FIGURE 6.1 Endometrial hyperplasia. Note that the stroma represents less than one-half of the cross-sectional area.

FIGURE 6.2 Endometrial hyperplasia, nuclear pseudostratification. Note the mitotic figure (arrow).

FIGURE 6.3 Endometrial hyperplasia, focal secretory change.

FIGURE 6.4 Endometrial hyperplasia, diffuse secretory change (top); higher magnification showing vacuolization of the cytoplasm—the presence of cytologic atypia is still recognizable (next page top).

FIGURE 6.5 Complex endometrial hyperplasia, focal (top) arising in a background of disordered proliferative endometrium (next page top).

SIMPLE VERSUS COMPLEX HYPERPLASIA

Simple hyperplasia is characterized by a proliferation of dilated endometrial glands of variable size, with no or slight outpouchings (Figs. 6.6 and 6.7). In contrast, the endometrial glands in complex hyperplasia are markedly irregular in size and shape with frequent outpouchings (Figs. 6.8 and 6.9, e-Figs. 6.11–6.14) (5).

FIGURE 6.6 Endometrial hyperplasia, simple.

FIGURE 6.7 Endometrial hyperplasia, simple, without atypia (top); higher magnification (bottom).

THE DIAGNOSIS OF ATYPIA

Atypia of the hyperplastic endometrial epithelium is characterized by nuclear enlargement, round rather than oval nuclei, irregular distribution of chromatin, and variably present conspicuous nucleoli (Figs. 6.10 and 6.11, e-Figs. 6.15–6.20) (6). In determining whether atypia is present, the following issues should be entertained:

FIGURE 6.8 Endometrial hyperplasia, complex.

FIGURE 6.9 Endometrial hyperplasia, complex, without atypia. Note the glandular proliferation with outpouchings (top); higher magnification shows the cigar-shaped and oval nuclei with evenly distributed chromatin (next page top).

1.Artifactual changes secondary to variation in tissue fixation or processing, as well as an occasional case of normal proliferative endometrium having a focus of apparently crowded glands with nuclei that are enlarged and vesicular with visible nucleoli, can lead to a misdiagnosis of atypia (e-Figs. 6.21–6.23).

To avoid this problem, it is crucial to obtain a reference point for each case by evaluating the nuclear features of normal endometrial glands in areas without hyperplasia.

2.Extent of atypia: Hyperplastic endometrial glands with atypia may be admixed with those displaying no atypia (Figs. 6.12–6.14, e-Figs. 6.24–6.29). Although the minimum threshold for the diagnosis of focal atypia has not been defined, focal atypia should be readily found without the need for an exhaustive search (i.e., clearly atypical nuclei seen in most of the cells of several glands) in order to be considered a significant finding. Surface epithelium should be avoided for the assessment of atypia. In addition, grading the atypia (e.g., mild, moderate, and severe) should be avoided because of the lack of reproducibility (7).

3.Metaplastic changes: Superimposed metaplastic changes such as eosinophilic cell or ciliated cell metaplasia should not be mistaken for atypia (Figs. 6.15 and 6.16). In these metaplastic changes, some of the nuclei can be enlarged and rounded; however, the distribution of the chromatin is uniform and the nuclear contour is regular.

4.Superimposed secretory change: When diffuse secretory changes are present in hyperplasia, this can be designated secretory hyperplasia (e-Figs. 6.30–6.34) (8,9). This can occur in pre- or perimenopausal women who have sporadic ovulation or who have been treated with progestins, estroprogestins, or gonadotropin-releasing hormone analogs prior to biopsy. However, in some cases it is idiopathic. This condition is characterized by the presence of crowded disorganized glands with variable cytoplasmic vacuolation and luminal secretion. The stroma can have decidual changes. Atypia may not be obvious in all areas, as a degree of differentiation often accompanies this hormone-induced change (9). Diagnosis may be facilitated by comparison to background endometrium if available. Frequently, areas of hyperplasia will have a relative cytologic change compared with the background (e-Figs. 6.35–6.37) (10).

FIGURE 6.10 Endometrial hyperplasia, simple, with atypia—lower power (top) and high power (bottom).

FIGURE 6.11 Endometrial hyperplasia, complex, with atypia. Higher magnification of Figure 6.8. Nuclei are round and show irregular distribution of the chromatin (top); higher magnification (bottom).

FIGURE 6.12 Endometrial hyperplasia, complex, extensive metaplastic changes and focal atypia.

FIGURE 6.13 Endometrial hyperplasia, complex, extensive eosinophilic metaplasia; higher magnification of Figure 6.12.

FIGURE 6.14 Endometrial hyperplasia, complex, focal atypia; higher magnification of Figure 6.12.

