PLOS ONE
RESEARCH ARTICLE
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OPEN ACCESS
Citation: Han JH, Chung DH, Cho MC, Ku JH,
Jeong CW, Kwak C, et al. (2023) Natural history of
incidentally diagnosed prostate cancer after
holmium laser enucleation of the prostate. PLoS
ONE 18(2): e0278931. https://doi.org/10.1371/
journal.pone.0278931
Editor: Wen-Wei Sung, Chung Shan Medical
University, TAIWAN
Received: August 17, 2022
Accepted: November 23, 2022
Published: February 2, 2023
Copyright: © 2023 Han et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: The author(s) received no specific
funding for this work.
Competing interests: The authors have declared
that no competing interests exist.
PLOS ONE | https://doi.org/10.1371/journal.pone.0278931 February 2, 2023
Natural history of incidentally diagnosed
prostate cancer after holmium laser
enucleation of the prostate
Jang Hee Han1, Dae Hyuk Chung1, Min Chul Cho2, Ja Hyeon Ku1,3, Chang Wook Jeong1,3,
Cheol Kwak1,3, Jae-Seung Paick4, Seung-June Oh ID1,3*
1 Department of Urology, Seoul National University Hospital, Seoul, South Korea, 2 Department of Urology,
SMG-SNU Boramae Medical Center, Seoul, South Korea, 3 Department of Urology, Seoul National
University College of Medicine, Seoul, South Korea, 4 Department of Urology, Mediplex Sejong Hospital,
Seoul, South Korea
* sjo@snu.ac.kr
Abstract
Objectives
There is no consensus on the management plan for incidental prostate cancer (IPCa) after
holmium laser enucleation of the prostate (HoLEP). This study aims to investigate the natu-
ral course of this disease and suggest appropriate treatment in real clinical practice.
Methods
The medical records of a prospective cohort of patients with LUTS/BPH who underwent
HoLEP between July 2008 and December 2020 at Seoul National University Hospital were
retrospectively reviewed. Patients who underwent HoLEP for palliative purpose of prostate
cancer control were excluded. The natural history of IPCa was assessed by the clinician in a
descriptive manner for each treatment option.
Results
Among 2630 patients, 141 (5.4%) were diagnosed with IPCa after HoLEP. Pathologic T
stage and magnetic resonance imaging results were highly associated with the physician’s
primary treatment decision-making for IPCa. Active surveillance (AS) was performed in
80% of patients, of whom 90% underwent follow-up without intervention, while the remaining
10% underwent deferred active treatment with a median follow-up of 46.3 months due to
International Society of Urological Pathology grade group upgrading or increasing core
involvement percentage. Meanwhile, 20% of patients underwent immediate active treat-
ment. With a median follow-up period of 88.3 months after treatment, only one of 25 patients
had biochemical recurrence.
Conclusions
The incidence of IPCa after HoLEP was 5.4%, and among these, approximately 20%
proceeded with immediate definitive therapy and an additional 6% ultimately received
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PLOS ONE Natural history of incidental prostate cancer

definitive therapy within a median of 4 years of AS but showed excellent oncological

outcomes.

1. Introduction
Benign prostatic hyperplasia (BPH) affects approximately 70% of men by the seventh decade
of life in the United States; among them, approximately 1% of patients ultimately undergo
active intervention [1], mostly transurethral endoscopic surgery, such as transurethral resec-
tion of the prostate (TURP), and holmium laser enucleation of the prostate (HoLEP). Theoret-
ically, HoLEP shares the surgical principle of enucleation, which allows complete removal of
adenoma tissue in the transition zone. HoLEP is currently accepted as the gold standard for all
prostate sizes [2, 3].
Prior to prostatectomy in patients with BPH with prostate-specific antigen (PSA) level ele-
vation, one of the critical steps is the preoperative exclusion of prostate cancer (PCa). With the
widespread use of PSA screening and the development of imaging techniques, such as multi-
parametric prostate magnetic resonance imaging (mpMRI) [4], the incidence of incidental
PCa (IPCa) detected in HoLEP seems to have decreased [5]. However, it still occurs in approx-
imately 8% of cases in the final pathology examination [5]. Moreover, in some respects, clini-
cians insist that the incidence of IPCa has increased compared to the previous TURP era due
to removal of the entire transition zone along the surgical capsule [5, 6].
Despite the considerable incidence rate, there are no clinical guidelines regarding the man-
agement of this group of patients for several reasons. First, most studies were conducted with a
small number of patients, even when mixed with both TURP and HoLEP cases [5]. Second,
most studies focused on the discovery of predictive factors for IPCa rather than its long-term
oncological outcome, lacking data on the real-world IPCa management practice.
Therefore, this study aimed to primarily focus on the natural history of IPCa after HoLEP.
It attempted to assess how clinicians make their decisions and how each decision led to long-
term oncological outcomes in a descriptive manner.

