Elsevier

Human Pathology

Volume 44, Issue 12, December 2013, Pages 2727-2735
Human Pathology

Original contribution
Heterogeneity of ERG expression in core needle biopsies of patients with early prostate cancer,☆☆

https://doi.org/10.1016/j.humpath.2013.07.019Get rights and content

Summary

Prostate cancer is a heterogeneous, frequently multifocal disease with a broad spectrum of clinical, pathologic, and molecular characteristics. The TMPRSS2-ERG gene rearrangement is highly specific for prostate cancer. We used immunohistochemistry as a surrogate marker of the TMPRSS2-ERG fusion to study the heterogeneity of ERG expression in 280 prostate core needle biopsy series from 256 patients with early prostate cancer defined as 3 or less positive cores with no more than 50% of cancer per biopsy and a Gleason score of 7 or lower (3 + 4). Among the 163 patients with 2 or 3 cancer-positive biopsies, we found a subset of 19 patients (11.7%) with heterogeneous ERG expression. Thirteen (68.4%) of these patients showed biopsies with distinct positive and negative ERG staining in separate cores. The remaining 6 patients showed a mixture of both positive and negative staining within 1 biopsy core. This was either caused by different cancer foci (n = 3) or by one single, ERG-heterogeneous cancer focus (n = 3) in 1 core. Furthermore, we observed a heterogeneous ERG staining pattern over time in 6 (2.3%) of the 256 patients, in biopsies taken at various time points. An interobserver study of 21 cases with 2 separate cancer foci revealed that heterogeneity of ERG status in different cancer foci can be suspected based on morphologic differences (κ = 0.44). We conclude that heterogeneity of ERG expression is detectable in 10% to 15% of core biopsies of early prostate cancer. Further studies are needed to explore the clinical impact of heterogeneous ERG status in this patient group.

Introduction

Prostate cancer is the second leading cause of cancer-related deaths among men in the United States [1]. Most prostate cancers will not progress and do not need any treatment. On the other hand, a minority of prostate cancers grows, spreads, and becomes life-threatening. Unfortunately, it remains difficult to distinguish between these 2 types of disease on the basis of clinical, morphologic, and pathologic parameters alone. Active surveillance is an attractive and increasingly popular approach to the management of patients with early prostate cancer because it aims at minimizing overtreatment [2]. However, new biomarkers are needed to better select patients for either active surveillance or definitive treatment.

Novel biomarkers for approximately half of clinically localized prostate cancers are translocations involving members of the ETS oncogene family [3]. Among these translocations, the TMPRSS2-ERG gene rearrangement appears to be the most common event in prostate cancer [4]. It is highly specific for prostate cancer because it is not observed in benign or hyperplastic prostatic epithelium [5]. Although the general clinical impact of the ERG status remains controversial, it seems that there is no association between ERG status and tumor phenotype or prognosis as shown in radical prostatectomy specimens [6], [7], [8], [9], [10].

Several studies have pointed to a considerable heterogeneity of the TMPRSS2-ERG rearrangement status in prostate cancer, especially in advanced multifocal prostate cancer [6], [7], [8], [10]. The availability of a reliable immunohistochemical assay for identifying ERG-rearranged prostate cancer provides a new opportunity for studying clonal heterogeneity that goes beyond the well-known morphologic heterogeneity in prostate cancer. We hypothesized that such clonal heterogeneity might particularly impact biopsies from patients with early prostate cancer qualifying for active surveillance and having 2 or 3 cancer foci. A concordant ERG status in 2 cancer foci suggests that they are clonally related and that they have been sampled from the same tumor. Assuming that approximately 50% of prostate cancers are ERG positive [6], [8], [9], [11], [12], the probability that 2 cancer foci with the same ERG status belong to the same clonal tumor cell population is 75%, whereas 25% of them may be clonally independent. In contrast, a discordant ERG status is in favor of 2 clonally independent tumors with a probability of 75%.

Given a certain cancer volume within a prostate, it is currently unknown if a tumor consisting of 1 dominant clonal population has another prognosis than the sum of 2 clonally unrelated tumors, each one being smaller than a single tumor of one clonal origin. However, one can hypothesize that hitting 2 foci of the same tumor in 2 biopsies points toward a high probability that these foci are actually part of a relatively large tumor that has been undersampled by the biopsies (Fig. 1). In contrast, 2 clonally independent cancer foci are likely to be from 2 small cancer areas with separate clonal origin. Thus, a discordant ERG status could be a factor in favor of active surveillance.

To this end, we analyzed ERG protein expression in a large cohort of prostate core needle biopsies from patients meeting the criteria that have been used to select patients for active surveillance. We discovered different patterns of ERG heterogeneity that occur in a proportion of early prostate cancers diagnosed in prostate core needle biopsies pointing to clonally independent tumor foci within the prostate. The major goal of this study was to explore the prevalence of ERG heterogeneity in biopsies of early prostate cancer as a basis for further studies on its clinical impact.

Section snippets

Selection of study population and clinical data

After approval by the Ethics Review Board Basel (EKBB No. 70/13), a total of 280 series of prostate core needle biopsies with prostate cancer diagnosed between January 2007 and January 2012, with at least 8 cores per series, of 256 patients were chosen from 4 different institutions including the Institute for Pathology Liestal (n = 113), the Institute for Pathology of the University Hospital Basel (n = 57), the Institute for Histological Diagnostics Aarau (n = 73), and the Department of

Results

Prostate needle biopsies from 256 patients were analyzed (Table 1). When taking the most recent biopsies into account for each of the 20 patients with more than 1 biopsy series (16 patients with 2 biopsy series, 4 patients with 3 biopsy series; Table 1), 127 (49.6%) of the 256 patients showed homogeneous ERG expression, 109 (42.6%) were homogeneously ERG negative and 20 patients (7.8%) had a heterogeneous ERG status in their biopsies. When analyzing the most recent biopsies of the subset of 163

Discussion

Tumor heterogeneity is notorious in prostate cancer and represents a significant problem for cancer therapy [18], [19], [20], [21], [22]. To provide insight into tumor origin and the molecular basis of advanced multifocal prostate cancer, the relevance of TMPRSS2-ERG gene rearrangement heterogeneity was addressed in several previous studies. These studies have reported remarkable heterogeneity of the TMPRSS2-ERG gene fusion status between multiple tumor foci in up to 70% of TMPRSS2-ERG–positive

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  • Cited by (17)

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    Conflict of interest: The authors state no conflict of interest.

    ☆☆

    This project was supported by a grant from the “Krebsliga beider Basel” (Basel, Switzerland; Grant No. 16-2012).

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