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Precursors of Endometrial Carcinoma

  • Lora Hedrick EllensonEmail author
  • Brigitte M. Ronnett
  • Robert J. Kurman
Living reference work entry

Abstract

Endometrial hyperplasia often precedes the development of endometrioid carcinoma, the most common type of endometrial carcinoma. Obesity, anovulatory cycles, and exogenous hormones are associated with both endometrioid carcinoma and hyperplasia. In addition, the risk of endometrial hyperplasia is associated with increasing body mass index and nulliparity (Epplein et al. 2008; Wise et al. 2016; Guraslan et al. 2016). All of these factors are thought to result in unopposed estrogen stimulation of the endometrium. The role of unopposed estrogen stimulation in the development of endometrial hyperplasia and carcinoma is further supported by studies demonstrating elevated serum estrogen levels in patients with endometrioid carcinoma (Brinton et al. 1992; Potischman et al. 1996). Atypical hyperplasia/endometrioid intraepithelial neoplasia is considered the direct precursor to endometrioid carcinoma. However, other histologic types of endometrial carcinoma are less commonly associated with estrogenic stimulation (Sherman et al. 1997). Serous carcinoma is the prototypic endometrial carcinoma that is typically not related to estrogenic stimulation or hyperplasia. It usually arises in atrophic endometrium through a precursor lesion called serous endometrial intraepithelial carcinoma (SEIC). The following discussion summarizes current knowledge about these precursor lesions including their differential diagnosis, treatment, and relationship to endometrial carcinoma.

Endometrial hyperplasia often precedes the development of endometrioid carcinoma, the most common type of endometrial carcinoma. Obesity, anovulatory cycles, and exogenous hormones are associated with both endometrioid carcinoma and hyperplasia. In addition, the risk of endometrial hyperplasia is associated with increasing body mass index and nulliparity (Epplein et al. 2008; Wise et al. 2016; Guraslan et al. 2016). All of these factors are thought to result in unopposed estrogen stimulation of the endometrium. The role of unopposed estrogen stimulation in the development of endometrial hyperplasia and carcinoma is further supported by studies demonstrating elevated serum estrogen levels in patients with endometrioid carcinoma (Brinton et al. 1992; Potischman et al. 1996). Atypical hyperplasia/endometrioid intraepithelial neoplasia is considered the direct precursor to endometrioid carcinoma. However, other histologic types of endometrial carcinoma are less commonly associated with estrogenic stimulation (Sherman et al. 1997). Serous carcinoma is the prototypic endometrial carcinoma that is typically not related to estrogenic stimulation or hyperplasia. It usually arises in atrophic endometrium through a precursor lesion called serous endometrial intraepithelial carcinoma (SEIC). The following discussion summarizes current knowledge about these precursor lesions including their differential diagnosis, treatment, and relationship to endometrial carcinoma.

Endometrial Hyperplasia

Definition and Classification

Endometrial hyperplasia is defined as a proliferation of glands of irregular size and shape with an associated increase in the gland/stroma ratio compared with proliferative endometrium. Although the process is often diffuse, it may also be focal.

The classification and terminology of endometrial hyperplasia has undergone several iterations over the past several decades. The modern-day classification was introduced in 1994 by the World Health Organization (WHO) and the International Society of Gynecologic Pathologists (ISGYP) and quickly gained widespread acceptance. The classification subdivided hyperplasia into four groups: simple hyperplasia, complex hyperplasia, simple atypical hyperplasia, and complex atypical hyperplasia. The 2003 WHO classification endorsed the same classification, but in 2014 the WHO made significant changes by simplifying the four-tier to a two-tier classification of hyperplasia without atypia and hyperplasia with atypia (atypical hyperplasia). In addition, a completely new term designated “endometrioid intraepithelial neoplasia (EIN)” was introduced and considered synonymous with atypical hyperplasia (Kurman et al. 2014). The pros and cons of both systems are discussed later in the chapter. Currently, both are being utilized in routine practice.

Clinical Features

Patients with endometrial hyperplasia typically have abnormal bleeding. Occasionally, the lesion is detected fortuitously by endometrial biopsy performed during the course of an infertility workup or before the start of hormone replacement therapy in postmenopausal women. Hyperplasia develops because of unopposed estrogenic stimulation, and consequently most patients with hyperplasia have a history of either persistent anovulation or exogenous unopposed estrogen usage. Although anovulation occurs at menarche and in perimenopausal women, hyperplasia is not usually encountered in young women. Although hyperplasia has been reported in a patient at 16 years of age (Lee and Scully 1989). This may be because bleeding in menarchial women is seldom evaluated by an endometrial biopsy. During the reproductive years, hyperplasia is relatively uncommon, typically occurring in women with polycystic ovary syndrome (Stein–Leventhal syndrome). In the original description of this syndrome, these women were reported to be anovulatory, obese, infertile, and exhibit hirsutism, but many women with this disorder lack these features. Conversely, women who are obese but who do not have polycystic ovarian disease may have hyperplasia, presumably because of peripheral conversion of androstenedione to estrogen in adipose tissue.

Diabetes mellitus and hypertension may occur in women with hyperplasia, but often these disorders are not present. Although hyperplasia or carcinoma should always be suspected in a postmenopausal woman with abnormal uterine bleeding, atrophy is the most common cause of bleeding in this age group. In one study of postmenopausal women with bleeding, 7% had endometrial cancer, 15% had various types of hyperplasia, and 56% had atrophy (Lidor et al. 1986). Typically, women with hyperplasia or carcinoma have moderate or heavy vaginal bleeding compared with women with atrophic endometria who present with spotting.

Pathologic Findings

Hyperplastic endometrium is not distinctive grossly. In hysterectomy specimens, hyperplasia may have a velvety, knobby surface of pale, spongy tissue with vague borders. Although diffuse thickening of the endometrium is common, hyperplasia can be focal and may simulate a polyp. The volume of tissue obtained in curettings is usually increased, but it may be quite variable and less than that obtained during the secretory phase of the normal cycle. A diagnosis of hyperplasia, therefore, depends on the histologic pattern and not on the volume of tissue.

Hyperplasia Without Atypia

Hyperplasia is characterized by an increased gland/stroma ratio and a variety of abnormal architectural patterns. Glands typically vary in size and shape. Dilatation and outpouching of glandular epithelium characterize the lesser degrees of architectural abnormalities. In simple hyperplasia, the glands are cystically dilated, with occasional outpouchings surrounded by abundant cellular stroma (Fig. 1). In other instances, the glands are only minimally dilated but focally crowded (Fig. 2). Admixtures of the various patterns frequently occur (Fig. 3). The cells lining the glands are stratified and columnar with amphophilic cytoplasm. Mitotic activity is variable. With increasing degrees of architectural abnormality, glands become complex and branched with irregular outlines and papillary infoldings into the lumens. In addition, with increased proliferation glands become crowded, compressing the intervening stroma, resulting in “back-to-back” glandular crowding. Thus, complex hyperplasia is composed of crowded glands with little intervening stroma (Kurman et al. 1985) (Figs. 4 and 5). Usually the glandular outlines are highly complex but at times are tubular, with or without dilatation (Figs. 4 and 5). Epithelial stratification can range from two to four layers, but some glands may exhibit little or no stratification. Mitotic activity is variable and is usually less than five mitotic figures per 10 high power fields. Even in highly complex hyperplasia with marked stratification, mitotic figures may be inconspicuous. In hyperplasia lacking atypia, the epithelial cells contain oval, basally oriented bland nuclei with smooth, uniform contours resembling those in normal proliferative glands (Figs. 6, 7, 8, and 9). In simple hyperplasia, the stromal cells are more densely packed than in proliferative endometrium. The cells retain their spindle shape but are plump, with enlarged nuclei and indistinct cytoplasm. Mitotic activity in endometrial stromal cells is variable but may be increased. In complex hyperplasia, the stromal cells are spindle shaped and compressed by the glandular proliferation. In addition to densely packed stromal cells, clusters of foamy, lipid-laden cells may be present in the stroma of hyperplasia, atypical hyperplasia, and well-differentiated adenocarcinoma (Dawagne and Silverberg 1982; Silver and Sherman 1998). Foam cells have small pyknotic nuclei and cytoplasm that contain lipid droplets but no mucin. The foam cells have been shown to be histiocytes by immunohistochemistry (Silver and Sherman 1998). These histiocytic cells may also be observed in atrophic and nonneoplastic endometria. The isolated finding of histiocytes in cervicovaginal smears of asymptomatic postmenopausal women has not been associated with an increased likelihood of detecting endometrial hyperplasia or carcinoma (Hall et al. 1982). The presence of histiocytes alone in cervicovaginal smears from postmenopausal women with abnormal uterine bleeding also has not been shown to predict the presence of either endometrial hyperplasia or carcinoma. However, the finding of histiocytes containing phagocytosed acute inflammatory cells or normal endometrial cells in postmenopausal women with abnormal uterine bleeding has been associated with a three- to four-fold greater likelihood of coexistent endometrial carcinoma or hyperplasia (Nguyen et al. 1998).
Fig. 1

Hyperplasia without atypia (simple). Glands are only minimally crowded but are dilated and have outpouchings

Fig. 2

Hyperplasia without atypia (simple). Glands are mildly crowded and some are cystically dilated

Fig. 3

Hyperplasia without atypia (simple). Glands are mildly crowded and dilated, with some exhibiting outpouchings and simple branching

Fig. 4

Hyperplasia without atypia (complex). Glands are sufficiently crowded for classification as complex hyperplasia, despite the presence of glands having only simple tubular profiles

Fig. 5

Hyperplasia without atypia (complex). Dilated glands resemble those seen in simple hyperplasia but are sufficiently crowded for classification as complex hyperplasia

Fig. 6

Hyperplasia without atypia. Nuclei are elongated, oriented perpendicular to the basement membrane and have even chromatin

Fig. 7

Hyperplasia without atypia. Nuclei are elongated, oriented perpendicular to the basement membrane and have even chromatin

Fig. 8

Hyperplasia without atypia. Nuclei are elongated, oriented perpendicular to the basement membrane and are evenly hyperchromatic

Fig. 9

Hyperplasia without atypia. Nuclei are elongated, oriented perpendicular to the basement membrane and are evenly hyperchromatic

