The significance of collagen IV type, Ki-67 and ММР-9 expression in non-invasive urothelial cancer of bladder for prediction of the disease

Яковцова И.И., Долгая О.В., Данилюк С.В.

Summary. Bladder cancer (BC) in 70–80% of cases are diagnosed as non-muscle-invasive (stage T1), the overall rate of recurrence for non-muscle-invasive bladder cancer (NMIBC) is approximately 70%. Immunohistochemistry represents an important objective complementary tool for the routine diagnosis of NMIBC and for the indentification of the tumor biological behavior and also serve as criteria for predicting recurrence and progression of the disease. The aim of present stady is to investigate the expression of Ki-67, matrix metalloproteinase-9 (ММР-9) and collagen IV type in NMIBC for identifation the criteria for recurrence and progression of the disease. Materials and methods. Three groups of research were formed: NMIBC without recurrence — group I (14 cases), the primary NMIBC with recurrence without progression — group II (14 cases) and the primary NMIBC with recurrence and progression in secondary tumors in the form of invasion in muscle layer — group III (14 cases). An immunohistochemical study was carried out using primary monoclonal antibodies of DAKO to type IV collagen, MMP-9 and Ki-67. The expression indicators of markers associated with the immune response were studied in three fields of view of the microscope of histological sections with the most pronounced expression at magnification ×400. Counting the number of cells expres­sing markers was carried out on a Primo Star microscope with a camera with an increase in ×400 lens using Adobe Photoshop CS6. The area of testing was 0.057 mm² (57,000 µm²). Reaction to Ki-67: 1 point — up to 20% of tumor cells in sight, 2 points — 20–50% of tumor cells, 3 points — more than 50% of tumor cells. Reaction to type IV collagen: 0 — no reaction or expression in less than 5% of the tumor area, 1 point — weak, intermittent expression of the marker, 2 points — continuous clear staining of the basement membranes. Reaction to MMP-9: 1 point — up to 50% of tumor cells, 2 points — more than 50% of tumor cells of varying degrees of intensity, 3 points — intense expression of 100% of tumor cells. Results and discussion. A high grade of malignancy is cha­racterized by expression of Ki-67 over 20% of tumor cells (p<0.0001), pronounced expression of MMP-9 (p<0.05) and lack of response to type IV collagen (p<0.01), which defines these markers as criteria for the malignancy of NMIBC. In group I expression of Ki-67 and MMP-9 is lower than in group III (p<0.01 and p<0.03, respectively). Weak expression of MMP-9 and Ki-67 (up to 20% of tumor cells) are characteristics of cancers of group I (p<0.03 and p<0.005, respectively), Ki-67 expression over 50% of tumor cells associated with group III (p<0.03). A direct correlation between the expression of Ki-67 and MMP-9 (p<0.01) and the inverse relationship between Ki-67 and type IV collagen (p<0.01), MMP-9 and type IV collagen are traced, which characterizes the relationship processes of increasing the proliferative activity of cancer cells with an increase in their ability to produce metalloproteinases and destroy the extracellular matrix, and type IV collagen in particular. These changes lead to a more aggressive biological behavior of the tumor and can serve as criteria for the prognosis of the disease.
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