An excess of estrogen relative to progestin, if sufficiently prolonged or marked, can induce exaggerated endometrial proliferation (hyperplasia), which is an important precursor of endometrial carcinoma. A common cause of estrogen excess is obesity, as adipose tissue converts steroid precursors into estrogens. Other potential causes of estrogen excess include failure of ovulation (such as in perimenopause), prolonged administration of estrogenic steroids without counterbalancing progestin, and estrogen-producing ovarian lesions (such as polycystic ovary syndrome and granulosa-theca cell tumors of the ovary).
Endometrial hyperplasia is placed in two categories based on the presence of cytologic atypia: hyperplasia without atypia and hyperplasia with atypia (
Fig. 19.11).
The importance of this classification is that the presence of cytologic atypia correlates with the development or concurrent finding of endometrial carcinoma. Hyperplasia without cellular atypia carries a low risk (between 1% and 3%) for progression to endometrial carcinoma, whereas hyperplasia with atypia, also called endometrial intraepithelial neoplasia (EIN), is associated with a much higher risk (20%–50%). When hyperplasia with atypia is discovered, it must be carefully evaluated for the presence of cancer and usually warrants a hysterectomy in patients no longer desiring fertility. In younger patients, treatment with high-dose progestins may be used in an attempt to preserve the uterus.
Unopposed estrogen is also a risk factor for the most common type of endometrial carcinoma (see later), and inactivation of the PTEN tumor suppressor gene has been identified at a substantial frequency in hyperplasia with atypia (approximately 50%) and endometrioid carcinoma (>70%). Along with clinicopathologic and epidemiologic studies, these findings indicate that hyperplasia with atypia is a precursor lesion for endometrioid endometrial carcinoma.
Fig.19.11Endometrialhyperplasia.(A)Anovulatoryor“disordered”endo-metriumcontainingdilatedglands.(B)Hyperplasiawithoutatypia,character-izedbynestsofcloselypackedglands.(C)Hyperplasiawithatypia,seenasglandularcrowdingandcellularatypia.
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In the United States and many other Western countries, endometrial carcinoma is the most frequent cancer occurring in the female genital tract. It generally appears between the ages of 55 and 65 years and is uncommon before age 40. Endometrial carcinoma can be broadly divided into two histologically and pathogenically distinct categories: endometrioid and serous carcinoma. There are other less common types of endometrial carcinoma, such as clear cell carcinoma and mixed Mullerian tumor (carcinosarcoma), but these will not be discussed further.