Case 1 -
PRO: EIN is Superior to WHO in the Diagnosis and Management of Precursors of Endometrioid Adenocarcinoma
Marisa R. Nucci, Brigham & Women’s Hosp, Boston, MA
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59 year old with postmenopausal bleeding; endometrial sampling.
Since the turn of the twentieth century, pathologists have attempted to categorize the spectrum of
endometrial glandular proliferations in order to distinguish normal (proliferative phase) from those
proliferations that are not diagnostic of carcinoma. The terminology used to describe these lesions has
changed many times and new definitions have been applied to the same term, which has led to diagnostic
confusion. In a attempt to clarify a diagnostically difficult area, a classification scheme
 was endorsed by the WHO, which divides endometrial hyperplasia into four categories based
on morphologic criteria alone, namely architecture and cytologic atypia. These four categories as issued
by the WHO in 1994, and carried forward unchanged in 2003 include: simple hyperplasia without atypia,
simple hyperplasia with atypia, complex hyperplasia without atypia and complex hyperplasia with atypia.
There have been innumerable proposed modifications of this 4-class WHO system before and since, both in
terminology and number of categories, but the EIN proposal is the only one that is based upon new
experimental evidence and precisely defined H&E diagnostic criteria.
New biologic data: there are two diseases.
This WHO94 classification system continues to be the most widely used system today in diagnostic
practice; however, since 1995, important evidence has emerged which requires integration into practice
under a new scheme. These new data includes objective morphometry, which has the advantage of high
reproducibility and the ability to separate component variables and assess their importance
independently.  In addition, molecular genetic assessment of precancer characteristics such
as monoclonal growth, acquisition of mutations, and documentation of lineage continuity with subsequent
carcinomas has been informative in definitive identification of individual examples of
This new data set has confirmed that there are two biologic processes that
need to be diagnosed: 1) hormonal field effect, an exaggerated but not uncontrolled form of a natural
process (estrogenic stimulation) that affects all cells within the endometrial compartment (polyclonal
process) and 2) endometrial precancerous change, a monoclonal neoplasm of uncontrolled proliferation that
arises from a transformed cell. Initial proposal of the 2-class diagnostic terminology employing EIN as
the moniker for the precancer group was done by an international panel of 17 gynecologic pathologists
(The Endometrial Collaborative Group) in response to the newly generated data above.
New diagnostic criteria for two diseases:
As part of this new evidence, key parameters – lesion size, lesion architecture and
relative standard of cytologic appearance- were objectively identified de novo by correlation of these features with: 1)fundamental biologic properties
(clonal growth and continuity with cancer), and 2) clinical cancer outcomes.
done using fragmented curetting and pipelle biopsy specimens. As it turned out, the histologic features
discovered by these independent correlations with either molecular properties or clinical cancer outcomes
were identical. Such objectively defined morphologic features thus were concordant with this newly
defined biologic model, as well as the need to manage patients based upon clinical outcomes. The
discovered features, which were never part of the WHO criteria set, were expressed as diagnostic criteria
for routine histopathologic diagnosis of the precancerous lesions, which were called EIN (Table 1).
Subjective application of these criteria has similar diagnostic performance to the more sophisticated
morphometric and molecular approaches which are impractical in a routine clinical setting. 
Table 1. EIN Diagnostic Criteria.
|EIN Criterion ||Comments|
|Architecture ||Area of glands greater than stroma (volume glands >50%)|
|Cytology ||Cytology differs between architecturally crowded focus and background|
|Size >1 mm ||Maximum linear dimension in 1 fragment exceeds 1mm.|
|exclude mimics ||such as normal LUS and basalis, secretory endometrium, artifact.|
|exclude cancer ||cancer if (nonsquamous) solid, villoglandular, or maze-like architecture.|
Validation of EIN diagnostic criteria
These objective diagnostic criteria, which can be assessed by routine H&E examination, have been
subsequently clinically validated:
1) Patients with EIN have a significant risk of
concurrent carcinoma. A recent Gynecologic Oncology Group trial of immediate hysterectomy
in women diagnosed with EIN on endometrial biopsy or curettage shows 38% (of 148 patients with EIN) had
concurrent adenocarcinoma at the time of hysterectomy. 
