Endometrial Precancer

  • John A. Maksem
  • Stanley J. Robboy
  • John W. Bishop
  • Isabelle Meiers
Part of the Essentials in Cytopathology book series (EICP, volume 7)

A situation generally dismissed as benign by pathologists and gynecologists alike is the clinically/sonographically thin endometrium that affords a paucicellular, essentially nondiagnostic (informatively noninformative) tissue specimen. Normal postmenopausal endometrium is grossly thin and microscopically inactive and oftentimes (in up to 50% of samplings) yields no tissue, but the corollary that grossly thin (sonographically <5-mm thickness) postmenopausal endometrium is microscopically inactive and uniformly benign may be false. Endometrial suction biopsy has a reasonable sensitivity and specificity for detecting symptomatic endometrial cancer in thickened endometrium. However, few data are available regarding its sensitivity and specificity among asymptomatic postmenopausal women.

While it is well understood that every endometrial cancer has a precursor state, the assumption that the precursor of endometrial carcinoma, similar to hyperplasia, must be diffuse and symptomatic is false. Theoretically, the cells of an endometrial precancer should be genetically different from normal endometrium yet should share some but not all the features of malignant endometrium. ­Precancerous endometrial cells should be neoplastic (Table 8.1) and demonstrate a monoclonal growth pattern and clonally distributed (geographically clustered) mutations. Progression of ­endometrial 
precancer to carcinoma, effectively a conversion from a benign neoplasm to a malignant neoplasm, would be expectedly accomplished through the acquisition of additional mutations and accompanied by a change in biological behavior most notably characterized by the ability of outspoken cancer cells to invade local tissues and to metastasize.


Endometrial Cancer Endometrial Carcinoma Clear Cell Carcinoma Serous Carcinoma Endometrial Hyperplasia 
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Suggested Reading