Atypical Hyperplasia

The most important feature in the evaluation of endometrial hyperplasia is the presence or absence of nuclear atypia. Cells with nuclear atypia are stratified and show loss of polarity and an increase in the nuclear/cytoplasmic ratio (Figs. 10, 11, 12, 13, 14, and 15). The nuclei are enlarged, irregular in size and shape, with coarse chromatin clumping, a thickened irregular nuclear membrane, and prominent nucleoli. Nuclei tend to be round as compared with the oval nuclei of proliferative endometrium and hyperplasia without atypia. As a result, the nuclei often have a cleared or vesicular appearance with condensation of the chromatin around the nuclear membrane. Nuclear atypia is variable, both qualitatively and quantitatively. Not all glands contain atypical cells, and in an individual gland some cells are atypical, and others are not. Rare atypical cells should be ignored, but if cellular atypia is evident without a diligent search, the diagnosis of atypical hyperplasia should be made. One of the main issues facing diagnostic surgical pathologists is the intra- and interobserver variability in the identification of atypia. Thus, grading atypia as mild, moderate, or severe is not recommended, as it is subjective and not reproducible. Furthermore, assessment of atypia is often problematic in the setting of metaplasia (see below). The nuclear enlargement, rounding, and vesicular change seen in tubal metaplasia, for example, can suggest cytologic atypia, but this metaplastic change is not interpreted as true atypia as it has not been shown to affect clinical outcome (Hendrickson and Kempson 1980). Moreover, metaplasia and atypia can occur together in the same glands, so if the nuclear changes are present in cells that are not metaplastic a diagnosis of atypical hyperplasia can be made even in the setting of metaplasia. (Fig. 16). Nuclear enlargement, pleomorphism, coarsening of chromatin, and presence of nucleoli are important features that constitute the morphologic features of cytologic atypia, but these changes can be subtle and as a result somewhat subjective. This problem is inherent in which ever classification system is used, atypical hyperplasia or endometrioid intraepithelial neoplasia (EIN) (see below). One of the most useful techniques in determining whether atypia is present is to compare the nuclear features of the glands in question to adjacent normal appearing proliferative endometrium. If the nuclei in the glands in question appear more atypical than those in the proliferative glands then lesion qualifies as atypical hyperplasia. If the nuclear features are similar to the adjacent proliferative glands, no matter how crowded the proliferative process is, the lesion qualifies as hyperplasia without atypia. If normal proliferative endometrium is not present in the tissue sample, the descriptive features described above must be employed to determine the presence of atypia.
Fig. 10

Atypical hyperplasia. Branching and tubular glands are crowded with very little intervening stroma

Fig. 11

Atypical hyperplasia. Nuclei are rounded and have vesicular chromatin

Fig. 12

Atypical hyperplasia. Nuclei are rounded, have vesicular chromatin, and display stratification and loss of polarity

Fig. 13

Atypical hyperplasia. Nuclei are enlarged and rounded, have vesicular chromatin with fine granularity, and display stratification and loss of polarity

Fig. 14

Atypical hyperplasia. Nuclei vary from ovoid to rounded, have even chromatin with evident nucleoli and mitotic figures, and display some stratification and loss of polarity

Fig. 15

Atypical hyperplasia. Nuclei are enlarged and rounded, have vesicular chromatin with fine granularity and evident nucleoli, and display stratification and loss of polarity

Fig. 16

Hyperplasia with tubal metaplasia and atypia. Nuclei vary from ovoid to rounded, have finely granular chromatin, and display some stratification and loss of polarity. Ciliated cells are present, indicating tubal metaplasia. Some nuclear changes are related to the tubal metaplasia, but the loss of polarity and stratification are beyond those attributable to metaplasia (compare with Figs. 35 and 36)

The architectural features of complex atypical hyperplasia are similar to its counterpart without cytologic atypia. In complex atypical hyperplasia, the glands almost invariably demonstrate marked structural complexity with irregular outlines and back-to-back crowding (Fig. 10). Epithelial stratification and mitotic activity are variable. Papillary infoldings also are seen. Some atypical hyperplasias have little stratification, and mitotic activity may be inconspicuous.

Differential Diagnosis

Hyperplasia should be distinguished from disordered proliferative phase, polyps, ciliated cell change (tubal metaplasia), cystic atrophy, and endometrial glandular and stromal breakdown. Disordered proliferative phase is similar qualitatively to hyperplasia without atypia but is a focal lesion characterized by irregularly shaped and enlarged glands that are interspersed among normal proliferative glands (Fig. 17). The latter may be focally crowded. The key feature that distinguishes disordered proliferative phase from hyperplasia without atypia is the focal nature of the glandular abnormality in disordered proliferative phase. The fragments of endometrium containing the disordered glands should not have the appearance of a polyp. Hyperplastic endometrial polyps often contain areas of hyperplasia without atypia that are confined to one or just a few fragments of polypoid tissue. The polyp usually stands out as a large rounded tissue fragment in sharp contrast to the remainder of the uninvolved endometrium. Polyps typically have dense fibrous stroma and contain clusters of thick-walled blood vessels near the center of the fragment. The fragments often are covered on three sides by surface endometrium (see chapter “Benign Diseases of the Endometrium”).
Fig. 17

Disordered proliferative endometrium. Cystically dilated glands with outpouchings are admixed with small tubular proliferative glands

Endometrial glands with ciliated cell change are often found in association with simple and complex hyperplasia. When found with hyperplasia, the presence of ciliated cell change does not need to be specified. Ciliated glands are usually slightly dilated. When a few isolated glands show ciliated cell change in the absence of hyperplasia, a diagnosis of ciliated cell change (tubal metaplasia) is justified (see following). Ciliated cell change often contains scattered vesicular nuclei with occasional nucleoli that should not be mistaken as cytologic atypia when found in association with hyperplasia.

Distinction of cystic atrophy from hyperplasia is seldom a problem in curettings because atrophic glands collapse as a result of the procedure. In hysterectomy specimens, glands are dilated and lined by a single layer of cells that are often flattened. Mitotic activity is not present. In contrast, in hyperplasia there is pseudo-stratification of columnar epithelial cells. Mitotic activity is variable but present.

In endometrial glandular and stromal breakdown caused by estrogen withdrawal, proliferative-type glands appear back-to-back because of loss of intervening endometrial stroma. Glands are often fragmented, and apoptotic bodies are present. Clusters of stromal cells and fragmented glands surrounded by blood are consistent features (see chapter “Benign Diseases of the Endometrium”). In contrast, in hyperplasia the glandular outlines are more irregular and complex than the tubular, proliferative-type glands in breakdown. Furthermore, glandular fragmentation, apoptotic bodies, and rounded clusters of stromal cells, so-called “stromal blue balls,” are usually absent in hyperplasia. In addition, the tissue fragmentation and artifactual apposition of segments of surface epithelium encountered in biopsy and curettage specimens can complicate interpretation and should be considered prior to rendering a diagnosis of hyperplasia (Fig. 18).
Fig. 18

Artifactual glandular crowding. Apposition of surface epithelium of fragments of proliferative endometrium simulates the cystically dilated glands of hyperplasia without atypia but is an artifact

Atypical hyperplasia must be distinguished from an atypical polypoid adenomyoma and from well-differentiated adenocarcinoma. The atypical polypoid adenomyoma is composed of glands that show variable architectural complexity and some cytologic atypia (Fig. 19). Squamous differentiation in the form of squamous morules is an almost constant feature of the atypical polypoid adenomyoma. Characteristically, the glands in the atypical polypoid adenomyoma are surrounded by smooth muscle, in contrast with the dense proliferative stroma found in hyperplasia and the altered or desmoplastic stroma found in association with well-differentiated carcinoma.
Fig. 19

Atypical polypoid adenomyoma. Crowded complex glands with squamous morules are surrounded by a fibromuscular stroma

Most endometrial carcinomas are readily identified. However, several studies highlight the difficulty in distinguishing some cases of well-differentiated carcinoma from atypical hyperplasia on preoperative endometrial sampling by either biopsy or curettage. Specific histologic features can often be used to separate hyperplasia from well-differentiated carcinoma that reduce the subjectivity of the evaluation. In the presence of invasion, the endometrial stroma interacts directly with malignant cells, and the morphologic changes it undergoes can serve as a means of identifying carcinoma. The stromal and epithelial alterations associated with invasive carcinoma are referred to collectively as endometrial stromal invasion. There are three useful criteria, any of which identifies stromal invasion: (1) an irregular infiltration of glands associated with an altered fibroblastic stroma (desmoplastic response); (2) a confluent glandular pattern in which individual glands, uninterrupted by stroma, merge at times creating a cribriform pattern; and (3) an extensive papillary pattern. It should be noted that on occasion hyperplasia can display a papillary architecture, including the presence of fibrovascular cores, but in contrast to the papillary pattern of carcinoma, hyperplasia is characterized by bland cytology, absence of epithelial stratification, and a low level of mitotic activity (Lehman and Hart 2001), It has been reported that a process manifesting the features of invasion must be sufficiently extensive to involve half (2.1 mm) of a low-power field 4.2 mm in diameter to have value in predicting the presence of a biologically significant carcinoma in the uterus (Kurman and Norris 1982; Norris et al. 1983). This criterion, however, should not be applied too rigidly in view of the potential of missing a carcinoma in small samples. If unequivocal evidence of stromal invasion is present in an area measuring less than one-half a low-power field, a diagnosis of well-differentiated carcinoma should be made (Figs. 20 and 21). The quantification criterion does not apply to moderately or poorly differentiated carcinomas. The three criteria for the identification of stromal invasion are described in greater detail below.
  1. 1.

    The altered stroma that reflects invasion contains parallel, densely arranged fibroblasts with more fibrosis than normal endometrial stroma and disrupts the usual glandular pattern (Fig. 22). The stromal cells are more spindle shaped than are the stromal cells of proliferative endometrium, with more elongated nuclei. Collagen compresses the stromal cells so that they have an eosinophilic and wavy appearance (Fig. 23), compared with the basophilic naked-nucleus appearance of stromal cells found in proliferative endometrium and hyperplasia. In specimens containing fragments of polyps with fibrous stroma, or specimens from the lower uterine segment, these features cannot be applied. The distinction of hyperplasia from carcinoma in these cases is based on the identification of a confluent pattern (see below). Atypical polypoid adenomyomas (see chapter “Benign Diseases of the Endometrium”) contain smooth muscle and may simulate myometrial invasion (see Fig. 19) (Mazur 1981). In contrast with the atypical polypoid adenomyoma, smooth muscle is rarely identified in curettings of well-differentiated carcinoma even when there is deep myometrial invasion because only the exophytic portion of the tumor is removed in biopsies and curettings.

