Endometrial intraepithelial neoplasia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Synonyms and Keywords: Atypical endometrial hyperplasia; Minimal uterine serous cancer (MUSC); Serous endometrial intraepithelial carcinoma (EIC); MUSC; Minimal uterine serous cancer

Overview

Endometrial intraepithelial neoplasia lesions have been discovered beginning in the 1990s which provide a multifaceted characterization of this disease. The endometrial intraepithelial neoplasia 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.Endometrial intraepithelial neoplasia may be classified according to WHO94 schema classifies histology based on glandular complexity and nuclear atypia into 4 groups: simple hyperplasia, complex hyperplasia, simple hyperplasia with atypia, and complex hyperplasia with atypia. On microscopic histopathological analysis, individual glands lined by an pseudostratified epithelium one cell layer thick is a characteristic finding of endometrial intraepithelial neoplasia. Hysterectomy is recommended following the diagnosis of endometrial intraepithelial neoplasia to prevent endometrial carcinoma.

Historaical Perspective

  • Endometrial intraepithelial neoplasia 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 Endometrial intraepithelial neoplasia 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.

Classification

  • Endometrial intraepithelial neoplasia may be classified according to WHO94 schema classifies histology based on glandular complexity and nuclear atypia into 4 groups:[3]
  • Simple hyperplasia
  • Complex hyperplasia
  • Simple hyperplasia with atypia
  • Complex hyperplasia with atypia

Pathophysiology

  • 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 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

Precancer Characteristics EIN Evidence
Precancers differ from normal tissue
  • Monoclonal EIN[4][5][6][7] arise from polyclonal normal field.[8]
  • Mutations are acquired in EIN.[7][9][10][11][12][13][14]
  • Precancers share some, but not all, features of cancer
  • EIN-cancer lineage hierarchy[15]
  • EIN may share PTEN,[12][14][16] K-ras,[10][11][13][17] MLH1[9][18] changes with cancer.
  • Both EIN and cancer are monoclonal.[4][6][7][19][20]
  • Precancers increase risk for carcinoma
  • Elevated concurrent cancer rate (39% in first year after EIN diagnosis)[21]
  • EIN elevates future cancer risk 45-fold.[21]
  • Precancers can be diagnosed
  • Morphometric reference standard (D-Score) for EIN diagnosis.[4][22][23][24]
  • Subjective EIN diagnosis using criteria (Table 2).[25]
  • Cancer must arise from cells within the precancer
  • EIN-cancer lineage hierarchy.[15]
  • EIN may share PTEN,[12][14][16] K-ras,[10][11][13][17] MLH1[9][18] changes with resultant cancer.
    • Endometrial intraepithelial carcinoma (EIC) to be the precursor of serous adenocarcinoma.
    • The mutation in p53 gene has been associated with the development of endometrial intraepithelial neoplasia.
    • On microscopic histopathological analysis, individual glands lined by an pseudostratified epithelium one cell layer thick are characteristic finding of endometrial intraepithelial neoplasia.

    Causes

    • Endometrial intraepithelial neoplasia may be caused by either estrogenic stimulation of the endometrium, unopposed by progestins.

    Differentiating Endometrial intraepithelial neoplasia from other Diseases

    • Endometrial intraepithelial neoplasia must be differentiated from other diseases that cause endometrial disorders such as:
    • Endometrial glandular dysplasia
    • Endometrial intraepithelial neoplasia
    • Hyperplastic polyp
    • Metastatic carcinoma
    • The spectrum of disease which must be distinguished from endometrial intraepithelial neoplasia includes benign endometrial hyperplasia and carcinoma:
    Disease
    Class
    Endometrial
    Topography
    Functional
    Category
    Treatment
    Benign
    endometrial
    hyperplasia
    Diffuse Hormone
    (estrogen)
    Effect
    Hormonal therapy
    EIN,
    Endometrial
    Intraepithelial
    Neoplasia
    Focal
    progressing to
    diffuse
    (clonal)
    Precancer Hormonal or
    surgical
    Endometrial
    Adenocarcinoma
    Focal
    progressing to
    diffuse
    (clonal)
    Cancer Surgical
    stage-based

    Epidemiology and Demographics

    Age

    • The average age at time of endometrial intraepithelial neoplasia diagnosis is approximately 52 years, compared to approximately 61 years for carcinoma.

    Gender

    • Females are affected with endometrial intraepithelial neoplasia.

    Risk Factors

    Natural History, Complications and Prognosis

    • If left untreated, according to a study, 38% of patients with endometrial intraepithelial neoplasia may progress to develop endometrial cancer.
    • Common complications of endometrial intraepithelial neoplasia include endometrial carcinoma, metastases and death.
    • Prognosis is generally good with treatment.

