Original contributionHeterogeneity of PTEN and ERG expression in prostate cancer on core needle biopsies: implications for cancer risk stratification and biomarker sampling☆
Introduction
Prostate cancer (PCa) is widely recognized as being a clinically and histologically heterogeneous disease [1], [2], [3], [4]. The clinical and histologic heterogeneity of PCa typically stems from the multifocal nature of the disease, generally consisting of a dominant (Index) tumor focus and one or more separate smaller tumors [3], [5], [6]. The current approach to stratify risk for PCa patients at the time of diagnosis relies heavily on the highest tumor grade assigned on the needle biopsy tumor core along with other clinical parameters [7]. Arora et al showed that of 115 PCa prostatectomy specimens, 87% (100) contained 2 or more widely separated tumors and only 9% of multifocal PCas had all tumor foci with primary and secondary Gleason grades that were same as the corresponding overall grades assigned to the whole specimen [8]. This heterogeneity along with sampling errors inherent in needle biopsies limits the accuracy of risk stratification models for PCa, resulting in potential under- or overtreatment.
Genomic rearrangements leading to the formation of TMPRSS2-ETS gene fusions and deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene are 2 of the most frequent somatic genetic alterations observed in prostate cancer [9], [10], [11], [12], [13], [14]. The TMPRSS2-ERG gene fusion is present in approximately half of all adenocarcinomas [15], [16], [17]. Rearrangements of ERG at the chromosomal level are generally found to be specific to neoplastic prostatic lesions (eg, adenocarcinoma or high-grade prostatic intraepithelial neoplasia (HGPIN) near an ERG-positive carcinoma), and are nearly undetectable in benign prostate tissue, or benign cancer mimics [18], [19], [20]. Taken together, ERG gene fusions are the most prostate cancer–specific biomarker yet identified and define a specific molecular subtype of PCa, potentially with implications for diagnosis and disease management. While there seems to be little utility of ERG oncoprotein as a prognostic marker by itself [21], molecular-based knowledge about ERG gene fusion status may help in at least 3 different scenarios. First, ERG may help in resolving an “atypical glands suspicious for cancer” diagnosis in prostate biopsies beyond that provided by basal cell and alpha-methylacyl-CoA-racemase markers since ERG-positive small atypical glands where the diagnosis of HGPIN is excluded strongly support the diagnosis of adenocarcinoma of the prostate [18], [19], [20]. Second, since individual tumor foci are generally either homogeneously positive or homogeneously negative for ERG in wholly submitted radical prostatectomy specimens [3], [10], [11], [22], if there is more than one pattern of ERG expression in a set of prostate biopsies then this can be used as strong evidence to indicate the presence of more than one clone of cancer [23]. Such information may be useful clinically in the management of patients who are candidates for active surveillance or focal therapy [24]. Third, it is possible that ERG status may help to determine overall sensitivity to specific systemic therapies for patients in which cancer either recurs after local therapy or that are not eligible for local therapies [25]. Thus, it is anticipated that knowledge of the ERG status and heterogeneity of a positive prostate biopsy may ultimately become an important feature of the pathology report for prostate cancer patients.
Work over the last decade has firmly established that loss of PTEN is one of the most common somatic genetic aberrations in prostate cancer and is frequently associated with high-risk disease [9], [14]. Deletion or mutation of at least one PTEN allele was reported to occur in 20%-40% of localized PCas and up to 60% of metastases [9], [14], [26]. Several studies have demonstrated that PTEN inactivation is consistently associated with a variety of different adverse pathologic outcomes including metastasis and disease- specific death [26], [27], [28], [29], [30], [31], [32]. Further, in recent studies of prostate needle biopsies using immunohistochemistry (IHC) for PTEN, Mithal et al [33], found that PTEN loss was predictive of poor clinical outcome, and Lotan et al [34], found that PTEN loss was associated with upgrading at radical prostatectomy. Thus, PTEN loss on prostate needle biopsy may become a useful marker to help, along with other clinical and pathological features, stratify patients into different risk groups prior to definitive therapy.
While ERG is generally homogeneous in a given lesion in prostatectomy specimens, a number of groups have shown that PTEN loss by IHC and flourescence in situ hybridization (FISH) is generally heterogeneous within a given tumor focus, even if that focus is uniformly ERG positive [35], [36], [37]. Thus, given the multifocal nature of prostate cancer and the subclonal heterogeneity of PTEN loss, the optimal strategy for assessing the status of these markers on needle biopsies when more than one core is positive for cancer is currently unknown. To this end, we evaluated PTEN and ERG expression in a large needle biopsy cohort containing >1 PCa cores in which we interrogated these markers by IHC in all positive cores. While both ERG and PTEN alterations occur at the genomic level, ERG and PTEN IHC has been shown to be a sensitive and specific approach to detect these underlying genetic abnormalities [18], [26], [38], [39], [40]. Given that IHC is much more readily performed in the workflow of anatomic pathology laboratories, is less expensive, and is easier for pathologists to assess, we used IHC for these assays.
Section snippets
Study population and biopsy characteristics
The study included 194 consecutively selected prostate needle biopsy specimens containing cancer on more than one core. All biopsies were performed from 2010 to 2013 and were sent to Miraca Life Sciences, and an institutional review board approved the study. A standard 10 or 12-core extended biopsy protocol with site-specific submission was routinely utilized.
Preoperative biopsy characteristics analyzed included the number of biopsy cores, the number of positive cores and % involvement of
Biopsy characteristics
The biopsy characteristics of the 194 PCa cases are summarized in Table 1. The biopsy characteristics were expressed as mean values and included the number of submitted biopsy cores (mean 8; range, 6-16), the number of positive biopsy cores (mean 6; range, 2-16), the percentage of tumor involvement of biopsy cores by PCa (mean 34%; range: 1.5%-100%). The range and distribution of Gleason score based on the highest Gleason score of prostate cancer case are summarized in Table 1. Ninety-eight
Discussion
As ERG and PTEN are increasingly utilized for the diagnosis and/or PCa risk stratification, it is critical to understand the pattern of heterogeneity for these biomarkers in the needle biopsy setting. To our knowledge this is the first study which systematically examines heterogeneity of either ERG or PTEN status in the setting of NBXs and assesses its implications in PCa risk stratification and sampling strategies. Since both ERG and PTEN status demonstrated high inter-tumor core, and PTEN
Acknowledgments
The authors would like to thank Tamara L. Lotan, MD, for careful reading and suggestions for the manuscript and Suzanne Ridner for editorial assistance. Dr De Marzo is the recipient of the Virginia and Warren Schwerin Scholar Award from the Patrick C. Walsh Prostate Cancer Research Fund.
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Disclosure/conflict of interest: Authors have no conflict of interest or funding disclosure to report related to this work.