     
  2. 2.

    Confluent glandular aggregates without intervening stroma reflect stromal invasion (Figs. 24 and 25). Confluent patterns are characterized by glandular configurations in which individual glands are not surrounded by stroma. Instead, glands appear to merge into one another to form a complex labyrinth. Some proliferations are cribriform, resulting from proliferation and bridging of epithelium (Fig. 26).

     
  3. 3.
    Complex papillary patterns represent stromal invasion if multiple, branching, fibrous processes lined by epithelium are present (Figs. 27 and 28). At times, these may create a villoglandular pattern. Intraglandular epithelial papillations lacking a fibrovascular core do not qualify as a feature of invasion; such proliferation is often encountered in eosinophilic metaplasia within complex hyperplasia (see below). Delicate papillary structures (with or without fibrovascular cores), often accompanied by metaplastic changes (mucinous, eosinophilic cell) and often occurring in polyps, are a feature of simple and complex papillary hyperplasias (Figs. 29 and 30) (Lehman and Hart 2001). In these lesions, the cytology is bland and the epithelium overlying the fibrovascular cores is not stratified. The mitotic index and Ki-67 proliferation index is very low.
    Fig. 20

    Atypical hyperplasia with foci of well differentiated endometrioid carcinoma. Small aggregates of fused glands consistent with early endometrioid carcinoma are architecturally distinct from the individual larger glands of associated atypical hyperplasia

    Fig. 21

    Atypical hyperplasia with foci of well differentiated endometrioid carcinoma. Small aggregates of glands demonstrate gland fusion and early cribriform growth

    Fig. 22

    Well-differentiated endometrioid carcinoma. Crowded atypical glands with early glandular confluence are surrounded by eosinophilic spindled stromal cells which constitute a desmoplastic stromal reaction, indicating stromal invasion by carcinoma

    Fig. 23

    Well-differentiated endometrioid carcinoma. Stromal desmoplasia, a manifestation of endometrial stromal invasion by endometrioid carcinoma, is characterized by spindled cells with a fibroblastic appearance

    Fig. 24

    Well-differentiated endometrioid carcinoma. Glands are fused and interconnected in a confluent glandular pattern, without intervening stroma, indicating endometrial stromal invasion by carcinoma

    Fig. 25

    Well-differentiated endometrioid carcinoma. Complex branching glands create a confluent glandular/labyrinthine pattern indicating endometrial stromal invasion by carcinoma

    Fig. 26

    Well-differentiated endometrioid carcinoma. Fused glands create a cribriform pattern indicating endometrial stromal invasion by carcinoma

    Fig. 27

    Well-differentiated endometrioid carcinoma. A papillary/villoglandular proliferation indicates carcinoma when the papillary/villous structures have an exophytic growth pattern and are not merely intraglandular epithelial papillae

    Fig. 28

    Well-differentiated endometrioid carcinoma. A papillary/villoglandular pattern indicates carcinoma when the papillary/villous structures are lined by endometrioid epithelium along the external aspect and have a central fibrovascular core

    Fig. 29

    Papillary hyperplasia. Intraglandular papillae reflect a papillary variant of hyperplasia rather than carcinoma (compare with Fig. 28)

    Fig. 30

    Papillary hyperplasia. Papillae contain fibrovascular cores; their intraglandular location indicates a hyperplasia rather than a papillary pattern of carcinoma

     

In the past, the presence of masses of squamous epithelium replacing the endometrial stroma was considered a feature of invasion (Kurman and Norris 1982). Masses of squamous epithelium with minimal nuclear atypia that extensively replace the endometrium (over a 2-mm2 area) reflect stromal invasion only if they are associated with a desmoplastic response or a confluent glandular pattern.

Increasing degrees of nuclear atypia, mitotic activity, and stratification of cells in curettings are associated with a higher frequency of carcinoma in the uterus but are of limited value because even a mild degree of these changes is associated with carcinoma in nearly one-third of cases (Lehman and Hart 2001). Even with mild atypia, low mitotic activity, and lesser degrees of stratification in curettings, 20% of residual carcinomas in the resected uterus are moderately or poorly differentiated, and 10% deeply invade the myometrium. These other features in curettings, although useful, therefore are not sufficiently accurate to predict whether a biologically significant lesion is present in the uterus. Unfortunately, assessing varying degrees of nuclear atypia in this borderline group of lesions is subjective and not easily reproduced. In contrast, when stromal invasion is absent in curettings, carcinoma is found in the uterus in only 17% of cases, and the carcinomas are well differentiated and either confined to the endometrium or only superficially invasive (Table 1).
Table 1

Hysterectomy findings when atypical hyperplasiaa is present in curettings (89 patients)

Finding

No. (%)

Carcinoma

15 (17)

Grade

 

Well differentiated

15 (100)

Moderately differentiated

0

Poorly differentiated

0

Myometrial invasion

 

None

8 (53)b

Inner one third

7 (47)b

1 mm or less

5

2–4 mm

2

Adapted with permission from Kurman and Norris (1982)

aA diagnosis of atypical hyperplasia based on cytological atypia in the absence of endometrial stromal invasion

bThe percentages refer to the proportion of carcinomas in the hysterectomy specimen

If stromal invasion is present in curettings, residual carcinoma is found in the uterus in half; more than one-third of the carcinomas are moderately or poorly differentiated, and a fourth of them invade deeply into the myometrium (Table 2). A small proportion (7%) of patients with invasion in curettings will have extrauterine metastases at hysterectomy, and half with metastasis will die of tumor (Kurman and Norris 1982). Thus, the absence of stromal invasion provides the basis for distinguishing atypical hyperplasia from a biologically significant, well-differentiated carcinoma (Kurman and Norris 1982; King et al. 1984). A number of more recent studies have found higher frequencies of endometrial carcinoma (43–52%) in hysterectomy specimens following a diagnosis of atypical hyperplasia (Janicek and Rosenshein 1994; Widra et al. 1995; Trimble et al. 2006). Of the carcinomas detected in two of these studies, 43% were stage 1C or greater. In the most recent study, only 10.6% were stage 1C while 30.9% were stage 1B and the remaining were stage 1A. These studies included patients who had been diagnosed by either curettage or biopsy, but there were no significant differences in the frequencies with which carcinoma was detected at hysterectomy in those patients who received a curettage compared to those who had been biopsied. However, in one of these studies, the biopsy and curettage specimens were not reviewed to confirm that features of stromal invasion were absent in these specimens (Janicek and Rosenshein 1994). More recently, additional studies have demonstrated that clinically significant endometrial proliferations, that is, those that have a high likelihood of myometrial invasion, can be recognized when either sufficient architectural complexity or nuclear atypia, including prominence of nucleoli, is present (Longacre et al. 1995; McKenney and Longacre 2009). In addition, the strong association of a desmoplastic stromal response with a myoinvasive lesion was confirmed.
Table 2

Hysterectomy findings when well-differentiated carcinomaa is present in curettings (115 patients)

Finding

No. (%)

Carcinoma

58 (50)

Grade

 

Well differentiated

38 (66)b

Moderately differentiated

14 (24)b

Poorly differentiated

6 (10)b

Myometrial invasion

42 (72)b

Inner one third

28 (48)b

Middle and outer third

14 (24)b

Adapted with permission from Kurman and Norris (1982)

aA diagnosis of well-differentiated carcinoma based on identification of endometrial stromal invasion

bThe percentages refer to the proportion of carcinomas in the hysterectomy specimen

The identification of stromal invasion is important because it is semiquantitative, therefore less subjective than other criteria, and it delineates a biologically significant lesion that has a much greater likelihood of metastasis than one in which invasion is absent. Experimental studies of neoplasms from the breast, colon, pancreas, and lung lend support to the division of endometrial proliferations into noninvasive and invasive forms based on the histologic alterations observed in the endometrial stroma. These studies demonstrate profound molecular and structural alterations in the stroma adjacent to invasive as compared with noninvasive tumors. Invasive tumors can induce a conversion of stromal fibroblasts into myofibroblasts, which elaborate extracellular matrix components, such as type V collagen and proteoglycans, that are increased in desmoplasia and are readily observed by light microscopy using the criteria for stromal invasion as outlined. It has been shown that tumor cells produce growth factors such as platelet-derived growth factor, epidermal-derived growth factor, and insulin-like growth factor, which may play a role in stimulating the growth of stromal cells surrounding tumors.

Reproducibility Studies and Adjunctive Techniques in the Classification of Endometrial Hyperplasias

Several studies have addressed the reproducibility of the diagnosis of endometrial hyperplasia and its distinction from well-differentiated carcinoma (Kendall et al. 1998; Bergeron et al. 1999; Zaino et al. 2006). One study of 100 endometrial biopsy and curettage specimens ranging from proliferative endometrium to well-differentiated carcinoma found substantial interobserver agreement for diagnoses of hyperplasia without atypia and well-differentiated carcinoma but only moderate agreement for the diagnosis of atypical hyperplasia (Kendall et al. 1998). Several histologic features, including nuclear enlargement, vesicular change, nuclear pleomorphism, chromatic irregularities, loss of polarity, nuclear rounding, and presence of nucleoli, were associated with a diagnosis of atypical hyperplasia by univariable logistic regression analysis. However, of the histologic features evaluated, the only feature that was associated with the distinction of atypical hyperplasia from hyperplasia without atypia in multivariable logistic regression analysis was the presence of nucleoli.

The features that were associated with the distinction of carcinoma from atypical hyperplasia in both univariable and multivariable analysis included stromal alteration (stromal desmoplasia) and glandular confluence. A more recent study found similar values for intraobserver agreement and slightly lower values for interobserver agreement (Bergeron et al. 1999). In addition, the study confirmed that the category of atypical hyperplasia has the lowest diagnostic reproducibility of the various categories. Similar histologic features were found to be useful for distinguishing the various diagnostic categories, although the utility of the presence of nucleoli for diagnosing atypical hyperplasia and of stromal alteration for diagnosing well-differentiated carcinoma were somewhat less, as evidenced by lower mean interobserver agreement values for these features. Thus, interobserver agreement is lowest for the diagnostic category of atypical hyperplasia, indicating that further refinement of the histologic criteria, enhanced endometrial sampling techniques, and novel objective analyses are required to improve the reproducibility of the diagnosis of atypical hyperplasia.

