Int Urol Nephrol (2014) 46:2079–2085 DOI 10.1007/s11255-014-0777-z
UROLOGY - ORIGINAL PAPER
Prostate cancer detected after Holmium laser enucleation of prostate (HoLEP): significance of transrectal ultrasonography Myong Kim • Sang Hoon Song • Ja Hyeon Ku Seung-June Oh • Jae-Seung Paick
•
Received: 1 June 2014 / Accepted: 18 June 2014 / Published online: 1 July 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Purpose To identify predictors of incidental prostate cancer following Holmium laser enucleation of the prostate (HoLEP). Methods We retrospectively analyzed 458 consecutive patients who underwent HoLEP. Patients were classified into two groups: patients who received prostate biopsy prior to HoLEP (biopsy group, n = 174) and patients who did not (non-biopsy group, n = 284). The two groups were compared. Logistic regression analysis was performed to determine the predictive factors. Results A total of 27 patients (5.9 %) were incidentally diagnosed with prostate cancer. The incidence of prostate cancer was not significantly different between the two groups (biopsy group vs. non-biopsy group: 6.9 vs. 5.3 %, p = 0.48). Using multivariate analysis, a hypoechoic lesion identified by transrectal ultrasonography (TRUS) was the only predictor of incidental prostate cancer (odds ratio 2.829; 95 % confidence interval 1.061–7.539; p = 0.038). In the biopsy group, there were no significant differences in baseline characteristics including prostate size, prostate-specific antigen (PSA), PSA density, digital rectal examination (DRE) findings, and TRUS findings, between patients with and without prostate cancer. However, in the non-biopsy group, a hypoechoic lesion was found more frequently in patients with prostate cancer M. Kim J. H. Ku S.-J. Oh J.-S. Paick (&) Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea e-mail: [email protected] S. H. Song Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
(prostate cancer vs. benign prostatic hyperplasia: 20.0 vs. 3.3 %, p = 0.02). Conclusions Prior negative prostate biopsy does not rule out the possibility of prostate cancer after HoLEP. The presence of a hypoechoic lesion on TRUS might be helpful to predict incidental prostate cancer after HoLEP in patients with normal PSA and negative DRE. Prostate biopsy prior to HoLEP should be considered in these patients. Keywords Benign prostatic hyperplasia Incidentaloma Holmium laser enucleation Prostate biopsy Hypoechoic lesion
Introduction Prostate cancer may be diagnosed as an incidental finding during the pathological examination of benign prostatic hyperplasia (BPH) specimens [1], although this presentation is less common following the introduction of prostatespecific antigen (PSA) test [2]. With better stratification of patients, the detection rates of incidental prostate cancer in transurethral prostatectomy (TURP) specimens have decreased. Reports have demonstrated a decreasing incidence of detection of T1a and T1b prostate cancer during TURP in the PSA era, with the detection rates decreasing from 13.0–14.9 to 5.2–6.4 % [3, 4]. These trends suggest that the frequency of incidental prostate cancer has decreased with the use of screening. However, the risk stratification of incidental prostate cancer in patients with BPH may not be complete. Moreover, the emergence of alternative energy therapies such as the laser vaporization technique has dramatically decreased the frequency of TURP in recent decades [5]. These
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emerging procedures have precluded the availability of prostate tissue for pathologic confirmation, and hence, the potential incidence of T1a and T1b prostate cancer in these patients remains unknown. Recently, Holmium laser enucleation of the prostate (HoLEP) has been increasingly used for surgical treatment of BPH [6]. HoLEP has the advantage of availability of prostate tissue for pathological confirmation. However, there are few data on the predictors of incidental prostate cancer after HoLEP. In an effort to identify the predictors of incidental prostate cancer after HoLEP, we reviewed our HoLEP series, in which the unified protocol of patient selection for prostate biopsy was followed. The aim of this study was to investigate the predictors as well as the prevalence of incidental prostate cancer after HoLEP.
Materials and methods
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Data collection We retrospectively reviewed the medical records of the subjects. Reviewed items included; history, digital rectal examination (DRE) findings, voiding diary, International Prostate Symptom Score, urinalysis, uroflowmetry with post-void residual urine, transrectal ultrasonography (TRUS) findings, PSA, previous history of prostate biopsy, perioperative parameters, and final report of pathological examination of prostate tissue obtained by HoLEP. Prostate with palpable nodular lesions or overall hardness of the prostate on DRE was regarded as suspicious for malignancy. All TRUS were performed using a color Doppler mode of 7– MHz end–firing endoluminal transducer (ATL HDI; Advanced Technology Laboratories, Bothell, Wash., USA) by the specialized uro-radiologists of our institution. Hypoechoic lesion on TRUS was determined by the examiners [8]. The pathologic stage was categorized according to the recent recommendation of the American Joint Committee on Cancer (AJCC) TNM staging system [9].
Study population Statistical analyses This study was approved by our Institutional Review Board. From July 2008 to June 2011, 512 consecutive patients who underwent HoLEP were included in our study. Fifty-four patients were excluded; 52 patients were excluded because their PSA level was higher than 4.0 ng/ ml without performing prostate biopsy prior to HoLEP, and two patients were excluded due to a concomitant urothelial carcinoma of the bladder. Therefore, we analyzed the data of 458 patients (Fig. 1). All of the operations were performed by two surgeons (JSP and SJO) according to a wellestablished technique fully described elsewhere [7]. Fig. 1 Inclusion and exclusion of patients for this study
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Patients were divided into two groups; those who received prostate biopsy prior to HoLEP (biopsy group) and those who did not receive prostate biopsy prior to HoLEP (non-biopsy group). The incidence of prostate cancer after HoLEP and other parameters was compared. Binary logistic regression analysis was performed to determine the independent predictive factors for incidentaloma. Two groups were subcategorized into BPH or prostate cancer subgroups, and some baseline characteristics were compared. Mann–Whitney U test and chi-square test were used for analysis. A two-sided
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p value \0.05 was considered to be statistically significant. All calculations were carried out using commercial software, SPSS version 18.0 (SPSS, Chicago, IL, USA).
