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Demystifying endometrial hyperplasia
MINI-SYMPOSIUM: ENDOMETRIAL PATHOLOGY
Demystifying endometrial hyperplasia
periodic oestrogeneprogesterone secretion is disrupted in favour of the former, and unopposed oestrogenic stimulation of the endometrium pursues setting the stage for endometrial hyperplasia (EH) and/or neoplasia. As it would be expected, most cases of EH arise from both glands and stroma (simple hyperplasia), with the overall cellular elements to produce what is in effect an exaggeration of the normal proliferative phase endometrium.1 However, not all endometrial hyperplasias (EHs) show this typical pattern and many assume a hyperplastic growth which involves exclusively glands, with crowding and branching, but certainly without cytological atypia (complex hyperplasia). The above two growth patterns appear to conform with the usual stereotype of a hyperplasia without crossing the boundaries of neoplasia. Hyperplasia is, in general terms, the increase in size of an organ or tissue as a result of an increase in the number of specialized cells per reference area or volume. The lesion is benign and the hyperplastic cells are, essentially, similar to normal or may appear slightly enlarged (hypertrophic). Genuine hyperplastic lesions, including those of the human endometrium, very rarely, if ever, progress into malignant disease. Yet, endometrial adenocarcinomas, particularly those of the endometrioid cell type (EACa), may at times preceded by a form of proliferative lesion which is composed exclusively of glands, often with crowding and complexity, and always with nuclear and cytoplasmic atypia1; this condition, which is most commonly known as “atypical endometrial hyperplasia” (AEH), may evolve into an EACa with an incidence which is too high to be dismissed as coincidental.
Efthimios Sivridis Alexandra Giatromanolaki
Abstract The endometrial hyperplasias form a spectrum of proliferative lesions, not all of which conform to conventional definition of hyperplasia. For whilst most hyperplastic lesions are composed of cells normally occurring in the late proliferative phase endometrium, there are those few which consist of genuine atypical cells. Lesions of this type, so-called “atypical endometrial hyperplasias”, tend to merge imperceptibly with well differentiated endometrioid adenocarcinomas, giving rise to major challenges: First and foremost, what are the very essential criteria that should be met before diagnosing such a lesion? And what are the very least that should be insisted upon for diagnosing malignancy once an atypical endometrial hyperplasia has been established? What is its true nature and how should ideally be classified? Other less conflicting, but equally interesting, aspects of endometrial hyperplasia which are covered in this account include the conventional hyperplasias, i.e. those lacking cytological atypia, and the overall incidence, risk factors and treatment of the disease. It is worth noting that “pure” stromal cell proliferations are, in itself, not necessarily neoplastic, for many take the form of endometrial stromal hyperplasia.
Keywords atypical endometrial hyperplasia; classification; endometrial hyperplasia; endometrial intraepithelial neoplasia (EIN); endometrial stromal hyperplasia
The endometrial hyperplasias e the WHO classification The term “endometrial hyperplasia” covers a spectrum of proliferative lesions in the endometrium some of which progress to or co-exist with endometrioid adenocarcinoma (EACa). There is, in general, good correlation between a particular histological type and the consequent biological behaviour of the lesion. However, this relationship between histological appearances and prognosis has been blurred by inconsistencies in terminology and definitions. Indeed, diagnostic terms like “atypical”, “adenomatous”, “adenomatoid”, “complex” and “irregular” hyperplasia have been used in a highly subjective manner to hyperplastic lesions of the endometrium having and having not a significant risk of progressing into an EACa.2 Other diagnostic labels which have been applied to hyperplastic lesions in the past and which denote some malignant potential include “atypical glandular proliferation”, “atypical epithelial proliferation”, “glandular hyperplasia with architectural atypia” and “glandular hyperplasia with cellular atypia”. Further, the term “hyperplasia” was applied without qualification by some workers to any form of endometrial hyperplasia irrespective of specific histological characteristics. This widespread confusion was reduced considerably with the introduction of an internationally agreed classification, that of the World Health Organization (WHO) 1975, as revised by WHO and the International Society of Gynecologic Pathologists (ISGYP)3 in 1994. According to this classification, the EHs are independently assessed for their architectural and cytological features. Thus, the glandular architecture can be either simple or complex: it is
Introduction The endometrium, a target tissue for sex-steroid hormones, consists of two main structural components e the endometrial glands and the specialized endometrial stroma. As part of its physiological function, these two elements proliferate and grow under the influence of ovarian oestrogens (first half of the menstrual cycle), a proliferation which would only cease with the antagonistic effect of progesterone which induces endometrial maturation and differentiation (second half of the menstrual cycle). However, under certain pathological conditions, such as a sequence of anovulatory cycles and granulosa cell tumours, this
Efthimios Sivridis MD PhD Emeritus Professor in Pathology, Department of Pathology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, Greece. Conflicts of interest: none declared. Alexandra Giatromanolaki MD Professor in Pathology, Department of Pathology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, Greece. Conflicts of interest: none declared.
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“simple” when the glands are widely spaced and have a smooth rounded outline, and it is “complex” when the glands are crowded and show multiple branchings into the surrounding stroma. The cells lining the endometrial glands are assessed as to whether are truly hyperplastic, i.e. normal in appearance (perhaps slightly enlarged), or whether they are atypical, i.e. display features which are obviously abnormal. This approach results in four diagnostic categories of endometrial hyperplasia: simple hyperplastic, complex hyperplastic, simple atypical, and complex atypical. Since atypical hyperplasia with a simple glandular architecture is fairly rare and onomatologically may be confused with SEH, many pathologists employ the term atypical hyperplasia to include cases of both simple and complex atypical hyperplasia. As a result, the following forms of endometrial hyperplasia are commonly used in practice: Simple hyperplasia; Complex hyperplasia; Atypical hyperplasia (simple and complex). Note that these forms may occur separately or in any combination within a single endometrial biopsy.
or elongated nuclei, with obvious pseudostratification and an amphophilic cytoplasm. Ciliated cells, usually in patches, and vesicular or “clear” cells (large clear cells with a central nucleus and abundant faintly staining cytoplasm), scattered among the glandular epithelial cells, are increased in numbers, reflecting an excessive oestrogenic stimulation (oestrogenized epithelial cells). The specialized endometrial stroma is conspicuously abundant and hypercellular, with the stromal cells having oval to elongated nuclei, scanty cytoplasm and ill-defined cell borders giving the well-known appearance of “naked” nuclei. Mitoses are noted in both epithelial and stromal cells. The spiral arteries are poorly developed in SEH, but the superficial thin-walled venules are prominent, and often dilated, congested or thrombosed, resulting in focal haemorrhage and stromal necrosis. Accumulation of polymorphs and focal areas of oedema are additional features. The overall picture resembles normal late proliferative phase endometrium, although the endometrial growth is more exuberant. The association with EACa is less than 1% (between 0.4 and 1%)4 e a figure which is in close approximation to that which would be expected to occur by chance.
