FIGURE 5.1 Glandular and stromal breakdown.
The endometrium of reproductive age and perimenopausal women can have an abnormal secretory pattern with glandular and stromal breakdown (Fig. 5.3, e-Figs. 5.11–5.15). This finding may reflect abnormalities of the luteal phase, such as luteal phase defect and irregular shedding. However, it can also be seen in undefined luteal phase abnormalities or other causes not detected with histologic examination (1).
FIGURE 5.2 Non-neoplastic endometrial stromal cells with a signet ring–like appearance in breakdown.
FIGURE 5.3 Underdeveloped secretory endometrium with glandular and stromal breakdown.
LUTEAL PHASE DEFECT. Luteal phase defect is a controversial clinical entity that has been characterized as a failure of the secretory endometrium to fully mature due to a corpus luteum deficiency. Although it has been associated with infertility and recurrent abortion, there is insufficient evidence to support these associations (3). In some cases, it may be the cause of DUB. When this occurs the endometrium has breakdown in an underdeveloped nonmenstrual secretory endometrium (Fig. 5.4, top and bottom) (1,4).
IRREGULAR SHEDDING. Irregular shedding is associated with a persistent corpus luteum and prolonged progesterone production. It appears to be an uncommon cause of DUB. This diagnosis is made when the endometrium has a mixture of secretory and proliferative endometrial glands in a sample obtained at least 5 days after the onset of bleeding (Fig. 5.5, e-Figs. 5.16 and 5.17) or when there is more than a 4-day difference in the morphologic date of different areas in a secretory endometrium. Glandular and stromal breakdown is usually focal but may be diffuse (1).
HORMONAL THERAPY EFFECT
Due to the increased risk of endometrial adenocarcinoma associated with unopposed exogenous estrogens, it is uncommon to see the effect of these compounds in an endometrial sample these days; however, it can be occasionally seen in peri- or postmenopausal women who have been treated with exogenous estrogens to control menopausal symptoms such as atrophic vaginitis and hot flashes as well as osteoporosis. The most commonly used estrogen preparations include conjugated estrogens, such as Premarin, and other synthetic estrogens, such as ethinyl estradiol or diethylstilbestrol (5). Unopposed estrogens induce the endometrium to proliferate with variable results that depend on the dose and duration of treatment. These changes range from proliferative endometrium with or without breakdown, to disordered proliferative endometrium, to atypical hyperplasia and adenocarcinoma (6–10). Patients who develop adenocarcinoma have received at least 2 to 3 years of unopposed estrogen and the highest risk is seen in patients with at least 10 years of unopposed estrogen use. Usually the adenocarcinomas in these patients are of low grade, although high-grade tumors can occur (5). Estrogen use has also been associated with metaplastic changes.
FIGURE 5.4 Luteal phase defect: underdeveloped secretory endometrium (top); breakdown (bottom).
FIGURE 5.5 Irregular shedding, proliferative endometrial glands, and breakdown (top) and secretory glands and breakdown (bottom).
Progestins (Progestogens or Progestagens) and Oral Contraceptives
Progestins and oral contraceptives are synthetic forms of progesterone that are used alone in the empiric management of DUB (progestin-only therapy), as a contraceptive in the form of a hypodermic implant or intrauterine delivery system to treat endometrial hyperplasias and low-grade endometrioid adenocarcinomas in patients who want to preserve their fertility, or in combination with an estrogen as a contraceptive. In progestin-only therapy, either medroxyprogesterone acetate or norethindrone acetate is used. They suppress ovulation and endometrial growth and induce secretory maturation and progesterone withdrawal bleeding. The combination of progestins and estrogens is the basis of oral contraceptives. Most of the oral contraceptives currently in use contain small daily doses of both estrogen and progestin; however, some oral contraceptives use a phase combination with an increment in the daily progestin dose over a 3-week period. In any case, the oral contraceptives are administered over a 21-day period, leaving the subsequent 7 days without medication for withdrawal bleeding to occur. The effects on the endometrium depend on the type and dosage of the hormones used and on the hormone receptor status of the patient. The progestin effect can be divided into three histologic patterns: (a) decidual “pregnancy like,” (b) underdeveloped secretory, and (c) atrophic. These patterns usually overlap and the prevalence of a pattern depends on the degree of endometrial priming by estrogen (5).