Results Patient characteristics and the incidence of prostate cancer
the hypoechoic lesion on TRUS was the only significant predictor of incidental prostate cancer after HoLEP [odds ratio (OR) 3.000, 95 % confidence interval (CI) 1.133–7.945]. We included two parameters in multivariate analysis; age (p \ 0.1) and hypoechoic lesion on TRUS. The hypoechoic lesion on TRUS was the only independent predictive factor for incidental prostate cancer after adjustment for age (OR 2.829, 95 % CI 1.061–7.539). Subgroup analysis
Of the 458 patients who underwent HoLEP at our institution, 27 patients (5.9 %) were diagnosed as having prostate cancer (Table 1). Of the 27 patients with incidental prostate cancer, 23 patients (85.2 %) were classified as T1a and four patients (14.8 %) were classified as T1b. Out of them, 25 patients (92.6 %) were Gleason score of 6 (3 ? 3) and two (7.4 %) were 7 (3 ? 4). Among these 458 patients, 174 patients (38.0 %) were classified to the biopsy group. Median number of cores at initial biopsy was 12 (range 6–14). The biopsy group showed statistically higher PSA and larger prostate volume than the non-biopsy group (p \ 0.01). Moreover, an abnormal finding on DRE or TRUS was more frequent in the biopsy group (p \ 0.01). In the biopsy group, a larger amount of prostate tissue was enucleated (p \ 0.01). However, the detection rate of incidentaloma was not significantly different between the two groups (biopsy vs. non-biopsy: 6.9 vs. 5.3 %, p = 0.48).
The biopsy and non-biopsy groups were subcategorized into prostate cancer, and BPH subgroups and the parameters were compared (Table 3). In the non-biopsy group, a hypoechoic lesion on TRUS was more frequent in the prostate cancer subgroup (20.0 vs. 3.3 %, p = 0.02). However, in the biopsy group, there were no differences in the parameters between prostate cancer and BPH subgroups. Among the 174 patients categorized into the biopsy group, the reason for biopsy was increased PSA in 112 patients (64.4 %), nodule on DRE in 12 patients (6.9 %), both increased PSA and nodule in 22 patients (12.6 %) and other reasons in the remaining 28 patients (16.1 %) (Table 4). The reason for biopsy, PSA level at biopsy, and number of prior biopsies did not affect the detection rate of incidental prostate cancer after HoLEP.
Discussion Independent predictors of prostate cancer To determine the independent predictors of incidental prostate cancer after HoLEP, we performed univariate and multivariate analyses using binary logistic regression for preoperative parameters (Table 2). In univariate analysis,
Detection rate of incidental prostate cancer after HoLEP There is little information in the literature regarding incidental prostate cancer after HoLEP. In recent reports, as
Table 1 Preoperative and intraoperative variables in the biopsy group, non-biopsy group, and total study population Average ± SD or No. median or (%)
Total (N = 458)
Biopsy group (N = 174)
Non-biopsy group (N = 284)
Incidental PCa
27 (5.9)
12 (6.9)
15 (5.3)
p value 0.48
Age (years)
68.4 ± 6.6 68.0
68.7 ± 5.8 69.0
68.2 ± 7.1 68.0
0.20
BMI Nodule on DRE
24.1 ± 2.8 24.0 44 of 347 (12.7)
23.8 ± 2.6 23.9 38 of 134 (28.4)
24.3 ± 3.0 24.0 6 of 213 (2.8)
0.12 \0.01
PSA (ng/ml)
3.38 ± 4.16 2.20
6.10 ± 5.68 4.73
1.70 ± 0.91 1.49
\0.01
PSAD (ng/ml2)
0.055 ± 0.051 0.042
0.086 ± 0.019 0.070
0.035 ± 0.019 0.033
\0.01
TPV on TRUS (ml)
58.0 ± 24.9 53.0
72.2 ± 27.9 70.0
49.3 ± 18.0 45.2
\0.01
TZV on TRUS (ml)
31.0 ± 20.2 26.0
43.0 ± 21.3 40.00
23.5 ± 15.3 20.0
\0.01
Hypoechoic lesion on TRUS
46 (10.0)
34 (19.5)
12 (4.2)
\0.01
Enucleated weight (g)
21.3 ± 17.3 16.4
32.2 ± 19.1 27.5
14.7 ± 11.9 11.1
\0.01
Enucleated volume/TPV (%)
33.5 ± 20.0 31.5
43.7 ± 21.2 41.4
27.2 ± 16.4 24.6
\0.01
Enucleated volume/TZV (%)
65.9 ± 38.5 59.0
78.0 ± 44.4 72.0
58.5 ± 32.1 53.8
\0.01
PCa prostate cancer, BMI body mass index, DRE digital rectal examination, PSA prostate-specific antigen, PSAD PSA density, TPV total prostate volume, TRUS transrectal ultrasonography, TZV transition zone volume, and HoLEP Holmium laser enucleation of the prostate
By chi-square test; others, by Mann–Whitney U test
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Table 2 Univariable and multivariable logistic regression analyses of risk factors for incidental prostate cancer after HoLEP Univariable
Multivariable
OR (95 % CI)
p value
OR (95 % CI)
p value
Age
1.060 (0.999-1.124)
0.055
1.035 (0.972-1.102)
0.290
BMI
0.976 (0.850-1.120)
0.729
–
–
Nodule on DRE
0.712 (0.160-3.167)
0.655
–
–
PSA
0.999 (0.908-1.098)
0.976
–
–
PSAD
7.801 (0.015-4,191.776)
0.522
–
–
TPV on TRUS
0.998 (0.981-1.014)
0.771
–
–
TZV on TRUS Hypoechoic lesion on TRUS
0.996 (0.974-1.107) 3.000 (1.133-7.945)
0.697 0.027*
– 2.829 (1.061-7.539)
– 0.038*
Biopsy prior to HoLEP
1.328 (0.607-2.909)
0.478
–
–
BMI body mass index, DRE digital rectal examination, PSA prostate-specific antigen, PSAD PSA density, TPV total prostate volume, TRUS transrectal ultrasonography, TZV transition zone volume, and HoLEP Holmium laser enucleation of the prostate * p value \0.05
By binary logistic regression analysis
Table 3 Subgroup analysis of BPH and incidental prostate cancer (PCa) Average ± SD or No. (%)
Nodule on DRE
Biopsy group (N = 174)
Non-biopsy group (N = 284)
PCa (N = 12)
BPH (N = 162)
p value
PCa (N = 15)
BPH (N = 269)
p value
2 of 9 (22.2)
36 of 125 (28.8)
0.67
0 of 12 (0.0)
6 of 201 (3.0)
0.54
PSA (ng/ml)
5.50 ± 5.57
6.14 ± 5.69
0.29
1.63 ± 0.89
1.70 ± 0.92
0.78
PSAD (ng/ml2)
0.090 ± 0.089
0.086 ± 0.069
0.73
0.037 ± 0.018
0.036 ± 0.019
0.67
Hypoechoic lesion on TRUS
3 (25.0)
31 (19.1)
0.62
3 (20.0)
9 (3.3)
0.02
Enucleated weight (g)
29.2 ± 19.9
32.4 ± 19.1
0.43
12.4 ± 10.9
