Benign prostatic hyperplasia (BPH) is a common cause of urinary symptoms in older men. The prostate can be anatomically divided into the transition zone (TZ), central zone (CZ), peripheral zone (PZ), and anterior fibromuscular stroma (1). An enlarged TZ, also known as adenoma, is considered the major component of BPH (1).

Transurethral resection of the prostate (TURP) is the gold standard surgical treatment for BPH. Transurethral enucleation of the prostate (TUEP) is a new technique for more complete adenoma removal by dissection along the surgical plane between TZ and PZ/CZ (2). The surgical cases of TUEP had tripled from 2008 to 2014 (3). It removes prostate adenomas almost completely, similar to open simple prostatectomy (4–7). With complete TUEP, only PZ, CZ, and anterior fibromuscular stroma of the prostate are left behind after surgery (8).

Serum prostate-specific antigen (PSA) levels can be affected by age, race, prostate volume, and prostate diseases (9–11). The “reset” PSA level after radical prostatectomy for prostate cancer (PCa) has been used as a marker of surgical completeness, presence of residual PCa, and postoperative follow-up (12). The nadir PSA level after TURP is theoretically produced from the remaining prostate tissue, including PZ, CZ, and residual TZ, if any. Compared with TURP, TUEP can remove the adenoma more completely and may generate a new nadir PSA secreted only from PZ+CZ (13, 14). The nadir PSA level after complete TUEP may serve as a new indicator for not only the completeness of TUEP but also the secretory activity in the remaining prostate.

We hypothesized that the nadir level of PSA secreted from the remaining PZ and CZ after TUEP remains stable and that the nadir and follow-up PSA levels may serve as biomarkers of residual and/or recurrent PCa (15, 16). Accordingly, the aim of this study was to investigate the oncological implications of the post-TUEP nadir PSA level and determine its association with PCa.

This study has several important clinical implications. First, after complete TUEP, nadir PSA ≥1.7 ng/ml may inform the presence of residual PCa nests and/or foci with GS ≥7 in the remaining prostate. In contrast, men with nadir PSA <1.7 after TUEP may have no significant PCa foci in the remaining prostate. Second, for men with de novo PCa found in the removed adenoma, active surveillance may be preferred overactive treatments if the nadir PSA is <1.7. Third, the basal PSA level secreted from the remaining benign prostate (PZ/CZ) seems to be stable and lower than the new threshold of 1.7 ng/ml. Fourth, for men with initial nadir PSA <1.7 ng/ml after TUEP and progressive PSA elevation to ≥1.7 ng/ml during follow-up, cancer foci or GS ≥7 cancer should be suspected and re-biopsy of the remaining prostate should be considered, which however needs a longer follow-up and more data to confirm. Traditionally, the nadir PSA after successful radical prostatectomy for PCa is undetectable or <0.1 ng/ml. Similarly, the 1.7-ng/ml threshold may be considered a new baseline for follow-up after complete TUEP.

Previous reports showed that PCa may be incidentally found in 5.4%–12% surgical specimens from TURP, most of which are considered indolent or clinically insignificant (19–21). PSA-derived markers after prostate enucleation can be used to differentiate BPH from incidental PCa and monitor possible cancer progression (22). Favorable oncological outcomes in men with incidental PCa detected during TUEP have made active surveillance an attractive option (15). Higher postoperative nadir PSA levels may indicate residual cancer foci after TUEP (13). However, complete removal of the prostate adenoma by TUEP or “complete TURP” is mandatory to use the nadir PSA level as a biomarker of oncological outcomes, and the nadir PSA level after incomplete TUEP may not be a reliable marker. Compared with conventional TURP, TUEP is more technically demanding and may pose a challenge for urologists-in-training. In our cohort, 22 (5.1%) of the 428 men who underwent TUEP were excluded because of incomplete adenoma removal (<70%). Up to 94.9% men underwent acceptable TUEP in terms of adenoma removal. It has been shown that the mean enucleation ratio for beginners’ hand was approximately 60% and increased to 65% after 90 patients (23, 24). This may explain why previous studies did not show a consistent nadir PSA threshold that predicts oncological outcomes.

