Skip to main content
SpringerLink
Log in

Precursors of endometrial and ovarian carcinoma

  • Review and Perspective
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

This review discusses precursor lesions of endometrial and ovarian carcinoma with an emphasis on the unique molecular alterations that have led to the development of binary classification schemes for tumors of both the endometrium and ovary. While such a system is well established for endometrial carcinoma, only recently has a binary classification scheme been proposed for ovarian carcinoma. For both, the morphologic and molecular genetic-defining characteristics of their respective precursor lesions are described in detail. Furthermore, similarities and differences of the precursor lesions of specific tumors of these two genital tract organs are also addressed with a brief discussion of the clinical implications of their diagnosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Singer G, Stohr R, Cope L et al (2005) Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol 29:218–224

    Article  PubMed  Google Scholar 

  2. Shih I, Kurman RJ (2004) Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 164:1511–1518

    CAS  PubMed  Google Scholar 

  3. Kurman RJ, Shih I (2008) Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol 27:151–160

    PubMed  Google Scholar 

  4. Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532

    CAS  PubMed  Google Scholar 

  5. Jemal A, Siegel R, Ward E et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96

    Article  PubMed  Google Scholar 

  6. Bokhman JV (1983) Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 15:10–17

    Article  CAS  PubMed  Google Scholar 

  7. Lax SF (2004) Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification. Virchows Arch 444:213–223

    Article  CAS  PubMed  Google Scholar 

  8. Cirisano FD Jr, Robboy SJ, Dodge RK et al (1999) Epidemiologic and surgicopathologic findings of papillary serous and clear cell endometrial cancers when compared to endometrioid carcinoma. Gynecol Oncol 74:385–394

    Article  PubMed  Google Scholar 

  9. Cirisano FD Jr, Robboy SJ, Dodge RK et al (2000) The outcome of stage I–II clinically and surgically staged papillary serous and clear cell endometrial cancers when compared with endometrioid carcinoma. Gynecol Oncol 77:55–65

    Article  PubMed  Google Scholar 

  10. Ronnett BM, Zaino R, Ellenson LH, Kurman R (2002) Endometrial carcinoma. In: Kurman RJ (ed) Blaustein's pathology of the female genital tract. Springer, New York, pp 501–559

    Google Scholar 

  11. Kurman RJ, Kaminski PF, Norris HJ (1985) The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 56:403–412

    Article  CAS  PubMed  Google Scholar 

  12. Bergeron C, Nogales FF, Masseroli M et al (1999) 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 23:1102–1108

    Article  CAS  PubMed  Google Scholar 

  13. Kendall BS, Ronnett BM, Isacson C et al (1998) Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma. Am J Surg Pathol 22:1012–1019

    Article  CAS  PubMed  Google Scholar 

  14. Sherman ME, Ronnett BM, Ioffe OB et al (2008) Reproducibility of biopsy diagnoses of endometrial hyperplasia: evidence supporting a simplified classification. Int J Gynecol Pathol 27:318–325

    Article  PubMed  Google Scholar 

  15. Baak JP, Kurver PH, Diegenbach PC et al (1981) Discrimination of hyperplasia and carcinoma of the endometrium by quantitative microscopy—a feasibility study. Histopathology 5:61–68

    Article  CAS  PubMed  Google Scholar 

  16. Baak JP (1986) Further evaluation of the practical applicability of nuclear morphometry for the prediction of the outcome of atypical endometrial hyperplasia. Anal Quant Cytol Histol 8:46–48

    CAS  PubMed  Google Scholar 

  17. Mutter GL (2000) Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? The Endometrial Collaborative Group. Gynecol Oncol 76:287–290

    Article  CAS  PubMed  Google Scholar 

  18. Mutter GL, Zaino RJ, Baak JP et al (2007) Benign endometrial hyperplasia sequence and endometrial intraepithelial neoplasia. Int J Gynecol Pathol 26:103–114

    Article  PubMed  Google Scholar 

  19. Lacey JV Jr, Mutter GL, Nucci MR et al (2008) Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies. Cancer 113:2073–2081

    Article  PubMed  Google Scholar 

  20. Mutter GL, Lin MC, Fitzgerald JT et al (2000) Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 92:924–930

    Article  CAS  PubMed  Google Scholar 

  21. Mutter GL (2001) Pten, a protean tumor suppressor. Am J Pathol 158:1895–1898

    CAS  PubMed  Google Scholar 

  22. Myers MP, Pass I, Batty IH et al (1998) The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A 95:13513–13518

    Article  CAS  PubMed  Google Scholar 

  23. Levine RL, Cargile CB, Blazes MS et al (1998) PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res 58:3254–3258

    CAS  PubMed  Google Scholar 

  24. Yoshinaga K, Sasano H, Furukawa T et al (1998) The PTEN, BAX, and IGFIIR genes are mutated in endometrial atypical hyperplasia. Jpn J Cancer Res 89:985–990

