The papilla as a biomarker in the molecular era of bladder oncology

摘要

Conventional optical microscopy has been fundamental in the diagnosis of cancer for over a century. Tumor morphology has prognostic value and impact on treatment choice, but integration with molecular knowledge can enhance the correlation with clinical behavior. A papillary structure implies that the proliferating epithelium has been able to interact with its microenvironment to conceive a fibrovascular core, suggesting a fair degree of differentiation. In the bladder, a papillary architecture carries a favorable outcome and its presence is uniform in all non-invasive urothelial lesions, except for carcinoma in situ. Despite the increase in bladder cancer incidence, mortality has remained fairly stable for the last three decades, raising concern for overdiagnosis. Therefore, bladder cancer nomenclature has evolved to better communicate with the clinical scenario, including clinicians and patients. During this time, the need to incorporate new tools into morphology has raised a search for molecular biomarkers that grew exponentially with technology and scientific foment. Activating mutations in oncogenes like HRAS, PIK3 and FGFR3 are a hallmark of non-invasive papillary neoplasms, and their detection in advanced carcinomas is a favorable predictor of outcome. These alterations result in sustained proliferative stimuli and independent control of metabolism. Through the amplified interface of a papillary axis, the lamina propria can continue to supply nutrients, oxygen, hormones and other vital cellular needs to an increasing population of urothelial cells. mTOR regulates processes that require a substantial amount of matter and energy and alterations in this pathway are among the most frequent in urothelial tumors. Recent genomic landscape studies have provided data for molecularly subtyping urothelial cancers as luminal and basal. Within the luminal subtype, a p53-like signature is associated with chemoresistance. Luminal tumors, which phenotype is reminiscent of mature differentiated superficial cells, are enriched for papillary morphology and downregulation of miRNA involved in mTOR pathway regulation. Because the papillary structure is the result of a transcriptional program and its post-transcriptional modifications, it is likely that its presence will be maintained in classification schemes as a powerful tool for clinical translation.