Endometrial intraepithelial neoplasia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The average age at time of EIN diagnosis is approximately 52 years, compared to approximately 61 years for carcinoma. The time frame 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.

Pathophysiology

Precancer Features of EIN

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

Precancer Characteristics EIN Evidence
Precancers differ from normal tissue
  • Monoclonal EIN[1][2][3][4] arise from polyclonal normal field.[5]
  • Mutations are acquired in EIN.[4][6][7][8][9][10][11]
    • Precancers share some, but not all, features of cancer
  • EIN-cancer lineage hierarchy[12]
  • EIN may share PTEN,[9][11][13] K-ras,[7][8][10][14] MLH1[6][15] changes with cancer.
  • Both EIN and cancer are monoclonal.[1][3][4][16][17]
    • Precancers increase risk for carcinoma
  • Elevated concurrent cancer rate (39% in first year after EIN diagnosis)[18]
  • EIN elevates future cancer risk 45-fold.[18]
    • Precancers can be diagnosed
  • Morphometric reference standard (D-Score) for EIN diagnosis.[1][19][20][21]
  • Subjective EIN diagnosis using criteria (Table 2).[22]
    • Cancer must arise from cells within the precancer
  • EIN-cancer lineage hierarchy.[12]
  • EIN may share PTEN,[9][11][13] K-ras,[7][8][10][14] MLH1[6][15] changes with resultant cancer.


    • References

    1. ↑ 1.0 1.1 1.2 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.
    2. ↑ 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.
    3. ↑ 3.0 3.1 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.
    4. ↑ 4.0 4.1 4.2 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.
    5. ↑ Mutter GL, Boynton KA. X chromosome inactivation in the normal female genital tract: Implications for identification of neoplasia. Cancer Res 1995; 55:5080-5084.
    6. ↑ 6.0 6.1 6.2 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.
    7. ↑ 7.0 7.1 7.2 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.
    8. ↑ 8.0 8.1 8.2 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.
    9. ↑ 9.0 9.1 9.2 Maxwell G, Risinger J, Gumbs C et al. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res 1998; 58:2500-2503.
    10. ↑ 10.0 10.1 10.2 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.
    11. ↑ 11.0 11.1 11.2 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
    12. ↑ 12.0 12.1 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.
    13. ↑ 13.0 13.1 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.
    14. ↑ 14.0 14.1 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.
    15. ↑ 15.0 15.1 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.
    16. ↑ 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
    17. ↑ Shroyer K, Gudlaugsson E. Analysis of clonality in archival tissues by polymerase chain reaction amplification of PGK-1. Hum Pathol 1994; 25:287-292
    18. ↑ 18.0 18.1 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.
    19. ↑ Mutter GL. Endometrial Precancer Type Collection [On Line]. http://www.endometrium.org 2000.
    20. ↑ Mutter GL, The Endometrial Collaborative Group. Endometrial intraepithelial neoplasia (EIN): Will it bring order to chaos? Gynecol Oncol 2000; 76:287-290.
    21. ↑ Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecol Pathol 2000; 19:301-309.
    22. ↑ 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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