Endometrioid Intraepithelial Neoplasia

In 2000, a new classification for endometrial hyperplasia was proposed based on histopathologic, molecular genetic changes and computerized morphometric analysis (Mutter et al. 2000; Mutter 2000). The system divides endometrial proliferative lesions into “endometrial hyperplasia (EH),” a benign condition, and “endometrial intraepithelial neoplasia (EIN),” a true carcinoma precursor based on glandular architecture and genetic abnormalities that were interpreted as clonal and neoplastic. Proliferations that are polyclonal were regarded as a response to an abnormal hormonal environment – either unopposed estrogenic stimulation associated with anovulatory cycles or exogenous estrogenic stimulation – and were designated “hyperplasia.” Monoclonal lesions, on the other hand, were associated with an increased risk of progression to carcinoma and were originally designated “endometrial intraepithelial neoplasia” and subsequently changed to “endometrioid intraepithelial neoplasia (EIN)” in the 2014 WHO Classification. The rationale cited for this approach was that therapy for hyperplasia should be aimed at treating the suspected cause and symptoms, whereas monoclonal lesions should be removed or ablated. Because clonality cannot be performed on diagnostic specimens in most laboratories, it was proposed that the diagnosis of EIN be made when glandular crowding that resulted in a volume percentage of stroma was less than 55% (Mutter 2000). Ideally, this parameter would be assessed by morphometric analysis, which has been shown to separate hyperplasias, particularly those classified as nonatypical by light microscopy, into monoclonal and polyclonal lesions. However, to make the system applicable for routine practice, diagnostic parameters that could be determined on light microscopy were developed. The morphometric analysis to determine the relationship of glandular crowding to intervening stroma was referred to as a “D-score.” A “D-Score” or “multivariate discriminant score” focuses on three features: (1) volume percentage stroma (VPS), (2) gland branching/convolution (outer surface density of glands), and (3) standard deviation of the shortest nuclear axis which is correlated with nuclear atypicality. This classification was used to predict the rate of progression to cancer. A “D-score” less or equal to 1 predicted a high rate of progression to endometrial carcinoma, whereas a score greater than 1 almost never indicated progression to cancer. Accordingly, the criteria for EIN are based on architecture (gland area that exceeds that of stroma, usually localized), cytological alterations (cytology in the lesion differs from the background), and lesion size (greater than 1 mm linear dimension) (Mutter 2000). Given that these criteria are essentially identical to those used to make the diagnosis of atypical hyperplasia the most recent WHO Classification system equated “atypical hyperplasia” with “EIN.” Although in many cases this is true, other lesions classified as EIN correspond to hyperplasia without atypia which can, therefore, lead to overdiagnosis and unnecessary treatment. Some studies have suggested improved reproducibility in the diagnosis of EIN versus atypical hyperplasia, but other studies have found similar reproducibility (Hecht et al. 2005; Ordi et al. 2014) Moreover, in a nested case-control study, the risk of progression to carcinoma was similar after either a diagnosis of EIN or atypical hyperplasia(Lacey et al. 2008).

Although not included in the current WHO classification system, it is noteworthy that the European Working Group (EWG) developed another classification system for endometrial proliferative lesions. In this system, simple and complex hyperplasia without atypia are referred to as “hyperplasia,” while atypical hyperplasia and well-differentiated carcinomas are combined into a single category designated “endometrial neoplasia.” It was stated that this system showed greater reproducibility than the hyperplasia/atypical hyperplasia and the EIN system. This is not surprising as the European Working Group classification is a two-tier system and it was compared to the older 4 tier hyperplasia/atypical hyperplasia system (Bergeron et al. 1999). We are unaware of a carefully performed study in which all three systems (specifically the 2014 WHO Classification of hyperplasia/atypical hyperplasia and EIN) are compared head to head with the European Working Group Classification to substantiate this claim. Nonetheless, use of the term “endometrial neoplasia” in the European Working Group Classification has a completely different meaning than EIN in the WHO Classification which further compromises both the EIN and the “endometrial neoplasia” classifications.

Molecular Genetics and Immunohistochemistry

Molecular genetic studies are mentioned only briefly here with a more detailed discussion in the chapter on Endometrial Carcinoma (see Chapter 9). There have been a number of molecular genetic alterations identified in atypical hyperplasia, including microsatellite instability and mutations in the PTEN tumor suppressor gene and the KRAS oncogene. Of note, these are the most common molecular genetic alterations in endometrioid carcinoma. These findings support clinicopathologic and epidemiologic data indicating that atypical hyperplasia is the immediate precursor for endometrioid carcinoma. A study, comparing mutations in atypical hyperplasia and associated carcinomas, found shared and unique mutations in both components, suggesting a process of complex subclone evolution versus a linear accumulation of molecular events from hyperplasia to carcinoma (Russo et al. 2017). PTEN mutations are found at approximately the same frequency in complex atypical hyperplasia and carcinoma and have rarely been described in hyperplasia without atypia (Hayes et al. 2006). In addition, KRAS mutations and microsatellite instability have been reported in atypical hyperplasia (Levine et al. 1998; Esteller et al. 1999; Enomoto et al. 1993). Only a relatively small number of hyperplasias without atypia have been analyzed for mutations in PTEN and KRAS and for microsatellite instability. Studies suggest that all of these alterations occur before the development of invasion, but it is not clear when in the progression of the disease they occur.

Recent immunohistochemical studies have confirmed a decrease or loss of PTEN expression in 70% of atypical hyperplasia with some containing focal areas of ARID1A loss (Ayhan et al. 2015). Of note, the areas with loss of both PTEN and ARID1A showed an increase in the proliferation index as measured by Ki67 immunohistochemistry, suggesting that ARID1A prevents PTEN inactivation from promoting cell proliferation. At the present time, it is not recommended that DNA mismatch repair immunohistochemistry be utilized on atypical hyperplasia to screen for Lynch syndrome. Although a number of studies have been done with a wide variety of antibodies, none have proven adequately robust for the diagnosis of endometrial hyperplasia.

Behavior

Many of the past studies designed to determine the outcome of women with endometrial hyperplasia did not consider cytologic and architectural features separately. This issue was addressed in a retrospective analysis of 170 patients with endometrial hyperplasia on curettings with a mean follow-up of 13.4 years in which hysterectomy was not performed before 1 year after the initial diagnosis. Various histologic features were evaluated, and cytologic and architectural abnormalities were analyzed independently in an effort to delineate the histologic features associated with an increased risk of progression to carcinoma. A third of the patients with both nonatypical and atypical hyperplasia were asymptomatic after the diagnostic curettage and required no further treatment. Only 2 (2%) of 122 patients with hyperplasia lacking cytologic atypia, one with simple and one with complex hyperplasia, progressed to carcinoma. The two cases of simple hyperplasia that progressed to carcinoma first developed atypical hyperplasia. In contrast, 11 (23%) of the 48 women with atypical hyperplasia progressed to carcinoma (Table 3); 8% of patients with simple atypical hyperplasia and 29% of patients with complex atypical progressed to carcinoma (Table 4). The presence of glandular complexity and crowding superimposed on atypia, therefore, appears to place the patient at greater risk than does cytologic atypia alone. The differences in progression to carcinoma among the four subgroups, however, were not statistically significant. A subsequent nested-case-control study of 138 cases diagnosed with endometrial hyperplasia followed by carcinoma at least 1 year later with 241 controls (matched for age, date and follow-up duration and counter-matched for endometrial hyperplasia diagnosis) showed that women with both simple and complex endometrial hyperplasia without atypia had a 10% probability of developing carcinoma in contrast to a 40% probability for women with atypical hyperplasia, both simple and complex (Lacey et al. 2008). These studies show that cytologic atypia is the most useful feature in identifying a lesion that might progress to carcinoma and provided a robust rationale for the adoption of a two-tiered classification system based solely on the presence of cytological atypia.
Table 3

Follow-up of hyperplasia and atypical hyperplasia in 170 patients

Type of hyperplasia

No. of patients

Regressed

Persisted

Progressed to carcinoma

No.

(%)

No.

(%)

No.

(%)

Hyperplasia

122

97

(80)

23

(19)

2

(2)

Atypical hyperplasia

48

29

(60)

8

(17)

11

(23)

Adapted with permission from Kurman et al. (1985)

Table 4

Follow-up of simple and complex hyperplasia and atypical hyperplasia in 170 patients

Type of hyperplasia

No. of patients

Regressed

Persisted

Progressed to carcinoma

No.

(%)

No.

(%)

No.

(%)

Simple

93

74

(80)

18

(19)

1

(1)

Complex

29

23

(80)

5

(17)

1

(3)

Simple atypical

13

9

(69)

3

(23)

1

(8)

Complex atypical

35

20

(57)

5

(14)

10

(29)

Adapted with permission from Kurman et al. (1985)

The carcinomas that develop in patients with hyperplasia are relatively innocuous (Kurman et al. 1985; Gusberg and Kaplan 1963). In one study, the mean duration of progression of hyperplasia without atypia to carcinoma is nearly 10 years, and it takes a mean of 4 years to progress from atypical hyperplasia to clinically evident carcinoma (Kurman et al. 1985). In another study, the median interval from atypical hyperplasia to carcinoma was 6.7 years.

It has been shown that 17–43% of women with atypical hyperplasia in curettings will have a well-differentiated carcinoma in the uterus if a hysterectomy is performed within 1 month of the curettage (King et al. 1984; Tavassoli and Kraus 1978). Increasing degrees of nuclear atypia, mitotic activity, and stratification of cells in curettings are associated with a higher frequency of carcinoma in the uterus. With long-term follow-up, however, only 11–40% of women with atypical hyperplasia develop carcinoma if a hysterectomy is not done (Kurman et al. 1985; Gusberg and Kaplan 1963). Thus, the lesion designated as well-differentiated carcinoma usually remains stable for a long period of time. Reasons that may account for the relatively low rate of progression to carcinoma in untreated patients with atypical hyperplasia include a general tendency for the highest grade of atypical hyperplasia to be selected for hysterectomy, leaving the lesser degree of atypia for conservative management. In addition, atypical hyperplasia may represent a heterogeneous group with different constellations of genetic or epigenetic abnormalities with varying propensities to develop carcinoma. And it is likely that patient factors (e.g., immune response, obesity, hormonal milieu) may also play an important role in determining progression to carcinoma.