Of these cancers, 67% (37/55) had no
myoinvasion, 25% (14/55) had myoinvasion within the inner half of the myometrium and 7% (4/55) had deep
myoinvasion into the outer half of the myometrium;
2)The risk of developing endometrial cancer is
significantly increased in women with EIN.  Cancer outcomes that occur more than one year
after an EIN diagnosis support the bona-fide progression from pre-malignant to malignant tumor.
Progression to cancer more than one year following a diagnosis of EIN is 45 times more likely compared to
women without EIN. A recent study by Lacey et al  states that atypical hyperplasia and EIN
have equivalent risk of cancer outcome; however, a revised 2-class form of hyperplasia (which is not the
same as WHO94) is used, similar to EIN. Diagnostic drift also emerged as a phenomenon in the Lacey
study, where there was no correlation between community and expert "WHO" atypical hyperplasia diagnosis,
but the academic expert diagnosis of atypical hyperplasia was highly correlated with expert EIN
3) Excluding EIN has a strong negative predictive
value for a cancer outcome.  EIN outperforms cancer prediction when compared
to WHO hyperplasia criteria. In a study of 97 endometrial biopsies initially diagnosed by WHO criteria
and re-diagnosed by EIN criteria shows all 8 cancer outcomes followed a diagnosis of EIN; however, 2/8
cancer occurrences were seen in the non-atypical hyperplasia group. These criteria are also
diagnostically reproducible, with kappa values ranging
from 0.73-0.90 , even in a study including only diagnostically challenging
Limitations of WHO94
In diagnostic practice, the four tiered WHO scheme lacks reproducibility as the histologic criteria
are largely subjectively defined. Reproducibility of the critical assessment of atypical cytology is
low, even among expert gynecologic pathologists.
This is even more dramatically evident
between expert gynecologic pathologists and the community, as data from a Gynecologic Oncology Group
study showed that the WHO94 diagnostic criteria are commonly misinterpreted in the community, as almost
30% of cases submitted as complex atypical hyperplasia were diagnostic of adenocarcinoma upon expert
review, while an additional 25% were considered non-atypical hyperplasia or benign.  This is
mirrored in a more recent study in which the diagnosis rendered in the community significantly different
from two panels of expert gynecologic pathologists.  Another limitation is that the four
diagnostic entities of WHO94 do not correspond to biologically distinct and clinically relevant
clinicopathologic groups, which is reflected by the tacit acceptance in the literature (and increasingly
in practice) to collapse simple hyperplasia with atypia and complex hyperplasia with atypia into one
diagnostic subgroup of atypical hyperplasia.
Evaluation of cytologic atypia
represents the key histologic criterion in this collapsed WHO scenario, a problem because it is so poorly
reproducible as a single variable, and because it ignores the substantial diagnostic value of lesion
Benefits of EIN
There seems to be a practical consensus amongst expert gynecologic pathologists that fewer
than four diagnostic entities should be diagnosed, and there is an observed trend for drift towards
practice of EIN style criteria amongst experts aspiring to implement this goal (as shown in the Lacey
study). The EIN classification system, unlikeWHO94, is tailored to this purpose, using objectively
defined diagnostic criteria which accurately identify clinically relevant precancerous endometrial
lesions. It is easy to use with substantial diagnostic reproducibility. With the EIN classification
system, endometrial precancers are distinguished from benign hormonal changes (termed benign endometrial
hyperplasia), which not only reflects a more accurate understanding of the pathophysiology of endometrial
carcinogenesis, but also has a more practical binary diagnostic scheme – is it premalignant or not?
Consolidation of current routine diagnostic practices under an EIN umbrella will not solve the problem
of predicting which individual precancer will progress based on its histologic appearance. While it is
possible that adjunctive biomarker or functional studies could increase overall prediction performance,
this has yet to be realized at a clinically significant level, much less with something that justifies
routine use. Biomarkers such as PTEN can highlight the clonal growth of EIN, but are not necessary (or
even advised) for diagnosis, nor should they modify management decisions of an EIN diagnosed routinely.
Current research is investigating the role of histomorphometry in accurately predicting myoinvasive
tumor, but even if successful must be translated to a non-computerized measure to be practical in the US
.  Whether these studies translate into improved histologic criteria that are validated by
clinical outcome studies remains to be seen and merits further study.
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