FIGURE 4.1 Lower uterine segment endometrium, fibrotic stroma.

FIGURE 4.2 Tangentially sectioned basalis showing weakly proliferative glands and spindled stroma not to be mistaken for hyperplasia.

Proliferative Endometrium

During this part of the menstrual cycle, the endometrial glands are lined by columnar epithelium with nuclear pseudostratification, dense chromatin, and variably present small nucleoli. Early proliferative endometrium (days 4 to 7 of the menstrual cycle) is characterized by thin surface endometrial epithelium and sparse, narrow, straight endometrial glands lined by cells with mild pseudostratification of the nuclei. There are a few mitoses in the epithelium and in the stroma (e-Fig. 4.2). In the midproliferative phase (days 8 to 10 of the menstrual cycle), the glands are slightly tortuous and the surface epithelium is columnar; the stroma is edematous and mitoses are present in both the epithelium and the stroma (Fig. 4.3, e-Figs. 4.3 and 4.4). Late proliferative endometrium (days 11 to 14 of the menstrual cycle) has a wavy surface and tortuous/coiled glands. Mitoses in the epithelium and the stroma become more abundant. The stromal edema disappears (Fig. 4.4, e-Figs. 4.5–4.7) (1,2).

FIGURE 4.3 Midproliferative endometrium, tubular glands, and stromal edema.

FIGURE 4.4 Late proliferative endometrium, coiled gland, and mitoses in the epithelium and the stroma.

Interval Endometrium

The term interval endometrium refers to the endometrium during the first 36 hours after ovulation. It is characterized by scattered glands, comprising <50% of the total, with subnuclear vacuoles in the context of nuclear pseudostratification and mitotic activity (e-Fig. 4.8) (1). Although suggestive of ovulation, this histologic picture by itself should not be considered as evidence of ovulation because it can be detected in anovulatory cycles and after estrogen therapy (2).

Secretory Endometrium

Dating the endometrium during the first half of the secretory phase is based mainly on glandular changes, whereas during the second half it

is based mostly on stromal changes (5).

EARLY SECRETORY ENDOMETRIUM. Early secretory endometrium encompasses postovulatory days (PODs) 2 to 5 (days 16 to 19 of the menstrual cycle). Vacuolated endometrial glands represent the hallmark of this part of the cycle. The first unequivocal histologic sign indicating that ovulation has occurred is the presence of uniform subnuclear vacuoles in >50% of the endometrial glands (POD 2, day 16 of the menstrual cycle). This finding is accompanied by exaggerated pseudostratification of the nuclei and mitotic figures in the epithelium (Fig. 4.5, e-Figs. 4.9 and 4.10). On POD 3 (day 17 of the menstrual cycle), the subnuclear vacuoles and the nuclei are uniformly aligned and mitotic figures in the epithelium are sparse (Fig. 4.6, e-Fig. 4.11). On POD 4 (day 18 of the menstrual cycle), the nuclei return to the base of the epithelium and the vacuoles become supranuclear. Mitotic figures in the epithelium are rare (e-Fig. 4.12). On POD 5 (day 19 of the menstrual cycle), a few vacuoles remain and intraluminal secretion starts to be seen. There are no mitoses in the epithelium (e-Figs. 4.13 and 4.14) (1,2).

FIGURE 4.5 Secretory endometrium, day 16 of the menstrual cycle (POD 2), pseudostratification of the nuclei, and subnuclear vacuoles (top). Note presence of a mitotic figure (bottom).

FIGURE 4.6 Secretory endometrium, day 17 of the menstrual cycle (POD 3)—uniformly distributed subnuclear vacuoles.

MIDSECRETORY ENDOMETRIUM. Midsecretory endometrium encompasses PODs 6 to 8 (days 20 to 22 of the menstrual cycle). On POD 6 (day 20 of the menstrual cycle), intraluminal secretion is prominent and the epithelial nuclei are round and basally located; stromal edema begins (Fig. 4.7, e-Fig. 4.15). On POD 7 (day 21 of the menstrual cycle), stromal edema increases (Fig. 4.8), reaching its peak during POD 8 (day 22 of the menstrual cycle). During PODs 7 and 8, intraluminal secretion becomes inspissated and centrally located in the luminal spaces (1,2).

