Abstract: The pathogenesis of ovarian carcinoma, the most lethal gynecological malignancy, is unknown because of the lack of a tumor progression model. Based on a review of recent clinicopathological and molecular studies, we propose a model for their development. In this model, surface epithelial tumors are divided into two broad categories designated type I and type II tumors that correspond to two main pathways of tumorigenesis. Type I tumors tend to be low-grade neoplasms that arise in a stepwise manner from borderline tumors whereas type II tumors are high-grade neoplasms for which morphologically recognizable precursor lesions have not been identified, so-called de novo development. As serous tumors are the most common surface epithelial tumors, low-grade serous carcinoma is the prototypic type I tumor and high-grade serous carcinoma is the prototypic type II tumor. In addition to low-grade serous carcinomas, type I tumors are composed of mucinous carcinomas, endometrioid carcinomas, malignant Brenner tumors, and clear cell carcinomas. Type I tumors are associated with distinct molecular changes that are rarely found in type II tumors, such as BRAF and KRAS mutations for serous tumors, KRAS mutations for mucinous tumors, and β-catenin and PTEN mutations and microsatellite instability for endometrioid tumors. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcoma), and undifferentiated carcinoma. There are very limited data on the molecular alterations associated with type II tumors except frequent p53 mutations in high-grade serous carcinomas andmalignant mixed mesodermal tumors (carcinosarcomas). This model of carcinogenesis reconciles the relationship of borderline tumors to invasive carcinoma and provides a morphological and molecular framework for studies aimed at elucidating the pathogenesis of ovarian cancer. The pathogenesis of ovarian carcinoma, the most lethal gynecological malignancy, is unknown because of the lack of a tumor progression model. Based on a review of recent clinicopathological and molecular studies, we propose a model for their development. In this model, surface epithelial tumors are divided into two broad categories designated type I and type II tumors that correspond to two main pathways of tumorigenesis. Type I tumors tend to be low-grade neoplasms that arise in a stepwise manner from borderline tumors whereas type II tumors are high-grade neoplasms for which morphologically recognizable precursor lesions have not been identified, so-called de novo development. As serous tumors are the most common surface epithelial tumors, low-grade serous carcinoma is the prototypic type I tumor and high-grade serous carcinoma is the prototypic type II tumor. In addition to low-grade serous carcinomas, type I tumors are composed of mucinous carcinomas, endometrioid carcinomas, malignant Brenner tumors, and clear cell carcinomas. Type I tumors are associated with distinct molecular changes that are rarely found in type II tumors, such as BRAF and KRAS mutations for serous tumors, KRAS mutations for mucinous tumors, and β-catenin and PTEN mutations and microsatellite instability for endometrioid tumors. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcoma), and undifferentiated carcinoma. There are very limited data on the molecular alterations associated with type II tumors except frequent p53 mutations in high-grade serous carcinomas andmalignant mixed mesodermal tumors (carcinosarcomas). This model of carcinogenesis reconciles the relationship of borderline tumors to invasive carcinoma and provides a morphological and molecular framework for studies aimed at elucidating the pathogenesis of ovarian cancer. Ovarian cancer is the most lethal gynecological malignancy and surface epithelial tumors (carcinomas) are the most common type of ovarian cancer. Despite considerable efforts aimed at elucidating the molecular mechanisms of ovarian carcinoma, its pathogenesis is still unknown, because unlike colorectal carcinoma,1Kinzler KW Vogelstein B The Genetic Basis of Human Cancer. McGraw-Hill, Toronto1998Google Scholar a progression model has not been described. Ovarian carcinomas are heterogeneous and are primarily classified by cell type into serous, mucinous, endometrioid, clear cell, and Brenner (transitional) tumors corresponding to different types of epithelia in the organs of the female reproductive tract.2Seidman JD Russell P Kurman RJ Surface epithelial tumors of the ovary.in: Kurman RJ Blaustein's Pathology of the Female Genital Tract. Springer Verlag, New York2002: 791-904Google Scholar, 3Scully RE International Histological Classification of Tumors: