Endometrial hyperplasia

AZFAR NEYAZ, JUNIOR RESIDENTSGPGIMS, LUCKNOW

Defined as an increased proliferation of the endometrial glands relative to the stroma, resulting in an increased gland-to-stroma ratio when compared with normal proliferative endometrium.

Risks factors

• Estrogen replacement therapy

• Polycystic ovary syndrome

• Estrogen producing tumours (e.g. granulosa cell tumour).

• Perimenopausal and menopausal period

• Excessive cortical function (cortical stromal hyperplasia)

• Obesity

• Diabetes Mellitus

• Presents with abnormal uterine bleeding

• Most common in postmenopausal women and with increasing age in premenopausal women

• Abnormal findings on cervical cytology

• Detected accidently by endometrial biopsy performed during the course of an infertility workup or before the start of hormone replacement therapy

• Hyperplasia is not usually seen in young women

Clinical Features

• Many classifications of endometrial hyperplasia have been proposed over the years

• The one which has been adopted by the WHO was originally proposed by Kurman and Norris.

• This classification, presently the most widely used

• It is a four-tier classification system that takes into account both cytologic and architectural abnormalities

• This results in four possible categories of endometrial hyperplasia:• Simple hyperplasia without atypia• Complex hyperplasia without atypia• Simple atypical hyperplasia• Complex atypical hyperplasia

Classification

Simple hyperplasia without atypia

• Also known as cystic/ mild hyperplasia.

• Characterized by glands of various sizes and irregular shapes with cystic dilatation.

• Mild increase in the gland/stroma ratio.

• The epithelial growth pattern & cytology are similar to those of proliferative endometrium

• These lesions uncommonly progress to adenocarcinoma (~1%).

• It largely reflect a response to persistent estrogen stimulation.

Complex hyperplasia without atypia

• There is an increase in the number and size of endometrial glands

• Marked gland crowding & branching of glands.

• Glands may be crowded back-to-back with little intervening stroma & abundant mitotic figures.

• Glands remain distinct and nonconfluent, and the epithelial cells remain cytologically normal.

• This class of lesions has about a 3% progression to carcinoma.

Atypical Hyperplasia(Simple and complex)

• Simple atypical hyperplasia is rare.

• Cells with nuclear atypia show loss of polarity and an increase in the n/c ratio

• The nuclei are : Enlarged, Irregular in size and shape Coarse/vesicular chromatin Thickened irregular nuclear membrane Prominent nucleoli

• Nuclei tend to be round as compared with the oval nuclei of proliferative endometrium and hyperplasia without atypia.

Differential microscopic criteria between endometrial hyperplasia and adenocarcinoma

• Studies have raised doubts about the clinical significance of the architectural categories in this classification system.

• Endometrial hyperplasia could be simply subdivided into two broad categories: • Hyperplasia without cytologic atypia • Hyperplasia with cytologic atypia (atypical hyperplasia).

• It has been seen that fewer than 2% of hyperplasias without cytologic atypia progressed to carcinoma, whereas 23% of hyperplasias with cytologic atypia (atypical hyperplasia) progressed to carcinoma. *

Baak JP et al (2001) Prospective multicenter evaluation of the morphometric D-score for prediction of the outcome of endometrial hyperplasias. Am J Surg Pathol 25:930–935

• Another study show that non-atypical hyperplasia (both simple and complex) had a 10% chance of progression whereas atypical hyperplasia (both simple and complex) had a 40% chance of progression to carcinoma. *

• Cytologic atypia appears to be the main characteristic of hyperplasia that determines the risk of progression.

• Although increasing degrees of architectural abnormalities show a trend in increasing the likelihood of progression to carcinoma, these features are not statistically significant.

Lacey JV Jr et al (2008) Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan. Br J Cancer 98:45–53

• In general, the WHO system correlates well with the risk of progression to endometrial carcinoma.

• However, a major limitation of this system is the intra- and interobserver variability in the identification of atypia.

• Thus, grading atypia as mild, moderate, or severe is not recommended, as it is subjective and not reproducible.

•Another drawback of the is that the category of complex atypical hyperplasia includes neoplasms bordering on invasive carcinoma and those that are clearly not invasive.

•Complex atypical hyperplasia is distinguished from grade 1 endometrial carcinoma by the presence of residual endometrial stroma.

•Variability is often noted across pathologists in making this distinction.

•In one study diagnosis of complex atypical hyperplasia made at a community hospital were reviewed by pathologists using WHO criteria; 25 percent of cases were downgraded to less severe histology than complex atypical hyperplasia and 29 percent were upgraded to endometrial carcinoma.*

Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006; 106:812.

• It has been proposed that endometrial proliferations can be broadly divided into two categories based on the molecular genetic analysis of clonality.

• Polyclonal lesions are regarded as a response to an abnormal hormonal

environment –and are designated ‘‘hyperplasia.’’

• Monoclonal lesions, are associated with an increased risk of progression to carcinoma and are designated ‘‘endometrial intraepithelial neoplasia’’ (EIN).

