Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis
2008; Elsevier BV; Volume: 198; Issue: 4 Linguagem: Inglês
10.1016/j.ajog.2008.01.005
ISSN1097-6868
AutoresRobert J. Kurman, Kala Visvanathan, Richard Roden, Tinghui Wu, Ie‐Ming Shih,
Tópico(s)Endometrial and Cervical Cancer Treatments
ResumoThe 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. 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. In the United States, the incidence of ovarian cancer ranks eighth among cancers (excluding skin cancer) in women but fifth in terms of age-adjusted mortality (http://www.cancer.org/docroot/home/index.asp). The high mortality rate is generally attributed to its occult development, resulting in advanced, widespread disease occurring in approximately 75% of women at diagnosis. However, in about 25% of women, disease is confined to the ovary (stage I) and 5 year survival is more than 90%, compared with 30% for women with advanced disease.1Ries L.A.G. Harkins D. Krapcho M. et al.SEER cancer statistics review, 1975-2003. National Cancer Institute, Bethesda, MD2006http://seer.cancer.gov/csr/1975_2003/Google Scholar This observation suggests that diagnosing ovarian cancer when confined to the ovary may improve survival. Accordingly, there has been a concerted effort to develop screening methods for the early detection of stage I ovarian cancer.For Editors’ Commentary, see Table of ContentsSee related editorial, page 349Current Approach to Ovarian Cancer ScreeningThe 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 challenging for several reasons: (1) the failure to identify a histologic precursor lesion or a molecular event that precedes malignant transformation; (2) the small number of true early-stage, high-grade carcinomas detected, often making it necessary to make inferences using cases that have advanced disease rather than early-stage disease (which may behave differently) when compared with controls; (3) the low prevalence in the general population, meaning that extremely large prospective cohorts over a long time are needed to evaluate the ability of the test to detect preclinical disease; and (4) the surgical morbidity associated with a positive screening test and the high disease specific mortality, meaning that a test with high specificity and sensitivity is required (most clinicians consider that a minimum positive predictive value of 10% is reasonable).The received view of ovarian carcinogenesis is that carcinoma begins in the ovary and spreads to adjacent organs in the pelvis and the abdominal cavity before metastasizing to distant sites. This is reflected by the International Federation of Gynecology and Obstetrics (FIGO) staging system in which cancer confined to the ovary is stage I, stage II when it has spread to the pelvis, and stage III when it involves abdominal organs. Spread beyond the abdominal cavity is stage IV.This concept of ovarian tumor progression, however, is probably not valid. Moreover, attempts to develop methods of early detection for ovarian cancer have been modeled on cervical cancer screening but that analogy is not appropriate. First, it appears that high-grade ovarian carcinoma spreads to extraovarian sites early in its development unlike cervical cancer in which the transit time from a precursor lesion to invasive carcinoma is about 10 years. Therefore, the time frame for detecting ovarian cancer before it has spread beyond the ovary is very brief. Second, unlike cervical cancer, which originates in the cervix, many ovarian cancers may not begin in the ovary. For example, it is well known that in women with BRCA mutations, the risk of developing ovarian-type cancer after prophylactic oophorectomy, although reduced, is not entirely eliminated. A recent prospective study of women with BRCA mutations has calculated that the risk of developing peritoneal carcinoma after prophylactic oophorectomy is 4.3% over a median follow-up period of 3 years (1-20 years).2Finch A. Beiner M. Lubinski J. et al.Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation.JAMA. 2006; 296: 185-192Crossref PubMed Scopus (489) Google Scholar These peritoneal carcinomas are identical histologically to high-grade ovarian serous carcinoma. Also, the majority of sporadic ovarian cancers that present with extensive disease in the peritoneum, omentum, mesentery, and other abdominal organs often display only minimal ovarian involvement, suggesting that they may be derived from the peritoneum and involve the ovaries secondarily.Another observation that lends support to the view that not all ovarian carcinoma begins in the ovary has come from studies of women with BRCA mutations undergoing prophylactic oophorectomy. Careful examination of the ovaries and fallopian tubes of these women has shown that there are small high-grade serous carcinomas in the fimbria of the fallopian tube and not in the ovary, suggesting that in these women, ovarian cancer begins in the fallopian tube and spreads to the ovaries.3Piek J.M. van Diest P.J. Zweemer R.P. et al.Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer.J Pathol. 2001; 195: 451-456Crossref PubMed Scopus (557) Google Scholar, 4Kindelberger D.W. Lee Y. Miron A. et al.Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship.Am J Surg Pathol. 2007; 31: 161-169Crossref PubMed Scopus (836) Google Scholar Thus, it is likely that a substantial number of what is considered ovarian cancer is in fact primary peritoneal or fallopian tube carcinoma. Based on FIGO ovarian cancer staging, these tumors are advanced stage at inception.New Model of Ovarian CarcinogenesisCorrelation 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, endometrioid, and clear cell carcinoma.In contrast, type II tumors nearly always present as high-stage, high-grade tumors that are extremely aggressive. Included in this group are high-grade serous carcinoma, malignant mixed mesodermal tumors, and undifferentiated carcinomas. In addition to the clinical and pathologic differences, there are molecular genetic differences between these 2 groups as well.5Shih I.-M. Kurman R.J. Ovarian tumorigenesis—a proposed model based on morphological and molecular genetic analysis.Am J Pathol. 2004; 164: 1511-1518Abstract Full Text Full Text PDF PubMed Scopus (1010) Google Scholar The low-grade tumors are relatively genetically stable and are characterized by mutations in a number of genes. For example, in low-grade micropapillary serous carcinoma (the prototypic type I tumor) and its precursor lesions, atypical proliferative serous tumor, so-called serous borderline tumor (SBT), the most well-characterized molecular alterations are sequence mutations in KRAS, BRAF, and ERBB2 oncogenes. Oncogenic mutations in BRAF, KRAS, and ERBB2 result in constitutive activation of the mitogen-activated protein kinase (MAPK) signal transduction pathway, which plays a critical role in the transmission of growth signals into the nucleus6Vogelstein B. Kinzler K.W. Cancer genes and the pathways they control.Nat Med. 2004; 10: 789-799Crossref PubMed Scopus (3285) Google Scholar and contributes to neoplastic transformation.Previous studies7Singer G. Oldt 3rd, R. Cohen Y. et al.Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (693) Google Scholar, 8Singer G. Kurman R.J. Chang H.-W. Cho S.K.R. Shih I.-M. Diverse tumorigenic pathways in ovarian serous carcinoma.Am J Pathol. 2002; 160: 1223-1228Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar demonstrated that KRAS mutations at codons 12 and 13 occur in one-third of invasive low-grade micropapillary serous carcinomas and another one third of SBTs. Similarly, BRAF mutations at codon 600 occur in 30% of low-grade serous carcinomas and 28% of SBTs.7Singer G. Oldt 3rd, R. Cohen Y. et al.Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (693) Google Scholar, 9Sieben N.L. Macropoulos P. Roemen G.M. et al.In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours.J Pathol. 2004; 202: 336-340Crossref PubMed Scopus (204) Google Scholar, 10Mayr D. Hirschmann A. Lohrs U. Diebold J. KRAS and BRAF mutations in ovarian tumors: A comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants.Gynecol Oncol. 2006; 103: 883-887Crossref PubMed Scopus (164) Google Scholar Mutations in ERBB2 occur in less than 5% of these tumors. Mutations in KRAS, BRAF and ERBB2 are mutually exclusive. Therefore, mutations in these genes are detected in about two thirds of low-grade micropapillary serous carcinomas and SBTs.Mutations of KRAS and BRAF appear to occur very early in the development of low-grade micropapillary serous carcinoma as evidenced by the demonstration that the same KRAS and BRAF mutations detected in SBTs are detected in the cystadenoma epithelium adjacent to SBTs.11Ho C.-L. Kurman R.J. Dehari R. Wang T.-L. Shih I.-M. Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors.Cancer Res. 2004; 64: 6915-6918Crossref PubMed Scopus (166) Google Scholar As compared with SBTs, the cystadenoma epithelium lacks cytologic atypia. These findings suggest that mutations of KRAS and BRAF occur in the epithelium of cystadenomas adjacent to SBTs and are very early events in tumorigenesis, preceding the development of SBTs.The most common molecular genetic alteration in mucinous borderline tumors (MBTs) and mucinous carcinomas (type I tumors) is point mutation of KRAS.10Mayr D. Hirschmann A. Lohrs U. Diebold J. KRAS and BRAF mutations in ovarian tumors: A comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants.Gynecol Oncol. 2006; 103: 883-887Crossref PubMed Scopus (164) Google Scholar, 12Enomoto T. Weghorst C.M. Inoue M. Tanizawa O. Rice J.M. K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary.Am J Pathol. 1991; 139: 777-785PubMed Google Scholar, 13Gemignani M.L. Schlaerth A.C. Bogomolniy F. et al.Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma.Gyncol Oncol. 2003; 90: 378-381Crossref PubMed Scopus (184) Google Scholar In mucinous carcinoma, morphologic transitions from cystadenoma to MBT to intraepithelial carcinoma and invasive carcinoma have been recognized for some time, and an increasing frequency of KRAS mutations at codons 12 and 13 has been described in cystadenomas, MBTs, and mucinous carcinomas, respectively.12Enomoto T. Weghorst C.M. Inoue M. Tanizawa O. Rice J.M. K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary.Am J Pathol. 1991; 139: 777-785PubMed Google Scholar, 13Gemignani M.L. Schlaerth A.C. Bogomolniy F. et al.Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma.Gyncol Oncol. 2003; 90: 378-381Crossref PubMed Scopus (184) Google Scholar, 14Mok S.C. Bell D.A. Knapp R.C. et al.Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy.Cancer Res. 1993; 53: 1489-1492PubMed Google Scholar, 15Ichikawa Y. Nishida M. Suzuki H. Mutation of KRAS protooncogene is associated with histological subtypes in human mucinous ovarian tumors.Cancer Res. 1994; 54: 33-35PubMed Google Scholar, 16Caduff R.F. Svoboda-Newman S.M. Ferguson A.W. Johnston C.M. Frank T.S. Comparison of mutations of Ki-RAS and p53 immunoreactivity in borderline and malignant epithelial ovarian tumors.Am J Surg Pathol. 1999; 23: 323-328Crossref PubMed Scopus (89) Google Scholar In addition, mucinous carcinoma and the adjacent mucinous cystadenoma and MBT share the same KRAS mutation,14Mok S.C. Bell D.A. Knapp R.C. et al.Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy.Cancer Res. 1993; 53: 1489-1492PubMed Google Scholar indicating that these tumors have a common lineage and support the view that mucinous carcinomas develop in a step-wise fashion from mucinous cystadenomas and MBTs. Besides KRAS, other genetic alterations in ovarian mucinous tumors have not been described.In endometrioid borderline tumors (EBTs) and endometrioid carcinomas (type I tumors), mutation of beta-catenin has been reported in approximately one third of cases.17Wu R. Zhai Y. Fearon E.R. Cho K.R. Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas.Cancer Res. 2001; 61: 8247-8255PubMed Google Scholar, 18Moreno-Bueno G. Gamallo C. Perez-Gallego L. deMora J.C. Suarez A. Palacios J. Beta-catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas.Diagn Mol Pathol. 2001; 10: 116-122Crossref PubMed Scopus (128) Google Scholar Mutations of KRAS and BRAF have also been reported in approximately 10% of endometrioid carcinomas.7Singer G. Oldt 3rd, R. Cohen Y. et al.Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (693) Google Scholar, 10Mayr D. Hirschmann A. Lohrs U. Diebold J. KRAS and BRAF mutations in ovarian tumors: A comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants.Gynecol Oncol. 2006; 103: 883-887Crossref PubMed Scopus (164) Google Scholar, 13Gemignani M.L. Schlaerth A.C. 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Sekizawa A. et al.p53 mutations and overexpression affect prognosis of ovarian endometrioid cancer but not clear cell cancer.Gynecol Oncol. 2003; 88: 318-325Crossref PubMed Scopus (81) Google Scholar Mutation of the tumor suppressor, PTEN, occurs in 20% of endometrioid carcinomas, rising to 46% in those tumors with 10q23 loss of heterozygosity.22Obata K. Morland S.J. Watson R.H. et al.Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors.Cancer Res. 1998; 58: 2095-2097PubMed Google Scholar Similar molecular genetic alterations including loss of heterozygosity at 10q23 and mutations in PTEN have been reported in endometriosis, atypical endometriosis, and ovarian endometrioid carcinoma in the same specimen.22Obata K. Morland S.J. Watson R.H. et al.Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors.Cancer Res. 1998; 58: 2095-2097PubMed Google Scholar, 23Sato N. Tsunoda H. Nishida M. et al.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. 2000; 60: 7052-7056PubMed Google Scholar, 24Saito M. Okamoto A. Kohno T. et al.Allelic imbalance and mutations of the PTEN gene in ovarian cancer.Int J Cancer. 2000; 85: 160-165PubMed Google Scholar, 25Thomas E.J. Campbell I.G. Molecular genetic defects in endometriosis.Gynecol Obstet Invest. 2000; 50: 44-50Crossref PubMed Scopus (75) Google Scholar, 26Obata K. Hoshiai H. Common genetic changes between endometriosis and ovarian cancer.Gynecol Obstet Invest. 2000; 50: 39-43Crossref PubMed Scopus (90) Google Scholar, 27Bischoff F.Z. Simpson J.L. Heritability and molecular genetic studies of endometriosis.Hum Reprod Update. 2000; 6: 37-44Crossref PubMed Scopus (138) Google ScholarThese molecular genetic findings together with the morphological data demonstrating a frequent association of endometriosis with endometrioid adenofibromas and EBTs adjacent to invasive well-differentiated endometrioid carcinoma provide evidence of step-wise tumor progression in the development of endometrioid carcinoma.28Prowse A.H. Manek S. Varma R. et al.Molecular genetic evidence that endometriosis is a precursor of ovarian cancer.Int J Cancer. 2006; 119: 556-562Crossref PubMed Scopus (131) Google Scholar The critical role of the genetic changes in PTEN and KRAS is highlighted by a recent report showing that inactivation of PTEN and an activating mutation of KRAS are sufficient to induce the development of ovarian endometrioid carcinoma in a mouse model.29Dinulescu D.M. Ince T.A. Quade B.J. Shafer S.A. Crowley D. Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer.Nat Med. 2005; 11: 63-70Crossref PubMed Scopus (483) Google Scholar More recently inactivation of the Wnt/beta-catenin and the PI3K/Pten pathways has been reported to be sufficient to induce endometrioid carcinoma in an engineered mouse model.30Wu R. Hendrix-Lucas N. Kuick R. et al.Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways.Cancer Cell. 2007; 11: 321-333Abstract Full Text Full Text PDF PubMed Scopus (253) Google ScholarAs compared with other types of ovarian epithelial tumors, the main molecular genetic changes associated with ovarian clear cell borderline tumors and clear cell carcinomas (type I tumors) remain to be identified. Although several molecular genetic changes have been reported in clear cell tumors, most studies have analyzed a limited number of cases, and therefore, the true prevalence of those changes is not known. For example, mutations in transforming growth factor-beta receptor type II have been reported in 1 small study of clear cell carcinomas but rarely in other histologic types of ovarian carcinomas.31Francis-Thickpenny K.M. Richardson D.M. van Ee C.C. et al.Analysis of the TGF-beta functional pathway in epithelial ovarian carcinoma.Br J Cancer. 2001; 85: 687-691Crossref PubMed Scopus (26) Google Scholar Microsatellite instability is present in endometrioid and clear cell carcinoma but is only rarely detected in serous and mucinous tumors.28Prowse A.H. Manek S. Varma R. et al.Molecular genetic evidence that endometriosis is a precursor of ovarian cancer.Int J Cancer. 2006; 119: 556-562Crossref PubMed Scopus (131) Google Scholar, 32Fujita M. Enomoto T. 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Varma R. et al.Molecular genetic evidence that endometriosis is a precursor of ovarian cancer.Int J Cancer. 2006; 119: 556-562Crossref PubMed Scopus (131) Google Scholar We have tentatively included clear cell carcinoma in the type I group because clear cell carcinomas typically present as stage I tumors, and they are frequently associated with precursor lesions such as endometriosis and clear cell borderline tumors. Also, like the other type I tumors, clear cell carcinomas do not demonstrate a high level of genetic instability (Shih I-M, et al, unpublished data). On the other hand, clear cell carcinomas are nearly always high grade and the frequency of KRAS, BRAF and TP53 is low.10Mayr D. Hirschmann A. Lohrs U. Diebold J. KRAS and BRAF mutations in ovarian tumors: A comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants.Gynecol Oncol. 