Histological Typing of Ovarian Tumors. World Health Organization, Geneva1999Crossref Google Scholar, 4Scully RE World Health Organization International Histological Classification of Tumours. Springer, New York1999Google Scholar The tumors in each of the categories are further subdivided into three groups, benign, malignant, and intermediate (borderline tumor) to reflect their behavior. Mucinous and endometrioid borderline tumors are often associated with invasive carcinomas but serous borderline tumors are rarely associated with serous carcinomas.2Seidman JD Russell P Kurman RJ Surface epithelial tumors of the ovary.in: Kurman RJ Blaustein's Pathology of the Female Genital Tract. Springer Verlag, New York2002: 791-904Google Scholar This latter observation as well as recent molecular genetic studies showing a very different frequency of p53 and KRAS mutations in serous carcinoma as compared to serous borderline tumors have led most investigators to conclude that serous borderline tumors and serous carcinomas are unrelated.5Singer G Kurman RJ Chang H-W Cho SKR Shih I-M Diverse tumorigenic pathways in ovarian serous carcinoma.Am J Pathol. 2002; 160: 1223-1228Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 6Ortiz BH Ailawadi M Colitti C Muto MG Deavers M Silva EG Berkowitz RS Mok SC Gershenson DM Second primary or recurrence? Comparative patterns of p53 and K-ras mutations suggest that serous borderline ovarian tumors and subsequent serous carcinomas are unrelated tumors.Cancer Res. 2001; 61: 7264-7267PubMed Google Scholar, 7Bell DA Scully RE Early de novo ovarian carcinoma. A study of fourteen cases.Cancer. 1994; 73: 1859-1864Crossref PubMed Scopus (192) Google Scholar, 8Caduff RF Svoboda-Newman SM Ferguson AW Johnston CM Frank TS 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 (88) Google Scholar, 9Dubeau L Ovarian cancer.in: Scriver CR Beaudet AL Sly WS Valle D Childs B Kinzler KW Vogelstein B The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, Toronto2001: 1091-1096Google Scholar The uncertainty about the nature of the borderline group of tumors, reflected by the ambiguous term “borderline,” is a major shortcoming of the current classification. Here we review recent histopathological and molecular genetic studies to re-examine this issue and propose a model of ovarian carcinogenesis that integrates clinical, histopathological, and molecular genetic findings. Throughout the last 10 years, we have conducted a systematic microscopic and clinical analysis of a large number of noninvasive and invasive epithelial ovarian tumors of all histological types in an effort to delineate their pathogenesis and behavior.2Seidman JD Russell P Kurman RJ Surface epithelial tumors of the ovary.in: Kurman RJ Blaustein's Pathology of the Female Genital Tract. Springer Verlag, New York2002: 791-904Google Scholar, 10Burks RT Sherman ME Kurman RJ Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors.Am J Surg Pathol. 1996; 20: 1319-1330Crossref PubMed Scopus (293) Google Scholar, 11Riopel MA Ronnett BM Kurman RJ Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas.Am J Surg Pathol. 1999; 23: 617-635Crossref PubMed Scopus (218) Google Scholar, 12Seidman JD Kurman RJ 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. 1996; 20: 1331-1345Crossref PubMed Scopus (276) Google Scholar These studies drew attention to a subset of low-grade serous tumors designated “micropapillary serous carcinoma (MPSC)” with characteristic histopathological features, low proliferative activity, and an indolent behavior that contrasts dramatically with the conventional type of serous carcinoma, an aggressive neoplasm that is high-grade and has high proliferative activity.2Seidman JD Russell P Kurman RJ Surface epithelial tumors of the ovary.in: Kurman RJ Blaustein's Pathology of the Female Genital Tract. Springer Verlag, New York2002: 791-904Google Scholar, 10Burks RT Sherman ME Kurman RJ Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors.Am J Surg Pathol. 1996; 20: 1319-1330Crossref PubMed Scopus (293) Google Scholar, 11Riopel MA Ronnett BM Kurman RJ Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas.Am J Surg Pathol. 1999; 23: 617-635Crossref PubMed Scopus (218) Google Scholar, 12Seidman JD Kurman RJ 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. 1996; 20: 1331-1345Crossref PubMed Scopus (276) Google Scholar The term “MPSC” was originally proposed to distinguish the noninvasive form of this tumor from the more common noninvasive tumor, termed an “atypical proliferative serous tumor,” both of which have been included under the rubric “borderline” or “low malignant potential.”10Burks RT Sherman ME Kurman RJ Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors.Am J Surg Pathol. 