Abstract
Introduction
The aim of this study was to evaluate the prognostic impact of favourable prostate cancer (PCa) pathology patterns through Briganti’s 2012 nomogram and beyond EAU risk classes in patients treated with robotic surgery.
Material and methods
We analysed 757 patients from January 2013 to December 2021 with favourable pathology features (ISUP 1-3, pT2/pT3a, and pN0/x) and available follow-up. Pathologic features were scored from zero (ISUP 1 + pT2) to three (ISUP 3 + pT3a). Associations with Briganti’s 2012 nomogram by EAU risk class were evaluated to determine the prognostic impact on PCa progression, defined as biochemical persistence/recurrence or loco-regional/metastatic recurrence.
Results
Favourable pathology risk scores were most commonly grades one (49%) and two (30.95%), followed by zero (15.2%) and three (4.9%). After adjusting for EAU prognostic groups, higher nomogram scores were associated with increased risk scores of two and three. PCa progression occurred in 12.7% of cases after a mean follow-up of 92.1 months. Patients with recurrence had a worse prognosis as risk scores increased from one to three, even after adjustment for Briganti’s 2012 nomogram by EAU class.
Conclusions
Favourable pathology risk scores, grouped by Briganti’s 2012 and EAU nomograms, impact prognosis. As scores increase, the likelihood of disease progression rises, potentially influencing treatment strategies.
Keywords: prostate cancer, EAU risk classes, prostate cancer nomograms, robot assisted radical prostatectomy, favorable prostate cancer pathology, prostate cancer progression
INTRODUCTION
The increasing incidence of clinical prostate cancer (PCa) has prompted the European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) to update guidelines to reduce overtreatment and prevent treatment-related patient regret [1, 2]. Treatment options include monitoring strategies like active surveillance (AS) and watchful waiting (WW), surgery (robotic-assisted radical prostatectomy [RARP] with or without extended pelvic lymph node dissection [ePLND]), radiation therapy, and combination therapies tailored to prognostic risk categories (low to high) [3, 4]. Prognostic risk classes differ between classification systems and remain heterogeneous due to a mix of favourable and unfavourable pathology features. Reliable predictors are lacking, as molecular biology is not yet part of routine practice and multiparametric magnetic resonance imaging (MRI) is not consistently reproducible in multicentre studies.
Preoperative nomograms, such as Briganti’s 2012 model, estimate the risk of pelvic lymph node invasion (PLNI) by integrating multiple clinical variables [5, 6]. Among these tools, Briganti’s 2012 nomogram is one of the most effective and widely used. This study aimed to evaluate the impact of favourable pathology patterns on PCa progression after assessing associations with the Briganti’s 2012 nomogram using EAU risk stratification in patients treated with robotic surgery.
MATERIAL AND METHODS
Evaluation of parameters in the investigated prostate cancer patient population
We analysed 757 patients (January 2013–December 2021) with no prior PCa treatment, including androgen blockade. Robotic surgery, with or without ePLND, was performed by five experienced surgeons following a standardised template. Data were collected prospectively and analysed retrospectively.
Clinical factors included age, body mass index (BMI), physical status, prostate-specific antigen (PSA), prostate volume (PV), biopsy positive cores percentage (BPC), and tumour grade and stage. Surgical specimens included the resected prostate and any sampled lymph nodes. Tumours were graded according to the International Society of Urological Pathology (ISUP) system and staged according to the TNM system. The samples were evaluated according to the pathological guidelines in force at the time of surgery. Patient follow-up adhered to guidelines, and a multidisciplinary team reviewed decisions regarding disease progression to optimise and personalise recommendations.
Model assumptions with evaluation of endpoints
The study focused on identifying favourable pathological features in surgical specimens, such as ISUP 1/3, pT2/3a, and pN0/x. These features were categorised into grades (0–3) based on different combinations. The study then assessed the relationship between these grades, Briganti’s 2012 nomogram, and EAU classes. The goal was to determine the impact of these combined patterns on PCa progression, including biochemical recurrence, local recurrence, or metastases. Individual cancer factor scores were not calculated for Briganti’s 2012 nomogram and EAU prognostic classes.