2006; 103: 883-887Crossref PubMed Scopus (164) Google Scholar Accordingly, clear cell carcinomas do not really fit into either type I or type II groups.In contrast to low-grade micropapillary serous carcinomas and other type I tumors, the only mutation that has been consistently detected in type II tumors are mutations in TP53, which are very rare in type I tumors. In addition, type II tumors are characterized by considerable genetic instability, which is not observed in type I tumors. Most studies have shown that approximately 50-80% of advanced stage, presumably high-grade, serous carcinomas have mutant TP53.34Chan W.-Y. Cheung K.-K. 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Runnebaum I.B. et al.p53 mutations and expression in ovarian cancers: Correlation with overall survival.Int J Gynecol Pathol. 1999; 18: 29-41Crossref PubMed Scopus (130) Google Scholar When purified tumor samples are analyzed, the frequency of TP53 mutations is over 80% in high-grade serous carcinomas.40Salani R, Kurman RJ, Giuntoli IRL, et al. Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a much higher mutation rate than previously reported and does not correlate with drug resistance Int J Gynecol Cancer, in press.Google ScholarIt has also been reported that mutant TP53 is present in 37% of stage I and stage II high-grade serous carcinomas.41Shelling A.N. Cooke I. Ganesan T.S. The genetic analysis of ovarian cancer.Br J Cancer. 1995; 72: 521-527Crossref PubMed Scopus (78) Google Scholar In fact, in BRCA heterozygote women who had undergone prophylactic oophorectomy, microscopic, stage I, high-grade serous carcinomas were identified in the ovaries identical to the usual high-grade serous carcinoma that is advanced stage. In addition, the overexpression of p53 and mutation of TP53 were found in the microscopic carcinomas as well as in the adjacent dysplastic epithelium.42Pothuri B, Leitao M, Barakat R, et al. Genetic analysis of ovarian carcinoma histogenesis. Presented at the 32nd Annual Meeting of the Society of Gynecologic Oncologists, 2001 (Abstract).Google Scholar It is plausible that inherited mutations in BRCA genes compromise DNA repair and predispose to genetic instability that may contribute to these dysplastic changes.Although sporadic ovarian carcinomas were not analyzed in this study, the clinical and pathologic features of BRCA-linked ovarian carcinomas and their sporadic counterparts are indistinguishable, suggesting that their histogenesis is similar. Thus, although the molecular genetic findings are preliminary, they suggest that conventional high-grade serous carcinoma, in its very earliest stage, resembles advanced stage serous carcinoma at a molecular as well as a morphologic level.Similar to high-grade serous carcinoma, other type II tumors, specifically malignant mixed mesodermal tumors (carcinosarcomas), also demonstrate TP53 mutations in almost all cases analyzed.43Gallardo A. Matias-Guiu X. Lagarda H. et al.Malignant mullerian mixed tumor arising from ovarian serous carcinoma: A clinicopathologic and molecular study of two cases.Int J Gynecol Pathol. 2002; 21: 268-272Crossref PubMed Scopus (36) Google Scholar, 44Kounelis S. Jones M.W. Papadaki H. Bakker A. Swalsky P. Finkelstein S.D. Carcinosarcomas (malignant mixed mullerian tumors) of the female genital tract: Comparative molecular analysis of epithelial and mesenchymal components.Hum Pathol. 1998; 29: 82-87Abstract Full Text PDF PubMed Scopus (161) Google Scholar, 45Abeln E.C. Smit V.T. Wessels J.W. de Leeuw W.J. Cornelisse C.J. Fleuren G.J. Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed mullerian tumours.J Pathol. 1997; 183: 424-431Crossref PubMed Scopus (119) Google Scholar This has led investigators to suggest that malignant mixed mesodermal tumors are in essence variants of carcinoma so-called metaplastic carcinoma.Implications of the Model for Early Detection and TreatmentThe 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 these approaches are inadequate for large-scale screening.The vast majority of ovarian cancers are type II tumors that are high grade and extremely aggressive and are advanced stage at presentation. Therefore, it is our opinion that the current approach to early detection of ovarian cancer, which focuses on the ovary alone, may selectively identify slow-growing, good progn
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