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Histological aspects of ovarian cancer. In terms of macroscopic features, epithelial ovarian cancer (here referring to endometrioid and clear cell carcinoma) is a cumulative entity, presenting various forms with imprecise delimitation and variable dimensions. In terms of microscopic features, schematic representation (upper image) with subsequent identification of important characteristics in the lower microscopic image outlines the disordered architecture with numerous atypical glands and nuclear variations. These are associated with elements presented and described in the benign inflammatory endometriosis or the non-endometriotic process.
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Ovarian endometriosis is a frequent chronic gynecological disease with an uncertain evolution regarding its progression or association with ovarian malignant lesions. The present review summarized the histological aspects, gene expression and microRNA (miRNA/miR) alterations associated with ovarian endometriosis and cancer and their possible intera...
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... The miR-548 members seem to have a crucial role in maintaining oocyte function. Oltean et al. reported that hsa-miR-548au-3p was down-regulated and hsa-miR-548ae-5p, hsa-miR-548t-3p and hsa-miR-548au-5p were up-regulated [41]. Zhang et al. examined 68 patients by collecting ovarian FF and detected 47 miRNAs, which were involved in oocyte quality. ...
Cellular metabolism, apoptosis, fertilization, and proliferation of granulosa cells belong to a battery of processes where microRNAs can be detected and associated with infertility. The aim of the present review is to focus on mammalian oocyte maturation events and the association between oocyte growth and miRNA expression. PubMed/Medline, Google Scholar and Scopus databases were searched, and 33 studies were included. Regarding the correlation among miRNA expression and the regulation of granulosa cells and cumulus cells, the most important miRNAs were let-7b, let-7c and miR-21. Additionally, the loss of Dicer, an enzyme involved in miRNA biogenesis, is probably a crucial factor in oogenesis, oocyte maturation and embryogenesis. Furthermore, miRNAs interfere with different cellular mechanisms like apoptosis, steroidogenesis, genome integrity, angiogenesis, antioxidative response and, consequently, oocyte maturation. Hence, it is of major importance to clarify the role and mechanism of each miRNA as understanding its action may develop new tools and establish new diagnostic and treatment approaches for infertility and ovarian disorders.
... Instead, architectural atypia or hyperplasia is comparable to endometrial hyperplasia (simple or complex atypia, with or without cytologic alterations) [30]. Extensive research has been conducted on the histologic transition between endometriosis, AE, and EAOC [32], with a proven connection between AE and EAOC, supporting its role as a pre-malignant lesion [32,33]. The criteria for cytologic atypia in endometriosis were first introduced by Czernobilsky in 1979 [34] and supported by LaGrenade in 1988 [32], defined as the presence of eosinophilic cytoplasm, large hyperchromatic or pale nuclei with moderate to marked pleomorphism, an increased nuclear to cytoplasmic ratio, cellular crowding, and stratification or tufting. ...
Endometriosis is a benign condition affecting women of reproductive age. A potential association with ovarian cancer has been documented. Atypical endometriosis (AE) is characterized by deviations from the typical microscopic appearance of endometriosis, including cytologic and architectural atypia. AE has been recognized as a potential precursor to endometriosis-associated ovarian cancers (EAOC), particularly endometrioid and clear cell subtypes. AE presents challenges in diagnosis due to its diverse clinical and pathological features, often requiring careful histological evaluation for accurate identification. Architectural AE, defined by localized proliferation of crowded glands with atypical epithelium resembling endometrial neoplasia, and cytologic AE, characterized by nuclear atypia within the epithelial lining of endometriotic cysts, are key subtypes. Immunohistochemical and molecular studies have revealed aberrant expression of markers such as Ki67, COX-2, BAF250a, p53, estrogen receptor, progesterone receptor, and IMP-3. Long-term follow-up studies suggest relatively low recurrence and malignant transformation rates among patients with AE, but uncertainties persist regarding its exact malignancy potential and optimal management strategies. Integration of artificial intelligence and shared molecular aberrations between AE and EAOC may enhance diagnostic accuracy. Continuous interdisciplinary collaboration and ongoing research efforts are crucial for a deeper understanding of the relationship between endometriosis and carcinogenesis, ultimately improving patient care and surveillance.
... Але припускають, що у пацієнток з ендометріозом у 17-44% випадків наявний саме ендометріоз яєчників [5]. Приблизно у 1% випадків ендометріоз асоціюється зі злоякісним ураженням яєчників [6]. ...