Statistical methods
Continuous variables were evaluated as medians with interquartile ranges (IQR), and categorical variables were evaluated as frequencies (percentages). Associations of risk score patterns were tested using the Kruskal-Wallis test for continuous variables and the χ2 test for categorical variables. The multinomial logistic regression model evaluated the associations between Briganti’s 2012 nomogram, EAU classes, and the risk of combined patterns. Time to event occurrence was censored as the time between surgery and PCa progression or the last follow-up. Cox’s proportional model was used to evaluate the risk of disease progression by examined patterns adjusted for Briganti’s 2012 nomogram beyond EAU classes. Unadjusted Kaplan-Meier related curves were also generated. IBM-SPSS version 26 was used for the analysis. All tests were two-tailed, and p <0.05 was considered statistically significant.
Bioethical standards
The Institutional Review Board of Univeristy of Verona approved the study, and all patients provided informed consent.
RESULTS
Associations of favourable pathology risk score patterns
Grades one and two were the most frequent favourable pathologic risk score patterns (49% and 30.95%, respectively), followed by grades zero (15.2%) and three (4.9%). Increasing risk score patterns were associated with older age, unfavourable cancer features, higher nomogram scores, and unfavourable EAU prognostic classes. Extended pelvic lymph node dissection (ePLND) was performed in 54.8% of cases, with a median of 26 lymph nodes counted (Table 1).
Table 1.
Associations of factors with favorable pathology risk cores patterns in 757 patients treated with robotic surgery
| Favorable pathology risk score pattern in the surgical specimen | p | ||||
|---|---|---|---|---|---|
| Zero | One | Two | Three | ||
| Cases, n (%) | 15 (15.2) | 371 (49.0) | 234 (30.9) | 37 (4.9) | |
| Physical features | |||||
| Age (years) | 63 (58–68) | 64 (58–69) | 65 (61–71) | 66 (60.5–70.5) | 0.005 |
| BMI [kg/m2] | 25.6 (23.7–28.0) | 25.8 (24.0–27.8) | 26.0 (23.9–28.1) | 26.1 (22.8–28.5) | 0.729 |
| ASA score 1 | 13 (4.3) | 36 (9.7) | 17 (7.3) | 5 (13.5) | 0.266 |
| ASA score 2 | 96 (83.5) | 304 (81.9) | 189 (80.8) | 27 (73.0) | |
| ASA score 3 | 6 (5.2) | 31 (8.4) | 28 (12.0) | 5 (13.5) | |
| PV [ml] | 42 (32–53) | 40 (30–50) | 36.7 (28.7–47.2) | 34 (30–47) | 0.054 |
| Clinical cancer features | |||||
| PSA [ng/ml] | 6.1 (4.6–7.9) | 6.2 (4.7–8.1) | 6.4 (5.0–8.6) | 8.1 (5.6–10.1) | 0.007 |
| BPC (%) | 21.4 (14.2–35.7) | 28.5 (16.6–42.8) | 30 (20–50) | 30 (21.8–51.6) | <0.0001 |
| ISUP 1 | 96 (83.5) | 156 (42.0) | 62 (26.5) | 7 (18.9) | <0.0001 |
| ISUP 2/3 | 19 (16.5) | 209 (56.3) | 160 (68.4) | 30 (81.1) | |
| ISUP 4/5 | 0 (0.0) | 6 (1.6) | 12 (5.1) | 0 (0.0) | |
| cT1 | 90 (78.3) | 232 (62.5) | 138 (59.0) | 16 (43.2) | <0.0001 |
| cT2/3 | 25 (21.7) | 139 (37.5) | 96 (41.0) | 21 (56.8) | |
| EAU risk class | |||||
| Low-risk | 92 (80) | 122 (32.9) | 51 (21.8) | 4 (10.8) | <0.0001 |
