How to combine the molecular profile with the clinicopathological profile of urothelial neoplastic lesions.

The current World Health Organization (WHO) 2004 classification of urothelial neoplasms was based on an attempt to reconcile molecular-genetic and pathology findings. This article provides an overview of the more recent molecular-genetic findings in the field and critically appraises their relationship with each of the WHO 2004 disease categories. Most of the WHO 2004 categories were successfully distinguished by means of expression and genome profiling and by distinct genetic alterations. Regarding urothelial papilloma, clinical and limited molecular-genetic data seem to suggest that they may not represent a precursor lesion for bladder cancer. It is more likely that urothelial papilloma is a benign neoplasm sharing mutations in the fibroblast growth factor-3 gene with seborrhoeic keratosis, allegedly its epidermal counterpart. Genetic alterations in papillary urothelial neoplasia of low malignant potential are identical to those found in non-invasive low-grade papillary urothelial carcinoma, implying that they are within a spectrum of the same neoplasm. Expression profiling data corroborate the view that (secondary) carcinoma in situ may act not only as a precursor lesion for invasive non-papillary urothelial carcinoma, but also as a precursor for non-muscle-invasive papillary urothelial carcinoma. Given the significant molecular genetic differences between non-invasive and invasive papillary urothelial carcinomas and their analogy with exophytic neoplastic precursor lesions in other organ systems, an alternative nomenclature is proposed, replacing papillary urothelial carcinoma with papillary intraurothelial neoplasm for the non-invasive (pTa) papillary carcinomas.