Faculty Bibliography

BACKGROUND: To assess associations between whole-lesion apparent diffusion coefficient (ADC) metrics and pathologic findings of Likert score 3 prostate lesions at MRI/ultrasound fusion targeted biopsy. METHODS: This retrospective Institutional Review Board-approved study received a waiver of consent. We identified patients receiving a highest lesion score of 3 on 3 Tesla multiparametric MRI reviewed by a single experienced radiologist using a 5-point Likert scale and who underwent fusion biopsy. A total of 188 score 3 lesions in 158 patients were included. Three-dimensional volumes-of-interest encompassing each lesion were traced on ADC maps. Logistic regression was used to predict biopsy results based on whole-lesion ADC metrics and patient biopsy history. Biopsy yield was compared between metrics. RESULTS: By lesion, targeted biopsy identified tumor in 22.3% and Gleason score (GS) > 6 tumor in 8.5%, although results varied by biopsy history: biopsy-naive (n = 80), 20.0%/8.8%; prior negative biopsy (n = 53), 9.4%/1.9%; prior positive biopsy (n = 55): 40.0%/14.5%. Biopsy history, whole-lesion mean ADC, whole-lesion ADC10-25 , and whole-lesion ADC25-50 were each significantly associated with tumor or GS > 6 tumor at fusion biopsy (P 6 tumor, which was significantly higher (P < 0.001) than specificity of PSA (17.5%) at identical sensitivity. CONCLUSION: For score 3 lesions in patients without prior negative biopsy, whole-lesion ADC metrics help detect GS > 6 cancer while avoiding negative biopsies. However, deferral of fusion biopsy may be considered for score 3 lesions in patients with prior negative biopsy (without applying whole-lesion ADC metrics) given exceedingly low ( approximately 2%) frequency of GS > 6 tumor in this group. J. Magn. Reson. Imaging 2015.

INTRODUCTION: There is increasing interest in using imaging in the detection and localization of prostate cancer (PCa). Both multiparametric magnetic resonance imaging (mpMRI) and HistoScanning (HS) have been independently evaluated in the detection and localization of PCa. We undertook a prospective, blinded comparison of mpMRI and HS for cancer localization among men undergoing radical prostatectomy. METHODS: Following approval by the institutional review board, men scheduled to undergo radical prostatectomy, who had previously undergone mpMRI at our institution, were offered inclusion in the study. Those consenting underwent preoperative HS following induction of anesthesia; mpMRI, HS, and surgical step-section pathology were independently read by a single radiologist, urologist, and pathologist, respectively, in a blinded fashion. Disease maps created by each independent reader were compared and evaluated for concordance by a 5 persons committee consisting of 2 urologists, 2 pathologists, and 1 radiologist. Logistic regression for correlated data was used to assess and compare mpMRI and HS in terms of diagnostic accuracy for cancer detection. Generalized estimating equations based on binary logistic regression were used to model concordance between reader opinion and the reference standard assessment of the same lesion site or region as a function of imaging modality. RESULTS: Data from 31/35 men enrolled in the trial were deemed to be evaluable. On evaluation of cancer localization, HS identified cancer in 36/78 (46.2%) regions of interest, as compared with 41/78 (52.6%) on mpMRI (P = 0.3968). The overall accuracy, positive predictive value, negative predictive value, and specificity for detection of disease within a region of interest were significantly better with mpMRI as compared with HS. HS detected 36/84 (42.9%) cancer foci as compared with 42/84 (50%) detected by mpMRI (P = 0.3678). Among tumors with Gleason score>6, mpMRI detected 19/22 (86.4%) whereas HS detected only 11/22 (50%, P = 0.0078). Similarly, among tumors>10mm in maximal diameter, mpMRI detected 28/34 (82.4%) whereas HS detected only 19/34 (55.9%, P = 0.0352). CONCLUSION: In our institution, the diagnostic accuracy of HS was inferior to that of mpMRI in PCa for PCa detection and localization. Although our study warrants validation from larger cohorts, it would suggest that the HS protocol requires further refinement before clinical implementation.