| Intermediate-risk | 19 (16.5) | 219 (59.0) | 149 (63.7) | 25 (67.6) | |
| High-risk | 4 (3.5) | 30 (8.1) | 34 (14.5) | 8 (21.6) | |
| Nomogram for PLNI | |||||
| Briganti 2012 (%) | 2 (1–3) | 2 (1–4) | 4 (2–8) | 4 (2.5–8.5) | <0.0001 |
| PLND | 32 (27.8) | 199 (53.6) | 157 (67.1) | 27 (73.0) | <0.0001 |
| Pathology features | |||||
| ISUP 1 | 115 (100) | 1 (0.3) | <0.0001 | ||
| ISUP 2 | 370 (99.7) | 20 (8.5) | |||
| ISUP 3 | 214 (91.5) | 37 (100) | |||
| pT2 | 115 (100) | 370 (99.7) | 214 (91.5) | <0.0001 | |
| pT3a | 1 (0.3) | 20 (8.5) | 37 (100) | ||
| R1 | 12 (10.4) | 74 (19.9) | 42 (17.9) | 20 (54.1) | <0.0001 |
Continuous variables are reported as medians (interquartile ranges) while categorical factors as frequencies (percentages); and methods; for further details see sections relative to material
ASA – American Society of Anesthesiologists; BMI – body mass index; EAU – European Association of Urology
Favourable pathology risk score patterns predicted by Briganti’s 2012 nomogram through EAU risk classes
As the nomogram score increased, patients were more likely to have less favourable patterns. This included risk scores two (OR = 1.088; 95% CI: 1.010–1.171; p = 0.025) and three (1.096; 95% CI: 1.096; 1.010–1.189; p = 0.028) compared to pattern zero. It also included risk scores two (OR = 1.075; 95% CI: 1.038–1.114; p <0.0001) and three (OR = 1.084; 95% CI: 1.032–1.139; p = 0.001) compared to pattern one. Risk score one showed no significant association with pattern zero on multivariate analysis (Table 2).
Table 2.
Impact of Briganti’s 2012 nomogram through EAU risk classes for predicting favourable pathology risk score patterns
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Statistics | OR (95% CI) | p | OR (95% CI) | p |
| a) Risk score one vs zero | ||||
| Briganti 2012 nomogram | 1.119 (1.030–1.217) | 0.008 | 1.011 (0.939–1.089) | 0.768 |
| EAU intermediate vs low risk | 8.692 (5.059–14.934) | <0.0001 | 8.524 (4.890–14.860) | <0.001 |
| EAU high vs low risk | 5.656 (1.925–16.618) | 0.002 | 5.435 (1.795–15.458) | 0.003 |
| b) Risk score two vs zero | ||||
| Briganti 2012 nomogram | 1.216 (1.119–1.322) | <0.0001 | 1.088 (1.010–1.171) | 0.025 |
| EAU Intermediate vs low risk | 14.147 (7.862–25.454) | <0.0001 | 11.733 (6.428–21.417) | <0.0001 |
| EAU high vs low risk | 15.333 (5.150–45.654) | <0.0001 | 10.042 (3.244–31.086) | <0.0001 |
| c) Risk score three vs zero | ||||
| Briganti 2012 nomogram | 1.236 (1.131–1.352) | <0.0001 | 1.096 (1.010–1.189) | 0.028 |
| EAU Intermediate vs low risk | 30.263 (9.437–97.052) | <0.0001 | 24.478 (7.532–79.544) | <0.0001 |
| EAU high vs low risk | 46.000 (9.638–219.542) | <0.0001 | 28.264 (5.603–142.579) | <0.0001 |
| d) Risk score two vs one | ||||
| Briganti 2012 nomogram | 1.086 (1.050–1.124) | <0.0001 | 1.075 (1.038–1.114) | <0.0001 |
| EAU Intermediate vs low risk | 1.628 (1.105–2.398) | 0.014 | 1.376 (0.925–2.049) | 0.115 |
