1)EIN differs from normal tissues.
EIN are bona fide neoplasms, comprised of a monoclonal outgrowth of a single
transformed cell 1-3 from a polyclonal source field. These
benign expansile clones have only a marginal advantage beyond normal endometrial
tissues, and in the absence of additional genetic damage lack the ability to
invade or metastasize. Lesions with microsatellite instability have marker
genotypes different than normal source tissues 4 .
2)EIN shares some, but not all features with carcinoma.
Cells in the early stages of endometrial carcinogenesis should have some
features which distinguish them from normal tissues, and whose retention during
progression establishes them as the physical progenitors of carcinoma. Both EIN
and endometrial carcinoma are monoclonal lesions, and those markers
characteristic of monoclonality (nonrandom inactivation of a particular X
chromosome copy, presence of a particular altered microsatellite) are conserved
between the EIN and carcinoma lesions of individual patients 1-3;5 .
High densities of acquired markers in microsatellite unstable disease has
permitted detailed lineage reconstruction, including hierarchical sequencing of
events 4 . Genetic alteration of specific genes implicated in
endometrial carcinogenesis has been shown to be conserved between EIN and
carcinomas which occur in individual patients. This is true for inactivation of
the PTEN tumor suppressor gene 6-8 , mutation of the KRAS oncogene 9-11
, epigenetic inactivation of the DNA repair gene MLH1 12 . 63% of EIN
lesions have lost the ability to express the tumor suppressor protein from the
PTEN gene, a phenotype shared with over 80% of endometrial cancers 8;13 .
3)EIN can be diagnosed.
Computerized morphometry of H&E stained slides of genetically ascertained
precancers (monoclonal, markers shared with associated carcinoma) has identified
discrete features which distinguish EIN 5 . In this system, cytologic
and architectural characteristics of H&E stained tissues are measured to
calculate a “D-Score” which indicates EIN when less than a threshold of 0 5;14
. These are presented elsewhere as a series of diagnostic criteria which can be
taught to practicing pathologists for application in a routine diagnostic
setting using H&E slides and a regular microscope. The option of objective
EIN diagnosis by computerized image analysis assures standardization of EIN
diagnosis in investigational studies carried out between multiple
institutions.
4)EIN increases risk for carcinoma.
Available clinical outcome studies have applied image analysis of pathologic
endometria to identify subsets of women with EIN and correlated this diagnosis
with future or concurrent carcinoma. 18/68 women evaluated in a multicenter
study developed endometrial adenocarcinoma during 10-20 years of clinical
followup. All 18 patients who developed cancer had EIN (D score <0)15.
Overall prediction of future carcinoma by morphometry-diagnosed EIN (D-score
<0) is 100% sensitivity and 78% specificity 15 , a result that is independently confirmed in
another multicenter clinical
outcome study 14 . In a related study, prediction of co-existent
carcinoma (10/45 patients) by morphometry-diagnosed EIN (D-score <0) is 100%
sensitive and 88% specific 16 .
5)Genetic and hormonal mechanisms of carcinogenesis converge in EIN.
Endometrial expression of the tumor suppressor gene PTEN normally increases in
an estrogenic environment 17 . This functional requirement for
increased tumor suppression activity of PTEN under estrogen rich conditions
cannot be met in PTEN-defective EIN lesions. Thus, most EIN lesions (those 63%
with lost PTEN protein) will have a defective tumor-suppressor response to
estrogens.
6)Introducing EIN genotype into an animal produces premalignant lesions and
heightened cancer risk.
63% of EIN lesions are comprised of cells which are defective in production of
the PTEN tumor suppressor gene product 8;13 . An association between
compromised PTEN function and endometrial cancer risk is further supported by
animal studies. Heterozygote PTEN mutant mice uniformly (100%) develop
endometrial “hyperplasia,” and 21% of these progress to carcinoma 18.
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