14.8 ± 12.0
0.35
Enucleated volume/TPV (%)
39.2 ± 12.1
44.1 ± 21.7
0.57
24.4 ± 13.0
27.4 ± 16.6
0.57
Enucleated volume/TZV (%) No. of biopsies
94.8 ± 69.4
76.7 ± 41.9
0.32
56.7 ± 22.6
58.5 ± 32.5
0.98
1
11 (91.7)
139 (85.8)
0.57
–
–
–
C2
1 (8.3)
23 (14.2)
–
–
DRE digital rectal examination, PSA prostate-specific antigen, PSAD PSA density, TRUS transrectal ultrasonography, TPV total prostate volume, and TZV transition zone volume
By chi-square test; others, by Mann–Whitney U test
many as 11.4–11.7 % of patients receiving HoLEP were found to have incidental prostate cancer [10, 11]. The authors hypothesized that a higher prostate cancer incidence after HoLEP compared with conventional TURP is due to the availability of tissue as it is well accepted that HoLEP retrieves more tissue than TURP [10, 12]. However, more consideration should be given to the hypothesis that HoLEP has a higher detection rate of incidental prostate cancer. First, a significant amount of prostatic tissue is vaporized in the process of HoLEP [13]. Therefore, the actual amount of tissue harvest may be decreased and the obtained tissue may have more architectural and cytological artifacts. Das et al. [14] reported that Holmium laser resection caused substantial tissue vaporization (up to 54 %) and greater thermal damage to
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the tissue than conventional TURP. However, a previous study by Naspro et al. [15] showed that although a higher percentage of prostate tissue is lost by vaporization with HoLEP, it does not affect the diagnostic performance of incidental prostate cancer. Secondly, there is some doubt regarding whether more tissue guarantees a higher detection rate of incidental prostate cancer. Vollmer et al. [16] showed that eight blocks of TURP chips (approximately 19.2 g) detected 95 % of all incidental prostate cancers. Previous numerous HoLEP series showed various detection rates of incidental prostate cancer (range 2.9–11.7 %) [10–12, 17–21]. The major reason for the diverse incidence is assumed to be the differences in preselection conditions to rule out malignancy prior to HoLEP. However, the stratification conditions for prostate
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Table 4 Subanalysis of the biopsy group according to the characteristics of prostate biopsy Patients (n)
Cancer (n)
Cancer rate (%)
p value
0.964
Reason for biopsy Increased PSA
112
7
6.3
Nodule on DRE Increased PSA and nodule
12 22
1 2
8.3 9.1
Other reasonsà
28
2
7.1
PSA level (ng/ml) \ 4.0 C 4.0– \ 10.0 C 10.0
40
3
7.5
116
8
6.9
18
1
5.6
0.362
No. of biopsy 1
150
11
7.3
C2
24
1
4.2
Total
174
12
6.9
0.570
PSA level not higher than 4.0 ng/ml, however, on medication of 5-alpha-reductase inhibitor: 12 patients, rapidly increased PSA: nine patients, relatively high PSA level compared with the prostate volume: five patients, unidentifiable reasons by the chart review: two patients
By chi-square test; àdetails of other reasons
biopsy are not well documented. The rate of incidental prostate cancer in our present study was 5.9 % (Table 1), which is in agreement with the rate of 5.2 % reported by Hurle et al. [19]. The indications for prostate biopsy were similar between two studies (PSA C 4.0 or abnormal DRE). These findings suggest that the rate of incidental prostate cancer is affected by patient selection. Among the well-known randomized controlled trials accessing the efficacy of HoLEP compared with TURP, two groups [12, 21] mentioned that the prostate cancer showed no statistically significant difference in the incidence (HoLEP vs. TURP, 11.5 vs. 8.3, 3.0 vs. 10.0 %, p value [0.05). Can prostate biopsy reduce the risk of incidental prostate cancer after HoLEP? After PSA screening and prostate biopsy were introduced in routine use, the rate of incidental prostate cancer after transurethral surgery was dramatically decreased within a few decades [2, 3]. However, a steady rate of incidental prostate cancer still exists after prostate biopsy. In the current study, the biopsy group had a greater risk for prostate cancer (Table 1). In spite of the difference, the detection rate of incidental prostate cancer was no different (6.9 vs. 5.3 %, p = 0.48) and a steady rate of incidental prostate cancer remained in the biopsy group. These findings are in line with findings of Mai et al. [22], which demonstrate that T1b prostate cancer incidence after TURP
was dramatically decreased after the PSA era, while the incidence of T1a prostate cancer remained unchanged. In this study, 23 of 27 patients with incidental prostate cancer (85.2 %) were classified into the T1a stage. Our results indicate that prostate biopsy increases the chances of making an appropriate diagnosis, but it could not completely rule out the possibility of prostate cancer, especially the low-stage incidental prostate cancer. In addition, it is possible that patients who undergo with medical or laser vaporization therapies have the same risk of incidental prostate cancer even after PSA and biopsy screening. Son et al. [20] introduced the modified technique of photoselective vaporization of the prostate (PVP) which enables acquisition of the prostatic tissue. They reported that the incidence of prostate cancer was 3.1 % in spite of strict prescreening (abnormal DRE or PSA C 3 ng/ ml). This result supports the fact that these patients may have occult prostate cancer which cannot be detected by prostate biopsy. The un-biopsied transition zone is postulated as one of the major causes of persistent cancer risk despite prior biopsy. Only the peripheral zone is routinely targeted in 6or 12-core prostate biopsy. Some studies have suggested the