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| {{SI}} | | __NOTOC__ |
| {{EH}} | | {{Endometrial intraepithelial neoplasia}} |
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| ==Overview== | | {{SK}} EIN; Endometrial intraepithelial neoplasia |
| '''Endometrial Intraepithelial Neoplasia, (EIN)''' is a premalignant lesion of the uterine lining that predisposes to endometrioid endometrial adenocarcinoma. It is composed of a collection of abnormal [[endometrial]] cells, arising from the glands that line the [[uterus]], which have a tendency, over time to progress to the most common form of uterine [[cancer]] - endometrial [[adenocarcinoma]], endometrioid type.
| | ==[[Endometrial intraepithelial neoplasia overview|Overview]]== |
| =History= | | ==[[Endometrial intraepithelial neoplasia historical perspective|Historical Perspective]]== |
| EIN lesions have been discovered by a combination of molecular, histologic, and clinical outcome studies beginning in the 1990s which provide a multifaceted characterization of this disease. They are a subset of a larger mixed group of lesions previously called "endometrial [[hyperplasia]]<ref name=A> Mutter GL, Duska L, Crum CP. Endometrial Intraepithelial Neoplasia. In: Crum CP, Lee K, editors. Diagnostic Gynecologic and Obstetric Pathology. Philadelphia, PA: Saunders, 2005: 493-518.</ref><ref name=B> 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.</ref>" The EIN diagnostic schema is intended to replace the previous "endometrial hyperplasia" classification as defined by the [[World Health Organization]] in 1994, which have been separated into [[benign]] (benign endometrial hyperplasia) and [[premalignant]] (EIN) classes in accordance with their behavior and clinical management.<br>
| | ==[[Endometrial intraepithelial neoplasia classification|Classification]]== |
| EIN should not be confused with an unrelated entity, serous intraepithelial carcinoma ("serous EIC"), which is an early stage of a different [[tumor]] type known as papillary serous adenocarcinoma that also occurs in the same location within the uterus.
| | ==[[Endometrial intraepithelial neoplasia pathophysiology|Pathophysiology]]== |
| =Clinical Aspects = | | ==[[Endometrial intraepithelial neoplasia causes|Causes]]== |
| The average age at time of EIN diagnosis is approximately 52 years, compared to approximately 61 years for carcinoma. The timeframe and likelihood of EIN progression to cancer, however, is not constant amongst all women. Some cases of EIN are first detected as residual premalignant disease in women who already have carcinoma, whereas other EIN lesions disappear entirely and never lead to cancer. For this reason, treatment benefits and risks must be individualized for each patient under the guidance of an experienced physician. <br>
| | ==[[Endometrial intraepithelial neoplasia differential diagnosis|Differentiating Endometrial intraepithelial neoplasia from other Diseases]]== |
| Risk factors for development of EIN and the endometrioid type of endometrial carcinoma include exposure to estrogens without opposing progestins, obesity, diabetes, and rare hereditary conditions such as [[hereditary nonpolyposis colorectal cancer]]. Protective factors include use of [[combined oral contraceptive pills]] (low dose estrogen and progestin), and prior use of a contraceptive [[intrauterine device]].
| | ==[[Endometrial intraepithelial neoplasia epidemiology and demographics|Epidemiology and Demographics]]== |
| | ==[[Endometrial intraepithelial neoplasia epidemiology and demographics|Risk Factors]]== |
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| =Biology= | | ==[[Endometrial intraepithelial neoplasia natural history|Natural History, Complications and Prognosis]]== |
| EIN lesions demonstrate all of the behaviors and characteristics of a premalignant, or precancerous, lesion.<br><br>
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| '''Precancer Features of EIN (Table I)'''. The cells of an EIN lesion are genetically different than normal and malignant tissues, and have a distinctive appearance under the light microscope. EIN cells are already [[neoplasm|neoplastic]], demonstrating a [[monoclonal growth pattern]] and clonally distributed mutations. Progression of EIN to carcinoma, effectively a conversion from a benign neoplasm to a malignant neoplasm, is accomplished through acquisition of additional mutations and accompanied by a change in behavior characterized by the ability to invade local tissues and metastasize to regional and distant sites.
