Abstract
Background
Active surveillance (AS) is the preferred initial management for low-risk prostate cancer; however, a substantial proportion of patients are found to harbor more advanced disease at radical prostatectomy. This study evaluated the clinicopathologic features and surgical outcomes of Filipino men with low-risk prostate cancer and identified predictors of unfavorable pathology.
Materials and methods
This retrospective cohort study included 65 Filipino men with low-risk prostate cancer who underwent radical prostatectomy. Low-risk disease was defined as grade group 1 (Gleason score: 3 + 3 = 6) and prostate-specific antigen (PSA) < 10 ng/mL. Clinicopathologic features included age, PSA, biopsy characteristics, and measures of tumor volume such as the number of positive cores and percent positive cores (PPC). Unfavorable pathology was defined as upgrading to grade group ≥2 or grade group 1 with tertiary pattern 4, pathologic upstaging (pT3–pT4 or pN1), or both. Logistic regression and receiver operating characteristic analyses were performed to identify predictors of unfavorable pathology and determine an optimal cutoff for PPC.
Results
Unfavorable pathology was observed in 56.92% of patients, predominantly due to upgrading, with fewer cases demonstrating upstaging. No cases of regional lymph node metastasis were identified. On multivariable analysis, PPC (per 10% increase) was a significant predictor of unfavorable pathology (odds ratio: 2.95, 95% confidence interval: 1.60–6.58; P = 0.003), whereas age and PSA were not significant predictors. The receiver operating characteristic analysis identified a cutoff value of 12.22% positive cores.
Conclusions
A substantial proportion of Filipino patients with low-risk prostate cancer harbor more advanced disease at radical prostatectomy. Tumor volume, as measured by PPC, may help identify patients at risk of unfavorable pathology and aid in refining selection of candidates for active surveillance.
Keywords: Biopsy, Prostatic neoplasms, Prostatectomy, Watchful waiting
1. Introduction
Prostate cancer is the second most common cancer affecting men worldwide1 and the third leading cause of cancer mortality among Filipino men.2 Accurate risk stratification is essential to guide management and predict disease progression and clinical outcomes.
The National Comprehensive Cancer Network classifies prostate cancer into risk categories based on clinical and pathologic parameters.3 Low-risk disease is defined by clinical stage T1–T2a, prostate-specific antigen (PSA) level <10 ng/mL, and grade group 1 (GG1; Gleason score: 3 + 3 = 6).3 Tumors classified as GG1 generally demonstrate favorable oncologic outcomes following prostatectomy, including high rates of biochemical recurrence–free survival,4 low rates of extraprostatic extension,5 rare seminal vesicle invasion,5 and minimal risk of lymph node metastasis.6 Given its indolent behavior and favorable outcomes,7 active surveillance (AS) is recommended as the preferred initial treatment for low-risk prostate cancer in patients with a life expectancy of at least 10 years.3 AS involves serial PSA testing, digital rectal examinations, and repeat biopsies, allowing patients to avoid treatment-related morbidity such as urinary, bowel, and sexual dysfunction associated with prostatectomy or radiotherapy.8
Despite classification as low-risk, a considerable proportion of patients are found to harbor higher-grade or more advanced disease at prostatectomy.9 Although multiple institutional AS protocols have been developed, there is no clear consensus on the optimal parameters for patient selection.9,10 Recent studies and guidelines have also explored expanding AS criteria to include patients with favorable intermediate-risk disease, reflecting continuously evolving approaches in patient selection.3,11 Factors commonly used to guide selection include tumor grade group, tumor volume on needle biopsy, clinical stage, and preoperative PSA levels.10
According to the Global Cancer Observatory, the Philippines has among the highest prostate cancer incidence and mortality rates in Southeast Asia.1 However, data on the clinicopathologic characteristics and surgical outcomes of Filipino men with prostate cancer remain limited. To date, no local studies in the Philippines have evaluated prostatectomy outcomes in risk-stratified groups, particularly among low-risk patients. Moreover, existing AS criteria are largely derived from Western populations, and their applicability to Filipino men remains uncertain.
This study aims to identify clinicopathologic features of Filipino men with low-risk prostate cancer, determine surgical outcomes at radical prostatectomy (RP), and determine which clinicopathologic features are predictive of unfavorable pathology, defined as upgrading, upstaging, or both. In doing so, the findings of this study may help refine selection of Filipino patients for AS and identify those who may benefit from closer monitoring or earlier definitive treatment.