1.Decidual “pregnancy like”: This pattern is usually seen after high-dose progestin therapy for anovulatory cycles or for endometrial hyperplasia. The tissue obtained in an endometrial sampling tends to be abundant and polypoid. The stromal cells are decidualized with occasional mitotic figures present; the glands are either hypersecretory with vacuolated cytoplasm and luminal secretions or atrophic. The latter can also have vacuolization of the cytoplasm. An Arias-Stella reaction and squamous metaplasia can be seen. Venules can be ectatic toward the superficial portion of the endometrium, and there can be areas with numerous granulocytes in the stroma (Fig. 5.6, e-Figs. 5.18–5.23). Cases with advanced decidual changes can have focal breakdown.
2.Underdeveloped secretory: This pattern is characterized by the presence of slightly coiled or straight, inactive, irregularly distributed glands in an abundant stroma. Cytoplasmic vacuolization may or may not be present. The stroma can have edema or decidualization and blood vessels become thinner and often ectatic. Intraluminal secretion can be seen. However, the glandular and stromal development do not correspond to any day of the normal cycle (Fig. 5.7).
3.Atrophic: In this pattern, the glands are straight and lined by inactive epithelium with basal nuclei and scanty cytoplasm. Weak secretory changes can be seen. The stroma can appear highly cellular with plump cells or can be edematous/myxoid. Ectatic blood vessels may be found (Fig. 5.8, e-Figs. 5.24–5.27) (5,11).
FIGURE 5.6 Progestin effect, decidual pattern.
FIGURE 5.7 Progestin effect, secretory pattern.
FIGURE 5.8 Progestin effect, atrophic pattern.
Combined Estrogen and Progestin as Hormone Replacement Therapy
When hormone replacement therapy is given sequentially, the endometrium usually has a weakly proliferative pattern. Sometimes a superimposed underdeveloped secretory pattern can be seen, especially if the sample was obtained during the progestin phase of the treatment. Atrophy or focal breakdown may be noted. When hormone replacement therapy is given in combination the endometrium is usually atrophic, although sometimes secretory changes can be seen (5).
Progestin-Like Effect Without Hormone Exposure
The endometrium of premenopausal and postmenopausal patients can have a progestin-like effect in the absence of exposure to these hormones. This can be idiopathic (12) or secondary to a persistent functioning corpus luteum or “luteinized unruptured follicle” (5).
Effects of Other Hormones
TAMOXIFEN. Although used for breast cancer because of its antiestrogenic properties, tamoxifen has a mild estrogenic effect on the endometrium. In addition to the endometrial polyps described later in this chapter, tamoxifen has been associated with proliferative endometrium, endometrial hyperplasia, metaplasias and carcinomas of endometrioid and non-endometrioid types, and uterine sarcomas (13–15).
RALOXIFENE. Raloxifene, a second-generation selective estrogen receptor modulator, is used as an antiestrogen for breast cancer and also for the prevention of osteoporosis in postmenopausal patients (16). It appears to lack the weak estrogen agonist effect of tamoxifen on the endometrium and so far has not been associated with an increment in endometrial lesions (17). The endometrium of patients treated with raloxifene is usually atrophic (5).
CLOMIPHENE CITRATE. Clomiphene citrate is an antiestrogen that is used to induce ovulation in infertile patients with ovulatory disorders (18). The endometrial biopsy is performed during the luteal phase of the clomiphene-induced cycle to assess the response to treatment. The pattern is secretory but varies; in some cases, the secretory endometrium appears normal and can be histologically dated (5), but in many cases there is a decrease in the number of glands, in the caliber of the glands, in the secretory activity, and in the stromal decidualization (19). The endometrium can also be out of phase (19). Some investigators have hypothesized that clomiphene citrate can induce a luteal phase defect except in women with polycystic ovary syndrome (20). The endometrium of patients with regular cycles who have received clomiphene citrate has shown decreased glandular density and a persistence of subnuclear vacuoles, indicating an impairment of secretory activity (21).
DANAZOL. Danazol, a steroid whose main metabolite has a weak progestin effect, is used for the treatment of endometriosis, menorrhagia, and endometrial hyperplasia (22–25). The endometrium usually becomes atrophic, but mild secretory changes can be seen (i.e., tubular glands lined by vacuolated cells, with a rare case having decidualization of the stroma) (26–28).
GONADOTROPINS. Human menopausal gonadotropins (hMGs) or menotropins are obtained from the urine of postmenopausal women. They contain follicle-stimulating hormone and luteinizing hormone (LH) and are used to induce ovulation in patients who are anovulatory. Human chorionic gonadotropin (hCG) shares similarities of structure and effect with LH and is used to stimulate and improve the midcycle surge of LH associated with ovulation. hCG is used in conjunction with either hMG or clomiphene citrate. The effects of hMG and hCG on the endometrium are variable. Some studies have found inadequate development of the endometrium, with either retarded development of >2 days when the histologic date is compared with the chronologic date or more advanced secretory changes than expected as per the chronologic date. In addition, glandular and stromal dyssynchrony or normal glandular development has been reported (5).