    CAS  PubMed  Google Scholar 

  25. Maxwell GL, Risinger JI, Gumbs C et al (1998) Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res 58:2500–2503

    CAS  PubMed  Google Scholar 

  26. Zaino RJ (2000) Endometrial hyperplasia: is it time for a quantum leap to a new classification? Int J Gynecol Pathol 19:314–321

    Article  CAS  PubMed  Google Scholar 

  27. Cirpan T, Terek MC, Mgoyi L et al (2006) Immunohistochemical evaluation of PTEN protein in patients with endometrial intraepithelial neoplasia compared to endometrial adenocarcinoma and proliferative phase endometrium. Eur J Gynaecol Oncol 27:389–392

    CAS  PubMed  Google Scholar 

  28. Burks RT, Kessis TD, Cho KR et al (1994) Microsatellite instability in endometrial carcinoma. Oncogene 9:1163–1166

    CAS  PubMed  Google Scholar 

  29. Caduff RF, Johnston CM, Frank TS (1995) Mutations of the Ki-ras oncogene in carcinoma of the endometrium. Am J Pathol 146:182–188

    CAS  PubMed  Google Scholar 

  30. Enomoto T, Inoue M, Perantoni AO et al (1991) K-ras activation in premalignant and malignant epithelial lesions of the human uterus. Cancer Res 51:5308–5314

    CAS  PubMed  Google Scholar 

  31. Kobayashi K, Sagae S, Nishioka Y et al (1999) Mutations of the beta-catenin gene in endometrial carcinomas. Jpn J Cancer Res 90:55–59

    CAS  PubMed  Google Scholar 

  32. MacDonald ND, Salvesen HB, Ryan A et al (2000) Frequency and prognostic impact of microsatellite instability in a large population-based study of endometrial carcinomas. Cancer Res 60:1750–1752

    CAS  PubMed  Google Scholar 

  33. Saegusa M, Hashimura M, Yoshida T et al (2001) beta-Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer 84:209–217

    Article  CAS  PubMed  Google Scholar 

  34. Lax SF, Kendall B, Tashiro H et al (2000) The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer 88:814–824

    Article  CAS  PubMed  Google Scholar 

  35. Duggan BD, Felix JC, Muderspach LI et al (1994) Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma. Cancer Res 54:1604–1607

    CAS  PubMed  Google Scholar 

  36. Duggan BD, Felix JC, Muderspach LI et al (1994) Microsatellite instability in sporadic endometrial carcinoma. J Natl Cancer Inst 86:1216–1221

    Article  CAS  PubMed  Google Scholar 

  37. Lauchlan SC (1981) Tubal (serous) carcinoma of the endometrium. Arch Pathol Lab Med 105:615–618

    CAS  PubMed  Google Scholar 

  38. Hendrickson M, Ross J, Eifel P et al (1982) Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 6:93–108

    Article  CAS  PubMed  Google Scholar 

  39. Ambros RA, Sherman ME, Zahn CM et al (1995) Endometrial intraepithelial carcinoma: a distinctive lesion specifically associated with tumors displaying serous differentiation. Hum Pathol 26:1260–1267

    Article  CAS  PubMed  Google Scholar 

  40. Sherman ME, Bitterman P, Rosenshein NB et al (1992) Uterine serous carcinoma. A morphologically diverse neoplasm with unifying clinicopathologic features. Am J Surg Pathol 16:600–610

    CAS  PubMed  Google Scholar 

  41. Sherman ME, Bur ME, Kurman RJ (1995) p53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis. Hum Pathol 26:1268–1274

    Article  CAS  PubMed  Google Scholar 

  42. Tashiro H, Isacson C, Levine R et al (1997) p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol 150:177–185

    CAS  PubMed  Google Scholar 

  43. Harris CC, Hollstein M (1993) Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329:1318–1327

    Article  CAS  PubMed  Google Scholar 

  44. Carcangiu ML, Chambers JT (1992) Uterine papillary serous carcinoma: a study on 108 cases with emphasis on the prognostic significance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma. Gynecol Oncol 47:298–305

    Article  CAS  PubMed  Google Scholar 

  45. Goff BA, Kato D, Schmidt RA et al (1994) Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol 54:264–268

    Article  CAS  PubMed  Google Scholar 

  46. Lee KR, Belinson JL (1992) Papillary serous adenocarcinoma of the endometrium: a clinicopathologic study of 19 cases. Gynecol Oncol 46:51–54