... Ризик розвитку злоякісного процесу набагато більше зростає на тлі попереднього атипового ендометріозу яєчників [5]. Повідомляють, що цитологічна атипія та архітектурна проліферація, якими характеризується атиповий ендометріоз, є проміжним станом між доброякісним та злоякісним процесом в ендометріомах яєчників, і саме в ньому відбуваються всі ті тригерні механізми, внаслідок яких виникає рак яєчників [23]. ...
... Стверджують, що мутації спостерігаються як при ендометріомах яєчників без атипових змін, так і при атиповому ураженні [16]. Але за появи атипового ендометріозу яєчників значно посилюються онкогенні мутації [5,28,29]. ...
Ovarian cancer is the second most common cause of death from gynaecological malignancies in the world, and in Ukraine it is the most serious type of gynecological cancer. Ovarian endometriomas significantly increase the risk of ovarian cancer, but
their malignant transformation occurs in approximately 1% of cases.
The article presents a literature review based on the scientific databases PubMed and Scopus for 2013–2023 on the incidence and frequency of ovarian malignant tumors on the background of ovarian endometriosis, carcinogenic mutations, immunological and hormonal disorders in ovarian endometriosis, which can cause its progression to ovarian cancer. Based on the analyzed scientific data, the connection between ovarian endometriosis and ovarian cancer is presented and all possible
pathogenetic pathways through which ovarian endometriosis can lead to the formation of ovarian cancer are determined. According to the scientific literature, ovarian endometriosis can indeed lead to the formation of endometrioid and clear cell carcinomas, as well as other subtypes of malignant ovarian tumors. The risk of malignant changes in patients with ovarian endometriomas increases with age, the highest risk is observed in patients over 50 years of age. Despite this, some researchers believe that there are no time limits in the occurrence of malignant transformation of endometrioid ovarian cysts.
Today, it is believed that atypical ovarian endometriosis, which is characterized by cytological atypia and architectural proliferation,
is a precursor to ovarian cancer, and this condition that has the greatest risk for malignant process development is observed. Ovarian endometriomas contain a huge amount of heme and free iron, which leads to the appearance of an excess
of free iron, and as a result, redox disorders occur, which cause carcinogenic mutations and destruction of cellular structures.
Mutations in such genes as ARID1A, PIK3CA, AKT1, ERBB2 and PIK3R1, CTNNB1, KRAS, BRAF, PPP2R1A and occasionally in TP53 gene are involved in the occurrence of malignant changes in ovarian endometriomas. The same mutations are
found in endometrioid foci of the ovaries and in endometrioid and clear cell carcinomas, which confirms the cancer development due to endometriosis. Disorders in the immune system in endometrioid lesions of the ovaries play a significant role in possible malignant transformation. The production of tumor necrosis factor, interleukin-1β, interleukin-6 increases, the function
of natural killers decreases, and immunosuppression increases.
Ovarian endometrioid cysts overexpress estradiol because they have increased amounts of the enzyme aromatase and lack the enzyme 17β-hydroxysteroid dehydrogenase type II, which is required to convert estradiol to estrone. Such changes lead to increased proliferative processes, which can also lead to the activation of oncogenic mutations.
Thus, ovarian endometriosis significantly increases the risk of developing ovarian cancer, especially endometrioid and clear cell carcinomas. The mechanism of malignant transformation occurs precisely with the appearance of atypical endometriosis of the ovaries. The main pathogenetic pathways through which a malignant process can develop in ovarian endometriomas include:
redox imbalance, which triggers a whole spectrum of oncogenic mutations, as well as immune disorders and exposure to high levels of estrogens. However, if patients with ovarian endometriomas are properly managed, the likelihood of ovarian cancer
development is low.
Keywords: ovarian endometriosis, atypical endometriosis, ovarian cancer, mutations, pathogenesis.
... P53 expression is absent in benign endometriosis but significantly present in benign endometriotic lesions adjacent to endometrioid or clear cell carcinoma [60]. There is some controversy regarding whether mutations in the P53 are present in atypical endometriosis [63]. ...
... PIK3CA The presence of mutations in the PIK3CA gene, identified in both nonatypical and atypical endometriosis, is believed to be an early occurrence in the development of cancer, likely at the onset of malignant transformation in endometriosis [63]. ...
... Ref.[40,[60][61][62][63][64][65]) summarizes the tumour suppressor gene mutations related to EAOC, whileTable 3(Ref.[52,60,63,66]) summarizes the oncogenic mutations related to EAOC. ...
