Endometria Intraepithelial Neoplasia (EIN) is a clonal proliferation of architecturally
and cytologically altered premalignant endometrial glands which are prone to malignant transformation to
endometrioid (Type I) endometrial adenocarcinoma. EIN lesions are non-invasive genetically altered
neoplasms which arise focally, and may convert to malignant phenotype upon acquisition of additional
genetic damage. Diagnostic criteria for EIN have been developed by histopathologic correlation with
clinical outcomes, molecular changes, and objective computerized histomorphometry.
EIN should not be confused with unrelated serous intraepithelial carcinoma (serous EIC),
which is an early phase of (Type II) papillary serous adenocarcinomas of the endometrium.
Management of EIN lesions follows guidelines long established for atypical endometrial
hyperplasia. A high concurrent cancer rate (26%), and concern that sampling errors may miss an occult
tumor, have led to a prevailing view that immediate hysterectomy is justified by its combined diagnostic
and therapeutic benefits. Young patients wishing to preserve fertility, and women who are poor surgical
risks, are candidates for hormonal (progestin) therapy. Systemic progestins can successfully ablate up
to 90% of endometrial precancers in young women  , although it is not possible in advance to
predict that fraction which will respond. A decision to treat hormonally must thus be made between the
clinician and patient in full light of the risks, and with the precondition that regular followup
surveillance can be performed.
Figure 1: Clonal Origin of EIN - The first genetic changes (such as PTEN
inactivation) which initiate endometrial carcinogenesis are unaccompanied by any phenotypic alterations
at the light microscopic level. This "latent", phase of cytologically and architecturally normal but
genetically altered cells may persist for years in a normally menstruating woman. Low cancer risk,
combined with lack of a rational therapeutic response, are reasons that systematic screening and
treatment of these "latent" phase lesions is unwarranted at present. As additional genetic damage
accumulates, higher risk morphologically altered mutant clones declare themselves by demonstrating those
architectural and cytologic alterations that distinguish EIN. Malignant transformation of EIN lesions,
which occurs at least 46-times more frequently than non-EIN tissues, warrants careful diagnosis and
treatment. Endocrine modifiers of endometrial cancer risk act upon the latent and EIN phases of this
sequence by tipping the balance of clonal expansion vs. involution.
A Combined Molecular and Histopathologic Model for EIN
Latent, premalignant, and malignant phases of EIN-mediated endometrial carcinogenesis are
diagrammed in Figure 1. In almost half of apparently normal women, histologically unremarkable
proliferative endometria contain a small fraction of (PTEN tumor suppressor gene) mutant endometrial
glands. This phase may be construed as "latent" because not only do the mutated glands look completely
normal under the microscope, but they progress to EIN and cancer at very low efficiency. This latent
phase may persist for years, with continued presence of scattered and interspersed mutant glands after
many menstrual cycles  . Mutant glands are probably represented in the reserve population of
cells that regenerate a new functionalis each month. 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, which then clonally expands from its
point of origin (indicated by expanding arrows) to form a contiguous grouping of a tightly packed and
cytologically altered glands recognizable as EIN. The monoclonal precancer (EIN) develops internal
heterogeneity through mutation, and advantageous events selected by local conditions result in
hierarchical subclones (left to right) of varying success. EIN lesions have only marginal increases in
growth potential, and retain susceptibility to further growth modulation by hormonal factors. Some
involute. Others, through additional mutation and selection, reach a stage where hormonal support is no
longer required for survival. Malignant transformation to cancer is defined by accumulation of
sufficient genetic damage to permit invasion of adjacent stromal tissues.
The Foundations of EIN
Endometrial Intraepithelial Neoplasia has its origins in molecular genetic, experimental,
clinical, and histopathologic studies. Each of these approaches has provided one facet of a
multidisciplinary perspective on this disease  .
Precancer Criteria fulfilled for EIN.
Much as the German pathologist Koch developed a series of postulates that must be
fulfilled in order to scientifically prove pathogenesis of disease by a specific infectious organism,
similar postulates may be formulated for premalignant disease. We here list predictions to be met for a
clinically relevant and biologically distinctive category of endometrial precancers, all of which have
been fulfilled in the case of EIN.
