Prostate-specific antigen clearance after surgery for benign prostate enlargement in a cohort with median prostate-specific antigen greater than 4ng/ml

Abstract

Background

Total prostate-specific antigen (tPSA) could be elevated in some cases of benign prostate enlargement (BPE). The aim of this study is to evaluate tPSA clearance after surgery for BPE with histologic confirmation of nodular hyperplasia.

Methods

Men for transurethral resection of the prostate (TURP), or open simple prostatectomy (OSP), with benign imaging features of the prostate were recruited. Those with tPSA >4ng/ml, but benign core-needle biopsy reports were recruited as well. A control arm of men on Tamsulosin+Dutasteride therapy (TDT) for BPE was also recruited. Participants with histologic finding of chronic prostatitis or malignancy at biopsy or post extirpation were excluded. Age, body mass index (BMI), prostate volume (PV) and presenting clinical features were noted. The tPSA values were taken at baseline, 6 weeks and 12 weeks post intervention. The mass of resected or enucleated prostate tissue was noted and the tPSA clearance curve was plotted.

Results

There were 154 participants: 77 were on TDT, 43 had monopolar TURP and 34 had OSP. The TDT patients were younger (61.57 ± 6.93years TDT vs. 65.4 ± 9.08years TURP vs. 63.71 ± 7.23years OSP; p 0.03), had lower median tPSA [5.6(4.0–7.6)ng/ml TDT vs. 10.0(5.7–13.1)ng/ml TURP vs. 15.8(9.0–20.0)ng/ml OSP; p < 0.001], and had lower PV (51.96 ± 5.22 ml TDT vs. 62.42 ± 7.16 ml TURP vs. 113.13 ± 29.57 ml OSP; p < 0.001) at recruitment. The 3 groups had similar BMI (26.25 ± 1.68 kg/m² TDT vs. 25.72 ± 2.72 kg/m² TURP vs. 26.05 ± 2.23 kg/m² OSP; p 0.44). The tPSA clearance post-surgery correlated with the pre-surgery tPSA and was at a rate of y = 11.168e^− 0.151x (y=tPSA; x=time). At 6 weeks post-surgery, 45.5% had tPSA < 4.0ng/ml, and at 12 weeks, 96.1% had tPSA < 4.0ng/ml.

Conclusion

Where tPSA is ≥ 1.5ng/ml in BPE, surgery in form of TURP or OSP results in exponential decrease in serum tPSA.

Background

There are clinical concerns whenever serum total prostate-specific antigen (tPSA) is elevated in men presenting with symptomatic enlargement of the prostate that appear otherwise benign. This clinical scenario is not unusual: Lee and colleagues in Seoul, Korea reports that 45.0% of the men who had extirpative procedure for symptomatic benign prostate enlargement (BPE) had elevated tPSA [1]. The possibility of missing a potentially curable, low volume malignancy is real. For instance, incidental prostate cancer was reported in 15.6%, in 16.3% and in 19.0% of men who had extirpative surgery for supposedly benign prostate enlargement in different settings [2-4]. So, despite applying recommended discriminatory investigations, some early malignancies escape detection until after the extirpative surgery for benign prostate enlargement.

Where there is no histological evidence of prostate cancer in men with otherwise benign prostate enlargement, but with raised tPSA levels it is expected that the tPSA levels should drop to levels that can only be attributed to the residual prostate tissue which should be mostly the peripheral zone of the prostate. The review by Bhat et al., reveals that the tPSA dynamics after surgical removal of prostate adenoma in benign prostate enlargement can be predicted with the knowledge of the potential residual prostate tissue [5]. Beyond this knowledge, the behaviour of tPSA post-surgery can also be influenced by the presence of any missed malignancy in the residual prostate tissue as well as other factors such as age of patient and the amount of tissue resected [6, 7]. It is therefore pertinent to monitor tPSA levels after surgical removal of the adenoma even where there has been histology confirmation of nodular hyperplasia. From Livingston et al., monitoring serum tPSA post simple prostatectomy can be an early pointer to the presence of malignant disease in the residual prostate [8]. This monitoring is particularly important where the tPSA was abnormal prior to the extirpative surgical procedure. Granted that serum tPSA assay has a low disease specificity, the behaviour of the serum tPSA after surgical removal of prostate adenoma in BPE could provide insight into any pathological activity in the residual prostate tissue [9].

