VOLUME 24 䡠 NUMBER 29 䡠 OCTOBER 10 2006

JOURNAL OF CLINICAL ONCOLOGY B I O L O G Y O F N E O P L A S I A

Molecular and Pathologic Aspects of

From the Department of Pathology,
Beth Israel Hospital; Department of
Pathology, Brigham and Women’s
Hospital, Boston, MA.
Submitted March 21, 2006; accepted
June 12, 2006.
Terms in blue are defined in the glossary,
found at the end of this article and online
at www.jco.org.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Endometrial Carcinogenesis
Jonathan L. Hecht and George L. Mutter
A B S T R A C T
Endometrial cancer is the most common gynecological malignancy, with 41,000 new cases projected in the
United States for 2006. Two different clinicopathologic subtypes are recognized: the estrogen-related (type I,
endometrioid) and the non– estrogen-related types (type II, nonendometrioid such as papillary serous and clear
cell). The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I
showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing
aneuploidy and p53 mutations. This article reviews the genetic aspects of endometrial carcinogenesis and
progression. We will define the precursor lesion of type I endometrioid cancer and the role of genetics and
estrogen in its progression.
J Clin Oncol 24:4783-4791. © 2006 by American Society of Clinical Oncology

Address reprint requests to Department
of Pathology, Beth-Israel Deaconess
Medical Center, 330 Brookline Ave,
Boston, MA 02215; e-mail: jlhecht@
BIDMC.harvard.edu
© 2006 by American Society of Clinical
Oncology
0732-183X/06/2429-4783/$20.00
DOI: 10.1200/JCO.2006.06.7173
INTRODUCTION
Current concepts of endometrial cancer successfully
integrate traditional histopathology with pathoge-
netic mechanisms. Endometrial cancers have long
been classified into two major divisions (types I and
II) based on light microscopic appearance, clinical
behavior, and epidemiology.1 Type I, those with
endometrioid histology, comprise 70% to 80% of
newly diagnosed cases of endometrial cancer in the
United States.2 They are associated with unopposed
estrogen exposure and are often preceded by pre-
malignant disease. In contrast, type II endometrial
cancers have nonendometrioid histology (usually
papillary serous or clear cell) with an aggressive clin-
ical course. Hormonal risk factors have not been
identified, and there is no readily observed prema-
lignant phase. The morphologic and clinical differ-
ences are paralleled by genetic distinctions, in that
type I and II cancers carry mutations of independent
sets of genes (Table 13-8). Most were identified as
candidate genes by analogy with other tumor sys-
tems, and were confirmed subsequently to be altered
in endometrial cancer. Open-ended gene discovery
by comparison of tumor subsets using genome-wide
methods such as expression profiling has further
broadened our understanding of relevant genetic
basis for these differences.9,10 The result is an en-
hanced understanding of early genetic events, rein-
forcement of the clinicopathologic subgroups
originally defined by histologic and clinical features,
and development of biomarkers informative in
identification of previously unknown or poorly de-
scribed precursor lesions.
In the last decade, progress has been greatest in
molecular and histologic resolution of precursors of
type I cancer, resulting in a cohesive model of endo-
metrial carcinogenesis encompassing both genetic
and hormonal factors, revised precancer diagnostic
criteria, and novel prevention strategies. We will pri-
marily focus on these advances and will describe
ongoing attempts at genetic substratification within
the endometrioid group.
GENETICS OF TYPE I CANCERS
While most serous (type II) cancers contain muta-
tions of p53,3 endometrioid (type I) adenocarcino-
mas demonstrate larger numbers of genetic changes
in which the temporal sequence of mutation, and
the final combination of defects differ substantially
between individual examples. Common genetic
changes in endometrioid endometrial cancers in-
clude, but are not limited to, microsatellite instabil-
ity (MSI),11-15 or specific mutation of PTEN,16-21
K-ras,12,22-28 and ␤-catenin genes.13,29-31
MSI
Approximately 20% of sporadic endometrioid
endometrial cancers of all grades demonstrate a mo-
lecular phenotype referred to as MSI.11,12,15,32 Mic-
rosatellites are short segments of repetitive DNA
bases that are scattered throughout the genome; they
are found predominantly in noncoding DNA. MSI
is the propensity to develop changes in the number
of repeat elements as compared with normal tissue
due to DNA repair errors made during replication.
