Case 2 -

Adenocarcinoma of the Prostate Mark A. Rubin Brigham and Women's Hospital Boston, Massachusetts

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Case History: P.J. is a 61 year old man, who during a recent routine medical check up was found to have a Prostate Specific Antigen (PSA) level of 5.4 ng./ml. (up from 3.5 ng./ml. from the previous yearly visit). The patient was in excellent physical health. He underwent sextant prostate needle biopsies by a local urologist, which revealed adenocarcinoma of the prostate, Gleason grade 7 (4+3=7) involving 4 of 6 biopsies from both sides. Endorectal MRI did not detect any evidence of extraprostatic extension or seminal vesicle involvement. He underwent a nerve sparing retropubic radical prostatectomy. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 This is a straightforward case from a clinical perspective. This H&E slide shows an adenocarcinoma of the prostate. The tumor has both typical invasive acinar and cribriform growth pattens. Case 2 - Figure 2 Immunohistochemistry confirms that the cribriform tumor represents intraductal tumor spread and not invasion. Case 2 - Figure 3 This is a straightforward case from a clinical perspective. This H&E slide shows an adenocarcinoma of the prostate. The tumor has both typical invasive acinar and cribriform growth pattens. Case 2 - Figure 4 Immunohistochemistry confirms that the cribriform tumor represents intraductal tumor spread and not invasion. Case 2 - Figure 5 This photomicrograph highlights prominent nucleoli and luminal secretions, both characteristics often found in prostate tumors and used as diagnostic features in prostate needle biopsies. Case 2 - Figure 6 Findings associated with more aggressive clinical course include Seminal vesicle invasion (slide 6) and extra-prostatic extension (slide 7). Case 2 - Figure 7 Findings associated with more aggressive clinical course include Seminal vesicle invasion (slide 6) and extra-prostatic extension (slide 7). Case 2 - Figure 8 FISH assay demonstrating ERG break apart on chromosome 21. Break apart of the ERG probes and loss of the green signal is characteristic of than TMPRSS2-ERG fusion prostate cancer. Gene fusion prostate cancers are believed to be more aggressive and have recently been found to be associated with a strong histologic phenotype including cribriform growth, blue-tinged mucin, and prominent nucleoli as seen in this case. Case 2 - Figure 9 FISH assay demonstrating ERG break apart on chromosome 21. Break apart of the ERG probes and loss of the green signal is characteristic of than TMPRSS2-ERG fusion prostate cancer. Gene fusion prostate cancers are believed to be more aggressive and have recently been found to be associated with a strong histologic phenotype including cribriform growth, blue-tinged mucin, and prominent nucleoli as seen in this case. Diagnosis: Adenocarcinoma of the prostate (2.2 cm), Gleason grade 8 (4+4=8), with focal extra-prostatic extension and invasion into both seminal vesicles. There is no cancer at any of the inked surgical margins. AJCC Stage: pT3b, N0, Mx. Additional molecular analysis (FISH) demonstrates that this tumor harbors the TMPSS2-ERG gene fusion. TMPRSS2-ETS Gene Fusion Prostate Cancer The recent identification of a common gene fusion in PCA was a surprising discovery [1] . 50-70% of PSA screened PCAs harbor a gene fusion between the prostate-specific, strongly androgen-regulated gene TMPRSS2 (21q22.3) and an ETS transcription family member, either ERG (21q22.2), ETV1 (7p21.2) or ETV4 (17q21) [1, 2, 3] . Since the original description, multiple groups from around the world have confirmed these findings that the TMPRSS2-ETS fusion in PCA is a common event [4, 5, 6, 7, 8, 9] . This fusion is detected in invasive PCA and in 20% of the precursor lesion high-grade prostatic intraepithelial neoplasia (PIN) [10] . Emerging data supports the view that this is a sub-type of PCA associated with a more aggressive clinical course and distinct morphologic features. Figure 1A-C. A. Using this multicolor FISH probe system, a nucleus without ERG rearrangement demonstrates two pairs of juxtaposed red and green signals. Juxtaposed red-green signals sometimes form a yellow fusion signal (B, arrow). A nucleus with an ERG rearrangement shows replacement of one juxtaposed red-green signal pair with a single red signal for the translocated allele). C. In a cumulative incidence regression model, we evaluated TMPRSS2-ERG as a determinant for the cumulative incidence or metastases or prostate cancer-specific death. We observed a significant difference in survival in favor of TMPRSS2-ERG gene fusion negative cases. The cumulative incidence ratio was 2.7, P < 0.01, 95%CI = 1.3 to 5.8). TMPRSS2-ERG gene fusion PCAs are significantly associated with a higher risk of disease progression [11]. In a recently published study on a population-based cohort