necessary of TURP to rule out the transition zone prostate cancer in patients with a previous negative prostate biopsy [23, 24]. Puppo et al. [24] reported that combination of peripheral prostate biopsy and TURP can raise the prostate cancer detection rate up to 57 % in patients with repeated negative biopsies. On these grounds, we suggest that patients who have LUTS with negative prostate biopsy are mandatory to be treated with the options which enable tissue acquisition such as HoLEP or TURP. The clinical implication of a hypoechoic lesion on TRUS prior to transurethral surgery Our multivariate analysis results showed that the hypoechoic lesion on TRUS is the only independent predictive factor for incidental prostate cancer (OR 2.829; 95 % CI 1.061–7.539; p value 0.038) (Table 2). Our data showed that patients with a hypoechoic lesion showed a higher rate of incidental prostate cancer (6 of 46 patients, 13.0 %) than those without a hypoechoic lesion (21 of 412 patients, 5.1 %) (p = 0.04). These results are in agreement with data suggesting that the prostate cancer detection rate by TURP is higher in patients with a suspicious nodule (16.5 vs. 5.5 %, p value \0.001), but with a previous negative prostate biopsy [25]. Hypoechoic lesions are predominantly located in the peripheral zone of the prostate, and prostate biopsy focuses on this peripheral zone. However, the HoLEP procedure routinely removes only the adenomatous tissue at the transition zone. In our data, three (8.8 %) of the 34 patients
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Fig. 2 Newly proposed prostate cancer-screening strategy for BPH patients who are considering transurethral surgery
who had a hypoechoic lesion on TRUS and a prior negative prostate biopsy showed a newly detected prostate cancer after HoLEP. Among the 34 hypoechoic lesions, nine lesions (26.5 %) underwent additional targeted core biopsy, but all of these lesions were negative in prior prostate biopsy. In one (11.1 %) of the nine patients who underwent targeted prostate biopsy, prostate cancer was detected during HoLEP. Shim et al. [26] reported that patients with only a hypoechoic lesion on TRUS and without any other indications for biopsy (high PSA or abnormal DRE) showed a prostate cancer detection rate of 11.5 % and additional targeted core biopsy of the lesion offered no benefit. Onur et al. [27] reported that per-core cancer detection rate of hypoechoic lesions was 9.3 % and that prostates with hypoechoic lesions tend to have cancers even though the lesions may not contain the tumor. These results suggest that a hypoechoic lesion on TRUS is an important risk factor for prostate cancer; however, the cancer is not always confined to the hypoechoic lesion on TRUS. This means that the patients who had a hypoechoic lesion on TRUS can also have prostate cancer in another site of the prostate. It is interesting that the non-biopsy group showed that hypoechoic lesions were more frequent in the prostate cancer subgroup (20.0 vs. 3.3 %, p = 0.02), but biopsy group was not (25.0 vs. 19.1 %, p = 0.62) (Table 3). That difference is postulated because that the biopsy group patients were fully screened about the hypoechoic lesion by the prior biopsy; therefore, the remained hypoechoic lesions are clinically insignificant. However, the hypoechoic lesions of non-biopsy group did not be screened; hence, those hypoechoic lesions had the mixed nature of clinically significance and insignificance. These results indicate that patients with a hypoechoic lesion on TRUS, particularly those who did not receive prostate biopsy, have a higher
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risk for incidental prostate cancer. It is therefore imperative that these patients are paid greater caution for incidental prostate cancer and should receive a prostate biopsy prior to HoLEP, even if they have a negative DRE or a low PSA level. A newly proposed prostate cancer-screening strategy On these grounds, we suggest a novel prostate cancerscreening strategy for BPH patients considering transurethral surgery (Fig. 2). First, we suggest that prostate biopsy prior to surgery should be considered in patients with a normal PSA and negative DRE and has a hypoechoic lesion on TRUS. Second, even though the patients have a previous negative prostate biopsy, they are considered to take a transition zone biopsy or preferred the transurethral modality such as TURP or HoLEP, which enables acquisition of the adenoma tissue in the transition zone. By using this strategy, we can expect to reduce the occult prostate cancer rate in the era of alternative transurethral surgery. Limitations of this study Our study does have some limitations. This study has a retrospective design. In addition, it was a non-randomized study, and it did not have a matched control group treated with other modalities instead of HoLEP. To confirm the characteristics of incidental prostate cancer after HoLEP, more well-designed studies are needed.
Conclusions Prostate biopsy cannot completely rule out the possibility of prostate cancer after HoLEP. Patients with a hypoechoic lesion, even though they have a normal PSA and negative
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DRE, are recommended to consider the prostate biopsy prior to transurethral surgery. Patients who have a previous negative prostate biopsy are mandatory to consider a treatment modality such as HoLEP, which enables acquisition of the adenoma tissue.
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13.
14. Conflict of interest All authors have no direct or indirect commercial financial incentive associated with publishing the article.