... A study by Anglesio et al. found that more than a quarter of lesions in deeply infiltrating endometriosis contained cancer driver mutations [36]. There is an association between endometriosis and ovarian cancer, particularly with its two subcategories: endometrioid and clear-cell carcinoma [37,38]. ...
Endometriosis is a chronic disease in which the endometrium cells are located outside the uterine cavity. The aim of this study was to evaluate circulating 20S proteasome and 20S immunoproteasome levels in plasma and peritoneal fluid in women with and without endometriosis in order to assess their usefulness as biomarkers of disease. Concentrations were measured using surface plasmon resonance imaging biosensors. Patients with suspected endometriosis were included in the study—plasma was collected in 112 cases and peritoneal fluid in 75. Based on the presence of endometriosis lesions detected during laparoscopy, patients were divided into a study group (confirmed endometriosis) and a control group (patients without endometriosis). Proteasome and immunoproteasome levels in both the plasma (p = 0.174; p = 0.696, respectively) and the peritoneal fluid (p = 0.909; p = 0.284, respectively) did not differ between those groups. There was a statistically significant difference in the plasma proteasome levels between patients in the control group and those with mild (Stage I and II) endometriosis (p = 0.047) and in the plasma immunoproteasome levels in patients with ovarian cysts compared to those without (p = 0.017). The results of our study do not support the relevance of proteasome and immunoproteasome determination as biomarkers of the disease but suggest a potentially active role in the pathogenesis of endometriosis.
... It is characterized by the presence of extra-uterine, functionally active, endometrial tissue, represented by stroma and glands, which can be found mostly in the pelvic cavity, ovaries, fallopian tubes, sigmoid colon, appendix, upper abdomen and in other sites such as the lungs [4,5]. In particular, in 44% of cases, the ovaries are the site of endometriosis, with an endometriotic cyst defined as ovarian endometrioma [6]. The latter is evident in ultrasound examination as a unilocular cyst with homogeneous low-level echogenicity defined ground glass and absent to moderate vascularization [7]. ...
... The latter is evident in ultrasound examination as a unilocular cyst with homogeneous low-level echogenicity defined ground glass and absent to moderate vascularization [7]. oncogene homolog (KRAS) activation [6]. However, the etiology of this disease is still enigmatic. ...
... To the best of our knowledge, there are no studies which have specifically assessed this issue. The main reason is that, in several clinical series, these two histologies are often considered as a single entity, which are referred to as "endometriosis-associated ovarian tumors" [6]. This, together with the lack of adherence to the criteria for the pathological diagnosis of endometriosis-associated endometrioid ovarian tumors, as originally described by Sampson and Scott [21,22], might have prevented the correct identification of the study population. ...
Evidence indicates that different pathways of malignant degeneration underlie the development of endometriosis-associated ovarian tumors of endometrioid and clear cell histotypes. The aim of this study was to compare data from patients affected by these two histotypes to investigate the hypothesis of a dichotomy in the histogenesis of these tumors. Clinical data and tumor characteristics of 48 patients who were diagnosed with either pure clear cell ovarian cancer and mixed endometrioid–clear cell ovarian cancer arising from endometriosis (ECC, n = 22) or endometriosis-associated endometrioid ovarian cancer (EAEOC, n = 26) were compared. A previous diagnosis of endometriosis was detected more frequently in the ECC group (32% vs. 4%, p = 0.01). The incidence of bilaterality was significantly higher in the EAOEC group (35% vs. 5%, p = 0.01) as well as a solid/cystic rate at gross pathology (57.7 ± 7.9% vs. 30.9 ± 7.5%, p = 0.02). Patients with ECC had a more advanced disease stage (41% vs. 15%; p = 0.04). A synchronous endometrial carcinoma was detected in 38% of EAEOC patients. A comparison of the International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis showed a significantly decreasing trend for ECC compared to EAEOC (p = 0.02). These findings support the hypothesis that the origin, clinical behavior and relationship with endometriosis might be different for these histotypes. ECC, unlike EAEOC, seems to develop within an endometriotic cyst, thus representing a window of possibility for ultrasound-based early diagnosis.
... Many miRNAs have also been studied as potential biomarkers of endometriosis [51][52][53][54][55][56]. However, their significance in this disease and participation in possible malignant transformation remain unexplored [57,58]. Research evidence suggests that the development of endometriosis may be facilitated by endometrial dysfunction involving both eutopic (EUE) and ectopic endometrium (ECE), associated with molecular changes within the endometrial cells [59,60]. ...