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| <br><br>
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| '''Table I''': Precancer Characteristics of EIN
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| {| border="1"
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| ! Precancer Characteristics !! EIN Evidence
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| |Precancers differ from normal tissue || <li> Monoclonal EIN<ref name=C>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.</ref><ref name=D> 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.</ref><ref name=E> 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.</ref><ref name=F> 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.</ref> arise from polyclonal normal field.<ref name=G> Mutter GL, Boynton KA. X chromosome inactivation in the normal female genital tract: Implications for identification of neoplasia. Cancer Res 1995; 55:5080-5084.</ref><li> Mutations are acquired in EIN.<ref name=F/><ref name=H>Esteller M, Catasus L, Matias-Guiu X et al. hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis. Am J Pathol 1999; 155(5):1767-1772.</ref><ref name=I>Enomoto T, Inoue M, Perantoni A et al. K-ras activation in premalignant and malignant epithelial lesions of the human uterus. Cancer Res 1991; 51:5304-5314.</ref><ref name=J>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.</ref><ref name=K>Maxwell G, Risinger J, Gumbs C et al. Mutation of the [[PTEN]] tumor suppressor gene in endometrial hyperplasias. Cancer Res 1998; 58:2500-2503.</ref><ref name=L>Sasaki H, Nishii H, Takahashi H et al. Mutation of the Ki-ras protooncogene in human endometrial hyperplasia and carcinoma. Cancer Res 1993; 53:1906-1910.</ref><ref name=M>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</ref>
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| |Precancers share some, but not all, features of cancer || <li> EIN-cancer lineage hierarchy<ref name=N>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.</ref> <li> EIN may share PTEN,<ref name=K/><ref name=M/><ref name=O> Mutter GL, Lin MC, Fitzgerald JT et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92:924-930.</ref> K-ras,<ref name=I/><ref name=J/><ref name=L/><ref name=P> 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.</ref> MLH1<ref name=H/><ref name=Q> Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG. MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 1998; 17:2413-2417.</ref> changes with cancer. <li> Both EIN and cancer are monoclonal.<ref name=C/><ref name=E/><ref name=F/><ref name=R> Doherty T, Connell J, Stoerker J, Markham N, Shroyer AL, Shroyer KR. Analysis of clonality by polymerase chain reaction for phosphoglycerate kinase-1. Heteroduplex generator. Diagn Mol Pathol 1995; 4(3):182-190</ref><ref name=S> Shroyer K, Gudlaugsson E. Analysis of clonality in archival tissues by polymerase chain reaction amplification of PGK-1. Hum Pathol 1994; 25:287-292</ref>
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| |Precancers increase risk for carcinoma || <li> Elevated concurrent cancer rate (39% in first year after EIN diagnosis)<ref name=T> Baak JP, Mutter GL, Robboy S et al. The molecular genetics and
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| morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system. Cancer 2005; 103(11):2304-2312.</ref> <li> EIN elevates future cancer risk 45-fold.<ref name=T/>
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| |Precancers can be diagnosed || <li>Morphometric reference standard (D-Score) for EIN diagnosis.<ref name=C/><ref name=U> Mutter GL. Endometrial Precancer Type Collection [On Line]. http://www.endometrium.org 2000.</ref><ref name=V> Mutter GL, The Endometrial Collaborative Group. Endometrial intraepithelial neoplasia (EIN): Will it bring order to chaos? Gynecol Oncol 2000; 76:287-290.</ref><ref name=W> Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecol Pathol 2000; 19:301-309.</ref> <li> Subjective EIN diagnosis using criteria (Table 2).<ref name=X> Hecht JL, Ince TA, Baak JP, Baker HE, Ogden MW, Mutter GL. Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Mod Pathol 2005; 18:324-330.</ref>
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| |Cancer must arise from cells within the precancer || <li> EIN-cancer lineage hierarchy.<ref name=N/> <li> EIN may share PTEN,<ref name=K/><ref name=M/><ref name=O/> K-ras,<ref name=I/><ref name=J/><ref name=L/><ref name=P/> MLH1<ref name=H/><ref name=Q/> changes with resultant cancer.
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| '''EIN Biomarkers. (Figure 1)'''. There are no single biomarkers which are completely informative in recognition of EIN. The tumour suppressor gene [[PTEN gene|PTEN]] is frequently inactivated in EIN, being abnormally turned off in approximately 2/3 of all EIN lesions. This can be seen with special tissue stains applied to histological sections known as PTEN [[immunohistochemistry]], in which the brown PTEN protein is seen to be absent in the crowded tubular glands that make up an EIN lesion.
| | ==Diagnosis== |
| <br>
| | [[Endometrial intraepithelial neoplasia staging|Staging]] | [[Endometrial intraepithelial neoplasia other diagnostic studies|Other Diagnostic Studies]] |
| [[Image:EIN_PTEN_1024.jpg|thumb|500px|none|
| | ==Treatment== |
| '''Figure I'''. Tissue stain ([[immunohistochemistry]]) for the [[PTEN gene|PTEN tumor suppressor gene]] showing loss of the PTEN protein in the round and tubular glands which are clustered tightly within an EIN lesion. Brown color indicates the PTEN protein is present.]]