The “simple endometrial hyperplasia” (SEH)
The “complex endometrial hyperplasia” (CEH)
This is the most common form of endometrial hyperplasia, occurring mainly at the perimenopause e an immediate sequence of anovulatory cycles. It is also the most genuine form of hyperplasia as the endometrium, in response to continuous oestrogenic stimulation, assumes a pattern of proliferative activity which involves both endometrial components, i.e. the glands and the stroma e as a result the normal gland to stroma ratio is maintained and there is no crowding of the glands. Further, the hyperplastic process is diffuse and affects the entire thickness of the endometrium, which loses the distinction between basal and functional layer and assumes a bulky and often polypoid appearance. The feature that stands out, however, is the great variability in the size and shape of the proliferating glands as many are large and cystic, probably with some epithelial budding, whereas others are small and have a smooth rounded outline (Figure 1). They are lined by normal columnar cells, having oval
Less commonly, the endometrial proliferations are focal and restricted to endometrial glands. Hyperplasia of this type may occur not only in the presence of prolonged unopposed oestrogenic stimulation of the endometrium, whatever the cause, but also in young women with normal menstrual cycles. Since the stroma does not participate in the hyperplastic process, the gland to stroma ratio becomes greater than normal and the glands show crowding and architectural complexity, mainly in the form of branchings rather than infoldings (Figure 2). The glandular epithelium, however, remains blunt, composed of columnar cells, with oval or elongated nuclei, having apparent pseudostratification and occasional mitoses e a cytology that closely resembles that of the normal late proliferative phase endometrium. The stroma between the hyperplastic glands is compressed, but not obliterated, in so far as a thin rim of tissue remains separating the glands. Elsewhere, the endometrium
Figure 1 SEH: cystic endometrial glands with pseudostratification, and abundance of a dense cellular stroma (H&E 200).
Figure 2 CEH: focal glandular crowding and branching, but normal proliferative type cells (H&E 200).
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remains normal, e.g. appropriate to the patient’s age and hormonal status. CEH has a <3% association with EACa.4
The “atypical endometrial hyperplasia” (AEH) There exists, however, a type of proliferative lesion in the endometrium which bears all the hallmarks of nuclear and cytoplasmic atypia, but which characteristically lacks stromal invasion. This lesion is usually focal or multifocal in distribution and affects exclusively glands. Architecturally, the glands tend to show crowding, with a typical “back-to-back” arrangement, although a thin rim of intervening stroma does remain in between; they also show complexity in the form of multiple branchings and intraglandular infoldings or tufts lacking fibrovascular cores. The condition has been variously termed “atypical endometrial hyperplasia”, “carcinoma in situ”, “intraepithelial carcinoma”, “intra-endometrial neoplasia” (IEN) or “endometrial intraepithelial neoplasia” (EIN) and possesses a strong natural tendency towards progression to EACa e indeed, between 22 and 52% of cases proceed to stromal invasion4,5 over a mean period of 4e6 years; there is also a high incidence of co-existent EACa. The essential criteria of recognizing cytological atypia and, thus, by implication, the diagnosis of AEH, are given below, with the vast majority of cases being accompanied by glandular crowding and complexity forming glands of irregular outline (“complex AEH”). In some cases, however, the glands exhibiting cytological atypia are widely spaced and have a regular smooth outline (“simple AEH”). Such lesions may be limited to a few glands, sometimes to one or two, and sometimes only part of a single gland may be affected.
Figure 3 AEH: Large rounded nuclei, often vesicular, with occasional prominent nucleoli; there is also stratification with loss of nuclear polarity and loss of cellular cohesion (H&E 1000).
impossible, task, and, under these circumstances, criteria indicative of “stromal invasion” are sought.1 In fact, a hyperplastic lesion exhibiting cytological atypia and any of the following features, alone or in combination, merit being classified as EACa: Small clusters of atypical epithelial endometrial cells or atypical endometrial glands invading a newly formed stroma (hyalinized and/or somewhat oedematous fibrosis) (Figures 4 and 5). A solid growth pattern formed by atypical endometrial cells (not squamous or squamoid in type) (Figure 6).
What are the very essential criteria for diagnosing AEH? It is apparent from the above description that the diagnosis of AEHs rests solely on specific nuclear and cytoplasmic features,1 whilst the architectural pattern of the lesion is only of secondary importance. Thus, the defining cytological features of AEH are: The presence of large nuclei, almost twice the normal size, which are characteristically round, instead of elongated, and vesicular rather than hyperchromatic, and which usually contain one or more prominent nucleoli (Figure 3). There must be loss of the normal nuclear polarity. There must be loss of cell-to-cell and cell-to-basement membrane cohesion. The loss of cellular cohesion, combined with the loss of nuclear polarity, may allow atypical cells to grow in syncytial-like aggregates, while the piling up of such cells into irregular masses form small intraluminal papillae or tufts, lacking fibrous cores. There should be abundant cytoplasm, with indistinct cell borders, and intense eosinophilia. Pseudostratification or true stratification of epithelial cells usually accompany cytological atypia, but this feature is not specific to AEH and may well occur, in other forms of EH. There must be no evidence of stromal invasion.
Figure 4 A cluster of atypical epithelial cells invading a newly formed stroma. Note also large round vesicular cells with abundant eosinophilic cytoplasm with indistinct cell borders. There is also loss of polarity, loss of cell-to-cell and cell-to-basement membrane cohesion, and papillary tufts lacking fibrovascular cores. Compare the upper left portion of the field (atypical cells) with that of the lower right (cells within normal limits) (H&E 400).
How is AEH distinguished from a well-differentiated EACa? There can be no doubt that myometrial invasion is the most reliable criterion for separating EACa from AEH. Yet, detecting this feature in a curettage specimen is a difficult, if not
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Figure 7 Stromal invasion in the form of a “giant tumour gland” e the merging of adjacent endometrial glands with obliteration of the intervening stroma (H&E 200).
Figure 5 Atypical endometrial glands invading a newly formed stroma (hyalinized and somewhat oedematous). Note a focus of solid growth pattern in the upper right portion of the field (H&E 200).
The formation of “giant tumour glands” by merging of individual glands having complete obliteration of the intervening stroma e the so-called “complex” or “confluent glandular pattern” (Figure 7) e an arrangement which may, at times, take the form of a “cribriform” pattern (Figure 8). Small intraluminal papillae/tufts of atypical cells, without any stromal support but having a tendency to fuse, may form intraglandular bridges and exhibit a somewhat similar pattern (Figure 9). The dominant presence of large, elongated and branching papillary fronds, having fibrous cores, albeit rather thin e a pattern commonly referred to as “papillary” (Figure 10). A newly formed stroma (stromal fibrosis), even in the absence of any demonstrable invasion, should alert the pathologist to this possibility. Similarly, focal stromal necrosis and the presence of neutrophils and nuclear debris
within glandular lumens may coexist with stromal invasion, necessitating extensive sampling (embedding all the material, deeper sections). Aggregates of foamy histiocytes and the presence of squamous morules or squamous differentiation are not, in general, specific are not specific diagnostic features since they have been noted in both EACa and AEH. Neither is mitotic activity in itself of any particular value, given that the normal proliferative phase endometrium contains more mitoses than AEH or an AECa; yet, the rare presence of abnormal mitoses does suggest an invasive disease.
What is the true nature of AEH? The question as to whether the AEH is hyperplastic or neoplastic in nature is less practical than to make its diagnosis or draw its
Figure 6 A solid growth pattern formed by atypical endometrial cells (H&E 200).