| EAU high vs low risk | 2.711 (1.503–4.890) | 0.001 | 1.848 (0.990–3.451) | 0.054 |
| e) Risk score three vs one | ||||
| Briganti 2012 nomogram | 1.104 (1.050–1.124) | <0.0001 | 1.084 (1.032–1.139) | 0.001 |
| EAU Intermediate vs low risk | 3.482 (1.184–10.237) | 0.023 | 2.872 (0.967–8.531) | 0.058 |
| EAU high vs low risk | 8.133 (2.296–28.816) | 0.001 | 5.201 (1.395–19.389) | 0.014 |
CI – confidence interval; EAU – European Associan of Urology risk classes; see also materials, methods and results for further details; OR – odds ratio
Prognostic impact of favourable pathology risk score patterns
Prostate cancer (PCa) progression occurred in 12.7% (Table 3) of cases after a mean follow-up of 92.1 months. Patients with higher risk scores were more likely to have a worse prognosis. Compared to score zero, the hazard ratios were 2.478 for score one, 4.361 for score two, and 7.227 for score three, after adjusting for Briganti’s 2012 and EAU classes. Kaplan-Meier survival risk curves for PCa progression are shown in Figure 1. There were 19 (2.5%) patient deaths, of which 4 (0.5%) were related to PCa. Androgen deprivation therapy was administered in 9.2% of patients and radiation therapy in 10.6%, with 4.9% receiving salvage therapy.
Table 3.
Impact of favourable pathology risk score patterns on prostate cancer progression through EAU risk classes and by Briganti’s 2012 nomogram in 757 cases treated with robotic surgery
| Total cases | Cases progressing | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|---|
| Statistics | 757 | 96 (12.7) | HR (95% CI) | P | HR (95% CI) | P |
| Briganti’s 2012 nomogram | ||||||
| one-two | 385 | 37 (9.6) | Ref. | Ref. | 0.03 | |
| > two | 372 | 59 (15.9) | 2.455 (1.616–3.693) | <0.0001 | 1.595 (1.030–2.470) | |
| EAU prognostic risk class | ||||||
| Low risk | 269 | 25 (9.3) | Ref. | Ref. | ||
| Intermediate risk | 412 | 59 (14.3) | 3.152 (1.962–5.063) | <0.0001 | 2.035 (1.234–3.355) | 0.005 |
| High risk | 76 | 12 (15.8) | 3.997 (1.990–8.030) | <0.0001 | 2.050 (0.971–4.330) | 0.06 |
| Favourable pathology pattern | ||||||
| Risk score zero | 115 | 6 (5.2) | Ref. | Ref. | ||
| Risk score one | 371 | 37 (10.0) | 3.307 (1.393–7.850) | 0.007 | 2.478 (1.027–5.981) | 0.044 |
| Risk score two | 234 | 42 (17.9) | 6.901 (2.925–16.283) | <0.0001 | 4.361 (1.793–10.612) | 0.001 |
| Risk score three | 37 | 11 (2.97) | 13.063 (4.803–35.526) | <0.0001 | 7.227 (2.520–20.724) | <0.0001 |
Figure 1.
Kaplan-Meyer survival risk curves of prostate cancer (PCa) progression in 757 patients treated with robotic surgery and stratified through favourable pathology risk score patterns in the surgical specimen. Accordingly, mean survival time of PCa progression decreased from favourable pathology pattern risk score zero (101.7 months; 95% CI: 98.6–104.9 months), one (94.5 months, 95% CI: 90.9–98.1 months), two (83.3 months; 95% CI: 78.6–87.9 months), and three (73.4 months; 95% CI: 63.3–83.5 months) with the difference being significant (Mantel-Cox log rank test: p <0.0001).
