Incidental prostate cancer after holmium laser enucleation of the prostate—A narrative review

Prostate cancer can be detected incidentally after surgical therapy for benign prostatic obstruction such as holmium laser enucleation of the prostate (HoLEP), thus called incidental prostate cancer (iPCa). We aimed to review the studies on iPCa detected after HoLEP and investigate its prevalence. A detailed search of original articles was conducted via the PubMed‐MEDLINE, Web of Science, Wiley Online Library and Cochrane Library databases in the last 10 years up to 1 May 2021 with the following search string solely or in combination: “prostate cancer”, “prostate carcinoma”, “holmium laser enucleation of the prostate” and “HoLEP”. We identified 19 articles to include in our analysis and divided them into six main categories: HoLEP versus open prostatectomy and/or transurethral resection of the prostate in terms of iPCa, oncological and functional outcomes, the role of imaging modalities in detecting iPCa, predictive factors of iPCa, the role of prostate‐specific antigen kinetics in detecting iPCa and the management of iPCa after HoLEP. We found that the iPCa after HoLEP rate ranges from 5.64% to 23.3%. Functional and oncological outcomes were reported to be encouraging. Oncological treatment options are available in a wide range.


| INTRODUC TI ON
Lower urinary tract symptoms caused by benign prostatic obstruction (BPO) is one of the most common health problems in adult males . In the last decade, holmium laser enucleation of the prostate (HoLEP) has come to the fore in the surgical treatment of BPO as an alternative to transurethral resection of the prostate (TURP) and open prostatectomy (OP) in efficiency, safety and complication terms (Nair et al., 2016;Patel et al., 2014;Rieken et al., 2010;Sivarajan et al., 2015;Vincent & Gilling, 2015). There is evidence that HoLEP is feasible regardless of the prostate size (Cornu et al., 2015).
Prostate cancer (PCa) is the second most common cancer in men, accounting for 15% of all cancers diagnosed (Ferlay et al., 2015). In addition to prostate-specific antigen (PSA) screening and subsequent prostate biopsy, PCa can be detected incidentally after the surgical treatment for BPO such as HoLEP, referred to as incidental prostate cancer (iPCa) (Kim et al., 2014). Although studies have reported iPCa after HoLEP (Elkoushy et al., 2015;Nunez et al., 2011;Rosenhammer et al., 2018b), its clinical prevalence and relevance have not been well investigated. A literature review is therefore needed. In this study, we aimed to review the studies on iPCa detected after HoLEP, to investigate its prevalence, to assess the functional and oncological outcomes as well as the role imaging modalities play, predictive factors and iPCa management.

| Literature search
A comprehensive search was conducted using the PubMed-MEDLINE, Web of Science, Wiley Online Library and Cochrane Library databases over the last 10 years until 1 May 2021 with the following search string solely or in combination: "prostate cancer", "prostate carcinoma", "holmium laser enucleation of the prostate" and "HoLEP". After the titles and abstracts of selected articles were retrieved, the full texts of related articles were screened. Our article selection process complying with the PRISMA criteria is shown in Figure 1. The PICOS (population [P], intervention [I], comparator [C], outcomes [O] and study design [S]) approach was used to determine the eligibility criteria (Liberati et al., 2009). We thus selected the studies providing that benign prostate hyperplasia (BPH)/BPO patients (P) had undergone HoLEP (I) as a single operation, or when they were compared with patients who had undergone TURP or OP (C), and if iPCa (O) had been revealed/diagnosed in prospective or retrospective studies (S).
We included studies reporting iPCa after HoLEP addressing functional and oncological outcomes, the role of imaging modalities, predictive factors, PSA kinetics and iPCa management. Studies not reporting iPCa after HoLEP, unassociated with HoLEP, not written in F I G U R E 1 Summary of the study selection process English, case reports, conference abstracts, review articles, editorials and replies to the authors were excluded.