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Figure 8 Stromal invasion in the form of a “cribriform” pattern (H&E 200).
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evidence in support of a neoplastic rather than hyperplastic origin of AEH? Firstly, it is the histology of the lesion; this is identical to or indistinguishable from an EACa. Secondly, it is the electron microscopy of AEH; this shows a morphological continuum of abnormalities with EACa. Thirdly, it is the continuous growth of the lesion; AEH will not revert to normal when the oestrogenic stimulus which initiated proliferation is withdrawn. Fourthly, it is the natural history of the disease; atypical endometrial hyperplasia, if left untreated, progresses to invasive endometrial adenocarcinoma with a frequency over 52%.5 Furthermore, many cases (42.6%) with a diagnosis of AEH on endometrial biopsy often co-exist with endometrial malignancy (EACa) in the hysterectomy specimen.9 Fifthly, it is the common molecular genetic changes; these include inactivation of PTEN tumour suppressor gene, microsatellite instability,10 and the activation of K-ras genes.11 None of the above aberrations are shown in simple or complex endometrial hyperplasia. Last but not least, it is the autophagic activity in the form of “stone-like” structures (SLS); these are compact and dense, spheroidal cytoplasmic structures, 5 mm on average, which are enclosed within cytoplasmic vacuoles; they encountered exclusively in epithelial neoplastic lesions, including EACas, but do also occur in AEH.12
Figure 9 Stomal invasion by forming intraglandular bridges of atypical cells, without any stromal support. Note also the merging of individual glands (H&E 200).
distinction from an EACa, but it is certainly equally interesting. The existence of such a lesion as a histological entity and its irreversible commitment to neoplasia was first noted by Thomas Cullen6 in 1900 and accumulated evidence since that date have indicated that AEH is probably a form of endometrial neoplasm e a view which is clearly reflected in its various designations given by several workers (see: The “atypical endometrial hyperplasia”). There are also those who equate AEH with a welldifferentiated endometrial adenocarcinoma of the endometrioid type (EACa) by the name of “endometrioid neoplasia” (EN).7 The term “atypical hyperplasia” (AEH), which was adopted by the WHO, may probably not be universally accepted as expressing the true nature of the disease, but it does not either contradict to the theory of neoplastic development as defined by Jacob Furth8: “Neoplasms are a heterogeneous group of diseases; they range from uncontrolled hyperplasia through hormone-responsive neoplasia to autonomous neoplasia”. But what is the available
Other classification schemes of endometrial hyperplasia The World Health Organization (WHO) classification of endometrial hyperplasia is now the most widely used system.3 This classification, based on the classical study of Kurman et al.,4 is useful in practice and has a considerable merit with respect to prognosis. Furthermore, by providing an internationally agreed terminology, the scheme was aimed to end the confusion surrounding definitions and nomenclature of EH. Despite this, the WHO classification has been criticized for complexity and low level of reproducibility; in particular, the assessment of nuclear atypia was considered as being “highly subjective” resulting in marked interobserver variation.7,13,14 This, however, has not been everyone’s experience15 and certainly not ours, but we must admit that the accurate identification of AEH and its distinction from a well differentiated EACa often presents difficulties. In line with these thoughts, Bergeron et al.7 proposed the amalgamation of AEH with EACa in a single diagnostic category so-called “endometrioid neoplasia” (EN); when their series was studied in this manner they found an increase in reproducibility, relative to the WHO classification, but their sample was too small (16 cases of EACa and 6 cases of AEH) for any firm conclusions to be drawn. In the same study, simple and complex endometrial hyperplasia were combined by the name of “hyperplasia”. Earlier Skov et al.13 had divided endometrial hyperplasias into those having cytological atypia (AEH) and those lacking this feature (combined SEH-CEH) and succeeded in improving the overall agreement of the WHO 1975 and 1994 classifications. It should be noted, however, that although this approach is, in itself, of undoubted clinical importance, the results obtained need
Figure 10 A typical “papillary” pattern of invasion (H&E 200).
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verification for “transitional forms between SEH and CEH are not seen, even when both are present in the same endometrium,” and “often there is a very sharp and clear boundary between the two abnormal patterns”.1 Following an essentially similar strategy, Mutter and the Endometrial Collaborative Group (ECG)16 used the name “benign endometrial hyperplasia” to include hyperplasias of both simple and complex form, and redefined AEH in terms of molecular, morphometric and morphological criteria; the condition, which was designated “endometrial intraepithelial neoplasia” (EIN) would not be diagnosed unless it satisfies the following criteria: A monoclonal growth. A size greater than 1 mm in diameter or more than ten glands. Closely packed glands, with a gland area exceeding that of stroma (volume percentage stroma <55%). Cytological change that is always different from that of the adjacent normal endometrium. Exclusion of benign conditions. Exclusion of EACa. With the application of these criteria which, by definition, will have to be taken in their entirety, Mutter and the ECG16 noted an increase in reproducibility of the WHO94 classification, but their claim was substantiated only by affiliated groups of workers; data derived from independently reported studies indicated that the WHO and EIN classifications are equally satisfactory in terms of reproducibility,5,17 frequency of co-existent EACa18 and expected risk of progression to EACa,19 the latter sometimes being more satisfactory by the application of the WHO system.20 Others found that the most effective scheme in improving interobserver reproducibility of the WHO94 classification is that which divides EHs into: SEH and less severe forms (negative, disordered proliferative endometirum) versus CEH and more severe forms (AEH and EACa).21 They reached this conclusion after testing various binary systems.
