Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications

Abstract

Purpose: More than 1,300,000 prostate needle biopsies are done annually in the United States with up to 16% incidence of isolated high-grade prostatic intraepithelial neoplasia (HGPIN). HGPIN has low predictive value for identifying prostate cancer on subsequent needle biopsies in prostate-specific antigen-screened populations. In contemporary series, prostate cancer is detected in approximately 20% of repeat biopsies following a diagnosis of HGPIN. Further, discrete histologic subtypes of HGPIN with clinical implication in management have not been characterized. The TMPRSS2-ERG gene fusion that has recently been described in prostate cancer has also been shown to occur in a subset of HGPIN. This may have significant clinical implications given that TMPRSS2-ERG fusion prostate cancer is associated with a more aggressive clinical course.

Experimental design: In this study, we assessed a series of HGPIN lesions and paired prostate cancer for the presence of TMPRSS2-ERG gene fusion.

Results: Fusion-positive HGPIN was observed in 16% of the 143 number of lesions, and in all instances, the matching cancer shared the same fusion pattern. Sixty percent of TMPRSS2-ERG fusion prostate cancer had fusion-negative HGPIN.

Conclusions: Given the more aggressive nature of TMPRSS2-ERG prostate cancer, the findings of this study raise the possibility that gene fusion-positive HGPIN lesions are harbingers of more aggressive disease. To date, pathologic, molecular, and clinical variables do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. Our results suggest that the detection of isolated TMPRSS2-ERG fusion HGPIN would improve the positive predictive value of finding TMPRSS2-ERG fusion prostate cancer in subsequent biopsies.

Figure 1. H&E stains and corresponding FISH images of TMPRSS2-ERG fusion assay

A: TMPRSS2-ERG fusion prostate cancer, Gleason grade 3+4=7. The inset picture shows a nucleus with one yellow and one red signal, demonstrating the presence of TMPRSS2-ERG fusion through deletion. B: Paired HGPIN lesion of prostate cancer in A. The HGPIN features tufting morphology. The inset picture shows a nucleus with two yellow signals, demonstrating absence of genetic aberration. C: TMPRSS2-ERG fusion prostate cancer, Gleason grade 4+4=8. The prostatectomy on this case showed predominant cribriform morphology. The inset picture shows a nucleus with one yellow and one red signal, demonstrating the presence of TMPRSS2-ERG fusion through deletion. D: Paired HGPIN lesion of prostate cancer in C. The HGPIN features tufting and micropapillary morphology. The inset picture shows a nucleus with the same pattern as the matching prostate cancer, demonstrating the presence of TMPRSS2-ERG fusion. Original magnification of H&E images, 20× objective. Original magnification of FISH images, 60× objective.

Figure 2. H&E stain and corresponding FISH image of TMPRSS2-ERG fusion assay

A: HGPIN lesion with adjacent atypical small acinar proliferation. This may represent either outpouching area or tangential section of HGPIN, or true early invasive adenocarcinoma. The red arrow points this area. The inset picture shows a nucleus with one yellow and one red signal, demonstrating the presence of TMPRSS2-ERG fusion through deletion. Original magnification of H&E images, 20× objective. Original magnification of FISH images, 60× objective. B: HGPIN and normal prostatic epithelium in the same gland. Red and green arrows point representative areas of HGPIN and normal prostatic epithelium, respectively. The inset pictures show a nucleus of normal epithelium with juxtaposed red-green signal pair (upper left), and a nucleus of HGPIN with one yellow and one red signal, demonstrating TMPRSS2-ERG fusion through deletion (lower right). The surrounding prostatic cancer, mostly Gleason pattern 4, also shared the same gene fusion pattern. Original magnification of H&E images, 20× objective. Original magnification of FISH images, 60× objective.