Endometrioid cancers arise in association with estrogen excess in the setting of endometrial hyperplasia in perimenopausal women, whereas serous cancers arise in the setting of endometrial atrophy in older postmenopausal women. The endometrioid type accounts for 80% of cases of endometrial carcinomas. These tumors are designated as endometrioid because of their histologic similarity to normal endometrial glands. Risk factors for this type of carcinoma include (1) obesity, (2) diabetes, (3) hypertension, (4) infertility, and (5) exposure to unopposed estrogen. Many of these risk factors result in increased estrogenic stimulation of the endometrium and are associated with endometrial hyperplasia. In fact, it is well recognized that prolonged estrogen replacement therapy and estrogen-secreting ovarian tumors increase the risk of the endometrioid type of endometrial carcinoma. Mutations in mismatch repair genes and the tumor suppressor gene PTEN are early events in the stepwise development of endometrioid carcinoma. Women with germline mutations in PTEN (Cowden Syndrome) and germline alterations in DNA mismatch repair genes (Lynch Syndrome) are at high risk for this cancer. TP53 mutations occur but are relatively uncommon and are late events in the genesis of this tumor type.
The serous type of endometrial carcinoma is less common but also far more aggressive. It accounts, for roughly 15% of tumors and is not associated with unopposed estrogen or endometrial hyperplasia. Nearly all cases of serous carcinoma have mutations in the TP53 tumor suppressor gene, whereas mutations in DNA mismatch repair genes and in PTEN are rare. Serous tumors are preceded by a lesion called serous endometrial intraepithelial carcinoma (SEIC) in which TP53 mutations are often detected, suggesting an early role for such mutations in the development of this form of endometrial carcinoma.
Fig.19.12A–B ).Theyincludearangeofhistologictypes,includingthoseshowingmucinous,tubal(ciliated),andsquamousdifferentiation.Endometrioidcarcinomasofteninfiltratethemyometriumandcanentervascularspaces(lymphovascularinvasion).Theymayalsometastasizetoregionallymphnodes.Endometrioidcarcinomasaregraded1to3,basedonthedegreeofdifferentiation.
Serouscarcinomastypicallygrowinsmalltuftsandpapillaewithmarkedcytologicatypia.Theycanalsoformglandsthatattimescreateconfusionwithendometrioidcarcinoma,howeverserouscarcinomasexhibitmuchgreatercytologicatypia.Serouscarcinomasbehaveaggressivelyandthusarebydefinitionhighgrade.Immunohistochemistryoftenshowsdiffuse,strongstainingforp53inserouscarcinoma(
Fig.19.12C–D ),afindingthatcorrelateswiththepresenceofTP53 mutations(mutantp53accumulatesandhenceismoreeasilydetectedbystaining).
Endometrial carcinomas usually manifest with irregular or postmenopausal bleeding. With progression, the uterus enlarges and may become affixed to surrounding structures as the cancer infiltrates surrounding tissues. Endometrioid carcinoma usually is slow to metastasize, but if left untreated, eventually disseminates to regional nodes and more distant sites. With therapy, the 5-year survival rate for early-stage endometrioid carcinoma is 90%, but survival drops precipitously in higher-stage tumors. The prognosis with serous carcinomas is strongly dependent on operative staging but because of its aggressive behavior it often presents as high-stage disease with a poor prognosis.
Endometrialhyperplasiaresultsfromunopposedendogenousorexogenousestrogen.