2. Materials and methods

2.1 Ethics approval and informed consent
This study was approved by the Institutional Review Board (IRB) of Seoul National University
Hospital (SNUH) (IRB no. 2201-084-1290). The requirement for informed consent was
waived owing to the retrospective nature of the study. The study was performed in accordance
with applicable laws and regulations, good clinical practice, and ethical principles provided in
the Declaration of Helsinki.

2.2 Patient population

The medical records of consecutive patients with LUTS/BPH who underwent HoLEP from
July 2008 to December 2020 at SNUH were obtained from our prospective BPH cohort.
Patients who underwent HoLEP for the palliative purposes of PCa control were excluded.

2.3 Collected parameters

We collected and reviewed the following items: patient’s demographic and clinicopathological
data, including age at surgery, accompanying comorbidities, preoperative transrectal ultraso-
nography, MRI findings, PSA level, digital rectal examination findings, preoperative prostate

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PLOS ONE Natural history of incidental prostate cancer

biopsy results, perioperative findings (operative time, resection time, resection volume, used
energy, intraoperative complications, and hospital stay), pathologic findings, follow-up data
with prostate biopsy, prostate MRI, PSA level, treatment information of IPCa, and oncological
outcomes.

2.4 Statistical analysis

All statistical analyses were performed using SPSS version 25 software (SPSS, version 25.0.0.2,
IBM Corp., Armonk, NY, USA). A P-value < 0.05 was considered statistically significant, and
all statistical tests were two-sided.

3. Results
3.1 Patient characteristics
A total of 2630 patients who underwent HoLEP were included in this study. Their median
PSA level was 2.7 ng/mL, and the mean prostate volume (PV) was 67.5 g. Among them, 141
(5.4%) were pathologically proven to have IPCa (Table 1). In the IPCa patient group, approxi-
mately 30% of patients underwent preoperative prostate biopsy, while 13% of patients under-
went concurrent prostate biopsy with HoLEP. The median PSA level was 3.3 ng/mL. Most
patients were classified in the International Society of Urological Pathology (ISUP) grade
group (GG) 1 (85.1%), followed by GG 2 (12.8%). Moreover, there were three patients (1.4%)
who showed higher than GG 3. According to the D’Amico risk stratification, approximately
79% were classified in the very low to low risk group, while the remaining 21% belonged to the
intermediate to high risk group. The median follow-up period was 48.9 months (Table 2).

3.2 Comparison of clinical features between T1a and T1b

Of patients with IPCa, 125 (88.7%) had T1a, and 14 (9.9%) had T1b (tumor volume percentage
was not annotated in two cases). Age, PSA level, and ISUP GG were not significantly different
between the two groups. In T1b, total PV tended to be smaller (p = 0.069), and PSA density

Table 1. Baseline characteristics.