| Data extraction
Articles relevant to our subject of interest were retrieved and evaluated independently by two authors (M.Y. and T.T). A total of 434 articles were identified after the search query. Authors and date of study, study design, number of patients included and mean age, preoperative prostate volume (ml), total serum PSA (ng/ml), PSA density (ng/ml 2 ), prostate biopsy history, the use of 5α-reductase inhibitors (5-ARI), tissue weight (g) removed at operation, iPCa ratio, Gleason score (GS) and T stage were recorded. We assessed the quality of evidence in the studies according to their study design applying National Institutes of Health (NIH) quality assessment tool for before-after (Pre-Post) studies with no control group or NIH assessment tool for observational cohort and cross-sectional studies (https://www.nhlbi.nih.gov/healt h-topic s/study -quali ty-asses sment -tools). These tools consist of 12 and 14 questions to evaluate studies' quality, respectively, according to "yes", "no", "cannot determine", "not applicable" or "not reported" options for each question. The following quality ratings were indicated: poor (<60%), adequate/fair (60%-69%), good (70%-79%) and strong (80%) (Linde et al., 2020;Musshafen et al., 2021). Discrepancies between two authors were resolved through discussion. A quality percentage score was calculated based on 'yes' responses divided by the total number of valid questions. The data were extracted by the authors (M.Y. and T.T) for qualitative and quantitative evidence and a narrative synthesis.
In iPCa terms, their cancer detection rate after surgery was significantly higher in the HoLEP group (23.3% vs. 8.3%; p = 0.043).
The majority of patients' GSs were Gleason 3 + 3 in both groups (Rosenhammer et al., 2018a). There was only one patient with GS 3 + 4 iPCa in each group. The authors note that the higher percentage of prostate tissue removed during the HoLEP procedure TA B L E 1 Summary of the studies including iPCa after HoLEP
The 5-year overall survival and progression-free survival rates were 100%.

| Role of PSA kinetics in detecting iPCa after HoLEP
Magistro et al. evaluated whether a high preoperative PSA level has diagnostic value for detecting iPCa in 1125 patients who underwent HoLEP with a prostate volume above 100 cc (Magistro et al., 2020). Their study cohort was divided into two groups, one having a preoperative PSA value <10 ng/ml and the other >10 ng/ml. They observed no significant difference between groups in terms of the overall iPCa detection rate (9.5% vs. 9.9%, p = 0.83) or GS (p > 0.05) and found that PSA and PSA density were not associated with iPCa (p > 0.05) (Magistro et al., 2020). Otsubo et al. (2015) evaluated PSA, PSA density and velocity in iPCa-diagnosed patients who underwent HoLEP. In their study, 25 patients (6.8%) were diagnosed with iPCa. They reported that a small prostate, higher preoperative PSA and higher PSA density were associated with iPCa. Furthermore, they found that preoperative PSA (6.06 ng/ml vs. 21.6 ng/ml, p = 0.0191) and postoperative PSA velocity (0.185 ng/ml/year vs. 1.32 ng/ml/year, p = 0.0382) differed significantly between GS 6 and >6 groups (Otsubo et al., 2015). of these patients after HoLEP. They observed that patients with a PSAD above 0.1 ng/ml 2 after HoLEP had a 95% probability of malignancy and an 88% risk of clinically significant PCa. can be applied alone or in combination with external beam radiation (XRT) in patients with a GS upgrade after HoLEP (Rivera et al., 2014).

| Managing iPCa after HoLEP
The authors stated that no stricture, bladder neck contracture, urinary retention or incontinence events were reported after XRT, radical prostatectomy or ADT (Rivera et al., 2014).

