Discussion
There has been a serious increase in the survival rates of WT in recent years due to the intensive treatment regimens. Unfortunately, late mortality and secondary malignancies caused by the side effects of these intensive treatments remain one of the important problems. For this reason, the aim of recent studies has been to identify low and high-risk groups for WT and to improve the treatment regimens of children in the low-risk group. Determination of risk groups is considered as the first step in the treatment8. COX-2 expression is found in most malignancies such as cervix9, brain10, breast11, colon12 and ovary13 and is associated with poor prognosis. In our study, we aimed to determine the prognostic significance of the COX-2 biomarker, the role of which has been studied in other malignancies in recent years, but the number of studies on its significance in WT is very few. In recent years, there are studies suggesting that COX-2 has a very important role in tumoral cell cell proliferation, tumor angiogenesis, increased invasion, and metastasis. Its low expression in normal tissues and overexpression in tumoral areas made this marker a therapeutic target14.
In our study, we detected COX-2 positivity in 22 (92%) of our patients. In their study of 14 patients, Fridman et al. stated that COX-2 expression was observed in all patients, except for one anaplastic WT. They also emphasized that there was expression in the area of lung metastasis in one of the patients. They reported that they observed a weaker expression in the normal kidney tissue compared to the tumoral areas and it was confined to the tubular epithelium in the cortex and medulla7. Similarly, in our study, we observed a weak staining with COX-2 in the tubular epithelium. Lee et al. also reported in their study of 26 patients that they observed COX-2 positivity in all patients15.
According to the International Society of Pediatric Oncology (SIOP) studies, clinical stage, histology, tumor diameter, and response to treatment are among the prognostic factors for WT16. Moreover, as in other kidney tumors, renal pelvis invasion, renal sinus soft tissue invasion, renal sinus lymphovascular invasion, renal vein invasion, renal capsular invasion, perirenal adipose tissue invasion, lymphovascular invasion, survival as well as presence of anaplasia and nephrogenic residue are significant prognostic parameters. In our study, there was no significant correlation between COX-2 expression and any of these important parameters.
In the literature, there are studies reporting that COX-2 overexpression is a poor prognostic factor, but few studies have been conducted on COX-2 in the genitourinary system. Oku et al. reported that they observed COX-2 expression in bladder carcinomas, and that increased expression was correlated with high pT stage, decreased cell differentiation (high histological grade), and low survival rate. Based on the fact that COX-2 is correlated with tumoral cell differentiation, they thought that this marker might be effective at every stage of carcinogenesis17. In their study, Chen et al. stated that they found a significant correlation between increased COX-2 expression and tendency to invasion in renal cell carcinomas, and that invasion decreased with COX-2 inhibition18.
There are very few studies investigating the significance of COX-2 expression in WT. With the observation of COX-2 expression in all tumoral areas in WT, Lee et al. emphasized that it was especially more in areas where vascularity was more intense15. Giordano et al. observed COX-2 expression in all cases, independent of anaplasia findings, dominant component, presence of heterologous and/or homologous elements, age, gender, stage, and survival. Based on these results, they argued that COX-2 inhibitors could be used to treat all WT cases19. Fridman et al. also reported that COX-2 expression was present at all stages of the tumor in WT and not related to the aggressiveness of malignancy7. As in our study, studies in the literature have found no significant correlation between significant prognostic parameters and COX-2 expression in WT, and COX-2 positivity has been observed in all or nearly all cases. The observation of COX-2 expression in most cases suggests that the COX-2 pathway is effective in WT development.
There are 3 different components in WT: blastemal, epithelial and stromal. Although some tumors have the predominance of any of these three components, all three components are usually present in most tumors2. In our study, similar to the studies in the literature, all three components were observed in most of our cases. In our study, the expression of COX-2 was observed especially in the epithelial component, and the rates in the blastemal and epithelial components were 3-5% and 60-70%, respectively. COX-2 expression was not observed in the mesenchymal component. When Lee et al examined the prevalence of staining with COX-2, they reported a rate of 69% in the blastemal component and 73% in the epithelial component15. Giardino et al. observed COX-2 expression in the blastemal component at a rate of 45%, in the epithelial component at a rate of 7.5%, and in heterologous composite areas at a rate of 25%. Recent SIOP studies are on the prognostic significance of the volume of blastemal component and the determination of biomarkers for resistant blastema. Kinoshita et al. reported that the prognosis of tumors with predominant blastemal component is worse compared with those of other subtypes20. Beckwith et al. reported that the diffuse blastemal pattern was more aggressive but the survival rate was higher due to the higher response to chemotherapy21. In our study, in addition to the absence of a connection between other prognostic parameters and COX-2 expression, more dominant staining was observed in epithelial component instead of blastamel component, which is a bad prognostic finding.
Based on the effects of COX-2 on tumorigenesis and angiogenesis in recent years, it has been suggested that COX-2 inhibitors can be useful both for preventing and treating cancer14. According to the result obtained using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), it has been reported that halting proliferation, angiogenesis and vascular condensation rather than increased apoptosis are effective in halting tumor growth15. With the use of the COX2 inhibitor, it has been been observed that changes leading to an increase or decrease in the expression of genes to suppress vascular proliferation and vascular stability in WT are achieved1. In their study on rats, Maturu et al. argued that COX-2 inhibitors were effective in tumor progression in WT, and their combined use with other inhibitors may be extremely useful in the treatment. They emphasized that these combinations could be much more advantageous than radiotherapy, conventional cytotoxic therapy and other treatments used for WT, therefore, more studies were needed to be conducted in this regard22. In their study on mice, Lee et al. showed that the use of SC-236, a specific COX-2 inhibitor, prevented vascular proliferation in WT, thus reducing tumoral growth15. Although the reduction/non-progression of tumoral formation was not investigated in our study with the use of COX-2 inhibitors, the observation of COX-2 expression in most cases suggests that the COX-2 pathway is effective in the development stage of WT. Our study indirectly suggests that the use of COX-2 inhibitors may be effective in the treatment.