Diagnosis of Endometrial Biopsies and Curettings: A Practical Approach

By Tricia A. Murdock, Emanuela F.T. Veras, Robert J. Kurman and Michael T. Mazur

Derived from the authors' long-running course presented at the International Academy of Pathology, this second edition, now with color illustrations, continues the tradition of its predecessor as being the concise and complete diagnostic guide to the endometrial biopsy. The text is structured so as to present a logical approach to formulating a pathologic diagnosis from the diverse array of tissue received in the surgical pathology laboratory. Color illustrations show typical artifacts and distortion, and explain their impact on diagnostic interpretation. Each chapter includes a section summarizing the features that must be discussed in the final pathology report.

• Language: English
• Publisher: Springer
• Release date: Nov 9, 2018
• ISBN: 9783319986081

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© Springer Nature Switzerland AG 2019

Tricia A. Murdock, Emanuela F.T. Veras, Robert J. Kurman and Michael T. MazurDiagnosis of Endometrial Biopsies and Curettingshttps://doi.org/10.1007/978-3-319-98608-1_1

1. Introduction

Tricia A. Murdock¹ , Emanuela F. T. Veras¹, Robert J. Kurman¹ and Michael T. Mazur²

(1)

Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA

(2)

Department of Pathology and Laboratory Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA

Indications for Biopsy

Clinical History and Biopsy Interpretation

Clinical Queries and Reporting

References

Keywords

Endometrial biopsiesEndometrial curettingsAbnormal uterine bleedingInfertilityProducts of conceptionHormonal therapy

Endometrial biopsies and curettings are among the most common tissue specimens received in the pathology laboratory. In several respects, these specimens present a unique challenge for the surgical pathologist. The normal endometrium undergoes a variety of morphologic changes , especially during the reproductive years, when cyclical hormonal influences and pregnancy affect uterine growth . Biopsy-induced artifacts confound this heterogeneous group of morphologic changes. Endometrial sampling techniques can vary from hysteroscopy with curettage, which is considered the gold standard [1–4], to a blind biopsy with no visualization of the tissue sampled. The final specimen contains multiple, irregularly oriented tissue fragments mixed with blood and contaminating cervical tissue and mucus.

Interpreting the biopsy material demands a logical approach that takes into account many factors, including patient history, the specific requests of the clinician performing the biopsy, and an appreciation of the limitations, potential pitfalls, and complex array of patterns encountered in the microscopic sections. As in evaluation of any pathologic specimen, proper interpretation requires appropriate fixation, processing, and sectioning of the tissue.

Indications for Biopsy

There are four main indications for endometrial biopsy or curettage [5–9]:

1.

Determination of the cause of abnormal uterine bleeding

2.

Evaluation of the status of the endometrium in infertile patients

3.

Evacuation of products of conception, either spontaneous abortions, termination of pregnancy, or retained tissue

4.

Assessment of the response of the endometrium to hormonal therapy , especially estrogen replacement in perimenopausal and postmenopausal women, progestin therapy in reproductive age women for treatment of endometrial hyperplasia or endometrioid carcinoma, and tamoxifen therapy for breast cancer

Other indications for biopsy may arise. An occasional patient will have atypical or abnormal glandular cells of undetermined significance (AGUS) in a cervical–vaginal cytologic specimen that requires endometrial sampling to exclude hyperplasia or carcinoma. Uterine screening with transvaginal ultrasound can show a thickened endometrial stripe in postmenopausal patients, and a biopsy can be performed to exclude significant pathology [10–12]. Some clinicians sample the endometrium prior to hysterectomy to exclude significant pathology, although this procedure reveals little pathology in the absence of a history of abnormal bleeding [13, 14]. Likewise, endometrial biopsy for screening of endometrial cancer or precursor lesions in asymptomatic perimenopausal and postmenopausal patients has a very low yield of significant abnormalities and is not cost-effective [15–17].

At times, these indications for endometrial sampling overlap. For example, some complications of pregnancy, such as a missed abortion or trophoblastic disease, are accompanied by abnormal uterine bleeding. Nonetheless, these broad categories provide a clinicopathologic framework for approaching the microscopic analysis of endometrial biopsy specimens. The text has therefore been divided into chapters that correspond to these clinical indications.

