Original Article

Prostate Cancer and Prostatic Diseases (2003) 6, 305–310. doi:10.1038/sj.pcan.4500681

Is low-grade prostatic intraepithelial neoplasia a risk factor for cancer?

L Goeman1, S Joniau1, D Ponette1, F Van der Aa1, T Roskams2, R Oyen3 and H Van Poppel1

  1. 1UZ Gasthuisberg, Department of Urology, Leuven, Belgium
  2. 2UZ Gasthuisberg, Department of Pathology, Leuven, Belgium
  3. 3UZ Gasthuisberg, Department of Radiology, Leuven, Belgium

Correspondence: S Joniau, UZ Leuven, Department of Urology, Herestraat 49, 3000 Leuven, Belgium. E-mail: steven.joniau@uz.kuleuven.ac.be

Received 9 September 2002; Revised 3 July 2003; Accepted 27 July 2003.

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Abstract

Introduction: High-grade prostatic intraepithelial neoplasia (HGPIN) is generally accepted to be a precursor lesion of prostate cancer. The likely outcome of isolated low-grade PIN (LGPIN) lesions in prostate biopsies remains unclear. A follow-up study of 106 patients with LGPIN- and HGPIN lesions was performed.

Materials and methods: In a 2-y period, 207 men were diagnosed with isolated PIN on standard systematic sextant biopsy of the prostate. In total, 104 patients had LGPIN and 103 had HGPIN. No patients had ever received androgen deprivation therapy, chemotherapy or radiation therapy. In all, 106 patients who underwent repeat second or third sextant biopsies were analysed in the study; 30% of these patients received a selenium–vitamin E supplement for at least 6 months.

Results: In total, 43 had LGPIN and 63 HGPIN on the first biopsy. The mean age was 63.5 y (range 46–77) in the LGPIN group and 64.9 y in the HGPIN group. The mean total PSA was 6.96 ng/ml (range 0.59–34.13) in the LGPIN group and 8.44 ng/ml (range 0.59–35.3) in the HGPIN group. In the LGPIN group, 30% of the patients had cancer in at least one of the repeat biopsy cores. In the HGPIN group, 27% had cancer in at least one of the repeat biopsy cores. The mean total PSA of patients who had cancer in repeat biopsies with LGPIN was 7.84 ng/ml (range 2.92–34.13). The mean total PSA of the patients who had cancer in repeat biopsy in the HGPIN was 6.73 ng/ml (range 0.56–25). There was no significant difference in PSA and pathological stage between those patients who did and those who did not receive selenium–vitamin E supplements.

Conclusions: These data are intriguing since the risk of finding prostate carcinoma on repeat sextant biopsy in the LGPIN group is 30%. This is higher than commonly reported. The importance of recognising and re-biopsying HGPIN was confirmed. If chemoprevention could be shown to be effective, it might be beneficial not only in HGPIN but also in LGPIN. The possible activity of chemopreventive agents and their combination with iso-flavonoids needs further investigation.

Keywords:

prostatic intraepithelial neoplasia, adenocarcinoma, chemoprevention

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Introduction

In the last decade there has been an increasing interest in the chemoprevention of prostate cancer. Adenocarcinoma of the prostate has a protracted course and may therefore be ideally suited for chemopreventive strategies.1,2,3,4 In this particular context, high-grade prostatic intraepithelial neoplasia (HPIN) is currently recognised to be the most likely precursor of invasive prostatic adenocarcinoma for clinical, epidemic logical, genetic, morphological and spatial reasons.5,6 HGPIN alone increased the risk 15-fold compared to those without HGPIN and provides the highest risk ratio in developing prostate cancer.

In 1965, Mc Neal emphasised the possible premalignant nature of proliferative changes in prostatic epithelium, but his description included a variety of morphological findings. Mc Neal and Bostwick7 first described reproducible diagnostic criteria for the recognition of what they referred to as 'intraductal neoplasia' in 1986. Initially, a three-step grading system was described. The following year, Bostwick and Brawer proposed the term prostatic intraepithelial neoplasia (PIN) as a replacement for 'intraductal neoplasia'. In 1989, at a workshop on prostate preneoplastic lesions sponsored by the American Cancer Society and National Cancer Institute, the previously designated grades 2 and 3 were grouped together to form a newly defined grade 2 (high-grade PIN). The previous grade 1 remained the same (low-grade PIN).