An additional study of the behavior of endometrial hyperplasia found that most cases of endometrial hyperplasia without atypia regressed spontaneously, whereas those with complex atypical hyperplasia were much more likely to persist (Terakawa et al. 1997). Another study confirmed the significance of cytologic atypia in predicting increased risk of associated endometrial carcinoma in hysterectomy specimens (Hunter et al. 1994). Because most atypical hyperplasias have complex architecture, it is complex atypical hyperplasia that is associated with a significant risk of persistence and progression to carcinoma. Hence, this lesion is regarded as a direct precursor of well-differentiated endometrioid carcinoma of the endometrium. However, hyperplasia is identified in a prior endometrial specimen or in the hysterectomy specimen in only 35–75% of women with endometrial carcinoma (Ayhan et al. 1991; Beckner et al. 1985; Bokhman 1983; Deligdisch and Cohen 1985; Gucer et al. 1998; Kaku et al. 1996). In those reports that specified the number of hyperplasias that were classified as atypical, 14–36% of women with endometrial carcinoma had associated atypical hyperplasia (Gucer et al. 1998; Kaku et al. 1996). It is unclear whether failure to identify an associated atypical hyperplasia in all cases of endometrioid carcinoma reflects overgrowth of a preexisting hyperplasia by carcinoma or the development of carcinoma through an alternative pathway.

Management

Management of patients with endometrial hyperplasia is based on clinical factors which include the desire to preserve fertility in young women and associated medical conditions that render older women at high risk for a surgical procedure in addition to the microscopic findings. (Kraus 1985)

Premenopausal Women (Less than 40 Years of Age)

Most premenopausal women who present with abnormal bleeding have nonspecific hormonal disorders that are self-limited. These women are at low risk of having carcinoma (Table 5). In a study of 460 women 40 years of age and younger, 6 (1.3%) had “mild” hyperplasia (simple hyperplasia) but none had atypical hyperplasia or carcinoma (Kaminski and Stevens 1985). Therefore, most women in this age group with abnormal bleeding do not require an endometrial biopsy. Women with risk factors for endometrial cancer, such as polycystic ovarian disease or obesity, and women with persistent bleeding should have an endometrial biopsy performed. Recent studies suggest that a body mass index (BMI) of greater than 30 in premenopausal women resulted in a four- to sevenfold increase in atypical hyperplasia or cancer compared to women with a BMI less than 30. Thus, endometrial sampling is recommended for premenopausal women with abnormal bleeding and a BMI greater than 30 (Wise et al. 2016; Guraslan et al. 2016).
Table 5

Pertinent findings in endometrium in women with abnormal bleeding according to age

 

Age

 

Premenopausal 40 years (n = 5,460)

Perimenopausal 40–55 years (n = 5,748)

Postmenopausal 55 years (n = 5,226)

Finding in endometrial specimena

No.

(%)

No.

(%)

No.

(%)

Carcinoma

0

(–)

3

(0.4)

15

(7)

Atypical hyperplasia

0

(–)

5

(0.7)

NKb

 

Hyperplasia

6

(1)

41

(6).0

34

(15)

Atrophy

7

(2)

51

(7).0

127

(56)

Polyp

6

(1)

13

(2).0

19

(8)

Proliferative

139

(29)

273

(36)

31

(14)

Secretory

241

(50)

287

(38)

0

(–)

NK not known

aNot all the endometrial findings in the study by Kaminski and Stevens are listed and therefore percentages do not total 100%

bA category of atypical hyperplasia was not specified in this study

If a diagnosis of hyperplasia without atypia is made, the patient can be treated conservatively because these lesions have an extremely low risk (1–2%) of progression to carcinoma. Because the transit time to carcinoma is approximately 10 years and hyperplasia without cytologic atypia first progresses through atypical hyperplasia before becoming carcinoma, follow-up and periodic endometrial biopsies suffice (Kurman et al. 1985). Conservative management of young women with simple hyperplasia and complex hyperplasia resulted in subsequent pregnancies in 29% and 20% of these women, respectively, in one study (Table 6) (Kurman et al. 1985).
Table 6

Subsequent pregnancies in “untreated” women with hyperplasia and atypical hyperplasia

Diagnosis

No. of patients,40

No. of patients who became pregnant

No. of full-term pregnancies

Simple hyperplasia

35

10 (29%)

19

Complex hyperplasia

15

3 (20%)

4

Atypical hyperplasia (simple and complex)

24

3 (13%)

4

Adapted from Kurman et al. (1985)

Women with atypical hyperplasia on an endometrial biopsy who wish to preserve their fertility should be treated with progestin suppression. In view of the very similar accuracy of endometrial biopsy and curettage and the low risk of an associated endometrial carcinoma in women younger than 40 years of age, a curettage need not be performed to exclude carcinoma, but close follow-up and periodic endometrial biopsies are necessary. A conservative plan of management is justified because the risk of progression to carcinoma in young women is low and the carcinomas that do develop tend to be innocuous (Table 7); 20% of those women less than 40 years of age can subsequently become pregnant and have normal deliveries (Randall and Kurman 1997). A recent study of complex hyperplasia with and without atypia found that progestin therapy resulted in regression of complex atypical hyperplasia (Table 8) but that the majority of complex hyperplasias without atypia regressed with or without progestin therapy (Reed et al. 2009). This study also found that higher doses and longer duration of progestin therapy increase the likelihood of regression of complex atypical hyperplasia (Table 9).
Table 7

Hysterectomy findings according to the presence of atypical hyperplasia or well-differentiated adenocarcinoma in curettings in women under 40 years of age

 

Curettings

 

Atypical hyperplasia (n = 517)

Well-differentiated carcinoma (n = 535)

Hysterectomy findings

No.

No.

Carcinoma

2 (12%)

13 (37%)

Grade 1

2

10

Grade 2

0

3

Myometrial invasion

Endometrium only

2

3

Inner one third

0

9

Middle one third

0

1

Adapted from Kurman and Norris (1982)

Table 8

Risk of persistence/progression of complex hyperplasia with and without atypia in relation to progestin therapy

 

Complex hyperplasia without atypia (n = 115)

Complex atypical hyperplasia (n = 70)

Treatment

Regression (n = 82)

Persist/progress (n = 33)

Regression (n = 44)

Persist/progress (n = 26)

No progestin (n = 20)

14 (70%)

6 (30%)

6 (33%)

12 (67%)

Progestin (n = 95)

68 (72%)

27 (28%)

38 (73%)

14 (27%)

Table 9

Risk of persistence/progression of complex hyperplasia with and without atypia in relation to duration of progestin therapy

 

Complex hyperplasia without atypia (n = 115)

Complex atypical hyperplasia (n = 70)

Duration of Rx

Regression (n = 82)

Persist/progress (n = 33)

Regression (n = 44)

Persist/progress (n = 26)

<3 months

71%

30%

62%

38%

>3 months

73%

28%

87%

13%

Conservative management also can be considered for women diagnosed with well-differentiated carcinoma. One study of progestin treatment of atypical hyperplasia and well-differentiated carcinoma in women under age 40 found that 75% of women with carcinoma and 95% with atypical hyperplasia had regression of their lesions (Randall and Kurman 1997). In addition, all patients were alive without evidence of progressive disease during the follow-up period. The median duration of progestin treatment necessary to effect regression was 9 months. In another study, 62% of women under 40 years treated with progestins alone for endometrial carcinoma responded to the hormonal therapy, although 23% of these later developed recurrent disease (Kim et al. 1997). Ninety percent of the patients were alive without evidence of disease during the follow-up period. The lower frequency of responders in this study may have been a result of the relatively short duration of the hormonal therapy. Thus, in premenopausal women, atypical hyperplasia and well-differentiated carcinoma can be regarded as a single clinicopathologic entity for management purposes. Nonetheless, pathologists should distinguish atypical hyperplasia from well-differentiated carcinoma since atypical hyperplasia is more likely to respond to progestin treatment. More recent studies suggest that levonorgestrel-releasing intrauterine systems may increase regression; however, clinical trials of hormone therapy are needed to establish standard therapeutic approaches (Chandra et al. 2016; Trimble et al. 2012). If conservative management is elected, magnetic resonance imaging (MRI) must be performed to exclude deep myometrial invasion or the presence of a coexisting ovarian neoplasm.

Perimenopausal Women (40–55 Years of Age)

Abnormal bleeding in the perimenopausal age group can be managed in a similar fashion as in younger women because perimenopausal women also are at low risk of having carcinoma (see Table 5). Most simple and complex hyperplasias in the 40- to 55-year-old age group are related to anovulation and are self-limited. Nonetheless, a biopsy is usually performed to exclude carcinoma. Patients with a diagnosis of atypical hyperplasia can be treated with progestins or a hysterectomy.

Nearly 60% of atypical hyperplasias regress, but the likelihood of residual carcinoma in the uterus after a curettage increases with age. For patients in the 40- to 55-year age range, treatment should be individualized. Regression occurs frequently, and the risk of residual carcinoma is lower than in older women. Therefore, observation or suppression with progestins monitored by endometrial biopsies every 3 months suffices. If the lesion persists, a hysterectomy may have to be performed.

Postmenopausal Women (Over 55 Years of Age)

Women in the postmenopausal age group who have abnormal bleeding have a significant risk of having either carcinoma or atypical hyperplasia (see Table 5). Accordingly, vaginal bleeding requires immediate evaluation with an endometrial biopsy. A diagnosis of hyperplasia or atypical hyperplasia should be evaluated with a fractional curettage. If the curettings demonstrate hyperplasia without atypia, conservative management is an option because these types of hyperplasia are related to unopposed estrogenic stimulation, either from exogenous hormone treatment or because of peripheral conversion of androgens to estrogen in adipose tissue. Most (80%) hyperplasias treated with cyclic medroxyprogesterone acetate at 10 mg/day for 14 days regress; none progressed to carcinoma in a prospective study of 65 postmenopausal women (Ferenczy and Gelfand 1989). Conservative management, either observation only or treatment with medroxyprogesterone to produce a medical curettage, therefore, is adequate. Repeated episodes of irregular bleeding that are not responsive to hormone treatment require a hysterectomy. Hysterectomy is the treatment of choice for a diagnosis of atypical hyperplasia based on a curettage. In postmenopausal women with surgical risk factors that preclude a hysterectomy, continuous treatment with 20–40 mg/day megestrol acetate can be used effectively to avoid surgery. In a study of 70 treated women with complex hyperplasia (38 women) and atypical hyperplasia (32 women), surgery was avoided in 93% of patients. The hyperplasias (atypical and nonatypical) completely regressed in 85% after a mean follow-up of more than 5 years. None of the lesions progressed to carcinoma (Gal 1986).