Clinical History and Biopsy Interpretation

Abnormal Uterine Bleeding

The most common reason for performing an endometrial biopsy is abnormal uterine bleeding (AUB) . Because of the inconsistent nomenclature used to describe variations of abnormal bleeding, the International Federation of Gynecology and Obstetrics (FIGO) developed a classification system. Categorization is based on the acronym PALM-COEIN (polyps, adenomyosis, leiomyoma, malignancy and hyperplasia – coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet specified) and is used for AUB in nongravid women of reproductive age. The first four terms are structural lesions, i.e., specific lesions. The latter five (COEIN) are used to describe causes that are not defined by imaging or histopathology and were previously under the term dysfunctional uterine bleeding (DUB) [18]. Abnormal uterine bleeding can be a sign of one or multiple uterine disorders ranging from nonstructural abnormalities to structural lesions such as polyps, hyperplasia, or carcinoma [8, 11, 18–22]. For the FIGO classification system, if the AUB is attributed to polyps , the patient chart would then read AUB-P; if a patient had multiple causes, such as a submucosal leiomyoma and a coagulopathy , AUB-L(SM), C would be an acceptable term (Table 1.1).

Table 1.1

Clinical terms for abnormal uterine bleeding (AUB)

Age and menstrual/menopausal status are especially important data to include in the pathology requisition, as causes of abnormal uterine bleeding vary significantly according to parameters, as discussed later. The prevalence of the various abnormalities that lead to abnormal bleeding is difficult to determine precisely, varying with the patient population and the previous terms used by investigators [5–7]. The nomenclature to describe menstrual bleeding related to regularity or frequency of onset, duration, and heaviness (volume) of menstrual flow has been reclassified as well, and terms such as menorrhagia and menometrorrhagia have been largely abandoned. A practical approach to the possible diagnoses associated with abnormal bleeding takes age into account (Tables 1.2 and 1.3). In adolescence, AUB may be secondary to ovulatory dysfunction, pregnancy, exogenous hormone administration, or coagulopathies. Pregnancy-related and nonstructural entities are more common in younger patients, whereas atrophy and structural lesions become more frequent in older individuals [24]. Polyps in perimenopausal and postmenopausal patients have been found in 2–26% of patients [25–33] with a mean age of 45.8 [34]. Hyperplasia is found in up to 16% of postmenopausal patients undergoing biopsy and endometrial carcinoma in fewer than 10% of patients [25, 32–34]. One consistent observation in studies of postmenopausal patients is that atrophy is a common cause of abnormal bleeding, being found in 25% or more of cases [25, 26, 28, 31, 33, 35, 36].

Table 1.2

Causes of abnormal uterine bleeding in the reproductive years

aSee Chap. 3 (Complications of pregnancy)

Table 1.3

Causes of abnormal uterine bleeding in perimenopausal years

aSee Chap. 3 (Complications of pregnancy)

There are a few exceptions where younger, premenopausal women are at higher risk for endometrial hyperplasia and carcinoma . Premenopausal women (<45 years of age) with AUB and a body mass index >30 kg/m² are four times more likely to develop endometrial hyperplasia or carcinoma than premenopausal women with a normal body mass index [37]. Hereditary cancer syndromes including Lynch, Cowden, Peutz-Jeghers, and Li-Fraumeni all have an elevated risk for endometrial cancer [38–41]. For Lynch syndrome, one surveillance strategy is for annual transvaginal ultrasound and/or endometrial sampling, followed by risk-reducing hysterectomy upon completion of childbearing [42]. In women aged 30–35 years with Cowden syndrome, consideration for annual transvaginal ultrasound and endometrial sampling with a discussion of hysterectomy following childbearing is a potential surveillance and risk reduction strategy, respectively [42]. In addition to endometrial cancer, women with Peutz-Jeghers syndrome have a risk of developing sex cord tumor with annular tubules (SCTAT) of the ovary and minimal deviation adenocarcinoma of the cervix [41]. Because of the additional ovarian and cervical cancer risk, an annual pelvic exam with Pap smear starting at age 18–20 years and consideration of an annual transvaginal ultrasound is a reasonable surveillance approach. There are no clear surveillance recommendations for Li-Fraumeni syndrome and no clear risk reduction strategies for Peutz-Jeghers or Li-Fraumeni syndromes [42].

