The large majority of bladder cancers are urothelial cell carcinomas. The aggressiveness of bladder cancer is determined by the stage and grade of the tumor. The grade is what the tumor looks like under the microscope and consists of low grade or high grade. This is from the 2004 International Society of Urologic Pathologists; however, some pathologists continue to use grades 1, 2 and 3. In general grade1 and 2 are low grade and grade 3 is considered high grade. The 2004 classification also introduced papillary neoplasia of low malignant potential. In addition to urothelial cell carcinoma are a number of histological variants that are thought to be more aggressive. These include micropapillary, small cell, glandular differentiation, squamous, sarcomatoid, lymphoepitheloid as well as a few others.

Stage is the depth of penetration of the bladder cancer. There are 2 main categories i.e. non muscle invasive (NMIBC) and muscle invasive bladder cancer. Low grade NMIBC has a recurrence rate of approximately 50% but at most 2-4% risk of progression. High grade NMIBC such as Ta, T1 and carcinoma in-situ have a slightly higher risk of recurrence with approximately 30-40% risk of progression. A number of risk stratifications for NMIBC have been developed taking into account grade, stage, number and size of tumors as well as number of recurrences to classify patients as having low, intermediate and high risk of tumor recurrence and progression. Muscle invasive bladder cancer is always high grade and is associated with microscopic metastatic disease in up to 50% of patients at the time of diagnosis. To date there are no consistent molecular or genetic markers that are able to accurately stratify patients. Pathologic staging i.e. presence of extravesical invasion, involvement of adjacent organs such as the prostate or vagina or lymph node involvement are all associated with a poor prognosis. The Cancer Genome Atlas (TCGA) project will aid in the identification of prognostic biomarkers for bladder cancer.

Platinum based chemotherapy i.e. Cis Platin is commonly used for the treatment of locally advanced and metastatic bladder cancer. In addition, Platinum based chemotherapy is used in the neoadjuvant (before radical cystectomy) and adjuvant setting (after radical cystectomy); however, presently there are no known biomarkers of disease response. Improving survival will require newer medications and moving beyond conventional histological staging and grading of tumors. Currently, chemotherapy for bladder cancer is the approach of “one size fits all”. However, we know that cancer is a diverse, complex heterogeneous process with multiple mutations and altered metabolic and genetic pathways. The goal of TCGA for bladder cancer is to perform complete genomic analysis of 500+ invasive bladder cancers to determine the various “genetic signatures” and altered metabolic pathways associated with bladder cancer. Ideally this will lead to new prognostic markers as well as therapeutic targets for novel and personalized drug development. Single gene markers such as p53, pRb, p16, p21, ERCC1, RRM1, hENT1, PTEN, pErb, Her2 Neu as well as microRNA markers have all been studied as prognostic predictors of survival as well as markers for chemotherapy responsiveness. To date clinical trials are ongoing to test agents that target the fibroblast, epidermal and vascular endothelial growth factor pathways. The goal is to augment cytotoxic chemotherapy with these targeted therapies; however, at present much work on the biology of bladder cancer is required.