Endometrial hyperplasia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] , Soujanya Thummathati, MBBS [3]

Overview

Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio. The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.

Pathophysiology

Pathogenesis

• Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio.
• The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.
• Normal endometrial changes during menstrual cycle:
  • The proliferative phase is the second phase in normal mentrual cycle when estrogen causes the lining of the uterus to proliferate. As the ovarian follicles mature, they begin to secrete increasing amounts of estradiol and estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium.
  • After ovulation, the remains of the dominant follicle in the ovary become a corpus luteum which produces large amounts of progesterone.
  • Anovulation results in the prolonged release of estrogen and the relative lack of progesterone resulting in excessive stimulation of the endometrium.
• Unopposed estrogen stimulation may be either from an endogenous or exogenous source.
  • Excessive endogenous estrogen in pre or perimenopausal women may result from chronic anovulation caused by obesity, polycystic ovary disease, and estrogen producing tumors (e.g. granulosa cell tumor).
  • Excessive exogenous estrogen may result from hormone replacement therapy or non-prescription herbal medications.
• Tamoxifen therapy in breast cancer patients results in an endometrial lesion within 6-36 months of therapy.
  • Tamoxifen is a non-steroidal anti-estrogen that binds to the estrogen receptor and is used primarily for adjuvant therapy in breast cancer
  • Tamoxifen may also act as an estrogen agonist in a low estradiol environment
  • Any patient who develops bleeding while on tamoxifen needs evaluation
• Endometrial hyperplasia may rarely result from the peripheral conversion of androgens to estrogens in androgen-secreting tumors of the adrenal cortex.

Genetics

It is assumed that there is association between endometrial hyperplasia and DNA repair gene (XPD, XRCC4, and XRCC1) polymorphisms. After experiments, it became evident the DNA repair gene XPD and XRCC4 polymorphisms had a role in the pathophysiology of endometrial hyperplasia.

Other Genes involved

• Oncogene bcl-2 in complex hyperplasia

mutations in PTEN and KRAS. [22, 39, 40] PTEN tumor suppressor gene mutations have also been found in 55% of hyperplasia cases and 83% of hyperplasia cases once it has progressed to endometrial cancer.

• Fas/FasL gene also has been investigated recently in the development of endometrial

Mtor Signallin pathway

• mTOR signaling is required for estrogen-mediated growth of endometrial cells
• Dysregulated mTOR signaling leads to female infertility due to defects in ovarian, oviductal, and endometrial functions .

Gross pathology

Endometrial hyperplasia typically represents as: 

• A thickened endometrial stripe on transvaginal ultrasound
• Increased volume of endometrial tissue on hysteroscopy or curettage,
• Hyperplasia may be associated with abundant endometrial tissue, the amount is typically equal to that observed in normal secretory-phase
• In some instances, localized hyperplasia may mimic a polyp, arise in a background of a polyp, or involve adenomyosis, including deep foci (the outer half of the myometrium).

Microscopic Pathology

• Prolonged estrogenic stimulation results in larger, more complex, and proliferating endometrial glands.
• On microscopic histopathological analysis, the proliferating endometrium is characterized by the following:

Character	Simple hyperplasia	Complex hyperplasia
Gland to stroma ratio	Normal or slightly increased	Increased
Endometrium	Irregularly dilated cystic glands Out‐pouching, infoldings, and budding of the glands may be present	Glandular crowding Luminal outpouching of glands
Mitoses	May or may not be present	Typically present
Location	Generalized	Focal
Nuclear atypia	Not seen	Not seen

Endometrial hyperplasia is morphologically defined as proliferating endometrium with architectural abnormalities. These architectural changes range from cystic dilatation to more complex glandular configurations, including budding and branching, papillary infoldings, villous and villoglandular growths, and cribriform structures. In addition to abnormal architecture, a diagnosis of hyperplasia usually requires increased glandular density with a gland-to-stroma ratio of ∼3:1 ( Figure 1 ). Some authors have proposed a lower gland-to-stroma ratio (>2:1), but because a variety of nonhyperplastic processes might exhibit a gland-to-stroma ratio that can approach this level (eg, focal artifactual compression of glands in curettage specimens, benign endometrial polyps, disordered proliferative endometrium, and occasionally pronounced morular metaplasia in the absence of glandular hyperplasia), the 3:1 threshold decreases the likelihood of overdiagnosis of hyperplasia, with minimal if any risk of underdiagnosing a lesion that is at risk for progression. We do not include disordered proliferative endometrium in the classification of endometrial hyperplasia because there is no evidence that it poses a risk for progression to carcinoma.

Luminal spaces and villoglandular structures are both included in the glandular component for this calculation. If the gland-to-stroma ratio fails to meet the required cut-off, a lesion is probably best classified as disordered proliferative endometrium rather than hyperplasia. In most instances, the constituent cells are larger than those of normal endometrium and exhibit proliferative features, including nuclear pseudostratification and increased mitotic rate ( Figure 2 ); in the absence of the latter features, a metaplastic endometrial process should be considered. Figure 1 Endometrial hyperplasia. There is gland crowding with a resultant gland-to-stroma ratio of ≥3:1. This feature is best detected on low magnification. Figure 2 Endometrial hyperplasia. Cells are enlarged (relative to the uninvolved normal endometrium, if present) with enlarged nuclei and nuclear pseudostratification, and mitotic figures are typically present (although not depicted in this image). Benign mimics (eg, florid secretory or gestational endometrium) can be excluded by evaluating suspected hyperplasic proliferations on higher magnification.

