A Modıfıed Partın Table to Better Predıct Extracapsular Extensıon in Clınıcally Localızed Prostate Cancer Erkan Merder,¹* Ahmet Arıman,¹ Fatih Altunrende¹ Purpose: Prediction of extracapsular extension (ECE) before radical prostatectomy in clinically localized prostate cancer (PCa) is very important for clinical practice. ECE affects our decision on treatment strategy. The aim of this study is to identify the predictors of ECE, determine cut-off values, and compare them with the accuracy of Partin Table parameters to improve tumor staging in clinical practice. Materials and Methods: 374 patients with clinically localized PCa who underwent open radical retropubic pros- tatectomy (RRP) were included in this study. Gleason Score (GS), age, digital rectal examination (DRE), prostate specific antigen (PSA), prostate specific antigen density (PSAD), free PSA, Free/Total PSA, prostate volume (PV), number of cores involved, tumor length, and tumor percentage in maximum involved core in biopsy were investigated. Results: PSAD, tumor percentage, and tumor length are predictive factors of ECE. The cut-off values of PSA, PSAD, maximum tumor length, and maximum tumor percentages in predicting ECE are: > 8.90 ng/mL, > 0.26 ng/mL2, >5mm, and >50%, respectively. The cut-off values for Partin extraprostatic extension (EPE) and organ confined (OC) disease are >29% and ≤ 64%, respectively. Conclusion: Partin tables could better predict extracapsular extension in clinically localized PCa if they include PSAD, tumor percentage, and tumor length. The cut-off values of these predictive factors can be beneficial in treatment strategies and in the decisions of lymphadenectomy and nerve-sparing surgery at radical prostatectomy. Keywords: extracapsular extension; localized prostate cancer; partin table; PSA; PSAD; radical prostatectomy INTRODUCTION Prostate cancer (Pca) takes second place among all cancers seen in men(1). The epidemiology of PCa differs between geographic regions, countries, and eth- nicities. The incidence rate of PCa in Turkish ethnicity was found to be 7.9 per 100.000 by Basiri, A et al.(2). Treatment strategy varies according to the clinical stage of PCa. Excellent results of radical prostatectomy (RP) are obtained when PCa is organ confined(3). Exceeding tumor cells beyond the prostatic capsule, presence of tumor cells in the periprostatic tissue and/ or neurovascular plexus, and ≥ pT3 with or without lymph positivity is defined as ECE. Clinically distin- guishing organ confined (T stage 1-2 and N0) from lo- cally advanced prostate cancer (LAPC) is very impor- tant. Locally advanced disease changes the treatment plan and the prognosis of PCa(4,5). In the presence of locally advanced disease, lymphadenectomy is needed, nerve-sparing surgery cannot be done on the affected side, and rate of positive surgical margin increases (4,6). If we can predict preoperative ECE, we can modify the treatment method and surgical technique in RRP. Lym- phadenectomy and nerve-sparing surgery are related to the ECE status of the patient. We can inform the patient about the course of the disease, prognosis, and addition- al postoperative treatments. All these factors affect the oncologic outcomes, morbidity, and the risk of recur- rence in patients. University of Health Sciences, Prof Dr. Cemil Taşçıoğlu City Hospital, Department of Urology, Istanbul, Turkey. *Correspondence: Department of Urology, University of Health Sciences, Prof Dr. Cemil Taşçıoğlu City Hospital, Istanbul, Turkey. Tel: +90 532 6161065, Email: drerkanmerder@gmail.com. Received September 2020 & Accepted December 2020 ECE or lymph node involvement have been seen after RP in some patients