Effect of prostate volume on the predictive value of prostate-specific antigen density for prostate cancer

Introduction

As a universal problem, cancer has been paid close attention to by scientists all over the world. According to the 2020 Cancer Epidemiology data, China and the United States exhibited differences in cancer incidence and mortality, with 1,756,921 newly diagnosed cancer cases and 607,636 deaths in the United States, accounting for 18.8% and 6.1% of the global cases, respectively, and the leading cause of cancer deaths in men is prostate cancer (PCa) (1). However, there has been an increasing trend in the incidence rate of PCa in Asian countries, particularly in China. This can be attributed to advancements in medical technology and widespread PCa screening practices (2). Combining serum prostate-specific antigen (PSA) with rectal examination has long been considered a crucial indicator for PCa screening and diagnosis (3). Long-term results of high-quality studies better illustrate the benefits of screening and detection. After 22 years of follow-up in the Gotebörg Screening Trial, all participants showed a mortality rate of 0.59 [95% confidence interval (CI): 0.43–0.80], comparable to other common cancers (4). Nevertheless, PSA levels may also be influenced by benign prostatic hyperplasia, prostatitis, age-related factors as well as prostate size variations. Consequently, distinguishing between benign prostatic hyperplasia and PCa becomes challenging. Moreover, the accuracy of rectal examination varies among individuals. Incorrect judgments have led to unnecessary prostate biopsies in some low-risk patients, thereby causing physical and psychological distress.

To enhance the precision of PCa diagnosis, we have introduced a novel parameter known as prostate-specific antigen density (PSAD), initially proposed by Epstein et al. (5), which characterizes the ratio of PSA to prostate volume (PV). Generally, higher PSAD values indicate an elevated risk of PCa. Previously, we primarily utilized PSAD values for supplementary assessment within the range of PSA 4–20 ng/mL. The clinical threshold for PSAD is 0.15 ng/mL/cm³ and this numerical standard has been widely accepted and acknowledged in Western countries as a means to differentiate between those suffering from PCa and those who are not (6). However, most guideline data were obtained based on Caucasians and it remains uncertain whether such data can be applied effectively to Chinese individuals. In our clinical experience, many patients with PSA levels between 4–20 ng/mL and PSAD ≥0.15 ng/mL/cm³ still exhibit negative results following ultrasound-guided transrectal prostate aspiration despite its safety profile; however, patients must still bear the risks associated with perineal pain, bleeding, and infection after puncture.

To date, there have been studies examining the impact of PV on PCa prediction (7); however, no definitive research has yet confirmed the influence of PV on the accuracy of PSAD in predicting PCa. In this study, we categorize the PV in the PCa database into three groups based on a threshold of 45–70 cm³ and employ various statistical methods to assess its effect on PCa prediction. We aim to establish a more precise volumetric criterion for patients with enlarged prostates to guide biopsy treatment. We present this article in accordance with the TRIPOD reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-490/rc).

Methods

Data collection

We conducted a retrospective analysis of 1,043 male patients who underwent transrectal prostate biopsy under ultrasound guidance at The First Hospital of Jilin University from 2013 to 2024. The study population consisted of the following groups: (I) patients with total prostate-specific antigen (TPSA) ≥4 ng/mL or abnormalities in PSAD, free/total prostate-specific antigen (F/TPSA). (II) Patients with palpable prostate lesions detected during digital rectal examination. (III) Patients with abnormal prostate images observed on ultrasound or computed tomography (CT). The prostate biopsies were performed by a team of experienced urologists at a single hospital using standardized biopsy needles, and each patient received a systematic biopsy involving 12 needles. Exclusion criteria included: (I) incomplete medical records, inability to obtain complete laboratory test information, or presence of extreme values that could affect statistical analysis. (II) Recent cystoscopy, digital rectal examination, or ongoing prostate hormone therapy within 2 weeks prior to PSA testing. (III) Previous history of prostate biopsy. (IV) TPSA value exceeding 20 ng/mL. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of The First Hospital of Jilin University (No. 2024-751) and informed consent was taken from all the patients.

Measurement of PSAD and PV

The doctor who specializes in ultrasound has accumulated 15 years of experience in measuring PV. We conducted separate measurements for the maximum transverse diameter (D1), maximum anteroposterior diameter (D2), and maximum longitudinal diameter (D3) of the prostate. The pathological volume of the prostate was calculated using the formula (D1 × D2 × D3 × π/6). Subsequently, we categorized the PV into three subgroups: less than 45 cm³, 45–70 cm³, and greater than 70 cm³, which were defined as small, medium, and large prostates respectively. This classification aimed to evaluate the predictive effect of PSAD on PCa at different volumes. PSAD was determined by dividing TPSA level by PV.

