Endometriosis-Associated Ovarian Carcinoma

The link between endometriosis and ovarian carcinoma has been recognized early on, initially termed endometriosis-associated ovarian carcinoma and subsequently referred to as endometriosis-associated ovarian carcinoma (EAOC). The relationship between endometriosis and cancer is well supported by epidemiological evidence, highlighting common risk factors. Two potential mechanisms have been proposed: one involving the direct malignant transformation of endometriotic lesions, and the other suggesting a shared origin in precursor mechanisms or risk factors, followed by distinct molecular pathways. This chapter explores the epidemiological links, molecular mechanisms, and clinical implications of endometriosis-associated ovarian carcinoma, highlighting its distinct subtypes and risk factors.

- endometriosis - endometriosis-associated ovarian carcinoma - endometriosis-related ovarian neoplasm - ovarian malignancy - malignant transformation 1. Introduction Endometriosis is a gynecological entity characterized by the presence of ectopic endometrium outside the uterus, in a multitude of locations, mainly in ovary (67%), followed by anterior and posterior cul de sac, uterosacral ligaments, posterior broad ligaments, fallopian tubes, round ligaments, and sigmoid colon or appendix [1]. Other less frequent locations are bladder and cervix, and more rarely skin, regional lymph nodes, or lung. The importance of the disease is given by its relatively high prevalence in women of reproductive age, its frequent association with infertility and with chronic pain, and its subsequent negative impact on the quality of life. Although many hypotheses have been postulated regarding the etiopathogenesis of endometriosis, its exact mechanisms remain unclear. Endometriosis is essentially a benign condition, but there are some common characteristics that suggest a connection to ovarian cancer, making the pathogenic pathways even more intriguing. One element that supports the correlation between the two clinical entities is the fact that they share some epidemiological characteristics. These include the common risk factors, such as early onset of menstruation, short menstrual cycles, nulliparity, and late menopause, alongside the protective factors like oral contraceptive use, multiparity, tubal ligation, and hysterectomy [2]. Two primary mechanisms are hypothesized for this correlation: the direct malignant transformation of the endometriotic lesions or a combination of shared precursor mechanisms and risk factors, leading to distinct molecular pathways [3, 4]. The linkage between endometriosis and ovarian cancer was initially recognized under the term “endometriosis-associated ovarian carcinoma” (EAOC) [5] and subsequently referred to as “endometriosis-related ovarian neoplasm” (ERON) [6, 7] or “endometriosis-associated ovarian carcinoma” [8, 9], predominantly manifesting as endometrioid carcinoma, clear-cell carcinoma, seromucinous borderline tumors, Müllerian adenosarcoma, and endometrioid stromal sarcoma. Notably, a majority of these tumors (70%) develop within the first decade following an endometriosis diagnosis, with 60% of cases exhibiting an intermediary stage of atypical endometriosis [9]. Furthermore, given the inherent invasive and metastatic abilities of endometriosis, its behavior closely resembles that of malignant conditions [10]. This profound connection has prompted investigations into potentially shared molecular pathways and the involvement of key molecules in their pathogenesis, thereby facilitating the assessment of endometriosis etiopathogenetic theories. Regarding these molecular pathogenic pathways, a multitude of molecules have been studied in both endometriosis and EAOC. In this regard, estrogen is acknowledged as a promoter of ovarian cell proliferation, enhancing the mobility of malignant cells and inhibiting intercellular adhesion [11, 12]. The mediation by estrogen and progesterone receptors in the actions of steroid hormones on both endometriosis and endometrioid EAOC has been established, and recent studies have also correlated the expression of these receptors with clinical outcomes in ovarian cancer [12, 13]. Furthermore, p53 alterations also represent a significant molecular event in the transformation of endometriosis into carcinomas [14]. Similarly, Ki-67 expression, which is closely associated with cell proliferation, is employed to evaluate the growth of various neoplastic lesions, including both endometriosis and EAOC [15]. 