Precancer Postulate 1:
EIN differs from normal tissues . EIN are bona fide neoplasms, comprised of a monoclonal
outgrowth of a single transformed cell
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  .
Precancer Postulate 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
. 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
, mutation of the KRAS oncogene
, epigenetic inactivation of the DNA repair gene MLH1  . 63% of EIN
lesions, for example, have lost the ability to express the tumor suppressor protein from the PTEN gene, a
phenotype shared with over 80% of endometrial cancers
Precancer Postulate 3:
EIN can be diagnosed.
Diagnostic criteria applicable to a routine pathology practice are presented below
Additionally, there is an objective reference standard for EIN diagnosis in computerized morphometry of
H&E stained slides  . 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 1
Precancer Postulate 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
. 26% of women diagnosed with EIN already have cancer at the time of diagnosis, and
the remainder have a 46 fold elevated cancer risk in the ensuing years  .
Precancer Postulate 5:
Genetic and hormonal mechanisms of carcinogenesis converge in EIN .
Endometrial expression of the tumor suppressor gene PTEN normally
increases in an estrogenic environment  . 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. Correspondingly, if the mitogenic effects of estrogens are mitigated by progestins, PTEN
mutant endometrial glands undergo selective involution relative to PTEN-intact glands  .
Precancer Postulate 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  . Heterozygote PTEN mutant mice uniformly (100%) develop
endometrial "hyperplasia," and 21% of these progress to carcinoma  .
PTEN Tumor Supressor: A Biomarker for Endometrial Carcinogenesis
Anti-PTEN antibodies are the first commercially available "special stain" for neoplastic
endometrioid (Type I) endometrial disease. Paraffin tissue immunohistochemistry with anti-PTEN antibody
6H2.1 (Cascade Biosciences, Winchester, MA)
shows that over half of endometrioid
endometrial adenocarcinomas and their precursor EIN lesions have lost PTEN protein due to genomic
mutational or deletional inactivation
. Many commercial anti-PTEN antibodies do not
work on paraffin embedded tissues. A working protocol for successful use of antibody 6h2.1 is available
online at www.endometrium.org. The most common problems are inadequate antigen retrieval, failure to
incubate primary antibody overnight at 4°C, too low an antibody titration (use 1:100 for older
blocks), use of old sections (must be cut and used within days), lack of adequate controls to recognize
when it is working, and use of dark obscuring counterstains.
Caution is advised in using PTEN immunohistochemistry to make diagnoses of individual
patients. It is an insensitive (half of EIN lesions have normal PTEN expression) and nonspecific (over a
third of normal proliferative and anovulatory endometria contain PTEN-null glands) marker for EIN. PTEN
expression is greatly affected by the endocrine and clinical context in which it is applied. Normal
endometrial PTEN expression is greatly reduced or lost in secretory and atrophic glands  .
Absence of expression in these circumstances cannot be equated with loss of function. Correspondingly,
an estrogenic environment increases endometrial stromal and normal gland PTEN expression, improving
contrast with a localizing PTEN-mutant clone.
PTEN immunohistochemistry can, however, be a useful educational tool for pathologists to
delineate extent and configuration of mutant clones, and relate these features to routinely stained
slides. Figure 2 shows a hematoxylin and eosin stained EIN lesion with matching PTEN
immunohistochemistry images to delimit clonal precancerous lesions with single cell resolution. This
educational objective can be segregated from the diagnostic process by setting aside interesting cases
and undertaking a batch staining after they have already been signed out. This provides the benefit of
comparison of multiple examples without compromising patient care. PTEN immunohistochemistry is not a
routine or requisite part of EIN diagnosis.
Figure 2: Loss of PTEN function in EIN - A localizing EIN lesion
occupying the right half of the large tissue fragment (Left Panel) has clonally inactivated the PTEN
tumor suppressor gene (Right Panel, Immunohistochemistry with anti-PTEN antibody 6h2.1). Note the
higher density and epithelial thickening in the EIN glands (pale, devoid of PTEN signal) compared to
Diagnosis OF EIN
A framework for EIN Diagnosis is shown in Table 1. Notable is the clear separation of
endometrial changes caused by unopposed estrogens, and carcinoma, from EIN.