diagnosed with localized PCa(7,8). There are many studies in the literature dealing with ECE, upstaging, and upgrading between prostate biop- sy and RP specimens(9). Several clinical parameters, such as digital rectal ex- amination (DRE), multiparametric magnetic resonance imaging (mpMRI), and preoperative Nomograms (Par- tin, Memorial Sloan Kettering Cancer Center, Kattan) are used in the prediction of disease extension in the literature. We use Partin table frequently in our clinical practice in the prediction of final pathologic stage before RP. Partin uses DRE, biopsy PSA, and biopsy Gleason Score (GS) in the nomogram to predict extraprostatic extension (EPE), organ confined (OC) disease, semi- nal vesicle involvement (Sv+), and lymph involvement (Ln+) before RP. Partin table has a 95 % confidence interval for predicting the probabilities of each patho- logic stage. Partin showed that using PSA, DRE, and biopsy GS together gives more accurate results than using these factors separately(7,8). In recent years there have been various studies on adding mpMRI and some other predictive factors to the preoperative nomograms to improve tumor staging. MATERIALS AND METHODS This study was carried out in the urology department Urology Journal/Vol 18 No. 1/ January-February 2021/ pp. 74-80. [DOI: 10.22037/uj.v16i7.6477] UROLOGICAL ONCOLOGY Vol 18 No 1 January-February 2021 20 of the university of health sciences, Prof. Dr. Cemil Taşçıoğlu city hospital, Istanbul, Turkey. 374 patients who had open RRP for clinical localized PCa (≤cT2c) between January 2015 and September 2020 were ana- lyzed retrospectively. Prof. Dr. Cemil Taşçıoğlu City Hospital ethics committee approval was obtained and all patients provided informed consent (Date 14.07.2020 and No:304). Patients with localized PCa (clinical stage ≤cT2) before RRP were included. Patients who were treated previ- ously (radiation therapy or androgen deprivation), those with ≥cT3 or lymph positive preoperatively, those who had an active surveillance program before, and those with missing data were excluded. All 374 patients in our study group were evaluated as localized PCa (≤ cT2) and N0 before RRP. PCa was diagnosed by transrectal ultrasound- guided prostate biopsy of minimum 12 cores based on elevated serum PSA, and mpMRI findings or palpable nodule at DRE. The clinical stage was evaluated using DRE, bone scan, computed tomography (CT), or mpMRI be- fore RRP. Table 1. Demographic, clinical and histopathological parameters in organ confined (group 1) and ECE group (group 2). Group 1 (n=248) (Organ Confined) Group 2 (n=126)(ECE) P value Age (Years) Min-Max (median) 53-82 (69) 54-82 (68) a0,866 Meann ± SD 68,48 ± 6,63 68,3 ± 6,76 Prostate Volume (cc) Min-Max (median) 12-125 (41,5) 15-90 (40) b0,101 Mean±SD 49,14±25,0 41,63 ± 18,14 Biopsy PSA ng/mL Min-Max (median) 3,4-28 (7) 3,3-42 (10) b0,001* Mean ± SD 8 ± 3,9 12,13 ± 7,59 <6,1 88 (35,5) 22 (17,5) c0,001* 6,1-10 116 (46,8) 42 (33,3) >10 44 (17,7) 62 (49,2) Free PSA ng/mL Min-Max (median) 0-2,3 (0) 0-2,4 (0) b0,608 Mean ± SD 0,19 ± 0,48 0,19 ± 0,53 PSAD ng/mL2 Min-Mak (median) 0,1-1,2 (0,2) 0,1-1 (0,3) 0,001* Mean ± SD 0,20±0,13 0,32 ± 0,19 F PSA/T PSA % Min-Max (median) 0-0,7 (0,2) 0,1-0,2 (0,1) b0,481 Mean ± SD 0,20 ± 0,18 0,14 ± 0,03 Number of positive cores Min-Max (median) 1-12 (3) 1-12 (5) b0,001* Mean ± SD 3,17 ± 2,09 5,38 ± 2,59 ≤2 114 (46,0) 16 (12,7) c0,001* ≥3 134 (54,0) 110 (87,3) Tumor length in maximum Min-Max (median) 1-12 (4) 2-18 (8) b0,001* involved core (mm) Mean ± SD 4,15 ± 1,99 8,72 ± 3,38 Percentage of tumor in Min-Max (median) 7-90 (30) 12,5-100 (67) b0,001* maximum involved core % Mean ± SD 33,64 ± 17,74 70,55 ± 23,45 < %25 106 (42,7) 4 (3,2) c0,001* %26-50 104 (41,9) 20 (15,9) > %51 38 (15,3) 102 (81,0) aStudent t test bMann Whitney U test cPearson Chi square test *p < 0,05 Figure 1. ROC curve of PSA,PSAD, tumor length and tumor percentage A modified partin table-Merder et al. Vol 18 No 1 January-February 2021 75 Findings of DRE, age, GS of biopsy, PSA, free PSA, PV, PSAD, free/total PSA, Partin table parameters (EPE, OC, SVI, Ln+), tumor positive core numbers, tumor length, and tumor percentage in maximum in- volved core in prostate biopsy were investigated preop- eratively and data were recorded retrospectively. Extracapsular extension, apical, bladder neck and sem- inal vesicle involvement, positive surgical margin, vas- cular and perineural invasion, histology of tumor sur- rounding tissue, lymph node dissection, and positivity after RRP were recorded. Biopsy Gleason Scores were graded according to the international society of urological pathology (ISUP) by two uropathology experts in our Hospital. These urop- athologists also evaluated the presence of extraprostatic disease and other criteria in the final pathologic analysis of surgical specimens. Invasion of adipose tissue and/or of the periprostat- ic neurovascular plexus and ≥pT3 with or without lymph-positivity were accepted as extraprostatic exten- sion (ECE) of disease. 248 of the patients were evaluated as the organ confined group (group 1). They had clinical and pathological stage ≤cT2 before and after RRP. 126 of the patients had clinical and pathological stage ≤cT2 before but pathologic stage ≥pT3 (N0 or N1) after RRP and were evaluated as the ECE group (group 2). We investigated clinical and histopathological param- eters, PSAD, and Partin Nomogram parameters in pre- dicting ECE in both groups and these values were com- pared to each other in terms of improving the accuracy of tumor staging. Statıstıcal analysıs We used the Number Cruncher Statistical System (NCSS) Statistical Software (NCSS, LLC, Kaysville, Utah, USA) in all statistical analysis. Student’s t- test, Mann-Whitney U test, Pearson’s Chi- squared test, and ROC curve analysis were used. Logis- tic regression analysis was also performed. P values were considered statistically significant if p ˂ 0.05. RESULTS Demographic, clinical and histopathological parame- ters in the organ confined (group 1) and ECE (group 2) groups are shown in Table 1. Nodule on DRE, PSA, PSAD, number of positive cores, tumor length, and tumor percentage on maximum in- volved core showed a statistically significant difference between the two groups. Age, prostate volume, free PSA, and free PSA/total PSA values were not statisti- cally different between the groups. Regarding PCa risk groups, distribution of patients with low, moderate, and high-risk groups were 52.4%, 38.5%, and 9.1%, respec- tively. Overall, DRE positivity, ECE, and upgrading rates were 17.6%, 33.7%, and 37.5%, respectively. Biopsy and postoperative GS, preoperative clinical and postoperative pathologic stages of the patients are shown in Table 2. We detected ECE in 126 of 374 (33.7%) patients (group 2). 82 of these 126 patients (65.1%) upstaged to pT3a, 26 (20.6%) upstaged to pT3b, 10 (7.9%) upstaged to T3a N1, and 8 (6.3%) upstaged to T3b N1. Upgrading rates in the ECE group in Gleason Score 3+3, 3+4, 4+3, and 4+4 patients were 24.2%, 7.3%, 3.5%, and 2.5%, respectively. Downgrading rates in Gleason Score 3+4, 4+3, and 4+5 patients were 2.4%, 2.6%, and 0.8%, respectively. Determination of cut-off values for PSA, PSAD, tumor length, and tumor percentage in maximum involved core related to ECE is shown in Table 3. Table 4 shows the logistic regression analysis of risk factors