We recently identified activating mutations of fibroblast growth factor receptor 3 (FGFR3) in bladder carcinoma. In this study we assessed the incidence of FGFR3 mutations in a series of 132 bladder carcinomas: 20 carcinoma in situ (CIS), 50 pTa, 19 pT1, and 43 pT2-4. All 48 mutations identified were identical to the germinal activating mutations that cause thanatophoric dysplasia, a lethal form of dwarfism. The S249C mutation, found in 33 of the 48 mutated tumors, was the most common. The frequency of mutations was higher in pTa tumors (37 of 50, 74%) than in CIS (0 of 20, 0%; P < 0.0001), pT1 (4 of 19, 21%; P < 0.0001) and pT2-4 tumors (7 of 43, 16%; P < 0.0001). Bladder cancer is the fourth most common malignancy in men and the ninth most common in women in the Western world. In these countries, more than 90% of bladder tumors are urothelial carcinomas. At the time of initial diagnosis, approximately 80% of urothelial carcinomas are confined to the epithelium (pTa, CIS) or lamina propria (pT1), whereas the remaining 20% invade the muscularis propria (pT2, pT3, pT4). pTa lesions, the most common form of bladder carcinoma, are papillary tumors. Carcinoma in situ (CIS) are flat, cytologically highgrade carcinomas. Primary isolated CIS is a very rare entity, CIS being more commonly associated with other malignant bladder lesions. 1 Clinical evidence and molecular studies suggest that there are two pathways in bladder carcinogenesis responsible for generating two types of urothelium-confined tumors (pTa and CIS) with very different behavior. 1-6 pTa tumors are associated with a high rate of recurrence (50 -75%) but a low probability (Ͻ5%) of progression to lamina propria-invasive (pT1) and muscleinvasive (pT2-4) tumors. CIS may be the most common precursor of invasive bladder cancer because CIS shows a strong tendency to progress (40 -50%), and because most muscle-invasive lesions arise with no history of a pTa precursor lesion. This clinical evidence is supported by various molecular studies showing that CIS and invasive tumors have many genetic alterations in common, such as specific chromosomal deletions and a high frequency of p53 mutations. 2,7 In our search for new markers of carcinoma progression, we recently reported specific missense mutations in a gene encoding a growth factor receptor, fibroblast

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Objectives To determine if a re-TUR in the presence or absence of muscle at the first TUR in T1-high grade (HG)/G3 bladder cancer patients makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS). Methods In a large retrospective multi-centre cohort of 2451 T1-HG/G3 patients initially treated with BCG, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in 4 groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the 4 groups. Results Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence (HR = 0.67, p = 0.08), progression (HR = 0.46, p = 0.06), CSS (HR = 0.31; p = 0.07) and OS (HR = 0.48, p = 0.05). Re-TUR in the presence of muscle in the primary specimen did not improve the outcome for any of the endpoints. Conclusions Our retrospective analysis suggests that re-TUR may not be necessary in T1-HG/G3 patients if muscle is present in the specimen of the primary TUR.

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ‐confined (OC) to non‐organ‐confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0–8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6–4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome. OBJECTIVES To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres. To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC. PATIENTS AND METHODS Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992–2010) and University of Turku, Turku, Finland (1986–2005) were analysed. RESULTS Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ‐confined (OC) to non‐organ‐confined (nOC) disease. During the study period, upstaging became more common in both centres. In multivariate analyses, T2 disease at initial presentation (P= 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44–4.77), high grade disease (P= 0.01, OR = 2.85, 95% CI: 1.21–6.7), lymphovascular invasion (LVI) (P < 0.001, OR = 5.17, 95% CI: 3.48–7.68), female gender (P= 0.038, OR = 0.6, 95% CI: 0.38–0.97, and histological variants (P < 0.001, OR = 2.77, 95% CI: 1.6–4.8) were associated with a risk of upstaging from OC to nOC disease. Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10‐year disease‐specific mortality, P < 0.001). CONCLUSIONS Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades. LVI and the presence of histological variants are strong predictors of upstaging at the time of RC. Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.