Evaluation of IGF1 Serum Levels in Malignant Melanoma and Healthy Subjects

Discussion

The role of growth factors in the development of the malignant melanoma has been recently discussed. Several clinical studies with reference to serum levels and tissue receptor expression for the individual growth factors have been already published. We have focused on the comparison of IGF1 serum levels between patients with melanoma and healthy controls.

The age of the control group of healthy individuals was similar to the age of the group of patients with melanoma. The age parameter appeared to be the most problematic factor for statistical evaluation. IGF1 serum levels are significantly decreasing with age (6). When stratifying into the sub-groups based on the other criteria, the age distribution of the small sub-groups was not equal. Therefore, we have also tested the statistical significance of the age difference between the sub-groups. When the age difference was statistically significant (p<0.05), age adjustment has been performed in order to rule-out any incorrect conclusions. Based on our personal experience from our previous clinical trials, the age adjustment has been a crucial factor for IGF1 serum levels changes interpretation (7).

Our group of healthy cases consisted of patients who were examined in the surgical ambulance of our Faculty Hospital. We had therefore all the current and history medical data. We applied a similar selection criteria as in the studies of IGF1 reference values in the population (8, 9). We excluded patients with diabetes, high blood glucose, high insulin levels, patients after surgery, polymorbid patients and persons with a history of cancer diseases. Even though a rigorous selection of the healthy persons has been implemented, the group of healthy probands exhibited a very large variation of IGF1 serum levels. Because we did not find any disease that might, according to current knowledge, influence IGF1 levels, we decided to keep all probands in the group of healthy subjects. Nobody was excluded from this group. For a better presentation of the data distribution in the healthy and melanoma groups the mean, median, both quartiles and minimum and maximum levels are presented in Table I. The distribution of IGF1 in the group of healthy subjects demonstrates a very large and unexplained, for the time being, individual variability in IGF1 levels (10).

When comparing data of serum levels between the patients with melanoma and healthy individuals, we found that IGF1 serum levels were significantly higher in the melanoma group. To our knowledge there are only two studies evaluating serum levels of IGF1 in melanoma and healthy controls with opposite results compared to our study results (11, 12). Frenkel et al. proposed IGF1 to be a predictive biomarker for metastatic uveal melanoma but also with opposite results since levels of IGF1 were lower in metastatic melanoma compared to healthy subjects (13). In our study, the age of the two groups was not significantly different (p=0.8876); therefore, no age adjustment was used.

Focusing on the melanoma patients group, we stratified this group further into four sub-groups based on the Breslow score, which is the most important prognostic factor in melanoma, if sentinel lymph node is not examined. As primary tumor thickness increases, there is a significant decrease in survival (14, 15). IGF1 serum levels in the individual sub-groups were evaluated and correlated with the degree of invasiveness. The Kruskal-Wallis test for evaluation of IGF1 changes through all the sub-groups was used. The sub-groups formed based on the Breslow score were significantly different according to the age parameters; therefore, IGF1 values were age-adjusted. IGF1 serum levels correlated with increasing Breslow score only till the third subgroup. When the Breslow score was higher than 4 millimeters, IGF1 serum levels were decreasing. This finding agrees with the literature data (11,12). The present clinical study supports the theory that IGF1 plays a certain role, particularly in the period of cancer initiation. It supports the tumor growth at the early stages and it has also anti-apoptotic properties, probable via the activation of Akt and MAP kinase pathways (16). Various factors play the role in subsequent stages of cancer. Hyperactivation and deregulation of Akt and MAP kinase pathway increase activity of the signal transductors. Recent studies support the theory that several transductors are common for several pathways and mediate the signal transduction between the several type of the cell growth pathways (17). Based on this knowledge we assume that the value of the serum levels of IGF1 is not the main promoter of the next development of the cancer cells in advanced cancer stages.

Finally, we have studied two sub-groups of patients based on the metastatic positivity of sentinel lymph nodes. The status of the sentinel lymph node is the most important prognostic factor for the recurrence and survival prediction (18). Comparing these sub-groups with negative and positive metastatic process in sentinel lymph nodes, we found that IGF1 serum level was statistically significantly higher in patients with positive metastatic affection (p=0.0407). To our knowledge, there is no literature evidence concerning this evaluation.