In PIN, the cytological abnormalities mimic those of the invasive carcinoma, but these are confined to the ductal and glandular components; the basal cell layer that is easily recognised on a 34-betaE12 staining remains present, although it may be disrupted6 (Table 1 and Figure 1). According to several authors, LGPIN is only a very early precursor, and might even not be considered a precancerous lesion. Moreover, the distinction between LGPIN and normal epithelium might be observer related.5,6,8

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Immunohistochemical staining of human prostatic tissues for Ki-67, 34-betaE12. (a) LGPIN (right arrow): the epithelium lining ducts and acini show 'tufting', crowding of nuclei and marked variation in the nuclear size. (b) The presence of the prominent nucleoli, often multiple, with a more pronounced cell crowding and stratification is typical for HGPIN (right arrow) (Ki 67). (c) HGPIN. Marked interruption of the basal layer is seen (34-betaE12 staining; red).

Full figure and legend (631K)


The primary aim of this study was to situate LGPIN and HGPIN as predictive factors in the development of prostate cancer and the secondary aim was to evaluate the possible chemopreventive effect of a short-term selenium–vitamin E supplement.

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Materials and methods

Between December 1998 and December 2000, 207 men were identified in our pathology database with isolated PIN in at least one of a minimum of six ultrasound-guided transrectal sextant biopsies of the prostate. Patients were excluded from the analysis if they had a previous diagnosis of prostate cancer, if they had received radiotherapy to the pelvis, chemotherapy or hormonal treatment. Ultrasound guidance was performed by diagnostic ultrasound equipment with a 7.5 MHz endfiring transducer. Biopsies were obtained with the patient in left lateral decubitus. An automatic spring-driven biopsy gun with an 18-gauge needle was used. Initial prostate biopsy was performed in accordance with the random systematic sextant biopsy technique, as described by Hodge et al, with two additional transition zone biopsies. In case of an abnormal digital rectal examination or transrectal ultrasound findings, additional biopsies were also directed to the suspect sites. Each core was individually labelled (namely the left apex, left mid, left base, right apex, right mid and right base) and collected in separate containers. All ultrasound studies were performed by one staff uroradiologist (RO). Prostate biopsies were performed because of elevated serum PSA (n=154), abnormal digital rectal examination (n=23) and/or abnormal transrectal ultrasound (n=87). PIN was classified as LGPIN or HGPIN strictly according to the criteria of Mc Neal and Bostwick7 (Table 1).

Initial biopsies revealed LGPIN in 104 patients and HGPIN in 103 patients. The analysis was however restricted to those 106 patients who underwent at least one repeat biopsy. These were taken 4–6 months after the first biopsies. Of these patients, 30% (13/43) in the LGPIN group and 40% (25/63) in the HGPIN group received a selenium–vitamin E supplement for at least 6 months (Selenium+Zinc®: selenomethionine 100 mug; zinc gluconate 15 mg; retinol 750 mug; pyridoxin 2 mg; ascorbin acid 90 mg; D-alpha-tocoferol 15 mg or Selenium-ACE®: selenium 100 mug; retinol 450 mug; vitamin C 90 mg and vitamin E 30 mg). No other dietary advice was given.

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Results

Of the 106 eligible patients, 43 had LGPIN and 63 had HGPIN on the initial biopsy. Mean age was 63.5 y (46–77) in the LGPIN group and 64.9 y (41–79) in the HGPIN group. The mean total PSA was 6.96 (range: 0.59–34.13) in the LGPIN group and 8.44 (range: 0.49–35.3) in the HGPIN group.

In the LGPIN group (n: 43), 13 patients (30%) had at least one of the repeat biopsy cores positive for cancer: 26% in the second biopsy and 4% in the third biopsy. In the HGPIN group (n: 63), 17 patients (27%) had cancer on the subsequent biopsy (Figure 2): 22% in the second biopsy and 5% in the third biopsy. The mean total PSA of the 12 patients who had cancer in repeat biopsies in the LGPIN group was 7.84 ng/ml (range: 2.92–34.13). The mean total PSA of the patients who had cancer in repeat biopsies in the HGPIN was 6.73 ng/ml (range 0.56–25). There was no significant difference in PSA and pathological outcome (chi2 test) between the group which did and the group which did not receive a selenium–vitamin E supplement (Table 2). The PSA level decreased in 70% of the men who took a selenium-vitamin E supplement but also in 63% of the men who did not. The mean PSA was 9.2 ng/ml before selenium intake and 5.77 ng/ml after treatment. In the control group, the mean PSA was 8.49 ng/ml at the beginning and 6.76 ng/ml at the end of the study.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Results of the second biopsy in men with PIN on initial prostate needle biopsy.