Even among perimenopausal and postmenopausal patients, the proportion of cases attributable to any of the aforementioned conditions is age dependent (Table 1.4). Atrophy and carcinoma occur more frequently in patients older than 60 years of age, while polyps and hyperplasia are more common in patients who are perimenopausal or more recently postmenopausal. In addition to these uterine causes of bleeding, other abnormalities, such as genitourinary syndrome of menopause, can cause vaginal bleeding, and this may be difficult to distinguish from uterine bleeding until the patient undergoes thorough clinical evaluation.

Table 1.4

Causes of abnormal uterine bleeding in postmenopausal years

A history of anovulation, obesity, hypertension, diabetes, and exogenous estrogen use should alert the pathologist that the patient is at increased risk for hyperplasia and endometrioid carcinoma, but this information is rarely included on the requisition. Typically, there is little accompanying clinical data except the patient’s age and a short history of abnormal bleeding. Consequently, hyperplasia and adenocarcinoma must be diagnostic considerations for most endometrial specimens received in the laboratory. On rare occasions, hyperplasia or even adenocarcinoma is found in biopsies performed during an infertility workup [28]. It should be kept in mind that women with unexplained infertility or diagnosed with polycystic ovarian syndrome (PCOS) at a young age are at risk of endometrial cancer [43, 44].

Infertility Biopsy

When a patient undergoes biopsy for evaluation of infertility, the clinical information often is limited, but here, too, the history should include the date of the last menstrual period (LMP) to place an approximate time in the menstrual cycle. This information is useful but not precise for determining the actual day of the cycle, as ovulatory frequency and length of the follicular phase are highly variable among patients. Usually the main objective of biopsies for infertility is to determine whether there is morphologic evidence of ovulation, i.e., secretory change (see Chap. 2). The gynecologist may seek other specific information, such as response to hormone therapy, so it is important that the pathologist be given any additional history that may be necessary for the interpretation.

Products of Conception

When endometrial sampling is performed to remove products of conception , clinical information often is sparse, as the main goal of the procedure is simply to remove the placental and fetal tissue. Significant pathologic changes are rare. Nonetheless, it is helpful to know if pregnancy is suspected, and, if so, the approximate gestational age of the pregnancy. If there is a suspicion of trophoblastic disease, this should be stated. In such instances, the serum human chorionic gonadotropin (hCG) titer is very important. If an ectopic pregnancy is suspected, alerting the pathologist can ensure rapid processing and interpretation of the specimen.

Hormone Therapy

Because the endometrium is responsive to hormones, the history of hormone use is important information. Clinical uses of steroid hormones (estrogens, progestins, or both) include oral, subcutaneous or vaginal contraception methods, progestin-releasing intrauterine devices, postmenopausal replacement therapy, and therapy for endometriosis, infertility, hyperplasia, and endometrial endometrioid or breast carcinoma. As with other facets of the clinical data, this information may be absent or, if present, unreadable on the requisition (in which case the gynecologist should be contacted). Consequently, the pathologist must be prepared to recognize hormonal effects in the absence of history indicating the use of hormones (see Chap. 6 – Effects of Hormones).

Other Considerations

Pregnancy history is useful, especially in premenopausal patients, regardless of the indication for biopsy, as recent and remote effects of pregnancy, such as a placental site nodule or gestational trophoblastic disease, may be encountered in biopsy material. The history of recent or past pregnancies is expressed as gravidity and parity. The letter G (gravidity) followed by a number (G1, G2, etc.) indicates the number of pregnancies, and the letter P (parity) followed by a number indicates the number of deliveries. For example, G4, P2 indicates that a woman has had four pregnancies and two deliveries. Further information on parity often is designated by four numbers indicating full-term pregnancies, premature pregnancies (>20 but <37 weeks’ gestation), abortions (<20 weeks’ gestation), and living children. Thus a patient who is G5, P3013 is currently pregnant and has had three previous full-term pregnancies and one abortion, and the three children from the term pregnancies are alive.