Mutter GL et al (2000) Endometrial precancer diagnosis by histopathology,clonal analysis, and computerized morphometry. J Pathol 190:462–469

• Almost half of apparently normal women, contain a small fraction of mutant endometrial glands.

• This latent phase may persist for years, with continued presence of scattered and interspersed mutant glands.

• Endocrine factors act upon these “latent precancers” to modulate involution, or progression to EIN.

• Transition to EIN requires accumulation of additional genetic damage in at least one “latent precancer” cell

• This cell clonally expands from its point of origin to form a contiguous

grouping of a tightly packed and cytologically altered glands recognizable as EIN.

The endometrial intraepithelial neoplasia classification system was proposed by an international group of gynecologic pathologists in 2000.

1.Mutter GL. Endometrial intraepithelial neoplasia (EIN): The Endometrial Collaborative Group. Gynecol Oncol 2000; 76:287.

Endometrial hyperplasia (EH)

•Changes typically observed with anovulation or other etiology of prolonged exposure to estrogen. •The morphology of EH varies from proliferative endometrium with a few cysts (persistent proliferative endometrium) to bulkier endometria with many dilated and contorted glands.

•In other systems this have been designated as cystic glandular hyperplasia, mild hyperplasia or simple hyperplasia.

Endometrial Intraepithelial neoplasia(EIN)

• A premalignant clonal neoplasm

• Precursor of endometrioid endometrial carcinoma.

• Is not subdivided into Grades.

• Is different than diffuse hormonal effects(benign endometrial hyperplasia)

• EIN system categories do not correspond directly to specific categories in the WHO system, but there is some consistency.

• Most simple and some complex hyperplasias fall into the EH category. • Many complex hyperplasia without atypia and most complex hyperplasia

with atypia fall into the EIN category.

Localized EIN lesion arising within an otherwise unremarkable endometrium

• Clonal origin of EIN lesions is responsible for their localized distribution in the majority of cases at the time of diagnosis.

• Only about 20 percent of EIN lesions at diagnosis have extended to involve the entire endometrial compartment

• EIN lesions emerge from all of these categories, but at differing likelihoods.

• Frequency of different types of hyperplasias is non-equivalent, so they disproportionately contribute to the final EIN pool.

• In all re-diagnosed EIN lesions. • 63% come from the atypical

hyperplasia category; • 27% from the complex non-atypical

hyperplasias, and • 10% from simple non-atypical

hyperplasias

WHO-EIN Discordance

• A cardinal architectural feature is glandular crowding.

• Epithelial crowding displaces stroma to a point at which stromal volume is less than half of total tissue volume (stroma + epithelium + gland lumen).

• It has been proposed that the diagnosis of EIN be made when glandular crowding results in a VPS < 55%.

• EIN lesions tend to cluster with a median volume percentage stroma of about 40% & non-EIN (benign) lesions cluster at a median of ~75%.

• Stromal volume should be measured using computerized morphometric analysis.

• For practicality, routine light microscopic assessment aided by an ocular graticule and a web-based tutorial that correlates patterns of endometrial proliferations has been proposed as an alternative to morphometry.

Architecture

series of calibrated tiles schematically representing glands (light grey circles include combined epithelium and lumen) against a field of dark grey stroma.

• There is no absolute standard for cytologic features of EIN lesions.

• Cytology of architecturally crowded area is different than background or clearly abnormal.

• The manner of cytologic change in EIN varies considerably from patient to patient.

• Changes not be limited to increased variation in nuclear size and contour, chromatin texture, change in nucleoli, change in n/c ratio and altered cytoplasmic differentiation.

• A fixed presentation of cytologic atypia is not a prerequisite for EIN.

• Attempts to define an absolute standard are confounded by the extreme morphologic plasticity of endometrial glandular cells under changing hormonal, repair, and differentiation conditions.

Cytologic features of EIN lesions

Contrasting Lesion & Background

Cytologic Demarcation

Minimum Size

• A minimum number of adjacent glands is required for an accurate assessment.

• The minimum lesion size, to achieve elevated cancer risk, is a diameter of 1mm.

• Lesions of lesser dimensions should be considered sub-diagnostic,

• For purposes of size measurement, the lesion perimeter is defined by that region in which the gland density is sufficiently high.

• Lesion diameter is measured from one perimeter edge to the other within a single fragment.

• Reactive changes may be caused by infection, physical disruption,

recent pregnancy, or recent instrumentation

EIN Criterion 4. Benign Things to Exclude

Artifacts

Apposition of surface epithelium of fragments of proliferative endometrium.

sampling problems like the telescoping artefact.

Endometrial breakdown

• Loss of estrogen leads to mitotically quiescent glands or tissue with massive stromal breakdown

• Altered cytology is due to piling up of epithelial cells unsupported by stroma

• Associated nuclear changes such as loss of polarity which may be accentuated under certain fixation conditions

Endometrial polyps• Polyps typically have dense fibrous stroma

& contain clusters of thick-walled blood vessels

• The cytology is uniform throughout.

• benign polyp lacks a consistent association between dense gland growth and a change in cytology

• When EIN lesions occur within polyps, they have the appearance of a localized lesion, with altered cytology

• Hyperplastic polyps often contain areas of simple and complex hyperplasia.

