Faculty Bibliography

OBJECTIVE: The purpose of this study was to evaluate the utility of multiparametric MRI in localization of the index lesion of prostate cancer. MATERIALS AND METHODS: Fifty-one patients who underwent 3-T MRI of the prostate with a pelvic phased-array coil that included T2-weighted, diffusion-weighted, and dynamic contrast-enhanced sequences before prostatectomy were included. Six radiologists assessed all images to identify the lesion most suspicious of being the index lesion, which was localized to one of 18 regions. A uropathologist using the same 18-region scheme reviewed the prostatectomy slides to localize the index lesion. MRI performance was assessed by requiring either an exact match or an approximate match (discrepancy of up to one region) between the MRI and pathologic findings in terms of assigned region. RESULTS: The pathologist identified an index lesion in 49 of 51 patients. In exact-match analysis, the average sensitivity was 60.2% (range, 51.0-63.3%), and the average positive predictive value (PPV) was 65.3% (range, 61.2-69.4%). In approximate-match analysis, the average sensitivity was 75.9% (range, 65.3-69.6%), and the average PPV was 82.6% (range, 79.2-91.4%). The sensitivity was higher for index lesions with a Gleason score greater than 6 in exact-match (74.8% vs 15.3%, p < 0.001) and approximate-match (88.7% vs 36.1%, p = < 0.001) analyses and for index lesions measuring at least 1 cm in approximate-match analysis (80.3% vs 58.3%, p = 0.016). In exact-match analysis, 30.0%, 44.9%, and 79.1% of abnormalities found with one, two, and three MRI parameters represented the index lesion (p < 0.001). CONCLUSION: The sensitivity and PPV of multiparametric MRI for index lesion localization were moderate, although they improved in the setting of more aggressive pathologic features and a greater number of abnormal MRI parameters, respectively.

In prostate cancer, the signals that drive cell proliferation change as tumors progress from castration-sensitive (androgen-dominant) to castration-resistant states. While the mechanisms underlying this change remain uncertain, characterization of common signaling components that regulate both stages of prostate cancer proliferation is important for developing effective treatment strategies. Here, we demonstrate that paxillin, a known cytoplasmic adaptor protein, regulates both androgen- and EGF-induced nuclear signaling. We show that androgen and EGF promoted MAPK-dependent phosphorylation of paxillin, resulting in nuclear translocation of paxillin. We found nuclear paxillin could then associate with androgen-stimulated androgen receptor (AR). This complex bound AR-sensitive promoters, retaining AR within the nucleus and regulating AR-mediated transcription. Nuclear paxillin also complexed with ERK and ELK1, mediating c-FOS and cyclin D1 expression; this was followed by proliferation. Thus, paxillin is a liaison between extranuclear MAPK signaling and nuclear transcription in response to androgens and growth factors, making it a potential regulator of both castration-sensitive and castration-resistant prostate cancer. Accordingly, paxillin was required for normal growth of human prostate cancer cell xenografts, and its expression was elevated in human prostate cancer tissue microarrays. Paxillin is therefore a potential biomarker for prostate cancer proliferation and a possible therapeutic target for prostate cancer treatment.

Deng F-M, Mendrinos S E, Das K & Melamed J (2012) Histopathology 60, 1004-1008 Periprostatic lymph node metastasis in prostate cancer and its clinical significance Aims: To evaluate the potential of periprostatic lymph node (LN) as a staging indicator, particularly with the use of methods for enhanced detection of micrometastasis. Methods and results: We retrieved cases with periprostatic LN from radical prostatectomy specimens accrued between 1997 and 2007 at our institution. Twenty-one (0.8%) of 2663 radical prostatectomy specimens had periprostatic LNs (total number of LNs = 22). LN size ranged from 0.8 to 4.7 mm. Most of the periprostatic LNs were located close to the posterior base. Seven (32%) of 22 LNs were involved by metastatic prostate cancer (PCa), including five detected on routine haematoxylin and ceosin slides and an additional two detected only by immunohistochemistry. Cases with periprostatic LNs had a significantly higher metastatic rate (29%; six of 21) compared to those with pelvic LNs sampled at radical prostectatomy in our institution (1.9%). When compared to cases with negative periprostatic LNs (n = 15), the tumour characteristics of cases with metastatic periprostatic LNs (n = 6) included higher tumour volume, Gleason score, stage and a greater propensity for prostate-specific antigen (PSA) recurrence. Conclusions: Despite their infrequent identification, periprostatic LNs if detected in the radical prostatectomy specimen should be evaluated with greater scrutiny (step sections and/or immunohistochemical studies) to evaluate their prognostic potential.