Total (n) 2630
Age (years) 69.8±7.3
2
BMI (kg/cm ) 24.2±3.1
PSA (ng/ml) † 2.7 [1.5, 5.1]
PSA density (ng/ml2) † 0.05 [0.03, 0.07]
Total prostate volume (TPV) 67.5±33.9
Transition zone volume (TZV) 38.7±25.9
Enucleated weight (g) 24.9±25.5
Enucleated volume / TPV (%) 33.9±27.9
Enucleated volume / TZV (%) 62.5±60.5
Pathology (n,%)
Benign prostatic hyperplasia 2482(94.3)
Prostate cancer 141 (5.4)
PIN / ASAP 2 (0.1)
Transitional cell carcinoma 2 (0.1)
Other cancers 3 (0.1)

†Data are presented as median (interquartile range)

PSA, prostate-specific antigen; PIN, prostate intraepithelial neoplasia; ASAP, atypical small acinar proliferation

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PLOS ONE Natural history of incidental prostate cancer

Table 2. Characteristics of incidental prostate cancer.

Total (n) 141
Age (years) 72.1±6.6
PSA (ng/ml) † 3.3 [1.8, 5.8]
PSA density (ng/ml2) † 0.05 [0.03, 0.09]
Total prostate volume 65.2±35.1
Prostate biopsy prior to HoLEP 42 (29.8)
Concurrent Prostate biopsy with HoLEP 18 (12.7)
T stage (n, %)
T1a 125 (88.7)
T1b 14 (9.9)
ISUP Grade Group
Grade Group 1 120 (85.1)
Grade Group 2 18 (12.8)
Grade Group �3 3 (1.4)
Risk stratification
Very low to Low risk 111 (78.7)
Intermediate risk 29 (20.6)
High risk 1 (0.7)
Median follow up period (months) 48.9 [23.5, 77.9]

†Data are presented as median (interquartile range)

PSA, prostate specific antigen; HoLEP, holmium laser enucleation of the prostate

https://doi.org/10.1371/journal.pone.0278931.t002

tended to be higher (0.07 vs 0.05, p = 0.054) with borderline significance compared to T1a.
Patients with T1b were more likely to undergo active treatment than active surveillance (AS)
(S1 Table).

3.3 Comparison of clinical characteristics between two different decision

groups: AS and immediate active treatment group
Of 141 patients, 18 were lost to follow-up, leaving 123 patients for analysis. Among these, 98
patients (79.7%) underwent AS, whereas 25 patients (20.3%) underwent immediate active
treatment. Age, PSA level, and ISUP GG were comparable between the two groups. Clinicians
tend to choose active treatment when the tumor volume exceeds 5% of the total specimen
(T1b) or when a tumorous condition is identified on postoperative mpMRI. Relatively low
prostate volume or high PSA density was also associated with the physician’s intent to treat
actively with borderline significance (Table 3).

3.4 Characteristics and oncological outcome of the active treatment group

Among 25 patients, radical prostatectomy was the most commonly performed treatment
(n = 18, 72%), followed by definitive radiation therapy (n = 5, 25%). Pathological findings
showed that 89% of tumors had multifocality, and ISUP upgrading was observed in 27.8%.
Meanwhile, no residual tumor was found in one patient. With a median follow-up period of
88.3 months after treatment, biochemical recurrence (BCR) occurred in one patient (S2 Table).

3.5 Characteristics of patients who discontinued AS

Among patients who chose AS as primary therapy, 88 continued AS with a median follow-up
period of 41.6 months, while nine discontinued AS after a median follow-up period of 46.3

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PLOS ONE Natural history of incidental prostate cancer

Table 3. Clinician’s decision toward active surveillance or immediate treatment.

Number of patients (n) Active Surveillance (N = 97) Active Treatment (N = 25) p-value
Age (years) 71.7±6.4 71.4±6.6 0.808
PSA (ng/ml) † 3.3 [1.9, 5.3] 3.3 [1.9, 6.8] 0.800
PSA density (ng/ml2) † 0.05 [0.03, 0.07] 0.07 [0.10, 0.14] 0.097
Total prostate volume 68.7±38.1 54.7±25.2 0.085
T stage (n, %) <0.01
T1a 90 (94.7) 18 (72.0)
T1b 5 (5.3) 7 (28.0)
ISUP Grade Group 0.111
Grade Group 1 84 (86.6) 19 (76.0)
Grade Group 2 12 (12.4) 4 (16.0)
Grade Group �3 1 (1.0) 2 (8.0)
Abnormal MRI (n, %) 36 (43.4) 20 (80.0) <0.01