In our sub-Saharan African setting, serum tPSA values are relatively higher [10, 11] and prostate volumes are possibly larger in benign prostate enlargements. The incidence of prostate cancer is higher as well [12]. It is therefore imperative to monitor serum tPSA even after surgical removal of adenoma by an appropriate technique. The pattern of serum tPSA post enucleation or resection of the prostate adenoma in patients with relatively high tPSA has not been adequately studied in sub-Saharan settings. This study aims to evaluate in quantitative terms the pattern of changes in serum tPSA post-surgery for BPE so as to inform subsequent clinical management decisions.

Methods

This was a prospective study conducted in 2 urology care centres in Enugu, southeast Nigeria: University of Nigeria Teaching Hospital Ituku-Ozalla, Enugu and 82 Division Military Hospital, Enugu. The sample size was estimated using the formula as provided in Dell et al. [13] where C = 7.85 at p=0.05 and power = 80%; SD (standard deviation of mean PSA from the high PSA group in Lee et al., [1]) = 4.7ng/ml; and d (effect size) set at 2.3ng/ml which was the minimum decrease in tPSA achieved by about 70% of the TURP and OSP studies reviewed by Bhat et al., [5]. With addition of 10% attrition rate, the calculated sample size was 74 participants.

Eligible participants were recruited consecutively from September 2022 to August 2023. The inclusion criteria were presentation with lower urinary tract symptoms (LUTS) from benign prostate enlargement identified using transrectal ultrasonography (TRUS), serum tPSA ≤4ng/ml, and TRUS-guided prostate biopsy report of nodular hyperplasia in patients with tPSA >4ng/ml. Patients with Prostate Imaging Reporting and Data Systems (PIRADS) score ≥ 4 on prostate Magnetic Resonance Imaging (MRI) were not included in the study. There was histologic confirmation of nodular hyperplasia for the participants that had surgical extirpation. Patients with pre op biopsy or post op histology reports of nodular hyperplasia with chronic prostatitis were excluded from the study.

At recruitment, the age and the body mass index (BMI) were obtained. The predominant clinical features at presentation were grouped as “lower urinary tract symptoms (LUTS)”, “indwelling catheter use” (due to acute or chronic urinary retention), or “haematuria”. The international prostate symptom score (IPSS) was determined for participants presenting with LUTS. Interviewer assistance was provided for the IPSS determination where necessary. Serum tPSA was determined using ELISA technique. Transrectal ultrasonography (TRUS) was used to determine the prostate volume (PV) and other benign sonographic features. Patients with significant bacteriuria were given appropriate antibiotics and then recruited after 4 weeks of no significant bacteriuria. All variables of interest were determined within 4 weeks to the intended therapeutic intervention.

Participants underwent monopolar transurethral resection of the prostate (M-TURP), open simple prostatectomy (OSP), or were continued on tamsulosin 0.4 mg + dutasteride 0.5 mg daily combination therapy (TDT). The interventions were with the informed consent of the participants and in line with the institution’s guidelines for management of BPE as adapted from AUA guidelines [14]. The weight of the extirpated prostate tissue post TURP or OSP was determined using an electronic weighing scale. Assuming a density of 1 g/ml for prostate tissue, the volume (ml) of the extirpated prostate tissue corresponded to the weight (g). To correct for tissue loss from heat effect in M-TURP, the volume of resected tissue was multiplied by a factor of 1.271 [15]. The residual prostate volume was derived as the difference between PV and weight of resected or enucleated specimen.

Serum tPSA was repeated 6 weeks and 12 weeks after commencement of TDT for the participants on TDT and after surgical intervention for the participants that had M-TURP and OSP.

The variables of interest were summarized using means, medians or percentages as appropriate. Changes in tPSA were compared across the groups and the pattern of change displayed in a trend graph. Multivariate analysis was used to evaluate the nature of the relationship between the study variables and the changes in the tPSA. All analyses were done using IBM SPSS Statistics version 25.0 (IBM Co., Armonk, NY, USA).

The bioethics committee of the University of Nigeria Teaching Hospital Ituku-Ozalla, Enugu approved of the study. All participants in the study were recruited with their written informed consent. The study was conducted responsibly in line the Declaration of Helsinki.

Results

In all, 154 of the 161 participants recruited completed the study. Figure 1 shows the flow diagram and Table 1 is a summary of the variables of interest in the study.

Fig. 1.

Participant flowchart through the study

Table 1.

