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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 29  |  Issue : 3  |  Page : 161-165

Outcomes of prostate atypical small acinar proliferation and high-grade prostate intraepithelial neoplasm patients


Department of Urology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan

Date of Web Publication27-Jun-2018

Correspondence Address:
Chung-Hsin Chen
Department of Urology, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_52_18

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  Abstract 

Objective: Atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) are two pathological findings occasionally noted in prostate biopsies. Previous Western studies reported that they were associated with prostate cancer. However, none Taiwanese series report the subsequent cancer detection in ASAP and HGPIN patients. This study aimed to examine the results of repeated biopsies in the patients with ASAP and HGPIN. Materials and Methods: A total of 220 consecutive patients with ASAP and/or HGPIN at our institute between January 1990 and December 2010 were enrolled. Patient demographics and clinical information were extracted from the electronic database of our institute. Prostate biopsies were performed through transrectal ultrasound guidance. The patients who had concurrent prostate cancer (n = 51) and no repeated prostate biopsies (n = 103) were excluded from the study. Patients with biopsy pathologies reporting low-grade prostatic intraepithelial neoplasia (n = 2) were also excluded. The remaining 64 patients were available for the final analysis. Results: Nearly, 38, 24, and 2 patients were initially diagnosed as ASAP, HGPIN, and ASAP along with HGPIN, respectively. After 10 years of follow-up, 36.8% patients in ASAP group developed prostate cancer, while 16.7% in HGPIN group and 100% in ASAP + HGPIN group. Median time to developing prostate cancer were 20 months in ASAP group, 31 months in HGPIN group, and 48 months in ASAP + HGPIN group. There was no significant difference of prostate cancer development between ASAP and HGPIN group (P = 0.291). Only older age, classified by 65 years, was significantly associated with a higher detection rate of prostate cancer. Conclusion: Patients with the initial diagnosis of ASAP or PIN has a high risk of developing prostate cancer. Therefore, those patients should be well announced and followed regularly.

Keywords: Atypical small acinar proliferation, prostate cancer, prostate intraepithelial neoplasm


How to cite this article:
Tung SY, Pu YS, Huang CY, Chang HC, Huang KH, Wang SM, Tai HC, Chen CH. Outcomes of prostate atypical small acinar proliferation and high-grade prostate intraepithelial neoplasm patients. Urol Sci 2018;29:161-5

How to cite this URL:
Tung SY, Pu YS, Huang CY, Chang HC, Huang KH, Wang SM, Tai HC, Chen CH. Outcomes of prostate atypical small acinar proliferation and high-grade prostate intraepithelial neoplasm patients. Urol Sci [serial online] 2018 [cited 2018 Oct 20];29:161-5. Available from: http://www.e-urol-sci.com/text.asp?2018/29/3/161/232456


  Introduction Top


Prostate cancer is one of the most common neoplasms in elderly men. Prostate cancer cases increase rapidly in Taiwan recently, and the crude incidence of prostate cancer in Taiwan is about 40/100,000 person-year in 2011, which is still lower than that in American and European.[1],[2],[3]

Prostate cancer is suspected by several clinical observations, such as an elevated prostate-specific antigen (PSA), abnormal digital rectal examination (DRE) findings, and abnormal sonographic results. It was confirmed mostly by either transrectal ultrasound-guided biopsy of the prostate or transurethral resection of the prostate. Nevertheless, 10.5% of men have negative results for malignancy in the first prostate biopsy.[4] The indications of the repeated biopsy contain rising and/or persistently elevated PSA, suspicious DRE findings, and previous prostate biopsy reporting atypical small acinar proliferation (ASAP) or high-grade prostatic intraepithelial neoplasia (HGPIN).

In clinical practice, ASAP and HGPIN are two occasionally pathological findings which indicate potential malignancy. However, prostate cancer detection rate varied among studies. Previous literature revealed the risk of prostate cancer in the patients with ASAP and extensive HGPIN were about 40%[5] and 30%,[5],[6] respectively. Meanwhile, those with atypical glands immediately adjacent to HGPIN had prostate cancer risk of about 50%.[7]

Our study was designed to investigate the repeated biopsy results and the subsequent cancer detection rate of the patients who had ASAP and HGPIN reported in the first biopsy. The information of risk for prostate cancer in these patients would greatly facilitate the decision of further biopsy or follow-up protocol between physician and patients.


