الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 258 |  |  |
| | | from | 258 | | |
Abstract
Urinary bladder carcinoma is the most common malignancy affecting the urinary tract. In Egypt, bladder cancer constitutes about 30% of all malignancies where it is the 4th most common malignant tumor among males. Excessive exposure to carcinogens, such as cigarette smoke and industrial chemicals as well as Bilharzial infection, has been suggested to be a cause of higher incidence of bladder cancer in men. Tumor recurrence and multifocality are two common features of bladder tumors making it one of the most expensive human malignancies to manage Also metastasis is the main cause of related mortality and so a great need for medical development and research is required to improve the survival rates in patients with UBC. The aim of the current work was: (1) Molecular classification of bladder cancer into basal and luminal subtypes employing GATA3 and CK5/6, (2) Evaluation of the relation between basal and luminal subtypes and the available prognostic parameters of bladder cancer and (3) Correlation of the immunohistochemical expression of Snail-1 with different subtypes of bladder cancer. Paraffin blocks from 80 cases of urinary bladder carcinoma patients including: 64 cases urothelial carcinoma, 10 cases SCC, 5 cases adenocarcinoma and one case neuroendocrine small cell carcinoma were collected and stained by H&E for routine histopathological examination as well as for GATA3, CK5/6 and Snail-1 for immunohistochemical study. The age of the studied cases ranged between 47 and 86 years, with mean age 64.69 years. Males (90%) were much more commonly affected than females (10%). Regarding urothelial carcinoma cases, the majority was high grade and muscle invasive. All SCC cases were muscle invasive, and half of them were moderately differentiated and the other half was poorly differentiated. Most of adenocarcinoma cases were moderately differentiated and muscle invasive. The neuroendocrine small cell carcinoma case showed also muscle invasion. In the current study, GATA3 showed positive nuclear expression in 75% of urothelial carcinoma cases, while all cases of SCC, adenocarcinoma and the neuroendocrine small cell carcinoma were GATA3 negative. All low grade urothelial carcinoma cases showed GATA3 positivity (100%), while 34 out of the 50 (68%) high grade cases showed positive GATA3 expression. Regarding the presence of muscle invasion in urothelial carcinoma cases, 91.6% of NMI cases showed GATA3 nuclear positivity, while 40% of MI cases showed GATA3 positive nuclear expression. These results indicated that reduction in GATA3 expression is associated with high grade and muscle invasive bladder carcinoma. Cytokeratin 5/6 is an intermediate-sized basic keratin, in the current study 71% of the urothelial carcinoma cases were positive CK5/6, the high expression in our study could be explained that normal urothelium showed expression of CK5/6 in the basal cell layers and metaplastic squamous cells and this basal layer staining may be retained in urothelial carcinomas especially that showed squamous differentiation. In the current study, there was significant association between CK5/6 expression and high grade tumor as 100% of high scores were high grade, and presence of muscle invasion which are considered poor prognostic parameters. In spite of advances in surgical and medical treatment in bladder cancer, no changes has been recorded in its mortality in comparison to the past decades and on therapeutic front, the management of non muscle invasive and muscle invasive tumors remain unchanged for decades. Recognition of other pathways could help to pick up patients with an aggressive illness by subtyping of bladder carcinoma patients based on the molecular alterations, permit stratification and predict prognosis. In the current study, by using CK5/6 and GATA3 cases were classified into three intrinsic molecular subtypes, as follow: GATA3 -ve/ CK5/6 +ve (basal), GATA3 +ve/ CK5/6 -ve (luminal) and GATA3 +ve/CK5/6 +ve (mixed), the latter showed intermediate prognostic parameters between basal and luminal subtypes. There was significant association between stratified intrinsic molecular subtypes, grade and muscle invasion as basal subtype (CK5/6+ve/GATA3-ve) showed high incidence with poor prognostic parameters like high grade and presence of muscle invasion. As metastasis is the main cause of cancer death. The process of metastasis is still difficult to understood or management therapeutically. Epithelial mesenchymal transition and mesenchymal-epithelial transition are dynamic and reversible processes that are influenced by micro-environmental signals and stimuli, EMT provides considerable degree of plasticity and reversibility for cells to differentiate or de-differentiate between cancer epithelial cells and mesenchymal cells. In the current study, 89% of urothelial carcinoma cases showed positive nuclear and/or cytoplasmic Snail-1 expression, while all cases of SCC, adenocarcinoma and neuroendocrine carcinoma (100%) were Snail-1 positive. As regards the relation between Snail-1 expression and the histopathological grade and muscle invasion, it showed statistically positive significant relation. In the current study, relation between Snail-1, CK5/6 and GATA3, there was significant direct relation between CK5/6 and Snail-1 expression. Also, both markers were positively associated with poor prognostic parameters as high grade and muscle invasion.