... Several studies have focused on the importance of BMP/SMAD signaling in endometriosis [41,61,62] as well as on the role of miRNA in the development and progression of the disease [57,58,63,64]. Among the many candidates, one potentially interesting miRNA is miR-542-3p, for which a suppressor function in tumor development is well characterized. ...
Alterations in the expression of numerous genes and the miRNAs that are recognized as their regulators in the endometrial cells of women with endometriosis may disrupt the intracellular signaling pathways associated with epithelial–mesenchymal transition (EMT). So far, the functional role of BMP7 in endometrial physiology has been confirmed, especially in the context of fertility, but the role of the activation of a specific mechanism operating through the BMP–SMAD–CDH1 axis in the formation of endometrial lesions remains unexplored. The aim of this study was to evaluate the expression profile of miR-542-3p and the EMT markers (BMP7, SMAD4, CDH1) in matched eutopic endometrium (EUE) and ectopic endometrium (ECE) samples from women with endometriosis in relation to healthy women. The levels of expression of the studied genes and miRNA in peripheral blood mononuclear cells (PBMCs) obtained from women diagnosed with endometriosis and those without the disease were also evaluated. Fifty-four patients (n = 54: with endometriosis—n = 29 and without endometriosis—n = 25) were included in the study. A comparative analysis of the relative mean expression values (RQ) of the studied mRNA and miRNA assessed by RT-qPCR demonstrated downregulation of BMP7, SMAD4, and CDH1 expression in ectopic lesions and upregulation in the eutopic endometrium compared with the control group. In the eutopic tissue of women with endometriosis, miR-542-3p expression was similar to that of the control but significantly lower than in endometrial lesions. We also confirmed a trend towards a negative correlation between miR-542-3p and BMP7 in ectopic tissue, and in PBMC, a significant negative correlation of miR-542-3p with further BMP signaling genes, i.e., SMAD4 and CDH1, was observed. These results indicate that the miRNA selected by us may be a potential negative regulator of BMP7-SMAD4-CDH1 signaling associated with EMT. The different patterns of BMP7, SMAD4, and CDH1 gene expression in ECE, EUE, and the control endometrium observed by us suggests the loss of the endometrial epithelium phenotype in women with endometriosis and demonstrates their involvement in the pathogenesis and pathomechanism of this disease.
... Endometriosis is a common chronic and painful gynecological disease characterized by the presence of endometrial tissue out of the uterus. The prevalence of endometriosis is not easy to estimate due to some asymptomatic patients (1). Endometriosis leading some symptoms such as dysmenorrhea, infertility, pelvic pain, and reduction in quality of life. ...
Background: Endometriosis is a common disease among women with the capacity to transform into ovarian neoplasms. KRAS mutation is a keystone in tumor-genesis of many malignant neoplasms. Objectives: In the current study, we investigated KRAS mutations in endometriosis-associated ovarian borderline and malignant epithelial tumors. Methods: The specimens of 42 consecutive patients undergoing a surgical procedure whose final diagnosis comprised endometriosis-associated borderline and malignant epithelial ovarian tumors including 12 borderline epithelial tumors and 30 ovarian epithelial carcinomas were histopathologically reviewed. All cases were evaluated regarding the type of tumor, differentiation and simultaneous presence of endometriosis or atypical endometriosis. DNA extraction from the selected paraffin block was done and mutation of codons 12 and 13 was assessed. Results: Due to the quality of genomic DNA for PCR study was not acceptable in 6 out of 42 cases, among remaining 36 cases, KRAS mutation was observed in 6 cases including 2 cases with mutations in 2nd base of 12th codon (G→T), 3 cases with substitution of G→A in the 2nd base of 12th codon, and one with substitution of G→T in the 1st base of 12th codon. Conclusions: We evaluated the KRAS mutation in the spectrum of ovarian epithelial tumors associated with endometriosis for treatment approaches including targeted therapies. Our results suggested a possible link between KRAS mutation and endometriosis-associated ovarian borderline and malignant tumors but there was no convincing evidence to prove a definite linkage.
... Details on the exosomal miRNA expression in ovarian cancer cells of different histological subtypes are shown in Table S1. CCCO and endometrioid cancer of the ovary develop from the basis of endometriosis [42][43][44]. In this study, we observed that miR-1281 was upregulated in CCCO cell lines, HAC-2 and OVAS, as well as in the endometrioid cancer cell line, TOV-112D (Table S1), suggesting that this miRNA may be involved in the development of tumors originating from endometriosis. ...