  Materials and Methods Top


Patient population and enrollment criteria

A total of 220 consecutive patients who underwent prostate biopsies reported as atypical glands, ASAP, and PIN at our institute between January 1990 and December 2010 was enrolled in this cohort [Figure 1]. This study was approved by the Research Ethics Committee of our institute. A total of 51 patients were excluded from the study because of concordant prostate cancer diagnosed by other biopsy cores. We also excluded 103 patients who never had repeated biopsies. Patients with biopsy pathologies reporting low-grade prostatic intraepithelial neoplasia (n = 2) were also excluded. Finally, a total of 64 patients remained in the analysis.
Figure 1: Flowchart of the study design

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Clinical data collection and outcome measurements

Patient demographics and clinical information were extracted from the electronic database of our hospital. Prostate biopsies were performed through transrectal ultrasound guidance and individually submitted according to the anatomic location. The indications for the first biopsy at our hospital included PSA of >4 ng/ml and abnormal DRE findings. Clinical factors triggering repeated biopsies contained rising and/or persistently elevated PSA, persistently abnormal DRE findings for malignancy, ASAP, and HGPIN.

Tumor grading and score were classified according to American Joint Committee on Cancer clinical grading; risk group classification was made according to the Epstein Criteria. ASAP is defined as a “focus of small acinar structures formed by atypical epithelial cells,” a condition in which the pathologist has insufficient data to make a diagnosis and thus raises the suspicion of cancer.[8] PIN is defined as “premalignant proliferation of atypical ductal and acinar cells.”[8]

Statistical methods

All analyses were performed with Excel 2016 (Microsoft, Washington) and SPSS 22 (IBM, New York, USA). Mann–Whitney signed t-tests were used for comparing medians between two groups. Pearson's Chi-square test, Fisher's exact test, or an exact binomial test was used for comparing proportions among groups. Two-sided P < 0.05 was considered statistical significance. Linear logistic regression analysis was performed for the univariable and multivariable analysis.


  Results Top


Patient demographics

In this cohort, 38 (59%) patients had the diagnosis of atypical glands/ASAP during the first biopsy (ASAP group), 24 (38%) patients had the diagnosis of HGPIN group;, and 2 (3.0%) patients had the diagnosis of ASAP along with HGPIN during the first biopsy (ASPA + HGPIN group). The three groups of patients did not differ in general demographics at initial atypical diagnosis including age, PSA, prostate volume, PSA density, and DRE finding [Table 1].
Table 1: Patient demographics at the first biopsy

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Among the 38 patients in the ASAP group, 35 had unilateral disease and 3 had bilateral disease. Among the 24 patients in the HGPIN group, 23 patients had unilateral disease and 1 had bilateral disease. Both patients in the ASAP + HGPIN group had bilateral disease.

Patient characteristics at the second biopsy

The change of PSA values between the first and second biopsy did not differ among groups. No statistically significant difference of PSA value at the second biopsy among ASAP and HGPIN groups was identified. All groups showed a wide intragroup diversity of the interval from the first to the second biopsy, and there was no significant intergroup difference among groups [Table 2].
Table 2: Patient demographics at the second biopsy

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Prostate cancer occurrence rates for patients with atypical small acinar proliferation/prostatic intraepithelial neoplasia

Patients not detected as developing prostate cancer during the follow-up period were shown in the prostate cancer-free survival curve [Figure 2]. During 5-year follow-up, 31.6% (12/38) patients in ASAP group, 12.5% (3/24) in HGPIN group, and 50% (1/2) in ASAP + HGPIN group had developed prostate cancer. When the follow-up duration extended to 10 years, 36.8% (14/38), 16.7% (4/24), and 100% (2/2) in ASAP, HGPIN, and ASAP + HGPIN groups, respectively, had prostate cancer.
Figure 2: Kaplan–Meier survival curve of prostate cancer-free survival

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Median time to developing prostate cancer were 20 months in ASAP group, 31 months in HGPIN group, and 48 months in ASAP + HGPIN group. ASAP group seemed to have a little higher chance of prostate cancer development than HGPIN group under Kaplan–Meier survival curve. However, there was no significant difference of prostate cancer development by log-rank test (P = 0.291).