Table 1 - EIN Diagnostic Schema
| EIN Nomenclature ||Topography ||Functional Category ||Treatment|
|Benign Architectural Changes of Unopposed Estrogen ||Diffuse ||Estrogen Effect ||Hormonal therapy|
Endometrial Intraepithelial Neoplasia
|Focal progressing to diffuse ||Precancer ||Hormonal or surgical|
|Carcinoma ||Focal progressing to diffuse ||Cancer ||Surgical stage-based|
Topography of EIN
The distribution of a lesion is useful in distinguishing between the diffuse, field-wide
effects, of an abnormal hormonal environment (anovulation, or persistent estrogen effect), surface
changes secondary to stromal breakdown, and more focal EIN. Clonal origin from a single cell requires
EIN lesions to begin as local processes within the endometrial compartment. Early EIN lesions are easily
diagnosed by their contrast in architecture and cytology with the background from which they have
emerged. Over time, EIN lesions may completely overrun the background endometrium, thereby removing the
convenient lesion-to-background contrast in morphology which assist in EIN diagnosis. For this reason,
or because of fragmentation, many EIN lesions must be diagnosed without the benefit of comparison with
companion benign tissues. Exclusion of artifact and careful evaluation of the architectural and
cytologic features of EIN usually permits accurate diagnosis in these instances.
EIN Diagnostic Criteria
All of the diagnostic criteria of Table 2, listed as A-E below, must be met in order to
make an EIN diagnosis. The entire slide should first be scrutinized under low magnification for
localizing lesions, and if found, these areas examined under higher power to assess possible changes in
cytology within the architecturally distinct focus. Widespread EIN lesions that have replaced the
entire endometrial compartment tend to have a sufficiently atypical cytology that background normal
endometrium is no longer required as a reference point for accurate diagnosis.
Size, architecture, and cytology features are easy EIN diagnostic criteria. Much more
difficult are exclusion of benign mimics and adenocarcinoma from the differential diagnosis. There are
no simple rules for benign mimic exclusion. The broad universe of competing entities can only be
recognized on sight by one who has the easy familiarity that comes with experience. Consistent
demarcation of the EIN-adenocarcinoma threshold remains important clinically because it provides a basis
for the clinician to evaluate the risks of electing hormonal rather than surgical therapy in younger
patients who wish to retain fertility.
Special diagnostic challenges, such as recognition of EIN within polyps, interpretation of
subdiagnostically small or fragmented lesions, and interpretation of lesions with non-endometrioid
differentiation have specific caveats presented below that should be carefully studied.
Table 2 - EIN Diagnostic Criteria. Modified after 
| EIN Criterion ||Comments|
|Architecture ||Area of Glands greater than Stroma|
|Cytology ||Cytology differs between architecturally crowded focus and background, or clearly abnormal.|
|Size >1 mm ||Maximum linear dimension exceeds 1mm.|
|Exclude mimics ||Benign conditions with overlapping criteria: Basalis, secretory, polyps, repair, etc..|
|Exclude Cancer ||Carcinoma if mazelike glands, solid areas, polygonal "mosaic-like" glands, myoinvasion, or significant cribriforming|
A. Architecture: Gland area exceeds stromal area:
A cardinal architectural feature of endometrial precancers is glandular crowding, with a
threshold quantitative cutoff for EIN lesions of less than half of the tissue area occupied by stroma
(Volume Percentage Stroma). Areas with large dominant cysts should always be avoided in making this
assessment. Although EIN is an epithelial disease, visual assessment of the glands themselves is
complicated by frequent artifactual displacement from associated stroma, pale staining of most epithelia,
and visual "shimmering" between gland epithelia and lumens. These may all be avoided by focusing on the
stromal compartment which has the significant advantages of a more uniform composition throughout the
specimen, and superior staining qualities. By focusing on the stroma itself only intact fragments in
which stroma has not been avulsed from glands will be evaluated.