Summary of variables of interest at recruitment in the 3 groups of patients

Variable	TDT Group [n = 77]	M-TURP Group [n = 43]	OSP Group [n = 34]	Statistic	p-value
Age (yrs)	61.57 ± 6.93	65.40 ± 9.08	63.71 ± 7.23	F 3.58	0.03
BMI (kg/m2)	26.25 ± 1.68	25.72 ± 2.72	26.05 ± 2.23	F 0.83	0.44
LUTS only (%)	75 (97.4%)	38 (88.4%)	25 (73.5%)	χ2 17.4**; df 4	0.002
Catheterized (%)	2 (2.6%)	5 (11.6%)	7 (20.6%)
Haematuria (%)	0	0	2 (5.9%)
Mean PV (ml)	51.96 ± 5.22	62.42 ± 7.16	113.13 ± 29.57	F 206.28	< 0.001
Median tPSA (ng/ml)	5.6(4.0–7.0)	10.0(5.7–13.1)	15.8(9.0–20.0)	χ2 53.35*; df 2	< 0.001
Mean %fPSA (%)	46.10 ± 6.88	44.90 ± 8.85	40.25 ± 8.75	F 6.56	0.002

TDT Tamsulosin+Dutasteride therapy, M-TURP Monopolar Transurethral Resection of the Prostate, OSP Open Simple Prostatectomy, BMI Body Mass Index, LUTS Lower Urinary Tract Symptoms, PV Prostate Volume, tPSA Total prostate-Specific Antigen, %fPSA Percentage Free Prostate-Specific Antigen 

** Cross-Tab analysis; *Kruskal-Wallis test

Of the 154 participants that were available for the 12th week assessment, the mean age was 63.1 ± 7.8years, the mean BMI was 26.06 ± 2.13 kg/m² and the mean PV was 68.39 ± 28.41 ml. The tPSA range was 1.8ng/ml – 34.3ng/ml, the median tPSA was 7.30(IQR 4.78–12.30) and the mean %fPSA was 44.47 ± 8.17%. Within the 154 participants, 77 were on TDT, 43 had TURP and 34 had OSP. Table 1 is a summary of the participants within the study groups.

Across the study groups, the body mass indices of participants were similar. However, participants that had surgical intervention were older, presented with larger prostates and higher serum tPSA values.

After correcting for loss of tissue from diathermy heat, the mass of prostate resected from the M-TURP was from a minimum of 25.1 g to a maximum of 58.9 g (mean 39.39 ± 8.89 g) representing a minimum of 46.83% to a maximum of 81.13% (mean 62.57 ± 8.89%) of the pre surgery prostate volume. In the case of OSP, the enucleated mass of adenoma ranged from a minimum of 56.0 g to a maximum of 137.3 g (mean 87.41 ± 23.94 g) representing a minimum of 57.62% to a maximum of 90.12% (mean 77.21 ± 5.74%) of pre surgery prostate volume. The proportion of prostate tissue removed by enucleation was significantly more than the proportion removed by resection (Welch 76.32; df1 1; df2 72.34; p < 0.001).

The serum tPSA dropped in all participants with the intervention instituted. The changes during the study period are shown in Table 2.

Table 2.

Serum tPSA clearance in the first 12 weeks of treatment in the 3 groups of participants

Variables	TDT Group (n = 77)	M-TURP Group (n = 43)	OSP Group (n = 34)
Median Pre-op tPSA(ng/ml)	5.6(4.0–7.0)	10.0(5.7–13.1)	15.8(9.0–20.0)
Median tPSA(ng/ml) at 6 weeks	4.2(3.0-5.5)	3.7(2.6–5.1)	4.7(3.5–6.9)
Median Decrease in tPSA(ng/ml) in 6 weeks	1.3(1.0-1.8)	6.4(2.8-9.0)	10.8(5.3–13.8)
Comparing tPSA at 6 weeks to Pre-op tPSA*	Z -7.627 p < 0.001	Z -5.700 p < 0.001	Z -5.086; p < 0.001
Median tPSA(ng/ml) at 12 weeks	2.4(1.7–3.5)	1.8(1.4–2.3)	2.1(1.7–2.8)
Median Decrease in tPSA(ng/ml) in 12 weeks	2.8(2.3–4.4)	8.1(4.3–11.3) [81.0% drop]	13.8(7.2–17.6) [87.3% drop]
Comparing tPSA at 12 weeks to tPSA at 6 weeks*	Z -7.630 p < 0.001	Z -5.714 p < 0.001	Z -5.088 p < 0.001

TDT Tamsulosin+Dutasteride therapy, M-TURP Monopolar Transurethral Resection of the Prostate, OSP Open Simple Prostatectomy, tPSA Total Prostate-Specific Antigen

*Wilcoxon Signed Ranks test

The serum tPSA decreased significantly in the first 12 weeks after surgical and medical intervention. The pattern of decrease in tPSA in the 3 groups is shown in Fig. 2.

Fig. 2.