particularly EACa, is self-evident, but it is worth reiterating here that whilst the premalignant lesions (AEH or EIN) lack clear evidence of stromal invasion, they do display cytological atypia which often is more pronounced than that of an invasive EACa.1 The importance of this feature, initially blamed as being “highly subjective” for diagnosing AEH by the ECG,16 it has now gained acceptance by the self-same proponents of the EIN taxonomy who withdrew monoclonality in favour of the “standard H&E slides viewed through a routine microscope”.22,23 For, indeed, any difficulty with the definition of cytological atypia should be resolved by improving the diagnostic skills of the students of endometrial pathology.15
Clinical features, aetiopathogenesis and treatment of endometrial hyperplasia Endometrial hyperplasia is a prevalent gynaecological disease that affects women from menarche to 75 years and over. In the United States the overall incidence of endometrial hyperplasia (simple, complex and atypical) is 133 per 100,000 women per year24; it is most common in women ages 50e54, and is rarely observed in women under 30 (6 per 100,000 woman per year).24 The disease is usually detected following investigation of abnormal uterine bleeding. The imaging technique most frequently employed for assessing the endometrium, particularly in postmenopausal women, is transvaginal ultrasound. A mean endometrial thickness of >5 mm may indicate the presence of pathology and requires endometrial biopsy or endometrial curettage. From a pathogenetic perspective, any condition resulting in prolonged (more than five years) oestrogenic stimulation of the endometrium unopposed by progesterone action, whether endogenous or exogenous, may cause endometrial hyperplasia. By far the commonest endogenous factor is repeated anovulatory cycles. These occur frequently during the perimenopause, and in women with polycystic ovary syndrome, ovarian cortical hyperplasia or oestrogen-secreting ovarian tumours (granulosatheca cell tumours) e conditions in which there is usually an excess production of androstenedione by the adrenal glands and the ovarian stroma. Androstenedione is converted to oestrone in the adipose tissue and leads to a persistently hyperoestrogenic state. Exogenous risk factors include the long-term administration of noncyclical oestrogens for the relief of menopausal symptoms (estrogene replacement therapy) and the treatment of breast cancer with the synthetic hormone Tamoxifen; this has an antioestrogen effect on the breast, but a pro-oestrogen effect on the uterus. In addition, women with the Lynch syndrome II (hereditary non-polyposis colon cancer) are at a greater risk of developing endometrial hyperplasia and neoplasia. Obesity plays a major contributory role in the development of endometrial hyperplasia and carcinogenesis by increasing the levels of circulating oestrogens. This may be the result of accelerated conversion of androstenedione to estrone or a decrease in the levels of sex hormone-binding globulin (SHBG), the former occurring with considerable frequency. The conversion takes place in the adipose tissues by the enzyme cytochrome p450 aromatase and increases with increasing body weight (increased numbers of fat cells) and with advanced age (increased specific
These somewhat controversial results have prompted a thorough re-evaluation of the design and the criteria used in these studies.2 Thus, the overall strategy to improve reproducibility of the WHO94 classification by reducing the four categories to two7,13,16,21 it would seem to us simplistic rather than simple, for any contraction of the number of diagnostic choices would compromise the evolution of the scientific knowledge, not infrequently, at the expense of the patient’s care15; a hypothetical acceptance of the concept of “endometrioid neoplasia”,7 for example, would lead to overtreatment. With regard to the validity of the EIN criteria, this deserves more than a passing comment. Thus, monoclonality (a most important feature in the EIN classification)16 is only suggestive, but not conclusive, of endometrial neoplasia as it occurs with greater frequency in simple endometrial polyps, endometriotic cysts and in CEH without atypia; in the small sample of Mutter’s et al. study16 only two of the four AEH were monoclonal. Neither a size of greater than 1 mm2 in diameter nor an increased gland to stroma ratio are, in themselves, evidence of neoplasia: lesions smaller than 1 mm2 occur early in neoplastic disease; glandular crowding is the sine qua non of CEH, whilst many AEHs (EIN) or EACas may not conform to this stereotype. The exclusion of other conditions that present with abnormal uterine bleeding,
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aromatase activity). Interestingly, the factors of ageing and obesity appear to be additive. Other oestrogen-related factors which may provide an added growth stimulus to the endometrium include the reduction in average parity, the early onset of menarchy and the late onset of menopause, which increase the life-time exposure of the endometrium to endogenous oestrogens, and the presence of diabetes and hypertension, although probably only among obese women. With regard to treatment, it is generally agreed that EHs without cytological atypia should be treated with progestins alone. It is also agreed that the primary mode of treatment for patients with AEH is by surgical excision, although high-doses of progestins for a duration of no less than six months may be offered to young women who wish to retain fertility.
a single circumscribed nodule of large size (4 cm on average) which, not infrequently, lies in the myometrium. The histology of such lesions, although resembles a normal proliferative or hyperplastic stroma, may reach a mitotic rate of up to 10 per highpower fields, and there is fusion of the gene JAZF1/JJAZ1 caused by a t(7;17)(p15;q21) translocation.27
Conclusion This discussion indicates that the human endometrium responds to unopposed estrogenic stimulation in three different ways: by proliferation of both glands and stroma (SEH), proliferation of only the endometrial glands (CEH, AEH, EACa) and/or by proliferation of only the endometrial stroma (STH, endometrial stromal neoplasms). SEH is the most common form of pathological proliferation in the endometrium, representing a genuine hyperplastic lesion. CEH and STH are also hyperplastic lesions, though less typical, in the sense that only one of their two main structural components are proliferating. AEH is probably a neoplastic (precancerous) lesion having a high incidence of progression to EACa. It should be separated from the other forms of hyperplasia by the presence of nuclear and cytoplasmic atypia, and from EACa from the lack of myometrial and/or stromal invasion. Stromal hyperplasia should be distinguished from endometrial stromal nodule and other stromal neoplasias from its small size, intraendometrial location, the multiplicity of the lesion and its lack of invasion. A
New perspectives This account on endometrial hyperplasia would not be complete without considering a rather under-recognized hyperplastic process which does occur in the endometrium and which specifically affects the endometrial stroma; it is the so-called focal endometrial “stromal hyperplasia”. The existence of such a lesion challenges the traditional view that endometrial proliferations, consisting solely of stromal cells, are invariably neoplastic. It is worth recalling here, that all proliferative lesions in the endometrium arise from two main structural components, the endometrial glands and the endometrial stroma, either of which, alone or in any combination, have the potentiality to undertake intense proliferation and growth affording three possible morphological patterns: (i) proliferation of both glands and stroma, (SEH), (ii) proliferation that is restricted to the endometrial glands (CEH, AEH, EACa), and (iii) proliferation restricted to the endometrial stroma e a pattern which, by convention, it has been taken as being invariably neoplastic (endometrial stromal nodule, low-grade endometrial stromal sarcoma, undifferentiated sarcoma), but which recent evidence indicates that may at times be hyperplastic. For indeed, EHs consisting solely of stromal cells were only exceptionally reported in the literature,25 largely because these lesions are not considered as a pathological entity distinct from the endometrial stromal nodule and the low-grade endometrial stromal sarcoma. Stewart et al. reported the first recognized hyperplastic lesion of endometrial stromal cells,25 and three similar cases were reported from our own laboratory recently.26 “Endometrial stromal hyperplasias” are invariably of small size (0.2e0.8 mm diameter), intra-endometrial in localization, multifocal in distribution, and have a tendency to become polypoid or to localize in a pre-existing polyp. They are formed of small uniform spindle-shaped cells of increased cellularity, having a remarkable similarity with the normal proliferative type stroma. There is lack of cytological atypia, mitotic activity or vascular invasion. Immunohistochemically, the stromal cells are usually positive for CD10, vimentin, oestrogen and progesterone receptors, but are negative for smooth muscle actin, desmin and usually for c-kit.27 A specific molecular genetic change is the translocation t(6;14)(p21;q24). The possibility of an endometrial stromal nodule or a low-grade endometrial stromal sarcoma should always be excluded. Features favouring neoplasia include
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comparison with WHO classification in endometrial hyperplasias. Pathol Res Pract 2012; 208: 708e12. Lacey Jr JV, Mutter GL, Nucci MR, et al. Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies. Cancer 2008; 113: 2073e81. Kane SE, Hecht JL. Endometrial intraepithelial neoplasia terminology in practice: 4-year experience at a single institution. Int J Gynecol Pathol 2012; 31: 160e5. Sherman ME, Ronnett BM, Ioffe OB, et al. Reproducibility of biopsy diagnoses of endometrial hyperplasia: evidence supporting a simplified classification. Int J Gyecol Pathol 2008; 27: 318e25. Quick CM, Laury AR, Monte NM, Mutter GL. Utility of PAX2 as a marker for diagnosis of endometrial intraepithelial neoplasia. Am J Clin Pathol 2012; 138: 678e84. Hecht JL, Ince TA, Baak JP, Baker HE, Ogden MW, Mutter GL. Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Mod Pathol 2005; 18: 324e30. Reed SD, Newton KM, Clinton WL, et al. Incidence of endometrial hyperplasia. Am J Obstet Gynecol 2009; 200: 678.e1e678.e6. Stewart CJ, Michie BA, Kennedy JH. Focal endometrial stromal hyperplasia. Histopathology 1998; 33: 75e9. Sivridis E, Koutsougeras G, Giatromanolaki A. Endometrial stromal hyperplasia e an under-recognized condition. Case Rep Pathol 2013; 2013: 204082. Chiang S, Oliva E. Cytogenetic and molecular aberrations in endometrial stromal tumors. Hum Pathol 2011; 42: 609e17.
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Demystifying endometrial hyperplasia
periodic oestrogeneprogesterone secretion is disrupted in favour of the former, and unopposed oestrogenic stimulation of the endometrium pursues setting the stage for endometrial hyperplasia (EH) and/or neoplasia. As it would be expected, most cases of EH arise from both glands and stroma (simple hyperplasia), with the overall cellular elements to produce what is in effect an exaggeration of the normal proliferative phase endometrium.1 However, not all endometrial hyperplasias (EHs) show this typical pattern and many assume a hyperplastic growth which involves exclusively glands, with crowding and branching, but certainly without cytological atypia (complex hyperplasia). The above two growth patterns appear to conform with the usual stereotype of a hyperplasia without crossing the boundaries of neoplasia. Hyperplasia is, in general terms, the increase in size of an organ or tissue as a result of an increase in the number of specialized cells per reference area or volume. The lesion is benign and the hyperplastic cells are, essentially, similar to normal or may appear slightly enlarged (hypertrophic). Genuine hyperplastic lesions, including those of the human endometrium, very rarely, if ever, progress into malignant disease. Yet, endometrial adenocarcinomas, particularly those of the endometrioid cell type (EACa), may at times preceded by a form of proliferative lesion which is composed exclusively of glands, often with crowding and complexity, and always with nuclear and cytoplasmic atypia1; this condition, which is most commonly known as “atypical endometrial hyperplasia” (AEH), may evolve into an EACa with an incidence which is too high to be dismissed as coincidental.
Efthimios Sivridis Alexandra Giatromanolaki
Abstract The endometrial hyperplasias form a spectrum of proliferative lesions, not all of which conform to conventional definition of hyperplasia. For whilst most hyperplastic lesions are composed of cells normally occurring in the late proliferative phase endometrium, there are those few which consist of genuine atypical cells. Lesions of this type, so-called “atypical endometrial hyperplasias”, tend to merge imperceptibly with well differentiated endometrioid adenocarcinomas, giving rise to major challenges: First and foremost, what are the very essential criteria that should be met before diagnosing such a lesion? And what are the very least that should be insisted upon for diagnosing malignancy once an atypical endometrial hyperplasia has been established? What is its true nature and how should ideally be classified? Other less conflicting, but equally interesting, aspects of endometrial hyperplasia which are covered in this account include the conventional hyperplasias, i.e. those lacking cytological atypia, and the overall incidence, risk factors and treatment of the disease. It is worth noting that “pure” stromal cell proliferations are, in itself, not necessarily neoplastic, for many take the form of endometrial stromal hyperplasia.
Keywords atypical endometrial hyperplasia; classification; endometrial hyperplasia; endometrial intraepithelial neoplasia (EIN); endometrial stromal hyperplasia
The endometrial hyperplasias e the WHO classification The term “endometrial hyperplasia” covers a spectrum of proliferative lesions in the endometrium some of which progress to or co-exist with endometrioid adenocarcinoma (EACa). There is, in general, good correlation between a particular histological type and the consequent biological behaviour of the lesion. However, this relationship between histological appearances and prognosis has been blurred by inconsistencies in terminology and definitions. Indeed, diagnostic terms like “atypical”, “adenomatous”, “adenomatoid”, “complex” and “irregular” hyperplasia have been used in a highly subjective manner to hyperplastic lesions of the endometrium having and having not a significant risk of progressing into an EACa.2 Other diagnostic labels which have been applied to hyperplastic lesions in the past and which denote some malignant potential include “atypical glandular proliferation”, “atypical epithelial proliferation”, “glandular hyperplasia with architectural atypia” and “glandular hyperplasia with cellular atypia”. Further, the term “hyperplasia” was applied without qualification by some workers to any form of endometrial hyperplasia irrespective of specific histological characteristics. This widespread confusion was reduced considerably with the introduction of an internationally agreed classification, that of the World Health Organization (WHO) 1975, as revised by WHO and the International Society of Gynecologic Pathologists (ISGYP)3 in 1994. According to this classification, the EHs are independently assessed for their architectural and cytological features. Thus, the glandular architecture can be either simple or complex: it is
Introduction The endometrium, a target tissue for sex-steroid hormones, consists of two main structural components e the endometrial glands and the specialized endometrial stroma. As part of its physiological function, these two elements proliferate and grow under the influence of ovarian oestrogens (first half of the menstrual cycle), a proliferation which would only cease with the antagonistic effect of progesterone which induces endometrial maturation and differentiation (second half of the menstrual cycle). However, under certain pathological conditions, such as a sequence of anovulatory cycles and granulosa cell tumours, this
Efthimios Sivridis MD PhD Emeritus Professor in Pathology, Department of Pathology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, Greece. Conflicts of interest: none declared. Alexandra Giatromanolaki MD Professor in Pathology, Department of Pathology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, Greece. Conflicts of interest: none declared.
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“simple” when the glands are widely spaced and have a smooth rounded outline, and it is “complex” when the glands are crowded and show multiple branchings into the surrounding stroma. The cells lining the endometrial glands are assessed as to whether are truly hyperplastic, i.e. normal in appearance (perhaps slightly enlarged), or whether they are atypical, i.e. display features which are obviously abnormal. This approach results in four diagnostic categories of endometrial hyperplasia: simple hyperplastic, complex hyperplastic, simple atypical, and complex atypical. Since atypical hyperplasia with a simple glandular architecture is fairly rare and onomatologically may be confused with SEH, many pathologists employ the term atypical hyperplasia to include cases of both simple and complex atypical hyperplasia. As a result, the following forms of endometrial hyperplasia are commonly used in practice: Simple hyperplasia; Complex hyperplasia; Atypical hyperplasia (simple and complex). Note that these forms may occur separately or in any combination within a single endometrial biopsy.
or elongated nuclei, with obvious pseudostratification and an amphophilic cytoplasm. Ciliated cells, usually in patches, and vesicular or “clear” cells (large clear cells with a central nucleus and abundant faintly staining cytoplasm), scattered among the glandular epithelial cells, are increased in numbers, reflecting an excessive oestrogenic stimulation (oestrogenized epithelial cells). The specialized endometrial stroma is conspicuously abundant and hypercellular, with the stromal cells having oval to elongated nuclei, scanty cytoplasm and ill-defined cell borders giving the well-known appearance of “naked” nuclei. Mitoses are noted in both epithelial and stromal cells. The spiral arteries are poorly developed in SEH, but the superficial thin-walled venules are prominent, and often dilated, congested or thrombosed, resulting in focal haemorrhage and stromal necrosis. Accumulation of polymorphs and focal areas of oedema are additional features. The overall picture resembles normal late proliferative phase endometrium, although the endometrial growth is more exuberant. The association with EACa is less than 1% (between 0.4 and 1%)4 e a figure which is in close approximation to that which would be expected to occur by chance.