Although hyperplastic endometrium might have cytologic atypia, this criterion is neither required nor sufficient for this diagnosis. The assessment of cytologic atypia is poorly reproducible, but the various criteria include nuclear rounding and enlargement, nuclear pleomorphism, loss of polarity, increased nuclear-to-cytoplasm ratio, prominent nucleoli, irregular nuclear borders, vesicular chromatin, and clumped chromatin. Atypical cells may show tufting and focal stratification, although extensive nuclear stratification merits a diagnosis of malignancy. Hyperplastic endometria with cytologic atypia pose a more significant risk for endometrial adenocarcinoma than hyperplastic endometria without atypia.

Although the morphologic features of hyperplasia usually occur in concert with increased overall volume when compared with the background endometrial tissue, in rare instances the architectural criteria for hyperplasia are satisfied in the absence of increased volume. Isolated foci of hyperplasia may also be identified in a background of otherwise unremarkable endometrium (“focal hyperplasia”); their significance is uncertain.

Hyperplasic endometria are often associated with a variety of metaplasias. The latter signify the presence of epithelial cell differentiation not ordinarily identified in endometrial cells or only in a minority of them (eg, ciliated cells). Squamous metaplasia ( Figure 3 ) and ciliated cell change ( Figure 4 ) are the most common, although eosinophilic ( Figure 5 ), mucinous ( Figure 6 ), papillary ( Figure 7 ), and clear cell or hobnail cell changes also occur. Mixed patterns of metaplasia are common ( Figure 8 ). Squamous metaplasia can be extensive, filling and expanding hyperplastic glands ( Figure 9 ), further architecturally complicating the crowded appearance of the lesion. Importantly, the presence and extent of these metaplasias have no bearing on prognosis and should be ignored when assessing for associated carcinoma. Other histologic features frequently seen in association with hyperplasia include ectatic blood vessels and stromal breakdown. Figure 3 Squamous metaplasia. (A) A spindled morular proliferation within the lumen of the endometrial glands is the more common type of squamous metaplasia and can be seen (rarely) in atrophic endometrium, disordered proliferative endometrium, endometrial hyperplasia, and carcinoma. It can be confused with squamous proliferations of the uterine cervix. (B) P16 positivity is seen. This finding may further pose differential diagnostic problems with cervical proliferations. Figure 4 Ciliated cell metaplasia. Ciliated cells are present in normal endometrium, but increase under estrogenic stimulation. The terms “ciliated cell change” or “ciliated cell prominence” have been proposed because their presence does not strictly qualify as a metaplastic process. Figure 5 Eosinophilic cell metaplasia. Note slightly enlarged nuclei and small nucleoli. Figure 6 (A) Mucinous metaplasia closely simulates endocervical mucinous epithelial cells and can be mistaken for an endocervical process (and vice versa). (B) The cells have tall cytoplasm and compressed basally located nuclei. A key that the lesion may be endometrial is the presence of other types of metaplasia, typically eosinophilic cell metaplasia. Figure 7 Prominent papillary change. The cytologic features are bland and the cells often have abundant eosinophilic cytoplasm. Figure 8 Mixed patterns of metaplasia. In this example, ciliated cell and eosinophilic cell changes are present within glands that exhibit complex architecture, but there is no overall increase of the gland-to-stroma ratio. Figure 9 Extensive morular metaplasia. The squamous cells fill the glands to the extent that their outer contours are essentially obliterated, imparting the appearance of infiltration into the adjacent stroma.

World Health Organization classification system

The most commonly used classification system for endometrial hyperplasia was outlined by the World Health Organization (WHO) in 1994 ( Table 1 ). The classification criteria used in this system derived from the 1985 study by Kurman and colleagues, which correlated morphologic features with clinical outcome. This study showed a 23% risk of progression to carcinoma for atypical endometrial hyperplasia but only 2% for nonatypical hyperplasia, informing the rationale for separating atypical and nonatypical hyperplasia. In this system, hyperplasias are further subdivided into “simple” and “complex” based on architectural features, although the subdivision has a less dramatic bearing on prognosis than the presence or absence of cytologic atypia. The latter has been linked to a 20-30% progression rate to carcinoma in subsequent reports.

