The attempt to further identify the patients at high risk to develop metastases for tumors is very necessary to avoid unnecessary therapeutic procedures. Although the survival rate of children and adolescents with nephroblastoma has increased, successful therapy has been associated with longterm toxicity. Strategies for prevention of treatment related toxicity includes developing new prognostic parameters.
Some recently studied prognostic factors for nephroblastoma include multidrug resistance-related protein 1 (MRP1), neurotrophin-receptor TrkB, heat shock protein 70 (HSP70), epidermal growth factor receptor (EGFR), transforming growth factor alpha and c-erb B-2 (12-15). Between these MRP1, TrkB and TGF-alpha were negatively correlated with prognosis and HSP70 expression were much expressed in cases who survived. Prognostic role of nm23 in nephroblastoma has not been studied yet.
It is suggested that biological significance of nm23 expression might be different in different tissues and neoplasms . Nm23-H1 is known as a differentiation inhibitory factor. Plasma levels of nm23-H1 can also be measured by ELISA method. In myelodysplastic syndrome, nm23-H1 level was low in patients with low international prognostic scoring system . This suggests that nm23- H1 may be useful as a prognostic marker for MDS, especially in low risk patients. IHC expression of nm23 was found more intensive in patients with nonrecurring disease and living patients among 50 ovarian cancer patients . In non-small cell lung cancer nm23 was found to be a suppressor of systemic but not lymphatic metastasis . In breast cancer, the expression of NDP kinase/nm23 has been reported to correlate with good prognosis and a lack of nodal metastasis . But in retinoblastoma nm23 staining was observed to indicate a tendency to metastases . In thyroid follicular carcinoma a significant inverse association was observed between metastatic disease and nm23-H1 expression . Nm23-H1 expression was related with tumor progression in nasopharyngeal carcinoma . In rectal cancer nm23 expression failed to correlate with distant metastasis in the series of Gunther et al . In vitro transfection experiments show that the nm23 gene suppresses metastasis, although the evidence from clinical studies is contradictory . In a series of human colorectal carcinoma reported by Ayhan et al. , reduced expression of nm23 protein detected by Western blotting technique was found to be associated with advanced tumor stage and distant metastasis.
It has been suggested that nm23 immunoreactivity might be a prognostic and differentiating factor in neuroblastoma [19,20]. Overexpression of wild type nm23-1 proteins was defined to stimulate differentiation in neuroblastoma cell lines . Nm23 gene has been documented as metastasis-suppressor gene in normal development and differentiation . It has been identified in several aggressive neuroblastomas; mutated proteins might be related to the aggressiveness of neuroblastoma . Increased number of nm23-H1 copies was thought to be a predictor for poor prognosis independently in a series of 154 neuroblastoma cases .
Predicting the focus for investigating the metastatic potential of tumors is somewhat controversial. Should we examine the probable factors in the primary tumor or metastatic focus? The metastatic tumor cells might sometimes change some of their phenotypic properties. In this study we studied nm23 protein IHC expression in primary tumor tissues. We did not include specimens from metastases, recurrences or resections after treatment, because this study is designed to elucidate the usefulness of searching nm23 expression in primary tumors.
In our series statistical significance of metastasis, prognosis, stage and survival time all indicate prognostic significance of nm23 negativity. Absence of molecular
genetic analysis is a disadvantage but it is not available in formalin-fixed paraffin embedded tissues for nm23. It is not possible yet to claim to decrease the amount of therapy by nm23 positivity alone. More series need to be studied both by genetic and IHC studies. Nm23 status must also be correlated by other prognostic factor.
We conclude that negative nm23 protein expression might be a predictor for metastasis in nephroblastomas and it is an independent prognostic factor. It would worth studying the prognostic importance of nm23 in nephroblastoma and other tumors.