008 BJU INTERNATIONAL

4 outcome for tumours clinically evaluated to involve both prostatic lobes compared with those involving one lobe [17,18]. However, again, these data were all obtained from analysing clinical staging of tumours rather than pathological staging. Moreover, studies investigating the significance of pathological stages of prostate cancer, as in the present study, have shown different results. By examining the 1992 and the 1997 TNM staging system in a series of men who underwent RRP for pt2 and pt3 prostate cancer, May et al. [19] reported that there were no significant differences in biochemical progression-free survival among pt2 subgroups. Also, Freedland et al. [20] reported from evaluating biochemical outcomes for 1606 men who had RRP for pathologically confirmed organ-confined prostate cancer that there was no difference in PSA recurrence rates between men with 1997 pt2a vs 1997 pt2b tumours. Such results are in accordance with data in the present study. Despite the relatively short duration of follow-up, 1997 pt2a and 1997 pt2b tumours also showed no significant difference in biochemical recurrence rate in the present study. Moreover, multivariate analysis showed that the pathological stage was not an independent predictor of pt2 patients biochemical outcome. The observed phenomena in the present study may, at least be partly, explained by the characteristics of prostate cancer as well as the anatomy of the prostate. As aforementioned, prostate cancer frequently presents as a multifocal tumour. Available data indicate that the proportion of pathologically confirmed multifocal prostate cancers in reported RRP series is 62 87% [21,22]. In the present series of pt2 tumours, 77.2% of the patients had tumour multifocality. Also, as mentioned by others, prostate cancer occupying more than a quarter of the prostate would, in all in likelihood, involve bilateral lobes of the prostate [5]. Only a few cases, if any, of organconfined prostate cancers would actually be included in the category of pt2b according to the 2002 TNM staging system. Thus, in the pathological sense, the 2002 pt2b subdivision would be insignificant. Meanwhile, both surgery and radiation therapy are currently known to provide superb outcomes for organconfined prostate cancer regardless of T2 subclassifications. Therefore, it can be suggested that there is no clear-cut reason for subdividing pt2 prostate cancer, which mostly shows excellent prognosis after definitive treatment. Also, that anatomically distinct lobes are not histologically definable in the prostate would make categorizing pt2 tumours according to uni- or bilateral lobe involvement unrealistic [14]. Moreover, as been shown by the aforementioned data and the present results, subdivision of T2 tumours by lobe involvement would not be logical, as there was no significant difference in prognosis according to tumour laterality. Some have mentioned that those with bilateral lobe pt2 tumours have a greater tumour volume than unilateral diseases, as seen in the present series. Meanwhile, as also reported by others, tumour volume was not a significant predictor of biochemical outcome for pt2 tumours in the present study when controlling for PSA level, Gleason score, and pathological stage [23]. The present study may be limited by the relatively few patients and that the cancers of the patients were of a relatively higher PSA level and tumour grade than those typically seen in contemporary Western series. Still, considering the huge difference in the incidence of prostate cancer between Asia and Western countries, the number of patients in the present series may not be too few for a single institutional study in Asia. In Korea, prostate cancer screening is currently not as widely spread as in Western countries and prostate cancers in Korea are generally not detected as early as in Western countries. However, the results of the present study indicate that problems indeed exist with the current subclassification of T2 prostate cancer, even when analysed in an Asian series such as ours. In conclusion, the results of the present study suggest that two- or three-tiered subclassification of pt2 organ-confined prostate cancer via methods used in the previous or current TNM staging system may not be appropriate. Efforts should be made to upgrade the current TNM staging system for prostate cancer. CONFLICT OF INTEREST None declared. REFERENCES 1 Wallace DM, Chisholm GD, Hendry WF. T.N.M. classification for urological tumours (U.I.C.C.) Br J Urol 1975; 47: Hermanek P, Sobin LH, eds. TNM Classification of Malignant Tumors. Berlin: Springer-Verlag, 1992: Fleming ID, Cooper JS, Henson DE et al. AJCC Cancer Staging Manual, 5th edn. Philadelphia: Lippincott Raven, Greene FL, Page DL, Fleming ID et al. AJCC Cancer Staging Manual, 6th edn. New York: Springer-Verlag, Eichelberger LE, Cheng L. 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