Each histologic type of renal cell carcinoma (RCC) has different pathologic and clinical parameters; however, the independent role of histologic type in outcome prediction remains contested. Most studies show relevance for outcome of each histologic type when correlated with survival by univariate analysis, whereas few studies show differences in outcome once other key prognostic factors, such as stage and grade, are considered. These studies highlight the challenges to prove outcome relevance. Despite the contested independent value of type for outcome prediction, separation of RCC into types is well accepted and can be substantiated on clinical, pathologic, molecular, and general outcome differences.

We report a soft tissue sarcoma from the thigh with morphologic features resembling Ewing sarcoma, clear cell sarcoma, and myoepithelial tumor of soft tissue. In addition, the genetic and immunohistochemical findings do not correspond to any established pattern, so the tumor does not clearly fit into any one classification. The karyotype analysis revealed a rare chromosomal rearrangement, t(6;22)(p22;q12), that previously has been reported in bone and epithelial tumors. Molecular studies confirmed the presence of an EWSR1-POU5F1 fusion creating a chimeric gene with the N-terminal transcriptional activation domain of EWSR1 and the C-terminal POU DNA binding domain of POU5F1. This report is novel in that to our knowledge, it is the first complete molecular characterization of an EWSR1-POU5F1 fusion in a soft tissue sarcoma. Evaluation of existing data on the known EWSR1-POU5F1 tumors suggests that the fusion gene functions in a wide variety of cell types and may modify the differentiation state of cells, resulting in susceptibility to tumorigenesis.

TMPRSS2 gene fusions with ETS transcription factor family members ERG, ETV1, or ETV4 have been recently discovered as a common molecular event in prostate cancer. Much attention has been focused on exploring their clinical application as a genetic tumor marker for the diagnosis, prognosis, and prediction of response to therapy. Although several studies have been done, the clinical utility of TMPRSS2 genetic alterations as biomarkers for prostate carcinoma remains indeterminate. In this study, we examined adenocarcinomas, prostatic intraepithelial neoplasia (PIN), and normal epithelium of the prostate retrieved from radical prostatectomy specimens to determine the frequency, specificity, tissue heterogeneity, and prognostic value of TMPRSS2 genetic alterations using a direct-labeled TMPRSS2 dual-color break-apart fluorescence in situ hybridization (FISH) probe cocktail designed to detect all known TMPRSS2-associated deletions or translocations. Seventy-one patients (161 samples) with normal prostate tissue, 60 patients (153 samples) with PIN, and 61 patients (142 samples) with carcinoma in formalin-fixed paraffin-embedded tissue microarrays were tested. None of the 161 normal prostate samples showed TMPRSS2 translocation or deletion. Sixty-two percent patients of prostate carcinomas demonstrated TMPRSS2 gene alterations, including 39% with translocation, 16% with deletion, and 7% with a mixed pattern. Tissue heterogeneity for TMPRSS2 gene alterations was identified in 28% of prostate carcinomas. No difference in the frequency of TMPRSS2 gene alterations was found between Gleason 6 and 7 tumors. Seventeen percent of PIN had TMPRSS2 gene alterations and showed the same FISH patterns as in the carcinomas from respective prostatectomy specimens. The TMPRSS2 dual-color break-apart FISH probe cocktail provides a simple and reliable method for the detection of TMPRSS2-related genetic alterations in formalin-fixed paraffin-embedded tissue. TMPRSS2 genetic alterations detectable by this method are strictly restricted in prostate neoplasia, and can be identified in the majority of prostate carcinomas. Tissue heterogeneity for TMPRSS2 alterations is common, and it should be considered when sampling and evaluating biopsy specimens.