  1. Archer DF, McIntyre-Seltman K, Wilborn WW Jr, Dowling EA, Cone F, Creasy GW, Kafrissen ME. Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol 1991; 165: 317–20.PubMedGoogle Scholar
  2. Baak JP, Mutter GL, Robboy S, van Diest PJ, Uyterlinde AM, Orbo A, 
Palazzo J, Fiane B, Løvslett K, Burger C, Voorhorst F, Verheijen RH. 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 (Phila) 2005; 103: 2304–12.CrossRefGoogle Scholar
  3. Bergeron C, Nogales FF, Masseroli M, Abeler V, Duvillard P, Müller-Holzner E, Pickartz H, Wells M. A multicentric European study testing the reproducibility of the WHO classification of endometrial hyperplasia with a proposal of a simplified working classification for biopsy and curettage specimens. Am J Surg Pathol 1999; 23: 1102–8.PubMedCrossRefGoogle Scholar
  4. Cheng L, Zhang S, Zhou Y, Zheng W. Endometrial glandular dysplasia: a putative precursor lesion of uterine papillary serous carcinoma. Part II: molecular features. Int J Surg Pathol 2004; 12: 319–31.PubMedCrossRefGoogle Scholar
  5. Dey P, Rajesh L. Fractal dimension in endometrial carcinoma. Anal Quant Cytol Histol 2004; 26: 113–6.PubMedGoogle Scholar
  6. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996; 275: 370–5.CrossRefGoogle Scholar
  7. Fadare O, Liang SX, Ulukus EC, Chambers SK, Zheng W. Precursors of endometrial clear cell carcinoma. Am J Surg Pathol 2006; 30: 1519–30.PubMedCrossRefGoogle Scholar
  8. Greene RR, Roddick JW Jr, Milligan M. Estrogens, endometrial hyperplasia, and endometrial carcinoma. Ann N Y Acad Sci 1959; 75: 586–600.PubMedCrossRefGoogle Scholar
  9. Hachisuga T, Sugimori H, Kaku T, Tsuneyoshi M. Microcarcinoma of the endometrium: a mapping study with special reference to cytologic atypia in the endometrium. Jpn J Clin Oncol 1992; 22: 400–5.PubMedGoogle Scholar
  10. 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: 324–30.PubMedCrossRefGoogle Scholar
  11. Horwitz RI, Feinstein AR, Horwitz SM, Robboy SJ. Necropsy diagnosis of endometrial cancer and detection-bias in case/control studies. Lancet 1981; 2: 66–8.PubMedCrossRefGoogle Scholar
  12. Karamursel BS, Guven S, Tulunay G, Kucukali T, Ayhan A. Which surgical procedure for patients with atypical endometrial hyperplasia? Int J Gynecol Cancer 2005; 15: 127–31.PubMedCrossRefGoogle Scholar
  13. Koss LG. Diagnosis of early endometrial cancer and precancerous states. Ann Clin Lab Sci 1979; 9: 189–94.PubMedGoogle Scholar
  14. Koss LG. Screening for endometrial cancer. IARC Sci Publ 1986; 76: 293–300.PubMedGoogle Scholar
  15. Koss LG. Detection of occult endometrial carcinoma. J Cell Biochem Suppl 1995; 23: 165–73.PubMedCrossRefGoogle Scholar
  16. Korhonen MO, Symons JP, Hyde BM, Rowan JP, Wilborn WH. Histologic classification and pathologic findings for endometrial biopsy specimens obtained from 2964 perimenopausal and postmenopausal women undergoing screening for continuous hormones as replacement therapy (CHART 2 Study). Am J Obstet Gynecol 1997; 176: 377–80.PubMedCrossRefGoogle Scholar
  17. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer (Phila) 1985; 56: 403–12.CrossRefGoogle Scholar
  18. Maksem JA. Endometrial brush cytology of advanced postmenopausal endometrium: does endometrial intraepithelial neoplasia exist in the absence of hyperplasia? Diagn Cytopathol 1998; 19: 338–43.PubMedCrossRefGoogle Scholar
  19. Maksem JA, Lee SS, Roose EB, Carlson JA, Dornbier DP, Belsheim BL. Rare epithelial sheets with “cancer-like” nuclei presenting against a background of cytologically normal-appearing endometrial epithelium in endometrial brush samplings: establishing a differential diagnosis. Diagn Cytopathol 1999; 21: 378–86.PubMedCrossRefGoogle Scholar
  20. Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecol Pathol 2000; 19: 301–9.PubMedCrossRefGoogle Scholar
  21. Mutter GL, Duska LR, Crum CP. Endometrial intraepithelial neoplasia. In: Crum CP, Kenneth RL, eds. Diagnostic Gynecology and Obstetric Pathology. Elsevier Saunders, Philadelphia, PA, p. 500, fig.17.4, 2006.Google Scholar
  22. Mutter GL, Zaino RJ, Baak JP, Bentley RC, Robboy SJ. Benign Endometrial Hyperplasia and EIN Pathology of the Female Reproductive Tract. Elsevier, Churchill Livingstone, London, 2nd edn, p. 1045, 2009.Google Scholar