Full figure and legend (109K)


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Discussion

HGPIN is considered to be the most important precursor of prostate cancer. In our study, there was at least a comparable percentage of the LGPIN patients who had cancer on repeat biopsies. This is rather worrying since LGPIN is not considered to be a prostate cancer precursor. These data might however be endorsed by a recent report in which Fatty Acid Synthase (FAS) expression was analysed in snap-frozen prostate biopsies. Immunohistochemical staining for FAS was evident in LGPIN lesions, HGPIN lesions and invasive carcinomas. Benign and hyperplastic glandular structures showed no immunohistochemical reactivity.9 As it is well known that FAS is expressed early in the development of cancer, the finding that FAS is expressed in LGPIN could also mean that this condition might indeed be considered a precancerous lesion. Similar findings were made by staining with monoclonal antibodies against glycoprotein A-80; LGPIN and HGPIN stained positive in, respectively, 73 and 92% of cases.10

Several reports discussed the risk of finding carcinoma in repeat biopsies. They show remarkable differences (Table 3). The most likely reason is an interobserver variability when distinguishing normal histology, LGPIN, HGPIN and carcinoma. Indeed, HGPIN is recognised primarily by the presence of prominent nucleoli. There might be a difference when using various fixation methods; some fixatives give more nuclear prominence and nuclear detail. Furthermore, a pathologist with a lower threshold for interpreting nucleoli as prominent will see HGPIN more frequently. Especially in a medicolegal context, there is a tendency to describe routinely PIN as HGPIN in order to mitigate potential liability should adenocarcinoma be detected on subsequent biopsy.


The reason for initial biopsies was an elevated PSA in 74.4%, a suspicious digital rectal examination in 11.1% and LUTS in 14.5%.

In our department, HGPIN was found in 11.2% of all systematic core biopsies of the prostate carried out during the study period. This is in accordance with the reported data (between 0.7 and 24%).11 All specimens were examined and controlled by the same expert uropathologist (TR).

Differences in prostate biopsy sampling techniques can also explain the variations reported. Obtaining more needle biopsy cores per patient does lead to an increased likelihood of identifying HGPIN.1,4,5 Finally, potential differences among patient populations exist. Black men with a serum PSA of less than 4 ng/ml have been reported to have a higher incidence of HGPIN than white men in the same PSA region.

The largest studies published on this issue show a 27–35% risk of cancer on subsequent biopsies.1,12 These data are confirmed in our study (Table 3).

There is no consensus on how to improve the prediction of the risk of finding prostate cancer on repeat biopsy in men with HGPIN. The finding of HGPIN on core biopsy does not indicate a specific site at risk for synchronous occult prostatic carcinoma but instead indicates a higher likelihood of detecting occult carcinoma in any area of the prostate on repeat biopsy. Langer et al12 concluded that repeat prostate needle biopsy in men with HGPIN should include random repeat sextant biopsies of the prostate. Directing repeat biopsy solely to the area with PIN will miss cancer in approximately 35% of the cases.13,14

The timing of repeat biopsy has also been a subject of discussion. Recently, follow-up is suggested at 3- or 6-month intervals for 2 y and thereafter at 12-month intervals for life.15

When comparing different regions of the world, the incidence of prostate cancer in American and in West European males is similar: it exceeds 10% and is approaching near to 15% in African Americans.16 This differs largely from the incidence rates found in Asian societies: the risk of developing clinically significant prostate cancer is 30 times lower in Japanese men, and approximately 120 times less in men from Shangai, China.17,18 Mortality rates of prostate cancer show similar global tendencies.19,20,21 Asian men migrating to the United States have an increased risk to develop prostate cancer within one or two generations: rates multiply three to nine times in comparison to men who remain in their native country. These figures suggest that genetic differences are not the only factor involved. There is also an environmental influence in the development of clinical significant prostate cancer. Autopsy studies in men in their eight decade, dying of diseases other than prostate cancer, demonstrate a very high prevalence of foci of microscopic prostate cancer. The development of micro focal prostate cancer starts at the age of 30 y and is present in at least 30% of men over 50 y. This rate is more or less the same throughout the world and is not affected by race or origin.22,23,24,25