Classification of endometrial cellular (cytoplasmic) changes:

• Eosinophilic (including syncytial change)• Squamous (squamous metaplasia)• Ciliated cell (tubal metaplasia)• Secretory and clear cell• Mucinous

Tubal metaplasia

Eosinophilic metaplasia.

• EIN needs to be distinguished from well-differentiated adenocarcinoma

• Some cases of well-differentiated carcinoma are difficult to differentiate

• In invasion the endometrial stroma interacts directly with malignant cells and the morphologic changes it undergoes can serve as a means of identifying carcinoma.

There are three useful criteria, which identifies stromal invasion:

(1) an irregular infiltration of glands associated with an altered fibroblasticstroma (desmoplastic response). (2) Confluent glandular aggregates without intervening stroma reflect stromal invasion, at times creating a cribriform pattern.

(3) an extensive papillary pattern.

EIN Criterion 5. Exclude Carcinoma

• The features of invasion must be sufficiently extensive to involve half (2.1 mm) of a LPF to have value in predicting of a biologically significant carcinoma

• If strong evidence of stromal invasion is present in an lesser area

• The quantification criterion does not apply to moderately or poorly differentiated carcinomas.

• The folded sheets of a villoglandular or mazelike architecture obscure individual gland structures required for EIN

• Significant areas of solid or cribriform patterns should raise the question of a well-differentiated carcinoma rather than an EIN

Molecular Genetics and Immunohistochemistry

• A number of molecular genetic alterations including microsatellite instability and mutations in the PTEN tumor suppressor gene and the KRAS oncogene are seen.

• These are also most common molecular genetic alterations in endometrioid carcinoma.

• PTEN tumor suppressor gene is a located on chromosome 10 that acts through an Akt-dependent pathway to suppress cell division ands enable apoptosis.

• PTEN mutations are found at approximately the same frequency in complex atypical hyperplasia and carcinoma and have rarely been described in hyperplasia without atypia.

• Serous carcinoma is the prototypic endometrial carcinoma that is not related to estrogenic stimulation or hyperplasia.

• It usually arises in atrophic endometrium through a precursor lesion called endometrial intraepithelial carcinoma (EIC).

The lesion also has been referred to as carcinoma in situ & uterine surface carcinoma

Studies have demonstrated immunohistochemical overexpression of p53 protein, loss of heterozygosity of chromosome 17p, and corresponding p53 gene mutations in a high proportion of serous carcinomas and EIC.

Endometrial intraepithelial carcinoma (EIC) involving a polyp.

Endometrial intraepithelial carcinoma (EIC).

• EIC is characterized by markedly atypical nuclei, identical to those of invasive serous carcinomas, lining the surfaces and glands of the atrophic endometrium

• The lesion can be very small and focal and is often present on the surface of a polyp

Comparing the WHO and EIN systems — Few studies have compared the diagnostic performance of the WHO and EIN systems.

The available observational data suggest that the EIN system may be better able to predict which lesions will progress to invasive disease

As an example, a retrospective multicenter study compared the performance of the EIN and WHO classification systems for predicting progression of endometrial hyperplasia to endometrial carcinoma

The EIN system was better able to distinguish between lesions likely to progress versus those not likely to progress.

With the EIN system, progression rates for the two categories were: EH (2 of 359 patients [0.6 percent]) versus EIN (22 of 118 patients [19 percent]).

With the WHO system progression rates were : hyperplasia without atypia (8 of 354 patients [2 percent]) versus atypical hyperplasia (16 of 123 patients [13 percent]).

1.Baak JP, Mutter GL, Robboy S, et al. The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system. Cancer 2005; 103:2304.

Baak JP, Mutter GL, Robboy S et al. The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system. Cancer 2005; 103(11):2304-2312.

• The largest clinical follow-up studies of patients with endometrial premalignant disease have been done using computerized morphometric approaches.

• A study published in 2005 in included 674 women with a endometrial hyperplasias diagnosed by the WHO hyperplasia system

• These were stratified by computerized morphometry into EIN and non EIN lesions.

• For patients who remain cancer-free in the first year, they have a 45-fold increased risk of long-term cancer development.

• In a recent nested case-control study the risk of progression to carcinoma was similar after either a diagnosis of EIN or atypical hyperplasia.

• The diagnostic reproducibility of the light microscopic assessment of volume percentage stroma has not been adequately determined.

• Cytologic atypia that allegedly differs from atypia as shown in the WHO classification is required for the diagnosis of EIN and is defined as cytology that differs from normal endometrial glands present in the same sample.

• When compared to a simplified version of the WHO classification system that collapses the four categories into two (hyperplasia and atypical hyperplasia) there are no apparent advantages to the use of the EIN system.

Lacey JV Jr et al (2008) Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies. Cancer 113:2073–2081

• In the future, molecular genetic data will undoubtedly play a role in the classification of these lesions,

• At present since the WHO system is well understood and in widespread use,

• The proposed hyperplasia–EIN classification system is not recommended for clinical practice.