DISTINCTIVE P53 AND MDM2 IMMUNOHISTOCHEMICAL EXPRESSION PROFILES SUGGEST DIFFERENT PATHOGENETIC PATHWAYS IN POORLY DIFFERENTIATED ENDOMETRIAL CARCINOMA

Endometrial serous carcinoma (ESC) and FIGO (International Federation of Gynecology and Obstetrics) grade 3 endometrioid adenocarcinoma (EC) are high-grade endometrial tumors that have different clinical and mo rphologic attributes. Alteration of p53 tumor suppressor protein funct ion has been implicated in the pathogenesis of both tumors, although t he mechanisms may differ. We sought to investigate this difference by comparing immunohistochemical expression of p53 and mdm2, p.S.7 immuno reactivity often correlates with gene mutation,whereas increased mdm2 expression is linked to complex formation with wild-type p53 resulting in its inactivation. Twenty cases of ESC and 21 cases of EC were eval uated and an immunoreactivity score (IRS) was assigned using both the percentage of cells stained and the intensity of staining. The overall IRSs were significantly different in ESCs versus ECs for both p53 and mdm2 (p <0.001 and p <0.01, respectively). Strong mean immunoreactivi ty for p53 was detected in 15 (75%) ESCs as compared to only weak mean immunoreactivity in 17 (81%) ECs. Conversely, for mdm2 expression, 17 (81%) ECs had moderate mean immunoreactivity whereas 9 (45%) ESCs sho wed only weak mean immunoreactivity. mdm2 expression more closely corr elated with p53 expression in ECs than in ESCs. In ECs, mdm2 was detec ted in 16 of 17 (94%) p53-positive tumors but in only 1 of 3 (33%) p53 -negative tumors (p <0.025). In ESCs, mdm2 was detected in 9 of 15 (60 %) p53-positive tumors but in none of the 5 p53-negative tumors (p <0. 10). Overall, our results demonstrate an inverse relationship between the expression of p53 and mdm2 in ESC versus high-grade EC. Specifical ly, strong p53 immunoreactivity is associated with weak mdm2 expressio n in ESC and weak p.S.7 expression is associated with moderate mdm2 ex pression in EC. These results suggest different pathogenetic pathways resulting in loss of normal p53 function in these two tumors: by p53 g ene mutation (strong p53 overexpression) in ESCs, or by mdm2 complex f ormation and inactivation of p53 in high-grade ECs.