that affect upstaging. The cut-off values for PSA, PSAD, tumor length, and tumor percentage were: >8.90ng/ml, >0.26ng/ml2, >5mm, and >50%, respectively. The accuracy rates of PSAD, tumor length, and tumor percentage were 73.8%, 79.7%, and 83.4% respectively. The ODDS ratios (95% CI) for tumor percentage, tu- mor length, and PSAD were 9.898, 4.259, and 3.361, respectively. ROC curves for PSA, PSAD, tumor length, and tumor percentage are shown in figure 1. The AuROC (95% CI) of PSAD was higher than PSA, and the AuROC of tumor length and tumor percentage Table 2. Biopsy and postoperative GS, preoperative clinical and postoperative pathologic stages of the patients. Biopsy GS 3+3 196 52.4 3+4 120 32.1 4+3 46 12.3 4+4 8 2.1 4+5 4 1.1 Postoperative GS 3+3 116 31.0 3+4 126 33.7 4+3 110 29.5 4+4 14 3.7 4+5 8 2.1 Preoperative Clinical Stage T1c 305 81.6 T2a 61 16.3 T2b - T2c 8 2.1 Postoperative Pathologic Stage pT2a 32 8.5 pT2b 46 12.3 pT2c 170 45.5 pT3a 82 21.9 pT3a N1 10 2.7 pT3b 26 7 pT3b N1 8 2.1 Table 3. Determination of cut off values of PSA, PSAD, maximum tumor length and tumor percentage related to ECE. Biopsy PSA ng/mL PSAD ng/mL2 Max Tumor Length (mm) Tumor Percentage (%95 CI 0.628-0.764) (%95 CI 0.661-0.793) (%95 CI 0.832-0.928) (%95 CI 0.831-0.927) Area Under the ROC 0.700 (0.628 0.764) 0.731 (0.661. 0.793) 0.886 (0.832. 0.928) 0.886 (0.831. 0.927) Curve AuROC (95%CI) Cut-off >8.90 >0.26 >5 >50 Sensitivity 61.90 (48.8-73.9) 52.38 (39.4-65.1) 84.13 (72.7-92.1) 80.95 (69.1-89.8) Specificity 70.97 (62.1-78.8) 84.68 (77.1-90.5) 77.42 (69.0-84.4) 84.68(77.1-90.5) Positive Predictive Value (PPV) 52.00 (43.6-60.3) 63.50 (51.9-73.7) 65.40 (57.3-72.7) 72.90 (63.6-80.5) Negative Predictive Value (NPV) 78.60 (72.4-83.7) 77.80 (72.8-82.1) 90.60 (84.4-94.5) 89.7 (83.9-93.6) Accuracy 67.9 (58.4-81.0) 73.8 (62.9-84.7) 79.7 (69.8-89.6) 83.4 (74.2-92.6) A modified partin table-Merder et al. Andrology 106Urological Oncology 76 were higher than PSA and PSAD. The cut-off values for Partin table parameters are shown in Table 5. The lowest accuracy rate was found in the Partin LN-positive parameter. The highest accuracy rate was in Partin OC. The ROC curves of Partin table parameters are shown in Figure 2. The AuROC of PSAD, max tumor length, and tumor percentage were 0.731, 0.886, and 0.886, respectively, all being higher than PSA (0.700), which is one of the Partin table criteria. The AuROC of Partin table EPE was 0.785, lower than max tumor length and tumor per- centage. 192 of the 374 patients (51.3 %) had lymph node dis- section. 122 of the 248 patients in the organ confined group (49.2 %) and 70 of the 126 patients in the ECE group (55.5%) had lymph node dissection. We found the rate of apical involvement after RP as 60.2%, perineural invasion as 72.6%, ECE as 33.7%, bladder neck involvement as 8.1%, vascular invasion as 8.0 %, capsular invasion as 33.9%, SV+ as 9.1%, positive surgical margin as 14.3 %, LN+ as 4.8%, and high pin as 60.7%. Histopathological characteristics in tumor surrounding tissues after surgery were nodular hyperplasia (89.3%), chronic prostatitis and nodular hyperplasia (5.9%), and chronic prostatitis (4.8%). DISCUSSION Some patients with prostate cancer have pathologic up- staging (ECE) and GS upgrading after RP(9). The rate of upstaging varies between 29%-34% and upgrading varies between 24%-41% in the literature(9,10,11,12). Up- staging and upgrading results may be associated with diagnostic problems in prostate biopsy like insufficient biopsy material and histopathologic evaluation of the Gleason grade of the tumor in biopsy(13). This is related to the experience of the histopathologist who examines the tissue, and the