For postmenopausal women with hyperplasia or atypical hyperplasia who are receiving exogenous estrogen, termination of the estrogen usually suffices even for atypical hyperplasia, because these proliferations regress after the stimulus for their growth has been removed. Alternatively, the addition of cyclically or continuous administered medroxyprogesterone in women being treated with estrogen can be considered because the use of even low doses of progestins substantially reduces the risk of development of endometrial hyperplasia and carcinoma. Using a 7- to 14-day regimen of orally administered 10 mg medroxy-progesterone to postmenopausal women receiving estrogen, five endometrial carcinomas were detected in 5402 woman-years of continuous estrogen therapy (Greenblatt et al. 1982). This incidence is not greater than that of untreated postmenopausal women, in whom the expected incidence of endometrial cancer is 1–2 per 1000 woman-years, that is, 5.4–9.8 cases.

Morphologic Changes Associated with Progestin Treatment

Treatment with progestins for women with complex atypical hyperplasi and well-differentiated carcinoma has become an accepted alternative to hysterectomy. Correct interpretation of the morphologic changes that result from the treatment is required for the appropriate management of women who chose this therapeutic approach. Unfortunately, there have been few studies to describe these changes. One study described a number of histologic changes including decreased gland-to-stroma ratio, decreased glandular cellularity, reduced to absent mitotic activity, loss of cytologic atypia and a variety of metaplastic changes (Figs. 31 and 32) (Wheeler et al. 2007). In addition, cribriform and papillary architectural changes may be induced by treatment and confused with disease progression. Importantly, the persistence of architectural abnormalities and/or cytologic atypia after 6 months of treatment were the only histologic features found to be associated with treatment failure. Based on these findings, a classification of progestin-treated lesions was proposed (Table 10). It is important that the pretreatment specimen be available for review for the pathologist to evaluate the response to progestin treatment and therefore provide information to the gynecologist that will assist in modifying or discontinuing therapy.
Fig. 31

Complex hyperplasia with treatment (progestin) effect. Individual glands with complex profiles are interspersed with inactive glands within endometrial stroma (a). The confluent glandular pattern of the prior endometrioid carcinoma is absent. Glands exhibit mucinous metaplasia (b)

Fig. 32

Complex hyperplasia with treatment (progestin) effect. Complex glands exhibit prominent metaplastic changes (eosinophilic, mucinous, tubal) which are commonly seen, along with reduction of nuclear atypia, as a result of progestin therapy

Table 10

Classification of progestin-treated lesions of the endometrium

Diagnosis

Histologic features

Progestin-treated complex hyperplasia

No cytologic atypia with crowded, back-to-back glands and/or a confluent glandular pattern (cribriform and/or papillary)

Progestin-treated CAH

Cytologic atypia with crowded, back-to-back glands that lack a confluent glandular pattern

Progestin-treated well-differentiated carcinoma

Cytologic atypia with confluent glandular pattern (cribriform and/or papillary pattern)

Adapted with permission from Wheeler et al. (2007)

Endometrial Cellular Changes: Metaplasia, Cellular Differentiation

In contrast to hyperplasia, which is a proliferative response to estrogenic stimulation, metaplasia represents cytoplasmic differentiation. The cytoplasmic alterations (metaplasia) are manifested by eosinophilic, ciliated cell (tubal), squamous, secretory/clear, and mucinous differentiation. Metaplasias develop most commonly in response to estrogenic and progestational stimulation, although these changes may develop in response to various other stimuli as well. Thus, the morphologic response of the endometrium to hormonal stimulation is complex and is reflected by a combination of architectural, nuclear, and cytoplasmic alterations. Although classifications separate hyperplasia and the various metaplasias, both are usually intimately associated and cannot always be separately classified.

Definitions and Classification

Metaplasia is defined as replacement of one type of adult tissue by another type that is not normally found in that location. In the endometrium, most of the changes that are designated as metaplasia represent a variety of cytoplasmic alterations or forms of differentiation that are not encountered in normal proliferative endometrium but do not qualify as true metaplasia. Accordingly, it has been suggested that a more appropriate term is change (Silverberg and Kurman 1992). Use of the term change also has the advantage of providing a descriptive designation without employing a specific mechanism of development. In this chapter, the terms metaplasia, change, and differentiation are used interchangeably. The various forms of cellular differentiation are typically focal when unaccompanied by hyperplasia but can be diffuse when hyperplasia is present. As previously noted, the endometrial epithelium can undergo a variety of cytoplasmic changes in response to different stimuli that can be observed in both benign and malignant conditions. A simplified classification of these is shown in Table 11. It is important to recognize the various cytoplasmic changes because they are benign and can be confused with hyperplasia. When hyperplasia and the cytoplasmic alterations coexist, as they often do, the hyperplasia should be classified, but it is not necessary to describe the cytoplasmic changes because they do not influence prognosis (see section “Behavior”).
Table 11

Classification of endometrial metaplasia

Papillary syncytial

Eosinophilic and ciliated

Mucinous

Hobnail

Squamous

Secretory

Papillary proliferation

Clinical Features

The frequent association of the various endometrial cytoplasmic changes with hyperplasia probably results from a hyperestrogenic state. More than 70% of perimenopausal and postmenopausal women with metaplasia had received exogenous estrogen in one study (Hendrickson and Kempson 1980). In addition, most young women with metaplasia have clinical manifestations of persistent anovulation and primary infertility, features of polycystic ovarian syndrome (Hendrickson and Kempson 1980; Crum et al. 1981). Metaplasia also may occur in various benign conditions, including polyps, endometritis, trauma, and vitamin A deficiency (Hendrickson and Kempson 1980; Crum et al. 1981; Fluhmann 1954).

Pathologic Findings

The various types of endometrial cytoplasmic changes have no distinctive gross features.

Papillary Syncytial Metaplasia

On the endometrial surface, cells with eosinophilic cytoplasm typically merge into a syncytium that either can be flat or more commonly form papillary processes (Rorat and Wallach 1984). Typically, the papillary processes lack connective tissue support and contain small cystic spaces filled with polymorphonuclear leukocytes. This lesion has been referred to as surface syncytial change, papillary syncytial change, or papillary metaplasia (Hendrickson and Kempson 1980; Silverberg and Kurman 1992). We prefer the term eosinophilic syncytial change because the lesion is characteristically composed of eosinophilic cells forming a syncytium and can involve glands as well as the surface. Eosinophilic syncytial change is commonly associated with endometrial stromal breakdown or inflammation, suggesting that it is a degenerative or a reparative process (Zaman and Mazur 1993). A recent study using immunohistochemical stains for proliferation further supports the regressive nature of this type of epithelial change (Shah and Mazur 2008). The nuclei within the syncytium are arranged haphazardly and piled up; they generally are small and bland but at times may be round and vesicular and display alterations in shape and chromatin texture. Mitotic figures are rare. Hyperchromatic nuclei with smudged chromatin and irregular nuclear membranes appear degenerated whereas enlarged, vesicular nuclei with a prominent nucleolus and smooth nuclear membranes appear reactive. These degenerative and reparative changes should not be interpreted as nuclear atypia.

Eosinophilic and Ciliated Cell Metaplasia

Eosinophilic change is the most common metaplasia (Figs. 33 and 34). Several types of eosinophilic cytoplasmic transformation occur, all of them innocuous. Ciliated cells, squamous cells, oncocytes, and papillary and surface syncytial change all may have eosinophilic cytoplasm. However, eosinophilic cells also occur in association with hyperplasia, particularly atypical hyperplasia. Glands may be partially or completely lined by eosinophilic cells. Eosinophilic cells that line glands can show considerable variation in shape. They may be columnar when associated with atypical hyperplasia, rounded when associated with ciliated cells, or polygonal, forming pavement-like aggregates, when they merge with cells that show squamous differentiation. In hyperplastic lesions, aggregates of eosinophilic cells often form intraglandular papillary tufts and bridges, thus simulating carcinoma. Eosinophilic cells contain variable amounts of cytoplasm that at times can be partially vacuolated. The nuclei tend to be round and somewhat stratified. In most instances, the nuclei are smaller, more uniform, and lack the irregular nuclear membrane, coarse chromatin, and nucleoli that characterize cells with true cytologic atypia. Occasionally, the nuclei can be enlarged and contain a single prominent nucleolus. Mitotic figures are rarely present.
Fig. 33

Hyperplasia without atypia with eosinophilic metaplasia. Intraglandular epithelial tufts composed of bland cells with abundant eosinophilic cytoplasm are present within hyperplasia without atypia

Fig. 34

Atypical hyperplasia with eosinophilic metaplasia. Intraglandular epithelial clusters composed of rounded cells with abundant eosinophilic cytoplasm are present within an atypical hyperplasia; assessment of atypia is based on the appearance of the glandular epithelium which displays vesicular nuclei with prominent nucleoli and loss of polarity

Eosinophilic change is often seen in combination with cliated cell change (tubal metaplasia). Cilia are not usually evident microscopically in proliferative endometrial glandular cells, although they may be observed on the endometrial surface (Masterton et al. 1975). Ciliated cells occasionally are observed in isolated glands in atrophic or inactive endometria or in polyps in the absence of hyperplasia. The presence of a significant number of ciliated glandular cells is referred to as ciliated cell change or tubal metaplasia because of the resemblance to the epithelium of the fallopian tube. The ciliated cells are often round and slightly enlarged, but the nuclear membranes are smooth and uniform and the chromatin is fine and evenly dispersed. There is no nuclear atypia. The ciliated cells may be interspersed singly or in small groups among nonciliated cells, or they may line a larger segment of a gland. Mitotic activity is limited to the adjacent nonciliated cells. Ciliated cell change may occur in glands in the absence of hyperplasia. Dilated venous sinusoids are also frequently present. All these changes reflect a mild degree of estrogenic stimulation. Ciliated cell change frequently accompanies simple, complex, or atypical hyperplasia (Figs. 35, 36, and 37).
Fig. 35

