Urothelial Neoplasms of the Urinary Bladder Occurring in Young Adult and Pediatric Patients: A Comprehensive Review of Literature With Implications for Patient Management Gladell P. Paner, MD,* Pascal Zehnder, MD,w z Anmol M. Amin,z Aliya N. Husain, MD,* and Mihir M. Desai, MDz Abstract: Bladder urothelial carcinoma is typically a disease of older individuals and rarely occurs below the age of 40 years. There is debate and uncertainty in the literature regarding the clinico- pathologic characteristics of bladder urothelial neoplasms in younger patients compared with older patients, although no consistent age criteria have been used to define “younger” age group categories. Use of the World Health Organization 2004/In- ternational Society of Urological Pathology 1998 grading nomen- clature and recent molecular studies highlight certain unique features of bladder urothelial neoplasms in young patients, particularly in patients below 20 years of age. In this meta-analysis and review, the clinical, pathologic, and molecular features and risk factors of bladder urothelial neoplasms in patients 40 years or less are presented and analyzed according to decades of presentation. Similar to older patients, bladder urothelial neoplasms in patients 40 years or younger occur more common in male patients, present mainly with gross painless hematuria, and are more commonly located at bladder trigone/ureteral orifices, but in contrast have a greater chance for unifocality. Delay in diagnosis of bladder urothelial neoplasms seems not to be uncommon in younger patients probably because of its relative rarity and the predomi- nance of benign causes of hematuria in this age group causing hesitancy for an aggressive work-up. Most tumors in patients younger than 40 years were low grade. The incidence of low-grade tumors was the lowest in the first 2 decades of life, with incremental increase of the percentage of high-grade tumors with increasing age decades. Classification according to the World Health Organiza- tion 2004/International Society of Urological Pathology grading system identified papillary urothelial neoplasms of low malignant potential to be relatively frequent among bladder tumors of young patients particularly in the teenage years. Similar to grade, there was marked predominance of low stage tumors in the first 2 decades of life with gradual inclusion of few higher stage and metastatic tumors in the 2 older decades. Bladder urothelial neoplasms occurring in patients <20 years of age lack or have a much lower incidence of aberrations in chromosome 9, FGFR3, p53, and microsatellite instability and have fewer epigenetic alterations. Tumor recurrence and deaths were infrequent in the first 2 decades and increased gradually in each successive decade, likely influenced by the increased proportion of higher grade and higher stage tumors. Our review of the literature shows that urothelial neoplasms of the bladder occurring in young patients exhibit unique pathologic and molecular features that translate to its more indolent behavior; this distinction is most pronounced in patients <20 years. Our overall inferences have potential implica- tions for choosing appropriate noninvasive diagnostic and surveil- lance modalities, whenever feasible, and for selecting suitable treatment strategies that factor in quality of life issues vital to younger patients. Key Words: bladder cancer, carcinoma, urothelial, young, pedia- tric, outcome, molecular abnormalities, diagnosis, treatment, prognosis, management (Adv Anat Pathol 2011;18:79–89) I t is estimated that there will be 70,530 cases of urinary bladder urothelial cancer (52,760 in men and 17,770 in women) in the United States in 2010, and it will remain the fourth most common type of cancer in men. 1 Bladder urothelial carcinoma is typically a disease of older indivi- duals and the majority of patients are above 60 years of age at the time of diagnosis. 2 Bladder carcinoma in patients <40 years of age is rare, accounting for only 1% to 2.4% of cases or about 700 to 1700 cases a year. 3–6 Much rarer is bladder carcinoma in the first 2 decades of life with reported in- cidence rates of only 0.1% to 0.4%. 3,7 Despite its relative rarity, recent information retrieved from Surveillance, Epi- demiology and End Results (SEER) 1973 to 2003 database shows urothelial neoplasms as the predominant bladder tumor occurring in patients <18 years (60% of cases), with preponderance for the late teenage years. 8 To date, <35 cases of bladder urothelial neoplasms have been reported to occur in patients younger than 10 years. 9–25 There is debate in the literature regarding the clinical behavior of bladder urothelial neoplasms in younger patients when compared with older patients. Some studies have observed a similar natural history in younger and older patients, 3,6,26–28 while others have observed more favorable pathologic characteristics and improved clinical outcome in the younger cohort. 4,13,29,30 Similarly, observa- tions about the genetic and molecular make-up of bladder urothelial neoplasms in young patients have varied. 31–35 One reason for this variability is the differing criteria to define “young” patients in published series which have used cut-offs of 20, 30, or 40 to 45 years of age. 3,4,6,13,26–35 Owing to conflicting opinions, currently there are no current standardized recommendations in terms of diagnostic Copyright r 2010 by Lippincott Williams & Wilkins From the *Department of Pathology, University of Chicago, Chicago, IL; wDepartment of Urology, University Hospital of Bern, Bern, Switzerland; and zDepartment of Urology, Norris Cancer Institute, University of Southern California, Los Angeles, CA. Reprints: Gladell P. Paner, MD, Department of Pathology, Section of Urology, Department of Surgery, The University of Chicago Hospitals, 5841 S. Maryland Avenue, Room AMB P321-MC 6101, Chicago, IL 60637 (e-mail: Gladell.Paner@uchospitals.edu). All figures can be viewed online in color at http://www.anatomicpathology. com. REVIEW ARTICLE Adv Anat Pathol  Volume 18, Number 1, January 2011 www.anatomicpathology.com | 79