The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded

Abstract

Since our proposal of a dualistic model of epithelial ovarian carcinogenesis more than a decade ago, a large number of molecular and histopathologic studies were published that have provided important insights into the origin and molecular pathogenesis of this disease. This has required that the original model be revised and expanded to incorporate these findings. The new model divides type I tumors into three groups: i) endometriosis-related tumors that include endometrioid, clear cell, and seromucinous carcinomas; ii) low-grade serous carcinomas; and iii) mucinous carcinomas and malignant Brenner tumors. As in the previous model, type II tumors are composed, for the most part, of high-grade serous carcinomas that can be further subdivided into morphologic and molecular subtypes. Type I tumors develop from benign extraovarian lesions that implant on the ovary and which can subsequently undergo malignant transformation, whereas many type II carcinomas develop from intraepithelial carcinomas in the fallopian tube and, as a result, disseminate as carcinomas that involve the ovary and extraovarian sites, which probably accounts for their clinically aggressive behavior. The new molecular genetic data, especially those derived from next-generation sequencing, further underline the heterogeneity of ovarian cancer and identify actionable mutations. The dualistic model highlights these differences between type I and type II tumors which, it can be argued, describe entirely different groups of diseases.

Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Expanded dualistic model of ovarian carcinogenesis. Ovarian carcinomas derive from endometrial tissue, fallopian tube tissue, germ cells, and transitional epithelium. Type I carcinomas comprise endometrioid, clear cell, LG serous, and mucinous carcinomas. Seromucinous carcinomas and malignant Brenner tumors are rare. It was recently proposed that seromucinous neoplasms be designated mixed Müllerian tumors. Type II carcinomas are largely composed of HG serous carcinoma, carcinosarcoma, and undifferentiated carcinoma. Transitional cell indicates metaplastic transitional epithelium at the tuboperitoneal junction. HG, high-grade; LG, low-grade; SET, solid pseudoendometrioid transitional.

Figure 2

The revised dualistic model in the pathogenesis of ovarian epithelial cancer. Type I carcinomas comprise low-grade serous, clear cell, endometrioid, and mucinous carcinomas. Seromucinous carcinomas and malignant Brenner tumors are rare and not shown. Type II carcinomas are largely composed of high-grade serous carcinomas. Carcinosarcoma and undifferentiated carcinoma are relatively uncommon and not illustrated. The areas in individual histotypes reflect their relative prevalence. The inner circle indicates the likely cell of origin of the different type I and type II neoplasms. The origin of mucinous carcinomas is not well established and is discussed in the text. The molecular pathway alterations that characterize each tumor subtype are summarized in the square boxes. Some of the pathway abnormalities are shared by some tumor types and they are shown in two-color fill in boxes. ARID1A, AT-rich interaction domain 1A; BRAF, B-Raf proto-oncogene, serine/threonine kinase; CCNE1, cyclin E1; ERRB2, estrogen-related receptor β2; HR DDR, homologous recombination-mediated DNA damage repair; KRAS, Kirsten rat sarcoma viral oncogene homolog; MEK, mitogen-activated protein (MAP) extracellular signal-related kinase (ERK) kinase; MMR, DNA mismatch repair; NF1, nuclear factor 1; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; Rb, retinoblastoma protein.