When Is "Type I" Ovarian Cancer Not "Type I"? Indications of an Out-Dated Dichotomy

Abstract

The dualistic classification of epithelial ovarian cancer (EOC) into "type I" and "type II" is widely applied in the research setting; it is used as a convenient way of conceptualizing different mechanisms of tumorigenesis. However, this classification conflicts with recent molecular insights of the etiology of EOC. Molecular and cell of origin studies indicate that while type II tumors could be classed together, type I tumors are not homogenous, even within the histological types, and can have poor clinical outcomes. Type II high grade serous carcinoma and type I low grade serous carcinomas best fit the description of the dualistic model, with different precursors, and distinct molecular profiles. However, endometriosis-associated cancers should be considered a separate group, without assuming an indolent course or type I genetic profiles. Furthermore, the very clear differences between mucinous ovarian carcinomas and other type I tumors, including an uncertain origin, and heterogeneous mutational spectrum and clinical behavior, indicate a non-type I classification for this entity. The impression that only type II carcinomas are aggressive, have poor prognosis, and carry TP53 mutations is an unhelpful misinterpretation of the dualistic classification. In this review, we revisit the history of EOC classification, and discuss the misunderstanding of the dualistic model by comparing the clinical and molecular heterogeneity of EOC types. We also emphasize that all EOC research, both basic and clinical, should consider the subtypes as different diseases beyond the type I/type II model, and base novel therapies on the molecular characteristics of each tumor.

Keywords: classification; dualistic model; epithelial ovarian cancer; ovarian carcinoma; type I-II tumors.

Figure 1

Timeline classification of epithelial ovarian cancer. Blue boxes on the left show author contributions to ovarian cancer (OC) classification over time. Red, yellow, and green boxes represent the evolution of OC classification from a single disease entity to a binary model. Finally, the different sub classifications of epithelial ovarian cancer (center red box), are presented from 1942 to the latest model in 2015.

Figure 2

Molecular factors and characteristics distinguishing type I and II tumors. The shade of each box represents the frequency of the characteristics listed at left in each subtype, grouped according to their previous type I/type II assignment. ENOC, endometrioid ovarian carcinoma; CCOC, clear cell ovarian carcinoma; LGSC, low grade serous carcinoma; MOC, mucinous ovarian carcinoma; HGSC, high grade serous carcinoma.