Faculty Bibliography

The microRNA-34a (miR-34a), a tumor suppressive microRNA (miRNA), is implicated in epithelial-mesenchymal transition (EMT) and cancer stem cells. Lymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor in the Wnt signaling pathway, and has been suggested to be involved in regulation of cell proliferation and invasion. Here, the molecular mechanism of miR-34a and LEF1 in cooperatively regulating prostate cancer (PCa) cell invasion is described. Molecular profiling analysis of miRNA levels in PCa cells revealed a negative correlation between miR-34a and LEF1 expression, and the downregulation of LEF1 by miR-34a was confirmed by luciferase assays. Further, miR-34a specifically repressed LEF1 expression through direct binding to its 3'-untranslated (3'-UTR) regions. miR-34a modulated the levels of LEF1 to regulate EMT in PCa cells. Functionally, miR-34a negatively correlated with the migration and invasion of PCa cells through LEF1. An analysis of miR-34a expression levels in matched human tumor and benign tissues demonstrated consistent and statistically significant downregulation of miR-34a in primary prostate cancer specimens. These data strongly suggest that miR-34a/LEF1 regulation of EMT plays an important role in PCa migration and invasion. Implications: The miR-34a/LEF1 axis represents a potential molecular target for novel therapeutic strategies in PCa.

PURPOSE: To retrospectively assess the utility of whole-lesion apparent diffusion coefficient (ADC) metrics in characterizing the Gleason 4 component of Gleason 7 prostate cancer (PCa) at radical prostatectomy. MATERIALS AND METHODS: Seventy patients underwent phased-array coil 3T-magnetic resonance imaging (MRI) before prostatectomy. A uropathologist mapped locations and Gleason 4 percentage (G4%) of Gleason 7 tumors. Two radiologists independently reviewed ADC maps, aware of tumor locations but not G4%, and placed a volume-of-interest (VOI) on all slices including each lesion on the ADC map to obtain whole-lesion mean ADC and ADC entropy. Entropy reflects textural variation and increases with greater macroscopic heterogeneity. Performance for characterizing Gleason 7 tumors was assessed with mixed-model analysis of variance (ANOVA) and logistic regression. RESULTS: Among 84 Gleason 7 tumors (G4% 5%-85%, median 30%; 59 Gleason 3+4, 25 Gleason 4+3), ADC entropy was significantly higher in Gleason 4+3 than Gleason 3+4 tumors (R1: 5.27 +/- 0.61 vs. 4.62 +/- 0.78, P = 0.001; R2: 5.91 +/- 0.32 vs. 5.57 +/- 0.56, P = 0.004); mean ADC was not significantly different between these groups (R1: 0.90 +/- 0.15*10-3 cm2 /s vs. 0.98 +/- 0.21*10-3 cm2 /s, P = 0.075; R2: 1.06 +/- 0.19*10-3 cm2 /s vs. 1.14 +/- 0.16*10-3 cm2 /s, P = 0.083). The area under the receiver operating characteristic (ROC) curve (AUC) for differentiating groups was significantly higher with ADC entropy than mean ADC for one observer (R1: 0.74 vs. 0.57, P = 0.027; R2: 0.69 vs. 0.61, P = 0.329). For R1, correlation with G4% was moderate for ADC entropy (r = 0.45) and weak for mean ADC (r = -0.25). For R2, correlation with G4% was moderate for ADC entropy (r = 0.41) and mean ADC (r = -0.32). For both readers, ADC entropy (P = 0.028-0.003), but not mean ADC (P = 0.384-0.854), was a significant independent predictor of G4%. CONCLUSION: Whole-lesion ADC entropy outperformed mean ADC in characterizing Gleason 7 tumors and may help refine prognosis for this heterogeneous PCa subset. J. Magn. Reson. Imaging 2014. (c) 2014 Wiley Periodicals, Inc.

PURPOSE: To report design of a simplified external transmit-receive coil array for 7 Tesla (T) prostate MRI, including demonstration of the array for tumor localization using T2-weighted imaging (T2WI) at 7T before prostatectomy. MATERIALS AND METHODS: Following simulations of transmitter designs not requiring parallel transmission or radiofrequency-shimming, a coil array was constructed using loop elements, with anterior and posterior rows comprising one transmit-receive element and three receive-only elements. This coil structure was optimized using a whole-body phantom. In vivo sequence optimization was performed to optimize achieved flip angle (FA) and signal to noise ratio (SNR) in prostate. The system was evaluated in a healthy volunteer at 3T and 7T. The 7T T2WI was performed in two prostate cancer patients before prostatectomy, and localization of dominant tumors was subjectively compared with histopathological findings. Image quality was compared between 3T and 7T in these patients. RESULTS: Simulations of the B1 + field in prostate using two-loop design showed good magnitude (B1 + of 0.245 A/m/w1/2 ) and uniformity (nonuniformity [SD/mean] of 10.4%). In the volunteer, 90 degrees FA was achieved in prostate using 225 v 1 ms hard-pulse (indicating good efficiency), FA maps confirmed good uniformity (14.1% nonuniformity), and SNR maps showed SNR gain of 2.1 at 7T versus 3T. In patients, 7T T2WI showed excellent visual correspondence with prostatectomy findings. 7T images demonstrated higher estimated SNR (eSNR) in benign peripheral zone (PZ) and tumor compared with 3T, but lower eSNR in fat and slight decreases in tumor-to-PZ contrast and PZ-homogeneity. CONCLUSION: We have demonstrated feasibility of a simplified external coil array for high-resolution T2-weighted prostate MRI at 7T.J. Magn. Reson. Imaging 2013. (c) 2013 Wiley Periodicals, Inc.

