Molecular subtyping may inform on prognosis and treatment response in bladder cancer. However, intratumoral molecular heterogeneity is not well studied in this disease and could complicate efforts to use molecular subtyping to guide patient management. To investigate intratumoral heterogeneity in bladder cancer, we examined molecular subtypes in a consecutive, retrospective cystectomy series of histologic variant bladder cancers and conventional urothelial carcinomas co-occurring with them. Molecular subtypes were assigned as per the approach reported by Lund University, an approach that incorporates cell cycle alterations and markers of differentiation, to give the urothelial-like, genomically unstable, basal-squamous, mesenchymal-like, and neuroendocrine-like subtypes. The majority (93%) of tumors were classified as urothelial like, genomically unstable, or basal squamous. Among patients with more than one tumor histology, 39% demonstrated molecular heterogeneity among the different tumor histologies. This was greatest for the basal-squamous subtype, 78% of which co-occurred with either urothelial-like or genomically unstable carcinoma (among cases with multiple histologies). In contrast, there was no co-occurrence of urothelial-like and genomically unstable carcinoma in the same patient. The findings indicate that bladder cancer is often molecularly heterogeneous, particularly in the basal-squamous subtype. This raises the concern for sampling error in laboratory tests that guide therapy based on molecular subtyping. Patient summary: In this report, we investigated molecular diversity among different areas from the same tumor in patients with bladder cancer. We found that different areas from the same tumor are often molecularly different. We conclude that this biological diversity must be taken into account when interpreting clinical molecular tests performed on bladder cancer samples.
European urology. 2018 Sep 25 [Epub ahead of print]
Joshua I Warrick, Gottfrid Sjödahl, Matthew Kaag, Jay D Raman, Suzanne Merrill, Lauren Shuman, Guoli Chen, Vonn Walter, David J DeGraff
Department of Pathology-Penn State College of Medicine, Hershey, PA, USA; Department of Surgery, Division of Urology-Penn State College of Medicine, Hershey, PA, USA. Electronic address: ., Division of Urological Research, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden., Department of Surgery, Division of Urology-Penn State College of Medicine, Hershey, PA, USA., Department of Pathology-Penn State College of Medicine, Hershey, PA, USA., Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA., Department of Pathology-Penn State College of Medicine, Hershey, PA, USA; Department of Surgery, Division of Urology-Penn State College of Medicine, Hershey, PA, USA.