    Article  CAS  PubMed  Google Scholar 

  47. Liang SX, Chambers SK, Cheng L et al (2004) Endometrial glandular dysplasia: a putative precursor lesion of uterine papillary serous carcinoma. Part II: molecular features. Int J Surg Pathol 12:319–331

    Article  CAS  PubMed  Google Scholar 

  48. Zheng W, Liang SX, Yu H et al (2004) Endometrial glandular dysplasia: a newly defined precursor lesion of uterine papillary serous carcinoma. Part I: morphologic features. Int J Surg Pathol 12:207–223

    Article  PubMed  Google Scholar 

  49. Jia L, Liu Y, Yi X et al (2008) Endometrial glandular dysplasia with frequent p53 gene mutation: a genetic evidence supporting its precancer nature for endometrial serous carcinoma. Clin Cancer Res 14:2263–2269

    Article  CAS  PubMed  Google Scholar 

  50. Fadare O, Liang SX, Ulukus EC et al (2006) Precursors of endometrial clear cell carcinoma. Am J Surg Pathol 30:1519–1530

    Article  PubMed  Google Scholar 

  51. Burks RT, Sherman ME, Kurman RJ (1996) Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors. Am J Surg Pathol 20:1319–1330

    Article  CAS  PubMed  Google Scholar 

  52. Seidman JD, Kurman RJ (1996) Subclassification of serous borderline tumors of the ovary into benign and malignant types. A clinicopathologic study of 65 advanced stage cases. Am J Surg Pathol 20:1331–1345

    Article  CAS  PubMed  Google Scholar 

  53. Longacre TA, McKenney JK, Tazelaar HD et al (2005) Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or  = 5-year) follow-up. Am J Surg Pathol 29:707–723

    Article  PubMed  Google Scholar 

  54. McKenney JK, Balzer BL, Longacre TA (2006) Lymph node involvement in ovarian serous tumors of low malignant potential (borderline tumors): pathology, prognosis, and proposed classification. Am J Surg Pathol 30:614–624

    Article  PubMed  Google Scholar 

  55. Seidman JD, Kurman RJ (2000) Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol 31:539–557

    Article  CAS  PubMed  Google Scholar 

  56. Nakayama K, Nakayama N, Kurman RJ et al (2006) Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol Ther 5:779–785

    CAS  PubMed  Google Scholar 

  57. Sieben NL, Macropoulos P, Roemen GM et al (2004) In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol 202:336–340

    Article  CAS  PubMed  Google Scholar 

  58. Singer G, Kurman RJ, Chang HW et al (2002) Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol 160:1223–1228

    CAS  PubMed  Google Scholar 

  59. Singer G, Shih I, Truskinovsky A et al (2003) Mutational analysis of K-ras segregates ovarian serous carcinomas into two types: invasive MPSC (low-grade tumor) and conventional serous carcinoma (high-grade tumor). Int J Gynecol Pathol 22:37–41

    Article  PubMed  Google Scholar 

  60. Singer G, Oldt R III, Cohen Y et al (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95:484–486

    Article  CAS  PubMed  Google Scholar 

  61. Mayr D, Hirschmann A, Lohrs U et al (2006) KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants. Gynecol Oncol 103:883–887

    Article  CAS  PubMed  Google Scholar 

  62. Ho CL, Kurman RJ, Dehari R et al (2004) Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. Cancer Res 64:6915–6918

    Article  CAS  PubMed  Google Scholar 

  63. Enomoto T, Weghorst CM, Inoue M et al (1991) K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary. Am J Pathol 139:777–785

    CAS  PubMed  Google Scholar 

  64. Gemignani ML, Schlaerth AC, Bogomolniy F et al (2003) Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol 90:378–381

    Article  CAS  PubMed  Google Scholar 

  65. Russell P (1979) The pathological assessment of ovarian neoplasms. I: introduction to the common ‘epithelial’ tumours and analysis of benign ‘epithelial’ tumours. Pathology 11:5–26

    Article  CAS  PubMed  Google Scholar 

  66. Fukunaga M, Nomura K, Ishikawa E et al (1997) Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 30:249–255

    Article  CAS  PubMed  Google Scholar 

  67. McMeekin DS, Burger RA, Manetta A et al (1995) Endometrioid adenocarcinoma of the ovary and its relationship to endometriosis. Gynecol Oncol 59:81–86

    Article  CAS  PubMed  Google Scholar 

  68. de la Sainz CR, Eichhorn JH, Rice LW et al (1996) Histologic transformation of benign endometriosis to early epithelial ovarian cancer. Gynecol Oncol 60:238–244

    Article  Google Scholar 

  69. Vercellini P, Parazzini F, Bolis G et al (1993) Endometriosis and ovarian cancer. Am J Obstet Gynecol 169:181–182

    CAS  PubMed  Google Scholar 

  70. Veras E, Mao TL, Ayse A et al (2009) Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases. Am J Surg Pathol 33:844–853