The “simple endometrial hyperplasia” (SEH)
The “complex endometrial hyperplasia” (CEH)
This is the most common form of endometrial hyperplasia, occurring mainly at the perimenopause e an immediate sequence of anovulatory cycles. It is also the most genuine form of hyperplasia as the endometrium, in response to continuous oestrogenic stimulation, assumes a pattern of proliferative activity which involves both endometrial components, i.e. the glands and the stroma e as a result the normal gland to stroma ratio is maintained and there is no crowding of the glands. Further, the hyperplastic process is diffuse and affects the entire thickness of the endometrium, which loses the distinction between basal and functional layer and assumes a bulky and often polypoid appearance. The feature that stands out, however, is the great variability in the size and shape of the proliferating glands as many are large and cystic, probably with some epithelial budding, whereas others are small and have a smooth rounded outline (Figure 1). They are lined by normal columnar cells, having oval
Less commonly, the endometrial proliferations are focal and restricted to endometrial glands. Hyperplasia of this type may occur not only in the presence of prolonged unopposed oestrogenic stimulation of the endometrium, whatever the cause, but also in young women with normal menstrual cycles. Since the stroma does not participate in the hyperplastic process, the gland to stroma ratio becomes greater than normal and the glands show crowding and architectural complexity, mainly in the form of branchings rather than infoldings (Figure 2). The glandular epithelium, however, remains blunt, composed of columnar cells, with oval or elongated nuclei, having apparent pseudostratification and occasional mitoses e a cytology that closely resembles that of the normal late proliferative phase endometrium. The stroma between the hyperplastic glands is compressed, but not obliterated, in so far as a thin rim of tissue remains separating the glands. Elsewhere, the endometrium
Figure 1 SEH: cystic endometrial glands with pseudostratification, and abundance of a dense cellular stroma (H&E 200).
Figure 2 CEH: focal glandular crowding and branching, but normal proliferative type cells (H&E 200).
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remains normal, e.g. appropriate to the patient’s age and hormonal status. CEH has a <3% association with EACa.4
The “atypical endometrial hyperplasia” (AEH) There exists, however, a type of proliferative lesion in the endometrium which bears all the hallmarks of nuclear and cytoplasmic atypia, but which characteristically lacks stromal invasion. This lesion is usually focal or multifocal in distribution and affects exclusively glands. Architecturally, the glands tend to show crowding, with a typical “back-to-back” arrangement, although a thin rim of intervening stroma does remain in between; they also show complexity in the form of multiple branchings and intraglandular infoldings or tufts lacking fibrovascular cores. The condition has been variously termed “atypical endometrial hyperplasia”, “carcinoma in situ”, “intraepithelial carcinoma”, “intra-endometrial neoplasia” (IEN) or “endometrial intraepithelial neoplasia” (EIN) and possesses a strong natural tendency towards progression to EACa e indeed, between 22 and 52% of cases proceed to stromal invasion4,5 over a mean period of 4e6 years; there is also a high incidence of co-existent EACa. The essential criteria of recognizing cytological atypia and, thus, by implication, the diagnosis of AEH, are given below, with the vast majority of cases being accompanied by glandular crowding and complexity forming glands of irregular outline (“complex AEH”). In some cases, however, the glands exhibiting cytological atypia are widely spaced and have a regular smooth outline (“simple AEH”). Such lesions may be limited to a few glands, sometimes to one or two, and sometimes only part of a single gland may be affected.
Figure 3 AEH: Large rounded nuclei, often vesicular, with occasional prominent nucleoli; there is also stratification with loss of nuclear polarity and loss of cellular cohesion (H&E 1000).
impossible, task, and, under these circumstances, criteria indicative of “stromal invasion” are sought.1 In fact, a hyperplastic lesion exhibiting cytological atypia and any of the following features, alone or in combination, merit being classified as EACa: Small clusters of atypical epithelial endometrial cells or atypical endometrial glands invading a newly formed stroma (hyalinized and/or somewhat oedematous fibrosis) (Figures 4 and 5). A solid growth pattern formed by atypical endometrial cells (not squamous or squamoid in type) (Figure 6).
What are the very essential criteria for diagnosing AEH? It is apparent from the above description that the diagnosis of AEHs rests solely on specific nuclear and cytoplasmic features,1 whilst the architectural pattern of the lesion is only of secondary importance. Thus, the defining cytological features of AEH are: The presence of large nuclei, almost twice the normal size, which are characteristically round, instead of elongated, and vesicular rather than hyperchromatic, and which usually contain one or more prominent nucleoli (Figure 3). There must be loss of the normal nuclear polarity. There must be loss of cell-to-cell and cell-to-basement membrane cohesion. The loss of cellular cohesion, combined with the loss of nuclear polarity, may allow atypical cells to grow in syncytial-like aggregates, while the piling up of such cells into irregular masses form small intraluminal papillae or tufts, lacking fibrous cores. There should be abundant cytoplasm, with indistinct cell borders, and intense eosinophilia. Pseudostratification or true stratification of epithelial cells usually accompany cytological atypia, but this feature is not specific to AEH and may well occur, in other forms of EH. There must be no evidence of stromal invasion.
Figure 4 A cluster of atypical epithelial cells invading a newly formed stroma. Note also large round vesicular cells with abundant eosinophilic cytoplasm with indistinct cell borders. There is also loss of polarity, loss of cell-to-cell and cell-to-basement membrane cohesion, and papillary tufts lacking fibrovascular cores. Compare the upper left portion of the field (atypical cells) with that of the lower right (cells within normal limits) (H&E 400).
How is AEH distinguished from a well-differentiated EACa? There can be no doubt that myometrial invasion is the most reliable criterion for separating EACa from AEH. Yet, detecting this feature in a curettage specimen is a difficult, if not
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Figure 7 Stromal invasion in the form of a “giant tumour gland” e the merging of adjacent endometrial glands with obliteration of the intervening stroma (H&E 200).
Figure 5 Atypical endometrial glands invading a newly formed stroma (hyalinized and somewhat oedematous). Note a focus of solid growth pattern in the upper right portion of the field (H&E 200).
The formation of “giant tumour glands” by merging of individual glands having complete obliteration of the intervening stroma e the so-called “complex” or “confluent glandular pattern” (Figure 7) e an arrangement which may, at times, take the form of a “cribriform” pattern (Figure 8). Small intraluminal papillae/tufts of atypical cells, without any stromal support but having a tendency to fuse, may form intraglandular bridges and exhibit a somewhat similar pattern (Figure 9). The dominant presence of large, elongated and branching papillary fronds, having fibrous cores, albeit rather thin e a pattern commonly referred to as “papillary” (Figure 10). A newly formed stroma (stromal fibrosis), even in the absence of any demonstrable invasion, should alert the pathologist to this possibility. Similarly, focal stromal necrosis and the presence of neutrophils and nuclear debris
within glandular lumens may coexist with stromal invasion, necessitating extensive sampling (embedding all the material, deeper sections). Aggregates of foamy histiocytes and the presence of squamous morules or squamous differentiation are not, in general, specific are not specific diagnostic features since they have been noted in both EACa and AEH. Neither is mitotic activity in itself of any particular value, given that the normal proliferative phase endometrium contains more mitoses than AEH or an AECa; yet, the rare presence of abnormal mitoses does suggest an invasive disease.