A previous study showed that PSA declined by 81%–86% after TUEP, which correlated with the amount of removed prostate tissue (25). We noted a higher PSA reduction rate (>90%) in our cohort. Elmansy et al. showed that percentage PSA reduction was significantly lower in the malignant group than in the benign group (47% vs. 75%, respectively, p < 0.001) (13). In contrast, Otsubo et al. reported that percentage PSA reduction was similar in the benign and cancer groups (83.2% vs. 83.2%, p = 0.962) (22). The major difference between the two studies was the inclusion of patients with different zonal distributions of cancer. Elmansy et al. excluded patients with incidental PCa in TZ but included patients with PCa in the remaining prostate that was newly diagnosed by TRUSP Bx during the post-TUEP follow-up period. Patients with newly diagnosed PCa may already have cancer in PZ that was not detected during TUEP; therefore, the post-TUEP PSA level was high and percentage PSA reduction was low. In Otsubo et al.’s study, the cancer group included men with incidental PCa found in TZ. They concluded that men with incidental PCa in TZ may exhibit PSA reduction similar to that in men with benign lesions, similar to our findings.

Tumor GS may also influence the magnitude of PSA reduction and PSA nadir. Rivera et al. showed that patients with GS ≥8 cancer had a significantly higher PSA nadir than did patients with GS ≤7 (p = 0.01); this was also observed in our PZ group (26). By categorizing cancer groups with different zonal distributions, we showed a more clear association between post-TUEP nadir PSA and oncological outcomes, thus making the nadir PSA more clinically meaningful.

Otsubo et al. also reported that men with incidental PCa had higher postoperative PSAV than men in the benign group after TUEP (0.22 vs. 0.04 ng/ml/year, p = 0.003); we believe this may largely relate to residual cancer nests in the remaining prostate (22). Elmansy et al. showed that PSAV was significantly higher in the late cancer group than in the benign group (13). Our results confirmed the findings of Elmansy et al. by showing that TTPP was longer in the benign group than in the three cancer groups.

About 78% incidental PCa lesions found in TUEP are reportedly indolent cancers with GS ≤6 (21). Although the majority of these cancers can be managed by active surveillance, the optimal treatment strategy for incidental PCa remains controversial (21, 26, 27). Interestingly, 2%–47.8% patients with incidental PCa showed no residual cancer after radical prostatectomy (pT0); this indicated that TUEP or TURP may have removed all cancer nests in these patients (20). In contrast, 5.6% patients showed extracapsular extension (pT3), and 31% showed upgraded GS (4, 12). In this context, the postoperative PSA nadir may be used to detect significant residual cancer after TUEP.

The prostate volume measured by TRUS is likely to underestimate the prostate weight (28). The inherent error rate varied with the prostate size. Prostate glands between 60 and 80 g had the best-calculated accuracy by TRUS (28). Rodriguez et al. reported that prostate volume measured by displaced water volume had a correlation coefficient of 0.997 with the prostate weight, indicating that the specific density of the prostate tissue is roughly 1.003 (29). Thus, it is not surprising that enucleated adenoma percentage was sometimes higher than 100% due to the volume and weight relationship.

Our study had several limitations. First, this was a retrospective study in which postoperative PSA levels were not measured at predefined time points; thus, the nadir PSA levels were not precisely determined. Second, cancer phenotypes may not represent the true spectrum of patients in this setting. Selection bias may exist when making TUEP-related decisions. However, if we categorize patients with cancer according to the anatomical zonal distribution, PSA kinetics are still reliable and useful in clinical applications. Third, only 63.3% of patients with suspected PCa underwent perioperative TRUSP Bx, which may have led to the underestimation of PZ cancer. Among 70 men who eventually presented with PSA ≧1.7 ng/ml, 16/70 (22.9%) men were re-biopsied following the surgery; 22/70 (31.4%) men were followed by MRI. In addition, five men without elevated PSA postoperatively were re-biopsied and followed by MRI for regular active surveillance protocol. Fourth, we adopted a cutoff value of ≥70% in the definition of complete adenoma removal according to prior studies (23, 24). The ideal criterion to define complete TUEP remains unclear.

After complete TUEP, nadir PSA ≥1.7 ng/ml may inform the presence of residual cancer and/or cancer foci with GS ≥7 in the remaining prostate. For men with incidental PCa found in the removed adenoma and a nadir PSA of <1.7 ng/ml, active surveillance or other conservative management may be preferred over active treatments. TUEP may generate a new baseline PSA to monitor PCa progression. Whether progressive PSA elevation from below to above 1.7 ng/ml after TUEP indicates recurrence of GS ≥7 cancer nests needs further investigation with a longer follow-up duration.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Research Ethics Committee Office of National Taiwan University Hospital (202009014RINA). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Study concept and design: Y-TC, Y-SP, and C-HC; Acquisition of data: Y-TC, J-HH, Y-CL, Y-KC, S-CH, K-KF, S-PL, P-MC, H-CC, and Y-SP; Data and statistical analysis: Y-TC, J-HH, Y-SP, and C-HC; Manuscript editing: Y-TC and Y-SP; Critical review of the manuscript: Y-SP, C-HC, and J-HH; All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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