The type of procedure, that is, biopsy versus curettage, is important for deciding whether focal changes represent significant abnormalities or whether small specimens are adequate (see Chap. 12 Methods of Endometrial Evaluation). Although office-based biopsies generally provide a representative sample, they may not contain sufficient tissue to ensure that the endometrium has been adequately sampled. For example, the irregular glands of hyperplasia may resemble patterns seen in some polyps, low-grade adenocarcinomas, and even artifactually distorted normal endometrium. Furthermore, atypia can be focal in hyperplasia; therefore, biopsy specimens may preclude a definitive diagnosis. In these cases, a more thorough biopsy or curettage is necessary.

Clinical Queries and Reporting

Diagnostic terms such as no pathologic diagnosis or no significant pathologic findings are unacceptable as there is a wide range of normal histology. When the tissue lacks abnormalities, stating the normal phase of the endometrium, for example, menstrual, proliferative, or secretory, provides useful information for the clinician.

In biopsies for abnormal uterine bleeding , the pathologic information sought varies with the patient’s age and clinical history. The gynecologist wishes to know the following:

1.

Is there an organic or structural lesion, such as a complication of pregnancy, inflammation, or a polyp?

2.

Is there evidence of active or old breakdown and bleeding?

3.

Is there evidence to suggest abnormalities in ovulation?

4.

Is there evidence of hyperplasia or carcinoma?

For example, in young premenopausal patients with a normal BMI, the possibility of pregnancy and related bleeding is a frequent question. In a perimenopausal patient, the concern shifts to hyperplasia and carcinoma, and in postmenopausal patients, the importance of ruling out carcinoma becomes paramount. In any of these conditions, glandular and stromal breakdown may be present either focally or diffusely. It is the underlying disorder that is most important to report. The changes of breakdown and bleeding are secondary and do not indicate a primary disorder by themselves. Nonetheless, when there is a history of abnormal bleeding, it can be helpful to note whether there is histologic evidence of glandular and stromal breakdown (see Chap. 5), especially if the tissue lacks evidence of an organic process such as hyperplasia or carcinoma. This information serves to document to the gynecologist that bleeding is, in fact, endometrial in origin. Even when there is no evidence of active bleeding, foci of stromal foam cells or hemosiderin, sometimes with fibrosis, indicate that abnormal bleeding has taken place and deserve comment.

Besides reporting the morphologic changes present, noting significant negative findings can be helpful to the clinician. As an example, the diagnosis of chronic endometritis is more helpful if it includes a comment regarding the presence or absence of specific etiologic factors such as evidence of a recent pregnancy. Likewise, if an structural lesion such as a polyp is present, it is helpful to indicate whether noninvolved tissue is present and, if so, its appearance. In perimenopausal and postmenopausal patients, if the gynecologist indicates a specific concern regarding the presence of hyperplasia, atypia, or carcinoma, then a statement noting the absence of these lesions is reassuring.

For all cases, specimen adequacy is a consideration, but this needs to be specifically addressed only in limited samples in which the diagnosis is not clear-cut. Scant tissue obtained by an office-based biopsy may be insufficient to allow thorough assessment of the status of the endometrium. In these cases, the pathologist should indicate in the report that the specimen is scant. For instance, small samples may reveal hyperplastic glands, but it may be difficult to determine whether the abnormality represents a localized polyp with a proliferative/hyperplastic pattern (see Chap. 8) or a diffuse hyperplasia. Some assessment of the endometrium can be done even on very limited specimens, for example, noting whether the endometrium is proliferative or secretory phase. Atrophic endometrium typically yields a very small amount of tissue, yet these specimens should not be regarded as inadequate (see Chap. 5). The subsequent chapters consider in greater detail the queries likely to arise in various circumstances and the information that the pathologist should incorporate in the final report.