Table 1 World Health Organization classification of endometrial hyperplasia Simple hyperplasia without atypia Complex hyperplasia without atypia Simple hyperplasia with atypia Complex hyperplasia with atypia

The four categories of endometrial hyperplasia recognized by the WHO classification schema are (1) simple hyperplasia without atypia, (2) complex hyperplasia without atypia, (3) simple atypical hyperplasia, and (4) complex atypical hyperplasia. 1 Simple hyperplasia without atypia

Simple hyperplasia is characterized by densely packed, cystically dilated, variable sized glands separated by normal intervening stroma ( Figure 10 ). Although the glandular patterns in simple hyperplasia may be similar to what is observed in disordered proliferative endometria, the later fails to meet the 3:1 gland-to-stroma ratio. Ciliated cells are often quite prominent and squamous morular metaplasia might occur. Figure 10 Simple hyperplasia. Minimally branched, closely packed glands with a gland-to-stroma ratio of 3:1 are seen.

Simple hyperplasia can be distinguished from cystic atrophy and normally occurring patches of inactive glands based on cytologic features. Hyperplastic glands are composed of columnar cells with pseudostratification and include mitotic figures, whereas atrophic/inactive glands bear a single layer of mitotically inactive flattened or cuboidal epithelium. 2 Complex hyperplasia without atypia

Complex hyperplasia without atypia is defined as glands with abnormal, irregular architecture set in a background of scant intervening stroma that is generally less prominent than in simple hyperplasia. Some stroma must be present, however, and even in cases where glands are apparently back to back, close examination reveals basement membrane lining individual glands and a rim of intervening endometrial-type stroma between them. In addition to back-to-back and cribriform-like arrangements, other glandular architectural abnormalities warranting designation of complex hyperplasia include outpouchings, infoldings, and budding ( Figure 11 ). Squamous or morular metaplasia as well as eosinophilic and ciliated cell changes are common. Complex hyperplasia may be seen next to areas showing simple hyperplasia. Figure 11 Complex hyperplasia. Increased gland-to-stroma ratio (≥3:1) and gland complexity—caused by branching, outward budding, internal papillary infoldings, or internal bridges—are depicted.

Cytologically, the epithelial cells are identical to those seen in simple hyperplasia and are characterized by pseudostratification (one to four layers of cells including focal tufting), smooth oval nuclei with evenly dispersed chromatin, inconspicuous nucleoli, and a variable number of mitoses ( Figure 12 ). These features are reminiscent of those seen in normal proliferative endometrial cells except for the nuclei that are often larger in hyperplasia. Figure 12 Hyperplastic glands (either simple or complex) are composed of enlarged cells (relative to normal endometrial cells) with enlarged nuclei, nuclear pseudostratification, and mitotic figures. However, the nuclear membranes are smooth and the chromatin is evenly dispersed. Nucleoli may be present, but they are small and rather indistinct.

3 Simple atypical hyperplasia

The finding of endometrial glands showing cytologic atypia in the absence of architectural complexity is rare. Criteria for nuclear atypia in this setting mirror those required for complex atypical hyperplasia and are described below. 4 Complex atypical hyperplasia

Most cases of atypical endometrial hyperplasia fall into this category, which is differentiated from complex nonatypical hyperplasia solely on the basis of cytologic abnormalities ( Figure 13 ). Unlike the smooth, oval nuclei seen in nonatypical hyperplasia, atypical nuclei are rounder and may have irregular membranes. Chromatin is often unevenly dispersed and clumpy, imparting a vesicular appearance, and enlarged nucleoli are seen (perhaps the most reproducible criterion for atypical endometrial hyperplasia). True stratification with loss of polarity in relation to the basement membrane is common and differs from the pseudostratification seen with nonatypical hyperplasia. Apoptotic bodies may be seen. Figure 13 Atypical hyperplasia. Distinct nucleoli, nuclear pleomorphism, irregular nuclear membranes, and dispersed or clumpy chromatin define this type of hyperplasia.

Neither the degree nor the extent of atypia needed to establish the diagnosis of atypical hyperplasia is well specified, but in general, atypia should involve a significant proportion of the hyperplastic proliferation rather than an isolated focus to warrant this diagnosis ( Figure 14 ). However, occasional curettage specimens may contain glandular tissue with marked complexity, but only focal cytologic atypia. In these instances, we classify the architecture (eg, complex hyperplasia, borderline, or carcinoma—see below) and note the degree and extent of atypia. The surrounding stroma is typically compressed, but may appear fibrous or exhibit features of stromal breakdown (the latter may artifactually increase the apparent gland-to-stroma ratio). Stromal foam cells may also be seen and help to localize the proliferation to the endometrium (vs cervix) in cases in which the morphologic features are ambiguous.

Figure 14 Atypical hyperplasia. There is extensive atypia in this proliferation. The significance of small foci of atypia set in a hyperplasic process that is otherwise banal is uncertain.

Although the criteria appear straightforward, the application of this system can be difficult in clinical practice. The determination of cytologic atypia is particularly troublesome and accounts for a considerable lack of reproducibility in the classification of endometrial hyperplasia (interobserver variability in the classification of simple vs complex hyperplasia also exists, but this distinction does not appear to carry the same clinical import). An additional confounding factor in the practical application of these criteria is the observation that occasional low-grade endometrial adenocarcinomas (and presumably their precursor lesions) exhibit minimal cytologic atypia; this is particularly a problem with complex mucinous endometrial proliferations.

Gallery

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  Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle

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  Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands