Endometrial Hyperplasia:TerminologicalClassification and Its Survival Impact

Murat DEDE. MD

University of Health Sciences

Gülhane Medical School

Definition of Endometrial Hyperplasia

Proliferation of endometrial glands resulting in a greater gland-to-stroma ratio (>50%) than observed in normal proliferative endometrium

Proliferating glands vary in size and shape, and cells may have cytologic atypia.

Diagnosis of EH::

• Should be reproducible

• Should distinguish neoplastic proliferation from non-neoplastic proliferation

• Should have surrogate markers to determine myometrial invasion in non-hysterectomy specimens

Different classification systems of endometrial hyperplasia

Classifying year Classifying type

1961 Benign hyperplasia Atypical hyperplasia type I Atypical hyperplasia type II Atypical hyperplasia type III

1963 Mild adenomatous hyperplasia Moderate adenomatous hyperplasia Marked adenomatous hyperplasia

1966 Cystic hyperplasia Adenomatous hyperplasia Anaplasia Carcinoma in situ

1972 Cystic hyperplasia Adenomatous hyperplasia Atypical hyperplasia Carcinoma in situ

1978 Cystic hyperplasia Adenomatous hyperplasia Atypical hyperplasia

1979 Hyperplasia without atypia Hyperplasia with mild atypia Hyperplasia with mild atypia Hyperplasia with severe atypia

1985 Simple, nonatypical Complex, nonatypical Simple atypical Complex atypical

WHO (1994) * Simple hyperplasia Complex hyperplasia Simple hyperplasia with atypia Complex hyperplasia with atypia

WHO (2003) (revised)

Proliferative endometrium Simple hyperplasia Complex hyperplasia Complex atypical hyperplasia

EIN (2000) ** Benign or endometrial hyperplasia

EIN Carcinoma

EGW Cyclic endometrium Hyperplasia Endometrioid neoplasia

WHO (2014) *** Hyperplasia without atipia Atypical hyperplasia

WHO 1994 classification

Simple hyperplasia

without atypia

Complex hyperplasia

without atypia

Simple atypical hyperplasia

Complex atypical hyperplasia

Scully RE, Uterine corpus. In: Histological Typing of Female Genital Tract Tumours, 2nd ed., Springer-Verlag, New York 1994. p.13.

The 1994 WHO system correlated with the risk of progression to endometrial carcinomaThere is high interobserver variability across pathologists reviewing the same slides

WHO 1994 classification

Kurman RJ, Cancer, 1995

• The system focused on theglandular/stromal architecturalpattern of the endometrium andthe presence or absence of cytological atypia

• Simple atypical hyperplasiagroup is very rarely seen and itsreproducibility and clinicalrelevance as a category has beenquestioned

Progression to invasive carcinoma

Simple hyperplasia 1%

Complex hyperplasia 3%

Simple hyperplasia with atypia 8%

Complex hyperplasia with atypia 29%

Peter A. Sanderson, Hum Rep Update. 2017

• Both underestimation and overestimation of the severity of the lesion are very common.

• Better criteria and better sampling are needed to improve reproducibility of this diagnosis, particularly if it is to be used for clinical decisions.

WHO 1994 classification

• The most important predictor of progression to (or concurrent) carcinomais nuclear atypia

• Definition of nuclear atypia has relatively poor interobserver agreement

• Among unblinded academic pathologists; the correlation coefficient of nuclear atypia is 0.28

• Interobserver variability improves with increasing specimen volume

• Simple EH with atypia and complex EH without atypia, are relatively rarefindings in the population

• Both are poorly represented statistically in EH studies and are of questionable biologic significance

Zaino RJ, Cancer. 2006Amy J, JMIG, 2012

WHO 1994 classification

• As a result, the subjective nature of this system has meant thatsignificant diagnostic variation occurs between pathologists andoverall reproducibility is poor

• The four-tier WHO94 system does not straightforwardly correspondto the separate therapeutic options available (i.e. surgical, medical orobservational)

• That may contribute to a tendency for surgical overtreatment due tothe fear of malignant progression for lesions with no underlyingsinister mechanism

Peter A. Sanderson, Hum Rep Update. 2017

WHO 1994 classificationSimple hyperplasia Complex hyperplasia

• Consists of glands that are mildly crowded.• Frequently cystically dilated with only occasional

outpouching• Mitoses are typically present in the glandular

cells

• Glands that are crowded (>50% gland/stroma)• The gland-to-stroma ratio is higher in complex

hyperplasia compared to simple hyperplasia• The glands appear disorganized and have luminal

outpouching• Mitoses are typically present

WHO 1994 classification

• Nuclear atypia:

• The presence of nuclear enlargement;

• Clumping of the chromatin

• Prominent nucleoli

• Gland crowding lined by atypical cells

Endometrial intraepithelial neoplasia(EIN) classification

Benign endometrial hyperplasia(EH, non-neoplastic)

Endometrial intraepithelial neoplasia (EIN)

• Changes typically observed withanovulation or other etiology of prolongedexposure to estrogen.

• Polyclonal proliferation

• Endometrial precancers.• Epithelial crowding in EIN displaces stroma

to a point at which stromal volume is lessthan approximately half of total tissuevolume in nonsecretory endometrium

• Typically cells appear morphologicallyclonal and distinct from the surroundingendometrium.

Endometrial intraepithelial neoplasia(EIN) classification

• D-score:

• It is a measure of stromal volume as a proportion of total tissue volume

• D-score = 0.6229+0.0439×(volume percentage stroma)−3.9934×natural logarithm, Ln (SD shortest nuclear axis)−0.1592× (glands outer surface density)

• specimens are classified as

• benign (D >1)

• indeterminate (0< D <1)

• EIN (D <0)

• The D-score is assigned based on evaluation with computerized morphometry.