15.
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UROLOGY - ORIGINAL PAPER
Prostate cancer detected after Holmium laser enucleation of prostate (HoLEP): significance of transrectal ultrasonography Myong Kim • Sang Hoon Song • Ja Hyeon Ku Seung-June Oh • Jae-Seung Paick
•
Received: 1 June 2014 / Accepted: 18 June 2014 / Published online: 1 July 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Purpose To identify predictors of incidental prostate cancer following Holmium laser enucleation of the prostate (HoLEP). Methods We retrospectively analyzed 458 consecutive patients who underwent HoLEP. Patients were classified into two groups: patients who received prostate biopsy prior to HoLEP (biopsy group, n = 174) and patients who did not (non-biopsy group, n = 284). The two groups were compared. Logistic regression analysis was performed to determine the predictive factors. Results A total of 27 patients (5.9 %) were incidentally diagnosed with prostate cancer. The incidence of prostate cancer was not significantly different between the two groups (biopsy group vs. non-biopsy group: 6.9 vs. 5.3 %, p = 0.48). Using multivariate analysis, a hypoechoic lesion identified by transrectal ultrasonography (TRUS) was the only predictor of incidental prostate cancer (odds ratio 2.829; 95 % confidence interval 1.061–7.539; p = 0.038). In the biopsy group, there were no significant differences in baseline characteristics including prostate size, prostate-specific antigen (PSA), PSA density, digital rectal examination (DRE) findings, and TRUS findings, between patients with and without prostate cancer. However, in the non-biopsy group, a hypoechoic lesion was found more frequently in patients with prostate cancer M. Kim J. H. Ku S.-J. Oh J.-S. Paick (&) Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea e-mail: [email protected] S. H. Song Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
(prostate cancer vs. benign prostatic hyperplasia: 20.0 vs. 3.3 %, p = 0.02). Conclusions Prior negative prostate biopsy does not rule out the possibility of prostate cancer after HoLEP. The presence of a hypoechoic lesion on TRUS might be helpful to predict incidental prostate cancer after HoLEP in patients with normal PSA and negative DRE. Prostate biopsy prior to HoLEP should be considered in these patients. Keywords Benign prostatic hyperplasia Incidentaloma Holmium laser enucleation Prostate biopsy Hypoechoic lesion
Introduction Prostate cancer may be diagnosed as an incidental finding during the pathological examination of benign prostatic hyperplasia (BPH) specimens [1], although this presentation is less common following the introduction of prostatespecific antigen (PSA) test [2]. With better stratification of patients, the detection rates of incidental prostate cancer in transurethral prostatectomy (TURP) specimens have decreased. Reports have demonstrated a decreasing incidence of detection of T1a and T1b prostate cancer during TURP in the PSA era, with the detection rates decreasing from 13.0–14.9 to 5.2–6.4 % [3, 4]. These trends suggest that the frequency of incidental prostate cancer has decreased with the use of screening. However, the risk stratification of incidental prostate cancer in patients with BPH may not be complete. Moreover, the emergence of alternative energy therapies such as the laser vaporization technique has dramatically decreased the frequency of TURP in recent decades [5]. These
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emerging procedures have precluded the availability of prostate tissue for pathologic confirmation, and hence, the potential incidence of T1a and T1b prostate cancer in these patients remains unknown. Recently, Holmium laser enucleation of the prostate (HoLEP) has been increasingly used for surgical treatment of BPH [6]. HoLEP has the advantage of availability of prostate tissue for pathological confirmation. However, there are few data on the predictors of incidental prostate cancer after HoLEP. In an effort to identify the predictors of incidental prostate cancer after HoLEP, we reviewed our HoLEP series, in which the unified protocol of patient selection for prostate biopsy was followed. The aim of this study was to investigate the predictors as well as the prevalence of incidental prostate cancer after HoLEP.
Materials and methods
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Data collection We retrospectively reviewed the medical records of the subjects. Reviewed items included; history, digital rectal examination (DRE) findings, voiding diary, International Prostate Symptom Score, urinalysis, uroflowmetry with post-void residual urine, transrectal ultrasonography (TRUS) findings, PSA, previous history of prostate biopsy, perioperative parameters, and final report of pathological examination of prostate tissue obtained by HoLEP. Prostate with palpable nodular lesions or overall hardness of the prostate on DRE was regarded as suspicious for malignancy. All TRUS were performed using a color Doppler mode of 7– MHz end–firing endoluminal transducer (ATL HDI; Advanced Technology Laboratories, Bothell, Wash., USA) by the specialized uro-radiologists of our institution. Hypoechoic lesion on TRUS was determined by the examiners [8]. The pathologic stage was categorized according to the recent recommendation of the American Joint Committee on Cancer (AJCC) TNM staging system [9].
Study population Statistical analyses This study was approved by our Institutional Review Board. From July 2008 to June 2011, 512 consecutive patients who underwent HoLEP were included in our study. Fifty-four patients were excluded; 52 patients were excluded because their PSA level was higher than 4.0 ng/ ml without performing prostate biopsy prior to HoLEP, and two patients were excluded due to a concomitant urothelial carcinoma of the bladder. Therefore, we analyzed the data of 458 patients (Fig. 1). All of the operations were performed by two surgeons (JSP and SJO) according to a wellestablished technique fully described elsewhere [7]. Fig. 1 Inclusion and exclusion of patients for this study
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Patients were divided into two groups; those who received prostate biopsy prior to HoLEP (biopsy group) and those who did not receive prostate biopsy prior to HoLEP (non-biopsy group). The incidence of prostate cancer after HoLEP and other parameters was compared. Binary logistic regression analysis was performed to determine the independent predictive factors for incidentaloma. Two groups were subcategorized into BPH or prostate cancer subgroups, and some baseline characteristics were compared. Mann–Whitney U test and chi-square test were used for analysis. A two-sided
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p value \0.05 was considered to be statistically significant. All calculations were carried out using commercial software, SPSS version 18.0 (SPSS, Chicago, IL, USA).