urologist or radiologist who makes the biopsy. Number of biopsy cores and involved cores may also cause this difference. Although our physicians who performed the prostate biopsy and the histopathologists who examined the tis- sue were very experienced, our ECE and upgrade rates were found very close to those in the literature.Extra- prostatic extension (ECE) and positive surgical margins in PCa affect prognosis and survival(14,15,16). In our study, 71.4% of overall upstaging occurred in cT1c patients, and 66.1% of overall upgrading occurred in biopsy Gleason score 3+3 patients. This shows that upstaging and upgrading occurs mostly in organ con- fined patients where ECE was not suspected according to preoperative findings. Therefore, predictive factors are very important in detecting upstaging, upgrading, ECE, and OC disease in clinical practice. In our study, the rates of upstaging (ECE) was 33.7% and upgrading was 37.5%. Several studies in the literature have investigated the clinical and pathological predictors in the diagnosis of ECE. Age has been reported as one of the significant predictors of ECE in some studies(17,18). However, we could not find age to be a significant predictor of ECE in our cohort (p = 0.866). Valette et al., showed that tumor percentage is a predic- tor of EPE and adding it to the preoperative nomograms increases the accuracy of the nomogram(19). We found the same result in our study. The highest accuracy rate for predicting ECE was found in tumor percentage (83.4%). X. Gao et al. included T1c-2b patients with Gleason scores ≤ 7 and PSA ≤ 10 ng/ml and found that the maximum percentage of tumor on the most involved core was predictive for EPE in both univariate and mul- tivariate analysis(20) similar to our findings. Horiguchi et al. found prostate volume to be a signif- icant predictor for ECE in localized PCa(21). However, Sayyid et al. did not find prostate volume to be a signif- icant factor, similar to findings(18). On the other hand, both Horiguchi et al. and Sayyid et al. found that PSA was a significant predictor of ECE, in parallel with our findings. Horiguchi et al. also deter- mined, PSAD and Gleason score to be significant pre- dictors (18,21). Their ECE rate was 33.4% (21). We found PSAD to be a significant predictor with an AuROC of 0.731 at 95% CI. Horiguchi et al. reported that PSAD showed the larg- est area under the ROC curve among other parameters p Odds 95% C.I.Odds Lower Upper Tumor length in max. involved core (mm) (>5) 0.030* 4.259 1.155 15.704 Tumor percentage % (>50) 0.000** 9.898 3.725 26.296 Number of positive cores (≥3) 0.096 2.480 0.851 7.224 PSAD ng/ml2 (>0.26) 0.005** 3.361 1.445 7.815 *p < 0.05 Table 4. Logistic regression analysis of factors that affect upstaging. Partin Epe (%95 CI) Partin Oc (%95 CI) Partin Sv+ (%95 CI) Partin Ln+ (%95 CI) AuROC (95%CI) 0.785 (0.716. 0.885) 0.791 (0.725. 0.847) 0.759 (0.684. 0.835) 0.773 (0.698. 0.848) Cut-off >29 ≤64 >4 >1 Sensitivity 49.20 (36.9-61.5) 52.38 (40.0-64.7) 49.21 (36.9-61.6) 84.12 (75.1-93.1) Specificity 91.13 (84.1-98.2) 90.32 (83.0-97.9) 91.94 (85.2-98.7) 50.81 (75.1-93.1) PPV 73.81 (63.0-84.7) 73.33 (62.4-84.3) 75.61 (65.0-86.2) 46.49 (34.2-58.8) NPV 77.93 (67.7-88.2) 78.87 (68.8-89.0) 78.08 (67.9-88.3) 86.30 (77.8-94.8) Accuracy 77.01 (66.6-87.4) 77.54 (67.2-87.8) 77.54 (67.2-87.8) 62.03 (50.0-74.0) Abbreviations: AuROC: Area under the ROC curve; PPV: Positive Predictive Value; NPV: Negative Predictive Value; CI: Confidence interval A modified partin table-Merder et al. Vol 18 No 1 January-February 2021 77 Table 5. Cut-off values for Partin table parameters in our study (AuC=0.732). They found that using PSAD, MRI find- ings, and biopsy Gleason scores all together could give more information on staging(21). Number of involved cores was found to be statistically different in our univariate analysis, but not in the multi- variate analysis (p = 0.096). We found DRE to be a predictive factor (p = 0.005). 