PCa detection

PCa was defined as any positive pathological result on a biopsy needle core.

Concomitant variables

Based on the patient’s medical records and other relevant studies, the following variables were included in the study: age, hypertension (HYP), diabetes (DIA), body mass index (BMI), TPSA, free prostate-specific antigen (FPSA), F/TPSA, neutrophil-to-lymphocyte ratio (NLR), absolute neutrophil count (ANC), and absolute lymphocyte count (ALC). These indicators may have a certain impact on the final outcome measure. All variables were obtained within one week of the prostate biopsy.

Statistical analysis

We employed the Shapiro-Wilks test to assess the normal distribution of the included variables. The t-test, Mann-Whitney U test, and Chi-squared test were utilized for comparing continuous data, categorical data, and continuous data with non-normal distribution respectively. Mean and standard deviation represented continuous data with normal distribution, while median and interquartile range (IQR) represented non-normal distribution. Categorical data were presented as percentage frequency. Restricted cubic spline (RCS) analysis was conducted to examine the dose-response relationship between PV and PCa while adjusting for covariates including age, HYP, DIA, BMI, F/TPSA, ANC, and ALC. PV was categorized into three groups (PV <45 cm³; 45 cm³≤ PV <70 cm³; PV ≥70 cm³), where multivariate logistic regression models were constructed for each group to explore the correlation between PSAD and PCa. Logistic regression was used to estimate 95% CI and odds ratio (OR). Receiver operating characteristic (ROC) curves were employed to evaluate the predictive ability of various indicators in different volume groups by obtaining sensitivity and specificity values. Differences among different volume groups were compared accordingly. Decision trees along with decision analysis methods were applied systematically to guide clinical decision-making by evaluating prostate biopsy results in different volume groups while determining the expected utility value of each decision path. Rstudio version 4.3.3 was used for all statistical analyses of collected data. P values were reported as two-sided tests with a significance level set at P<0.05.

Results

Baseline information

Table 1 presents the baseline information stratified by the presence of PCa, providing information on their demographic and clinical features. Following a thorough screening process based on inclusion and exclusion criteria, a total of 424 patients were included in the statistical analysis study. Among them, 109 (25.7%) had PCa while 315 (74.3%) did not. The median age of PCa patients was 67.0 (IQR, 62.0, 72.0) years, whereas for those without PCa it was 66.0 (IQR, 61.0, 71.0) years. There was no statistically significant difference in terms of age between these two groups (P=0.21). Regarding PSAD, out of all the patients, 288 (67.9%) had PSAD ≥0.15 ng/mL/cm³ while 136 (32.1%) had PSAD <0.15 ng/mL/cm³; there was a notable disparity between these two groups. Furthermore, we categorized the patients into three groups based on the size of PCa: small (<45 cm³, n=169), medium-sized (45 cm³≤ PV <70 cm³, n=132), and large (≥70 cm³, n=123). As expected, there was an incremental increase in PCa detection rate as the size of PCa increased. In terms of specific indicators examined in this study group, TPSA and PSAD values were significantly higher among PCa individuals compared to those without it; however, NLR value showed lower levels in the PCa group when compared to non-PCa cases. No significant differences were observed between these two groups regarding other assessed indicators.

The relationship between PSAD and PCa at different volumes

Table 2 presents univariate and multivariate analyses to determine the association between PSAD and PCa. In the univariate logistic regression model, for volumes less than 45 cm³, PSAD ≥0.15 ng/mL/cm³ was statistically significant for diagnosing PCa compared to PSAD <0.15 ng/mL/cm³ (OR =3.916; 95% CI: 1.501–12.242; P=0.009). However, for volume groups of 45–70 mL and greater than 70 cm³, PSAD ≥0.15 ng/mL/cm³ was not statistically significant for diagnosing PCa compared to PSAD <0.15 ng/mL/cm³ (P=0.50 and P=0.45). In the multivariate logistic regression model, after adding confounding variables, PSAD ≥0.15 ng/mL/cm³ was statistically significant for diagnosing PCa compared to PSAD <0.15 ng/mL/cm³ in the volume group less than 45 cm³ (OR =4.587; 95% CI: 1.667–15.091; P=0.006). However, for volume groups of 45–70 cm³ and greater than 70 cm³, PSAD ≥0.15 ng/mL/cm³ was not statistically significant for diagnosing PCa compared to PSAD <0.15 ng/mL/cm³ (P=0.51 and P=0.27).