Results Patient characteristics and the incidence of prostate cancer
the hypoechoic lesion on TRUS was the only significant predictor of incidental prostate cancer after HoLEP [odds ratio (OR) 3.000, 95 % confidence interval (CI) 1.133–7.945]. We included two parameters in multivariate analysis; age (p \ 0.1) and hypoechoic lesion on TRUS. The hypoechoic lesion on TRUS was the only independent predictive factor for incidental prostate cancer after adjustment for age (OR 2.829, 95 % CI 1.061–7.539). Subgroup analysis
Of the 458 patients who underwent HoLEP at our institution, 27 patients (5.9 %) were diagnosed as having prostate cancer (Table 1). Of the 27 patients with incidental prostate cancer, 23 patients (85.2 %) were classified as T1a and four patients (14.8 %) were classified as T1b. Out of them, 25 patients (92.6 %) were Gleason score of 6 (3 ? 3) and two (7.4 %) were 7 (3 ? 4). Among these 458 patients, 174 patients (38.0 %) were classified to the biopsy group. Median number of cores at initial biopsy was 12 (range 6–14). The biopsy group showed statistically higher PSA and larger prostate volume than the non-biopsy group (p \ 0.01). Moreover, an abnormal finding on DRE or TRUS was more frequent in the biopsy group (p \ 0.01). In the biopsy group, a larger amount of prostate tissue was enucleated (p \ 0.01). However, the detection rate of incidentaloma was not significantly different between the two groups (biopsy vs. non-biopsy: 6.9 vs. 5.3 %, p = 0.48).
The biopsy and non-biopsy groups were subcategorized into prostate cancer, and BPH subgroups and the parameters were compared (Table 3). In the non-biopsy group, a hypoechoic lesion on TRUS was more frequent in the prostate cancer subgroup (20.0 vs. 3.3 %, p = 0.02). However, in the biopsy group, there were no differences in the parameters between prostate cancer and BPH subgroups. Among the 174 patients categorized into the biopsy group, the reason for biopsy was increased PSA in 112 patients (64.4 %), nodule on DRE in 12 patients (6.9 %), both increased PSA and nodule in 22 patients (12.6 %) and other reasons in the remaining 28 patients (16.1 %) (Table 4). The reason for biopsy, PSA level at biopsy, and number of prior biopsies did not affect the detection rate of incidental prostate cancer after HoLEP.
Discussion Independent predictors of prostate cancer To determine the independent predictors of incidental prostate cancer after HoLEP, we performed univariate and multivariate analyses using binary logistic regression for preoperative parameters (Table 2). In univariate analysis,
Detection rate of incidental prostate cancer after HoLEP There is little information in the literature regarding incidental prostate cancer after HoLEP. In recent reports, as
Table 1 Preoperative and intraoperative variables in the biopsy group, non-biopsy group, and total study population Average ± SD or No. median or (%)
Total (N = 458)
Biopsy group (N = 174)
Non-biopsy group (N = 284)
Incidental PCa
27 (5.9)
12 (6.9)
15 (5.3)
p value 0.48
Age (years)
68.4 ± 6.6 68.0
68.7 ± 5.8 69.0
68.2 ± 7.1 68.0
0.20
BMI Nodule on DRE
24.1 ± 2.8 24.0 44 of 347 (12.7)
23.8 ± 2.6 23.9 38 of 134 (28.4)
24.3 ± 3.0 24.0 6 of 213 (2.8)
0.12 \0.01
PSA (ng/ml)
3.38 ± 4.16 2.20
6.10 ± 5.68 4.73
1.70 ± 0.91 1.49
\0.01
PSAD (ng/ml2)
0.055 ± 0.051 0.042
0.086 ± 0.019 0.070
0.035 ± 0.019 0.033
\0.01
TPV on TRUS (ml)
58.0 ± 24.9 53.0
72.2 ± 27.9 70.0
49.3 ± 18.0 45.2
\0.01
TZV on TRUS (ml)
31.0 ± 20.2 26.0
43.0 ± 21.3 40.00
23.5 ± 15.3 20.0
\0.01
Hypoechoic lesion on TRUS
46 (10.0)
34 (19.5)
12 (4.2)
\0.01
Enucleated weight (g)
21.3 ± 17.3 16.4
32.2 ± 19.1 27.5
14.7 ± 11.9 11.1
\0.01
Enucleated volume/TPV (%)
33.5 ± 20.0 31.5
43.7 ± 21.2 41.4
27.2 ± 16.4 24.6
\0.01
Enucleated volume/TZV (%)
65.9 ± 38.5 59.0
78.0 ± 44.4 72.0
58.5 ± 32.1 53.8
\0.01
PCa prostate cancer, BMI body mass index, DRE digital rectal examination, PSA prostate-specific antigen, PSAD PSA density, TPV total prostate volume, TRUS transrectal ultrasonography, TZV transition zone volume, and HoLEP Holmium laser enucleation of the prostate
By chi-square test; others, by Mann–Whitney U test
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Table 2 Univariable and multivariable logistic regression analyses of risk factors for incidental prostate cancer after HoLEP Univariable
Multivariable
OR (95 % CI)
p value
OR (95 % CI)
p value
Age
1.060 (0.999-1.124)
0.055
1.035 (0.972-1.102)
0.290
BMI
0.976 (0.850-1.120)
0.729
–
–
Nodule on DRE
0.712 (0.160-3.167)
0.655
–
–
PSA
0.999 (0.908-1.098)
0.976
–
–
PSAD
7.801 (0.015-4,191.776)
0.522
–
–
TPV on TRUS
0.998 (0.981-1.014)
0.771
–
–
TZV on TRUS Hypoechoic lesion on TRUS
0.996 (0.974-1.107) 3.000 (1.133-7.945)
0.697 0.027*
– 2.829 (1.061-7.539)
– 0.038*
Biopsy prior to HoLEP
1.328 (0.607-2.909)
0.478
–
–
BMI body mass index, DRE digital rectal examination, PSA prostate-specific antigen, PSAD PSA density, TPV total prostate volume, TRUS transrectal ultrasonography, TZV transition zone volume, and HoLEP Holmium laser enucleation of the prostate * p value \0.05
By binary logistic regression analysis
Table 3 Subgroup analysis of BPH and incidental prostate cancer (PCa) Average ± SD or No. (%)
Nodule on DRE
Biopsy group (N = 174)
Non-biopsy group (N = 284)
PCa (N = 12)
BPH (N = 162)
p value
PCa (N = 15)
BPH (N = 269)
p value
2 of 9 (22.2)
36 of 125 (28.8)
0.67
0 of 12 (0.0)
6 of 201 (3.0)
0.54
PSA (ng/ml)
5.50 ± 5.57
6.14 ± 5.69
0.29
1.63 ± 0.89
1.70 ± 0.92
0.78
PSAD (ng/ml2)
0.090 ± 0.089
0.086 ± 0.069
0.73
0.037 ± 0.018
0.036 ± 0.019
0.67
Hypoechoic lesion on TRUS
3 (25.0)
31 (19.1)
0.62
3 (20.0)
9 (3.3)
0.02
Enucleated weight (g)
29.2 ± 19.9
32.4 ± 19.1
0.43
12.4 ± 10.9
14.8 ± 12.0
0.35