2. Materials and methods
2.1. Study design
This is a retrospective observational cohort study conducted at two tertiary hospitals.
2.2. Patient selection
For the purposes of this study, low-risk prostate cancer was defined as GG1 on needle biopsy and a PSA level of <10 ng/mL. Clinical stage was not included due to unavailability of this information in the official medical records. Patients meeting these criteria who underwent RP from January 2014 to December 2023 were selected for the study. Patients who had received androgen receptor–directed therapy, radiotherapy, or chemotherapy, or had clinical or radiologic evidence of metastatic disease, were excluded. Patients with prior prostate biopsies or concurrent primary malignancies were also excluded. A total of 65 patients met the selection criteria.
Biopsy specimens included both in-house cases and referred cases and consisted of systematic ultrasound-guided biopsies, with and without magnetic resonance imaging–targeted cores. RP specimens were limited to in-house cases. All specimens were reviewed by at least 2 board-certified anatomic pathologists, including a genitourinary pathologist.
2.3. Data collection
Patient age and PSA at biopsy were obtained from electronic medical records. Biopsy parameters, biopsy procedure, and surgical outcomes at RP were extracted from surgical pathology reports and operative records. The total number of cores was determined from the gross description and the number of positive cores from the final diagnosis. In 8 cases with core fragmentation, the number of positive cores was estimated based on percent tumor involvement and the total cores submitted. Percent positive cores (PPC) was calculated by dividing the number of positive cores by the total number of cores biopsied and multiplying the resulting value by 100.
Surgical outcomes at RP including upgrading, positive surgical margins, seminal vesicle invasion, extraprostatic extension, and regional lymph node metastasis were recorded. Unfavorable pathology was defined as the composite outcome of upgrading, upstaging, or both. Upgrading was defined as Grade Group ≥2 (3 + 4 = 7) or GG1 with tertiary pattern 4. Upstaging was defined as pT3–pT4 or pN1 disease, in accordance with College of American Pathologists guidelines.12
2.4. Data analysis
Baseline clinicopathologic characteristics were summarized using descriptive statistics. Continuous variables were reported as mean with standard deviation or median with interquartile range, while categorical variables were reported as frequencies and percentages.
Univariable logistic regression was performed to assess associations between clinicopathologic variables and unfavorable pathology at RP. Tumor volume was evaluated using PPC, which was selected to account for differences in biopsy sampling9; PPC was also analyzed per 10% increase to allow for easier clinical interpretation of tumor volume. Multivariable logistic regression identified independent predictors of unfavorable pathology, with odds ratios (ORs), 95% confidence intervals (CIs) and P values reported.
A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal PPC cutoff for predicting unfavorable pathology, with the threshold identified using the Youden index. Sensitivity and specificity corresponding to the cutoff were calculated.
All statistical analyses were conducted using R software (version 4.2.3; R Foundation for Statistical Computing, Vienna, Austria), and statistical significance was set at a two-sided P value <0.05.
2.5. Ethical considerations
This study was approved by the St. Luke’s Medical Center Institutional Ethics Review Committee (reference number: SL-24134). Given the retrospective nature of the study and the use of deidentified data, the requirement for informed consent was waived. All procedures were conducted in accordance with the ethical standards of the institutional research committee and with the principles of the Declaration of Helsinki.
3. Results
3.1. Clinicopathologic features of low-risk prostate cancer patients
The clinicopathologic characteristics of the 65 patients with low-risk prostate cancer diagnosed on needle biopsy are summarized (Table 1). Patients had a mean age of 63.83 years at the time of biopsy, with a mean preoperative PSA level of 6.42 ng/mL. The median number of cores biopsied was 18. The median number of positive cores was 3, while the median percentage of positive cores was 15.38. In all cases, RP was performed within a year of diagnosis, with a median interval of 69 days from biopsy.
Table 1.
Clinicopathologic features of low-risk prostate cancer patients
| Clinicopathologic Features | Resultsa) (n = 65) |
|---|---|
| Age, yr | 63.83 ± 6.41 |
| PSA, ng/mL | 6.42 ± 1.89 |
| Total number of cores biopsied | 18 (14, 23) |
| Total number of positive cores | 3 (2, 4) |
| Percent positive cores, % | 15.38 (7.69, 23.08) |
| Biopsy procedure | |
| Systematic | 41, 63.08 |
| Systematic with MRI targeted | 24, 36.92 |
| Biopsy-to-prostatectomy interval, d | 69 (47, 93) |
MRI, magnetic resonance imaging; PSA, prostate-specific antigen.
