The cause of uterine serous carcinoma is not clear but it has been associated with several pathologic entities, including a pre-existing endometrioid carcinoma, serous intraepithelial carcinoma and endometrial glandular dysplasia. 4
Endometrial glandular dysplasia is a strong candidate for a pre-existing (precursor) lesion that is not malignant but harbors the potential to progress to serous intraepithelial carcinoma. There is a growing body of morphologic and molecular evidence implicating endometrial glandular dysplasia as a putative precursor of endometrial serous carcinoma.5
Briefly, foci of endometrial glandular dysplasia are characterized by atypical cells exhibiting serous differentiation, with nuclear atypia that falls short of the degree seen in serous carcinoma. 21
Recent reports have linked the p53 signature to serous carcinogenesis in the fallopian tube, highlighting a series of properties that this process has in common with serous carcinoma of the fallopian tube, including location in the distal fallopian tube, involvement of the secretory cell phenotype, strong immunostaining for p53, p53
mutations, evidence of DNA damage (punctate staining for γ-H2AX), physical association with serous intraepithelial carcinoma and shared risk factors with ovarian cancer .15
Prior to this report, a similar entity had not been described in the endometrium.
This report describes foci of p53-positive benign epithelium in the endometrium raising the possibility that an entity similar to the p53 signature develops in the endometrial surface lining. The strongest case can be made for the p53-positive epithelia seen adjacent to serous intraepithelial carcinoma. First, these foci are typically immunopositive for γ-H2AX, defined as punctate immunostaining that presumably signifies a response to DNA damage. Second, γ-H2AX is invariably present in serous carcinoma. Third, based on the p53 sequence data, some p53 signatures are genetically related to their malignant counterparts. However, is important to emphasize that not all p53 signatures shared the same mutation with the corresponding malignancy, consistent with the fact that the two entities are not always biologically related. We have previously shown that multiple p53 signatures, each with a different p53
mutation, can be found adjacent to serous carcinomas, suggesting that multiple early events can occur, with only a subset progressing to malignancy.15
Based on the findings in this report and the existence of other pathways to uterine serous cancer, the p53 signature associates with, and probably accounts for, only a subset of uterine serous malignancies. It should be emphasized that this study focused on classic examples of early serous carcinoma, primarily serous intraepithelial carcinoma. Based on this report, a subset of serous malignancies appears to be related etiologically to a p53 signature. Not studied was the greater spectrum of these tumors, included those with mixed serous and endometrioid phenotypes including those with abrupt or gradual transitions from endometrioid to serous differentiation. These tumors appear much less likely to arise within p53 signatures. Nevertheless, all of these pathways appear to share a common feature, which is the emergence of a p53 mutation. The mutation may develop prior to morphologic atypia (p53 signature), associate with minor epithelial atypia (endometrial glandular dysplasia) or emerge from a pre-existing malignancy previously lacking a p53 mutation, resulting in biphasic tumor patterns. When serous intraepithelial carcinoma is encountered, the presence of endometrial glandular dysplasia, the p53 signature, or both, appears more likely, as shown in this report.
Although the p53 signature appears to be a common entity in the fallopian tube, its frequency in the endometrium remains unclear, as does the significance of the p53 staining seen in the benign polyps. In contrast to the p53 signatures described in the fallopian tube, the p53-positive foci in the endometrial polyps did not stain for γ-H2AX. Thus, the significance of such changes, when found in otherwise benign glands, remains to be determined.