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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.

History

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^[1][2]" 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.
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.

Clinical Aspects

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.
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.

Biology

EIN lesions demonstrate all of the behaviors and characteristics of a premalignant, or precancerous, lesion.

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 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.

Table I: Precancer Characteristics of EIN

EIN Biomarkers. (Figure 1). There are no single biomarkers which are completely informative in recognition of EIN. The tumour suppressor 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.

Figure I. Tissue stain (immunohistochemistry) for the 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.

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 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.
The spectrum of disease which must be distinguished from EIN (Table II) includes benign endometrial hyperplasia and carcinoma:^[2]

Table II: Disease classes that need to be distinguished from EIN.

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).

Table III: EIN diagnosis.

References

1. ^ 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.
2. ^ ^{a 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.
3. ^ ^{a b 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.
4. ^ 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.
5. ^ ^{a b} 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.
6. ^ ^{a b c} 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.
7. ^ Mutter GL, Boynton KA. X chromosome inactivation in the normal female genital tract: Implications for identification of neoplasia. Cancer Res 1995; 55:5080-5084.
8. ^ ^{a b c} 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.
9. ^ ^{a b c} 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.
10. ^ ^{a b c} 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.
11. ^ ^{a b c} Maxwell G, Risinger J, Gumbs C et al. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res 1998; 58:2500-2503.
12. ^ ^{a b c} 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.
13. ^ ^{a b c} 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
14. ^ ^{a b} 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.
15. ^ ^{a b} 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.
16. ^ ^{a b} 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.
17. ^ ^{a b} 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.
18. ^ 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
19. ^ Shroyer K, Gudlaugsson E. Analysis of clonality in archival tissues by polymerase chain reaction amplification of PGK-1. Hum Pathol 1994; 25:287-292
20. ^ ^{a b} Baak JP, Mutter GL, Robboy S et al. The molecular genetics and 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.
21. ^ Mutter GL. Endometrial Precancer Type Collection [On Line]. http://www.endometrium.org 2000.
22. ^ Mutter GL, The Endometrial Collaborative Group. Endometrial intraepithelial neoplasia (EIN): Will it bring order to chaos? Gynecol Oncol 2000; 76:287-290.
23. ^ Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecol Pathol 2000; 19:301-309.
24. ^ 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.

External links

• American Cancer Society
  
• Women's Cancer Network an educational and research organization
  
• Gynecologic Oncology Group an NIH-Funded research group that runs clinical trials
  
• OncoLink an excellent educational site from the U. of Pennsylvania
  
• Find a board certified specialist at the Society of Gynecologic Oncologists
  
  Pathology
  
• US and Canadian Academy of Pathology
  
• www.endometrium.org a pathology site focusing on endometrial disease
  
  PTEN Gene
  
• Cancer Genetics Web PTEN entry
  
• PTEN and the Endometrium at PubMed
  
• Entrez Gene PTEN entry
  
  Other
  
• CancerNet an NIH database with clinical and scientific information
  
• PubMed a search engine and database for Medical Literature