1996; 20: 1319-1330Crossref PubMed Scopus (293) Google Scholar, 12Seidman JD Kurman RJ 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. 1996; 20: 1331-1345Crossref PubMed Scopus (276) Google Scholar Histological transitions from adenofibromas and atypical proliferative serous tumors to noninvasive MPSCs are observed in nearly 75% of cases.13Sehdev AES Sehdev PS Kurman RJ Noninvasive and invasive micropapillary serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases.Am J Surg Pathol. 2003; 27: 725-736Crossref PubMed Scopus (126) Google Scholar In addition, areas of infiltrative growth (stromal invasion) immediately adjacent to the noninvasive component are found in a significant proportion of cases (Figure 1).13Sehdev AES Sehdev PS Kurman RJ Noninvasive and invasive micropapillary serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases.Am J Surg Pathol. 2003; 27: 725-736Crossref PubMed Scopus (126) Google Scholar These invasive MPSCs are synonymous with low-grade serous carcinoma. The former term describes its histopathological features and the latter its clinical behavior. The histopathological findings strongly suggest that there is a morphological and biological spectrum beginning with a benign serous cystadenoma/adenofibroma, through a proliferative tumor (atypical proliferative serous tumor) to a noninvasive carcinoma (noninvasive MPSC) ending with an invasive low-grade serous carcinoma (invasive MPSC). Low-grade serous carcinomas typically pursue an indolent course that may last more than 20 years.12Seidman JD Kurman RJ 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. 1996; 20: 1331-1345Crossref PubMed Scopus (276) Google Scholar, 13Sehdev AES Sehdev PS Kurman RJ Noninvasive and invasive micropapillary serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases.Am J Surg Pathol. 2003; 27: 725-736Crossref PubMed Scopus (126) Google Scholar Approximately 50 to 60% of patients ultimately succumb because of widespread intra-abdominal carcinomatosis but the tumor maintains its low-grade appearance and low proliferative index throughout its course (Silva et al, 1997 and unpublished data).13Sehdev AES Sehdev PS Kurman RJ Noninvasive and invasive micropapillary serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases.Am J Surg Pathol. 2003; 27: 725-736Crossref PubMed Scopus (126) Google Scholar This contrasts with conventional high-grade serous carcinoma that presents as a clinically aggressive neoplasm that spreads rapidly and is associated with a poor outcome. Analysis of mucinous, endometrioid, clear cell carcinomas, and malignant Brenner tumors reveals that they are often associated with cystadenomas, borderline tumors, and intraepithelial carcinomas.2Seidman JD Russell P Kurman RJ Surface epithelial tumors of the ovary.in: Kurman RJ Blaustein's Pathology of the Female Genital Tract. Springer Verlag, New York2002: 791-904Google Scholar Furthermore, it has been long recognized that endometrioid carcinoma and clear cell carcinoma are associated with endometriosis in the ovary or pelvis in 15 to 50% of cases14Okuda T Otsuka J Sekizawa A Saito H Makino R Kushima M Farina A Yuzuru K Okai T p53 mutations and overexpression affect prognosis of ovarian endometrioid cancer but not clear cell cancer.Gynecol Oncol. 2003; 88: 318-325Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 15Modesitt SC Tortolero-Luna G Robinson JB Gershenson D Wolf JK Ovarian and extraovarian endometriosis-associated cancer.Obstet Gynecol. 2002; 100: 788-795Crossref PubMed Scopus (208) Google Scholar leading investigators to propose that endometriosis is a precursor of these tumors. Rarely, a high-grade serous carcinoma is associated with ovarian endometriosis but this is viewed as an independent, coincidental finding; a causal relationship of endometriosis and serous carcinoma has never been proposed. A recent clinical study using serial transvaginal ultrasonography has shown that ∼50% of ovarian carcinomas develop from pre-existing cystic lesions whereas the remaining 50% develop in ovaries without apparent abnormality on ultrasound.16Horiuchi A Itoh K Shimizu M Nakai I Yamazaki T Kimura K Suzuki A Shiozawa I Ueda N Konishi I Toward understanding the natural history of ovarian carcinoma development: a clinicopathological approach.Gynecol Oncol. 