D-Score

• The EIN classification system, in contrast to the WHO 1994 system, has itsorigins in molecular studies

• The EIN system has not gained widespread acceptance, most likely due tocost and/or lack of experience with the computerized D-scoringcomponent.

• A potential alternative to computerized morphometry is subjective EIN classification

• This approach appeared to correlate well with estimates using thecomputerized D-score

• Hyperplastic biopsies with a score of ≤1 have a high rate of progression toEC, whereas biopsies with a score of >1 almost never progress to EC

Hecht JL, Mod Pathol. 2005Baak JP, Cancer. 2005

Subjective EIN criteria

• Objective EIN criteria are based on a computerized morphometric analysis of:

• gland to stroma ratio,

• glandular perimeter,

• nuclear diameter,

• calculating a prognostic score (D-score)

• Subjective EIN criteria include:

• gland to stroma ratio,

• cytologic differences with the adjacent endometrium,

• lesion dimensions,

• exclusion of mimics and cancer

Interobserver variability for EIN systemcompared with WHO system

Lacey JV, Cancer, 2008

Correlation of WHO and EIN diagnoses

• EIN lesions are defined as monoclonal proliferations of architecturally and cytologicallyaltered premalignantendometrial glands, which areprone to transformation toendometrioid EC

• The EIN mechanism proposesthat genetic alterations withinthe endometrium initially occurat a level undetectable by lightmicroscopy.

Hecht, 2005

1994 WHO vs EIN

Study group Control group

• Women with same age and samediagnosis but did not progress tocarcinoma

CASE-CONTROL STUDY

Conclusion: Among women observed for at least 1 year after receiving a biopsy-basedEH diagnosis, EIN and AH were both found to have similarly increased risks of progression to carcinomaRR to carcinoma for AEH: 9.9 vs. 7.7 for EIN

• 138 patients Incidentally diagnosedwith EH and diagnosed with EC at least 1 year later

All specimens were assigned according to WHO 1994 and EIN classifications withcentral pathology review by experienced panel of pathologists

RETROSPECTIVE COHORT STUDY

• 477 patients diagnosed with EH and EIN and followed up at least 1 year

• Patients who develop EC in the first year are accepted as concurrent carcinoma andexcluded from the study

WHO 1994 system EIN system

• Progression of EH with atypia toEndometrial cancer: 13%

• Progression of EH without atypia toEndometrial cancer: 2.3%

• Progression of EIN to Endometrial cancer: 19%

• Progression of benign pathology toEndometrial cancer: 0.6%

1994 WHO vs EIN

1994 WHO vs EIN

Distinguishinghyperplasia

fromendometrial

carcinoma

• Grade 1 EC has

• invasive pattern of glands infiltrating reactivestroma (the most definitive)

• cribriform glands

• confluent growth (lack of stroma betweenglands)

• Marked nuclear atypia, especially in the context of atrophic background endometrium may be indicative for serous carcinoma or serousintraepithelial neoplasia.

• However, it is still a diagnostic challenge forpathologists to distinguish CAEH/EIN fromendometrial cancer in non-hysterectomy specimens

RETROSPECTIVE COHORT STUDY

• 289 patients diagnosed with AEH underwent hysterectomy within 12 weeks

• Central pathology review both for biopsy and hysterectomy specimens

• The study panel consensus diagnosisfor the biopsies:• “less than AEH” in 25.6% of the specimens• AEH in 39.8% of the specimens• carcinoma in 29.1% of the specimens

• The hysterectomy review showedendometrial carcinoma in 42.6% of specimens

• 25% of cases were downgraded to less severe histology than CAEH

• 29% were upgraded to EC

The European Working Group of Experts –EWG Classification• It was proposed in 1999 to overcome poor reproducibility of the WHO

system

• The EWG classification, established for use only on endometrial biopsy/curettage specimens, has two diagnostic categories• Hyperplasia

• Endometrioid neoplasia

Bergeron, 1999

Features useful in distinguishing between diagnostic categories

WHO 2014 classification

Hyperplasia without atypia (non-neoplastic)

Atypical hyperplasia (endometrial intraepithelial neoplasm)

• The 2015 WHO system is intended to reduce the confusion associated with numerous pathologic terms

• Hyperplasia without atypia is a non-neoplastic change• Hyperplasia with atypia is associated with invasive carcinoma

WHO 2014 vs EIN

• Systematic review of 16 cohort and 3 case-control studies

• 2582 women with EH

• Exclusion criteria:• latency time from EH diagnosis to hysterectomy > 1 year;

• cancer presence assessed by endometrial sampling and not by hysterectomy;

• inclusion of only benign or only premalignant EH;

• classification system other than WHO or EIN;

• EIN criteria assessed solely through morphometric analysis;

• total sample size < 20 EH or sample size <10 in each EH category; reviews;

• overlapping patient data with a study already included.

Travaglino A, Histopathology. 2018

CONCLUSION• Objective EIN system based on computerized morphometry has superior clinical

accuracy compared to WHO classification in identifying neoplastic lesions

• Objective EIN system with computing »D-score» is complex and software depended.

• Subjective EIN criteria have reliability similar to WHO criteria in predicting the risk of coexistent cancer in EH

• WHO criterion of cytologic atypia seems more specific for high-risk lesions and confersthe highest risk of progression to endometrioid EC

FUTURE PROPOSAL:Integration of EIN criteria with cytologic atypia may be considered, being the firstmore appropriate for the initial selection of patients for treatment

Kurman, 1985