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Archer DF, McIntyre-Seltman K, Wilborn WW, Dowling EA, Cone F, Creasy GW, Kafrissen ME. Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol. 1991;165:317–20. discussion 320–322.Crossref

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McPencow AM, Erekson EA, Guess MK, Martin DK, Patel DA, Xu X. Cost-effectiveness of endometrial evaluation prior to morcellation in surgical procedures for prolapse. Am J Obstet Gynecol. 2013;209:22.e1–9.Crossref

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© Springer Nature Switzerland AG 2019

Tricia A. Murdock, Emanuela F.T. Veras, Robert J. Kurman and Michael T. MazurDiagnosis of Endometrial Biopsies and Curettingshttps://doi.org/10.1007/978-3-319-98608-1_2

2. The Normal Endometrium

Tricia A. Murdock¹ , Emanuela F. T. Veras¹, Robert J. Kurman¹ and Michael T. Mazur²

(1)

Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA

(2)

Department of Pathology and Laboratory Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA

General Considerations in Histologic Evaluation

Histologic Features of Normal Cycling Endometrium

Pitfalls in The Histologic Assessment of The Normal Endometrium

Sample Adequacy and Standardized Reporting

Artifacts and Contaminants

Irregular Secretory Endometrium

Clinical Queries and Reporting

References

Keywords

Endometrial biopsyEndometrial datingEndometrial histology

The histologic features of what constitutes normal endometrium change with a woman’s age, through the premenarchal, reproductive, perimenopausal, and postmenopausal years [1–3]. Throughout the reproductive years, the cyclical hormonal changes of the menstrual cycle provide a continuously changing morphologic spectrum from proliferative to secretory to menstrual phenotypes which is considered normal. Once menopause is reached, the presence of only rare strips of atrophic epithelium in biopsy/curettage sampling becomes the new normal. The same normal in a postmenopausal woman would be deemed abnormal in a premenopausal woman or, alternatively, would raise the possibility of exogenous hormonal effect. Likewise, finding only cervical or lower uterine segment tissue in a woman known to have an ultrasonographic lesion such as thickened endometrium supports under sampling. These examples emphasize the importance of clinical information including patient’s age and hormonal status. In biopsy specimens, the combination of these cyclical changes along with potential processing artifacts, limited sampling, or the presence of mimics can make normal patterns difficult to interpret. Deviations from normal, either in histologic pattern or in temporal relationship to ovulation, often indicate underlying abnormalities that may contribute to female infertility and abnormal uterine bleeding.

Over the past 6 decades, pathologists have used the histologic criteria originally described by Noyes et al. [1, 4] to date secretory phase endometrial biopsies (Table 2.1), as part of an infertility workup. The original study by Noyes et al. described discrete changes that varied daily following ovulation, culminating with menstruation. Over the last decades, multiple studies critically evaluating the Noyes dating criteria have shown that they are not reproducible and that the criteria themselves are seriously flawed [5–12]. More importantly, gynecologists appear to be less inclined to utilize this information in the evaluation of infertility. For these reasons, the traditional dating schema is not discussed in detail in this chapter but is briefly outlined in Table 2.1. Of interest, the Gynecologic Pathology Interest Group of the Canadian Association of Pathologists (GPIG-CAP) published a guideline for pathologists standardizing terminology to assist in communicating with our clinical colleagues. One recommendation was that formal dating of secretory endometrium is optional but that it should be provided if specifically requested by the clinician. Consequently, the use of terms such as early, mid, and late secretory endometrium suffices [13]. Nonetheless, an appreciation of the various morphologic changes that occur in the secretory phase of the cycle is important for pathologists so that normal phases of secretory endometrium are not misinterpreted as abnormal (Table 2.1).