Hyperplasia without atypia with ciliated metaplasia. Crowded glands have multiple cell types, including ciliated cells and those with rounded nuclei and cytoplasmic clearing (halos), similar to those seen in fallopian tube epithelium

Fig. 36

Hyperplasia without atypia with ciliated metaplasia. Crowded glands have some ciliated cells and cells with nuclear rounding and cytoplasmic clearing

Fig. 37

Atypical hyperplasia with ciliated metaplasia. Markedly crowded glands have some cells with rounded nuclei and cytoplasmic clearing indicating underlying tubal metaplasia, but the nuclear enlargement and loss of polarity are beyond that attributable to metaplasia and indicate atypia

Mucinous Metaplasia

Mucinous change is characterized by mucinous epithelium resembling that of the endocervix cytologically, histochemically, and ultrastructurally (Demopoulos and Greco 1983). Although it is one of the least commonly encountered cytoplasmic alterations, it occurs more frequently than generally described. The mucinous epithelium tends to be distributed focally and is composed of tall columnar cells with bland, basally oriented nuclei and clear, slightly granular cytoplasm (Figs. 38 and 39). At times mucinous change is accompanied by a papillary proliferation. The papillary processes contain normal but compressed stromal cells and are lined by nonstratified columnar epithelium, which is mucinous in areas. Mitotic figures are rare. The cytoplasm is clear in hematoxylin and eosin (H&E) stains because it contains mucin, which is periodic acid–Schiff (PAS) positive and diastase resistant and stains with mucicarmine, toluidine blue, and alcian blue. In contrast to mucinous epithelium, the vacuolated cytoplasm of secretory endometrium contains glycogen. On rare occasion the mucinous epithelium may contain goblet cells and is referred to as intestinal metaplasia.
Fig. 38

Hyperplasia without atypia with mucinous change. Crowded glands have abundant pale mucinous cytoplasm and basally situated small nuclei

Fig. 39

Hyperplasia without atypia with mucinous change. Crowded glands are lined by cells with pale mucinous cytoplasm and small round nuclei, with some forming papillary tufts

Mucinous differentiation can be seen in a spectrum of epithelial proliferations ranging from benign to malignant. In one study, the likelihood of finding carcinoma associated with mucinous proliferations of the endometrium varies according to the degrees of architectural complexity and cytologic atypia of the lesions (Nucci et al. 1999). Architecturally simple lesions with papillary projections into luminal spaces and no cytologic atypia were found to have carcinoma on follow-up only when the initial specimen also contained atypical hyperplasia; otherwise, none of these simple mucinous proliferations was associated with carcinoma on follow-up. More complex proliferations with microglandular or cribriform patterns and minimal cytologic atypia, often presenting as endometrial surface lesions without coexistent atypical hyperplasia, were found to have well-differentiated noninvasive or minimally invasive carcinoma on follow-up in 65% of cases. Highly complex proliferations with glandular budding, cribriform growth, and branching of villous structures that also displayed moderate to severe cytologic atypia were invariably associated with carcinoma on follow-up (Fig. 40). Importantly, 80% of the study patients were over age 50. Thus, in perimenopausal and postmenopausal women with complex mucinous proliferations, including those with and without cytologic atypia, the risk of finding coexistent carcinoma is high.
Fig. 40

Complex atypical mucinous proliferation. This term is used for limited specimens in which crowded, fused or cribriform glands with mucinous cytoplasmic change and atypical nuclei are concerning for at least complex atypical hyperplasia, but there is little or no associated stroma to diagnose stromal invasion. Such lesions are often associated with FIGO grade 1 stage 1A endometrioid carcinoma on follow-up, as occurred in this case

Hobnail Metaplasia

Hobnail change is characterized by luminal glandular epithelial cells with a nucleus that protrudes into the gland lumen. The cells are often eosinophilic so there is overlap with eosinophilic change, but hobnail metaplasia is recognized separately when there are an abundance of cells with protruding nuclei that produce a striking finding (Fig. 41). Unlike Arias-Stella reaction, the cells do not have prominent cytoplasmic clearing or cytologic atypia.
Fig. 41

Hyperplasia without atypia with hobnail change. Crowded glands with cells containing hyperchromatic rounded nuclei that bulge into the gland lumen and some cytoplasmic clearing with vacuolization are reminiscent of the Arias-Stella reaction

Squamous Metaplasia (Squamous Differentiation)

Squamous differentiation may occur in all forms of hyperplasia (Figs. 42, 43, and 44) as well as in carcinoma. It is especially common in the more atypical endometrial proliferations and is rare in normally cycling endometrium or in simple and complex hyperplasias. The squamous cells are usually cytologically bland. The degree of nuclear atypia, when present, generally parallels that of the glandular cells. Typically, the squamous cells have a moderate amount of eosinophilic cytoplasm and are surrounded by a well-defined cell membrane. Often they merge with eosinophilic cells that qualify as eosinophilic change. The squamous cells tend to be rounded or polygonal but may be spindle shaped, forming a circumscribed nest (squamous morule) within the gland lumen (Fig. 43). Morules reflect immature or incomplete squamous differentiation. The cells are smaller and the cytoplasm is less prominent than in more completely differentiated squamous cells. Central keratinization and necrosis rarely occur. Eventually, proliferation results in protrusion of the squamous cells into the lumen, leading to replacement of the lumen by nests of squamous cells and coalescence with neighboring glands undergoing the same process. Mitotic activity is rare. A recent study found that squamous morules in hyperplastic proliferations lack expression of the estrogen and progesterone receptors and demonstrate rare to undetectable Ki-67 proliferative activity when compared to the associated hyperplastic epithelium. However, the glandular and squamous components had identical PTEN mutations indicating that the squamous component is clonally related to the glandular component. The authors concluded that the squamous morules are inert elements of the proliferative lesions. Importantly, since they are often associated with complex atypical hyperplasia and endometrioid carcinoma, their presence on endometrial sampling, in the absence of an identifiable proliferative process, should result in close follow-up of the patient for the possibility of an under sampled or occult glandular lesion (Lin et al. 2009).
Fig. 42

Hyperplasia without atypia with squamous metaplasia. Islands of squamous metaplastic epithelium are intimately admixed with nonatypical hyperplastic glands

Fig. 43

Hyperplasia without atypia with squamous metaplasia. Squamous morules are intimately admixed with nonatypical hyperplastic glands exhibiting tubal metaplasia as well

Fig. 44

Hyperplasia without atypia with squamous metaplasia. Squamous metaplastic epithelium with central necrosis forms a confluent mass intimately admixed with nonatypical hyperplastic glands but should not be interpreted as an indicator of stromal invasion when the glandular component does not manifest confluence or induce desmoplasia

Secretory

Secretory change is characterized by columnar cells with sub- or supranuclear vacuoles containing clear glycogenated cytoplasm resembling the glandular cells of early secretory endometrium. These cells also can be observed in nonneoplastic proliferative endometria but are seen more often in association with hyperplasia or carcinoma (Fig. 45). Rarely, the cells in secretory change can display hobnail morphology reminiscent of the Arias–Stella reaction (Fig. 41); such hobnail change, with or without the cytoplasmic vacuolization of secretory change (Fig. 46), should not be misinterpreted as endometrial intraepithelial carcinoma (see below). At times secretory change can result from progestational stimulation, but often there is no such association. Columnar cells with secretory change may merge with polygonal-shaped clear cells and with squamous cells containing clear glycogenated cytoplasm. The accumulation of glycogen can occur in the cytoplasm of a variety of cell types.
Fig. 45

Hyperplasia without atypia with secretory change. Crowded glands have elongated nuclei and discrete sub- and supranuclear vacuoles, reminiscent of day 18 secretory endometrium

Fig. 46

Hyperplasia with hobnail change. Crowded glands are partially lined by epithelial tufts containing cells with hyperchromatic rounded nuclei that bulge into the gland lumen. These tufts also share features with eosinophilic cell change

Papillary Proliferation

This entity consists of papillary proliferations of fibrovascular stromal cores that are lined by benign endometrial epithelium. The papillae range from small, simple papillae to very complex, branching papillae. The epithelium is usually flattened, but may be tufted and often shows cytoplasmic change including mucinous metaplasia, eosoinophilic, ciliated, and hobnail changes. Squamous metaplasia has also been described. The entity is thought to be benign and should be distinguished from carcinoma with papillary growth patterns (Ip et al. 2013; Lehman and Hart 2001).

Differential Diagnosis

The most important aspect of the evaluation of the various metaplasias and cellular changes is not to confuse them with hyperplasia or carcinoma, which is best accomplished by evaluating the glandular architecture and cytological features. In hyperplasia, the glandular outlines are irregular and complex and there is stratification of the epithelium reflecting a proliferative process. In contrast, in the various cytoplasmic changes, the glandular outlines are regular and have a tubular configuration, although cystic dilatation and slight glandular irregularity occasionally can occur.

Although the various cellular changes may be accompanied by slight nuclear enlargement, the cells lack the abnormal chromatin patterns that characterize the nuclei in atypical hyperplasia. At times the various cellular changes may look ominous and suggest carcinoma, but evidence of stromal invasion is lacking and therefore a diagnosis of carcinoma is not justified. For example, extensive squamous metaplasia may suggest a diagnosis of carcinoma but without a desmoplastic response or a confluent glandular pattern a diagnosis of carcinoma should not be made. Squamous and eosinophilic change associated with hyperplasia can fill and bridge gland lumens but lack a true confluent or cribriform pattern. Mucinous change at times can form complex papillary processes, but the stroma of the papillae are composed of normal endometrial stroma and the epithelium lacks cytologic atypia.

Behavior

Cytoplasmic changes, other than eosinophilic syncytial change, rarely occur in the absence of hyperplasia or carcinoma (Kaku et al. 1992). In the absence of hyperplasia, these changes (metaplasia) had no clinical significance in one study of 89 patients (Hendrickson and Kempson 1980). In a long-term follow-up study of endometrial hyperplasia, 5 of 11 patients with atypical hyperplasia and associated squamous metaplasia eventually developed carcinoma, indicating that atypical hyperplasia with squamous metaplasia has malignant potential (Kurman et al. 1985). Since the cytoplasmic changes by themselves have no prognostic significance, the importance of recognizing them lies in not confusing these benign processes with hyperplasia or carcinoma.

Management

The management of endometrial cytoplasmic changes depends entirely on the nature of the associated proliferative process. If hyperplasia is present, it should be managed accordingly. Endometrial cytoplasmic changes without hyperplasia do not require treatment.