| DISCUSS ION
Lower urinary tract symptoms caused by BPH is common in older men; it occurs in 70% of men over 60 years of age (Nafie et al., 2017).
As with BPH, the PCa incidence is mainly age-related (Mottet et al., 2020). Although there is evidence that the iPCa detection rate fell from 31% to 5.4% through PSA screening, one can expect to detect iPCa after BPH surgery in older men (Bhojani et al., 2015;Elkoushy et al., 2015). The incidence of iPCa after TURP has been reported to range from 5% to 14% (Abedi et al., 2020). Regarding the studies we reviewed, the rate of iPCa after HoLEP ranges between 5.64% and 23.3%. Although we would expect the iPCa rate to be higher because more tissue is removed in HoLEP surgery than during TURP, the outcomes of these comparative studies are conflicting. Herlemann et al. (2017) stated that there was no significant difference between HoLEP and TURP in assessing iPCa rates, whereas Rosenhammer et al. (2018a) and He et al. (2020) detected significantly more iPCa in patients who had undergone HoLEP. While there was no significant difference in iPCa detection in the study comparing OP and HoLEP (Rosenhammer et al., 2018b), another study including TURP, HoLEP and OP reported that their HoLEP group's chance of having an iPCa detected was higher (Capogrosso et al., 2018).
Recently, multiparametric MRI of the prostate has gained popularity in PCa diagnoss, thanks to its high accuracy rates (Rhudd et al., 2017). Porreca et al. (2019) suggested that to rule out an iPCa, a negative mpMRI can benefit patients suspected of harbouring PCa who are undergoing HoLEP. Another study of the authors also proposed that in their patients with suspected PCa, in-bore mpMRIguided biopsy is a potentially useful tool to avoid unnecessary TRUS-guided biopsy before HoLEP (Porreca et al., 2020). Kim et al. (2014) suggested that patients with abnormal PSA and negative DRE and hypoechoic lesions on TRUS can undergo a prostate biopsy before HoLEP. Overall, it probably makes good sense to carry out an MRI before biopsy in case of a hypoechoic lesion in TRUS. Clinicians should consider mpMRI before HoLEP, a rational option to detect PCa in case PCa is suspected.
We know that there is an association between PSA, PSA density and the clinical significance of PCa (Mottet et al., 2020). However, the role that PSA and PSA density play in iPCa after HoLEP is controversial. Otsubo et al. found that a higher preoperative PSA value and higher PSA density were associated with iPCa (Otsubo et al., 2015).
In addition, higher PSA density was shown to be an independent predictor for iPCa after HoLEP (Elkoushy et al., 2015;Herlemann et al., 2017). Rivera et al. suggested (Bhojani et al., 2015;Gellhaus et al., 2015;Kretschmer et al., 2020;Rivera et al., 2014). Pentafecta is a concept that includes urinary continence, potency, cancer control, postoperative complications and negative surgical margins after RARP and that shows the functional and oncological results of surgery (Patel et al., 2011).
RARP after HoLEP does not preclude improved oncological outcomes, or alleviating incontinence and erectile function. In addition, positive surgical margins, biochemical recurrence rates and perioperative complication rates resembled those in HoLEP-naive patients (Abedali, Calaway, Large, Koch, et al., 2020;Gellhaus et al., 2015;Kretschmer et al., 2020). RARP after HoLEP appears to be a safe surgical and oncological method in suitable patients. Active surveillance, WW or ADT treatment options can also be considered in certain cases (Rivera et al., 2014;Tominaga et al., 2019).
We conducted a comprehensive review of iPCa after HoLEP.
However, this review has certain limitations. Firstly, retrospective nature of the studies, widely varying study designs, different study objectives/outcomes and large differences in patient numbers-all these factors make our data heterogeneous. Secondly, the paucity of comparative studies means that there are insufficient data to reveal differences in PCa detection between other transurethral surgical methods and HoLEP.

| CON CLUS IONS
We found that the iPCa after HoLEP rate ranges from 5.64% to 23.3%. However, iPCa was usually detected as lower GSs. There is a wide range of treatment options for iPCa after HoLEP. Patients diagnosed with iPCa after HoLEP should be informed about their treatment options. Nonrestricted postsurgical functional outcomes can be expected. The oncological follow-up should be individually discussed. An iPCa diagnosis after HoLEP can be a serious concern for both patients and urologists. We believe that this review will be useful in the clinical practice of urologists who perform HoLEP.

E TH I C S
This research did not involve human subjects or animals. As this is a review of the literature, no ethics approval was necessary.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.