Enucleated volume/TPV (%)
39.2 ± 12.1
44.1 ± 21.7
0.57
24.4 ± 13.0
27.4 ± 16.6
0.57
Enucleated volume/TZV (%) No. of biopsies
94.8 ± 69.4
76.7 ± 41.9
0.32
56.7 ± 22.6
58.5 ± 32.5
0.98
1
11 (91.7)
139 (85.8)
0.57
–
–
–
C2
1 (8.3)
23 (14.2)
–
–
DRE digital rectal examination, PSA prostate-specific antigen, PSAD PSA density, TRUS transrectal ultrasonography, TPV total prostate volume, and TZV transition zone volume
By chi-square test; others, by Mann–Whitney U test
many as 11.4–11.7 % of patients receiving HoLEP were found to have incidental prostate cancer [10, 11]. The authors hypothesized that a higher prostate cancer incidence after HoLEP compared with conventional TURP is due to the availability of tissue as it is well accepted that HoLEP retrieves more tissue than TURP [10, 12]. However, more consideration should be given to the hypothesis that HoLEP has a higher detection rate of incidental prostate cancer. First, a significant amount of prostatic tissue is vaporized in the process of HoLEP [13]. Therefore, the actual amount of tissue harvest may be decreased and the obtained tissue may have more architectural and cytological artifacts. Das et al. [14] reported that Holmium laser resection caused substantial tissue vaporization (up to 54 %) and greater thermal damage to
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the tissue than conventional TURP. However, a previous study by Naspro et al. [15] showed that although a higher percentage of prostate tissue is lost by vaporization with HoLEP, it does not affect the diagnostic performance of incidental prostate cancer. Secondly, there is some doubt regarding whether more tissue guarantees a higher detection rate of incidental prostate cancer. Vollmer et al. [16] showed that eight blocks of TURP chips (approximately 19.2 g) detected 95 % of all incidental prostate cancers. Previous numerous HoLEP series showed various detection rates of incidental prostate cancer (range 2.9–11.7 %) [10–12, 17–21]. The major reason for the diverse incidence is assumed to be the differences in preselection conditions to rule out malignancy prior to HoLEP. However, the stratification conditions for prostate
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Table 4 Subanalysis of the biopsy group according to the characteristics of prostate biopsy Patients (n)
Cancer (n)
Cancer rate (%)
p value
0.964
Reason for biopsy Increased PSA
112
7
6.3
Nodule on DRE Increased PSA and nodule
12 22
1 2
8.3 9.1
Other reasonsà
28
2
7.1
PSA level (ng/ml) \ 4.0 C 4.0– \ 10.0 C 10.0
40
3
7.5
116
8
6.9
18
1
5.6
0.362
No. of biopsy 1
150
11
7.3
C2
24
1
4.2
Total
174
12
6.9
0.570
PSA level not higher than 4.0 ng/ml, however, on medication of 5-alpha-reductase inhibitor: 12 patients, rapidly increased PSA: nine patients, relatively high PSA level compared with the prostate volume: five patients, unidentifiable reasons by the chart review: two patients
By chi-square test; àdetails of other reasons
biopsy are not well documented. The rate of incidental prostate cancer in our present study was 5.9 % (Table 1), which is in agreement with the rate of 5.2 % reported by Hurle et al. [19]. The indications for prostate biopsy were similar between two studies (PSA C 4.0 or abnormal DRE). These findings suggest that the rate of incidental prostate cancer is affected by patient selection. Among the well-known randomized controlled trials accessing the efficacy of HoLEP compared with TURP, two groups [12, 21] mentioned that the prostate cancer showed no statistically significant difference in the incidence (HoLEP vs. TURP, 11.5 vs. 8.3, 3.0 vs. 10.0 %, p value [0.05). Can prostate biopsy reduce the risk of incidental prostate cancer after HoLEP? After PSA screening and prostate biopsy were introduced in routine use, the rate of incidental prostate cancer after transurethral surgery was dramatically decreased within a few decades [2, 3]. However, a steady rate of incidental prostate cancer still exists after prostate biopsy. In the current study, the biopsy group had a greater risk for prostate cancer (Table 1). In spite of the difference, the detection rate of incidental prostate cancer was no different (6.9 vs. 5.3 %, p = 0.48) and a steady rate of incidental prostate cancer remained in the biopsy group. These findings are in line with findings of Mai et al. [22], which demonstrate that T1b prostate cancer incidence after TURP
was dramatically decreased after the PSA era, while the incidence of T1a prostate cancer remained unchanged. In this study, 23 of 27 patients with incidental prostate cancer (85.2 %) were classified into the T1a stage. Our results indicate that prostate biopsy increases the chances of making an appropriate diagnosis, but it could not completely rule out the possibility of prostate cancer, especially the low-stage incidental prostate cancer. In addition, it is possible that patients who undergo with medical or laser vaporization therapies have the same risk of incidental prostate cancer even after PSA and biopsy screening. Son et al. [20] introduced the modified technique of photoselective vaporization of the prostate (PVP) which enables acquisition of the prostatic tissue. They reported that the incidence of prostate cancer was 3.1 % in spite of strict prescreening (abnormal DRE or PSA C 3 ng/ ml). This result supports the fact that these patients may have occult prostate cancer which cannot be detected by prostate biopsy. The un-biopsied transition zone is postulated as one of the major causes of persistent cancer risk despite prior biopsy. Only the peripheral zone is routinely targeted in 6or 12-core prostate biopsy. Some studies have suggested the necessary of TURP to rule out the