What is the true nature of AEH? The question as to whether the AEH is hyperplastic or neoplastic in nature is less practical than to make its diagnosis or draw its
Figure 6 A solid growth pattern formed by atypical endometrial cells (H&E 200).
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Figure 8 Stromal invasion in the form of a “cribriform” pattern (H&E 200).
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evidence in support of a neoplastic rather than hyperplastic origin of AEH? Firstly, it is the histology of the lesion; this is identical to or indistinguishable from an EACa. Secondly, it is the electron microscopy of AEH; this shows a morphological continuum of abnormalities with EACa. Thirdly, it is the continuous growth of the lesion; AEH will not revert to normal when the oestrogenic stimulus which initiated proliferation is withdrawn. Fourthly, it is the natural history of the disease; atypical endometrial hyperplasia, if left untreated, progresses to invasive endometrial adenocarcinoma with a frequency over 52%.5 Furthermore, many cases (42.6%) with a diagnosis of AEH on endometrial biopsy often co-exist with endometrial malignancy (EACa) in the hysterectomy specimen.9 Fifthly, it is the common molecular genetic changes; these include inactivation of PTEN tumour suppressor gene, microsatellite instability,10 and the activation of K-ras genes.11 None of the above aberrations are shown in simple or complex endometrial hyperplasia. Last but not least, it is the autophagic activity in the form of “stone-like” structures (SLS); these are compact and dense, spheroidal cytoplasmic structures, 5 mm on average, which are enclosed within cytoplasmic vacuoles; they encountered exclusively in epithelial neoplastic lesions, including EACas, but do also occur in AEH.12
Figure 9 Stomal invasion by forming intraglandular bridges of atypical cells, without any stromal support. Note also the merging of individual glands (H&E 200).
distinction from an EACa, but it is certainly equally interesting. The existence of such a lesion as a histological entity and its irreversible commitment to neoplasia was first noted by Thomas Cullen6 in 1900 and accumulated evidence since that date have indicated that AEH is probably a form of endometrial neoplasm e a view which is clearly reflected in its various designations given by several workers (see: The “atypical endometrial hyperplasia”). There are also those who equate AEH with a welldifferentiated endometrial adenocarcinoma of the endometrioid type (EACa) by the name of “endometrioid neoplasia” (EN).7 The term “atypical hyperplasia” (AEH), which was adopted by the WHO, may probably not be universally accepted as expressing the true nature of the disease, but it does not either contradict to the theory of neoplastic development as defined by Jacob Furth8: “Neoplasms are a heterogeneous group of diseases; they range from uncontrolled hyperplasia through hormone-responsive neoplasia to autonomous neoplasia”. But what is the available
Other classification schemes of endometrial hyperplasia The World Health Organization (WHO) classification of endometrial hyperplasia is now the most widely used system.3 This classification, based on the classical study of Kurman et al.,4 is useful in practice and has a considerable merit with respect to prognosis. Furthermore, by providing an internationally agreed terminology, the scheme was aimed to end the confusion surrounding definitions and nomenclature of EH. Despite this, the WHO classification has been criticized for complexity and low level of reproducibility; in particular, the assessment of nuclear atypia was considered as being “highly subjective” resulting in marked interobserver variation.7,13,14 This, however, has not been everyone’s experience15 and certainly not ours, but we must admit that the accurate identification of AEH and its distinction from a well differentiated EACa often presents difficulties. In line with these thoughts, Bergeron et al.7 proposed the amalgamation of AEH with EACa in a single diagnostic category so-called “endometrioid neoplasia” (EN); when their series was studied in this manner they found an increase in reproducibility, relative to the WHO classification, but their sample was too small (16 cases of EACa and 6 cases of AEH) for any firm conclusions to be drawn. In the same study, simple and complex endometrial hyperplasia were combined by the name of “hyperplasia”. Earlier Skov et al.13 had divided endometrial hyperplasias into those having cytological atypia (AEH) and those lacking this feature (combined SEH-CEH) and succeeded in improving the overall agreement of the WHO 1975 and 1994 classifications. It should be noted, however, that although this approach is, in itself, of undoubted clinical importance, the results obtained need
Figure 10 A typical “papillary” pattern of invasion (H&E 200).
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verification for “transitional forms between SEH and CEH are not seen, even when both are present in the same endometrium,” and “often there is a very sharp and clear boundary between the two abnormal patterns”.1 Following an essentially similar strategy, Mutter and the Endometrial Collaborative Group (ECG)16 used the name “benign endometrial hyperplasia” to include hyperplasias of both simple and complex form, and redefined AEH in terms of molecular, morphometric and morphological criteria; the condition, which was designated “endometrial intraepithelial neoplasia” (EIN) would not be diagnosed unless it satisfies the following criteria: A monoclonal growth. A size greater than 1 mm in diameter or more than ten glands. Closely packed glands, with a gland area exceeding that of stroma (volume percentage stroma <55%). Cytological change that is always different from that of the adjacent normal endometrium. Exclusion of benign conditions. Exclusion of EACa. With the application of these criteria which, by definition, will have to be taken in their entirety, Mutter and the ECG16 noted an increase in reproducibility of the WHO94 classification, but their claim was substantiated only by affiliated groups of workers; data derived from independently reported studies indicated that the WHO and EIN classifications are equally satisfactory in terms of reproducibility,5,17 frequency of co-existent EACa18 and expected risk of progression to EACa,19 the latter sometimes being more satisfactory by the application of the WHO system.20 Others found that the most effective scheme in improving interobserver reproducibility of the WHO94 classification is that which divides EHs into: SEH and less severe forms (negative, disordered proliferative endometirum) versus CEH and more severe forms (AEH and EACa).21 They reached this conclusion after testing various binary systems.
