Endometrial hyperplasia is the most common precursor to endometrioid adenocarcinoma. In 1994, the World Health Organization defined a classification system of endome-trial hyperplasia based on four types of simple and com-plex hyperplasia, with or without atypia (see Table 45.1).
Simple hyperplasia is the least significant form of endome-trial hyperplasia and is not commonly associated with pro-gression to endometrial carcinoma. In this type of hyperplasia,both glandular elements and stromal cell elements proliferate excessively. Histologically, glands vary markedly in size, fromsmall to cystically enlarged (the hallmark of this hyper-plasia). Cystic glandular hyperplasia should not be confused with a normal postmenopausal variant—cystic involution of the endometrium—which is histologically not a hyper-plastic condition.
Complex hyperplasia represents an abnormal proliferation ofprimarily glandular elements without concomitant proliferation of stromal elements. This increased gland-to-stroma ratio givesthe endometrium a “crowded” picture, frequently with glands appearing almost back-to-back. As the severity of the hyperplasia increases, the glands become more crowded and more structurally bizarre. It is thought that complex hyper-plasia represents a true intraepithelial neoplastic process, and it is occasionally found coexisting with areas of endome-trial adenocarcinoma.
Hyperplasia characterized by significant numbers of glandu-lar elements that exhibit cytological atypia and disordered maturation (loss of cellular polarity, nuclear enlargement with increased nucleus-to-cytoplasm ratio, dense chromatin, and prominent nucleoli), is considered a precursor lesion to endometrial carcinoma (Fig. 45.1).
The primary process central to the development of endometrial hyperplasia (and most endometrial cancer) is overgrowth of the endometrium in response to excess unopposed estrogen. Sourcesof estrogen may be endogenous (ovarian; peripheral con-version of androgenic precursors) or exogenous (Box 45.1). Endometrial proliferation represents a normal part of the menstrual cycle and occurs during the follicular, or estrogen-dominant, phase of the cycle. With continued estrogen stimulation through either endogenous mecha-nisms or by exogenous administration, simple endometrial proliferation will become endometrial hyperplasia.
Research suggests that this transformation may be time- and dose-dependent. When proliferation becomes hyperplasia is not clear, although studies showing sequential change suggest it requires 6 months or longer of stimulation without proges-terone opposition. The risk factors for hyperplasia and endometrial cancer are identical (Table 45.2).
The risks of underlying endometrial cancer following biopsy-proven hyperplasia are as follows: 1% for simple, 3% for complex, and 8% for simple atypia. Complex atyp-ical hyperplasia was reported to occur in 29% of cases. Inone study, more than 42% of women with endometrial atypia had invasive endometrial cancer demonstrated when hysterec-tomy was performed within 3 months.