World J Urol (2015) 33:329–333 DOI 10.1007/s00345-014-1310-9

ORIGINAL ARTICLE

Significance of prostate‑specific antigen‑related factors in incidental prostate cancer treated by holmium laser enucleation of the prostate Satoshi Otsubo · Akira Yokomizo · Osamu Mochida · Masaki Shiota · Katsunori Tatsugami · Junich Inokuchi · Seiji Naito 

Received: 15 August 2013 / Accepted: 22 April 2014 / Published online: 8 May 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract  Purpose  Recently, more vaporization techniques are available for the treatment of benign prostate hyperplasia (BPH). However, the detection of incidental prostate cancer (Pca) is impossible in vaporization techniques because of unavailability prostate tissue for histopathological analysis. To evaluate the clinical backgrounds and the usefulness of prostate-specific antigen (PSA)-related factors in incidental Pca, we employed our BPH patients cohort treated by holmium laser enucleation of the prostate (HoLEP). Methods  A total of 365 HoLEPs were performed by a single surgeon. The pathological results and pre- and postHoLEP PSA, PSA density and PSA velocity were analyzed retrospectively. Results  Incidental Pca was identified in 25 (6.8 %) of the 365 patients treated with HoLEP. There were significant differences between BPH and Pca in terms of prostate volume (55.5 vs. 47 ml, p  = 0.0365), preoperative PSA (4.50 vs. 7.14 ng/ml, p = 0.0107), PSA density (0.079 vs. 0.155 ng/ ml/cm3, p = 0.0005), and postoperative PSA velocity (0.04 vs. 0.22 ng/ml/year, p  = 0.0033), respectively. Comparisons of Gleason score subgroups in the 25 patients with incidental Pca identified significant differences in preoperative PSA (6.06 vs. 21.6 ng/ml, p = 0.0191) and postoperative PSA velocity (0.185 vs. 1.32 ng/ml/year, p = 0.0382)

S. Otsubo · A. Yokomizo (*) · M. Shiota · K. Tatsugami · J. Inokuchi · S. Naito  Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3‑1‑1 Maidashi, Higashi‑ku, Fukuoka 812‑8582, Japan e-mail: [email protected]‑u.ac.jp O. Mochida  Southwest Urological Clinic, Fukuoka, Japan

between the Gleason score 3 + 3 and Gleason score >3 + 3 groups, respectively. Conclusions  Risk factors associated with incidental Pca were smaller prostate volume, higher preoperative PSA, and higher PSA density. Postoperative PSA velocity was also significantly increased in patients with incidental Pca, especially those with higher Gleason score. These finding may be useful in incident Pca patients treated by the vaporization technique. Keywords  Incidental prostate cancer · Benign prostatic hyperplasia · Holmium laser enucleation of the prostate · Prostate-specific antigen

Introduction The rate of incidental prostate cancer (Pca) following surgery for benign prostatic hyperplasia (BPH) has decreased from around 25 % in the era before prostate-specific antigen (PSA) testing to 19; (3) first surgical treatment for BPH; and (4) clinical stage N0M0, if Pca was identified. Exclusion criteria were (1) previous or concurrent malignant disease and (2) history of radiation or chemotherapy of anticancer agents. A total of 385 HoLEPs for BPH were performed at the Southwest Urological Clinic by a single surgeon (Dr. Osamu Mochida) between September 2006 and December 2011. No patients had a history of Pca. Twenty patients were excluded because of incomplete PSA data. Pathological features, pre- and post-HoLEP PSA, PSA density, and PSA velocity, and additional treatment of incidental Pca were reviewed retrospectively in the remaining 365 patients. Prostate biopsy was strongly recommended to excluded Pca in patients with increased preoperative

