Bladder cancer: pathogenesis.

Several clinical studies have shown that bladder neoplasms can be subdivided into two broad groups: those that recur and basically remain non-invasive, and those that become invasive and therefore progress. The exact interrelation between these categories, if any, is not known. Traditionally, the evaluation of bladder neoplasms and their natural history has been based on morphological analysis of tissue and urine samples. The former has been classified according to the tumour, node, metastasis (TNM) system and different histological grading criteria. There has been a continuous refinement of the histological and cytological criteria for the classification of the lesions, for the identification of the early preneoplastic conditions and lesions, and definition of development and progression pathways. At present, the 2002 TNM classification is used for staging, while several systems are in use for grading. The classification proposed by the World Health Organization in 2004, known as the 2004 WHO classification, subdivides the lesions into flat and papillary, each further subdivided and defined on the basis of the degree of cellular and architectural changes. The early preneoplastic conditions and lesions are well characterized. Flat and papillary hyperplasia and dysplasia are included among them. The potential clinical significance of this classification as well as of the previous one, known as the 1973 WHO classification, has been shown in several investigations. Clinical studies have also shown the limitations of the morphological approach. Morphology alone does not detect reliably those early lesions that represent the onset of bladder neoplasms and of its recurrence or progression, i.e. the steps in which the neoplasm can be successfully treated and/or prevented. The histopathological profile does not clearly distinguish those lesions that recur from those that have the potential to progress. In the past few years several molecular studies have been initiated to explain the host of morphological features of the bladder neoplasms and to identify novel markers that could better explain their origins and behaviour. This has been possible thanks to the development of new analysis techniques or refinement of those already in existence, including the use of tissue microarrays. New markers are constantly being identified at the genetic and epigenetic levels. Genotyping, gene epidemiology and risk-adapted gene signatures have led to an expanded knowledge of bladder neoplasms. Molecular alterations in initiation and progression have been partly identified. Molecular changes have been successfully observed not only on tissue but also in urine samples, through a process of urine profiling. Molecular analyses have not replaced the morphological evaluation of bladder neoplasms. Indeed, they have contributed to a better knowledge of the morphological changes. A strong molecular basis has been demonstrated for the various patterns of bladder neoplasms. In particular, the molecular profile has been combined with the morphological profile of the bladder neoplasms, providing more accurate information on the clinical behaviour of