Pathogenesis and the role of ARID1A mutation in endometriosis-related ovarian neoplasms

Abstract

Endometriosis-related ovarian neoplasms (ERONs) are a unique group of tumors as they are associated with endometriosis, especially endometriosis presenting as an ovarian endometriotic cyst (endometrioma). ERONs include clear cell carcinoma, endometrioid carcinoma, and seromucinous borderline tumor. A growing body of evidence from both clinicopathologic and molecular studies suggests that most, if not all, ERONs develop from endometriotic cyst epithelium through different stages of tumor progression. The endometriotic cyst contains abundant iron-induced reactive oxygen species that are thought to be mutagenic, and chronic exposure of cystic epithelium to this microenvironment facilitates the accumulation of somatic mutations that ultimately result in tumor development. Molecular analyses of ERONs, including genome-wide screens, have identified several molecular genetic alterations that lead to aberrant activation or inactivation of pathways involving ARID1A, PI3K, Wnt, and PP2A. Among all molecular genetic changes identified to date, inactivating mutations of the ARID1A tumor suppressor gene are the most common in ERON. Understanding the molecular changes and pathogenesis involved in the development of ERON is fundamental for future translational studies aimed at designing new diagnostic tests for early detection and identifying critical molecular features for targeted therapeutics.

Fig. 1

Gross appearance and morphological continuum in tumor progression in an endometrioid carcinoma. A. An ovarian endometriotic cyst containing an intracystic polyploid endometrioid carcinoma. B–E. Photomicrographs show a morphological continuum of different stages of tumor progression from normal-appearing endometriotic cyst epithelium to invasive endometrioid carcinoma.

Fig. 2

An example of a seromucinous borderline tumor of the ovary arising from an endometriotic cyst. A. A lower magnification view shows the typical papillary growth of the tumor with abundant mucinous material in the lumen. B. A higher magnification reveals the mixed histologic features of the tumor cells exhibiting serous, mucinous, and hobnail-shaped differentiation. A prominent leukocyte infiltration is also present. C. portion of endometriotic cyst adjacent to the ovarian tumor.

Fig 3. Molecular genetic alterations and pathway aberrations in ERON

The common molecular genetic changes shared by clear cell and endometrioid carcinomas include ARID1A mutation, PIK3CA/PTEN mutation, and PP2R1A mutation. Mutations in CTNNB1 and mismatch repair genes such as MHL1 and MSH2 leading to microsatellite instability are almost always detected in endometrioid carcinoma but not in clear cell carcinoma. Genes in red indicate inactivating (loss of function) mutations, and genes in blue represent activating (gain of function) mutations. The larger the font, the greater the observed frequency of mutation of the gene. Asterisks indicate molecular changes that are predominantly found in ovarian endometrioid carcinoma.

Fig. 4

Types of ARID1A mutations and correlation of mutation and protein expression. A. Analysis of reported ARID1A mutations demonstrates that most of the mutation types belong to frameshift, nonsense, and in-frame mutations that are associated with loss of the tumor suppressor functions of ARID1A. B. ARID1A mutational status in 27 uterine endometrioid carcinomas. All the tumors with ARID1A mutation (in one or both alleles) have lost ARID1A immunoreactivity, and interestingly, two of 15 ARID1A wildtype cases also lost ARID1A staining probably due to epigenetic inactivation. Occasionally, clonal loss of ARID1A expression, as defined by undetectable ARID1A immunoreactivity contiguous to ARID1A positive tumor areas, is found in tumors harboring ARID1A mutations, probably as a result of intra-tumoral heterogeneity. Red boxes denote ARID1A mutation in both alleles (allele 1 and allele 2). Red boxes in the column of ARID1A staining indicate a complete loss (dark red) or clonal loss (light red) of ARID1A expression. Examples of ARID1A staining from two tumors are shown. Asterisk: the tumor area showing clonal loss of ARID1A staining.