Careful review of graphic and histologic examples of varying stromal densities will assist
in training your eye to classify patient material as above or below the diagnostic threshold. EIN
lesions tend to cluster with a median volume percentage stroma of about 40% and non-EIN (benign) lesions
cluster at a median of approximately 75%. These differences are sufficiently great that visual
assessment by a trained eye can be informative.
B. Cytology of
architecturally crowded area is different than background, or clearly abnormal:
There is no
absolute standard for cytologic features of EIN lesions, but the cytology of EIN is usually clearly
demarcated as divergent from that of co-existing benign endometrial tissues in the same patient. The
manner of cytologic change in EIN varies considerably from patient to patient, and can include but not be
limited to, increased variation in nuclear size and contour, clumped or granular chromatin texture,
change in nucleoli, change in nuclear/cytoplasmic ratio, and altered cytoplasmic differentiation.
Stereotypical static descriptions of cytologic atypia, such as nuclear rounding and appearance of
nucleoli are met in many but not all EIN lesions. In this sense, 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
Cytologic changes in some EIN lesions are manifest as a change in differentiation state to
a tubal, mucinous, micropapillary, or eosinophilic phenotype. These must be distinguished from the
scattered random pattern of hormonally, or surface located repair-induced "metaplasias." Further details
of how to interpret non-endometrioid EIN lesions are presented in the "Pitfalls" section below.
In those cases with no normal glands for internal reference, it is necessary to assess the
freestanding cytology of relevant fragments in the context of their architectural features. Some EIN
lesions occupy the entire tissue sample, and should not be underdiagnosed for lack of a convenient benign
gland in the area.
C. Size >1mm in maximum dimension:
Accurate EIN diagnosis requires a contiguous field of glands
sufficiently large to enable reliable assessment of architecture. A minimum lesion size of 1 mm maximum
dimension was required in the previous clinical outcome studies
for an EIN lesion
to achieve elevated cancer risk. That area of an EIN lesion which meets architectural (gland area) and
cytologic (changed) criteria for diagnosis must measure a minimum of 1mm in maximum dimension, a scale
which usually encompasses more than 5-10 glands. Most biopsy formats produce tissue fragments in excess
of 1.5-2mm. The size requirement must be met in a single tissue fragment, not added amongst multiple
fragments. There is no formal evidence that once beyond the minimum 1mm, EIN lesions should be
stratified by size, but if a lesion is discretely focal, it may be of interest to the clinician to know
what fraction of the available curettings contain lesion.
Individual or small clusters of cytologically altered glands have an undefined natural
history and are best diagnosed descriptively (See Pitfalls section below).
D. Exclusion of Benign Mimics
Patients with one of the conditions listed below may still have an EIN, but this diagnosis
should be made with careful consideration into how the coexisting factor(s) may modify the criteria for
EIN diagnosis. If a specimen is refractory to confident diagnosis, a comment as to the nature of the
problem may be useful in directing management.
- Reactive changes caused by infection, physical disruption, recent pregnancy, or recent instrumentation. These can cause piling up of the epithelium, and loss of nuclear polarity..
- Artifactual gland displacement. Beware diagnosing an EIN lesion if the cytology is identical between areas with crowded compared to uncrowded glands! Many of these are artifactual disruptions where the stroma is sheared and glands pushed in apposition .
- Persistent Estrogen Effect: Randomly scattered cysts of protracted estrogen exposure and occasional branching glands are commonly encountered in anovulatory or estrogen-exposed endometria. Gland density is uniformly irregular throughout the endometrial compartment, with occasional clusters of glands having a cytology identical to the uncrowded areas. These can be diagnosed as "proliferative endometrium with architectural changes of unopposed estrogens". With increasing duration, microthrombi form and scattered stromal breakdown may be associated with epithelial piling along the collapsed stromal surfaces.