2. EAOC risk factors Endometriosis is a condition relatively often associated with various types of neoplasms. EAOC occurs in 5–10% of endometriosis cases, and an intermediate stage of atypical endometriosis can be detected in 0.7–1.6% of cases [16]. A recent meta-analysis of 24 observational studies evaluated the link between endometriosis and ovarian cancer, revealing a calculated summary relative risk of 1.93 for ovarian cancer in women diagnosed with endometriosis compared to those without the condition [17]. In order to assess the individual risk for EAOC among endometriosis patients, Thomsen et al. have shown that in a group of women over the age of 45 years with endometriosis, factors, such as nulliparity, postmenopausal status, larger endometriomas (>9 cm), and either endogenous or exogenous hyperestrogenism, along with the presence of cysts containing solid components, were identified as risk indicators for EAOC [18]. Regarding the risk for a specific histological type of EAOC, a recent study has utilized genetic markers as proxies for epithelial ovarian cancer. The analysis revealed a significant correlation between these entities, with an odds ratio (OR) of 1.23. More detailed analysis, investigating for specific ovarian cancer histotypes possibly linked to endometriosis, showed an association of endometriosis with the risk of endometrioid carcinoma, clear-cell carcinoma, and low malignant potential tumors [19]. Some researchers have hypothesized the influence of the microenvironment, specifically the high iron concentration in the walls of endometriotic cysts in cases with prolonged evolution, through the persistence of oxidative stress induced by iron, resulting in subsequent DNA damage and numerous genetic mutations, such as PTEN (phosphatase and tensin homolog), ARID1 (AT-rich interactive domain-containing protein 1), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and loss of heterozygosity [16]. Oncogenic mutations of the β-catenin phosphorylation site (catenin beta 1 (CTNNB1)) lead to the formation of a stable protein, detected both in endometriosis and in EAOC associated with endometriosis [16]. A significant role in the pathogenesis of endometriosis should be attributed to polygenic susceptibility, which implies a metabolic, endocrine, and immune association responsible for decreased immune surveillance, alongside pelvic inflammation [20, 21, 22]. Additionally, progressive accumulations of genetic alterations in tumor suppressor genes and oncogenes are likely responsible for the development of endometriosis and its possible association with the development of malignant conditions [23, 24, 25, 26, 27, 28, 29]. Premalignant lesions (atypical endometriosis) are characterized by multiple mutations in tumor suppressor genes, oncogenes, cell adhesion molecule (CAM), as well as loss of heterozygosity (LOH) and inflammatory immunomodulation [30]. 3. Pathogeny/molecular mechanisms involved in the development of endometriosis and EAOC Various endometriosis pathogenic pathways make this condition very similar to neoplastic processes. Among the widest spread and accepted pathogenetic theories in endometriosis are retrograde menstruation, immune dysregulation, coelomic metaplasia, hematogenous or lymphatic spread, endometrial stem cell recruitment theory, bone marrow-derived stem cells, alteration in epigenetic regulation, hormonal imbalance, and microRNAs (miRNAs). Besides these theories, the carcinogenetic pathways and external environmental factors are also believed to have a significant impact on endometriosis behavior and outcome [31, 32]. Although first proposed in the late nineteenth century, the most recently introduced hypothesis is the embryogenetic theory with Müllerian remnants’ induction [32]. This is considered a type of metaplasia theory [31], stipulating that remnants of embryonic cells of Müllerian or Wolffian duct may transform into endometriotic lesions [31], by spreading the primordial endometrial cells towards the posterior pelvic floor during embryogenesis [32]. Most clinicians and theoreticians agree upon the menstrual reflux theory, which implies that endometrial cells are being expelled during menstruation, via the fallopian tubes, into the peritoneal cavity. Here, under yet unknown influences, these cells gain the capacity of adhesion to the peritoneal surface, invasion of the peritoneal lining, and further cellular survival and division. Their ectopic surviving capacity is provided by a mechanism of escaping the immune supervision of these newly formed implants. Furthermore, these implants have the capacity of neoangiogenesis, which promotes growth and development by providing nutrients and growth factors to the already-established implants. Although a key role is attributed to the reflux of stem cells into the peritoneal cavity, the microenvironmental factors that stimulate stem cell functions and allow the development of endometriotic implants are very important as adjuvants to the mechanism of retrograde menstruation. Relatively recent data have demonstrated the existence of mesenchymal stem cells and endometrial progenitor cells in endometriosis and their potential evolution towards differentiation into nine cell lines, as follows: adipocytic, osteogenic, cardiomyocytic, respiratory epithelial, neurocytic, myocytic, endothelial, pancreatic, and hepatic [33]. Considering the widespread distribution of endometriosis in the human body, modern theories attempt to combine the effect of multiple factors contributing to its development, as multifactorial, multi-compartmental pathogenic phenomena, associated with epiphenomena, such as estrogen dependence [34], genetic susceptibility [35], and the possibility of direct spread through “transplantation” [34]. These processes add to the immune system’s inability to neutralize