Urologic Oncology: Seminars and Original Investigations 32 (2014) 32.e11–32.e16 Review article Squamous cell carcinogenesis and squamous cell carcinoma of the urinary bladder: A contemporary review with focus on nonbilharzial squamous cell carcinoma Steffen Rausch, M.D. a, *, Yair Lotan, M.D. b , Ramy F. Youssef, M.D. b a Department of Urology, Klinikum Fulda gAG, Fulda, Germany b Department of Urology, University of Texas, Southwestern Medical Center, Dallas, TX Received 25 October 2012; received in revised form 20 November 2012; accepted 27 November 2012 Abstract Bladder squamous cell carcinoma, squamous metaplasia, and transitional cell carcinoma with squamous differentiation are infrequent findings in Western countries. A common risk factor for their development consists of chronic bladder irritation and inflammation. The prognostic and clinical relevance and natural history of squamous cell lesions has been under investigation, revealing individual premalignant characteristics. Recent developments in molecular characterization of squamous alterations of the urinary tract indicate pathogenetic similarities and interrelations and might lead to more precise tumor classification and risk stratification in the future. Nevertheless, current clinical management of patients with premalignant and malignant bladder squamous cell lesions remains challenging, as high evidence level studies are not available and prognosis of invasive squamous carcinoma is poor. Our review summarizes the available data on clinical presentation, treatment, and outcome of bladder squamous cell carcinoma, metaplastic lesions, and transitional cell carcinoma with squamous differentiation and discusses implementable current advances in the understanding of bladder cancer tumorigenesis. r 2014 Elsevier Inc. All rights reserved. Keywords: Squamous cell carcinoma; Squamous metaplasia; Leukoplakia; Inflammation; Bladder cancer; Nonbilharzial squamous cell carcinoma 1. Introduction Squamous cell carcinoma (SCC) of the bladder is uncommon in Western countries, comprising 2% to 5% of all the bladder tumors [1,2]. In contrast, in countries with endemic schistosomiasis, SCC is the most frequent urothelial neoplasm [2]. Multiple tissue alterations like keratinizing squamous metaplasia, bladder ulcers, bladder contracture and ureteral stricture, and ultimately bladder cancer are associated with urinary schistosomiasis [3,4]. Previous studies indicated individual characteristics of bilharzial-associated squamous cell carcinoma (BSCC) and non–bilharzial-associated squamous cell carcinoma (NBSCC) in comparison with transitional cell carcinoma (TCC), with typically more advanced local stages at presentation despite a low tendency of nodal and distant metastatic spread [1,5,6]. However, NBSCC has been described as a highly aggressive entity with poor patient outcome. Although established adjuvant and neoadjuvant treatment strategies are lacking, radical cystectomy is the recommended standard treatment for invasive SCC, regard- less of the etiology [2]. Patients with chronic indwelling catheters, persistent infection, or both are at risk for developing squamous metaplasia, dysplasia, and eventually SCC due to con- tinuous mucosal irritation and chronic inflammation [7,8]. Genetic variations in inflammatory genes have been associated with poor oncological outcomes of bladder cancer [9]. The prognostic role of squamous differentiation in transitional carcinoma (TCC/SCC) has been evaluated with demonstration of influence on the natural history of TCC. As previously suggested, the genesis and natural history of squamous metaplasia, SCC, and TCC/SCC are closely 1078-1439/$ – see front matter r 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.urolonc.2012.11.020 * Corresponding author. Tel.: þ49-661-84-5951; fax: þ49-661-84-5952. E-mail address: steffen.rausch@gmx.net (S. Rausch). URL: http://www.klinikum-fulda.de (S. Rausch).