MSI is rare (⬍ 5%) in type II endometrial can-
cers,33,34 where the primary genetic defect is in the

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 Hecht and Mutter
Table 1. Genetic Differences Between Cancers With and Without Endometrioid Histology
Gene Alteration
p53 Inactivating mutation
PTEN Loss of function through deletion
and/or mutation
K-ras Mutational activation
␤-catenin (CTNNB1) Gain of function mutation
MLH1 Epigenetic silencing causes
microsatellite instability
p53 gene and genetic instability is manifest globally at the chromo-
somal rather than microsatellite level. Thus, type II tumors frequently
demonstrate high-order aneuploidy while having an intact mismatch-
repair mechanism.34,35
MSI is due to inactivation of any of a number of intranuclear
proteins that comprise the mismatch repair system, leading to accu-
mulation of structural changes in coding and noncoding repetitive
elements of many genes.36 MLH1 inactivation, a component of the
mismatch repair system, is the most common mechanism in the
endometrium and is accomplished by hypermethylation of CpG is-
lands in the gene promoter, a process known as epigenetic silencing.5
This mechanism stands in contrast to colon cancer, where MSI is due
to mutations in the MSH2, MLH1, and MSH6 genes.37 Inherited or
somatically acquired mutations of MSH6, another mismatch repair
element, are also common in patients with MSI endometrial can-
cers.34 A single nucleotide insertion (frameshift) mutation in MSH3
has been described less frequently in MSI endometrial cancers with
MSI. This deletion occurs in a string of eight consecutive adenosine
residues (A8). Because simple repeat sequences are unstable in cells
with MSI, the observed mutation may be secondary to the MSI derived
from defective MLH1 expression.38,39 Since MLH1 is important in
repair of short segments (two to four bases), and MSH2:MSH3 serves
to repair larger insertion-deletion mutations, the combined defect of
the mismatch repair system results in inhibition of both small and
large insertion-deletion mismatch repair.40
MSI, and abnormal methylation of MLH1, is an early event in
endometrial carcinogenesis that has been described in precancerous
lesions.11,18,41 Once established within a tumor lineage, MSI leads to
creation of genetic heterogeneity within carcinoma cells of a single
tumor. MSI may specifically target for inactivation those genes which
contain susceptible repeat elements, such as transforming growth
factor ␤receptor type II, (TGF-␤RII), BAX, insulin-like growth factor
II receptor (IGFIIR), and hMSH3, resulting in secondary tumor sub-
clones with an altered capacity to invade and metastasize.42-46 Indeed,
screening of MSI endometrial cancers has shown frameshift muta-
tions in the coding region repeats of FAS, BAX, CASP5, and IGF-␤RII
genes that are infrequent in microsatellite stable cancers.47,48
PTEN
Inactivation of the PTEN tumor-suppressor gene (formerly
known as MMAC1) is the most common genetic defect in endometri-
oid carcinoma and is seen in up to 83% of tumors that are preceded by
a histologically discrete premalignant phase.16 PTEN is a tumor sup-
pressor gene encoding a lipid phosphatase which acts to maintain G1
arrest and enable apoptosis through an AKT-dependent mecha-
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Endometrioid Nonendometrioid
(type 1; %) (type 2; %) Reference
5-10 80-90 3, 8
55 11 6
13-26 0-10 3, 7
25-38 Rare 7
17 5 4, 5
nism.49,50 The most commonly observed PTEN defect is inactivation
of both alleles to generate a protein null, or complete loss of function,
phenotype. There is some evidence that even a PTEN hemizygous
inactivation leading to a protein deficient, rather than null state, may
be functionally significant when combined with abnormalities of
other genes which converge on its downstream pathway. PTEN acts in
opposition to phosphotidylinositol-3-kinase (PIK3CA) to control lev-
els of phosphorylated AKT. PIK3CA mutation, seen in 36% of endo-
metrial carcinomas, is most frequent in those tumors which also bear
PTEN mutation.51 This is consistent with a cooperative effect between
these two elements in promoting neoplastic transformation.