Analysis for factors associated with the detection of prostate cancer

We analyzed candidate factors which might be associated with prostate cancer including initial biopsy results, age at the first biopsy, PSA value, PSA density, and DRE finding [Table 3]. Only older age, classified by 65 years, was significantly associated with a higher detection rate of prostate cancer in both univariable and multivariable analysis.
Table 3: Univariable and multivariable analyses for prostate cancer detection in the patients with ASAP or HGPIN

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Higher PSA value also predicted prostate cancer detection, but statistically insignificant. For the patients, who had PSA value of 50 ng/ml or more (n = 4) were finally diagnosed as prostate cancer. On the other hand, none of those with PSA of 4 ng/ml or less (n = 3) or PSA density of 0.15 or less (n = 8) were confirmed to have prostate cancer at the end of this study.

Among the patients who were diagnosed as prostate cancer finally (n = 20), 35% (n = 7) had tumor with Gleason score <7, 55% (n = 11) had tumor with Gleason score 7, and 10% (n = 2) had tumor with Gleason score >7; 80% (n = 16) had nonmetastatic disease.


  Discussion Top


This is the first article addressing following outcomes of patients with ASAP or PIN in Taiwan. The patients with initial ASAP or PIN has a high risk of prostate cancer diagnosed in the future.

Previous series revealed ASAP and PIN at the initial biopsy was associated with a significant risk of prostate cancer.[9],[10] Meanwhile, multifocal and bilateral disease are adverse features associated with high risk of prostate cancer among those patients with HGPIN.[6],[11] In this study, prostate cancer detection rates were 36.8% and 16.7% in ASAP and HGPIN groups, respectively, which was comparable to the previous series.

A large retrospective study (n = 1,525), reported by Adamczyk et al., concluded patients with either ASAP or extensive HGPIN should be subjected to urgent second biopsy within 4–6 weeks after the initial biopsy.[12] In this study, however, the interval between the first and second biopsies varied wildly among patients. In fact, about half of the patients did not receive the second biopsies after the initial diagnosis of either ASAP or PIN. It was likely due to lack of consensus before the establishment of current EAU guidelines recommending the need for the second biopsy. Therefore, it was impossible to avoid the variation of treatment offered by different physicians.

Kronz et al. reported that HGPIN with adjacent small atypical glands prostatic intraepithelial neoplasia with adjacent small atypical glands appeared to be a greater risk factor for prostate cancer than HGPIN alone.[7] In this study, two patients in ASAP + HGPIN group developed prostate cancer, but the interval between the initial and second biopsy differed largely (3 and 90 months).

A systematical biopsy was suggested by Mallén et al.for all the patients with a histological ASAP.[13] The rebiopsy strategy should increase the number of cores (or a saturation biopsy) over where ASAP areas were diagnosed in the initial biopsy and where the areas were possibly not sampled (anterior gland, distal apex, and midline).[14] In this study, increased biopsy cores or targeted biopsies at previous lesion sites or undersampled sites were conducted in most our patients.

Leone et al. revealed that 77% of ASAP or HGPIN patients were diagnosed as prostate cancer of Gleason score 3 + 3 = 6. Only 23% were found to have intermediate-risk disease and none of high-risk disease was identified.[10] Prostatic adenocarcinomas discovered after the initial diagnosis of HGPIN are more likely to be organ confined and pose similar grade compared with those diseases diagnosed at the first biopsy.[15] In this study, most of the patients detected at the second or more biopsies were clinically significant prostate cancer, indicating intervention rather than active surveillance should be done for them. The reason for the higher risk of significant prostate cancer in this study might possibly be due to a longer duration between the first and second biopsy and high PSA values compared with previous studies.[10],[12],[16] After the confirmation of prostate cancer in the patients who had ASAP or HGPIN initially in our cohort, most of them received prostate radiotherapy as primary definitive therapy.

Several limitations should be addressed in the current study. First, the data collection and analysis were limited by the nature of the retrospective design. The final decision when to perform repeat biopsy was made according to doctors' clinical judgment. Second, the small sample size impeded the extensive and powerful investigation for the search of predictive factors. Third, a wide review of all benign samples to identify the unreported ASAP or HGPIN was not conducted. This lead our study nested in the previous pathologists' inconsistent diagnosis of ASAP and HGPIN.


