Investigação das alterações moleculares nos receptores de fator de crescimento epidermol(HER-1 e HER-2) e da proteína P16 em carcinoma de células escamosas de língua e assoalho de pacientes jovens e adultultos

Abstract

Squamous Cell Carcinoma (SCC) is increasing in young patients, especially in the tongue and it corresponds to 6% of all oral cancers. It has been suggested that this malignancy is a distinct disease from that occurring in older patients with different etiological factors and clinical progression. HER family receptors play an important role in the pathogenesis and progression of SCC, including head and neck cancer. Overexpression of p16 in HPV infected tumors may represent a sign of inactivation of the cell cycle caused by viral oncoproteins and can be associated with carcinogenesis in oral SCC. A retrospective sample composed of young (18 &#8804; age &#8804; 40 years) and adults (age &#8805; 41) patients diagnosed with SCC of the tongue and / or floor of the mouth at the Brazilian National Institute of Cancer between 1999 and 2006 was selected. Histopathological analysis was performed using the parameters of the WHO grading system (2005) and Histopathologic Risk Assessment (HRA). Immunohistochemical staining method was used to evaluate HER-1 HER-2 and p16 expression.. Molecular analysis was performed through PCR to amplify sequences contained in exons 18, 19, 20 and 21. All analysis were performed for both age groups and compared later. Chi-square tests were used to verify association among variables studied and age groups. Survival analysis was performed through Kaplan-Meier method and log rank test. A p value &#8804; .05 was considered significant. Statistical program for Social Sciences (SPSS) computer software was used for all analysis. The study population consisted of 34 young patients and 31 adults. Among the young patients, there was no gender predilection , in both age groups tobacco users predominated, but alcoholism was more prevalent among adults (p = 0.009). Tongue was the most affected site, and most cases were found in young patients (p = 0.010). Tumor from young and adult patients were classified mostly as moderately differentiated (73.5%/80.6%). Young patients were characterized mostly as intermediate risk (50.0%) and adults as high risk for recurrence and poor survival (45.2%),using AHR . All cases (100%) were immunopositive for HER-1, which showed membrane and cytoplasmic staining. All sample was negative for HER-2. p16 immunostaining showed cytoplasmic and nuclear expression and was higher in young patients (p = 0.008). When analyzing the presence of mutations that lead to alteration of the primary structure of the protein (missense and nonsenses), it a higher prevalence in younger patients (p = 0.038) was found. As for overall and disease free survival analysis, it was found that the pstage influenced overall survival in adults (p = 0.005). Lymph nodes involvement indicated a worst overall survival in adults (p = 0.020 log rank) as well asworst disease-free survival in young patients (p = 0.001). Overall survival was influenced by the presence of recurrence in young (p < 0.0001) and adults (p = 0.004). There was an association of overall survival and HRA with young patients (p = 0.011). SCC in young patients occurs mainly in the tongue and has no gender predilection. Usually these patients consume less amounts of alcohol in comparison to adults. Positivity observed for antibodies against HER-1 and p16 demonstrates the involvement of these proteins in carcinogenesis of tongue and floor of the mouth SCC. Mutations present at hot spot regions of the HER-1 gene reinforce its involvement in tongue and floor of the mouth SCC development in young patients. Further investigations in this research field are suggested in order to evaluate proteins involved in HER-1 signaling pathway, as well as HPV virus presence in p16 positive cases