PTEN inactivation is a functionally significant in carcinogenesis
as is demonstrated by the high prevalence of endometrial cancer in
PTEN knockout mice. Heterozygous PTEN inactivation produces an
abnormal endometrial phenotype in mice, with 100% of mice develop-
ing hyperplastic lesions, and 20% of animals progressing to endometrial
carcinoma.52 Humans with constitutive germline PTEN mutations may
present with the heritable cancer syndrome of Cowden’s disease, which
includes high rates of breast, thyroid, and other cancers in conjunction
with hamartomas of multiple organs.6 There appears to be an in-
creased risk of endometrial cancer in women with Cowden’s disease,
but only small numbers of these patients have been available for study,
and the magnitude of increased risk is modest.
PTEN inactivation may be caused by a variety of mechanisms.
Mutation, or deletions resulting in loss of heterozygosity (LOH) at
chromosome 10q23, are detected in 37% to 61% of cancers.6,53 The
pattern of PTEN mutation is different in MSI and microsatellite stable
cancers. MSI-positive tumors have a higher frequency of deletions
involving ⱖ three base pairs when compared with the MSI-negative
group. In addition, the mutations observed in MSI tumors only rarely
involve the polyadenine repeat of exon 8 that is the expected target
(containing a microsatellite marker). The mechanism for these MSI
related changes is unknown.40 Promoter methylation has been postu-
lated an alternative transcriptional inactivating event, but has been
difficult to prove experimentally because of technical limitations in
quantification of methylation level and assay interference by a co-
amplified pseudogene.
The PTEN locus on chromosome 10 may be flanked by other
tumor suppressor genes that are codeleted with PTEN itself.54,55
The homeodomain containing gene EMX2 is a strong candidate for
just such a gene.56 Increased native EMX2 expression is associated
with diminished endometrial proliferative activity, a pattern that
might be predicted for a tumor suppressor. Deletion of EMX2,
JOURNAL OF CLINICAL ONCOLOGY
 Molecular Biology of Endometrial Cancer
with commensurate decline in expression, is seen in some endo-
metrial adenocarcinomas.
K-ras
K-ras mutations have been identified in 10% to 30% of type I
endometrial cancers.26,27,57 There is a higher frequency of K-ras mu-
tations in MSI cancers, and many of these are characterized as meth-
ylation related GC 3 AT transitions.28
␤-catenin (CTNNB1)
Gain of function mutations in exon 3 of CTNNB1 gene at 3p21
are seen in 25% to 38% of type I cancers.29-31 These mutations in exon
3 result in stabilization of the protein, cytoplasmic and nuclear accu-
mulation, and participation in signal transduction and transcriptional
activation through the formation of complexes with DNA-binding
proteins.58 ␤-catenin is a component of the E-cadherin-catenin unit
essential for cell differentiation and maintenance of normal tissue
architecture, and plays an important role in signal transduction. In-
creased nuclear levels of ␤-catenin produce transcriptional activation
through the LEF/Tcf pathway.59 The APC protein downregulates
␤-catenin levels by cooperating with glycogen synthase kinase 3␤
(GSK-3␤), inducing phosphorylation of serine-threonine residues
coded in exon 3 of the ␤-catenin gene and its degradation through the
ubiquitin-proteasome pathway.60,61
␤-catenin mutation may represent a pathway to endometrial
carcinogenesis characterized by squamous differentiation and inde-
pendent of PTEN.60,61 Although MSI, PTEN, and K-ras mutations
frequently coexist with each other, these molecular abnormalities are
not usually seen in tumors with ␤-catenin alterations.58 When abnor-
mal, ␤-catenin expression changes are usually seen throughout all tumor
cells, and ␤-catenin changes are present in some premalignant lesions.
This suggests that ␤-catenin mutation is an early step of endometrial
tumorigenesisthatisclonallyrepresentedin all tumor cells.7,64 However,
changes in ␤-catenin activity may contribute to later tumor progres-
sion as well.65,66 Based on analogy with colon cancer, several genes
may be potential targets for a dysregulated WNT/␤-catenin pathway.
