Urothelial cancer

Urothelial carcinoma, also termed transitional cell carcinoma, originates in transformed cells of epithelium lining renal pelvis, ureters, urinary bladder, and urethra. It occurs more frequently in urinary bladder while tumors in upper parts of urinary tract represent only 5% of urothelial carcinomas. Bladder urothelial carcinoma is one of the most prevalent tumors throughout the world, namely Southern and Western Europe and North America, especially in Lebanon (highest rate among men) and Greece (highest rate among women). Urothelial cancer typically presents in patients over the age of 50 years and is approximately four times more common in males than in females. Environmental risk factors are considered as the most important for the development of urothelial carcinoma. Smoking and occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons, and chlorinated hydrocarbons are the main causative factor for bladder urothelial carcinoma. Squamous cell carcinoma of the bladder is common in regions where schistosomiasis is endemic (the Middle East and Africa). In areas where schistosomiasis is endemic, squamous cell carcinomas account for approximately 75% of all bladder carcinomas, unlike other regions where this type represents 5% of all cancers in the urinary bladder. Balkan endemic nephropathy and Chinese herb nephropathy, progressive kidney diseases associated with exposure to aristolochic acid, are characterized by frequent development of urothelial carcinoma in upper parts of urinary tract.

The majority of patients present with symptoms of hematuria (blood in the urine) and/or dysuria (painful urination).

Urothelial tumors can exhibit papillary and non-papillary morphology and are generally classified into two groups: infiltrating carcinomas and non-invasive tumors, which also include urothelial carcinoma situ and non-invasive papillary urothelial carcinoma. Approximately 25% of all urothelial tumors are non-invasive papillary tumors. However, 10-15% of these patients will subsequently develop an invasive tumor. Histologically, most of urothelial carcinomas are characterized by tall and branched papillae covered by several layers of tumor cells with varying atypia. Grading of urothelial carcinoma is based on the degree of nuclear atypia and its distribution, mitotic activity, and on the presence of invasion of detrusor muscle. Invasive carcinomas are considered as high grade, while non-invasive carcinomas can be classified as low- or high-grade. Sarcomatoid, micropappilary, plasmacytoid and nested variants of urothelial carcinoma are rare but more likely to present with advanced disease or have very aggressive behavior and poor prognosis.

Diagnosis of urothelial carcinoma is often based on morphological fetarures but differentiation between invasive and non-invasive tumors as well as between unusual subtypes or metatic tumors can represent diagnostic pitfalls. It shows expression of GATA3, p63, p40, and several cytokeratins (KRT7, KRT20) including positive staining with antibody to anti-high molecular weight cytokeratins. Positive staining for thrombomodulin (THBD) and uroplakins 2 and 3 (UPII and UPIII) can be usefull as well. Immunohistochemical evaluation of PD-L1 expression in infiltrating immune cells or both in infiltrating immune cells and tumor cells (depending on assay) is used for selection of patients for the treatment with immune checkpoint inhibitors. Molecular investigations and detection of mutations in FGFR2 and FGFR3 genes are important for selection of patients with targeted therapies. Detection of copy number changes in chromosomes 3, 7 and 17 and in 9p21 locus by fluorescent in situ hybridization on urine cytology samples is used as screening method for early detection of cancer.

Prognosis and therapy of urothelial cancer depends on the histological type, grade, and tumor stage. Non-invasive forms have excellent prognosis with a 5-year relative survival rate of 96%, compared to 69% in localized disease (no spread outside the bladder), and very poor survival in distant disease (6%). Most frequently, treatment includes surgical resection of tumor alone or with bladder (its parts or whole). Non-invasive carcinomas can be treated locally with intravesical application of chemotherapy or immunotherapy using Bacillus Calmette-Guerin (BCG). Radiotherapy can be both used in localized and advanced diseases. Advanced disease can be treated with chemotherapy, targeted therapy with a small molecule inhibitor of fibroblast growth factor receptor, and immunotherapy with checkpoint inhibitors.