GONADOTROPIN-RELEASING HORMONE AGONISTS. Gonadotropin-releasing hormone agonists include leuprolide acetate, buserelin acetate, and goserelin acetate. These compounds are used to decrease the size of leiomyomas before surgery, to suppress the endometrium before resectoscopic ablation, to prevent spontaneous surges of LH before oocyte retrieval, and to improve follicular development for ovulation induction during in vitro fertilization and gamete intrafallopian transfer. As endometrial tissue suppressors, gonadotropin-releasing hormone agonists cause involution of the endometrium, which appears weakly proliferative, inactive, or atrophic. If used in conjunction with a progestin as a contraceptive, they produce a progestin effect (5,11).
Atypia Related to Hormone Therapy
Occasionally, the endometrium of patients who have received tamoxifen, combined hormone therapy, or norethisterone has focal nuclear atypia consisting of enlarged, hyperchromatic nuclei. The cytoplasm may be eosinophilic. Although in a previous report no mitotic activity or nucleoli were found (29), in our experience scattered mitotic activity and nucleoli can be seen. The atypical cells in these cases have been reported to be Ki-67, p53, and p16 negative (29); however, in our experience p53 can be positive in scattered cells and Ki-67 is focally increased, but not diffusely (Fig. 5.9, e-Figs. 5.28–5.39).
Endometritis can be acute or chronic. Acute endometritis is usually seen in the postpartum or postabortum period and is characterized by a neutrophilic infiltrate in the glands and surface endometrium with microabscess formation (Fig. 5.10).
FIGURE 5.9 Atypia related to hormone therapy, hyperchromatic and enlarged nuclei.
FIGURE 5.10 Acute and chronic endometritis. (Courtesy of Dr. Carmen Tornos)
Chronic endometritis is typically found in premenopausal patients, although it can be seen in older patients as well, and in most cases is secondary to common bacteria such as streptococci, Enterococcus faecalis, and Escherichia coli and mycoplasma species (Mycoplasma genitalium and Ureaplasma urealyticum) (30). Chronic endometritis is usually associated with the postpartum or postabortum period, active pelvic inflammatory disease, an intrauterine device, instrumentation such as biopsy or curettage, cervical stenosis, or the presence of a uterine lesion such as an endometrial polyp, leiomyoma, endometrial hyperplasia, or carcinoma (31). Although the identification of plasma cells has been considered to be the hallmark of chronic endometritis (32), the search for these cells at high magnification is prompted by the identification at low magnification of certain features such as stromal edema, spindle-shaped stromal cells that can have a swirled arrangement, patches of increased stromal density, necrosis, patchy inflammatory infiltrate, inflammatory cells in the glandular lumens, and the presence of eosinophils (Figs. 5.11 and 5.12) (33,34). The endometrial glands can be in proliferative phase or secretory phase; the latter is rarely typical for a specific day of the cycle, and more often the extent of the secretory changes differs from gland to gland. The epithelium can have metaplastic changes and reactive atypia (e-Fig. 5.40) (31). Focal breakdown may be seen. Plasma cells tend to be located around endometrial glands, distended sinusoidal blood vessels, and lymphoid follicles and in the subepithelial stroma (31). They are characterized by their eccentrically placed nucleus with perinuclear halo and are distinguished from stromal cells with similar features by their clumped clockface chromatin pattern. It is important to be aware that the endometrium of fertile, asymptomatic, healthy women can contain an isolated plasma cell (35) and that occasional plasma cells have been described in menstrual endometrium, proliferative endometrium, disordered proliferative endometrium, endometrium with breakdown, endometrium following hormone therapy, polyps, and uterine prolapse (32,33,36,37). On the other hand, the recognition of plasma cells can be problematic (38). Although some investigators have advocated the use of special techniques such as histochemical staining for methyl green–pyronin, immunohistochemical staining for immunoglobulin G or syndecan-1 (CD138), and in situ hybridization for kappa and lambda mRNA to improve the detection of plasma cells (33,36,39,40), these are rarely used in regular practice.
FIGURE 5.11 Endometritis, stromal cells are markedly spindled (top) and plasma cells indicated by an arrow (bottom).