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n=10

n= 9

PSA >4 ng/ml. A total of 198 of the 365 patients had PSA >4 ng/ml and 126 of the 198 (63.6 %) had undergone prostate biopsy before HoLEP. Patients who were diagnosed without malignancies were included in this study. After HoLEP, incidental Pca was identified in 25 patients, while the remaining 340 patients had no evidence of malignancy. A flow diagram of the study patients is shown in Fig. 1. Entire specimens resected by HoLEP were examined and diagnosed by dedicated genitourinary pathologists. If Pca was detected, the pathological stage was classified as T1a if ≤5 % of the HoLEP sample was tumorous and T1b if >5 % was tumorous. Prostate-specific antigen measurements were taken every 1 month in Pca, while 4 months in BPH. Median follow-up periods were 31.5 (14–59) months in Pca and 12.2 (4–54) months in BPH. The PSA-related factors were calculated only from the PSA values during no additional treatments after HoLEP in Pca patients. The mean PSA value and the number of the Pca patients we followed at 3, 12, or 24 months are 1.46 (n  = 25), 1.67 (n  = 25), and 2.14 (n  = 14), respectively. The lost follow-up was observed 4/25 (16 %) in Pca and 144/340 (42.3 %) in BPH, and there are no statistical differences between two groups (p = 0.089, Mann–Whitney U tests). PSA velocity was calculated based on the definition of Prostate-Specific

World J Urol (2015) 33:329–333 Table 1  Baseline characteristics and PSA-related factors in BPH and incidental prostate cancer

SD standard deviation * Significant differences between BPH and prostate cancer patients PSAD, PSA density; PSAV, PSA velocity by Wilcoxon’s rank sum test

331 Parameter

BPH

Prostate cancer

p value

No. patients Age Preoperative prostate volume (ml) Preoperative PSA (ng/ml) Preoperative PSAD (ng/ml/ml) Postoperative PSA (ng/ml) PSA reduction (%), SD Weight of resected tissue (g)

340 68 (49–85) 55.5 (15–230) 4.5 (0.43–34.08) 0.079 (0.0153–1.558) 0.75 (0.1–7.16) 83.2 (7.2–98.1), 18.94 30 (5–215)

25 70 (55–82) 47 (25–100) 7.14 (1.26–37.3) 0.155 (0.027–0.533) 1 (0.14–6.44) 83.2 (9.8–99.6), 19.47 20 (10–75)

0.138 0.0365* 0.0107* 0.0005* 0.206 0.962 0.0889

PSAV after HoLEP (ng/ml/year)

0.04 (−2.11 to 1.36)

0.22 (−0.9 to 1.85)

0.0033*

Table 2  PSA kinetics in Gleason score subgroup (a) and T categories (b) Gleason score

3 + 3

>3 + 4

p value

(a) No. patients Preoperative PSA (ng/ml) Postoperative PSA (ng/ml) PSA velocity after HoLEP (ng/ml/year)

20 6.06 (1.26–16.9) 1.06 (0.26–6.44) 0.185 (−0.9 to 1.09)

5 21.6 (4.95–37.3) 1 (0.14–2.12) 1.32 (−0.01 to 1.85)

0.019* 0.786 0.0382*

T stage

T1a

T1b

p value

(b) No. patients Preoperative PSA (ng/ml) Postoperative PSA (ng/ml)

17 5.87 (1.52–33.1) 1.22 (0.26–4.21)

8 8.69 (1.26–37.3) 0.8 (0.14–6.44)

0.19 0.884

PSA velocity after HoLEP (ng/ml/year)

0.21 (−0.9 to 1.09)

0.37 (−0.02 to 1.85)

0.232

(a) Significant difference between Gleason score 3 + 3 and > 3+4 group by Wilcoxon’s rank sum test (b) No significant difference between T1a and T1b group by Wilcoxon’s rank sum test

Antigen Working Group guidelines [7] using PC risk calculator (AstraZeneca Urology Japan) contains a software to calculate PSA velocity based on the date of sampling and PSA value. In short, date of sampling is put on the X-axis and PSA values are put on the Y-axis, then linear regression analysis was programmed automatically. The PSA velocity is estimated using the rate of change in 1 year based on the slope of the linear equation. The data were analyzed using Wilcoxon’s rank sum and Chi square tests using JMP version 9.0.2. A two-sided p value 3 + 3. Additional therapies for Pca were performed in four of the 20 patients with Gleason scores 3 + 3 and four of the five patients with Gleason scores >3 + 3. Treatment was initiated at the patient’s request, rather than the doctor’s recommendation, in three of the four 3 + 3 patients. There were significant differences in preoperative PSA (6.06 vs.