Mean ± standard deviation or median (interquartile range) or frequency, percentage.
3.2. Unfavorable pathology at prostatectomy
Surgical outcomes identified on RP specimens are shown (Table 2). Notably, more than half of patients (55.38%) upgraded to a higher grade group. Of these patients, majority (72.22%) upgraded to grade group 2. Upstaging was observed in 9 patients (13.85%), all of whom exhibited nonfocal extraprostatic extension, including 2 patients (3.08%) with seminal vesicle invasion. In 9 patients (13.85%), the tumor extended to the surgical margins. Regional lymph node dissection was performed in 16 patients, and all were negative for metastasis.
Table 2.
Surgical outcomes and unfavorable pathology at radical prostatectomy
| Surgical Outcomes | Resultsa) (n = 65) |
|---|---|
| Upgrade | |
| Present | 36, 55.38 |
| GG1 (3 + 3 = 6) with tertiary pattern 4 | 7, 19.44 |
| GG2 (3 + 4 = 7) | 26, 72.22 |
| GG3 (4 + 3 = 7) | 2, 5.56 |
| GG3 (4 + 3 = 7) with tertiary pattern 5 | 1, 2.78 |
| Absent | 29, 44.62 |
| Extraprostatic extension (pT3a) | |
| Present | 9, 13.85 |
| Non-focal | 9, 100 |
| Absent | 56, 86.15 |
| Seminal vesicle invasion (pT3b) | |
| Present | 2, 3.08 |
| Absent | 63, 96.92 |
| Positive surgical margin | |
| Present | 9, 13.85 |
| Absent | 56, 86.15 |
| Unfavorable pathology (upgrading and/or upstaging) | |
| Present | 37, 56.92 |
| Absent | 28, 43.08 |
GG1, grade group 1; GG2, grade group 2; GG3, grade group 3.
Frequency, percentage.
A total of 37 patients (56.92%) exhibited unfavorable pathology. Among patients with extraprostatic extension (pT3a), 8 of 9 also demonstrated upgrading, while one patient had isolated upstaging. Both patients with seminal vesicle invasion (pT3b) likewise had concurrent upgrading. No cases of pT4 or pN1 disease were identified.
3.3. Predictors of unfavorable pathology
In the univariable logistic regression analysis (Table 3), PPC, modeled per 10% increase, was significantly associated with unfavorable pathology (OR = 2.92, 95% CI: 1.60–6.45; P = 0.002). This association remained significant in the multivariable analysis (OR = 2.95, 95% CI: 1.60–6.58; P = 0.003). Age and PSA were not significant predictors.
Table 3.
Logistic regression analysis for predictors of unfavorable pathology at prostatectomy
| Predictor | Univariable |
Multivariable |
||
|---|---|---|---|---|
| OR (95% CI) | Pa) | OR (95% CI) | Pa) | |
| Age, yr | 1.04 (0.96–1.13) | 0.325 | 1.04 (0.96–1.15) | 0.348 |
| PSA, ng/mL | 1.04 (0.80–1.36) | 0.753 | 1.03 (0.76–1.38) | 0.865 |
| Percent positive cores per 10% increase, % | 2.92 (1.60–6.45) | 0.002 | 2.95 (1.60–6.58) | 0.003 |
CI, confidence interval; OR, odds ratio; PSA, prostate-specific antigen.
Significant at a P value <0.05.
The ROC analysis (Fig. 1) demonstrated that PPC had an area under the curve of 0.792 (95% CI: 0.673–0.897), indicating good discrimination. The optimal cutoff value was 12.22%, corresponding to a sensitivity of 83.78% and specificity of 64.29%.
Fig. 1.
Receiver operating characteristic (ROC) curve for percent positive cores (PPC) as a predictor of unfavorable pathology at radical prostatectomy. The optimal cutoff of 12.22% was determined by the Youden index (sensitivity: 83.78%, specificity: 64.29%). Area under the curve (AUC) = 0.792 (95% CI: 0.673–0.897). CI, confidence interval.
4. Discussion
4.1. Surgical outcomes and unfavorable pathology in low-risk patients
Gleason upgrading was seen in 55.38% of patients classified as low-risk on biopsy. Reported upgrading rates in comparable Western cohorts typically range from 30% to 50%,13, 14, 15, 16, 17, 18 with few studies reporting rates approaching 70%.19,20 Asian studies likewise showed variable upgrading rates ranging from 20% to 50%.21, 22, 23, 24, 25 The rate observed in this study falls within the upper range of previously reported values.