2003; 88: 309-317Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar The former group was composed mainly of mucinous, endometrioid, clear cell carcinomas, and borderline tumors whereas the latter group was composed almost exclusively of high-grade serous carcinomas. This distribution corresponds to the type I and II tumors described below. Our clinicopathological and molecular genetic studies provide the basis for a proposed model of ovarian carcinogenesis in which there are two main pathways of tumorigenesis, corresponding to the development of type I and type II tumors (Table 1, Table 2). It should be emphasized that the terms, type I and type II, describe pathways of tumorigenesis and are not specific histopathological terms. Type I tumors (low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma) develop in a stepwise manner from well-recognized precursors, namely borderline tumors that in turn develop from cystadenomas and adenofibromas (Figure 1 and Table 1).5Singer G Kurman RJ Chang H-W Cho SKR Shih I-M Diverse tumorigenic pathways in ovarian serous carcinoma.Am J Pathol. 2002; 160: 1223-1228Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar The latter benign tumors appear to develop from the surface epithelium or inclusion cysts in the case of serous and mucinous tumors and from endometriosis or endometriomas in the case of endometrioid and clear cell tumors. Type I tumors are slow growing as evidenced by the observation that they are large and often confined to the ovary at diagnosis. In contrast, type II tumors are high-grade at presentation. Type II carcinomas include what are currently classified as high-grade serous carcinoma (moderately and poorly differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma (Figure 1 and Table 2). In addition, it is likely that some high-grade serous and undifferentiated carcinoma containing cells with clear cytoplasm have been classified as clear cell carcinoma and would be included in this group. Although malignant mixed mesodermal tumors (carcinosarcomas) were once thought to be mixed tumors comprised of carcinoma and sarcoma, recent studies have demonstrated that they are monoclonal.17Masuda A Takeda A Fukami H Yamada C Matsuyama M Characteristics of cell lines established from a mixed mesodermal tumor of the human ovary. Carcinomatous cells are changeable to sarcomatous cells.Cancer. 1987; 60: 1697-2703Crossref Scopus (68) Google Scholar, 18Moritani S Moriya T Kushima R Sugihara H Harada M Hattori T Ovarian carcinoma recurring as carcinosarcoma.Pathol Int. 2001; 51: 380-384Crossref PubMed Scopus (22) Google Scholar Accordingly, these tumors are now regarded as high-grade carcinomas with metaplastic sarcomatous elements. Type II carcinomas are rarely associated with morphologically recognizable precursor lesions and it has been proposed that they develop de novo from the surface epithelium or inclusion cysts of the ovary.7Bell DA Scully RE Early de novo ovarian carcinoma. A study of fourteen cases.Cancer. 1994; 73: 1859-1864Crossref PubMed Scopus (192) Google Scholar They evolve rapidly, metastasize early in their course, and are highly aggressive. It is likely that the apparent de novo conventional high-grade serous carcinoma does develop in a stepwise manner but precursor lesions have not yet been elucidated molecularly or morphologically (Figure 1). Presumably, this is because of rapid transit from inception as a microscopic carcinoma to a clinically diagnosed neoplasm. This is supported by the significantly higher Ki-67 nuclear labeling (proliferation) index in conventional high-grade serous carcinomas compared to low-grade serous carcinomas (unpublished data).19Garzetti GG Ciavattini A Goteri G De Nictolis M Stramazzotti D Lucarini G Biagini G Ki67 antigen immunostaining (MIB 1 monoclonal antibody) in serous ovarian tumors: index of proliferative activity with prognostic significance.Gynecol Oncol. 1995; 56: 169-174Abstract Full Text PDF PubMed Scopus (105) Google ScholarTable 1Precursors and Molecular Genetic Alterations of Type I Tumors of the OvaryType I tumorsPrecursors*Atypical proliferative serous tumors and noninvasive MPSC have been termed “borderline” tumors in the literature. Similarly for mucinous, endometrioid, clear cell, and Brenner tumors, atypical proliferative tumor and intraepithelial carcinoma have been combined and designated “borderline tumor” in the literature.Known molecular genetic alterationsLow-grade serous carcinomaSerous cystadenoma/adenofibromaBRAF and KRAS mutations (∼67%)(invasive MPSC)Atypical proliferative serous tumorNoninvasive MPSCMucinous carcinomaMucinous cystadenomaKRAS mutations (>60%)Atypical proliferative mucinous tumorIntraepithelial carcinomaEndometrioid carcinomaEndometriosisLOH or mutations in PTEN (20%)Endometrioid adenofibromaβ-catenin gene mutations (16–54%)Atypical proliferative endometrioid tumorKRAS mutations (4–5%)Intraepithelial carcinomaMicrosatellite instability (13–50%)Clear cell carcinomaEndometriosisKRAS mutations (5–16%)Clear cell adenofibromaMicrosatellite instability (∼13%)Atypical proliferative clear cell tumorTGF-β RII mutation (66%)†Based on preliminary results analyzing three cases.57Intraepithelial carcinomaMalignant BrennerBrenner tumorNot yet identified(transitional) tumorAtypical proliferative Brenner tumorAbbreviation: MPSC, micropapillary serous carcinoma; LOH, loss of heterozygosity; TGF, transforming growth factor.