†Data are presented as median (interquartile range)

PSA, prostate-specific antigen

https://doi.org/10.1371/journal.pone.0278931.t003

months. The AS discontinuation group showed a higher ISUP GG and higher proportion of
abnormal mpMRI findings. Moreover, the total PV tended to be smaller in the AS discontinu-
ation group (p = 0.056), while PSA or PSA ratio (post-HoLEP/pre-HoLEP) did not differ
between the two groups (Table 4). The most common reason for AS discontinuation was ISUP
GG upgrading following prostate biopsy (n = 5, 55.6%), followed by increasing core involve-
ment percentage (n = 3, 33.3%) (Table 5).

4. Discussion
Previous reports have defined IPCa as a low-grade, indolent disease that does not require sub-
sequent intervention [1, 6–8]. Thus, most patients were considered reliable candidates for AS

Table 4. Characteristics of patients who discontinued active surveillance.

Number of patients (n) AS continue (N = 88) AS discontinue (N = 9) p-value
Age (years) 71.9 [68.1, 76.1] 70.9 [67.9, 75.6] 0.486
PSA (ng/ml) 3.4 [1.9, 5.6] 2.8 [2.3, 4.4] 0.816
PSA ratio (post/pre) 0.27 [0.18, 0.53] 0.34 [0.26, 0.70] 0.111
PSA density (ng/ml2) 0.05 [0.03, 0.07] 0.06 [0.03, 0.10] 0.550
Total prostate volume 62.4 [48.4, 82.0] 50.9 [40.7,54.9] 0.056
T stage (n, %) 0.399
T1a 82 (95.3) 8 (88.9)
T1b 4 (4.7) 1 (11.1)
ISUP Grade Group (n,%) 0.039
Grade Group 1 77 (87.5) 7 (77.8)
Grade Group 2 11 (12.5) 1 (11.1)
Grade Group �3 0 (0.0) 1 (11.1)
Follow-up period 41.6 [26.5, 67.6] 50.3 [37.7, 93.2] 0.087
Follow-up period 46.3 [24.7, 93.6]
Until AS discontinue

PSA, prostate-specific antigen; AS, active surveillance

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PLOS ONE Natural history of incidental prostate cancer

Table 5. Reason for AS discontinuation (N = 9).

Total (n) 9
ISUP Grade group upgrading
GG1 ! GG2 2 (22.2)
GG1 ! GG3 1 (11.1)
GG1 ! GG5 1 (11.1)
GG2 ! GG4 1 (11.1)
Core involvement percentage � 50% 3 (33.3)
Abnormal MRI and PSA velocity increased 2 (22.2)
Patient wants 1 (11.1)

†Data are presented as median (interquartile range)