For example, in colonic adenocarcinoma, elevated ␤-catenin levels
caused by mutations in CTNNB1 or APC result triggers cyclin-D1
gene expression, and subsequently, uncontrolled progression of tu-
mor cells into the cell cycle.67 ␤-catenin might regulate the expression
of the matrix metalloprotease-7, which would have a role in the estab-
lishment of the microenvironment necessary for the initiation and
maintenance of growth of the primary tumors and their metastasis.68
Nuclear localization (activation) of ␤-catenin is also induced by
the WNT signaling pathway, which is abnormal in some MSI tumors.
Gene expression profiling of cancers with and without MSI shows two
members of the secreted frizzled related protein family (SFRP1 and
SFRP4) as more often downgraded in MSI cancers.69 These proteins
are negative regulators of the WNT signaling pathway. Fibroblast
growth factor 18 (FGF18), a direct target of the WNT pathway, was
upregulated in MSI cancers.
OTHER GENES
The phenotype and behavior of type I cancers are codetermined by
cumulative genetic factors that can include mutations other than
mentioned above.
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p53 is a nuclear phosphoprotein that induces proliferative arrest
or apoptosis through induction of P21Waf1/Cip1 and hMdm2 in
response to cellular stress. Although more common in serous and
clear-cell type carcinoma, aberrant accumulation of inactivated p53
protein is seen in approximately 5% of endometrioid cancers.27 High
protein levels correlate with high grade and stage, but are also an
independent prognostic factor.70 Unlike serous cancers, p53 trunca-
tion mutations are rare in endometrioid tumors.71 In p53 “positive”
endometrioid endometrial tumors, p53 protein accumulation may be
secondary to changes in its upstream regulatory proteins rather than
the p53 gene itself.72 Several genes, including MDM2 and p14 ARF,
that regulate p53 levels have been shown to cause detectable levels of
p53 in the absence of p53 mutation, and their dysregulation may be
associated with adverse clinical outcomes.71-73 Alternatively, nonspe-
cific DNA damage such as that induced by irradiation are also known
to induce accumulation of wild-type p53.74
Other candidate prognostic markers investigated in endometrial
adenocarcinoma have differing degrees of evidence supporting clini-
cal relevance. Many have only been described in in vitro models, and
others fail to achieve a level of clinical outcome prediction indepen-
dent of existing pathologic tumor classification. Expression of
HOXB13, a member of the homeobox (HOX) gene family, is induced
by estrogens in endometrial cancer cell lines and confers invasive
potential.75 High rates of inactivation by promoter methylation of
another homeobox gene HOXA11 correlates with tumor recurrence
in stage I to II cancers.76 E-cadherin functions to maintain cell-to-cell
adhesion and its loss is has been associated with invasive capacity
in breast, esophagus and ovarian cancers.77 Inactivation of the E-
cadherin gene by methylation is present in a subset of cancers and with
increasing frequency at higher stage and grade. In addition to MSI,
inactivation of MLH1 may create a selective growth advantage under
conditions of oxidative stress or cross-linking agents via the deregula-
tion of apoptosis.78 Comparison of expression profiling of endome-
trial cancer cell lines before and after treatment with a demethylation
agent have revealed tumor suppressor genes that undergo epigenetic
silencing through promoter methylation.79 Reported genes include
Tazarotene-induced gene-1 (TIG1) and CCAAT/enhancer binding
protein-alpha (C/EBPalpha).
ROLE OF SEX HORMONES
Estrogens and progestins act reciprocally on the hormonally respon-
sive endometrial tissue field to modify endometrial cancer risk. Pro-
gestins have the ability to abrogate, or “oppose” the biologic effects of
coexisting estrogens through down-regulation of the estrogen recep-
tor itself. For this reason the biologic effects of admixtures of circulat-
ing progestins and estrogens are dominated by the progestational
component. Women exposed to estrogens without opposing effects of
progestins show a dose and duration dependant 2- to 10-fold in-
creased cancer risk.80-83 The protective effects of progestins are evident
in women using combined oral contraceptives, who have a 0.5 to 0.7
endometrial cancer risk relative to controls.84,85 There are several
postulated mechanisms by which sex hormones affect endometrial
cancer risk, and it is likely that all are relevant to varying degrees.