- Mid to late secretory endometrium displays loss of nuclear polarity, nuclear enlargement, and variation in nuclear size which if measured objectively by computerized morphometry overlaps substantially with EIN lesions. Stromal responsiveness to progesterone is not homogenous at all endometrial depths. Lack of stromal pre-decidualization in the deeper functionalis and superficial basalis makes glands appear crowded, and these same glands may display a worrisome cytology and complicated saw-toothed luminal profiles
- Endometrial polyps contain irregularly spaced glands in which scattered glands may differ from native endometrium due to their tendency to have reduced hormonal responsiveness. Benign polyps may also have low volume percentage stroma caused by cysts (senile polyps) or random aggregations of glands. Approximately 10% of EIN lesions, however, will present within an endometrial polyp and these must be diagnosed as described below in the "Pitfalls" section.
- Endometrial breakdown is one of the most common settings for overdiagnosis of a benign endometrium as a precancer or cancer. Breakdown may follow an ovulatory or anovulatory cycle and persist into the transitional period between late menses and early proliferative endometrium. Altered cytology is due to piling up of epithelial cells unsupported by stroma, and associated nuclear changes such as loss of polarity which may be accentuated under certain fixation conditions which exaggerate chromatin texture (Bouin's fixative).
E. Exclusion of Carcinoma
Cancer may coexist with EIN in an individual patient, but should be always be separately
diagnosed because current management of carcinoma differs from that for EIN. Keep in mind that absence
of carcinoma in a tissue biopsy does not exclude the possibility of that the patient has a cancer which
was unsampled during the biopsy procedure. An opinion should always be rendered based upon available
material, and clearly stated.
EIN is composed of individual glands lined by an epithelium one cell layer thick. The
epithelium may be pseudostratified, but should not be cribriform or composed of solid areas of epithelial
cells. Presence of any of the following features involving neoplastic glands is inconsistent with EIN,
and a diagnosis of carcinoma should be entertained.
Myoinvasion. Unfortunately, myometrium is rarely available for evaluation in a biopsy or curettage
- Meandering or "mazelike" lumens
- Solid epithelium
- Cribriform architecture.
- "Mosaic" gland pattern of distorted polygonal glands with threadlike intervening stroma
Acknowledgements and Credits
Some of the text and many of the Figures have been used, with permission, from the website
www.endometrium.org  . All rights reserved by G.
- Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997; 90(3):434-440.
- Mutter GL, Ince TA, Baak JPA, Kust G, Zhou X, Eng C. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res 2001; 61:4311-4314.
- Baak JP, Mutter GL. EIN and WHO94. J Clin Pathol 2005; 58(1):1-6.
- Jovanovic AS, Boynton KA, Mutter GL. Uteri of women with endometrial carcinoma contain a histopathologic spectrum of monoclonal putative precancers, some with microsatellite instability. Cancer Res 1996; 56:1917-1921.
- Mutter GL, Chaponot M, Fletcher J. A PCR assay for non-random X chromosome inactivation identifies monoclonal endometrial cancers and precancers. Am J Pathol 1995; 146:501-508.
- Mutter GL, Boynton KA, Faquin WC, Ruiz RE, Jovanovic AS. Allelotype mapping of unstable microsatellites establishes direct lineage continuity between endometrial precancers and cancer. Cancer Res 1996; 56:4483-4486.
- Mutter GL, Baak JPA, Crum CP, Richart RM, Ferenczy A, Faquin WC. Endometrial precancer diagnosis by histopathology, clonal analysis, and computerized morphometry. J Pathol 2000; 190:462-469.
- Esteller M, Garcia A, Martinez-Palones JM, Xercavins J, Reventos J. Detection of clonality and genetic alterations in endometrial pipelle biopsy and its surgical specimen counterpart. Lab Invest 1997; 76:109-116.
- Faquin WC, Fitzgerald JT, Boynton KA, Mutter GL. Intratumoral genetic heterogeneity and progression of endometrioid type endometrial adenocarcinomas. Gynecol Oncol 2000; 78:152-157.
- Levine RL, Cargile CB, Blazes MS, Van Rees B, Kurman RJ, Ellenson LH. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res 1998; 58:3254-3258.
- Maxwell G, Risinger J, Gumbs C, Shaw H, Bentley R, Barrett J et al. Mutation of the PTEN tumor supressor gene in endometrial hyperplasias. Cancer Res 1998; 58:2500-2503.
- Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JPA, Lees J et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92:924-930.
