Nyholm et al. (16) suggested in 1993 that EC is a complex disorder with two distinct variants, which have since been designated as type I and type II. Type I is characterized by endometrioid histology and occurs in women with certain classical features associated with hyperestrogenism, including obesity, anovulation, nulliparity, exogenous estrogen, and endometrial hyperplasia. Type II is of serous cell type, which appears to lack direct hormonal influence and may arise as anaplastic cancer in older women even in the presence of atrophic endometrium.
The most common EC variant is the endometrioid type, with an indolent biological behavior. The aggressive serous, papillary, and clear cell types of EC fortunately are rarer. Other types of ECs include pure squamous, mixed adenosquamous, mucinous, and mixed types. It is the endometrioid type carcinoma that is often preceded by endometrial precursor lesions, such as complex and atypical endometrial hyperplasia. Type I cancers (prototype endometrioid carcinomas) (Fig. 4) are often well differentiated, typically slow-growing cancers with usually excellent prognosis. Type I ECs (approx 80% of all ECs) tend to occur in perimenopausal or recently postmenopausal women with preceding endometrial hyper-plasia and other indications of excessive estrogenic effects unopposed by progesterone. Endometrioid tumors may show glandular, solid, or villoglandular histological patterns. Occasional morules of benign squamous metaplasias can be seen. Predictably, these tumors have high estrogen receptor (ER) and progesterone receptor (PR) content and respond well to treatment. However, there is marked heterogeneity in the expressions of these receptors
as demonstrated by tissue immunohistochemistry, which makes interpretation difficult in routine clinical situations. Because there is excellent correlation of tissue hormone receptors with histological type and grade of the tumor, ER and PR are not routinely measured in type I ECs (17,18). To date, there has been no reported systematic comparison of the hormone receptors in sporadic and hereditary endometrial carcinomas.
Type II cancers (prototype serous papillary carcinomas) (Fig. 5) on the other hand, tend to occur in older, late postmenopausal women with no previous sign of excess estrogen effect. These tumors (approx 10% of all ECs) are high grade, biologically aggressive, hormone receptor negative, and have a poor prognosis. They are characterized by distinct papillae with fibrovascular cores and markedly atypical nuclei. Clear cell and "hobnail" features are not uncommon. The histology closely resembles serous papillary tumors of the ovary. The precursor lesion of this tumor is flat, and superficial glandular change is characterized by marked nuclear atypia. This is termed endometrial intraepithelial neoplasia (EIN) and is usually seen in an atrophic background. The predominant molecular marker for this tumor is mutation of p53, a tumor inhibitor gene. Immunoperoxidase stains with DO7 (anti-p53) marks 70-100% of serous papillary ECs as well as the precursor EIN lesions (19,20). Other useful molecular markers include high cell proliferation markers, such as MIB-1 and Ki-67, and loss of heterozygosity (LOH) in multiple chromosomal regions. In contrast to the serous papillary tumors of the ovary, these ECs are negative for WT-1 (21,22).
Both endometrioid and serous EC can manifest a primary genetic etiology, although most studies show that hereditary EC more commonly is of endometrioid histology and hereditary serous EC is rare. Hereditary endometrioid EC shares pathological features with type I EC. However, because the role of estrogen in hereditary EC is still elusive, if type I is defined as involving hyperestrogenism, it is unclear whether hereditary ECs would fall into that category. Sporadic and hereditary endometrioid ECs follow separate molecular genetic pathways during carcinogenesis (infra vide). Recently (22a), MLH1 promoter hypermethylation has been found in 91% of ECs with micro-satellite instabilities causing loass of MLH1 expression. Moreover, primary hereditary factors may predispose susceptible individuals to the perturbation of endogenous or exogenous cofactors.
Endometrioid carcinoma is the most frequently diagnosed EC in HNPCC syndrome patients, and no survival or prognostic differences are found between sporadic type I and hereditary EC (23). However, recent studies (23a) have shown the HNPCC related ECs to be more poorly differentiated, more often associated with Crohn-like lymphoid infiltrates and more often exhibiting angiolymphatic invasion than its sporadic counterpart.
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