Nevus displásico: graduación de la atipia y correlación de la atipia con marcadores de proliferación y de migración celular

Resumen

El nevus displasico (ND), factor de riesgo de melanoma maligno (MM), ha sido fuente de controversia en diferentes sentidos desde su descripcion, desde el nombre asignado, los criterios clinicos e histologicos que la caracterizan hasta la gradacion de los mismos en tres grados de atipia: leve, moderado y severo. Se ha evaluado en primer lugar si el grado de atipia de los ND tiene alguna relacion con el riesgo de padecer melanoma mediante un estudio de datos clinicos y en segundo lugar, buscar un marcador que permita realizar una clasificacion del grado de atipia de los nevus displasicos basada en criterios objetivos mediante el estudio de la expresion del marcador de proliferacion Ki-67 y el marcador de migracion ChAT (Acetil-colina transferasa). En la primera parte del estudio se revisaron los informes de 20.275 nevus recibidos entre 1989 y 1996, constatandose que 6.275 eran ND que pertenecian a 4.481 pacientes. Los pacientes fueron clasificados con respecto a su lesion con mayor grado de atipia y se reviso sus datos clinicos con respecto a la historia de melanoma. Se calculo la Odds Ratio (OR) como medida de asociacion entre los grados de atipia de los ND e historia de melanoma. En la segunda parte del estudio se realizo estudio inmunohistoquimico con doble marcaje para HMB-45 y Ki-67 en 36 ND con atipia leve, 36 ND con atipia moderada, 36 ND con atipia severa, 18 nevus melanociticos benignos (NMB) y 18 MM in-situ, evaluandose la proporcion de celulas melanociticas de la union dermo-epidermica positivas para Ki-67. Asi mismo se realizo estudio inmunohistoquimico para ChAT en 30 ND con atipia leve, 30 con atipia moderada y 30 con atipia severa. Los resultados pusieron de manifiesto que 2.504 pacientes presentaban ND con atipia leve como nevus con mayor grado de atipia, 1.657 ND con atipia moderada y 320 ND con atipia severa. La revision de sus datos clinicos puso de manifiesto que 142 pacientes del grupo de atipia leve, 133 pacientes del grupo con atipia moderada y 63 pacientes del grupo con atipia severa tenian historia de melanoma (c2= 59,89; p<0,001). El estudio de la asociacion del grado de atipia con historia de melanoma dio como resultado una OR de 4,08 (2.91-5,7) para los ND con atipia severa versus ND con atipia leve, 2,81 (2-3,95) para los ND con atipia severa vs ND con atipia moderada y 1,45 (1,13-1,87) para ND con atipia moderada vs leve. El estudio inmunohistoquimico con doble marcaje con HMB-45 y Ki-67 mostraron diferencias significativas entre ND vs NMB vs MM (p<0,0001) y entre ND con atipia severa vs ND con atipia leve y moderada (p<0,0003). No se observaron diferencias significativas en el estudio mediante ChAT. En conclusion, la gradacion de la atipia citologica de los ND se correlaciona con el riesgo de presentar historia de melanoma y el estudio del indice de proliferacion Ki-67 puede ser de ayuda para diferenciar entre NMB, ND y MM, asi como para distinguir entre ND con alto y bajo grado de atipia (leve y moderada). Classification of the different aspects of dysplastic nevus (DN), a risk factor of malignant melanoma (MM), has been source of controversy from its decription, its assigned name and clinical and histological criteria, by which it is chacarcterized, to the ranking of the same into three grades of atypia: mild, moderate, and severe. In the first place, through a study of clinical data, it has been assessed if the grade of DN atypia has some relationship to the risk of suffering from MM; and, in the second place, through studies of the proliferation marker Ki-67 and the ChAT migration marker (acetyl choline transferase), a marker has been searched for, which will allow the classification of the grade of atypia for DN, based on objective criteria. In the first part of the study, reports on 20,275 nevi received between 1989 and 1996 were examined, verifiying that 6,275 of them were DN belonging to 4,481 patients. The patients were classified with respect to their lesions, having the greatest grade of atypia, and their clinical data was also examined, with respect to their history of melanoma. The Odds Ratio (OR) was calculated as a measure of association between the grades of DN aypia and the history of melanoma. In the second part of the study, an immunohistochemical study was conducted, with double staining for HMB-45 and Ki-67 on 36 DN with mild atypia, 36 DN with moderate atypia, 36 DN with severe atypia,18 BMN and 18 MM in-situ, evaluating the proportion of melanocytic cells in the dermo-epidermic junction, showing positive for Ki-67. In this way, an immunohistochemical study was also carried out for ChAT in 30 DN with mild atypia, 30 with moderate atypia and 30 with severe atypia. Results made clear that 2,504 patients presented DN with mild atypia as the highest presenting grade of atypia, 1,657 DN presented with moderate atypia, and 320 presented DN with severe grade of atypia. The review of the clinical data made clear that there were 142 patients in the group having mild atypia, 133 having moderate atypia, and 63 with sever atypia, who all had personal histories of MM (c2= 59,89; p<0,001). The study of the association of the grade of atypia with the history of MM gave as its result an OR of 4.08 (2.91-5.7) for the DN with severe atypia: DN with mild atypia; 2.81 (2-3.95) for the DN with severe atypia: DN with moderate atypia; and 1.45 (1.13-1.87) for DN with moderate atypia : DN with mild atypia. The immunohistochemical study with double staining for HMB-45 and Ki-67 showed significant differences between DN:BMN:MM (p<0.0001) and between DN with severe atypia : DN with mild and moderate atypia (p<0.0003). No significant differences were observed in the study using ChAT. In conclusion, the ranking of the cytological atypia of DN is correlated to the risk of presenting a history of melanoma, and the study of the proliferation rate of Ki-67 can help in the differentiation between BMN, DN, and MM, such as between DN with severe and mild+moderate atypia.