transition zone prostate cancer in patients with a previous negative prostate biopsy [23, 24]. Puppo et al. [24] reported that combination of peripheral prostate biopsy and TURP can raise the prostate cancer detection rate up to 57 % in patients with repeated negative biopsies. On these grounds, we suggest that patients who have LUTS with negative prostate biopsy are mandatory to be treated with the options which enable tissue acquisition such as HoLEP or TURP. The clinical implication of a hypoechoic lesion on TRUS prior to transurethral surgery Our multivariate analysis results showed that the hypoechoic lesion on TRUS is the only independent predictive factor for incidental prostate cancer (OR 2.829; 95 % CI 1.061–7.539; p value 0.038) (Table 2). Our data showed that patients with a hypoechoic lesion showed a higher rate of incidental prostate cancer (6 of 46 patients, 13.0 %) than those without a hypoechoic lesion (21 of 412 patients, 5.1 %) (p = 0.04). These results are in agreement with data suggesting that the prostate cancer detection rate by TURP is higher in patients with a suspicious nodule (16.5 vs. 5.5 %, p value \0.001), but with a previous negative prostate biopsy [25]. Hypoechoic lesions are predominantly located in the peripheral zone of the prostate, and prostate biopsy focuses on this peripheral zone. However, the HoLEP procedure routinely removes only the adenomatous tissue at the transition zone. In our data, three (8.8 %) of the 34 patients
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Fig. 2 Newly proposed prostate cancer-screening strategy for BPH patients who are considering transurethral surgery
who had a hypoechoic lesion on TRUS and a prior negative prostate biopsy showed a newly detected prostate cancer after HoLEP. Among the 34 hypoechoic lesions, nine lesions (26.5 %) underwent additional targeted core biopsy, but all of these lesions were negative in prior prostate biopsy. In one (11.1 %) of the nine patients who underwent targeted prostate biopsy, prostate cancer was detected during HoLEP. Shim et al. [26] reported that patients with only a hypoechoic lesion on TRUS and without any other indications for biopsy (high PSA or abnormal DRE) showed a prostate cancer detection rate of 11.5 % and additional targeted core biopsy of the lesion offered no benefit. Onur et al. [27] reported that per-core cancer detection rate of hypoechoic lesions was 9.3 % and that prostates with hypoechoic lesions tend to have cancers even though the lesions may not contain the tumor. These results suggest that a hypoechoic lesion on TRUS is an important risk factor for prostate cancer; however, the cancer is not always confined to the hypoechoic lesion on TRUS. This means that the patients who had a hypoechoic lesion on TRUS can also have prostate cancer in another site of the prostate. It is interesting that the non-biopsy group showed that hypoechoic lesions were more frequent in the prostate cancer subgroup (20.0 vs. 3.3 %, p = 0.02), but biopsy group was not (25.0 vs. 19.1 %, p = 0.62) (Table 3). That difference is postulated because that the biopsy group patients were fully screened about the hypoechoic lesion by the prior biopsy; therefore, the remained hypoechoic lesions are clinically insignificant. However, the hypoechoic lesions of non-biopsy group did not be screened; hence, those hypoechoic lesions had the mixed nature of clinically significance and insignificance. These results indicate that patients with a hypoechoic lesion on TRUS, particularly those who did not receive prostate biopsy, have a higher
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risk for incidental prostate cancer. It is therefore imperative that these patients are paid greater caution for incidental prostate cancer and should receive a prostate biopsy prior to HoLEP, even if they have a negative DRE or a low PSA level. A newly proposed prostate cancer-screening strategy On these grounds, we suggest a novel prostate cancerscreening strategy for BPH patients considering transurethral surgery (Fig. 2). First, we suggest that prostate biopsy prior to surgery should be considered in patients with a normal PSA and negative DRE and has a hypoechoic lesion on TRUS. Second, even though the patients have a previous negative prostate biopsy, they are considered to take a transition zone biopsy or preferred the transurethral modality such as TURP or HoLEP, which enables acquisition of the adenoma tissue in the transition zone. By using this strategy, we can expect to reduce the occult prostate cancer rate in the era of alternative transurethral surgery. Limitations of this study Our study does have some limitations. This study has a retrospective design. In addition, it was a non-randomized study, and it did not have a matched control group treated with other modalities instead of HoLEP. To confirm the characteristics of incidental prostate cancer after HoLEP, more well-designed studies are needed.
Conclusions Prostate biopsy cannot completely rule out the possibility of prostate cancer after HoLEP. Patients with a hypoechoic lesion, even though they have a normal PSA and negative
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DRE, are recommended to consider the prostate biopsy prior to transurethral surgery. Patients who have a previous negative prostate biopsy are mandatory to consider a treatment modality such as HoLEP, which enables acquisition of the adenoma tissue.
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13.
14. Conflict of interest All authors have no direct or indirect commercial financial incentive associated with publishing the article.
15.
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