The decay curves of tPSA in the TDT, M-TURP and OSP groups

The decay curve for the TDT group is represented by y = 5.8596e^− 0.071x, that for the M-TURP group is y = 9.5541e^− 0.143x while that for the OSP group is y = 14.764e^− 0.168x.

Focusing on the participants that had surgical intervention (M-TURP and OSP; n = 77), the serum tPSA before surgical intervention was mean 12.79 ± 6.99ng/ml; median 11.7(7.0–17.8)ng/ml. The median decrease in serum tPSA in 6 weeks and in 12 weeks were 7.1(4.0–11.2)ng/ml and 9.4(5.3–14.4)ng/ml respectively. Correspondingly, the mean decrease in tPSA at 6 weeks post intervention was 8.35 ± 5.55ng/ml and at 12 weeks post intervention was 10.67 ± 6.45ng/ml. At 6 weeks post-surgical intervention, 45.5% of participants had tPSA < 4.0ng/ml and at 12 weeks post op, 96.1% had tPSA < 4.0ng/ml. Figure 2 shows the trend of tPSA in the study period. The decay was at a rate of y = 11.168e^− 0.151x (y=tPSA; x=time in weeks post surgery).

The clearance of the serum tPSA after surgical removal of prostate adenoma in benign prostate enlargement can be predicted with an exponential equation.

The factors that influenced the magnitude of drop in serum tPSA in the first 12 weeks post-surgery are shown in Table 3. The multivariate linear regression model has an R value of 0.996 and the independent variables predicted 99.0% of the total variation in the magnitude of drop in the tPSA in 12 weeks post op. The model is a good fit (F 863.949; df 9; p < 0,0005).

Table 3.

The relationship between the magnitude of decrease in serum tPSA 12 weeks post op and the other study variables

Variables	Univariate Analysis	Multivariate Logistics Analysis
		B	OR	t-value	p-value
Age	ρ 0.09; p 0.43	-0.008	0.992	-0.841	0.403
BMI	ρ 0.33; p < 0.01	-0.014	0.986	-0.426	0.671
Volume of Prostate Preop	ρ 0.57; p < 0.001*	-0.005	0.995	-0.689	0.493
Indwelling Catheter Preop	χ2 4.65; p 0.03**	-0.130	0.878	-0.549	0.585
Preop tPSA	ρ 0.99; p < 0.001*	0.917	2.502	65.881	< 0.001
Preop %fPSA	ρ -0.22; p 0.05	0.006	1.006	0.706	0.482
Type of Surgery	χ212.68; p < 0.001**	0.093	1.097	0.336	0.738
Residual Prostate Volume	ρ 0.09; p 0.45	0.026	1.026	0.958	0.341
Proportion of Prostate Extirpated	ρ 0.42; p < 0.001*	0.017	1.017	0.720	0.474

BMI Body Mass Index, tPSA Total Prostate-Specific Antigen, %fPSA Percentage Free Prostate-Specific Antigen, OR Odds Ratio 

*Spearman Correlation; **Kruskal Wallis Test

A number of variables demonstrated significant association with the tPSA clearance in univariate analyses (column 2 of the table), but only pre-op serum tPSA demonstrated a significant association with tPSA clearance while controlling for other variables in multivariate logistic regression analysis (columns 3–6 of the table).

Discussion

Where serum tPSA is elevated and prostate biopsy report is nodular hyperplasia in men with prostate enlargement, management of the tPSA post removal of the adenoma becomes very important. It is expected that in the absence of any missed malignancy, the serum tPSA value should decay to non-suspicious levels promptly based on the known clearance rate of circulating tPSA post extirpative procedures of the prostate [16]. The observed median serum tPSA of 7.30 (4.78–12.30) could be attributable to the mean prostate volume of 68.39 ± 28.41 ml in this cohort of men with mean age of 63.1 ± 7.8years.

Though the age and the body mass index of participants were similar across the groups, the prostates of participants who had surgical intervention were generally larger than the prostates of participants managed by non-surgical approach (Table 1). Similarly, the serum tPSA values were significantly higher for groups with larger prostates which is in keeping with reports that larger prostates tend to secrete more prostate-specific antigen [17-19].

