E-CADHERIN EXPRESSION PREDICTS CLINICAL OUTCOME IN CARCINOMA IN SITU OF THE URINARY BLADDER SHAHROKH F. SHARIAT, SILEN PAHLAVAN, ADAM G. BASEMAN, RICHARD M. BROWN, AARON E. GREEN, THOMAS M. WHEELER, AND SETH P. LERNER ABSTRACT Objectives. The clinical course of carcinoma in situ (CIS) of the bladder is highly variable. Our objective in this study was to describe E-cadherin expression patterns in CIS with and without papillary disease and to determine whether altered E-cadherin expression is associated with disease progression and survival in patients with CIS of the bladder. Methods. Tumor specimens from 53 patients who had CIS in the absence of muscle-invasive carcinoma on bladder biopsy were identified. Formalin-fixed paraffin sections were processed using a hot citric acid antigen retrieval method, followed by immunostaining with anti-E-cadherin monoclonal antibody. Expression patterns were evaluated in a blinded fashion and scored as normal and abnormal, which included absent and various degrees of heterogeneous immunostaining. Outcomes analyzed were recurrence, progression, and survival. Results. Loss of normal membrane E-cadherin immunoreactivity was found in 17 patients (32%). At a median follow-up of 131 months, abnormal E-cadherin expression was significantly associated with disease recurrence (P = 0.0087), disease progression (P = 0.0003), and bladder cancer-specific survival (P = 0.0285). In multivariate analyses, E-cadherin expression was independently associated with disease recur- rence (P = 0.019, 95% confidence interval [CI] 1.342 to 5.940), disease progression (P = 0.002, 95% CI 2.049 to 17.989), and bladder cancer-specific survival (P = 0.025, 95% CI 1.179 to 10.432). Conclusions. Loss of E-cadherin expression in patients with CIS with and without papillary disease of the bladder predicts disease recurrence, disease progression, and bladder cancer-specific death. CIS with and without papillary disease associated with abnormal E-cadherin expression may represent a biologically more aggressive cancer, requiring early definitive therapy. This hypothesis should be evaluated in larger studies and prospective clinical trials. UROLOGY 57: 60–65, 2001. © 2001, Elsevier Science Inc. C arcinoma in situ (CIS) is a high-grade and po- tentially aggressive manifestation of transi- tional cell carcinoma of the bladder. Historically, up to 83% of patients developed invasive carci- noma if left untreated, 1 and up to 39% died of their disease. 2 Recent advances in intravesical chemo- therapy and immunotherapy have, however, mark- edly improved the management of CIS, allowing a high number of patients to achieve a cancer-free status with preservation of a normally functioning bladder. Maintenance bacille Calmette-Gue ´rin (BCG) has been shown to favorably affect the rate of progression or need for cystectomy. 3 Neverthe- less, on average 28% and 52% of patients are refrac- tory to BCG immunotherapy and chemotherapy, respectively, putting them at risk for disease pro- gression. 4 As molecular alterations precede phenotypic changes, immunohistochemical studies may be a valuable tool for screening patients for early iden- tification of aggressive cancers. To invade the sur- rounding tissues and metastasis to distant organs, cancer cells have to detach from their site of origin as an initial step. This requires disruption of nor- mal cell-cell adhesion in epithelial tissues. There- fore, analysis of alterations in the adhesion proper- ties of neoplastic cells is an important aspect of the study of cancer progression. The cadherins are a family of transmembrane Supported in part by grants from the Frost Foundation, Inc., and from the Max Kade Foundation, Inc. From the Scott Department of Urology and Department of Pa- thology, Baylor College of Medicine and The Methodist Hospital, Houston, Texas Reprint requests: Seth P. Lerner, M.D., Scott Department of Urology, 6560 Fannin, Suite 2100, Houston, TX 77030 Submitted: March 6, 2000, accepted (with revisions): Septem- ber 8, 2000 ADULT UROLOGY © 2001, ELSEVIER SCIENCE INC. 0090-4295/01/$20.00 60 ALL RIGHTS RESERVED PII S0090-4295(00)00892-X