Faculty Bibliography

Background: Urothelial carcinoma of the upper tract (UTUC) is relatively rare. Urine cytology has been used in the diagnosis and surveillance of UTUC but its utility is not well established. Another method of UTUC detection is via endoscopic biopsy which itself can be limited due to inadequate sampling. Our study aims to explore the efficacy of urine cytology alone and in combination with endoscopic biopsy results in detecting UTUC. Design: We searched our pathology database for cases with both urine cytology specimen and subsequent histologic followup including endoscopic biopsies, ureterectomy, nephrectomy or nephroureterectomy over a 10 year period. Urine cytology and biopsies done concurrently or within 6 months follow-up are included in the study and the highest degree of abnormality was selected if multiple specimen available. For cases with both biopsies and surgical specimen diagnoses, the final diagnosis from surgery was used. Results: 154 cases of confirmed UTUC were included in the study. Among them, urine diagnoses of suspicious or positive for malignancy were made in 106 cases (69%): 7 cases were low grade UC (LGUC) and 99 cases were high grade UC (HGUC) upon surgical pathology evaluation. 32/154 cases (21%) were atypical urothelial cells (AUC) on cytology, among which 27 had confirmed HGUC and 5 cases had LGUC on surgical pathology. 16/154 urine cytology cases (10%) were negative: 11/16 had HGUC and 5/16 cases had LGUC in the concurrent or follow-up biopsies or surgery. The sensitivity for abnormal urine cytology was 89.6% for detecting UTUC. We also compared the urine cytology and endoscopic biopsies (within 6 months) in detecting UTUC. There are 62 cases are positive for both methods. Four cases show positive urine but negative biopsy, and 1 with negative urine but positive biopsy (HGUC). The sensitivity for combined urine cytology and biopsy is slightly higher for one method alone. Conclusions: Urine cytology is highly sensitive for detecting UTUCespecially for HGUC. Combining urine cytology and endoscopic biopsy results increases the sensitivity for detecting UTUC and should therefore be recommended for clinical practice

Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion. The cell proliferative effects were observed both in vitro, as well as in vivo. Immunohistochemical analysis of human PCa tissue samples indicated ACSL4 expression is increased in malignant cells compared with adjacent benign epithelial cells, and particularly increased in castration-resistant PCa (CRPC) when compared with hormone naive PCa. In cell lines co-expressing both ACSL4 and AR, proliferation was independent of exogenous androgens, suggesting that ACSL4 expression may lead to CRPC. In support for this hypothesis, ectopic ACSL4 expression induced resistance to treatment with Casodex, via decrease in apoptosis. Our studies further indicate that ACSL4 upregulates distinct pathway proteins including p-AKT, LSD1 and beta-catenin. These results suggest ACSL4 could serve as a biomarker and potential therapeutic target for CRPC.

BACKGROUND: Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences. OBJECTIVE: To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity. DESIGN, SETTING, AND PARTICIPANTS: Tumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102). RESULTS AND LIMITATIONS: Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed. CONCLUSIONS: High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma. PATIENT SUMMARY: Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.