Large-scale expression profiling of endometrial tissue RNAs has
enabled comparison of hormonally induced transcriptional changes
in benign endometrium to those seen in carcinoma.86 The profile of
4785
 Hecht and Mutter
type 1 endometrioid carcinoma resembles the expression profile seen
in estrogen-driven proliferative endometrium and lacks expression of
those genes induced by progestins. Overall, cancers are characterized
by a loss of gene relative to benign endometrium, accounting for eight
of 10 discriminating changes in RNA abundance. Among the genes
with reduced or lost expression in carcinoma are a small number of
tumor-suppressor genes affected by primary mutation or deletion and
a larger number of downstream target genes affected secondarily.
Estrogen promotes cell proliferation and inhibits apoptosis
through a complex downstream cascade of transcriptional changes
that may include modulation of tumor suppressor function. An ex-
ample is PTEN expression in normal endometrial glands, which is
greatly elevated by estrogens and reduced by progestins during hor-
monal fluctuations of the normal menstrual cycle.87 This expression
pattern reflects the role of PTEN as regulator of mitosis and enabler of
apoptosis in the estrogen stimulated proliferative phase. Unopposed
estrogens thus act as positive selection factor for PTEN mutant cells, by
unmasking the inability of mutant compared with wild-type cells to
check the proliferative process. In the presence of circulating proges-
tins, the proliferative advantage of PTEN mutant cells is lost, and as a
result, PTEN mutant clones have a tendency to involute.88 The cancer
protective effects of progestins are further mediated by induction of
apoptosis through the increased expression of Bcl-2 and BAX.89 The
ability of progestins to induce endometrial epithelial apoptotic cell
death extinguishes after just a few days, but increases dramatically on
withdrawal of progestins.90 The net effect cannot be simply viewed as
simple opposition of estrogen and progesterone on a static gland
population, but must also incorporate a dynamic element of changing
tissue responsiveness over time. Estrogens may also increase the rate of
mutagenesis through free radical formation,91 but the magnitude of
this effect is minimal compared with the increased likelihood of ran-
dom mutation conferred by increases in proliferative activity.92
Less specific information is available regarding estrogen influ-
ence on cellular differentiation and growth. PAX2 is a paired-box gene
known to be overexpressed in cancers of the kidney, prostate, breast,
and ovary.93 PAX2 expression is increased by estrogens in neoplastic
endometrial epithelium but not in normal endometrium,94 indicating
that neoplastic tissues have an intrinsically altered estrogen response
mechanism. Whether this is a cause or effect of malignant transforma-
tion is unclear. Endometrial cancer cell line expression of HOXB13, a
member of the HOX gene family can be induced by estrogens and
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imparts invasive potential.75 Cables, a cyclin-dependent kinase bind-
ing protein that is upregulated by progesterone and down-regulated
by estrogen in benign endometrium, is lost in the majority of endo-
metrial cancers. Mice deficient in cables develop hyperplasia and can-
cer, and overexpression in cell lines slows proliferation.95
MODEL FOR TYPE I CARCINOGENESIS
Type I cancers are frequently preceded by pan-endometrial hormonally
induced changes referred to as endometrial hyperplasia, from which a
localized monoclonal population of genetically altered glands emerges
as a discrete premalignant lesion, endometrial intraepithelial neopla-
sia (EIN). In the past, distinction between generalized hormonal field
effects and actual premalignant lesions was obscured by imprecise
diagnostic criteria and a nomenclature system that did not accurately
segregate lesions by natural history. The common term “hyperplasia”
was applied to all entities, with the assumption that nonatypical hy-
perplasia and atypical hyperplasia subgroups correspond to benign
and premalignant. Diagnosis of atypia is itself poorly reproducible96
and architectural features were underutilized as relevant discriminators
between hormonal field effects and premalignant disease. Improved res-
olution was possible with the advent of polymerase chain reaction–based
clonal assays and relevant biomarkers that facilitated a molecular, rather
than purely histopathologic, approach to precancer diagnosis. Careful
correlation of genetically ascertained premalignant disease with his-
topathologic presentation and clinical cancer outcomes launched the
molecular entity of EIN into a clinically relevant lesion that may be rou-
tinely diagnosed by pathologists and used for therapeutic intervention.
