In a histopathological perspective, endometriosis is defined as the presence of endometrial-like glandular epithelium and stroma outside the uterus. At the immunohistochemical level, the phenotype of endometrial glands is similar to that of normal endometrial tissue (27). However, there are certain microscopic alterations specific of ovarian endometriosis, which are listed in Table I and illustrated in Fig. 1.

Regarding the presence of ectopic endometrial epithelium, several studies have documented the presence of hyperplasia and/or atypia in cytologic endometrial lesions (25-27). Atypical endometriosis has been indicated to confer a higher increase risk of malignant transformation to ovarian cancer (28). A total of ~8% of ovarian endometriosis exhibits histopathological features of atypical endometriosis (4). The presence of hyperplastic lesions in the glandular epithelium is less frequent compared with that in atypia but may be present in some ovarian endometriosis cysts (28).

Ovarian cancer is classified in two distinct subgroups, type I and II, taking into account the clinical features, histopathological characteristics and gene expression pattern (24,27). Type I subgroup is characterized by a low rate of proliferation, while type II subgroup exhibits a higher proliferation rate and is more aggressive (24,27). In addition, type I subgroup includes low-grade serous, borderline serous, mucinous, endometrioid and clear cell carcinoma, while type II subgroup is comprises high-grade serous carcinoma, mixed malignant mesodermal carcinosarcomas and undifferentiated carcinoma (28,29).

Two subcategories of type I epithelial ovarian cancer, endometrioid and clear cell carcinoma, appear to be more often derived from or coexist with ovarian endometriosis (9,10,18,30). These two subcategories are the most frequent types after serous carcinoma. Two previous population-based studies which reviewed the pathology using modern diagnostic criteria presented an estimated frequency of 12-13% for clear cell and 9-11% for endometrioid carcinoma, among 20% of all epithelial ovarian cancer (18,31).

The main histological characteristics of these two ovarian cancer subtypes are presented in Table II and Fig. 2.

EAOC is defined as one of the following three conditions: i) Detection in the same ovary of endometriosis and ovarian cancer; ii) detection of endometriosis in one ovary and of ovarian cancer in the other; iii) coinciding identification of ovarian cancer in any of the ovaries and pelvic endometriosis (28). Considering the initial assumption of Sampson regarding the malignant transformation of endometriosis to ovarian cancer (2), when currently EAOC is considered as a single entity, it has been defined as cumulative histological features characteristic to benign endometriosis, endometriosis contiguous with or associated with an ovarian malignancy and malignant lesions intercalated with several intermediary lesions (Fig. 3) (32).

Several studies reporting histopathological characteristics of EAOC have been performed. Of these, Fukunaga et al (33) reported atypical endometriosis for 54% of clear cell and 42% of endometrioid carcinoma. Ballouk et al (34) indicated that half of the endometrial cysts demonstrated severe atypia and presented with an invasive capacity of malignancies.

From a molecular point of view, ovarian endometriosis is characterized by a broad and important genetic variety which can result in a wide genetic instability (32). Histologically, molecular abnormalities can be concealed in benign endometriosis, which subsequently may lead to a malignant transformation (28).

In ovarian endometriosis, several studies have reported genetic mutations with important contributions in this pathology and its possible malignant transformation (Table III).

ARID1A is a gene identified to exhibit a tumor suppressor role, and the loss of ARID1A expression is considered to be responsible for the activation of early carcinogenic mechanisms (28). Mutations of ARID1A have been indicated to be directly connected with atypical endometriosis (35). However, no alterations in the ARID1A expression level have been identified in paired samples of distal nonatypical endometriotic tissue (27).

PTEN, which is another tumor suppressor gene, has been reported to be present in endometriotic lesions, while it has been indicated that PTEN inactivation exhibits a significant role in the malignant evolution of endometriosis (36).

PIK3CA has been recognized for its oncogenic role. Mutations in this gene have been evaluated in nonatypical and atypical endometriosis, and are considered to be an early event in carcinogenesis, possibly at the beginning of malignant transformation of endometriosis (37).

CTNNB1 gene also exhibits an oncogenic function, which has been highlighted by its important role in the diagnosis of nonatypical and atypical endometriosis (38). CTNNB1 has been indicated to exhibit a prominent function in the early events of the transformation of endometriosis to ovarian cancer (38).