Ovarian cancer is the most common cause of gynecological malignancy-related mortality since early-stage disease is difficult to diagnose. Advanced clear cell carcinoma of the ovary (CCCO) has dismal prognosis, and its incidence has been increasing in Japan, emphasizing the need for highly sensitive diagnostic and prognostic CCCO biomarkers. Exosomal microRNAs (miRNAs) secreted by tumor cells are known to play a role in carcinogenesis; however, their involvement in ovarian cancer is unclear. In this study, we performed expression profiling of miRNAs from exosomes released by five cell lines representing different histological types of ovarian cancer. Exosomes isolated from culture media of cancer and normal cells were compared for miRNA composition using human miRNA microarray. We detected 143 exosomal miRNAs, whose expression was ≥1.5-fold higher in ovarian cancer cells than in the control. Among them, 28 miRNAs were upregulated in cells of all histological ovarian cancer types compared to control, and three were upregulated in CCCO cells compared to other types. Functional analyses indicated that miR-21 overexpressed in CCCO cells targeted tumor suppressor genes PTEN, TPM1, PDCD4, and MASP1. The identified miRNAs could represent novel candidate biomarkers to diagnose or monitor progression of ovarian cancer, particularly CCCO.
... This difference is a likely factor in many of the pathological pathways in endometriosis. For example, miRNA-200 family, which is known to play a crucial role in "epithelial-mesenchymal transition" [10], is dysregulated in endometrioid and clear cell ovarian cancer which represent endometriosis associated ovarian cancer (EAOC) [11,12]. PTEN mutation has a significant role in the malignant transformation of endometriosis tissue, and its down-regulation by a number of miRNAs is reported to occur in endometriosis and ovarian cancer [12]. ...
... For example, miRNA-200 family, which is known to play a crucial role in "epithelial-mesenchymal transition" [10], is dysregulated in endometrioid and clear cell ovarian cancer which represent endometriosis associated ovarian cancer (EAOC) [11,12]. PTEN mutation has a significant role in the malignant transformation of endometriosis tissue, and its down-regulation by a number of miRNAs is reported to occur in endometriosis and ovarian cancer [12]. miR-200a-3p is one of the miR-NAs that target PTEN in endometriosis and ovarian cancer [12] and miR-200b targets PTEN in metastatic prostate cancer [13]. ...
... PTEN mutation has a significant role in the malignant transformation of endometriosis tissue, and its down-regulation by a number of miRNAs is reported to occur in endometriosis and ovarian cancer [12]. miR-200a-3p is one of the miR-NAs that target PTEN in endometriosis and ovarian cancer [12] and miR-200b targets PTEN in metastatic prostate cancer [13]. Recently, it has been shown that miRNAs are exceptionally stable and can be readily and reliably detected in most tissues, and in formalin-fixed paraffin-embedded tissue (FFPE) samples [14]. ...
Micro-RNAs expression can vary between different forms of endometriosis, but data on miRNA expression in cesarean scar endometriosis is lacking. The present study is comprised of 30 patients with endometriosis in the cesarean scar (scar endometriosis, SE), 14 patients with deep infiltrating endometriosis (DIE), 47 patients with endometrioma (ovarian endometrial cyst, OE), and 33 patients with healthy ovarian tissue as the control group (CG). In the initial experiment to identify possible dysregulated miRNAs, the levels of 754 miRNAs in formalin-fixed paraffin-embedded tissue (FFPE) samples from OE, high-grade ovarian cancer, endometrioid ovarian cancer, and CG were measured. We identified seven potentially dysregulated miRNAs: miR-1-3p, miR-31-3p, miR-125b-1-3p, miR-200b-3p, miR-548d, miR-502, and miR-503. We then examined the expression profiles of each of these miRNAs individually in the SE, DIE, OE, and CG FFPE samples using RT-qPCR. miR-31-3p had significantly higher levels of expression and miR-125b-1-3p had significantly lower levels of expression in SE compared to the controls. Overall, the higher expression levels of miR-31-3p and the lower expression levels of miR-125b-1-3p are consistent with the benign nature of SE. Importantly, the results of the present study demonstrate the possibility of using miRNA to monitor the risk of malignant transformation of endometriosis tissue.