Pathologic upstaging was identified in a smaller subset, as evidenced by extraprostatic extension (13.85%) and seminal vesicle invasion (3.08%). Similar rates have also been reported alongside upgrading in prior studies.5,15,16,18,22,26, 27, 28 Positive surgical margins (13.85%) were observed but were excluded from the composite outcome of unfavorable pathology as this is influenced by surgical technique and does not necessarily reflect tumor biology. No lymph node metastasis was identified, consistent with prior studies demonstrating rare to absent nodal involvement in low-risk patients.5,6,18
Overall, 56.92% of patients exhibited unfavorable pathology, suggesting that despite low-risk features on biopsy, a substantial proportion of Filipino patients harbor more advanced disease at prostatectomy, most commonly in the form of upgrading, with a minority exhibiting upstaging to non–organ-confined disease.
4.2. Predictors of unfavorable pathology
Tumor volume measured as PPC was a significant predictor of unfavorable pathology, with each 10% increase associated with an approximately three-fold increase in odds. When adjusting for other predictors such as age and PSA levels, PPC remained a significant predictor. These findings are consistent with published literature demonstrating PPC as a predictor of upgrading, upstaging, or their combined occurrence as a composite outcome.9,15,16,19,26,28
Tumor volume on biopsy can be assessed using several parameters, including the number of positive cores,13,20,21,27 PPC, maximum percent of tumor involvement in a core,14 or maximum length of tumor.20,27 Higher tumor volume has been associated with increased likelihood of upgrading or upstaging at prostatectomy,9 which is primarily attributed to sampling error and intratumoral heterogeneity. Greater tumor volume on biopsy has been shown to correlate with larger tumor volume at prostatectomy.14,24,26 In heterogeneous tumors, higher-grade components may be missed on biopsy, resulting in misclassification.14,24,29 These same limitations may also explain upstaging in patients initially classified as low risk. Higher-volume tumors may be more predisposed to invade beyond the prostate and into surrounding tissues.26 Similarly, unsampled higher-grade components may have greater propensity for extraprostatic spread.26
Higher tumor volumes have been associated with earlier clinical progression and conversion to treatment from AS30; however, evidence also suggests that true progression occurs over long timeframes.31 Given the short interval of 69 days between biopsy and RP in the present study, upgrading and upstaging observed are more consistent with biopsy misclassification or sampling limitations than true disease progression.
The ROC analysis identified a cutoff value of 12.22% for PPC in predicting unfavorable pathology, which is lower than thresholds reported in other studies, typically ranging from 20% to 25% to predict upgrading, upstaging, or both.15,18,28 Differences in reported cutoffs may partly reflect variations in methodological approaches, with some studies using median-based thresholds15 and others using predefined thresholds and categorical groupings.18,28 The calculated cutoff demonstrated relatively high sensitivity (83.78%) and moderate specificity (64.29%), indicating that it may be effective in identifying patients at risk of unfavorable pathology, with some false-positive classifications. In the context of AS, prioritizing sensitivity may be preferable to minimize the risk of missing clinically significant disease, making this cutoff more suitable for risk stratification rather than definitive decision-making. Notably, the lower cutoff observed in this study suggests that unfavorable pathology may occur at relatively lower tumor volumes in Filipino patients.
Many Western and Asian institutional protocols use the number of positive cores as a measure of tumor volume to guide patient selection for AS.10,32 However, the increasing use of targeted biopsies may confound tumor volume assessment based on core counts alone; thus, PPC has been proposed as a more flexible and standardized measure.9 The 12.22% cutoff identified in the present study may be more applicable to extended biopsy schemes and less reliable in lower-core approaches such as sextant biopsies where involvement of a single core would exceed this threshold. In contrast, the median number of cores biopsied in this cohort is 18, which would correspond to involvement of approximately 2 cores when the cutoff is applied. This cutoff, however, requires external validation in larger cohorts of Filipino patients before its clinical utility can be established and should be interpreted in conjunction with other clinicopathologic factors.