Endometrial Intraepithelial Carcinoma

Definition and Pathologic Findings

Serous carcinoma is the prototypic endometrial carcinoma that is usually not related to estrogenic stimulation and typically occurs in the setting of endometrial atrophy. Serous carcinoma is frequently associated with a putative precursor lesion, termed “serous endometrial intraepithelial carcinoma” (SEIC). The lesion also has been referred to as “carcinoma in situ” (Spiegel 1995) and “uterine surface carcinoma” (Zheng et al. 1998), but we prefer the term SEIC because it can be associated with metastatic disease (see following), whereas the term CIS implies a lesion that does not have metastatic potential. In view of the association of SEIC with serous, as opposed to endometrioid carcinoma, it is reasonable to use the term serous EIC as has been proposed in the WHO classification. Furthermore, given its metastatic potential the latest WHO classification has included it as a type of carcinoma versus a precursor. SEIC is characterized by markedly atypical nuclei, identical to those of invasive serous carcinomas, lining the surfaces and glands of atrophic endometrium. The lesion can be very small and focal and is often present on the surface of a polyp (Figs. 47, 48, 49, 50, 51, 52, and 53) (Ambros et al. 1995; Sherman et al. 1992). SEIC often has a slightly papillary contour and some cells display hobnail morphology and smudged, hyperchromatic nuclei. The nuclei are enlarged and frequently display enlarged eosinophilic nucleoli. Numerous mitotic figures, including atypical ones, are present. On occasion, the abnormal proliferation involves only a portion of an endometrial gland (Fig. 49). More recently a lesion has been described, termed endometrial glandular dysplasia, which also exhibits cytologic atypia with serous features but lacks the marked atypia associated with SEIC (Zheng et al. 2004). It has been proposed that this lesion represents the precursor of SEIC and serous carcinoma.
Fig. 47

Serous endometrial intraepithelial carcinoma (SEIC) involving a polyp. The surface epithelium of the polyp (best seen in blunt papillary structures along upper left and middle surface) is lined by markedly atypical cells of SEIC (see Fig. 49)

Fig. 48

Serous endometrial intraepithelial carcinoma (SEIC) involving a polyp. Higher magnification of an area of the polyp in Fig. 48 shows markedly atypical cells containing enlarged vesicular nuclei with prominent nucleoli, hobnail cells, and apoptotic bodies lining the surface and involving an underlying gland

Fig. 49

Serous endometrial intraepithelial carcinoma (SEIC). Markedly atypical cells containing enlarged vesicular nuclei with prominent nucleoli, hobnail cells, and apoptotic bodies are lining the surface epithelium and partially involving an underlying gland

Fig. 50

Serous endometrial intraepithelial carcinoma (SEIC). Markedly atypical cells lining the surface epithelium have enlarged vesicular nuclei with prominent nucleoli and prominent hobnail morphology

Fig. 51

Serous endometrial intraepithelial carcinoma (SEIC). Markedly atypical cells lining endometrial glands have enlarged vesicular nuclei with prominent nucleoli, numerous mitotic figures and apoptotic bodies, and prominent hobnail morphology

Fig. 52

Serous endometrial intraepithelial carcinoma (SEIC). Markedly atypical cells lining endometrial surface and underlying glands (upper, middle, and lower left) have enlarged vesicular nuclei with prominent nucleoli, distinct from the elongated nuclei in the normal glands (lower middle and middle right)

Fig. 53

Serous endometrial intraepithelial carcinoma (SEIC). Markedly atypical cells lining endometrial glands have enlarged vesicular nuclei with prominent red nucleoli

Molecular Biology and Immunohistochemistry

Molecular genetic evidence supports the concept that SEIC is a precursor lesion of serous carcinoma. Several studies have demonstrated immunohistochemical overexpression of p53 protein, loss of heterozygosity of chromosome 17p, and corresponding p53 gene mutations in a high proportion of serous carcinomas and SEIC (Fig. 54) (Sherman et al. 1995; Tashiro et al. 1997). The finding of diffuse, intense staining for p53 is highly correlated with identification of p53 mutation in these cases. Lack of immunoreactivity for p53, however, does not exclude the presence of a mutation in p53 because mutations have been detected in a small number of serous carcinomas that were nonreactive for p53 due to the formation of a truncated or unstable protein (Tashiro et al. 1997). Identical p53 gene mutations have been found in SEIC and adjacent serous carcinoma in several cases. Examples of pure SEIC unassociated with serous carcinoma also have been shown to contain p53 mutations. In addition, a case of pure SEIC has been shown to contain p53 mutation in the absence of loss of heterozygosity of chromosome 17p, suggesting that p53 mutation occurs early in the evolution of serous carcinoma (Tashiro et al. 1997). The finding of SEIC unassociated with invasive carcinoma and the presence of identical p53 mutations in both lesions support the view that SEIC is the precursor lesion of serous carcinoma. As mentioned above, endometrial glandular dysplasia has been suggested as a precursor to SEIC, in part based on a study that has shown that these lesions show intense staining for p53, as well as p53 mutations. Additional preliminary studies have suggested that endometrial glandular dysplasia is preceded by histologically normal lesions that demonstrate increased expression of p53 and p53 mutations. These histologically normal appearing glands have been called “p53 signatures” because of the expression of p53 (Jarboe et al. 2009; Zhang et al. 2009). Presently, their relationship to serous carcinoma has not been definitely determined, but future studies will likely be done to further our understanding of their biologic significance in the pathogenesis of serous carcinoma. A recent study has found cyclin E amplification in 41% of SEIC, which is similar to the frequency found in endometrial serous carcinoma, suggesting that like TP53 mutations it is an early event in the pathogenesis of serous carcinoma (Kuhn et al. 2014).
Fig. 54

Serous endometrial intraepithelial carcinoma (SEIC). Surface epithelium and underlying glands involved by SEIC are highlighted by diffuse/strong nuclear expression of p53; normal glands are negative

Differential Diagnosis

The distinction of extensive SEIC from early serous carcinoma has not been well defined. Crowded glands involved by SEIC within a polyp or within the endometrium should be classified as extensive SEIC when the proliferation lacks a confluent glandular pattern, demonstrates no evidence of stromal desmoplasia (stromal invasion), and is less than 1 cm in greatest dimension. When either glandular confluence or stromal invasion is present and the proliferation exceeds 1 cm in greatest dimension, the lesion qualifies as serous carcinoma. Lesions with glandular confluence or stromal invasion but measuring less than 1 cm can be subclassified as minimal uterine serous carcinoma (Figs. 55 and 56; see following). It is important to note, however, that metastatic serous carcinoma can be found in other sites in the genital tract and in the abdomen in the absence of demonstrable invasion in uteri with SEIC, indicating that SEIC is capable of metastasizing without first invading the stroma of the endometrium (Soslow et al. 2000; Baergen et al. 2001).
Fig. 55

Extensive serous endometrial intraepithelial carcinoma (SEIC)/minimal uterine serous carcinoma. An endometrial polyp involved by SEIC on its surface, as well as in the adjacent endometrium (left), contains crowded glands measuring less than 1 cm but verging on being confluent, suggesting early stromal invasion

Fig. 56

Extensive serous endometrial intraepithelial carcinoma (SEIC)/minimal uterine serous carcinoma. Immunohistochemical stain for p53 highlights the extent of the lesion in Fig. 55

SEIC must be distinguished from benign metaplastic endometrial lesions that can mimic the nuclear changes seen in SEIC, which include eosinophilic cell change, hobnail change, and tubal metaplasia. At times eosinophilic cell change and hobnail change can display enlarged, smudged, hyperchromatic nuclei, but these nuclei usually have a degenerative appearance and typically lack the prominent nucleoli seen in SEIC. On occasion, however, the nuclei can appear more overtly atypical, with prominent nucleoli, suggesting SEIC (see Figs. 41 and 46). Tubal metaplasia typically displays enlarged, hyperchromatic nuclei, but these are admixed with other cell types, including ciliated cells and intercalated cells, and nucleoli are usually not prominent. Immunohistochemistry for Ki-67, a proliferation marker, is very useful for distinguishing SEIC from eosinophilic cell change and tubal metaplasia in that SEIC typically displays a very high proliferation index (virtually all the nuclei express Ki-67), whereas the metaplasias have very low proliferation indices. In addition, EIC is usually diffusely and strongly positive for p53, whereas eosinophilic metaplasia is typically negative or occasionally displays weak or scattered moderate nuclear staining. Preliminary data based on a small number of cases indicate that tubal metaplasia and eosinophilic metaplasia do not strongly overexpress p53 (Quddus et al. 1999). Thus, the combination of Ki67 and p53 immunohistochemical stains are useful to distinguish SEIC from metaplasia when the distinction is difficult by morphologic assessment alone.

Behavior and Treatment

There are limited data on the behavior of pure SEIC. One study found that patients with pure SEIC, and those with minimal uterine serous carcinoma (less than 1 cm of carcinoma in the endometrium) lacking myometrial or vascular invasion and no evidence of extrauterine disease, had an overall survival of 100% after a mean follow-up of 27 months (Wheeler et al. 2000). The majority of these patients received no treatment after hysterectomy. In addition, the few patients with involvement of endocervical glands by SEIC (stage IIA disease) were also alive without evidence of disease at intervals ranging from 12 to 54 months. Similarly, in another study of stage IA serous carcinoma, 11 of 13 patients were alive without evidence of disease after a median follow-up of 38 months (Carcangiu et al. 1997). In contrast, patients with either SEIC or minimal serous carcinoma and evidence of extrauterine disease (even microscopic disease) all died of disease despite intensive chemotherapy (Wheeler et al. 2000). Accordingly, patients with a diagnosis of SEIC in an endometrial biopsy or curettage specimen should undergo careful surgical staging at the time of hysterectomy.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Lora Hedrick Ellenson
    • 1
    Email author
  • Brigitte M. Ronnett
    • 2
  • Robert J. Kurman
    • 3
  1. 1.Department of Pathology and Laboratory Medicine, Division of Gynecologic PathologyWeill Cornell Medical College and New York Presbyterian HospitalNew YorkUSA
  2. 2.Department of Pathology, Division of Gynecologic PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Departments of Gynecology, Obstetrics, Pathology and Oncology, Division of Gynecologic PathologyJohns Hopkins University School of MedicineBaltimoreUSA

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