Table 2.1

Secretory phase endometrial changes

ad. = day of ideal 28-day menstrual cycle

General Considerations in Histologic Evaluation

Histologic evaluation begins with identification of surface epithelium, a prerequisite for orienting the underlying glands and stroma. The surface epithelium is less responsive to sex steroid hormones than the underlying glands, but it often shows alteration in pathologic conditions, especially when the abnormalities are subtle or focal. For example, during the proliferative phase, estrogenic stimulation results in ciliated cells along the surface [10, 14]. Ciliated surface epithelial cells are, however, far more frequent in pathologic conditions, particularly those associated with unopposed estrogen stimulation, such as hyperplasia and metaplasia (see Chap. 9) [2, 3, 15–17].

The subsurface endometrium is divided into two regions, the functionalis (stratum spongiosum) and the basalis (stratum basalis) (Fig. 2.1). The functionalis is situated between the surface epithelium and is important to evaluate because it shows the greatest degree of hormonal responsiveness. The size and distribution of glands as well as the cytologic features of the glandular epithelial cells are important features in the histologic evaluation. Under normal conditions, the glands should be regularly spaced and have a perpendicular arrangement from the basalis to the surface epithelium. In the secretory phase, the endometrium also shows a stratum compactum, a thin region beneath the surface epithelium. In the stratum compactum, the stroma is dense, and the glands are straight and narrow, even when the glands in the functionalis are tortuous. The basalis adjoins the myometrium, serving to regenerate the functionalis and surface epithelium following shedding during menses. The endometrium of the basalis is less responsive to steroid hormones and typically shows irregularly shaped, inactive-appearing glands, dense stroma, and aggregates of spiral arteries. The spiral arteries of the basalis (basal arteries) have thicker muscular walls than those in the functionalis. In biopsies, tissue fragments that contain basalis often do not have surface epithelium. The glands and stroma of the basalis are unresponsive to steroid hormones.

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Fig. 2.1

Normal secretory phase endometrium. Surface epithelium orients the tissue (far right). The midportion of the tissue consists of functionalis where glands, stroma, and blood vessels demonstrate the typical patterns of maturation through the menstrual cycle. The stratum compactum is composed of the surface-type epithelium and a subjacent thin layer of dense stroma

Lower uterine segment/isthmus is another region of the endometrium that is less responsive to steroid hormones. In the lower uterine segment, the endometrium has shorter, poorly developed, inactive glands dispersed in a distinctive stroma (Figs. 2.2 and 2.3). The columnar cells lining the glands resemble those of the corpus. Some glands near the junction with the endocervix show a transition to mucinous endocervical-type epithelium. The stromal cells in the lower uterine segment are elongate and resemble fibroblasts with more abundant eosinophilic cytoplasm, in contrast to the oval to rounded stromal cells with minimal cytoplasm seen in the corpus.

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Fig. 2.2

Lower uterine segment in curettage specimen. At the right side of the image, lower uterine segment shows inactive glands embedded in a fibrotic stroma which are juxtaposed to hormonally responsive endometrium (left)

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Fig. 2.3

Lower uterine segment. Small, poorly developed glands are seen in nonreactive stroma. Tissue from the lower uterine segment cannot be dated

Tangential orientation of the functionalis in biopsies and the tortuosity of the glands, particularly in the late proliferative and secretory phases, often lead to irregular cross sections of the tissue. In this instance, gland development can be difficult to assess. Furthermore, not all fragments of tissue in a biopsy or curettage include surface epithelium, which helps to orient the glands. Nonetheless, at least focally, portions of better-oriented glands usually can be traced through the functionalis to the surface epithelium, and these foci are critical for assessing appropriate glandular and stromal development.

Histologic Features of Normal Cycling Endometrium

The endometrium displays two distinct phases in ovulatory cycles. The first is the proliferative (follicular or preovulatory) phase which is characterized by growth of glands, stroma, and vessels that is influenced by estradiol produced mainly by granulosa cells in the ovarian follicles. Following ovulation, the secretory (luteal or postovulatory) phase reflects the effect of the combined production of progesterone and estradiol by luteinized granulosa and theca cells of the corpus luteum [18].

The day 1 of the menstrual cycle was arbitrarily defined as the first day of bleeding in a normal cycle of 28 days [1]. Proliferative phase changes are not as discrete as those in the secretory phase; the latter can be roughly divided into early, mid-, and late secretory phases.

