Phospho–Akt: a new prognostic factor in uveal melanoma

Abstract

Abstract: : Purpose:Despite successful local treatment with radiotherapy and/or enucleation, systemic prognosis for uveal melanoma patients has not improved in the past decades. Tumor–related death is primarily due to liver metastasis and metastatic disease is usually diagnosed several years after the diagnosis of the primary tumor. Therefore, the search for new treatment strategies, especially those focusing on metastatic spread, continues. Protection from apoptosis is one of the neoplastic cell features necessary for survival and dissemination. Phospho–Akt, the active form of the anti–apoptotic protein Akt, has been found to play a major role in tumorigenesis. Moreover, recently developed phospho–Akt inhibitors have been shown to decrease neoplastic cell survival in vitro. The purpose of this sudy is to evaluate the immunohistochemical expression of phospho–Akt and its role as a prognostic factor in uveal melanoma. Methods:Thirty–four patients with choroidal melanoma, whose affected eyes were enucleated between 1980 and 2001, were included in the study. The formalin–fixed, paraffin–embedded specimens were retrieved from the Henry C. Witelson Ophthalmic Pathology Laboratory and Registry. Clinical and pathologic data were obtained. Follow–up time was at least 72 months. Immunohistochemistry for phospho–Akt was performed using an anti–phospho–Akt (Ser 473) rabbit antibody. Samples were classified as negative or positive. Curves of cumulative metastasis development according to phospho–Akt immunostaining were plotted using Kaplan–Meier survival analysis. The log–rank test was used to assess statistically significant differences. Results:Of 34 patients, 13 patients were females and 21 were males. The mean age at diagnosis was 61.6 years (range: 41 to 81 years). Metastasis was observed in 15 patients and 12 of these had liver involvement. Phospho–Akt was positive in 19 cases (55.9%) and 11 of these cases developed metastasis (57.9%), whereas among the 15 phospho–Akt negative cases (44.1%) only 4 developed metastasis (36.4%). A statistically significant association between positive phospho–Akt immunostaining and metastatic disease was found (p=0.028). Conclusions:Immunohistochemical expression of phospho–Akt is a predictor of metastatic disease in uveal melanoma patients. These findings warrant further in vitro and in vivo investigations of phospho–Akt inhibitors in the treatment of uveal melanoma.

Keywords: melanoma • uvea • immunohistochemistry