1 3 World J Urol DOI 10.1007/s00345-014-1383-5 ORIGINAL ARTICLE Mixed low- and high-grade non-muscle-invasive bladder cancer: a histological subtype with favorable outcome Tina Schubert · Matthew R. Danzig · Srinath Kotamarti · Rashed A. Ghandour · Danny Lascano · Byron P. Dubow · G. Joel Decastro · Mitchell C. Benson · James M. McKiernan Received: 28 June 2014 / Accepted: 11 August 2014 © Springer-Verlag Berlin Heidelberg 2014 Conclusions Mixed low- and high-grade NMIBC exhibits a significantly better response profile to intravesical BCG therapy compared to PHG NMIBC. The implications of these results are that less aggressive treatment strategies for this unique cancer entity may be needed and that there is a benefit to the reporting of tumor heterogeneity in transure- thral resection of bladder tumor specimens. Keywords Bladder cancer · BCG vaccine · Mixed grade · Prognosis Introduction Urothelial carcinoma of the bladder (UCB) is the most costly malignancy to treat, with one of the highest recurrence rates of all solid tumors [1–4]. Approximately 70 % of UCB patients initially present with non-muscle-invasive blad- der cancer (NMIBC) [1]. Tumor grade is a well-established determinant of therapeutic options and prognosis. Grad- ing of UCB has historically been controversial. In 1998, the World Health Organization (WHO) G1-G3 classification sys- tem was replaced by a binary low- or high-grade system [5]. Tumors are classified based on the highest grade in the patho- logical specimen, and heterogeneity is therefore not reflected. There is no consensus regarding the minimal percentage required to classify a tumor as high grade (HG), so tumors are often labeled as such even with only a small HG focus. Stud- ies have demonstrated a high prevalence (28–32 %) of UCB specimens containing different histological grades within the same tumor [6, 7]. Pathologists often describe such tumors as focally low and high grade (mixed grade, MG). The optimal clinical course for patients presenting with a heterogeneous grade has not yet been elucidated; such patients have most likely been treated as having pure HG NMIBC. Abstract Objective To determine whether heterogeneity of tumor grade affects the response to Bacillus Calmette-Guérin (BCG) treatment for patients with non-muscle-invasive bladder cancer (NMIBC). Methods Patients with Ta or T1 NMBIC receiving a 6-week induction course of intravesical BCG therapy after transurethral resection were divided according to the tumor grade. Clinical and pathological variables were compared. Advanced intervention-free survival (AIFS), defined as duration of freedom from advanced intervention (includ- ing non-BCG intravesical agents or cystectomy) or metas- tasis, was plotted using Kaplan–Meier methods. The effect of grade on survival duration was assessed by multivariate Cox proportional hazards modeling. Results One hundred and fifty-three patients were iden- tified: 17 with mixed low- and high-grade (MG) and 136 with pure high-grade (PHG) NMIBC. Demographic and additional pathologic variables were comparable between groups (p > 0.05). Five-year AIFS was 88.2 % for MG patients, compared to 48.5 % for PHG patients (p = 0.030 by log-rank test). On multivariate analysis, PHG was an independent risk factor for worse AIFS (HR 4.4, 95 % CI 1.1–18.4, p = 0.040). Among patients failing to respond to primary BCG induction, who underwent a secondary induction of BCG with interferon, MG patients had better response than PHG patients (100 vs. 26.3 %, p = 0.035). T. Schubert · M. R. Danzig (*) · S. Kotamarti · R. A. Ghandour · D. Lascano · B. P. Dubow · G. J. Decastro · M. C. Benson · J. M. McKiernan Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, Herbert Irving Pavilion 11th Floor, New York, NY 10032, USA e-mail: danzig.matthew@gmail.com