There are nine histologic features of the glands and stroma that determine the phase of the cycle [1]. Five of these features affect the glands, namely, tortuosity, gland mitoses, orientation of nuclei (pseudostratified versus basal), basal subnuclear cytoplasmic vacuoles, and glandular serrations with increased luminal secretions and secretory exhaustion. Four features relate to the stroma: edema, mitoses, predecidual change, and infiltration of granular lymphocytes. Practically, the most important glandular features are orientation of nuclei, subnuclear cytoplasmic vacuoles, and luminal secretions with secretory exhaustion, and the most important stromal features are edema, predecidual change, and granular lymphocytic infiltration (Table 2.1).

Proliferative Phase

During the proliferative phase , the endometrium grows from about 0.5 mm up to 4.0–5.0 mm in thickness, so by the late proliferative phase, a biopsy obtains a moderate amount of tissue. Proliferative endometrium has three phases: early, mid, and late [2]. There is considerable overlap between these phases so the diagnosis of proliferative phase alone is sufficient, indicating that the endometrium is growing and shows a normal glandular distribution and evidence of ovulation is not present.

Growth of endometrium is the main characteristic of the proliferative phase (Figs. 2.4, 2.5, 2.6, and 2.7). Glands and stroma show brisk mitotic activity. In early proliferative endometrium, the functionalis contains small, tubular glands. The glands progressively elongate and become tortuous from the mid- to the late proliferative phase because the gland growth is disproportionate to the stromal growth. Despite the tortuosity, the glands maintain a relatively regular spacing between each other. Throughout the proliferative phase, the epithelium lining the glands has pseudostratified, oval nuclei with small nucleoli and dense basophilic cytoplasm. The pseudostratified nuclei remain oriented to the basement membrane, but some nuclei are raised above the basement membrane, giving a two-dimensional layering of the nuclei. The pseudostratification of the nuclei and the presence of mitotic activity in the glands and stroma are two constant features of the proliferative phase.

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Fig. 2.4

Proliferative endometrium. Focal hemorrhage beneath the surface epithelium is a result of the biopsy and does not represent a pathologic change

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Fig. 2.5

Proliferative endometrium. Glands are tubular and dispersed in abundant stroma

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Fig. 2.6

Proliferative endometrium. In this tangential section, the glands are regularly spaced. The gland to stroma ratio is 1:1

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Fig. 2.7

Proliferative endometrium. The proliferative phase gland shows pseudostratified nuclei with mitotic activity. The stromal cells have oval nuclei and indistinct cytoplasm. Scattered lymphocytes are normally present

In the proliferative phase, the stromal cells are widely separated in the functionalis. They are small and oval, with dense nuclei, scant wisps of cytoplasm, and ill-defined cell borders. Some stromal edema is normal at mid-proliferative phase. A few lymphocytes also are scattered throughout the stroma, being most prominent around the vessels. Small spiral arteries and thin-walled venules are present.

The orientation and outline of proliferative phase glands and their relationship to intact stroma are important features for recognizing this normal pattern, as hyperplastic glands or glands in a polyp can have cytologic features identical to those of glands in the proliferative phase. The regular spacing and uniform shape of the glands are characteristics of normal proliferative endometrium. Assessing gland orientation can be complicated, however, by biopsy-induced fragmentation, an especially common artifact in early to mid-proliferative phase biopsies when the mucosa is still thin. Detached and disrupted glands may appear abnormally crowded or irregular.

To distinguish fragmentation artifact from true abnormalities, it is important to assess the integrity of the stroma as well as the glands and to use surface epithelium to help orient the tissue fragments. Detached and poorly oriented glands that show pseudostratified nuclei and mitotic activity usually represent proliferative endometrium unless better-oriented tissue suggests another diagnosis. Also, proliferative phase glands frequently show the telescoping artifact (see below).

Secretory Phase

In the secretory phase , the glands and stroma develop in a somewhat orderly sequence, displaying histologic features of (post-ovulation) secretory activity. The endometrium attains a thickness of up to 7.0–8.0 mm. Unlike the proliferative phase, the changes in the glands and stroma are relatively discrete, changing more abruptly from one day to the next. The first half of the secretory phase is characterized primarily by glandular changes, whereas in the second half, stromal alterations become more prominent.