  Conclusion Top


Patients with the initial diagnosis of ASAP or HGPIN has a higher risk of prostate cancer in the future. Further, a prospective study including a larger population and multiple medical center cooperation should be conducted for confirmation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Health Promotion Administration Ministry of Health and Welfare. The Incidence of Prostate Cancer in Taiwan; 2011. Available from: http://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=269&pid=6520. [Last accessed on 2018 Mar 01].  Back to cited text no. 1
    
2.
UK Cancer Research. Prostate Cancer Statistics. Available from: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/prostate-cancer. [Last accessed on 2018 Mar 01].  Back to cited text no. 2
    
3.
Statistics Stomach Cancer. Cancer Stat Facts: Prostate Cancer. Available from: https://www.seer.cancer.gov/statfacts/html/prost.html. [Last accessed on 2018 Mar 01].  Back to cited text no. 3
    
4.
Leite KR, Camara-Lopes LH, Cury J, Dall'oglio MF, Sañudo A, Srougi M, et al. Prostate cancer detection at rebiopsy after an initial benign diagnosis: Results using sextant extended prostate biopsy. Clinics (Sao Paulo) 2008;63:339-42.  Back to cited text no. 4
    
5.
Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: Implications for patient care. J Urol 2006;175:820-34.  Back to cited text no. 5
    
6.
Lee MC, Moussa AS, Yu C, Kattan MW, Magi-Galluzzi C, Jones JS, et al. Multifocal high grade prostatic intraepithelial neoplasia is a risk factor for subsequent prostate cancer. J Urol 2010;184:1958-62.  Back to cited text no. 6
    
7.
Kronz JD, Shaikh AA, Epstein JI. High-grade prostatic intraepithelial neoplasia with adjacent small atypical glands on prostate biopsy. Hum Pathol 2001;32:389-95.  Back to cited text no. 7
    
8.
Koca O, Calışkan S, Oztürk Mİ, Güneş M, Karaman MI. Significance of atypical small acinar proliferation and high-grade prostatic intraepithelial neoplasia in prostate biopsy. Korean J Urol 2011;52:736-40.  Back to cited text no. 8
    
9.
Dorin RP, Wiener S, Harris CD, Wagner JR. Prostate atypia: Does repeat biopsy detect clinically significant prostate cancer? Prostate 2015;75:673-8.  Back to cited text no. 9
    
10.
Leone A, Rotker K, Butler C, Mega A, Li J, Amin A, et al. Atypical small acinar proliferation: Repeat biopsy and detection of high grade prostate cancer. Prostate Cancer 2015;2015:810159.  Back to cited text no. 10
    
11.
Bastarós J, Placer J, Celma A, Planas J, Morote J. Current significance of the finding of high grade prostatic intraepithelial neoplasia in the prostate biopsy. Actas Urol Esp 2014;38:270-5.  Back to cited text no. 11
    
12.
Adamczyk P, Wolski Z, Butkiewicz R, Nussbeutel J, Drewa T. Significance of atypical small acinar proliferation and extensive high-grade prostatic intraepithelial neoplasm in clinical practice. Cent European J Urol 2014;67:136-41.  Back to cited text no. 12
    
13.
Mallén E, Gil P, Sancho C, Jesús Gil M, Allepuz C, Borque A, et al. Atypical small acinar proliferation: Review of a series of 64 patients. Scand J Urol Nephrol 2006;40:272-5.  Back to cited text no. 13
    
14.
Leone L, Lacetera V, Montironi R, Cantoro U, Conti A, Sbrollini G, et al. Biopsy follow-up in patients with isolated atypical small acinar proliferation (ASAP) in prostate biopsy. Arch Ital Urol Androl 2014;86:332-5.  Back to cited text no. 14
    
15.
Al-Hussain TO, Epstein JI. Initial high-grade prostatic intraepithelial neoplasia with carcinoma on subsequent prostate needle biopsy: Findings at radical prostatectomy. Am J Surg Pathol 2011;35:1165-7.  Back to cited text no. 15
    
16.
De Nunzio C, Albisinni S, Cicione A, Gacci M, Leonardo C, Esperto F, et al. Widespread high grade prostatic intraepithelial neoplasia on biopsy predicts the risk of prostate cancer: A 12 months analysis after three consecutive prostate biopsies. Arch Ital Urol Androl 2013;85:59-64.  Back to cited text no. 16
    


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