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21.6 ng/ml, p  = 0.0191) and postoperative PSA velocity (0.185 vs. 1.32 ng/ml/year, p = 0.0382) between the Gleason score 3 + 3 and >3 + 3 groups (Table 2a). Of the 25 patients with incidental Pca, 17 had T1a tumors (tumor in ≤5 % of resected prostate tissue) and eight patients had T1b tumors (tumor in >5 % of resected prostate tissue). There were no significant differences in preoperative PSA and postoperative PSA velocity between these two groups (Table 2b). As shown in Fig. 1, incidental Pca was detected in six out of 167 patients (3.6 %) with PSA levels ≤4 ng/ml and in 10 out of 126 patients (7.9 %) who had prostate biopsy and nine out of 72 patients (12.5 %) without prostate biopsy, both with PSA levels >4 ng/ml. There were significant differences in the detection rate of incidental Pca between the low PSA group (≤4 ng/ml) and the high PSA group (>4 ng/ml) (p  = 0.038, by χ2 analysis). However, there were no significant differences in the detection of incidental Pca between patients with and without prostate biopsy in the higher PSA subgroup (>4 ng/ml) (p = 0.457, by χ2 analysis). After the diagnosis of incidental Pca, the additional hormone therapy was performed in eight patients and radical prostatectomy was done in one patient. The other 16 patients chose active surveillance.

Discussion Prostate cancer incidentally detected in men undergoing transurethral resection of the prostate (TURP) for BPH has been decreasing over the past several decades. Before the introduction and use of PSA screening, unsuspected or occult malignancy was found in 30 % of TURP specimens [8]. Since the routine use of PSA screening and prostate biopsy, reports have shown a decreasing incidence of T1a and T1b prostate cancer, with detection rates of approximately 5.4 % after TURP [9]. However, Nunez et al. reported that the rate of incidental detection of prostate cancer after HoLEP was 11.7 %, double that of TURP (5.4 %) [5]. From a histopathological point of view, holmium laser enucleation with morcellation allows adequate histological evaluation without affecting the pathologist’s ability to detect incidental Pca and high-grade prostatic intraepithelial neoplasia, compared with standard TURP [10]. However, the detection rate in the present cohort was only 6.9 % (25/365). This low rate of incidental Pca detection may have been because preoperative biopsies were performed in 63.6 % of patients with PSA> 4 ng/ml in this study, while Nunez et al. [5] reported a prostate biopsy rate of only 44 %. The increased frequency of prostate biopsy may thus have reduced the detection rate of incidental Pca in our series.

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Declines in serum PSA are well known to occur after HoLEP, as well as after TURP. Tinmouth et al. [11] found that HoLEP produces a significant diminution in PSA that correlates well with the weight of adenoma resected in a study at 2 institutions—Methodist Hospital, Indiana, and McGill University Health Centre. The mean decrease in PSA was 81.7 % in the McGill group and 86 % in the Methodist Hospital group, which was compatible with our report, as described in 83.2 % both in BPH and Pca group (Table 1). While focused on the resected volume, Elmansy et al. [6] reported that preoperative prostate volume was 82 ml and resected volume is 44.4 g (54.1 %) in BPH patients. In our series, preoperative prostate volume was 55.5 ml and resected volume was 30 g (54.1 %) in BPH patients. The percentage of resected tissue was same between these two report; however, resected volume was small in our series. The other report from Japan [12] concerning to compare the photoselective vaporization of the prostate and TURP, and preoperative prostate volume was reported as 50.5 and 42.8 ml respectively. While, Hirasawa et al. [13] reported the comparison of transurethral enucleation with bipolar (TUEB) and transurethral resection in saline (TURis) for Japanese BPH Patients. They reported that the median preoperative prostate volume was 65.6 ml in TUEB and 55.7 ml in TURis 12. As these numbers are compatible with our data in this manuscript, it is possible that Japanese prostate volume may be smaller than that in Western countries in the surgical treatment for BPH. Elmansy et al. [6] reported that PSA reduction rate is significantly different between benign group (75.39 % ± 21.7) and malignant group (47.49 % ± 31.2) (p 3 + 4 group (1.32 ng/ml/year) compared with those with a Gleason score of 3 + 3 (0.185 ng/ml/year), though there was no significant difference between the T1a and T1b subgroups,

World J Urol (2015) 33:329–333

suggesting that PSA velocity depended on higher Gleason score, but not relative Pca volume (i.e., ≤5 or >5 %) in HoLEP specimens. Few studies have investigated PSA kinetics before and after HoLEP. Elmansy et al. [6] showed that PSA velocity at 1 and 3 years was higher in patients with Pca than in those without Pca (1.28 vs. 0.13 and 2.4 vs. 0.09, p