DISCUSSION
Managing PCa is challenging due to the heterogeneity of prognostic risk groups, which differ between the two main systems [1, 2, 9–12]. Treated PCa can become life-threatening, with progression occurring in about 35% of cases and mortality affecting about 16% of patients [1, 2, 7–12]. The Cambridge Prognostic Group Classification reports mortality rates between 1.2% and 13.7% [1, 2, 9–12]. Surgically treated PCa may present with various pathological features, categorised as unfavourable (e.g. high-grade tumours with seminal vesicle invasion or lymph node invasion) or favourable [13–20]. Molecular biology and mpMRI are not yet reliable tools for resolving this issue in daily practice [1, 2, 5, 6, 9–20].
This study highlights new considerations for evaluating surgically treated PCa patients with favourable pathological features.
Higher pathology risk scores were associated with increased disease progression, regardless of EAU risk classes or Briganti’s 2012 nomogram [21–24]. These findings require further confirmation.
Given these results, it is crucial to consider whether patients with favourable pathology should undergo more intensive follow-up or alternative management strategies. While current protocols primarily focus on high-risk features, our findings suggest that patients with intermediate favourable pathology risk scores may benefit from a more tailored surveillance approach. For example, patients with a pathology risk score of 2 or 3 could undergo closer PSA monitoring, earlier imaging assessment, or discussions about adjuvant therapy options, particularly in those with additional risk factors such as high PSA levels or adverse molecular markers. However, prospective studies are needed to validate these recommendations before modifying current standard protocols.
Grouping favourable pathology features into risk scores, as predicted by Briganti’s 2012 nomogram and EAU classifications, may help improve patient counselling [1, 2, 21–24]. This study shows that patients with favourable features may have different prognostic risk patterns predictable preoperatively.
Although Briganti’s 2012 nomogram independently predicted prognosis, it did not significantly differentiate between risk scores zero and one in multivariate analysis. This suggests that, for very low-risk patients, additional factors may be required to refine prognostic accuracy.
Briganti’s 2012 nomogram is associated with the risk of several favourable pathologic prognostic patterns and disease progression. This may be because it combines several clinical variables into a risk score associated with an aggressive cancer biology phenotype.
However, the role of preoperative nomograms in risk stratification is evolving, particularly with the widespread use of mpMRI and targeted biopsies. These modern imaging techniques improve tumour localisation and risk assessment, potentially reducing the reliance on traditional nomograms. Despite this, our study demonstrates that Briganti’s 2012 nomogram retains prognostic value, particularly in settings where mpMRI access remains variable or where additional risk stratification is needed beyond imaging findings.
Managing PCa is complex because EAU prognostic groups are not homogeneous [1, 2, 9–12]. Unrecognised aggressive cancers classified as indolent and vice-versa can lead to undertreatment or overtreatment [1, 2, 9–12].
The natural history of PCa is influenced by a combination of favourable and adverse pathology features that combine into patterns with varying prognostic impacts. This study showed that favourable pathology risk score zero had the best prognosis, while pattern risk score three (ISUP grade group 3 with extracapsular extension) had the worst. Briganti’s 2012 nomogram predicted this outcome through EAU risk classes. These results have implications for clinical practice. These findings suggest that integrating pathology risk scores with existing nomograms may refine risk stratification and potentially influence postoperative management strategies.
This study has limitations, as it was retrospective, included several surgeons, and did not evaluate the extent of cancer invasion in each biopsy core or mpMRI findings. However, its strengths include the cohort size, the adequate number of lymph nodes counted when ePLND was performed, and its reflection of daily practice in urologic units.
CONCLUSIONS
Favourable pathology risk score characteristics clustered into risk score groups predicted by Briganti’s 2012 nomogram by EAU risk classes showed prognostic impact. As the favourable pathology risk score increased, patients were more likely to progress, regardless of Briganti’s 2012 nomogram and/or EAU risk class. Different patterns of favourable pathology risk scores impact prognosis and may alter treatment paradigms.
Funding Statement
FUNDING This research received no external funding.
CONFLICTS OF INTEREST
The authors declare no conflict of interest.
ETHICS APPROVAL STATEMENT
The Institutional Review Board of Univeristy of Verona approved the study.
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