Expression status and prognostic significance of mammalian target of rapamycin pathway members in urothelial carcinoma of urinary bladder after cystectomy

Authors

  • Luciana Schultz MD,

    1. Department of Pathology, Johns Hopkins University, Baltimore, Maryland
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  • Roula Albadine MD,

    1. Department of Pathology, Johns Hopkins University, Baltimore, Maryland
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  • Jessica Hicks MS,

    1. Department of Pathology, Johns Hopkins University, Baltimore, Maryland
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  • Sana Jadallah MD,

    1. Department of Pathology, Johns Hopkins University, Baltimore, Maryland
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  • Angelo M. DeMarzo MD, PhD,

    1. Department of Pathology, Johns Hopkins University, Baltimore, Maryland
    2. Department of Urology, Johns Hopkins University, Baltimore, Maryland
    3. Department of Oncology, Johns Hopkins University, Baltimore, Maryland
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  • Ying-Bei Chen MD, PhD,

    1. Department of Pathology, Johns Hopkins University, Baltimore, Maryland
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  • Matthew E. Neilsen MD,

    1. Department of Urology, Johns Hopkins University, Baltimore, Maryland
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  • Mark L. Gonzalgo MD,

    1. Department of Urology, Johns Hopkins University, Baltimore, Maryland
    2. Department of Oncology, Johns Hopkins University, Baltimore, Maryland
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  • David Sidransky MD,

    1. Department of Pathology, Johns Hopkins University, Baltimore, Maryland
    2. Department of Urology, Johns Hopkins University, Baltimore, Maryland
    3. Department of Oncology, Johns Hopkins University, Baltimore, Maryland
    4. Department of Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland
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  • Mark Schoenberg MD,

    1. Department of Urology, Johns Hopkins University, Baltimore, Maryland
    2. Department of Oncology, Johns Hopkins University, Baltimore, Maryland
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  • George J. Netto MD

    Corresponding author
    1. Department of Pathology, Johns Hopkins University, Baltimore, Maryland
    2. Department of Urology, Johns Hopkins University, Baltimore, Maryland
    3. Department of Oncology, Johns Hopkins University, Baltimore, Maryland
    • Johns Hopkins University, Surgical Pathology, Weinberg 2242, 401 N Broadway, Baltimore, MD 21231
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    • Fax: (443) 287-3818

Errata

This article is corrected by:

  1. Errata: Erratum Volume 117, Issue 21, 5021, Article first published online: 11 April 2011

Abstract

BACKGROUND:

Bladder urothelial carcinoma has high rates of mortality and morbidity. Identifying novel molecular prognostic factors and targets of therapy is crucial. Mammalian target of rapamycin (mTOR) pathway plays a pivotal role in establishing cell shape, migration, and proliferation.

METHODS:

Tissue microarrays were constructed from 132 cystectomies (1994-2002). Immunohistochemistry was performed for Pten, c-myc, p27, phosphorylated (phos)Akt, phosS6, and 4E-BP1. Markers were evaluated for pattern, percentage, and intensity of staining.

RESULTS:

Mean length of follow-up was 62.6 months (range, 1-182 months). Disease progression, overall survival (OS), and disease-specific survival (DSS) rates were 42%, 60%, and 68%, respectively. Pten showed loss of expression in 35% of bladder urothelial carcinoma. All markers showed lower expression in invasive bladder urothelial carcinoma compared with benign urothelium with the exception of 4E-BP1. Pten, p27, phosAkt, phosS6, and 4E-BP1 expression correlated with pathologic stage (pathological stage; P<.03). Pten, 4E-BP1, and phosAkt expression correlated with divergent aggressive histology and invasion. phosS6 expression inversely predicted OS (P = .01), DSS (P = .001), and progression (P = .05). c-myc expression inversely predicted progression (P = .01). In a multivariate analysis model that included TNM stage grouping, divergent aggressive histology, concomitant carcinoma in situ, phosS6, and c-myc expression, phosS6 was an independent predictor of DSS (P = .03; hazard ratio [HR], −0.19), whereas c-myc was an independent predictor of progression (P = .02; HR, −0.38). In a second model substituting organ-confined disease and lymph node status for TNM stage grouping, phosS6 and c-myc remained independent predictors of DSS (P = .03; HR, −0.21) and progression (P = .03; HR, −0.34), respectively.

CONCLUSIONS:

We found an overall down-regulation of mTOR pathway in bladder urothelial carcinoma. phosS6 independently predicted DSS, and c-myc independently predicted progression. Cancer 2010. © 2010 American Cancer Society.

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