These data suggest that the diet consumed in Western societies may be one of the main environmental factors affecting progression from microscopic to clinically significant prostate cancer. The occidental diet is characterised by a high intake of energy, total fat and animal products (specifically milk, meat and poultry) and is positively linked to prostate cancer mortality. Traditional oriental cuisine uses more vegetables, cereals, soy, fruit, nuts and fish; there is a negative relationship to mortality from carcinoma of the prostate.26

Selenium is a trace element found in bread, cereals, fish and meat. It is an essential element in the functioning of glutathion peroxidase, which protects cellular molecules and DNA against oxidative stress.27 Selenium concentration in soils tends to be lower in geographical areas with a high cancer rate.28,29 The Health Professionals Follow Up study collected over 30 000 pieces of toenails for the measurement of long-term selenium plasma concentration. There was a strong inverse association between the prediagnostic selenium level assessed in toenails and the risk of advanced prostate cancer. The odds ratio was 0.35 for the high vs low selenium population.30 A prospective double-blind randomised trial by Clark et al demonstrated a statistically significant 50% reduction in total cancer mortality and a statistically significant 63% decrease in the incidence of prostate cancer in a group of men who received 200 mug of selenium daily vs placebo for 4.5 y. The only negative point of this study was that prostate cancer incidence was not a primary end point, since it was designed to reduce the incidence of skin carcinomas.31,32 Before routinely administrating exogenous selenium to prevent prostate cancer, data from the SELECT (Selenium and vitamin E Cancer prevention Trial) study should be awaited. This phase III, randomised, double-blind, placebo-controlled trial is designed to test the efficacy of selenium and vitamin E alone and in combination for preventing prostate cancer. It is a 2 times 2 design in which one-fourth of all participants will receive placebo, one-fourth 200 mug selenium, one-fourth will receive 400 mg vitamin E and the rest will receive both the drugs. A total of 32 400 men are planned for randomisation in SELECT. These results should become available by the year 2013.

Vitamin E is a major antioxidant acting on the level of membrane phospholipids. It is attributed with a wide range of antitumour properties. Several in vivo and in vitro cell lines from various human prostate cancers have been inhibited by vitamin E.33,34 The Health Professionals Follow Up Study pointed out that supplemental vitamin E does not affect prostate cancer incidence in an average population, but it provokes a 44% risk reduction of metastatic or fatal prostate cancer in current smokers.35 A Finnish randomised 2 times 2 intervention study was performed to assess the effect of vitamin E and beta-carotene on the incidence of lung cancer in nearly 3000 adult male smokers. Although neither of the substances caused a reduction in lung cancer, there were fewer cases of prostate cancer in the intervention group receiving 50 mg daily of vitamin E. At 6 y of follow-up, there was a statistically significant reduction of prostate cancer incidence and mortality of 32 and 41%, respectively.36

Additional data to clarify the role of vitamin E in the prevention of prostate cancer will also be provided by the SELECT study.

Unfortunately, dietary changes, such as decreasing fat intake and increasing fruit and vegetable intake, are difficult to initiate. Most men rather prefer to take a tablet to achieve vitamin supplementation.37,38 In the presented study, no significant difference in the incidence of cancer in the subsequent biopsy was shown in the group that was on selenium–vitamin E supplements (n: 38) compared to the group that was not (n: 68). However, it has to be stressed that our patient series are not randomised and a supplement was given for only 6 months.

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Conclusions

HGPIN on needle biopsy is recognised as a strong risk factor for prostate cancer on repeat biopsy. The risk percentages fluctuate between 27 and 79% in the literature. Based on the presented data of 106 men (PSA range between 0.5 and 35 ng/ml), the predictive value for prostate cancer on second or third subsequent biopsy is shown to be equal with both isolated LGPIN and HGPIN at sextant biopsies. For this reason, we think it is important that LGPIN is recognised and repeat biopsies are mandatory.

Even though some patients received a selenium–vitamin E supplement between biopsies, this did not appear to influence the pathological outcome or PSA.

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