BRCA1 and BRCA2 are important early onset tumor suppressors genes. Mutations in the BRCA1 and BRCA2 genes have been reported in the evolution of various human cancers, including ovarian tumors. However, regarding their role in endometriosis, there are fewer reports (18,39).

The presence of TP53 tumor suppressor gene mutations in atypical endometriosis is debated. Certain studies have indicated that alterations in the TP53 gene were present in atypical and low levels or absent in nonatypical endometriosis (37-39). It has been speculated, according to microarray results, that TP53 cancer-related pathways may participate in endometriosis progression (40).

KRAS is an oncogene, whose activation was detected in de novo endometriosis in mice. This suggested that activation of KRAS is an important pathway in the initiation and progression of this disease (18). KRAS mutations have also been observed at an important level in the eutopic endometrium of patients with endometriosis (40).

The classification of ovarian cancer based on histopathological and clinical features is accompanied by the gene expression pattern and mutational determination, which reflect the main factors responsible for the malignant transformation of ovarian cancer. These genes include KRAS, BRAF, PTEN, PIK3CA, CTNNB1 (the gene encoding β-catenin), ARID1A, PPP2R1A and rarely TP53 (18,28,29,41). Considering the differentiation of ovarian cancers in two subtypes (I and II) as artificial and limiting in managing the complex biology of the disease, another classification consisting of five different subcategories has been proposed, based on clinical, morphological and molecular abnormalities (28).

Among all subcategories of ovarian cancer introduced in routine classification, the two subcategories associated with endometriosis, endometrioid and clear cell carcinoma, are extensively studied at the molecular level (42). In these two subcategories, gene mutation patterns have been identified in a different frequency, which conferred heterogeneous reports on the progression of malignant ovarian lesions (Table IV). According to the experimental data, the inactivation of ARID1A and PTEN tumor suppressor gene pathways and the activation of the oncogenic pathways regulated by PI3KCA, KRAS and CTNNB1 are responsible for initiating complex processes, which have been suggested as potential mechanisms associated with the early carcinogenesis and transformation of ovarian cancer (28,38). Regarding the inactivating mutations in BRCA1/2 in endometrioid and clear cell carcinoma, there is no unanimously accepted opinion that BRCA gene mutations contribute to the pathology of the two cancers (29,43). BRCA mutations or inactivation of gene expression have been indicated to occur more frequently in high grade serous carcinoma (29).

The molecular pathways associated with the malignant transformation of EAOC remain to be fully elucidated. Endometriosis has been indicated to comprise mutations highlighted in coexisting tumors, which may designate a primary stage of evolution towards ovarian malignant transformation (44).

EAOC has been reported to exhibit a high percentage of PIK3CA and KRAS activating mutations and ARID1A and PTEN inactivating mutations (35,37,38), whilst a reduced percentage of cases has been indicated to comprise TP53 and BRCA1/2 mutations (45,46). A previous study has identified KRAS mutations in 29% of EAOC cases and only in 3% of tumors with no endometriosis (47). Lakhani et al (43) reported a smaller, but significant association between BRCA1/2 and endometrioid and clear cell carcinoma, namely for endometrioid: 33% of BRCA1, 29% of BRCA2 and for clear cell: 10% of BRCA; 1.4% of BRCA2.

Endometriosis has been regarded as an ideal target for genomic sciences, since it lacks an efficient diagnostic and therapeutic management, as it represents a heterogeneous disease with multiple phenotypes and a complex pathophysiology (55). Several studies have indicated that miRNAs were implicated in the progression of endometriosis (2,20,56). However, at present there is no specific clinical biomarker to be used in patients with endometriosis.

miR-200 family is one of the most widely studied miRNA families in endometriosis, and comprises miR-200a, miR-200b, miR-200c, miR-141 and miR-429(57). miR-200b has been demonstrated to be the most downregulated transcript in previous studies on the molecular regulation of endometriosis (20). miRNAs of this family have been indicated to target PTEN and CTNNB1 genes (22).

miR-20a and miR-20b have been found to be dysregulated in ovarian endometriosis (55,58). miR-20b has been indicated to contributes to the process of neovascularization in endometriosis (55) and target PTEN and BRCA1 genes.

miR-17-5p was reported by Jia et al (59) to be upregulated in patients with endometriosis compared with those without the disease, and has been indicated to target the PIK3CA gene.

