Prognostic importance of proliferative index of tumoral markers Ki67 and pHH3 in thin cutaneous melanoma in survival and positivity prediction of sentinel lymphonod

Abstract

Cutaneous melanoma results from the interaction of environmental factors and the host, and although the sunlight is the main environmental determinant of melanoma, also genetic mechanisms involved in its genesis are studied today. Among these, the most important gene in sporadic and familiar melanoma is CDKN2A, which encodes the protein p16, and inhibits cyclin-dependent kinases CDK4 and Cdk6, inhibiting both protein phosphorylation retinoblastoma (pRb) and subsequent cell cycle progression of G1 to S. It is also known that one of the ways to negative control tumor is apoptosis and in these cases the genes Bcl-2, c-myc and p53 and the expressions of their protein products have been linked the blocking of growth and the apoptotic process. Studies prove that 15% of deaths result from thin metastatic melanoma lesions (thickness d 1 mm). However prognosis of a patient with melanoma depends on several factors such as thickness tumor, ulceration, anatomic site, Clark level, Breslow, patient's age and sex. Several attempts to improve survival prediction of patient with cutaneous melanoma have been researched. According to the latest version of AJCC, other potential factors have not been assessed due to insufficient data, as the tumor mitotic index, which measures the proportion of cells occupying a given fraction of the cell cycle at a point of total cell population. Growing interest in the use of markers is due to its usefulness in assessing individual risk patients. Among these, the proteins included in this study: Ki67 protein, expressed in all stages of cell cycle, except G0, whose expression has been presented as diagnosis biomarker; and the protein pHH3, that is maximun phosphorylated during the mitotic cell cycle, becoming a marker for mitosis. To measure the mitotic tumor index, it is used the total number of mitoses per mm² in the component of invasive melanoma, method of greater reproduction among pathologists. Therefore we intend to investigate the prognostic role of the mitotic index through the use of tumoral markers pHH3 and Ki67 in patients survival with thin primary cutaneous melanoma and the prediction of positivity lymph sentinel. For it, we will make a retrospective cohort study with 450 patients with thin primary cutaneous melanoma enrolled in the Department of Cutaneous Oncology of AC Camargo Hospital attended since 1990. After completing the questionnaire according to medical records information, will be used t test Student and Chi-square test for relationship between the data predictions. Will be evaluated overall and disease-free survival, using the Kaplan-Meier method, and for comparison between survivals, log-rank test and its relationship with different prognostic factors evaluated (mitotic index, pHH3, Ki67 and positive sentinel lymph node) will be used. Four variables will be considered: 1. disease-free survival: interval time from diagnosis to recurrence; 2. global survival: interval time between diagnosis and death related to melanoma; 3. positivity for sentinel lymph node 4. mitotic index. We understand that our work as pioneer, whereas there are few studies on this subject and to believe that the parameters of clinical practice needs to be accessed by simple methods such as mitosis, Ki67 and PHH3, which are reproducible, involving larger numbers of melanoma at risk. (AU)