Review
Oncology
Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis

https://doi.org/10.1016/j.ajog.2008.01.005Get rights and content

The goal of ovarian cancer screening is to detect disease when confined to the ovary (stage I) and thereby prolong survival. We believe this is an elusive goal because most ovarian cancer, at its earliest recognizable stage, is probably not confined to the ovary. We propose a new model of ovarian carcinogenesis based on clinical, pathological, and molecular genetic studies that may enable more targeted screening and therapeutic intervention to be developed. The model divides ovarian cancer into 2 groups designated type I and type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis and develop from well-established precursor lesions so-called borderline tumors. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing, highly aggressive neoplasms that lack well-defined precursor lesions; most are advanced stage at, or soon after, their inception. These include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. The type II tumors are characterized by mutation of TP53 and a high level of genetic instability. Screening tests that focus on stage I disease may detect low-grade type I neoplasms but miss the more aggressive type II tumors, which account for most ovarian cancers. A more rational approach to early detection of ovarian cancer should focus on low volume rather than low stage of disease.

Section snippets

Current Approach to Ovarian Cancer Screening

The serum assay for the tumor marker CA125, alone or in combination with pelvic or transvaginal ultrasound, continues to be evaluated as a potential screening test for ovarian cancer. At present, screening tests are not recommended for use in the general population and are considered to have limited use in the high-risk population because of their insufficient sensitivity and their inability to detect early stage disease.

Evaluating potential screening tests for ovarian cancer has been extremely

New Model of Ovarian Carcinogenesis

Correlation of the results of recent molecular genetic studies with clinical and histopathologic findings has led us to propose a new model of ovarian carcinogenesis. In this model all ovarian surface epithelial tumors are divided into 2 groups designated type I and type II. Type I tumors tend to present as stage I, low-grade neoplasms that develop slowly from well-recognized precursors and behave in an indolent fashion. They include low-grade micropapillary serous carcinoma, mucinous,

Implications of the Model for Early Detection and Treatment

The proposed model draws attention to the fact that ovarian cancer is a heterogeneous group of diseases that not only behave differently but also develop differently. Therefore, different approaches to detection and treatment are required. Type I tumors tend to be low grade, low stage, and slow growing. Current approaches for their detection based on pelvic examination and transvaginal ultrasound are appropriate in most cases. However, type I tumors constitute only 25% of ovarian cancers, so

Conclusions

A new model for the pathogenesis of ovarian cancer, which divides surface epithelial tumors into 2 groups, designated type I and type II, is proposed. Type I tumors are slow growing, are generally confined to the ovary at diagnosis, and develop from well-established precursor lesions that are termed borderline tumors. Type I tumors included low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and characterized by mutations in

References (53)

  • B.J. Druker

    Perspectives on the development of a molecularly targeted agent

    Cancer Cell

    (2002)
  • L.A.G. Ries et al.

    SEER cancer statistics review, 1975-2003

    (2006)
  • A. Finch et al.

    Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation

    JAMA

    (2006)
  • J.M. Piek et al.

    Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer

    J Pathol

    (2001)
  • D.W. Kindelberger et al.

    Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship

    Am J Surg Pathol

    (2007)
  • B. Vogelstein et al.

    Cancer genes and the pathways they control

    Nat Med

    (2004)
  • G. Singer et al.

    Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma

    J Natl Cancer Inst

    (2003)
  • N.L. Sieben et al.

    In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours

    J Pathol

    (2004)
  • C.-L. Ho et al.

    Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors

    Cancer Res

    (2004)
  • T. Enomoto et al.

    K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary

    Am J Pathol

    (1991)
  • S.C. Mok et al.

    Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy

    Cancer Res

    (1993)
  • Y. Ichikawa et al.

    Mutation of KRAS protooncogene is associated with histological subtypes in human mucinous ovarian tumors

    Cancer Res

    (1994)
  • R.F. Caduff et al.

    Comparison of mutations of Ki-RAS and p53 immunoreactivity in borderline and malignant epithelial ovarian tumors

    Am J Surg Pathol

    (1999)
  • R. Wu et al.

    Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas

    Cancer Res

    (2001)
  • G. Moreno-Bueno et al.

    Beta-catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas

    Diagn Mol Pathol

    (2001)
  • M. Cuatrecasas et al.

    K-ras mutations in nonmucinous ovarian epithelial tumors: A molecular analysis and clinicopathologic study of 144 patients

    Cancer

    (1998)
  • Cited by (172)

    • Cancer proteomics: Application of case studies in diverse cancers

      2023, Proteomics: A Promising Approach for Cancer Research
    • The use of natural compounds for the targeting and chemoprevention of ovarian cancer

      2017, Cancer Letters
      Citation Excerpt :

      Type-1 cells are characterized by a slow-growing phenotype, and women diagnosed in stage 1 disease who exhibit type-1 cells (25–30% at diagnosis), have a high 5-year survival rate (90%). On the contrary, type-2 cells mainly express a mutated or null isoform of the gene TP53 (60–80% of cases), or aberrations in BRCA1 (30–50%) and BRCA2 (15–30%) genes [16–18], and the majority of the detected ovarian cancers belong to the aggressive type-2 at diagnosis [19]. It has been shown that several tumors, including ovarian cancer, are characterized by the presence of cell subpopulations with stem-like features, commonly defined as cancer stem cells (CSCs), which have the ability to initiate tumor formation in immunocompromised mice [20–22].

    • ACR Appropriateness Criteria<sup>®</sup> Ovarian Cancer Screening

      2017, Journal of the American College of Radiology
    View all citing articles on Scopus

    Reprints not available from the authors.

    View full text