Proposed Model of Ovarian Carcinogenesis

Recent clinicopathologic and molecular genetic studies as previously discussed provide the basis for a more comprehensive model of ovarian carcinogenesis, which proposes that there are two main pathways of tumorigenesis, corresponding to the development of type I and type II tumors (Tables 2-1 and 2-2 and Fig. 2-1). Note that

Table 2-1. Precursors and Molecular Genetic Alterations of Type I Tumors of the Ovary Precursors* Known Molecular Genetic Alterations

Low-Grade Serous Carcinoma (Invasive MPSC)

Serous cystadenoma/adenofibroma

Intraepithelial carcinoma Noninvasive MPSC Mucinous Carcinoma

Mucinous cystadenoma

Atypical proliferative mucinous tumor Intraepithelial carcinoma

Endometrioid Carcinoma Endometriosis

Endometrioid adenofibroma

Atypical proliferative endometrioid tumor

Intraepithelial carcinoma

Clear Cell Carcinoma

Endometriosis

Clear cell adenofibroma Atypical proliferative clear cell tumor Intraepithelial carcinoma Malignant Brenner (Transitional) Tumor Brenner tumor

Atypical proliferative Brenner tumor

BRAF and KRAS mutations (~67%)

KRAS mutations (>60%)

LOH or mutations in PTEN (20%) P-catenin gene mutations (16-54%) KRAS mutations (4-5%) Microsatellite instability (13-50%)

KRAS mutations (5-16%) Microsatellite instability (13%) TGF-P RII mutation (66%)

Not yet identified

LOH, loss of heterozygosity; MPSC, mlcropaplllary serous carcinoma; 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.

Table 2-2. Precursors and Molecular Genetic Alterations of Type II Tumors* of the Ovary

Precursors Known Molecular Genetic Alterations

Table 2-2. Precursors and Molecular Genetic Alterations of Type II Tumors* of the Ovary

Precursors Known Molecular Genetic Alterations

High-Grade Serous Carcinoma

Not yet Identified

p53 mutations (50-80%)

Amplification and overexpression of HER2/neu (10-20%) and AKT2 (12-18%)

Inactivation of p16 gene (10-17%)

Undifferentiated Carcinoma

Not yet identified

Not yet identified

Malignant Mixed Mesodermal Tumor

(Carcinosarcomas)

Not yet identified

p53 mutations (>90%)

*Type II tumors can contain neoplastic cells with clear cytoplasm and have sometimes been classified as "clear cell carcinoma."

*Type II tumors can contain neoplastic cells with clear cytoplasm and have sometimes been classified as "clear cell carcinoma."

Type I pathway Type II pathway

Type I pathway Type II pathway

Frequent BRAF/KRAS mutations Low cellular proliferation Gradual increase in CIN Five-year survival ~ 55%

Figure 2-1. A simplified diagram of types I and II ovarian epithelial cancers. CIN, cervical intraepithelial neoplasia; MPSC, micropapillary serous carcinoma; SBT, serous borderline tumor.

type I and type II tumors describe pathways of tumorigenesis and are not specific histopathologic terms. Thus, they are not designed to replace the conventional terminology in pathology reports. Rather, the proposed model provides another view to classify ovarian epithelial tumors that may have clinical or translational implications in studying ovarian cancer.

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