Carcinoma of the endometrium

Endometrial carcinoma is the most common invasive cancer of the female genital tract and accounts for 7% of all invasive cancer in women, excluding skin cancer. At one time, it was far less common than cancer of the cervix, but earlier detection and eradication of squamous intraepithelial lesions and an increase in endometrial carcinomas in younger age groups have reversed this ratio. There are now 39,000 new endometrial cancers per year, compared with 11,000 new invasive cervical cancers. Although they occur at a high frequency, endometrial cancers arise mainly in postmenopausal women. Because they cause abnormal (postmenopausal) bleeding, early detection and cures are possible.

T ype I carcinomas

These are the most common type, accounting for greater than 80% of all cases. The majority are well differentiated and mimic proliferative endometrial glands and, as such, are referred to as endometrioid carcinoma. As discussed above, they typically arise in the setting of endometrial hyperplasia and like endometrial hyperplasia they are associated with (1) obesity, (2) diabetes (abnormal glucose tolerance is found in more than 60%), (3) hypertension, (4) infertility (women who develop cancer of the endometrium tend to be nulliparous and have a history of functional menstrual irregularities consistent with anovulatory cycles), and (5) unopposed estrogen stimulation. Recent molecular studies have provided further evidence that endometrial hyperplasia is a precursor to endometrioid carcinoma (Fig. 22-27).

As mentioned earlier, mutations in the PTEN tumor suppressor gene have been identified in 30% to 80% of endometrioid carcinomas and in approximately 20% of endometrial hyperplasias, both with and without atypia. In hysterectomy specimens containing complex hyperplasia with atypia and carcinoma, identical PTEN mutations have been identified in each component.54 These findings support complex hyperplasia with atypia as a precursor to carcinoma and demonstrate that PTEN mutations occur before the development of invasion. Of interest, PIK3CA mutations have recently been reported in approximately 39% of endometrioid carcinomas, and they have been found in tumors with and without PTEN mutations.55 PIK3CA is the catalytic subunit of PI3K, a lipid kinase that phosphorylates PIP2 to PIP3, directly antagonizing the action of PTEN. However, in contrast to PTEN mutations, PIK3CA mutations rarely occur in complex hyperplasia with atypia, suggesting that mutations in PIK3CA play a role in invasion.56 Additional molecular changes that are common in type I carcinomas include microsatellite instability and mutations in the KRAS and β-catenin oncogenes. Microsatellite instability occurs in about 20% of sporadic tumors but is also found in tumors in women from families with hereditary non-polyposis colorectal carcinoma (HNPCC), as discussed in Chapter 17. While microsatellite instability in HNPCC-related carcinomas is caused by germline mutations, in sporadic endometrioid carcinomas it is most commonly due to epigenetic silencing (via promoter hypermethylation) of one of the DNA mismatch repair genes. Mutations in KRAS are found in approximately 25% of cases and have also, but less commonly, been found in complex atypical hyperplasia. These molecular genetic alterations in endometrioid carcinoma, are rarely, if ever, found in type II carcinomas. One of the genes altered in both tumor types is p53. In the more poorly differentiated endometrioid carcinomas, mutations in p53 can be found in up to 50% of cases. They are not identified in well-differentiated tumors or in complex atypical hyperplasias. Thus, it is thought that p53 mutations are a late-occurring event in endometrioid carcinoma, in contrast to what is seen in serous endometrial carcinoma, as discussed below.

M orphology. On gross inspection, endometrial carcinoma can be either a localized polypoid tumor or a diffuse tumor involving the endometrial surface (Fig. 22-28A). Spread generally occurs by direct myometrial invasion with eventual extension to the periuterine structures by direct continuity. Spread into the broad ligaments may create a palpable mass. Dissemination to the regional lymph nodes eventually occurs, and in the late stages, the tumor may metastasize to the lungs, liver, bones, and other organs.

On histologic examination, most endometrial carcinomas (about 85%) are endometrioid adenocarcinomas characterized by gland patterns resembling normal endometrial epithelium. A three-step grading system is applied to endometrioid tumors and includes well differentiated (grade 1) (Fig. 22-28B), with easily recognizable glandular patterns; moderately differentiated (grade 2) (Fig. 22-28C), showing well-formed glands mixed with solid sheets of malignant cells; or poorly differentiated (grade 3) (Fig. 22-28D), characterized by solid sheets of cells with barely recognizable glands and a greater degree of nuclear atypia and mitotic activity (see below).

• G1. Well-differentiated adenocarcinoma, less than 5% solid growth

• G2. Moderately differentiated adenocarcinoma with partly (less than 50%) solid growth

• G3. Poorly differentiated adenocarcinoma with predominantly solid growth (greater than 50%)

Up to 20% of endometrioid carcinomas contain foci of squamous differentiation. Squamous elements may be histologically benign-appearing when they are associated with well-differentiated adenocarcinomas. Less commonly, moderately or poorly differentiated endometrioid carcinomas contain squamous elements that appear frankly malignant. Current classification systems grade the carcinomas based on glandular differentiation alone and do not include areas of solid squamous differentiation when considering grading.