In our study, we employed RCS to depict the dose-response association between PV and the risk of PCa, as illustrated in Figure 1A. With increasing PV, there is a significant decrease in the risk of PCa (P=0.15), indicating a negative linear relationship between them (P<0.001). As depicted in Figure 1B, even after adjusting for confounding variables, the RCS curve remains unaltered and continues to exhibit a significantly negative linear relationship (P=0.12; P<0.001). Notably, from the graphical representation, it can be observed that the point of intersection between the curve and a straight line with an odds ratio value of 1 occurs at PV =45 cm³. PVs below this threshold are associated with higher risks of PCa, while higher PVs correspond to lower risks.

Figure 1 Dose-response curves for PV and PCa. (A) Dose-response curve for PV and PCa. The horizontal coordinate is PV, with increasing prostate volume, there is a significant decrease in the risk of PCa. (B) Dose-response curve of PV and PCa after adding covariates. Its trend broadly similar to (A). PV, prostate volume; PCa, prostate cancer; OR, odds ratio; CI, confidence interval.

The prognostic value of PSAD in different volumes of PCa

The ROC curves were utilized to assess the predictive ability of TPSA, PSAD, and F/TPSA in PCa detection. The area under the curve (AUC) was employed as a measure of ROC performance, as depicted in Figure 2A. In the overall population, PSAD exhibited an AUC value of 0.742, while F/TPSA and TPSA demonstrated AUC values of 0.625 and 0.574 respectively. Notably, PSAD outperformed the other tests as a diagnostic tool for PCa.

Figure 2 ROC curves of different groups. (A) Overall ROC curve. (B) ROC curve of the small prostate group (PV <45 cm³]. (C) ROC curve of the medium-sized prostate group (45 cm³≤ PV <70 cm³). (D) ROC curve of the large prostate group (PV ≥70 cm³). The closer the AUC value converges to 1, the more accurate the variable is. ROC, receiver operating characteristic; PV, prostate volume; AUC, area under the curve; PSAD, prostate-specific antigen density; F/TPSA, free prostate-specific antigen to total prostate-specific antigen ratio.

In the small prostate group, the ROC results are shown in Figure 2B, with an AUC value of 0.752 for PSAD, 0.702 for TPSA, and 0.556 for F/TPSA. The diagnostic value of PSAD is stronger than that of other indicators. In the medium-sized prostate group, the ROC results are shown in Figure 2C, with an AUC value of 0.608 for PSAD, 0.577 for TPSA, and 0.583 for F/TPSA. The diagnostic value of PSAD is also higher than that of other indicators. In the large prostate group, as shown in Figure 2D, the ROC results show an AUC value of 0.511 for PSAD, 0.543 for TPSA, and 0.677 for F/TPSA. Using PSAD as a predictor for PCa may have limitations, particularly in certain PV ranges. As shown in Table 3, the sensitivity of PSAD is highest at 0.69 in the small prostate, higher than that in the medium-sized prostate at 0.52 and the large prostate at 0.18. The accuracy of confirming PCa using PSAD as an indicator is higher in the small prostate, with a specificity of 0.75 in the small prostate, 0.7 in the medium-sized prostate, and 0.99 in the large prostate. In the subpopulation above 70, the proportion of negative patients is significantly increased, and PSAD <0.15 ng/mL/cm³ has no significance in excluding PCa.

Construction of decision tree

The results of the decision tree model are presented in Figure 3. We identified a subset of patients with PSAD ≥0.15 ng/mL/cm³ and observed that when the volume exceeded 37 cm³, approximately 63% of these patients fell within this range, indicating an estimated probability of PCa after biopsy at around 0.18. Conversely, for patients with a volume less than 26 cm³, there was a significant increase in the probability of PCa after biopsy to approximately 0.69. Among patients with a volume ranging from 26 to 37 cm³ (excluding certain extreme values), the probability of prostate cancer after biopsy was found to be approximately 0.38.

Figure 3 Decision tree for determining PCa. In the first row in each data, 0 represents not having PCa and 1 represents having PCa. The second row represents the likelihood of having PCa within this volume range. The last row represents the proportion of this set of data that is contained within this range. PCa, prostate cancer; PV, prostate volume.

Discussion

Common urologic malignancies include PCa, bladder, and kidney cancers, which account for 191,930, 62,100, and 45,520 cases, respectively, among male citizens of the United States. It is estimated that there will be approximately 893,660 new cancer cases in 2020. PCa is significantly more common than bladder cancer and kidney cancer, with a 5-year survival rate of >60% in localized disease, compared to about 5% for patients with distant metastases. This emphasizes the importance of early diagnosis and treatment of PCa (8).