* Atypical proliferative serous tumors and noninvasive MPSC have been termed “borderline” tumors in the literature. Similarly for mucinous, endometrioid, clear cell, and Brenner tumors, atypical proliferative tumor and intraepithelial carcinoma have been combined and designated “borderline tumor” in the literature.† Based on preliminary results analyzing three cases.57Francis-Thickpenny KM Richardson DM van Ee CC Love DV Winship IM Baguley BC Chenevix-Trench G Shelling AN Analysis of the TGF-beta functional pathway in epithelial ovarian carcinoma.Br J Cancer. 2001; 85: 687-691Crossref PubMed Scopus (26) Google Scholar Open table in a new tab Table 2Precursors and Molecular Genetic Alterations of Type II Tumors of the OvaryType II tumors*Type II tumors can contain neoplastic cells with clear cytoplasm and have sometimes been classified as “clear cell carcinoma.”PrecursorsKnown molecular genetic alterationsHigh-grade serous carcinomaNot yet identifiedp53 mutations (50–80%)Amplification and overepxression of HER2/neu gene (10%–20%) and AKT2 gene (12%–18%)Inactivation of p16 gene (10%–17%)Undifferentiated carcinomaNot yet identifiedNot yet identifiedMalignant mixed mesodermal tumor (carcinosarcomas)Not yet identifiedp53 mutations (> 90%)* Type II tumors can contain neoplastic cells with clear cytoplasm and have sometimes been classified as “clear cell carcinoma.” Open table in a new tab Abbreviation: MPSC, micropapillary serous carcinoma; LOH, loss of heterozygosity; TGF, transforming growth factor. This dualistic model is the first step in an attempt to elucidate the molecular pathogenesis of ovarian carcinoma, but should not be construed as implying that other pathways of tumorigenesis do not exist. For example, it is not certain whether there are other subsets of type II carcinomas. Molecular profiling and epidemiological studies will be important to determine whether there are distinct subsets of type II tumors. Also it is not clear whether some low-grade serous carcinomas (type I) progress to high-grade serous carcinomas (type II). We have observed serous carcinomas with high-grade nuclei and abundant mitotic activity that display a micropapillary architecture, simulating invasive MPSC (low-grade serous carcinoma). We thought that these high-grade tumors may have arisen from invasive MPSCs (low-grade serous carcinoma) but like conventional high-grade tumors without a micropapillary architecture these tumors did not harbor KRAS mutations, indicating that they are not derived from invasive MPSCs (low-grade serous carcinomas) (see below).20Singer G Oldt III, R Cohen Y Wang BG Sidransky D Kurman RJ Shih Ie M Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (689) Google Scholar These data are preliminary and do not rule out the possibility that some low-grade serous carcinomas progress to high-grade carcinomas but the findings do support the view that ovarian serous carcinomas can be graded into low- and high-grade based on nuclear rather than architectural features. Preliminary clinicopathological studies of other type I carcinomas (mucinous, endometrioid, and clear cell carcinomas) have demonstrated that some are moderately and even poorly differentiated, suggesting that some type I carcinomas can evolve from low- to high-grade neoplasms. Serous carcinoma is the most common type of ovarian carcinoma and therefore low-grade and high-grade serous carcinomas serve as the prototypes of type I and type II carcinomas, respectively (Table 3). Accordingly, the molecular genetic data that are being advanced in support of the dualistic model are derived mainly from studies of serous carcinoma.Table 3Summary of Clinicopathological Features of the Prototypic Type I and Type II Tumors: Low-Grade and High-Grade Serous Carcinoma, RespectivelyFrequencyHistologic featuresPrecursor lesionsClinical behavior†Advanced stage tumors.Response to chemotherapyLow grade∼25% of serous carcinomas*Based on a survey at the Johns Hopkins Hospital. Most patients will eventually die from the disease after a protracted clinical course.Micropapillary architecture; low-grade