PSA, prostate-specific antigen

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[9, 10]. However, due to the small number of patients included in each study and relative short
follow-up time with absence of subsequent treatment description (treatment plan was
unknown for approximately 40% of previous studies [5]), no clinical consensus could be
made. In the real-world setting, there are still controversies regarding the risk of progression
of IPCa, which is the most appropriate management for these patients [5].
Moreover, several additional points emphasize the necessity of this study. Since the AS cri-
teria have been established [11], there has been a trend of continuous increase in AS [12–14],
based on the hypothesis that low-risk PCa is indolent and cancer-specific mortality is lower
than other-cause mortality. However, these criteria are based on prostate biopsy results rather
than on specimens acquired from minimally invasive endoscopic surgery. We still cannot con-
firm whether we can apply the same AS criteria, based on a previous study that showed that
transition zone PCa has a different biology than peripheral zone cancer [13, 15, 16]. Thus, we
tried to comprehensively demonstrate the natural course of IPCa using prospectively regis-
tered large population-based cohorts with long-term follow-up.
In this study, we focused on several issues that have been less investigated in previous stud-
ies. Our study cohort had relatively low PSA and PSA density levels compared with those in
previous studies, indicating that PCa was more sensitively screened before surgery. For the
similar reason, PSA reduction ratio at 6 months (PSA 6months/Pre-operative PSA) after sur-
gery was not significantly different between IPCa and BPH patients (IPCa 0.33 [0.22, 0.58] vs
BPH 0.29 [0.16, 0.57], p = 0.091).
The first issue we demonstrate was the descriptive feature that affects the clinician’s deci-
sion to perform AS or active treatment in a real-world setting. We revealed that approximately
80% of patients with IPCa underwent AS, while 20% of patients underwent active treatment.
We clearly demonstrated that clinical stage T1b disease and abnormal mpMRI results were
associated with immediate active treatment (Table 3). To be more specific, among 25 patients
of active treatment, 20 patients (80%) showed suspicious prostate cancer lesions (16 peripheral
zone, 4 transitional zone) on prostate MRI at a median of 1.2 months after HoLEP surgery.
Among them, 7 patients also harbored a higher pathological tumor burden (>5%). For the
other 5 patients who did not show abnormal findings on MRI, most of them showed clinically
significant PCa in either HoLEP specimen or prostate biopsy performed post-operatively,
which may have led to immediate active treatment. This decision was supported by previous
studies showing that T1b is an independent predictor of BCR and disease-specific mortality
[17, 18] and that patients with undistinguishable lesions on mpMRI should be considered for
AS because they have the least risk of residual cancer development after TURP [19].

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PLOS ONE Natural history of incidental prostate cancer

Furthermore, as in a previous study [20], high PSA density was also associated with active
treatment decisions, while PSA level did not show any difference, probably due to active exclu-
sion of suspicious patients with PCa preoperatively. Interestingly, PCa volume percentage
(pathologic T stage) had a greater impact than ISUP GG on decision making.
The second objective was to demonstrate the characteristics of T1a and T1b. PCa is now
being more widely screened preoperatively in the real-world setting with the help of PSA
screening and mpMRI, thus increasing the prostate biopsy performance. For this reason, con-
tradictory to the previous study by Capitanio et al., which showed small PV with high PSA in
patients with T1b compared to patients with T1a [7], our cohort showed higher PSA density in
T1b with borderline significance (p = 0.054), while having comparable results for PSA level
and PV. Because of the small number of patients who underwent AS in T1b, we could not
compare the prognosis between T1a and T1b patients who underwent AS.
The third issue was to comprehensively describe the natural history of patients who under-
went AS. Of 97 patients who primarily underwent AS, approximately 90% maintained AS with
a median period of 41.6 months, while 10% discontinued AS after a median period of 46.3
months. This AS continuation and discontinuation ratio was comparable to that in the
HAROW study, showing 12.1% of AS discontinuation [21], and these rates are lower than
those reported from most AS trials with a general low-risk PCa population [10]. This indicates
that the patient may be informed preoperatively that AS may be safely recommended, and
after 4 years, with regular check-up, residual cancer may show progression, such as GG
upgrading or increased core involvement. However, even in these cases, cancer may be safely
controlled. Furthermore, it is interesting to note that a small prostate is associated with AS dis-
continuation, and it is noteworthy that it is also known as a predictor of IPCa preoperatively in
many studies [5].
The fourth issue was determination of whether the immediate active treatment group was
truly worthy of active treatment rather than AS. For a median period of 7.5 years, all but one
patient showed no recurrence. Based on the pathologic diagnosis, the tumor multifocality rate
(88.9%) and HGPIN accompanying rate (61.1%) were considerably high, which was a distinct
feature in this study compared to the previous studies [7, 22, 23]. This supports the innate
characteristics of multifocality in PCa; thus, the message from this descriptive analysis is that
we should essentially rule out the co-existence of peripheral zone cancer, which may harbor
more aggressive features, using regular follow-up biopsy and mpMRI.
This study had several limitations. First, this was a single-center study, which may not have
reflect the heterogeneous treatment policy for IPCa. However, we believe that this study still
has a great advantage in offering more conclusive information using the largest prospective
registered database with a long follow-up period. Second, less than half of patients diagnosed
with IPCa underwent prostate biopsy or prostate MRI before HoLEP. This is partly due to the
rapidly increasing role of mpMRI in PCa diagnosis recently. However, we made our best
efforts to exclude PCa by applying the PCa risk calculator preoperatively [24]. As a result, the
IPCa incidence rate (5.4% in our cohort) was lower than the pooled incidence of 8% reported
in a recent systematic review and meta-analysis [5]. Furthermore, patients with pathologically
proven BPH and IPCa did not show a difference in PSA levels preoperatively in our cohort
compared to previous studies showing higher PSA levels in IPCa [25], indicating well screened
patients preoperatively. Moreover, many patients were referred from urology oncologists after
excluding the possibility of PCa. Third, due to the limited information, we could not consider
socioeconomic status in diagnosis of IPCa, which may have affected the diagnosis and treat-
ment of IPCa. And fourth, patients who underwent AS did not follow a uniform protocol.
Most of the patients underwent multiparemetric prostate MRI-based or both MRI and biopsy
based surveillance. However, for a certain group of low risk patients (38.1%), PSA-only