The prostate-specific antigen (PSA) has been utilized as an early screening indicator for PCa due to its convenience, affordability, and longstanding usage. However, it lacks specificity in diagnosing PCa and is easily influenced by factors such as inflammation and external stimulation (9). The elevation of PSA can be caused by an increase in PV, leading to challenges in determining the need for biopsy with less-than-ideal results. Some researchers have introduced additional indicators like PSAD to differentiate between benign and malignant prostate diseases; nevertheless, the success rate of biopsy remains low (10). Even within the range of 10–20 ng/mL of PSA, the detection rate for PCa through biopsy is merely 26.2% (11). Certain scholars have also proposed new monitoring indicators for PCa such as PCA3, Prostate Health Index, and 4kScore (12), which aim to enhance the specificity of PSA in diagnosing this condition through blood and urine analysis. Currently, biopsy remains the gold standard for diagnosing PCa; however, increasing the number of biopsy needles raises risks including bleeding, infection, or even fatal shock. Biopsy can create surgical difficulties while adhesions resulting from it may reduce treatment effectiveness post-surgery; thus, necessitating more precise and standardized approaches after undergoing a biopsy procedure (13). Consequently, selecting a more appropriate timing for biopsies has become a popular research focus in recent years.

In this study, we not only identified the optimal timing for biopsy but also drew additional significant conclusions. PSAD remained a significant predictor of outcome indicators even after incorporating clinical adjustment variables such as age, neutrophils, and BMI into multifactor regression analysis. The area under the ROC curve for PSAD was >0.7 in both overall and subgroup analyses, which significantly outperformed other predictors. Furthermore, including PV as an additional factor not only provided guidance for biopsy decisions but also served as a risk stratification tool in the development of PCa tests.

In our study, we categorized the prostate into small, medium, and large groups based on body volume. We found that PV significantly influenced the predictive value of PSAD for PCa. Specifically, in the small gland group with PSAD ≥0.15 ng/mL/cm³, there was a higher likelihood of having PCa compared to the medium and large gland groups. Additionally, the sensitivity of diagnosing PCa in this group was 69%, which was significantly higher than the other two groups. In contrast, among patients with a large prostate sub-group and PSAD ≥0.15 ng/mL/cm³, we observed a specificity of 99%. Therefore, it would be advisable to encourage these patients to undergo conservative treatment and regular follow-up in medical practice. Active surveillance has the advantages of preserving erectile function, reducing treatment costs, and avoiding unnecessary treatment for inactive cancers. Patients with normal urination can be instructed to review their PSA once a month to observe if there is a significant upward trend. If the elevation exceeds 5 ng/mL in 3 months and 10 ng/mL in 6 months, a prostate biopsy is necessary. If the patient experiences dysuria and lower urinary tract symptoms, a puncture biopsy should be performed as soon as possible to confirm the diagnosis (14). Furthermore, within the small volume range (less than 26 cm³), after constructing a decision tree model analysis, we discovered that biopsy held great clinical significance for patient management.

Many individuals opt to adjust the threshold range of PSAD to guide biopsy decisions. In a prospective study conducted by Jue in the United States (15), it was demonstrated that PSAD exhibited significantly superior diagnostic performance for PCa compared to PSA alone. The AUC ratio between PSAD and PSA was found to be 0.72 versus 0.59, which is similar to the AUC values observed in this current study (0.74 versus 0.57). In this particular investigation, a PSAD threshold of 0.15 ng/mL/cm³ was determined as the criterion for deciding whether or not to proceed with a biopsy procedure. Raising this threshold can reduce unnecessary biopsies but may lead to missed diagnoses among certain cancer patients; conversely, lowering the threshold would increase the number of prostate biopsies performed, causing undue discomfort for many patients involved in such procedures. However, Nordström et al. established an optimal PSAD threshold value of 0.08 ng/mL/cm³, achieving a negative predictive value of 96% for clinically significant disease while potentially avoiding approximately 13% of unnecessary biopsies and only missing around 2.7% cases of PCa (16). The clinical guidelines currently recommend a PSAD threshold value of 0.15 ng/mL/cm³; however, it should be noted that this value depends on factors such as prostate gland size which may correlate with an individual’s weight, height, and BMI. Furthermore, racial disparities particularly between Caucasians and Asians can influence PSAD measurements significantly; therefore, determining an appropriate PSAD threshold value and identifying suitable biopsy volumes within clinical practice are tasks that require careful consideration.