nuclei; low mitotic indexSerous cystadenomaIndolent; slow progression 5-year survival ∼55%‡See Sehdev et al.13PoorSerous atypical proliferative (borderline) tumorHigh grade∼75% of serous carcinomas*Based on a survey at the Johns Hopkins Hospital. Most patients will eventually die from the disease after a protracted clinical course.Solid nests and masses; high-grade nuclei; high mitotic indexNot known; probably from ovarian surface epithelium or inclusion cysts (de novo)Aggressive; rapid progression; 5-year survival∼30%Good, although recurrence is common* Based on a survey at the Johns Hopkins Hospital. Most patients will eventually die from the disease after a protracted clinical course.† Advanced stage tumors.‡ See Sehdev et al.13Sehdev AES Sehdev PS Kurman RJ Noninvasive and invasive micropapillary serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases.Am J Surg Pathol. 2003; 27: 725-736Crossref PubMed Scopus (126) Google Scholar Open table in a new tab There are several distinctive molecular changes that distinguish low-grade and high-grade serous carcinomas (Table 4). Among them, the most significant molecular genetic alterations are mutations in BRAF and KRAS oncogenes. The RAS, RAF, MEK, ERK, and MAP cascade is important for the transmission of growth signals into the nucleus.21Peyssonnaux C Eychene A The Raf/MEK/ERK pathway: new concepts of activation.Biol Cell. 2001; 93: 53-62Crossref PubMed Scopus (605) Google Scholar Oncogenic mutations in BRAF and KRAS result in constitutive activation of this pathway and contribute to neoplastic transformation. Recent studies have demonstrated that KRAS mutations at codons 12 and 13 occur in 35% of low-grade serous carcinomas (invasive MPSCs) and 33% of borderline tumors (atypical proliferative tumor and noninvasive MPSC) but not in high-grade serous carcinomas.5Singer G Kurman RJ Chang H-W Cho SKR Shih I-M Diverse tumorigenic pathways in ovarian serous carcinoma.Am J Pathol. 2002; 160: 1223-1228Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 20Singer G Oldt III, R Cohen Y Wang BG Sidransky D Kurman RJ Shih Ie M Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (689) Google Scholar Similarly, BRAF mutations at codon 599 occur in 30% of low-grade serous carcinomas and 28% of borderline tumors but not in high-grade serous carcinomas.20Singer G Oldt III, R Cohen Y Wang BG Sidransky D Kurman RJ Shih Ie M Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (689) Google Scholar Mutations in BRAF and KRAS, therefore, were found in 65% of low-grade invasive serous carcinomas and in 61% of atypical proliferative tumors and noninvasive MPSCs, their putative precursors, but neither of the genes was mutated in high-grade serous carcinomas. It is of interest that BRAF mutations were found only in tumors with wild-type KRAS.20Singer G Oldt III, R Cohen Y Wang BG Sidransky D Kurman RJ Shih Ie M Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (689) Google Scholar The mutually exclusive nature of BRAF mutations at codon 599 and KRAS mutations at codons 12 and 13 in ovarian carcinoma is consistent with similar findings in melanoma and colorectal carcinoma22Davies H Bignell GR Cox C Stephens P Edkins S Clegg S Teague J Woffendin H Garnett MJ Bottomley W Davis N Dicks E Ewing R Floyd Y Gray K Hall S Hawes R Hughes J Kosmidou V Menzies A Mould C Parker A Stevens C Watt S Hooper S Wilson R Jayatilake H Gusterson BA Cooper C Shipley J Hargrave D Pritchard-Jones K Maitland N Chenevix-Trench G Riggins GJ Bigner DD Palmieri G Cossu A Flanagan A Nicholson A Ho JW Leung SY Yuen ST Weber BL Seigler HF Darrow TL Paterson H Marais R Marshall CJ Wooster R Stratton MR Futreal PA Mutations of the BRAF gene in human cancer.Nature. 2002; 417: 949-954Crossref PubMed Scopus (8096) Google Scholar, 23Rajagopalan H Bardelli A Lengauer C Kinzler KW Vogelstein B Velculescu VE Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.Nature. 2002; 418: 934Crossref PubMed Scopus (1047) Google Scholar and lends support for the view that BRAF and KRAS mutations have an equivalent effect on tumorigenesis. Mutations of BRAF and KRAS seem to occur very early in the development of low-grade serous carcinoma as evidenced by the detection of these mutations in small atypical proliferative serous tumors but not in serous cystadenomas.24Cheng EJ, Kurman RJ, Wang M, Oldt III R, Berman DM, Shih I-M: Molecular genetic analysis of ovarian serous cystadenomas. Lab Invest 2004, in pressGoogle Scholar These data provide cogent evidence that the development of conventional high-grade serous carcinomas involves molecular mechanisms not related to mutations in BRAF and RAS