LATE SECRETORY ENDOMETRIUM. Late secretory endometrium encompasses PODs 9 to 14 (days 23 to 28 of the menstrual cycle). On POD 9 (day 23 of the menstrual cycle), spiral arterioles become prominent due to condensation of the surrounding stroma; this finding is considered the earliest predecidual reaction (e-Fig. 4.16). On POD 10 (day 24 of the menstrual cycle), predecidual cells around the spiral arterioles become conspicuous, mitoses are evident, and the stromal edema subsides (Fig. 4.9, e-Fig. 4.17). The involution of the glandular epithelium starts about POD 10; the glands are tortuous and dilated with tufting of the lining epithelium, which also has ragged luminal “sawtooth” edges. On POD 11 (day 25 of the menstrual cycle), predecidualization occurs under the surface epithelium. By POD 12 (day 26 of the menstrual cycle), the predecidual changes are more prominent, forming sheets, and polymorphonuclear leukocytes appear (Fig. 4.10, e-Figs. 4.18 and 4.19). By POD 13 (day 27 of the menstrual cycle), the predecidual changes are extensive and the polymorphonuclear leukocytes become prominent (Fig. 4.11, e-Figs. 4.20–4.22). On POD 14 (day 28 of the menstrual cycle), fibrin thrombi and foci of hemorrhage in the stroma are noted (1,2).

FIGURE 4.7 Secretory endometrium, day 20 of the menstrual cycle (POD 6)—prominent intraluminal secretion.

FIGURE 4.8 Secretory endometrium, day 21 of the menstrual cycle (POD 7)—stromal edema and coiled gland.

FIGURE 4.9 Secretory endometrium, day 24 of the menstrual cycle (POD 10). Note the predecidual cells around spiral arterioles.

FIGURE 4.10 Secretory endometrium, day 26 of the menstrual cycle (POD 12)—sheets of predecidual cells.

FIGURE 4.11 Secretory endometrium, day 27 of the menstrual cycle (POD 13).

Menstrual Endometrium

Menstrual endometrium is characterized by glandular and stromal breakdown, condensed stroma, and necrotic debris (Fig. 4.12, e-Figs. 4.23–4.32) (1,2). The stromal breakdown can result in artifactual glandular crowding, which should not be misinterpreted as hyperplasia or carcinoma. On days 2 to 4 of the menstrual period, the functionalis progressively becomes detached from the basalis and is discharged from the uterus. This explains the scarcity of tissue obtained in curettages during the late part of the menstrual period (6).

FIGURE 4.12 Menstrual endometrium, fibrin deposition and breakdown.

FIGURE 4.13 Atrophic, scanty, and disrupted fragments of endometrium with crushed endometrial stroma.

ATROPHY

Atrophic endometrium is normal during the premenarcheal and late postmenopausal years. However, it is commonly associated with postmenopausal bleeding (1). The hallmark of atrophy is the presence of low columnar, cuboidal, or flattened epithelium with a high nuclear/cytoplasmic ratio and no mitoses. The glands vary from tubular to cystic (Fig. 4.13, e-Figs. 4.33–4.37) and the endometrial stroma is either spindled or fibrotic. Tubal or ciliated cell metaplasia can be seen. The impression of hyperplasia can be caused by cases in which the glands are dilated or in which the procurement of the endometrial sample has created artifactual distortion, causing the glands to be crowded. However, the epithelium in these cases has atrophic, rather than hyperplastic, features.

ENDOMETRIAL STROMA

Atypical (Bizarre) Stromal Cells

Atypical (bizarre) stromal cells can be seen in endometrial polyps and, less frequently, in proliferative endometrium. These cells have enlarged, hyperchromatic nuclei, with or without nucleoli, and no mitotic activity; some of the cells can be multinucleated (Fig. 4.14, e-Figs. 4.38–4.41). The lack of mitotic activity is crucial in ruling out a malignancy in the stroma. Atypical (bizarre) stromal cells are usually a focal finding, although they can be multifocal or even diffuse. Immunohistochemically, these cells stain for vimentin and estrogen, progesterone, and androgen receptors (e-Fig. 4.42). They also can express CD10, smooth muscle actin, and desmin (7,8).

FIGURE 4.14 Atypical cells in endometrial stroma. (Courtesy of Dr. Gaetano Magro)

Lymphoid Aggregates/Follicles

Lymphoid aggregates/follicles are usually located in the basalis (e-Figs. 4.43–4.45) and represent a normal finding (1,9,10).

Foamy Cells and Histiocytes

Foamy cells can represent either stromal cells that have undergone changes secondary to estrogenic stimulation (11) or macrophages (12). They are characterized by fine vacuolization of the cytoplasm and nuclei that are either small, eccentric, round, and dark or oval, centrally located, and lobulated/folded (Fig. 4.15, e-Figs. 4.46–4.49). Although these cells can be associated with endometrial polyps, hyperplasia, or carcinoma, they can also be seen in pyometra, hydrometra, and non-neoplastic uterine bleeding (5,11,12). Occasionally, they form nodules that have been designated either “nodular histiocytic hyperplasia” (13) or “nodular histiocytic aggregates” (e-Fig. 4.50) (14