  23. Norimatsu Y, Shimizu K, Kobayashi TK, Moriya T, Tsukayama C, Miyake Y, Ohno E. Cellular features of endometrial hyperplasia and well differentiated adenocarcinoma using the Endocyte sampler: diagnostic criteria based on the cytoarchitecture of tissue fragments. Cancer (Phila) 2006; 108: 77–85.CrossRefGoogle Scholar
  24. Orbo A, Rise CE, Mutter GL. Regression of latent endometrial precancers by progestin infiltrated intrauterine device. Cancer Res 2006; 66: 5613–7.PubMedCrossRefGoogle Scholar
  25. Parazzini F, La Vecchia C, Bocciolone L, Franceschi S. The epidemiology of endometrial cancer. Gynecol Oncol 1991; 41: 1–16.PubMedCrossRefGoogle Scholar
  26. Porrazzi LC, Quarto F, Maiello FM, De Falco ML, Antonucci T. The value of endometrial cytology by scraping in 1,798 cases: screening in asymptomatic women and diagnosis in symptomatic ones. Diagn Cytopathol 1987; 3: 112–20.PubMedCrossRefGoogle Scholar
  27. 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: 434–40.PubMedCrossRefGoogle Scholar
  28. Shapiro S, Kelly JP, Rosenberg L, Kaufman DW, Helmrich SP, Rosenshein NB, Lewis JL Jr, Knapp RC, Stolley PD, Schottenfeld D. Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 1985; 313: 969–72.PubMedCrossRefGoogle Scholar
  29. Sherman ME, Ronnett BM, Ioffe OB, Richesson DA, Rush BB, Glass AG, Chatterjee N, Duggan MA, Lacey JV Jr. Reproducibility of biopsy diagnoses of endometrial hyperplasia: evidence supporting a simplified classification. Int J Gynecol Pathol 2008; 27: 318–25.PubMedCrossRefGoogle Scholar
  30. Shu YJ, Ikle FA. Cytopathology of the Endometrial Cancer. McGraw-Hill, New York, 1992.Google Scholar
  31. Sivridis E, Giatromanolaki A. Proliferative activity in postmenopausal endometrium: the lurking potential for giving rise to an endometrial adenocarcinoma. J Clin Pathol 2004; 57: 840–4.PubMedCrossRefGoogle Scholar
  32. Tanaka M, Kyo S, Kanaya T, Yatabe N, Nakamura M, Maida Y, Okabe M, Inoue M. Evidence of the monoclonal composition of human endometrial epithelial glands and mosaic pattern of clonal distribution in luminal epithelium. Am J Pathol 2003; 163: 295–301.PubMedCrossRefGoogle Scholar
  33. Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke JJ II, Alberts D, Curtin J. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: A Gynecologic Oncology Group study. Cancer (Phila) 2006; 106: 812–9.CrossRefGoogle Scholar
  34. Yi XF, Zheng WX. Endometrial glandular dysplasia and endometrial intraepithelial neoplasia. Cur Opin Obstet Gynecol 2008; 20(1): 20–5.CrossRefGoogle Scholar
  35. Zaino RJ. Endometrial hyperplasia: is it time for a quantum leap to a new classification? Int J Gynecol Pathol 2000; 19: 314–21.PubMedCrossRefGoogle Scholar
  36. Zaino RJ, Kauderer J, Trimble CL, Silverberg SG, Curtin JP, Lim PC, Gallup DG. Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer (Phila) 2006; 106: 804–11.CrossRefGoogle Scholar
  37. Zeleniuch-Jacquotte A, Akhmedkhanov A, Kato I, Koenig KL, Shore RE, Kim MY, Levitz M, Mittal KR, Raju U, Banerjee S, Toniolo P. Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study. Br J Cancer 2001; 84: 975–81.PubMedCrossRefGoogle Scholar
  38. Zheng W, Baker HE, Mutter GL. Involution of PTEN-null endometrial glands with progestin therapy. Gynecol Oncol 2004; 92: 1008–13.PubMedCrossRefGoogle Scholar
  39. Zheng W, Liang SX, Yu H, Rutherford T, Chambers SK, Schwartz PE. Endometrial glandular dysplasia: a newly defined precursor lesion of uterine papillary serous carcinoma. Part I: morphologic features. Int J Surg Pathol 2004; 12: 207–23.PubMedCrossRefGoogle Scholar
  40. Zheng WX, Schwartz PE. Serous EIC as an early form of uterine papillary serous carcinoma: recent progress in understanding its pathogenesis and current opinions regarding pathologic and clinical management. Gynecol Oncol 2005; 96(3): 579.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • John A. Maksem
    • 1
  • Stanley J. Robboy
    • 2
  • John W. Bishop
    • 3
  • Isabelle Meiers
    • 4
  1. 1.Orlando HealthOrlando
  2. 2.Duke University Medical CenterDurham
  3. 3.University of California, DavisSacramento
  4. 4.University Hospital LewishamLondonEngland

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