Other miRNAs associated with endometriosis include miR-34a/b/c, which were demonstrated by Burney et al (23) to be downregulated in ovarian endometriosis and target CTNNB1 and PTEN genes. miR-1-3p has been also reported to be upregulated in patients with endometriosis (20), and target the PIK3CA gene. The CTNNB1 gene has been indicated to be a target of miR-155-5p, which has been demonstrated to be dysregulated in endometriosis (60). miR-21-5p has been revealed to be involved in the pathogenesis of endometriosis exhibiting aberrant expression profiles (60) has been indicated to directly target BRCA1 and PTEN affecting their expression. PIK3CA, BRCA1 and BRCA2 have also been indicated to be targets of miR-335(22).

miRNAs present regulatory functions, certain of which exhibit important implications in carcinogenesis (61). Transcriptional microarray data have demonstrated that there is a different expression level of miRNAs between normal and tumor tissue (60). The up- and downregulation of miRNA expression have been associated with cancer development and progression (62). Alterations in miRNAs expression have been implicated in invasion and migration in ovarian carcinogenesis (63).

miR-200 family has been indicated to be involved in the metastasis of ovarian cancer (19). Notch signaling is considered to be a regulator of cell invasion in tumors (59). Notch signaling blockade via the miR-200 family has been indicated to represent a promising therapeutic approach for ovarian cancer (64).

miR-335 has been demonstrated to be downregulated in primary ovarian cancer tissue compared with normal tissue (65). Cao et al (65) also reported that patients with primary ovarian cancer who exhibited a low expression of miR-335 had a shorter survival period. In addition, miR-335 level has been revealed to be an important prediction factor of tumor recurrence (65). miR-335 has been indicated to target PIK3CA, BRCA1 and BRCA2 genes (22).

miR-17-5p has been reported to be overexpressed in ovarian cancer. Liu et al (66) demonstrated that miR-17 stimulated the proliferation rate, accelerated cell cycle progression and affected the invasion capacity of the ovarian cancer cells in vitro. miR-17 has been also indicated to be involved in the transition from low to high degree ovarian cancer (66) and directly target the PIK3CA gene (22).

miR-34a-3p has been revealed to be frequently downregulated in ovarian cancer, being directly transactivated by the TP53 tumor suppressor gene, which is frequently dysregulated in ovarian epithelial cancer (67). miR-34 has been indicated to affect the motility, proliferation and migration of ovarian cancer cells (67) and directly target the CTNNB1 gene (22).

miR-1 level has been demonstrated to be decreased in ovarian cancer compared with normal ovarian tissue, indicating the potential tumor suppressor role of this gene (68).

miR-155-5p was revealed by Gulei et al (69) to exhibit increased expression in endometriosis, which was further accentuated in ovarian cancer samples but without statistical significance. miR-155 has been indicated to affect apoptosis and target the CTNNB1 gene (22).

miR-21-5p upregulation has been associated with ovarian cancer, where Liu et al (70) revealed that suppression of miR-21 reduced cell proliferation and promoted cell apoptosis by increasing PTEN expression. Apart from PTEN, miR-21 has been indicated to target the BRCA1 gene (22).

miR-148a is part of the miR-148/152 family. Downregulation of miR148/152 family members has been associated with unfavorable prognostic outcomes in ovarian cancer (71). miR-148a-5p targets the BRCA1 and BRCA2 genes (22).

Another miRNA associated with ovarian cancer is miR-20 which has been indicated to target the PIK3CA gene (22).

Endometriosis presents a biological behavior with increased invasiveness similar to that of tumors. The invasion process is mediated by the downregulation of E-cadherin and alterations in the cell phenotype following epithelial-to-mesenchymal transition (72). This comprises a complex process converting the immotile epithelial cells into motile ones, as a response to injury (73). Therefore, endometriosis may be induced by epithelial-to-mesenchymal transition.

Fig. 4 presents the network of miRNAs-target genes in the context of ovarian endometriosis, EAOC and ovarian cancer. The three pathological states depicted in Fig. 4 have different common denominators of altered genes and miRNAs. However, large patient cohorts need to be employed before establishment of specific clinical signatures, such as a miRNA signature for the prediction of the evolution of endometriosis towards malignancy.

A synthesis of histological and molecular aspects encountered in ovarian endometriosis and ovarian cancer are highlighted in Fig. 5.