Large cell neuroendocrine carcinoma of the prostate (LCNEC), de novo in particular, is an extremely rare entity that has only been described in the literature in case reports. Historically, the majority of the cases of LCNEC reported in the literature represent typical prostatic adenocarcinomas that transformed after long standing androgen deprivation therapy (ADT). These cases were admixed with histological areas of usual adenocarcinoma and showed hybrid features of both neuroendocrine and usual adenocarcinoma. Here we present a case of an LCNEC without admixed areas of usual prostatic adenocarcinoma arising de novo in a patient without prior history of hormonal therapy. The tumor also shows morphologic evidence of neuroendocrine differentiation; composed of large sheets and nests of cells with moderate amphophilic cytoplasm with peripheral palisading, and vesicular clumpy chromatin with prominent nucleoli. The carcinoma's prostatic origin is indicated by positive immunohistochemical staining for PSA, PAP, PSMA, racemase, and Nkx3.1. Diffusely positive staining for chromogranin and synaptophysin, as well as the presence of secretory granules in the cytoplasm of the tumor cells demonstrated by electron microscopy supports the NE differentiation. NE prostate cancer usually does not express AR and is refractory to ADT therapy while AR and ERG are positive in this case. In summary, we report a de novo LCNEC of the prostate with review of literature, in particular, clinical implications.

Localized urinary tract amyloidosis (UTA) is a rare disease that mimics neoplasia clinically, cystoscopically, and radiologically. We report eleven cases of isolated UTA from the urinary bladder (n=7) and upper urinary tract including the ureter (n=2) and renal pelvis (n=2). All cases clinically presented as mass lesions prior to histologic examination and clinically suggested a neoplastic process. The amyloid composition in most cases was mixed Kappa and Lambda light chains. All cases were cured after surgical excision except one case which was diagnosed as plasmacytosis/plasmacytoma six months later. Localized amyloidosis of the urinary tract usually has a benign clinical course and simple resection is recommended after systemic disease is ruled out.

BACKGROUND: Tumors of the kidney are uncommon in children and young adults. Accurate classification is crucial for both prognostication and therapeutic intervention. However, majority of the tumors in this age group have unusual morphology that renders classification challenging. Tubulopapillary architecture is one of the most common morphological patterns observed in renal tumors of children and young adults. METHODS: A patient with epithelial predominant Wilms tumor was reported. Differential diagnosis of renal tumors with tubulopapillary morphology was discussed with an emphasis on the histological and immunohistochemical features, and the literature was reviewed. RESULTS: A 25 year-old female patient presented with bilateral multilocular cystic masses. She underwent right radical nephrectomy and left partial nephrectomy. The pathological examination revealed a tumor with tubulopapillary architecture which was lined with low columnar epithelial cells. During the work-up of this case, several entities were considered and ruled out by careful gross, microscopic examination and prudent use of immunohistochemistry. The tumor cells were positive for WT-1, and variably positive for cytokeratin AE1/3, CD56, CD57, and negative for cytokeratin 7 and EMA. Fluorescent in-situ hybridization revealed no gain of chromosome 7 and 17. A diagnosis of epithelial predominant adult Wilms tumors was rendered for both kidneys. The patient received systemic chemotherapy and radiation to the remnant left kidney and was free of disease three years after the initial surgery. CONCLUSION: The differential diagnosis of renal tumors with tubulopapillary features in children and young adults include papillary renal cell carcinoma, metanephric adenoma, epithelial predominant Wilms tumor, translocation renal cell carcinoma and metastatic adenocarcinoma to the kidney. An accurate classification relies on careful examination of clinical and pathological features and immunohistochemical characteristics.

INTRODUCTION: Tumor grade plays a critical role in the management of papillary non-invasive urothelial carcinoma (UC). Since grading of UC relies on morphologic criteria, variability in interpretation exists among pathologists. The objective of this study was to examine inter-observer variability in the grading of papillary non-invasive UC at a single academic medical center. MATERIALS AND METHODS: One general pathologist and two genitourinary pathologists were blinded to patient identity and graded 98 consecutive UC specimens using the 1973 and 2004 classification systems. Kappa statistics (kappa) were used to measure inter-observer reproducibility to account for agreement expected purely by chance. By convention, varkappa values from 0.21-0.4 represent "fair", from 0.41-0.6 represent "moderate", and > 0.6 represent "substantial" agreement. RESULTS: Raw percentage agreement among all three pathologists was only 26% using the 1973 system and 47% using the 2004 system. When measured by kappa, overall agreement was only "fair" for both systems and while higher for the 2004 system than the 1973, this was not significant (: 0.38 versus 0.26, respectively). There were no significant differences in agreement when comparing the specialists agreement between themselves with agreement between each specialist and the generalist (varkappa: 0.31-0.37 versus varkappa: 0.18-0.46). CONCLUSIONS: The current grading system continues to demonstrate challenges in reproducibility among general and specialized pathologists. The degree of variability has significant implications on management decisions for non-invasive UC. Our findings underscore the need to identify molecular markers that can provide a more objective and reliable risk stratification system to guide patient management.