- Duggan BD, Felix JC, Muderspach LI, Tsao J-L, Shibata DK. Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma. Cancer Res 1994; 54:1604-1607.
- Sasaki H, Nishii H, Takahashi H, Tada A, Furusato M, Terashima Y et al. Mutation of the Ki-ras protooncogene in human endometrial hyperplasia and carcinoma. Cancer Res 1993; 53:1906-1910.
- Mutter GL, Wada H, Faquin W, Enomoto T. K-ras mutations appear in the premalignant phase of both microsatellite stable and unstable endometrial carcinogenesis. Mol Pathol 1999; 52:257-262.
- Esteller M, Catasus L, Matias-Guiu X, Mutter GL, Prat J, Baylin SB et al. hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis. Am J Pathol 1999; 155(5):1767-1772.
- Silverberg SG, Mutter GL, Kurman RJ, Kubik-Huch RA, Nogales F, Tavassoli FA. Tumors of the uterine corpus: epithelial tumors and related lesions. In: Tavassoli FA, Stratton MR, editors. WHO Classification of Tumors: Pathology and Genetics of Tumors of the Breast and Female Genital Organs. Lyon, France: IARC Press, 2003: 221-232.
- Mutter GL. Diagnosis of premalignant endometrial disease. J Clin Pathol 2002; 55(5):326-331.
- Mutter GL, The Endometrial Collaborative Group. Endometrial intraepithelial neoplasia (EIN): Will it bring order to chaos? Gynecol Oncol 2000; 76:287-290.
- Baak JPA, Nauta J, Wisse-Brekelmans E, Bezemer P. Architectural and nuclear morphometrical features together are more important prognosticators in endometrial hyperplasias than nuclear morphometrical features alone. J Pathol 1988; 154:335-341.
- Baak JPA, Mutter GL, Robboy S, van Diest PJ, Uyterlinde AM, Orbo A et al. In endometrial hyperplasias, the molecular-genetics and morphometry-based EIN classification more accurately predicts cancer-progression than the WHO94. Cancer 2004; In Press.
- Hecht JL, Ince TA, Baak JP, Baker HE, Ogden MW, Mutter GL. Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Mod Pathol 2004; In Press.
- Dunton C, Baak J, Palazzo J, van Diest P, McHugh M, Widra E. Use of computerized morphometric analyses of endometrial hyperplasias in the prediction of coexistent cancer. Am J Obstet Gynecol 1996; 174:1518-1521.
- Orbo A, Baak JP, Kleivan I, Lysne S, Prytz PS, Broeckaert MA et al. Computerised morphometrical analysis in endometrial hyperplasia for the prediction of cancer development. A long-term retrospective study from northern Norway. J Clin Pathol 2000; 53(9):697-703.
- Baak JP, Orbo A, van Diest PJ, Jiwa M, de Bruin P, Broeckaert M et al. Prospective multicenter evaluation of the morphometric D-score for prediction of the outcome of endometrial hyperplasias. Am J Surg Pathol 2001; 25(7):930-935.
- Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Ziebold U, Eng C. Changes in endometrial PTEN expression throughout the human menstrual cycle. J Clin Endocrinol Metab 2000; 85:2334-2338.
- Zheng W, Baker HE, Mutter GL. Involution of PTEN-Null Endometrial Glands with Progestin Therapy. Gynecol Oncol 2004; 92:1008-1013.
- Stambolic V, Tsao MS, Macpherson D, Suzuki A, Chapman WB, Mak TW. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res 2000; 60(13):3605-3611.
- Perren A, Weng L, Boag A, Ziebold U, Thakore K, Dahia P et al. Immunocytochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol 1999; 155:1253-1260.
- Baak JPA, Mutter GL, Robboy S, van Diest PJ, Uyterlinde AM, Orbo A et al. The molecular genetics and morphometry-based Endometrial Intraepithelial Neoplasia (EIN) classification scheme predicts the risk of progression to cancer more effectively than the WHO94 "Endometrial hyperplasia" system. Am J Obstet Gynecol 2004; Submitted.
- Mutter GL. www.endometrium.org : A focus on premalignant lesions of the endometrium. www.endometrium.org . 2003.