    Article  PubMed  Google Scholar 

  71. Oliva E, Sarrio D, Brachtel EF et al (2006) High frequency of beta-catenin mutations in borderline endometrioid tumours of the ovary. J Pathol 208:708–713

    Article  CAS  PubMed  Google Scholar 

  72. Obata K, Morland SJ, Watson RH et al (1998) Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 58:2095–2097

    CAS  PubMed  Google Scholar 

  73. Sato N, Tsunoda H, Nishida M et al (2000) Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 60:7052–7056

    CAS  PubMed  Google Scholar 

  74. Thomas EJ, Campbell IG (2000) Molecular genetic defects in endometriosis. Gynecol Obstet Invest 50(Suppl 1):44–50

    Article  CAS  PubMed  Google Scholar 

  75. Cuatrecasas M, Erill N, Musulen E et al (1998) K-ras mutations in nonmucinous ovarian epithelial tumors: a molecular analysis and clinicopathologic study of 144 patients. Cancer 82:1088–1095

    Article  CAS  PubMed  Google Scholar 

  76. Kuo K-T, Mao TL, Jones S et al (2009) Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol 174:1597–1601

    Article  CAS  PubMed  Google Scholar 

  77. Kohler MF, Marks JR, Wiseman RW et al (1993) Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer. J Natl Cancer Inst 85:1513–1519

    Article  CAS  PubMed  Google Scholar 

  78. Kupryjanczyk J, Thor AD, Beauchamp R et al (1993) p53 gene mutations and protein accumulation in human ovarian cancer. Proc Natl Acad Sci U S A 90:4961–4965

    Article  CAS  PubMed  Google Scholar 

  79. Salani R, Kurman RJ, Giuntoli R et al (2008) Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. Int J Gynecol Cancer 18:487–491

    Article  CAS  PubMed  Google Scholar 

  80. Bell DA, Scully RE (1994) Early de novo ovarian carcinoma. A study of fourteen cases. Cancer 73:1859–1864

    Article  CAS  PubMed  Google Scholar 

  81. Hutson R, Ramsdale J, Wells M (1995) p53 protein expression in putative precursor lesions of epithelial ovarian cancer. Histopathology 27:367–371

    Article  CAS  PubMed  Google Scholar 

  82. Werness BA, Parvatiyar P, Ramus SJ et al (2000) Ovarian carcinoma in situ with germline BRCA1 mutation and loss of heterozygosity at BRCA1 and TP53. J Natl Cancer Inst 92:1088–1091

    Article  CAS  PubMed  Google Scholar 

  83. Balkwill F, Bast RC, Berek J et al (2003) Current research and treatment for epithelial ovarian cancer. A position paper from the Helene Harris Memorial Trust. Eur J Cancer 39:1818–1827

    Article  CAS  PubMed  Google Scholar 

  84. Piek JM, van Diest PJ, Zweemer RP et al (2001) Dysplastic changes in prophylactically removed fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 195:451–456

    Article  CAS  PubMed  Google Scholar 

  85. Crum CP, Drapkin R, Miron A et al (2007) The distal fallopian tube: a new model for pelvic serous carcinogenesis. Curr Opin Obstet Gynecol 19:3–9

    Article  PubMed  Google Scholar 

  86. Jarboe E, Folkins A, Nucci MR et al (2008) Serous carcinogenesis in the fallopian tube: a descriptive classification. Int J Gynecol Pathol 27:1–9

    Article  PubMed  Google Scholar 

  87. Medeiros F, Muto MG, Lee Y et al (2006) The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 30:230–236

    Article  PubMed  Google Scholar 

  88. Folkins AK, Jarboe EA, Saleemuddin A et al (2008) A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations. Gynecol Oncol 109:168–173

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest statement

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Departments of Gynecology and Obstetrics, and Pathology, The Johns Hopkins University School of Medicine and Hospital, Baltimore, MD, USA

    Robert J. Kurman

  2. Department of Pathology, The Johns Hopkins University School of Medicine and Hospital, Baltimore, MD, USA

    Thomas G. McConnell

  3. Department of Pathology, The Johns Hopkins Hospital, Weinberg 2242, 401 N. Broadway, Baltimore, MD, 21231, USA

    Robert J. Kurman

Authors
  1. Robert J. Kurman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas G. McConnell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert J. Kurman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kurman, R.J., McConnell, T.G. Precursors of endometrial and ovarian carcinoma. Virchows Arch 456, 1–12 (2010). https://doi.org/10.1007/s00428-009-0824-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-009-0824-9

Keywords

Search

Navigation