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PLOS ONE Natural history of incidental prostate cancer

surveillance was performed after confirmation of no existence of PCa on post-HoLEP follow-

up biopsy (S3 Table).
This study is meaningful in that it comprehensively demonstrated the long-term observed
natural course of IPCa, which was further analyzed using each subsequent treatment method
in the real-world setting. Overall, we revealed that, compared to the previous study, a higher
number of patients with IPCa had an intermediate risk (approximately 21%). Patients who
underwent AS through the long follow-up period, after approximately 4 years of AS, may be
definitive treatment candidates due to ISUP GG increment or core percentage increment,
which may also be safely treated (S1 Fig).

5. Conclusions
We comprehensively demonstrated the long-term observed natural course of IPCa, which was
further analyzed using each subsequent treatment method in the real-world setting. The inci-
dence of IPCa after HoLEP was 5.4%, and among these, approximately 20% proceeded with
immediate definitive therapy and an additional 6% ultimately received definitive therapy
within the median of 4 years of AS but showed excellent oncological outcomes.

Supporting information
S1 Dataset.
(XLSX)
S1 Fig. Kaplan-Meier curve of time to the active treatment for incidental prostate cancer
after HoLEP surgery.
(TIF)
S1 Table. Comparison between T1a and T1b incidental prostate cancer.
(DOCX)
S2 Table. Characteristics and oncological outcome of the active treatment group.
(DOCX)
S3 Table. Active surveillance protocol in this study.
(DOCX)

Author Contributions
Conceptualization: Jang Hee Han.
Data curation: Jang Hee Han, Dae Hyuk Chung, Seung-June Oh.
Formal analysis: Jang Hee Han, Dae Hyuk Chung, Seung-June Oh.
Investigation: Dae Hyuk Chung, Seung-June Oh.
Methodology: Jang Hee Han, Dae Hyuk Chung, Min Chul Cho, Ja Hyeon Ku, Chang Wook
Jeong, Cheol Kwak, Jae-Seung Paick, Seung-June Oh.
Project administration: Jang Hee Han, Dae Hyuk Chung, Min Chul Cho, Ja Hyeon Ku,
Chang Wook Jeong, Cheol Kwak, Jae-Seung Paick, Seung-June Oh.
Resources: Jang Hee Han, Dae Hyuk Chung, Min Chul Cho, Ja Hyeon Ku, Chang Wook
Jeong, Cheol Kwak, Jae-Seung Paick, Seung-June Oh.
Supervision: Seung-June Oh.

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PLOS ONE Natural history of incidental prostate cancer

Writing – original draft: Jang Hee Han, Seung-June Oh.

Writing – review & editing: Jang Hee Han, Seung-June Oh.

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