Somatic mutation of endometrial glandular cells is very common
in normal endometrium, and occurs in advance of any discernable
histopathologic changes. The term “latent precancer” has been ap-
plied to this condition to emphasize that endometrial cancer risk is not
necessarily increased without additional genetic change and onset of
morphologic change. This preclinical phase of disease is recognizable
only through genetic analysis of mutant cells or identified by biomar-
kers (Fig 1), and may persist through several years of cyclical menstrual
shedding. During that interval, systemic hormonal factors positively
or negatively select for growth of these mutant cells. Inactivation of
the PTEN gene through deletion and/or mutation97 and acquisition
of microsatellite instability33 are two examples of such early genetic
Fig 1. PTEN inactivation is one of the
earliest events in endometrial precancers.
Loss of expression is detectible by immuno-
histochemistry16 in scattered glands of
normal-appearing proliferative endometrium
(A), and carries forward to endometrial intra-
epithelial neoplasia (B) and carcinoma (C). In
each panel, notice the absence of staining in
the neoplastic glands; normal admixed
glands and stroma serve as an internal pos-
itive control.
JOURNAL OF CLINICAL ONCOLOGY
 Molecular Biology of Endometrial Cancer
events documented in otherwise normal appearing endometrium.
The mutant cells in these cases participate in normal monthly endo-
metrial regeneration, and may become widely dispersed by remodel-
ing of the endometrial compartment. More work is needed to define
the long-term behavior of latent phases of carcinogenesis.
Clinically evident premalignant lesions that can be diagnosed
by a pathologist arise as localized clonal outgrowths of cytologically
and architecturally altered endometrial glands that sequentially
acquire additional somatic mutations leading to cancer (Fig 2). The
premalignant lesions are referred to as EIN to distinguish them from
the diffuse estrogen associated changes of benign endometrial hyper-
plasia. EIN is a histologically recognizable localized lesion composed
of a clonal proliferation of glands and that usually carry one or several
of the genetic abnormalities associated with endometrioid carcino-
ma.11,98 Markers that have been informative in clonal evaluation of
putative premalignant endometrial lesions include nonrandom
X-chromosome inactivation (HUMARA assay) and clonal propaga-
tion of altered micosatellites.99,100 Identification of such monoclonal
lesions, combined with demonstration of lineage continuity with sub-
sequent carcinomas that occur in the same patient, provide a robust
standard for molecular definition of precancers.98
Comparison of the extent and range of genomic damage between
premalignant EIN and malignant carcinoma phases indicates a greater
cumulative mutational load in cancers, a feature that must contribute
to their differing morphology and behavior. For example, while 55%
of EIN lesions have demonstrable PTEN inactivating events the pro-
portion rises to 83% in those cancers which follow an EIN diagnosis.16
Similarly, for those lesions with microsatellite instability, the burden
of altered microsatellite alleles increases between EIN and carcino-
ma.11,98 Based on similarities between the length of DNA micro-
satellites in adenocarcinoma and associated EIN in hysterectomy
specimens, Faquin et al4 constructed philogenetic trees linking clonal
foci of EIN to surface cancer and invasive cancer. These findings were
confirmed in a larger series of hysterectomy specimens.98 Although it
is convenient to label PTEN and microsatellite alterations as “early”
events, these genetic targets may in fact be altered in the latent, prema-
lignant, or malignant disease phases.
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PREMALIGNANT EIN LESIONS CAN BE RECOGNIZED
BY SPECIFIC HISTOLOGIC CRITERIA
Accurate diagnosis of type 1 endometrial precancers has presented a
major challenge to pathologists. The WHO endometrial hyperplasia
schema captures many precancers in the atypical hyperplasia sub-
group, but is a poorly reproducible system,101-103 which, because of its
vintage, is missing diagnostic elements that have only become clear in
the last 15 years. For example, the clonal origin of precancers is re-
flected in an initially localizing topographic distribution and a need to
establish size thresholds for diagnosis, and morphometric studies have
precisely quantified diagnostic architectural changes.
The application of computer based morphometry has been success-
ful at further improving diagnostic reproducibility of precursor diagnosis.