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| <br>
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| =Diagnosis = | |
| Diagnosis of EIN lesions is of clinical importance because of the increased risk of coexisting (39% of women with EIN will be diagnosed with carcinoma within one year) or future (the long term endometrial cancer risk is 45 times greater for a woman with EIN compared to one with only a benign endometrial histology) endometrial cancer. Diagnostic terminology is that used by [[pathology|pathologists]], physicians who diagnose human disease by examination of histologic preparations of excised tissues. Critical distinctions in EIN diagnosis are separation from benign conditions such as benign endometrial hyperplasia (a field effect in endometrial tissue caused by excessive stimulation by the hormone [[estrogen]]), and cancer.
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| <br>
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| The spectrum of disease which must be distinguished from EIN '''(Table II)''' includes benign endometrial hyperplasia and carcinoma:<ref name=B/>
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| <br><br>
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| '''Table II:''' Disease classes that need to be distinguished from EIN.
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| {| border="1" style="text-align:center"
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| ! Disease<br> Class !! Endometrial<br> Topography !! Functional<br> Category !! Treatment
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| |Benign<br> endometrial<br> hyperplasia || Diffuse || Hormone<br> (estrogen)<br> Effect || Hormonal therapy
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| |EIN,<br> Endometrial<br> Intraepithelial<br> Neoplasia || Focal<br> progressing to<br> diffuse<br> (clonal) || Precancer || Hormonal or<br> surgical
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| |Endometrial<br> Adenocarcinoma || Focal<br> progressing to<br> diffuse<br> (clonal) || Cancer || Surgical<br> stage-based
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| |}
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| <br>
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| EIN may be diagnosed by a trained pathologist by examination of tissue sections of the endometrium. All of the following diagnostic criteria must be met in a single area of one tissue fragment to make the diagnosis '''(Table III)'''.
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| '''Table III:''' EIN diagnosis.
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| {| border="1"
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| !
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| ! EIN Criterion
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| !Comments
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| |1 || Architecture || Gland area exceeds that of stroma, usually in a localized region.
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| |2 || Cytological<br> Alterations || Cytology differs between architecturally crowded focus and background.
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| |3 || Size greater than 1mm || Maximum linear dimension should exceed 1mm. Smaller lesions have unknown natural history.
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| |4 || Exclude mimics || Basalis, normal secretory, polyps, repair, lower uterine segment, cystic atrophy, tangential sections, menstrual collapse, disruption artifact, etc.
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| |5 || Exclude Cancer || Carcinoma should be diagnosed if: glands are mazelike and rambling, there are solid areas of epithelial growth, or there are significant bridges or cribriform areas.
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| |}
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| =References=
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| <references/>
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| =Resources=
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| <ul>'''Patient Resources'''</ul>
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| <li>[http://www.cancer.org American Cancer Society]<br>
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| <li>[http://www.wcn.org Women's Cancer Network] an educational and research organization<br>
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| <li>[http://www.gog.org Gynecologic Oncology Group] an NIH-Funded research group that runs clinical trials<br>
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| <li>[http://oncolink.upenn.edu OncoLink] an excellent educational site from the U. of Pennsylvania<br>
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| <li>Find a board certified specialist at the [http://www.sgo.org Society of Gynecologic Oncologists]
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| <br>
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| <br>
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| '''Pathology'''<br>
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| <li>[http://www.uscap.org US and Canadian Academy of Pathology]<br>
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| <li>[http://www.endometrium.org www.endometrium.org] a pathology site focusing on endometrial disease
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| <br>
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| <br>
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| '''PTEN Gene'''<br>
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| <li>[http://www.cancerindex.org/geneweb/PTEN.htm Cancer Genetics Web] PTEN entry<br>
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| <li>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=PTEN+endometr* PTEN and the Endometrium at PubMed]<br>
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| <li>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=5728 Entrez Gene] PTEN entry
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| <br>
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| <br>
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| '''Other'''<br>
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| <li>[http://www.cancer.gov/cancer_information/ CancerNet] an NIH database with clinical and scientific information<br>
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| <li>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed PubMed] a search engine and database for Medical Literature
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| ==References== | | [[Endometrial intraepithelial neoplasia surgery|Surgery]] |
| {{reflist|2}}
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| | ==Case Studies== |
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| | :[[Endometrial intraepithelial neoplasia case study one|Case #1]] |
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| [[Category:Disease]] | | [[Category:Disease]] |
| [[Category:Types of cancer]] | | [[Category:Types of cancer]] |
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| [[Category:Gynecology]] | | [[Category:Gynecology]] |
| [[Category:Oncology]]
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