    Diagnosis

    Diagnostic Criteria

    • The diagnosis of endometrial intraepithelial neoplasia is made when the following diagnostic criteria are met:
    • Area of glands greater than stroma (volume percentage stroma less than 55%)
    • Cytology differs between architecturally crowded focus and background
    • Maximum linear dimension exceeds 1 mm
    • Benign conditions with overlapping criteria (ie, basalis, secretory, polyps, repair)
    • Carcinoma if maze-like glands, solid areas, or appreciable cribriforming
    EIN Criterion Comments
    1 Architecture Gland area exceeds that of stroma, usually in a localized region.
    2 Cytological
    Alterations
    Cytology differs between architecturally crowded focus and background.
    3 Size greater than 1mm Maximum linear dimension should exceed 1mm. Smaller lesions have unknown natural history.
    4 Exclude mimics Basalis, normal secretory, polyps, repair, lower uterine segment, cystic atrophy, tangential sections, menstrual collapse, disruption artifact, etc.
    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.

    Symptoms

    • Symptoms of endometrial intraepithelial neoplasia may include the following:
    • Postmenopausal bleeding

    Physical Examination

    • Physical examination may be remarkable for:
    • Palpable pelvic masses

    Laboratory Findings

    • There are no specific laboratory findings associated with endometrial intraepithelial neoplasia.

    Imaging Findings

    • Transvaginal ultrasonography is indicated for postmenopausal patient who has bleeding to detect malignancy.
    • If transvaginal ultrasonography demonstrate an endometrial thickness greater than 4 mm or an inability to adequately visualize endometrial thickness should warrant further evaluation using sonohysterography, office hysteroscopy, or endometrial biopsy.

    Other Diagnostic Studies

    • Endometrial intraepithelial neoplasia is mainly diagnosed using endometrial suction curette and hematoxylin and eosin staining.

    Treatment

    Medical Therapy

    • The mainstay of medical therapy for endometrial intraepithelial neoplasia is progestin therapy.

    Surgery

    • Hysterectomy is recommended following the diagnosis of endometrial intraepithelial neoplasia to prevent endometrial carcinoma.

    Prevention

    • Hysterectomy is recommended following the diagnosis of endometrial intraepithelial neoplasia to prevent endometrial carcinoma.

    References

    1. Mutter GL, Duska L, Crum CP (2005). "Endometrial Intraepithelial Neoplasia". In Crum CP, Lee K. Diagnostic Gynecologic and Obstetric Pathology. Philadelphia PA: Saunders. pp. 493–518. 
    2. Silverberg SG, Mutter GL, Kurman RJ, Kubik-Huch RA, Nogales F, Tavassoli FA (2003). "Tumors of the uterine corpus: epithelial tumors and related lesions". In Tavassoli FA, Stratton MR. WHO Classification of Tumors: Pathology and Genetics of Tumors of the Breast and Female Genital Organs. Lyon, France: IARC Press. pp. 221–232. 
    3. Wang, Steven; Wang, Zhenglong; Mittal, Khushbakhat (2015). "Concurrent endometrial intraepithelial carcinoma (EIC) and endometrial hyperplasia". Human Pathology: Case Reports. 2 (1): 1–4. ISSN 2214-3300. doi:10.1016/j.ehpc.2014.07.003. 
    4. 4.0 4.1 4.2 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.
    5. 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.
    6. 6.0 6.1 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.
    7. 7.0 7.1 7.2 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.
    8. Mutter GL, Boynton KA. X chromosome inactivation in the normal female genital tract: Implications for identification of neoplasia. Cancer Res 1995; 55:5080-5084.
    9. 9.0 9.1 9.2 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.
    10. 10.0 10.1 10.2 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.
    11. 11.0 11.1 11.2 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.
    12. 12.0 12.1 12.2 Maxwell G, Risinger J, Gumbs C et al. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res 1998; 58:2500-2503.
    13. 13.0 13.1 13.2 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.
    14. 14.0 14.1 14.2 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
    15. 15.0 15.1 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.
    16. 16.0 16.1 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.
    17. 17.0 17.1 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.
    18. 18.0 18.1 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.
    19. 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
    20. Shroyer K, Gudlaugsson E. Analysis of clonality in archival tissues by polymerase chain reaction amplification of PGK-1. Hum Pathol 1994; 25:287-292
    21. 21.0 21.1 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.
    22. Mutter GL. Endometrial Precancer Type Collection [On Line]. http://www.endometrium.org 2000.
    23. Mutter GL, The Endometrial Collaborative Group. Endometrial intraepithelial neoplasia (EIN): Will it bring order to chaos? Gynecol Oncol 2000; 76:287-290.
    24. Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecol Pathol 2000; 19:301-309.
    25. 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.

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