Biopsylesionsthatprogresstocarcinomacanbediscriminatedfromthose
unlikely to progress using a series of discrete measurable variables.104,105
Volume percent stroma (a measure of gland crowding), standard devia-
tion of the shortest nuclear axis (a measure of nuclear pleomorphism),
and gland outer surface density (a measure of branching and folding)
when combined into a threshold D-score were effective at discriminat-
ing those endometrial lesions which progress to adenocarcinoma
from those that do not.104,106-108 A recent meta-analysis combining
the cumulative outcome prediction experience of the D-score (Fig 3)107
shows that patients with a D-score less than 1 have an overall 89-fold
increased cancer risk than those with D-score more than 1. Even if
one excludes concurrent cancers, those diagnosed within 12 months
of EIN, cancer risk over the next two decades is 45-fold elevated.
Molecular, histologic, and clinical outcome definitions of prema-
lignant disease have merged into a unified EIN concept. This was
possible through a study which showed that those high cancer risk
lesions identified through molecular analysis (monoclonal lesions
with lineage continuity to subsequent carcinoma) and morphometric
analysis (D-Score) are essentially identical.98
SUBJECTIVE (HISTOLOGIC, HUMAN-EYE) CRITERIA
In order to develop histologic criteria that could be reproducibly
recognized by a practicing pathologist, a “type” collection of EIN
Fig 2. Initial genetic changes, including
PTEN inactivation and microsatellite instabil-
ity may occur in the absence of a change in
histomorphology. Endometrial intraepithelial
neoplasia arises through clonal expansion of
the mutant cells and is characterized by
altered cytology and architecture. The com-
bination and order of additional mutations
leading to invasive carcinoma differs be-
tween patients, but may include changes in
K-ras and ␤-catenin. Nongenetic factors such
as sex hormone exposures may act as pos-
itive (estrogens) or negative (progestins) se-
lectors of mutated clones.
4787
 Hecht and Mutter

risk by morphometry alone.110 While all morphometrically low-risk

endometria (D-score ⬎ 1) are consistently recognized by pathologists
as non-EIN, morphometrically high-risk endometria (D-score ⬍ 1),
comprise an admixture of subjectively benign endometria and EIN.
Pathologists are able to recognize a subset of endometria such as
normal secretory endometrium as low risk, whereas these benign
patterns demonstrate morphometric characteristics which mimic
those seen in EIN. Cases that progress to adenocarcinoma are mutu-
ally recognized as high risk by both D-score (D-score ⬍ 1) and sub-
jective (EIN) classification, emphasizing the need for the human
element in diagnosis to ensure diagnostic specificity.

CONCLUSION

For the most part, the dichotomous classification of endometrial can-

Fig 3. Overall cancer free survival of 674 patients with “endometrial hyperpla-
sia” stratified by morphometry into endometrial intraepithelial neoplasia (EIN) or
(benign) non-EIN categories.106 Almost all cancer occurrences occur in patients
with EIN, with a relative risk of 89 compared to those without EIN. Carcinomas
following EIN might be considered concurrent when seen within the first year of
EIN diagnosis. Excluding these, the longer term risk for carcinoma is 45 times
higher for EIN patients.
lesions complete with photomicrographs and associated specialized
studies was created.109 Computerized morphometric analysis of these
and other samples with respect to clinical follow-up have defined
architectural and cytologic features of endometrial precancers; a de-
tailed description and examples are available at www.endometrium.org.
Application of these criteria has been shown to be reproducible, and
reliable in predicting concurrent cancer and the presence of monoclo-
nal growth.110-112
Pathologists applying EIN diagnostic criteria subjectively, are
able to recognize some lesions as low risk that would be scored as high
cers holds up to genetic analysis and the histologic subtypes are under-
scored by systematic changes in a limited set of genes. Combined
molecular, histomorphometric, and clinical outcome analysis of
premalignant lesions, has provided a clearer multidisciplinary def-
inition of endometrial precancers, known as EIN. Genetic and
endocrine disease mechanisms have been integrated into a multi-
step model for oncogenesis in which hormonal exposures act as
selection factors for mutated endometrial cells. Of particular inter-
est is the newly defined preclinical phase of “latent” precancers
in which mutant cells capable of responding to the modulating
influences of hormones have been shown to commonly occur in
“normal” endometrium. This is a potentially exciting target for pre-
ventative therapy.
