Prognostic role of nuclear and cytoplasmic p16INK4A expression and expression of E2F1 in gastrointestinal stromal tumors (GIST)

Aims: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Assessing the risk of malignant potential is currently based on the clinicopathological parameters of tumor size, mitotic count, and anatomical site. In some cases, the prediction of biological potential is difficult, because larger tumors with lower mitotic activity may also occasionally metastasize. Several proteins have been analyzed by immunohistochemistry for their potential value as prognostic markers in GISTs. In particular, the G1- phase cyclin-dependent kinase inhibitor p16INK4A (CDKN2A) has been evaluated in numerous studies. Two different forms of p16INK4A were identified, presenting with predominantly nuclear and cytoplasmic expression pattern. Secondly E2F1, a central promoter of cell proliferation was evaluated. Materials & Methods: A series of 122 primary surgically resected GISTs was analyzed by tissue-microarray-technology and immunohistochemical staining. For the quantitative expression of the G1-phase-proteins E2F1 and the nuclear p16INK4A expression computer based evaluation methods were used. The evaluation of cytoplasmic p16INK4A immunoreactivity was performed semiquantitatively. The proteins were evaluated dependence on the clinicopathological parameters of anatomical localization, tumor size, mitotic count, risk classifications by Miettinen and Lasota (2006) and by Fletcher (2002) and the prognosis. Results: E2F1 up-regulation correlated with low nuclear p16INK4A expression and higher mitotic counts. Although low or high E2F1 expression had no significant influence on the prognosis. However there was a tendency that up-regulation of E2F1 correlate with tumor progression. Strong expression of the cytoplasmic p16INK4A was significantly associated with shorter disease-free survival. There was an weak association between higher mitotic counts and strong expression of the cytoplasmic p16INK4A , nevertheless there was no correlation with the transcription factor E2F1. This observation implies that E2F1 may not be directly related to the biological mechanism constituting up-regulation of the cytoplasmic form of p16INK4A. The expression of these two forms was not correlated with each other and there was no significant prognostic value of nuclear p16INK4A expression. Tendentially low nuclear p16INK4A expression was associated with tumor progression. In a Cox prognostic model for association of the three proteins, anatomical site and risk classification of Fletcher (2002) as well as Miettinen and Lasota (2006) with disease-free survival showed that only the risk criteria of Fletcher (2002) and Miettinen and Lasota (2006) are significant in assessing the prognosis of patients with gastrointestinal stromal tumors. Conclusions: The expression of the cytoplasmic p16INK4A, the nuclear p16INK4A expression and the E2F1 expression give no additional information to the risk criteria of Fletcher (2002) and Miettinen and Lasota (2006) with disease-free survival. Those are more cost-effective and easier to provide.2016-05-2