Abstract
Simple SummaryHistorically, cancers presenting with their main tumor mass in the ovary have been classified as ovarian carcinomas (a concise term for epithelial ovarian cancer) and treated with a one-size-fits-all approach. Over the last two decades, a growing molecular understanding established that ovarian carcinomas consist of several distinct histologic types, which practically represent different diseases. Further research is now delineating several molecular subtypes within each histotype. This histotype/molecular subtype subclassification provides a framework of grouping tumors based on molecular similarities for research, clinical trial inclusion and future patient management.The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). Since histotypes arise from different cells of origin, cell lineage-specific diagnostic immunohistochemical markers and histotype-specific oncogenic alterations can confirm the morphological diagnosis. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish the five principal histotypes with high accuracy, and additional immunohistochemical markers can be used depending on the diagnostic considerations. Histotypes are further stratified into molecular subtypes and assessed with predictive biomarker tests. HGSCs have recently been subclassified based on mechanisms of chromosomal instability, mRNA expression profiles or individual candidate biomarkers. ECs are composed of the same molecular subtypes (POLE-mutated/mismatch repair-deficient/no specific molecular profile/p53-abnormal) with the same prognostic stratification as their endometrial counterparts. Although methylation analyses and gene expression and sequencing showed at least two clusters, the molecular subtypes of CCCs remain largely elusive to date. Mutational and immunohistochemical data on LGSC have suggested five molecular subtypes with prognostic differences. While our understanding of the molecular composition of ovarian carcinomas has significantly advanced and continues to evolve, the need for treatment options suitable for these alterations is becoming more obvious. Further preclinical studies using histotype-defined and molecular subtype-characterized model systems are needed to expand the therapeutic spectrum for women diagnosed with ovarian carcinomas.
Highlights
The subclassification of ovarian carcinomas is based on a hierarchical approach; the first step is to subclassify based on traditional histopathological phenotypes into histotypes
This study shows the power of quantitative multigene signatures in better reflecting the complex cellular biology of high-grade serous carcinoma (HGSC)
The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification
Summary
The subclassification of ovarian carcinomas is based on a hierarchical approach; the first step is to subclassify based on traditional histopathological phenotypes into histotypes. With changes in site assignment, primary peritoneal high-grade serous carcinoma is exceedingly rare. The other histotypes are generally assigned to an ovarian primary, endometrioid (EC) and clear cell carcinoma (CCC) arise from endometriosis, which is ectopic endometrium, meaning that the tissue of origin is not the ovary [8,9]. Low-grade serous carcinomas (LGSCs) are of fallopian tube-type cell lineage, are often meta- or synchronously associated with serous borderline tumors and show frank invasion in the ovary (ovarian primary). If metastatic adenocarcinomas (mostly from the lower or upper gastrointestinal tract) are excluded, ovarian mucinous carcinomas (MCs) arise from the ovary Despite their obvious progression from benign/borderline to malignant, a convincing normal cell of origin in the ovary remains elusive. Rare cases are associated with Brenner tumors or are of germ cell origin (associated with teratomas) [13,14]
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