The morphologic changes of the secretory phase begin within 48 hours after ovulation; however, that interval varies among women and from cycle to cycle in the same woman. During this interval, the glands become more tortuous and begin to show subnuclear vacuoles (Fig. 2.8). The first diagnostic evidence of ovulation, however, is the presence of abundant subnuclear glycogen vacuoles in the undulating, tortuous glands (Fig. 2.9a, b). At this time, the stroma is indistinguishable from that of the late proliferative phase. If confirmation of ovulation is a requirement, substantial amounts of glands with conspicuous vacuoles should be present.

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Fig. 2.8

Interval endometrium. The glands maintain proliferative phase characteristics and show scattered subnuclear vacuoles. The extent of cytoplasmic vacuolization is not sufficient to be certain ovulation has occurred

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Fig. 2.9

Early secretory endometrium. (a) Postovulatory changes are clearly present with a regular distribution of subnuclear vacuoles in the serpiginous glands. The stroma shows no changes compared to the late proliferative phase. (b) Every glandular cell contains a subnuclear vacuole, resulting in a uniform alignment of nuclei away from the basement membrane

During the early secretory endometrium, subnuclear vacuoles are abundant, progressively moving from the basal to a supranuclear position (Figs. 2.10 and 2.11). Concurrently, the nuclei become basally oriented and line up in a single layer perpendicular to the basement membrane. The cytoplasmic contents then form mucin that is expelled into the gland lumen, culminating with a peak in luminal secretions (Figs. 2.12 and 2.13).

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Fig. 2.10

Early secretory endometrium. Glandular cell vacuoles remain prominent but begin to migrate to the supranuclear cytoplasm

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Fig. 2.11

Early secretory endometrium. A portion of the endometrial stroma shows mild edema

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Fig. 2.12

Mid-secretory endometrium. Maximum intraglandular secretion is present, and the glands are dilated. The stroma shows edema and there is no predecidual change

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Fig. 2.13

Mid-secretory endometrium. The glands are tortuous with intraluminal secretions that may appear washed out depending on the H&E preparation. The stroma is edematous and there is no predecidual change. The nuclei of stromal cells acquire a naked nucleus appearance with scant cytoplasm

During the mid-luteal phase, edema, the first noticeable stromal change, is most prominent. Because of the edema, the stromal cells take on the so-called naked nucleus appearance. With this change, the stromal cells are widely dispersed and have small nuclei with scant, imperceptible cytoplasm. This phase of pure stromal edema is brief, and the subsequent predecidual transformation of the stroma becomes the main feature in the late secretory phase. Edema may occur in the earlier portion of the secretory phase which does not connote an irregularity of maturation. The glands show increasing tortuosity, and variable amounts of luminal secretions persist until just before menses.

Finally, during the late secretory phase, secretory exhaustion is achieved (Figs. 2.14, 2.15). Secretory exhaustion is characterized by the presence of a single layer of cells that lie in disarray with loss of orientation. The cytoplasmic border along the luminal surface becomes ragged with gland serration or a saw-toothed luminal border (Figs. 2.16a), and luminal secretions are usually, although not invariably, present. Spiral arterioles, which started to become prominent during the mid-secretory phase, now are surrounded by predecidualized stromal cells with abundant cytoplasm (Fig. 2.16b). Predecidual change, the main characteristic of the late secretory phase, makes the vessel walls appear thicker, leading to their prominence. The glandular cells may continue to show a variable degree of vacuolization throughout the remainder of the secretory phase. Toward the end of the secretory phase, cellular necrosis (apoptosis) becomes evident with accumulation of nuclear debris in the basal cytoplasm of the glandular epithelial cells. Throughout the secretory phase, the glands in the stratum compactum immediately beneath the surface epithelium remain small and tubular despite their increasing tortuosity in the functionalis.

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Fig. 2.14

Late secretory endometrium. The glands show a typical tortuous architecture and secretory exhaustion with secretions