particularly EACa, is self-evident, but it is worth reiterating here that whilst the premalignant lesions (AEH or EIN) lack clear evidence of stromal invasion, they do display cytological atypia which often is more pronounced than that of an invasive EACa.1 The importance of this feature, initially blamed as being “highly subjective” for diagnosing AEH by the ECG,16 it has now gained acceptance by the self-same proponents of the EIN taxonomy who withdrew monoclonality in favour of the “standard H&E slides viewed through a routine microscope”.22,23 For, indeed, any difficulty with the definition of cytological atypia should be resolved by improving the diagnostic skills of the students of endometrial pathology.15
Clinical features, aetiopathogenesis and treatment of endometrial hyperplasia Endometrial hyperplasia is a prevalent gynaecological disease that affects women from menarche to 75 years and over. In the United States the overall incidence of endometrial hyperplasia (simple, complex and atypical) is 133 per 100,000 women per year24; it is most common in women ages 50e54, and is rarely observed in women under 30 (6 per 100,000 woman per year).24 The disease is usually detected following investigation of abnormal uterine bleeding. The imaging technique most frequently employed for assessing the endometrium, particularly in postmenopausal women, is transvaginal ultrasound. A mean endometrial thickness of >5 mm may indicate the presence of pathology and requires endometrial biopsy or endometrial curettage. From a pathogenetic perspective, any condition resulting in prolonged (more than five years) oestrogenic stimulation of the endometrium unopposed by progesterone action, whether endogenous or exogenous, may cause endometrial hyperplasia. By far the commonest endogenous factor is repeated anovulatory cycles. These occur frequently during the perimenopause, and in women with polycystic ovary syndrome, ovarian cortical hyperplasia or oestrogen-secreting ovarian tumours (granulosatheca cell tumours) e conditions in which there is usually an excess production of androstenedione by the adrenal glands and the ovarian stroma. Androstenedione is converted to oestrone in the adipose tissue and leads to a persistently hyperoestrogenic state. Exogenous risk factors include the long-term administration of noncyclical oestrogens for the relief of menopausal symptoms (estrogene replacement therapy) and the treatment of breast cancer with the synthetic hormone Tamoxifen; this has an antioestrogen effect on the breast, but a pro-oestrogen effect on the uterus. In addition, women with the Lynch syndrome II (hereditary non-polyposis colon cancer) are at a greater risk of developing endometrial hyperplasia and neoplasia. Obesity plays a major contributory role in the development of endometrial hyperplasia and carcinogenesis by increasing the levels of circulating oestrogens. This may be the result of accelerated conversion of androstenedione to estrone or a decrease in the levels of sex hormone-binding globulin (SHBG), the former occurring with considerable frequency. The conversion takes place in the adipose tissues by the enzyme cytochrome p450 aromatase and increases with increasing body weight (increased numbers of fat cells) and with advanced age (increased specific
These somewhat controversial results have prompted a thorough re-evaluation of the design and the criteria used in these studies.2 Thus, the overall strategy to improve reproducibility of the WHO94 classification by reducing the four categories to two7,13,16,21 it would seem to us simplistic rather than simple, for any contraction of the number of diagnostic choices would compromise the evolution of the scientific knowledge, not infrequently, at the expense of the patient’s care15; a hypothetical acceptance of the concept of “endometrioid neoplasia”,7 for example, would lead to overtreatment. With regard to the validity of the EIN criteria, this deserves more than a passing comment. Thus, monoclonality (a most important feature in the EIN classification)16 is only suggestive, but not conclusive, of endometrial neoplasia as it occurs with greater frequency in simple endometrial polyps, endometriotic cysts and in CEH without atypia; in the small sample of Mutter’s et al. study16 only two of the four AEH were monoclonal. Neither a size of greater than 1 mm2 in diameter nor an increased gland to stroma ratio are, in themselves, evidence of neoplasia: lesions smaller than 1 mm2 occur early in neoplastic disease; glandular crowding is the sine qua non of CEH, whilst many AEHs (EIN) or EACas may not conform to this stereotype. The exclusion of other conditions that present with abnormal uterine bleeding,
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aromatase activity). Interestingly, the factors of ageing and obesity appear to be additive. Other oestrogen-related factors which may provide an added growth stimulus to the endometrium include the reduction in average parity, the early onset of menarchy and the late onset of menopause, which increase the life-time exposure of the endometrium to endogenous oestrogens, and the presence of diabetes and hypertension, although probably only among obese women. With regard to treatment, it is generally agreed that EHs without cytological atypia should be treated with progestins alone. It is also agreed that the primary mode of treatment for patients with AEH is by surgical excision, although high-doses of progestins for a duration of no less than six months may be offered to young women who wish to retain fertility.
a single circumscribed nodule of large size (4 cm on average) which, not infrequently, lies in the myometrium. The histology of such lesions, although resembles a normal proliferative or hyperplastic stroma, may reach a mitotic rate of up to 10 per highpower fields, and there is fusion of the gene JAZF1/JJAZ1 caused by a t(7;17)(p15;q21) translocation.27
Conclusion This discussion indicates that the human endometrium responds to unopposed estrogenic stimulation in three different ways: by proliferation of both glands and stroma (SEH), proliferation of only the endometrial glands (CEH, AEH, EACa) and/or by proliferation of only the endometrial stroma (STH, endometrial stromal neoplasms). SEH is the most common form of pathological proliferation in the endometrium, representing a genuine hyperplastic lesion. CEH and STH are also hyperplastic lesions, though less typical, in the sense that only one of their two main structural components are proliferating. AEH is probably a neoplastic (precancerous) lesion having a high incidence of progression to EACa. It should be separated from the other forms of hyperplasia by the presence of nuclear and cytoplasmic atypia, and from EACa from the lack of myometrial and/or stromal invasion. Stromal hyperplasia should be distinguished from endometrial stromal nodule and other stromal neoplasias from its small size, intraendometrial location, the multiplicity of the lesion and its lack of invasion. A
New perspectives This account on endometrial hyperplasia would not be complete without considering a rather under-recognized hyperplastic process which does occur in the endometrium and which specifically affects the endometrial stroma; it is the so-called focal endometrial “stromal hyperplasia”. The existence of such a lesion challenges the traditional view that endometrial proliferations, consisting solely of stromal cells, are invariably neoplastic. It is worth recalling here, that all proliferative lesions in the endometrium arise from two main structural components, the endometrial glands and the endometrial stroma, either of which, alone or in any combination, have the potentiality to undertake intense proliferation and growth affording three possible morphological patterns: (i) proliferation of both glands and stroma, (SEH), (ii) proliferation that is restricted to the endometrial glands (CEH, AEH, EACa), and (iii) proliferation restricted to the endometrial stroma e a pattern which, by convention, it has been taken as being invariably neoplastic (endometrial stromal nodule, low-grade endometrial stromal sarcoma, undifferentiated sarcoma), but which recent evidence indicates that may at times be hyperplastic. For indeed, EHs consisting solely of stromal cells were only exceptionally reported in the literature,25 largely because these lesions are not considered as a pathological entity distinct from the endometrial stromal nodule and the low-grade endometrial stromal sarcoma. Stewart et al. reported the first recognized hyperplastic lesion of endometrial stromal cells,25 and three similar cases were reported from our own laboratory recently.26 “Endometrial stromal hyperplasias” are invariably of small size (0.2e0.8 mm diameter), intra-endometrial in localization, multifocal in distribution, and have a tendency to become polypoid or to localize in a pre-existing polyp. They are formed of small uniform spindle-shaped cells of increased cellularity, having a remarkable similarity with the normal proliferative type stroma. There is lack of cytological atypia, mitotic activity or vascular invasion. Immunohistochemically, the stromal cells are usually positive for CD10, vimentin, oestrogen and progesterone receptors, but are negative for smooth muscle actin, desmin and usually for c-kit.27 A specific molecular genetic change is the translocation t(6;14)(p21;q24). The possibility of an endometrial stromal nodule or a low-grade endometrial stromal sarcoma should always be excluded. Features favouring neoplasia include
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