In the first 6 weeks after the surgical removal of the prostate adenoma either by TURP or by OSP, the tPSA was observed to have decreased significantly compared to the observed decrease in the TDT group (Table 2; Fig. 2). A further, but less intense decrease was observed in the second 6 weeks after the surgical procedure. With the 2 surgical groups combined, the tPSA value observably dropped to about 39.0% of the pre-surgery value in the first 6 weeks and to 20.0% in 12 weeks (Fig. 3). This remarkable drop in serum tPSA is a recognized feature with surgical removal of the adenoma in BPE, and the exponential is similar to findings elsewhere [16, 20]. The clearance rate is driven by the level of circulating tPSA with higher rates of decrease in the initial weeks post op. The decrease in tPSA in the second 6 weeks of the study, as seen in Fig. 3, is similar to the observed decrease in PSA reported by Viitala et al., deploying transurethral ultrasound ablation [21]. In Viitala et al., the pre-surgery tPSA was low and the clearance rate was low as in the second 6 weeks of our study participants where the tPSA had already become low. In our study, the value of tPSA at any time x in weeks after surgical extirpation of obstructing prostate adenoma could be derived with the formula y = 11.168e^− 0.151x. More specifically, the formula y = 9.5541e^− 0.143x and the formula y = 14.764e^− 0.168x could be used to derive tPSA values at anytime x in weeks after M-TURP and after OSP respectively.

Fig. 3.

The aggregate decay curve of the serum tPSA after surgery for BPE

Open simple prostatectomy resulted in enucleation of a greater proportion of the enlarged prostate and correspondingly, to a greater magnitude of decrease in tPSA in the first and the second 6 weeks after the intervention (Table 2; Fig. 2). This finding is in keeping with the report from Bhat et al., that enucleation of adenoma resulted in greater decrease in tPSA compared to resection [5]. There were some evidences that the magnitude of decrease in tPSA in the 12 weeks post-surgery varied with the volume of the prostate before surgery, the proportion of prostate tissue removed at surgery, the type of surgical intervention deployed and the preop level of the tPSA (Table 3). This pattern of association can be explained with the understanding that the mass of prostatic acinar cells prior to surgical intervention in BPE contributed to the level of PSA in the serum [7]. However, with multivariate analysis, only preop tPSA demonstrated a significant positive association with the magnitude of decrease in tPSA post-surgery (Table 3): the higher the serum tPSA level pre-surgery, the larger the decay in tPSA post-surgery. This is similar to the report by Lee et al., [1]. The residual volume of the prostate was not seen to vary with the magnitude of decrease in tPSA akin to the finding from Furuya et al., [22]. With adequate surgical removal of the adenoma in BPE, the magnitude of decrease in tPSA per unit time is related to the preop tPSA rather than to the residual prostate volume. So, it can be observed that with appropriate extirpative procedure in histologically confirmed benign prostate enlargement presenting with abnormal tPSA, the tPSA decays exponentially to reasonably low levels in 12 weeks post-surgery. The review by Bhat et al., [5] reported greater than 80% drop in tPSA for enucleation procedures and greater than 50% drop for resection procedures. The corresponding figures from our study are 87.3% drop after OSP and 81.0% drop after M-TURP.

Limitations

There was no routine repeat biopsy of the residual prostate at the exit point in the study. This was considered unethical. Repeat MRI prostate and/or repeat biopsy was approved in the event that there was an increase in the tPSA during the period of the study. However, this condition was not observed during the study.

Longer period of monitoring may be needed to provide further information on possible missed malignancy. However, the longer the period of monitoring post op, the higher the chances of also picking new-onset malignancies in the residual prostates.

Conclusions

Irrespective of the age and the body mass index of the patient, the volume of the prostate preop, the type of surgical intervention appropriately deployed, the tPSA will drop precipitously in the first 12 weeks post-surgery for BPE in the absence of chronic prostatitis.

Abbreviations

BMI

Body mass index

BPE

Benign prostate enlargement

IPSS

International Prostate Symptoms Score

LUTS

Lower urinary tract symptoms

M-TURP

Monopolar Trans-urethral Resection of the Prostate

MRI

Magnetic Resonance Imaging

OSP

Open simple prostatectomy

PV

Prostate volume

TDT

Tamsulosin-Dutasteride therapy

TURP

Trans-urethral Resection of the Prostate

tPSA

Total prostate-specific antigen

%fPSA

Percentage free prostate-specific antigen

Authors' contributions

EON, OMM, NIN, ISO, IIN contributed in study conception and design. EON, INA, CAN wrote the draft manuscript. EON, INA, ISO contributed in data collection. CAN, IIN performed the data analysis. OMM, IIN revised the draft manuscript. All authors reviewed and agreed on the final version of the manuscript being submitted.

Funding

None funding was received for this study.

Data availability

The dataset generated and analysed in this study is reposited at the Mendeley Data Repository [Mendeley Data V1, doi: 10.17632/jb29r86gpd.1.

Declarations

Ethics approval and consent to participate

This study was approved by the bioethics committee of the University of Nigeria Teaching Hospital Ituku-Ozalla, Enugu. Informed consent to participate was obtained from all participants in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.