of men with localized PCA diagnosed in a pre-PSA era and followed by expectant (watchful waiting) therapy, a significant association between TMPRSS2-ERG fusion and PCA specific death (cumulative incidence ratio = 2.7, P < 0.01, 95% confidence interval=1.3-5.8) were observed (Figure 1). These data suggest that TMPRSS2-ERG fusion PCA may have a more aggressive phenotype, possibly mediated through increased ERG expression. It is believed that ETS genes act as oncogenes. The presence of distinct morphologic phenotype associated with the TMPRSS2-ERG fusion PCA. In work that will be presented at the 2007 USCAP meeting, we explored gene fusion status of 253 PCA samples by FISH and significant associations with common morphological features. After logistic regression analysis five morphological features were independently associated with positive TMPRSS2-ERG fusion status: blue-tinged mucin, cribriform pattern, macronucleoli, intraductal tumor spread, and signet-ring cell-like features (Figure 2, table). In detail, 85% (n=23/27) of cases with blue-tinged mucin (Figure 2A and B), 68% (n=50/74) of cases with cribriform pattern (Figure 2C and D), 78% (n=39/50) of cases with macronucleoli, 88% (n=38/43) of cases with intraductal tumor spread, and 82% (n=9/11) of cases with signet-ring cell-like features were TMPRSS2-ERG fusion positive. These five morphologic features comprise the best model to predict TMPRSS2-ERG fusion status. In addition to some potentially useful clinical implications for diagnosis and risk assessment, the association between phenotype and TMPRSS2-ERG fusion suggest that there are molecular alterations associated with gene fusion PCA. This is the first time that a specific somatic alteration has been tied to phenotypic changes in PCA. Figure 2: H&E stains and corresponding FISH images of TMPRSS2-ERG fusion assay. A: PCA Gleason pattern 3 showing blue-tinged mucin. Note benign prostatic glands at 12 and 3 o'clock. B: FISH image of the red-boxed area in A. One yellow and one red signal are present in each nucleus, demonstrating the presence of TMPRSS2-ERG fusion through deletion. The double-framed yellow inset is a magnification of the yellow-boxed area, showing two representative nuclei of the PCA gland. C: PCA Gleason pattern 4 with cribriform appearance. D: FISH image of the red-boxed area in C. One yellow and one red signal are present in each nucleus, demonstrating the presence of TMPRSS2-ERG fusion through deletion. The double-framed yellow inset is a magnification of the yellow-boxed area showing two representative nuclei of the PCA area. Original magnification of H&E images, 20x objective. Original magnification of FISH images, 60x objective. (Mosquera et al., submitted) In summary, TMPRSS2-ETS gene fusion PCA is common and occurs early in the development of invasive PCA. Considering the high incidence of PCA and the high frequency of the fusion, TMPRSS2-ERG is the most frequent gene rearrangement described, although the exact frequency needs to be determined in population-based studies. The clinical utility as a tissue biomarker and diagnostic tool is promising given the high specificity. Emerging data suggest that gene fusion PCA demonstrate a distinct morphology and clinical course thus support its use as a prognostic biomarker and the fusion as an important candidate for the development of clinical therapy. Acknowledgments: A special thanks to Paula Abreau e Lima and Juan-Miguel Mosquera for identifying this case. References Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644-8 (2005). Tomlins, S. A. et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res 66, 3396-400 (2006). Perner, S. et al. TMPRSS2:ERG Fusion-Associated Deletions Provide Insight into the Heterogeneity of Prostate Cancer. Cancer Res 66, 8337-41 (2006). Yoshimoto, M. et al. Three-Color FISH Analysis of TMPRSS2/ERG Fusions in Prostate Cancer Indicates That Genomic Microdeletion of Chromosome 21 Is Associated with Rearrangement. Neoplasia 8, 465-9 (2006). Wang, J., Cai, Y., Ren, C. & Ittmann, M. Expression of Variant TMPRSS2/ERG Fusion Messenger RNAs Is Associated with Aggressive Prostate Cancer. Cancer Res 66, 8347-51 (2006). Soller, M. J. et al. Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer. Genes Chromosomes Cancer (2006). Liu, W. et al. Comprehensive assessment of DNA copy number alterations in human prostate cancers using Affymetrix 100K SNP mapping array. Genes Chromosomes Cancer (2006). Clark, J. et al. Diversity of TMPRSS2-ERG fusion transcripts in the human prostate. Oncogene (2006). Cerveira, N. et al. TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 8, 826-32 (2006). Perner, S. et al. TMPRSS2-ERG Fusion Prostate Cancer: an early molecular event associated with invasion.. Am J Surg Pathol (In Press). Demichelis, F. et al. TMPRSS2:ERG Gene Fusion Associated with Lethal Prostate Cancer. Oncogene (In Press).