ENDOMETRIAL INTRAEPITHELIAL NEOPLASIA

A group of investigators have proposed a nomenclature for precancerous lesions of the endometrium in an attempt to provide a classification system with better reproducibility and prediction of biologic behavior (11). Endometrial intraepithelial neoplasia (EIN) is considered to be the histologic manifestation of a monoclonal preinvasive glandular proliferation, and its diagnosis requires the following criteria:

1.Architectural alteration: Crowded glands (i.e., the area of glands, combining epithelium and luminal spaces, is greater than that of the stroma that contains them; the stroma represents <50% of the tissue). The glands may vary in shape and branch slightly (Fig. 6.17, left, e-Fig. 6.38), but architectural pattern (i.e., complex versus simple) is eliminated as a diagnostic criterion.

2.Cytologic alterations: Nuclear and cytoplasmic features of the epithelium in the glands with abnormal architecture differ from those in the background endometrium (Fig. 6.17, e-Fig. 6.39). Classic cytologic atypia, although often present, is not required for an EIN diagnosis.

3.Size: Maximum linear dimension exceeds 1 mm.

4.Elimination of mimics such as endometrial polyps, basalis endometrium, repair changes, and metaplastic or hormonal changes (i.e., disordered proliferative endometrium). These entities are discussed under differential diagnosis.

5.Exclusion of cancer.

FIGURE 6.15 Complex endometrial hyperplasia with eosinophilic cell metaplasia: low magnification (top); high magnification (bottom).

FIGURE 6.16 Complex endometrial hyperplasia with ciliated cell or tubal metaplasia: low magnification (top); high magnification (bottom).

FIGURE 6.17 Endometrial intraepithelial neoplasia, note the crowded and branching glands (top), with nuclear and cytoplasmic features that differ from the background endometrium (bottom, arrow).

A 45-fold increase in the risk of endometrial cancer has been reported in women with EIN when EIN criteria are strictly applied (11,12), and limited studies including both gynecologic and general pathologists have shown interobserver reproducibility of the EIN criteria (13). As such, the new WHO criteria for endometrial hyperplasia have essentially categorized those lesions fulfilling EIN criteria as “atypical hyperplasia.” Those lesions falling short of EIN are considered hyperplasia without atypia (1). It remains to be determined whether the new WHO criteria adopting EIN concepts will prove to have the same predictive value when applied on a global scale.

DIFFERENTIAL DIAGNOSIS

Endometrial Atrophy with Cystic Change

Atrophic endometrium can undergo cystic change, producing an apparent shift of the gland to stroma ratio that can be misinterpreted as endometrial hyperplasia. However, in contrast to hyperplastic endometrium, atrophic endometrial epithelium is either low columnar, cuboidal, or flattened with rare or no mitotic figures (Fig. 6.18).

Endometrial Polyp

An endometrial polyp can contain irregularly shaped and crowded glands representing a hyperplastic polyp or a polyp with areas of hyperplasia (Fig. 6.19, e-Figs. 6.40–6.43). This does not pose a problem when the typical features of an endometrial polyp are present; however, when these features are not identified (often due to the small size of the sample), the presence of fragments of normal endometrium in the background can help suggest the diagnosis. In some cases, hysteroscopy and curettage may be required to render the correct diagnosis (8).

Endometritis

In endometritis, the glands may be irregularly distributed, especially in cases with marked inflammation (e-Fig. 6.44). Plasma cells and usually a reactive-looking stroma with spindle cells characterize endometritis (e-Figs. 6.45 and 6.46). Nuclear enlargement in these cases should not be misinterpreted as atypia.

Disordered Proliferative Endometrium

Often, this is an estrogen-related condition associated with anovulatory cycles. It is characterized by variability in the size and shape of the endometrial glands, without a shift of the normal gland to stroma ratio (Fig. 6.20, e-Figs. 6.47–6.50). There is lack of uniformity in the development of the proliferative glands, with some of the glands becoming enlarged or having cystic changes or an irregular contour, without a decrease in the amount of stroma that separates them (5).

FIGURE 6.18 Endometrial atrophy with cystic changes: low magnification (top); high magnification (bottom). Note the cuboidal or flattened endometrial epithelium.

Endometrioid Adenocarcinoma, FIGO Grade 1

The diagnosis of endometrial endometrioid adenocarcinoma, International Federation of Gynecology and Obstetrics (FIGO) grade 1, is made on the basis of one of the following criteria: (a) a confluent glandular pattern, (b) an extensive papillary pattern, or (c) an irregular infiltration of glands associated with a desmoplastic response (14). We require a 2 × 2 mm area of confluent glandular growth, at a minimum, for the diagnosis of adenocarcinoma (Fig. 6.21, e-Figs. 6.51–6.53); smaller foci represent complex atypical hyperplasia. However, some authors have proposed classifying any back-to-back glandular proliferation exceeding four glands and under a 2.1 mm threshold in a biopsy specimen as adenocarcinoma in situ as an association with frank adenocarcinoma and myoinvasive adenocarcinoma in a subsequent hysterectomy specimen has been found (15). In our practice, we do not use the latter approach.