الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
Bladder cancer is considered one of the most-common urological malignancies, and is among the leading causes of cancer deaths worldwide. In males, approximately 4.4% of all new cancer diagnoses worldwide and 2.9% of all cancer deaths are due to bladder cancer. The high incidence, prevalence, mortality, and recurrence rate of bladder cancer indicate that it remains an unsolved clinical and social problem.
Two-thirds of patients present with non-muscle-invasive bladder cancer. Although current therapies can achieve a good prognosis, approximately 40% of these patients will progress to muscle-invasive disease after 5 years. Moreover, the 5-year survival rate of muscle-invasive bladder cancer is only 60%.
Management of urothelial carcinoma is variable according to the extent of the disease. The urinary bladder is removed by radical cystectomy for cases of MIUC, while non- muscle invasive urothelial carcinoma is generally managed by bladder conserving transurethral resection of bladder tumor (TURBT). Because of the presence of a category from the non-muscle invasive carcinoma that have a high risk of progression some patients are treated more aggressively with cystectomy.
Although many tumors may show similar histological diagnosis, the prognosis and response to therapy can be completely different. These differences are believed to stem from molecular varieties among histologically similar tumors. Thus, molecular subtyping of bladder cancer emerged as an important prognostic and predictive factor affecting the choice of treatment and definitely the clinical outcome. Two main molecular classes of bladder cancer have been distinguished by immunohistochemistry, namely; luminal and basal subtypes.
The aim of the present work is to molecularly classify cases of non-muscle invasive urothelial carcinoma of the urinary bladder using immunohistochemistry to assess luminal-basal phenotype based on tissue expression of GATA3 and CK5/6 as surrogate markers for luminal or basal subtypes, respectively and to correlate, subsequently, the immunohistochemical expression of insulin-like growth factor mRNA binding protein 3 (IMP3) with the different molecular subtypes as well as with disease progression.
The material of the present retrospective study included formalin fixed, Paraffin embedded tumor sections of 120 cases of bladder cancer. Cases were divided into three groups; group A which included 50 patients of low grade non-muscle invasive urothelial carcinoma, group B which included 50 patients of high grade non-muscle invasive urothelial carcinoma and group C which include 20 patients of muscle invasive urothelial carcinoma used for correlation of immunostaining. Cases were obtained from the archive of Pathology Department of Alexandria Police Hospital and other private clinics depending on the availability of patients follow up records.
Tissue microarray (TMA) blocks with 0.1 diameter cores were constructed from each formalin-fixed paraffin-embedded bladder cancer tissue block of TURBT specimens using a tissue microarrayer
Summary, Conclusions and Recommendations
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Serial of 4μm thick paraffin sections from all obtained microarray blocks have been subjected to:
1. Routine H&E staining.
2. GATA3 immune staining.
3. CK5/6 immune staining.
4. IMP3 immune staining.
The expression of GATA3 was detected as brown colouration in the nuclei of the tumor cells. Immunoreactivity score for GATA3 expression was calculated by multiplying the number representing the percentage of immunoreactive cells by the number representing staining intensity and the cases were categorized in four groups which are negative (score 0-1), weak positive (score 2-4), moderately positive (score 6-8) and strongly positive (score 9-12).
The expression of CK5/6 was detected as cytoplasmic staining of the tumor cells with perinuclear enhancement and scored as negative (0, <5% of cells stained), focally positive (1+, 5%–10% of cells stained), positive (2+, 11%–50% of cells stained) or diffusely positive (3+, >50% of cells stained).
According to the expression of GATA3 and CK5/6, the studied cases were molecularly classified into luminal, basal, mixed and null molecular subtypes. In the current work, molecular subtypes were significantly correlated with the tumor progression but not with tumor stage, tumor grade or recurrence of the tumor during the follow up period.
The expression of IMP3 was detected as cytoplasmic staining of the tumor cells in the tumor areas with the densest positive staining and scored as mild, moderate or strong. IMP3 was significantly correlated with higher tumor grade, higher tumor stage and highly correlated with tumor progression and the molecular subtype of the progressed cases.
In conclusion, our results demonstrated that the expression of IMP3 in non-muscle invasive bladder cancer could serve as an independent predictor that would help clinician to identify the molecular subtype of the patients and highlight patients with a high ability to relapse, progress, and metastasize and who might get the maximum benefit from an early and more aggressive treatment strategy
Summary, Conclusions and Recommendations
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6.2 Conclusions
Bladder cancer incidence is higher in the age group 41 – 59 years with a male to female ratio approximately 4:1.
Age, initial tumor size, tumor grade and tumor stage are factors affecting tumor recurrence of urothelial carcinoma.
Tumor grade and tumor stage with special emphases on the level of muscularis muscoa invasion seemed to be important predictive factors for tumor progression during follow up of the patients.
Stratification of NMIUC cases according to the molecular subtype is feasible and divides this group of patients into prognostically and potentially predictive categories.
Molecular subtypes were significantly correlated with the tumor progression but not with tumor stage, tumor grade or recurrence of the tumor during the follow up period.
The luminal subtype is the most prevalent molecular subtype of BC and it is an independent predictor of most aggressive tumors in NMIUC.
Luminal molecular subtype is divided into 2 categories, one of good prognosis and the other is associated with more aggressive behavior of poor prognosis and high progression rate.
IMP3 was significantly correlated with higher tumor grade, higher tumor stage and the molecular subtype of the progressed cases.
The expression of IMP3 in non-muscle invasive bladder cancer is an independent prognostic marker that highlights patients with a high ability to relapse, progress, and metastasize.
Summary, Conclusions and Recommendations
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6.3 Recommendations
Verification of molecular subtype of bladder cancer in individual cases is strongly advocated with application on a large scale. This approach is apt to affect tailored targeted therapy, prognosis and overall patient survival.
Entirely separate study would be necessary to address molecular phenotypes in bladder carcinoma with variant histology.
Longer follow up period to study the effect of intravesical therapy especially on basal phenotype.
More interest should be directed to studying early onset bladder cancer with particular emphasis on elucidating the possible effects of molecular subtype