Although the model in Figure 2 is appealing, it is incomplete. We
have described the role of several candidate genes active in this pro-
gression scenario, but not all genes are effective in each case. Clearly,
there are other primary events that drive progression. These could be
abnormalities of genes elsewhere in the regulatory pathways repre-
sented by the exemplars described here, or perhaps entirely new path-
ways that have yet to be discovered. Finally, the heterogeneity of
endometrioid cancers has not been fully explained.

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Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
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Final approval of manuscript: Jonathan L. Hecht, George L. Mutter
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JOURNAL OF CLINICAL ONCOLOGY
 Molecular Biology of Endometrial Cancer
GLOSSARY
␤-catenin: Originally identified as a component of cell-cell
adhesion complexes composed of cadherins and actin, ␤-catenin
has now been shown to be a downstream signaling molecule in
the Wnt signaling pathway.
EIN (endometrial intraepithelial neoplasia): EIN is a
premalignant lesion of the endometrium composed of a localized
monoclonal population of genetically altered glands. The pres-
ence of EIN on biopsy indicates a 30% chance of concurrent type
I (endometrioid) endometrial cancer and a 45 fold increased risk
for developing cancer 1 or more years later.
K-ras: The gene that encodes K-Ras, a protein that is a member
of the small GTPase superfamily, in which a single amino acid
substitution results in an activating mutation. Alternative splicing
gives rise to variants encoding two isoforms that differ in the
C-terminal region.
LOH (loss of heterozygosity): A situation where one
chromosome has a normal allele of a gene and one chromosome
has a mutant or deleted allele.
Mismatch repair: One of four major pathways of DNA re-
pair in mammalian cells. Mismatch repair recognizes and cor-
rects errors in DNA replication leading to single base-pair
mismatches or insertions/deletions in small repetitive tracts of
DNA known as microsatellites.
MSI (microsatellite instability): Microsatellites are re-
peating units of 1-4 DNA base pairs that are distributed widely
throughout the genome and have a high degree of repeat length
variation in the population. Their length remains stable with cell
division and inheritance so they may be used as molecular mark-
ers of cell lineage, in population genetic studies or paternity test-
ing. Defects in the genes involved in DNA mismatch repair result
in genomic instability that may be detected as MSI, an alteration
in the length of the microsatellites from cell to cell.
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Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved.
Non-random X-chromosome inactivation (HUMARA
assay): Tumors arise from a single genetically altered cell. Conse-
quently, detection of monoclonality, a genetic similarity among the
cells in a tumor mass, can be used to distinguish neoplastic from
polyclonal or hyperplastic lesions. Clonality can be established based
on X-chromosome inactivation analysis. During early embryonic
development of mammalian female embryos, one of the two
X-chromosomes in each cell is randomly deactivated by the methyl-
ation of deoxycytosine residues. Once established, genetic imprinting
retains X-chromosome inactivation through all subsequent cell divi-
sions. The cells in a clonal tumor all show inactivation of the same
copy of the X-chromosome. One common assay detects this inactiva-
tion by examining inactivation of the human androgen receptor
(HUMARA) on the X-chromosome.
Null: Complete loss of function phenotype. This term is used in refer-
ence to the mutation or inactivation of specific genes, resulting in com-
plete absence of protein expression.
p53: p53 is a tumor suppressor gene. The normal function of p53 is
to act as a transcriptional activator of genes with a p53-binding site
and an inhibitor of genes lacking a p53 binding site. Expression of
high levels of wild-type p53 is associated with cell cycle arrest and
apoptosis through induction of P21Waf1/Cip1 and hMdm2. Muta-
tions in p53 are seen in many tumors as well as in the Li-Fraumeni–
inherited cancer syndrome.
PTEN (phosphatase and tensin homolog): PTEN is a tumor
suppressor gene with a gamut of regulatory activities. The gene product
is a multifunctional molecule. The predominant activity identified for
PTEN is its lipid phosphatase activity that converts inositol trisphos-
phates into inositol bisphosphates, thus inhibiting survival and prolifer-
ative pathways that are activated by inositol trisphosphates. PTEN acts
to maintain arrest in the G1 phase of the cell cycle and enable apoptosis
through an AKT-dependent mechanism.
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