BACKGROUND: The human papilloma virus (HPV) is a carcinogen known for its strong association with cervical cancers and cervical lesions. It is also known to be associated with a variety of squamous cell carcinomas in other areas, such as the penis, vulva, anus and head and neck. However, the association with urothelial carcinoma remains controversial. Here, we report a case of urothelial carcinoma with squamous differentiation associated with HPV-6/HPV-11. CASE PRESENTATION: This is a case of a 70 year old man who presented with nocturia and pressure during urination. During the TURP procedure for what was clinically thought to be benign prostate hyperplasia with pathologic diagnosis as prostate carcinoma, a 2 cm papillary mass was found in the distal penile urethra. The papillary mass was found to be a high grade urothelial carcinoma positive for GATA 3 expression, with focal areas of squamous differentiation. The areas with squamous differentiation demonstrated koilocytic differentiation, which were positive for strong p16 expression. The tumor was found to harbor low risk HPV 6/11 by in situ hybridization. CONCLUSIONS: This study case demonstrates HPV infection with a low risk subtype (HPV 6/11) associated with an urothelial carcinoma with squamous differentiation and condylomatous features.

Renal cell carcinomas comprise a heterogeneous group of tumours with diverse clinicopathological and molecular characteristics as well as therapeutic options. Accurate diagnosis and classification are critical for patient management and prognosis prediction. They have traditionally been classified according to histopathological features. Recent advances in high throughput technologies, including next generation sequencing, have enabled us to search genome-wide for genomic, transcriptomic and proteomic changes in large number of renal cancer specimens. Studies have demonstrated that different histological subtypes harbour unique genomic and epigenetic alterations and gene expression and protein profile that can be integrated with clinicopathological features for diagnosis, classification, prognosis and individualized treatment and "n-of-1" trials. This review will discuss the immunoprofiles of major renal cell carcinoma subtypes, immunohistochemical markers that are commonly used in clinical laboratories, and recent genomic and epigenetic discoveries in renal cell carcinomas

Treatment protocols for breast cancer depend predominantly on receptor status with respect to estrogen (estrogen receptor alpha), progesterone (progesterone receptor) and human epidermal growth factor [human epidermal growth factor receptor 2 (HER2)]. The presence of one or more of these receptors suggests that a treatment targeting these pathways might be effective, while the absence of, or in the case of HER2, lack of overexpression of, all of these receptors, termed triple negative breast cancer (TNBC), indicates a need for the more toxic chemotherapy. In an effort to develop targeted therapies for TNBC, it will be necessary to differentiate among specific TNBC subtypes. The subset of TNBC that expresses androgen receptor (AR) has been determined to express genes consistent with a luminal subtype and therefore may be amenable to therapies targeting either AR, itself, or other pathways typical of a luminal subtype. Recent investigations of the AR signal pathway within breast cancer lead to AR as a significant target for breast cancer therapy with several clinical trials currently in progress. The subclass of TNBC that lacks AR, which we have termed quadruple negative breast cancer (QNBC) currently lacks a defined targetable pathway. Unlike AR-positive TNBC, QNBC predominantly exhibits a basal-like molecular subtype. Several subtypes and related pathway proteins are preferentially expressed in QNBC that may serve as effective targets for treatment, such as ACSL4, SKP2 and EGFR. ACSL4 expression has been demonstrated to be inversely correlated with expression of hormone/growth factor receptors and may thus serve as a biomarker for QNBC as well as a target for therapy. In the following review we summarize some of the current efforts to develop alternatives to chemotherapy for TNBC and QNBC.

Estrogen receptors (ER) play important roles in the development and progression of breast and ovarian cancers. ERs mediate transcriptional regulation through interaction with cofactors and binding to response elements within the regulatory elements of target genes. Here, we examined the expression and function of TBLR1/TBL1XR1, a core component of NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid receptor) corepressor complexes, in breast and ovarian cancers. We found that although TBLR1 is present in both the nucleus and cytoplasm of normal and neoplastic breast and ovarian cells, it is expressed at significantly higher levels in the nucleus of malignant breast and ovarian cells compared to benign cells. TBLR1 functions as an ER corepressor to inhibit ER-mediated transcriptional activation in both breast and ovarian cell lines, but it has no effect on androgen receptor (AR) mediated transcriptional activation in these cells. Furthermore, ectopic expression of nuclear TBLR1 in breast and ovarian cancer cells stimulates cell proliferation. The increased cell proliferation by nuclear TBLR1 is through both ER-independent and ER-dependent mechanisms as evidenced by increased growth in hormone-free medium and estrogen medium, as well as reduced growth with ER knockdown by siRNA. Nuclear TBLR1 overexpression also increased migration and invasion in both breast and ovarian cancer cells. Determining the functional relationship between TBLR1 and ER may provide insights to develop novel treatment strategies and improve response to hormonal therapy in breast and ovarian cancers.