Uterine papillary serous carcinoma evolves via a p53-driven pathway

Uterine papillary serous carcinoma (UPSC) is a highly aggressive type of endometrial cancer that occurs in the absence of hyperestrogenism and endometrial hyperplasia. Biologically, UPSC belongs to a distinct group of aggressive neoplasms of the extended Mullerian epithelium that are characterized by hypoestrogenism, advanced disease at diagnosis, a serous papillary histotype, and a dismal prognosis. There is mounting evidence that loss of p53 function is critical for the molecular genetic cause of all tumors in this group. To further assess the role of p53 alterations in UPSC, we studied 40 patients using immunohistochemical expression analysis. Thirty- four tumors (85%) showed intense nuclear overexpression of p53, whereas six tumors (15%) were p53 negative. Thirteen p53-positive tumors had multiple samplings from distinct anatomic sites, and all showed complete concordance in p53 staining, suggesting that p53 alterations occur early in UPSC carcinogenesis. p53 positivity was associated with loss of hormone receptors. Thirty-nine cases were concomitantly analyzed for estrogen or progesterone receptor expression. Among those, 31 tumors were p53 positive but hormone receptor negative throughout, in contrast to only two tumors that were diffusely p53 positive and focally hormone receptor positive. Patients whose tumors overexpressed p53 had a statistically significant shorter survival than those whose tumors did not at 24 and 48 months (P = .03). This study represents one of the two largest analyses published to date that confirm the strong association between UPSC and p53 overexpression. Furthermore, we suggest that the concept of UPSC be broadened: UPSC is a p53-driven neoplasm that biologically is a kin to other serous papillary malignancies of the ovaries and peritoneum. This group of tumors bypasses the slow hormone- dependent pathway of tumorigenesis but instead undergoes early p53 alterations that lead to rapid tumor development.