The role of tumor volume on biopsy in selecting patients for AS remains controversial. Prior studies have reported mixed findings, with some showing limited ability of different measures of tumor volume to predict adverse pathology22,33 and others demonstrating association with upgrading alone but not with other clinically significant outcomes such as non–organ-confined disease and metastasis.18 Despite this, the present findings support the utility of biopsy tumor volume as a predictor of upgrading or upstaging and suggest its potential role as an adjunct in selecting candidates for AS and identifying patients who may benefit from closer monitoring or earlier intervention.
The effects of age and PSA levels were also taken into account in the regression analysis of this study. Increasing age is associated with a higher risk of disease progression9 and has been identified in several studies as a significant predictor of adverse outcomes.14,15,17,18,25 Similarly, PSA has been widely evaluated as a predictor of adverse pathology, although there remains no clear consensus on the PSA-based parameter that best predicts clinically significant disease. While several studies have demonstrated higher PSA levels as a significant predictor of adverse outcomes,14,15,17,19,24 others have asserted that PSA level alone has poor predictive value and underperforms in comparison to PSA density.9 In this study, neither age nor PSA levels were found to be significant predictors of unfavorable pathology. PSA density, on the other hand, could not be calculated due to the lack of available data on prostate volume.
It is important to identify patients who are at the risk of reclassification to higher risk stratification groups as this has direct implications for treatment decisions. In our cohort of purportedly low-risk patients, 56.92% were found to harbor pathologic features that would warrant reclassification and consideration of more definitive treatment options. In cases where patients upgraded to grade group 3 or exhibited upstaging at prostatectomy, AS may not be ideal as it would entail delaying treatment of an already advanced tumor.
4.3. Significance in Filipino patients
In a study conducted by Grageda et al.34 at our institution, the clinicopathologic characteristics of prostate cancer in Filipino men who underwent RP were compared with those of American men. The authors found that Filipino men exhibited more adverse pathologic features at RP, including higher Gleason grades and increased rates of extraprostatic extension, seminal vesicle invasion, and positive surgical margins compared with their American counterparts.
In our cohort of Filipino men, more than half were found to exhibit unfavorable pathology at RP, with upgrading rates toward the upper range of those reported in Western and Asian populations. As previously discussed, this may reflect baseline undergrading due to sampling limitations rather than rapid disease progression. Taken together, the findings reported by Grageda et al.34 and the unfavorable pathology observed in this study highlight the need for population-specific evaluation of risk stratification and AS criteria in Filipino men. With further validation, the 12.22% cutoff for PPC identified may provide an additional tool for risk stratification as it suggests that upgrading or upstaging may occur even at relatively low levels of tumor involvement in biopsies. In a resource-limited setting such as the Philippines where access to more advanced diagnostic modalities often used in AS protocols is constrained, PPC may provide a practical measure of tumor volume readily derived from the initial biopsy specimens.
4.4. Limitations
This study has several limitations. Its retrospective design relies on the completeness and accuracy of medical records and is subject to selection bias as only patients eligible for AS who subsequently underwent RP were included. Outcomes of other low-risk patients managed nonsurgically could not be assessed. Decisions to proceed with definitive treatment were made at the discretion of the treating clinician and patient, and the specific factors influencing these decisions were not available for analysis. Several variables associated with adverse pathology, including PSA density, magnetic resonance imaging–targeted biopsy findings, alternative tumor volume measures, and clinical stage, could not be evaluated due to incomplete reporting in medical records. Variability in biopsy technique, surgical approach, and operator experience may also contribute to variability in the results. The cutoff value of 12.22% for PPC derived from the study cohort should also be considered exploratory and requires further validation. Finally, the relatively small sample size limited statistical power and the ability to detect modest associations. Future prospective studies with larger cohorts and standardized data collection are needed to validate these findings.
4.5. Conclusion
According to recent guidelines, AS is the preferred treatment option for low-risk prostate cancer. However, a significant proportion of patients still exhibit more advanced disease at prostatectomy despite their low-risk features. The findings of this study, consistent with existing literature, highlight the importance of incorporating other factors such as tumor volume in identifying patients who may be at risk of unfavorable pathology and who may benefit from closer monitoring, further evaluation, or earlier treatment. Given the limited representation of Filipino patients in established AS cohorts, these findings highlight the need for population-specific analyses to guide the use of AS in Filipino men.
Declaration of Generative AI and AI-assisted technologies in the manuscript preparation process
During the preparation of this work, the authors used artificial intelligence (ChatGPT, OpenAI) to assist with language editing, sentence restructuring, and formatting of references. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.
Conflicts of interest
The authors declare no conflict of interest.
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