In recent years, the widespread clinical application of prostate magnetic resonance imaging (MRI) has facilitated accurate diagnosis of PCa. T2 weighted image (T2WI) is the initial sequence employed for PCa diagnosis, which effectively distinguishes the peripheral zone, central zone, and surrounding tissues of the prostate. The combination of Prostate Imaging Reporting and Data System (PI-RADS) scoring and PSAD has emerged as a novel non-invasive diagnostic method for PCa (17). A study demonstrated that measurements of PV using ultrasound and MRI yielded comparable results (18). De Gorski et al. observed that the detection rate of PCa in prostates with volumes below 30 cm³ was 77%, whereas it dropped to 55% for prostates with volumes greater than 34 cm³ (19). This finding aligns with our decision tree study where we also found lower detection rates in larger PVs. In our dataset, the detection rate of PCa in prostates below 26 cm³ was 69% but decreased to 38% in prostates around 34 cm³. Notably, higher PV corresponded to lower PCa detection rates. Yusim et al.’s study revealed that patients with PSAD above 0.34 ng/mL/cm³ had a diagnosis rate of PCa at approximately 56.4%, while those with PSAD below 0.09 ng/mL/cm³ had a very low probability (4%) of having cancer present. By constructing a decision tree within this patient subgroup residing within an uncertain range, they discovered that when the PV exceeded 33 cm³, the detection rate was only about 6.8%. However, when the volume fell below this threshold at less than or equal to 33 cm³, there was a significantly higher risk of PCa at approximately 17% (20).

In the study by Falkenbach et al., a combination of PSAD and digital rectal examination for prostate puncture had an AUC of 0.79 in patients with prostate nuclear PI-RADS 5. Only 7 (1%) of 493 patients with PI-RADS 5 had normal prostate tissue, and most negative biopsies indicated inflammation. All of 54 patients with PI-RADS 5 and PSAD >0.5 ng/mL/cm³ had clinically significant PCa. This suggests that patients with PSAD >0.5 ng/mL/cm³ must undergo a biopsy to make a definite diagnosis when PI-RADS5 is present (21). Despite the absence of a significant statistical difference in age between the two groups in our data, Shan et al. demonstrated that a novel indicator prostate-specific antigen-age-volume (PSA-AV), incorporating age, PV, and TPSA, exhibited superior predictive ability. Notably, it displayed enhanced performance for patients under 50 years old with a PV less than 20 cm³ (22). In future research endeavors, there is potential to develop a comprehensive model integrating age, PI-RADS score of the prostate, and PSAD to provide improved guidance for biopsy procedures.

Among circulating biomarkers, prostate health index (PHI), an emerging molecular marker for tumors, demonstrates higher specificity than PSA and is significantly correlated with poor clinical prognosis (23). Gentile et al. demonstrated that a combinatorial neural network analysis of multiparametric MRI and PHI better identified PCa at initial diagnosis (24). A combination of a biomarker and imaging might be the best way to reduce unnecessary biopsies and definitive treatments, thus representing the best treatment options for each patient. This type of testing deserves wide application in the future. In recent years, puncture-free biopsy of PCa has also been tried in some regions. Patients suspected of PCa due to abnormally elevated PSA and/or digital rectal examination (DRE) and suspicious lesions in multiparametric MRI (PI-RADS ≥4) were scheduled for prostate-specific membrane antigen positron emission tomography, However, the risk of false positive results may lead to unnecessary surgery. Experienced nuclear medicine physicians and radiologists need to minimize this risk (25). PSAD-guided prostate biopsy is fundamental to all treatments at any time.

There are several limitations in our study: firstly, our study is a retrospective single-center study based on data from The First Hospital of Jilin University, which may introduce selection bias and has a relatively small sample size. We aim to incorporate data from multiple centers specializing in PCa to validate our research findings. Secondly, during the data collection process, there were instances of missing patient information and only a limited number of patients had MRI detection results available. Consequently, we did not obtain complete MRI measurement data and PI-RADS scores. We hope to have the opportunity to include this additional dataset in future studies to guide and enhance our diagnostic conclusions. Nonetheless, we still urge clinicians to consider prostate gland size when determining the necessity for biopsy in patients with prostate diseases.

Conclusions

In the gray area, PSAD’s predictive accuracy for PCa surpasses that of other indicators. When PSAD exceeds 0.15 ng/mL/cm³, a close association is observed between small prostate glands (PV <45 cm³) and PCa, particularly in cases with PV <26 cm³. For patients exhibiting large prostate glands (PV ≥70 cm³) without clinical symptoms, observation and regular follow-up may be considered viable options. Our conclusion can be applied to the clinical decision-making process for patients with prostate diseases whose PSA falls within the range of 20 ng/mL.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-490/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-490/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-490/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-490/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of The First Hospital of Jilin University (No. 2024-751) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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