Dysregulation of mammalian target of rapamycin pathway in plasmacytoid variant of urothelial carcinoma of the urinary bladder

• Type of Material: Article
• Authors: Nilda D. Gonzalez-Roibon, The Johns Hopkins School of Medicine; Alcides Chaux, The Johns Hopkins School of Medicine; Turki Al-Hussain, The Johns Hopkins School of Medicine; Adeboye O. Osunkoya, Emory University; Stephania Martins Bezerra, The Johns Hopkins School of Medicine; Jessica Hicks, The Johns Hopkins School of Medicine; Jonathan I. Epstein, The Johns Hopkins School of Medicine; George J. Netto, The Johns Hopkins School of Medicine
• Language: English
• Date: 2013-04-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.humpath.2012.07.009
• Title of Journal or Parent Work: Human Pathology
• ISSN: 0046-8177
• Volume: 44
• Issue: 4
• Start Page: 612
• End Page: 622
• Grant/Funding Information: This study was partially supported by the Johns Hopkins Medicine–Patana Fund for Research and Clinical Innovator Award from Flight Attendant Medical Research Institute (FAMRI) Fund.
• Keywords: Proto-Oncogene Proteins c-akt; Male; Carcinoma, Transitional Cell; Female; Aged, 80 and over; Phosphorylation; Aged; Middle Aged; Plasma Cells; Humans; Urinary Bladder Neoplasms; PTEN Phosphohydrolase; Biomarkers, Tumor; Georgia; Survival Rate; Maryland; TOR Serine-Threonine Kinases; Prognosis
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

Abstract

Plasmacytoid urothelial carcinoma is a rare but aggressive variant of bladder cancer with no clear therapeutic guidelines. Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been linked to oncogenesis in conventional bladder cancer. Several antineoplastic agents targeting mTOR pathway are currently available. This study assesses mTOR pathway status as well as c-myc and p27 expression. We retrieved 19 archival cases of plasmacytoid urothelial carcinoma from two institutions. Whole tissue sections were evaluated for immunoexpression of phosphatase and tensin homolog (PTEN), phosphorylated mTOR, phosphorylated protein kinase B (AKT), phosphorylated S6, c-myc, and p27. We evaluated intensity (0 to 3+) and extent (0%-100%) of expression for all markers. An H score was calculated as the sum of products of intensity and extent for each marker and used during analysis. In addition, PTEN loss was defined as absence of expression in > 10% of tumor cells. We encountered PTEN loss in 28%. Higher H score for nuclear phosphorylated AKT and a lower H score for phosphorylated S6 was encountered in muscle invasive tumors compared to non-muscle invasive tumors (P =.007 and P =.009, respectively). Although a trend for negative prognostic impact on overall survival for higher phosphorylated mTOR expression was noted (P =.051), markers expression levels failed to predict survival in our cohort. We found dysregulation of mTOR pathway members in urinary bladder plasmacytoid urothelial carcinoma, suggesting that the use of mTOR pathway inhibitors might be beneficial for patients with this aggressive tumor.