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.