82.4% of our patients had no positive finding in DRE. DRE is an easy, low-cost, and practical method, al- though with low sensitivity and a tendency to under- stage the disease(22). It is difficult to find or feel small, centrally or anteriorly located tumors in DRE. Obesity is another problem for DRE. In our opinion, DRE is the weakest of the 3 criteria used in Partin Table to predict ECE, OC, SVI, and Ln+. Biopsy and clinical parame- ters are the findings at our disposal, that do not require anything else, are practical, useable, easily accessible, and cheaper; hence, we use them routinely in our clin- ical practice. Tumor percentage, tumor length, and PSAD can be added to the Partin Table to predict tumor staging more accurately or these predictive factors can be used in- stead of DRE to predict ECE, OC, SVI, and Ln+ in localized PCa. In the coming years, depending on the advancements in technology, mpMRI criteria can may be added to Partin Tables (instead of DRE) to increase the accuracy of preoperative staging. So, we can make treatment plans more preicisely and make decisions of lymphadenectomy and nerve-sparing surgery more ac- curately. Partin Tables have low sensitivity (28.1%) and PPV (42.9%), but high specificity (88.1%) and NPV (79.5%) for the diagnosis of EPE(23). Here, we found Partin Ta- bles to have a sensitivity, specificity, PPV, and NNP of 49.20%, 91.13%, 73.81%, and 77.93%, respectively for EPE. De Rooij et al. found the sensitivity and specific- ity of mpMRI in the detection of ECE as 57% and 91%, respectively(24). There are different studies in the literature about adding mpMRI and some other predictive factors to preopera- tive nomograms to improve the accuracy of tumor stag- ing. Jansen et al. showed that combining mpMRI with Partin and Memorial Sloan Kettering Cancer Center nomograms did not increase the accuracy rate of stag- ing(25). Gupta et al. compared the accuracy of mpMRI and Partin tables and showed that the diagnosis of organ confined disease was superior in mpMRI compared to Partin tables. They found the AuROC of mpMRI and Partin Tables to be 0.88 and 0.70, respectively(26). We found the AuROC of Partin Table 0.791 and the AuROC of both tumor percentage and tumor length as 0.886, higher than the findings of Gupta et al. The retrospective, and single-center nature of our re- search, along with the relatively small number of pa- tients and the lack of mpMRI and targeted biopsies were the limitations in this study. The indication and role of lymph node dissection in lo- calized PCa has not been standardized yet. We use the value of Partin Ln+ as >5% for lymphadenectomy in our clinical practice. In this study, we found that Partin Ln+ had a cut-off value of >1%. If Partin Ln+ is >1%, we must perform lymphadenectomy without nerve-sparing surgery on the affected side in these patients due to the high possibility of ECE. We found Partin Sv+ to have a cut-off value of >4%. We should consider lymphadenectomy in these patients as well. Figure 2. ROC Curves of Partin Table Parameters A modified partin table-Merder et al. Urological Oncology 78 CONCLUSIONS PSA, PSAD, tumor percentage, and tumor length are predictive of ECE. If these factors are included in the content of the Partin Table, the accuracy rate of the Par- tin Table in tumor staging will increase significantly. 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