ectopic endometrial cells [36, 37, 38, 39], environmental factors, and the coexistence of congenital defects, such as hymenal atresia, for example. Last but not least, the most plausible pathogenic mechanism involves stem cells as the main factors responsible for the process of ectopic implantation via retrograde menstruation. The evasion of immune clearance, as the first step in the development of endometriotic lesions, is supported by various studies suggesting a modification of the immune system. Endometriosis may be associated with autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, autoimmune thyroiditis, and multiple sclerosis) or atopic diseases (allergies, asthma, and eczema) [40]. Considering that multiple autoantibodies can be identified in endometriosis [41], it may be considered that this autoimmune reactivity could be a consequence of chronic inflammation. In the last decade, studies have identified genetic, angiogenetic [42], endocrine, metabolic, and immunological anomalies, such that the pathogenesis of endometriosis is multifactorial, multi-compartmental, and associated with epiphenomena, many of which represent, in fact, consequences of the primary lesion. Neoplastic transformation of some of these endometriotic implants has been a subject of research and debate. Nearly a century ago, John A. Sampson first identified ectopic endometrium-like tissue as a potential cause of ovarian carcinoma. He proposed that “metastatic or embolic endometriosis results from the menstrual dissemination of endometrial tissue into the venous circulation” [43]. This idea of retrograde menstruation leading to the implantation of endometrial cells in the peritoneal cavity, eventually transforming into ovarian cancer through atypical endometriosis, has since been widely studied. It seems that the ovarian microenvironment plays specific role in this malignant transformation [44], as it is an essential condition of such neoplasia. Even though endometriosis might have other locations, except the ovary, these sites are almost never the site of a malignant transformation [44, 45]. For example, the literature provides reports of only a few cases of carcinomas arising in rectovaginal endometriosis [46, 47]. Regarding the intermediate steps between endometriosis and EAOC, Kurman et al. [48] proposed the eutopic endometrium as the precursor site of origin of EAOC, endometriosis as the potential precursor lesion, and atypical endometriosis as the immediate precursor lesion. In the same context, Karnezis et al. consider endometriosis as the tissue of origin of EAOC, endometrial epithelial cells as the cells of origin, and endometrioid borderline tumors as the precursor lesion [49]. They also propose a classification of endometriosis as “high risk” and “low risk” depending on the presence of atypical endometriosis. The molecular features of EAOC have been intensely studied in the last few years, and the results lead to different conclusions, depending on the type of EAOC. In this regard, endometriosis is considered a precursor to two completely different histological entities, endometriosis-associated ovarian clear-cell carcinoma (OCCC) and endometriosis-associated ovarian endometrioid carcinoma, without any recurrent genetic mutation that is unique to either of them [50]. 3.1 Genetic mutations Several genetic mutations have been identified as key drivers in the malignant transformation of endometriosis and the development of endometriosis-associated ovarian cancer (EAOC). Common mutations include those in p53, K-ras (Kirsten rat sarcoma virus), ARID1A, PIK3CA, and PPP2R1A (serine/threonine-protein phosphatase 2A regulatory subunit A). Although breast cancer (BRCA) mutations are prevalent in ovarian carcinomas, they are less frequently associated with EAOC [51]. Mutations in the ARID1A gene, which encodes the BAF250a (BRG-associated factor 250a) protein—a critical component of the switch/sucrose non-fermentable (SWI/SNF) adenosine triphosphate (ATP)-dependent chromatin remodeling complex—are found in nearly half of clear-cell and endometrioid carcinomas [52]. Loss of BAF250a in EAOC tissues is associated with increased expression of gamma H2A histone family member (γH2AX), a marker for DNA damage response, of the pro-apoptotic regulators, such as B-cell lymphoma 2-interacting mediator (BIM) and Bcl-2-associated X-protein (BAX), and decreased expression of the anti-apoptotic gene B-cell lymphoma 2 (Bcl-2). These findings suggest that chromatin remodeling and DNA damage response pathways may be involved in the early stages of precancerous lesions. ARID1A also shares downstream targets with p53, and its loss can lead to the dysregulation of p53-controlled genes [53]. In clear-cell EAOC, somatic mutations in the PIK3CA gene, which encodes a catalytic subunit of phosphatidylinositol-3 kinases (PI3K), often occur early and frequently coincide with the loss of ARID1A protein expression, potentially having synergistic effects [54]. Additional early markers in ARID1A-deficient carcinomas include the activation of RAC-alpha serine/threonine-protein kinase (AKT) through increased AKT serine/threonine kinase 1 (AKT1) expression and phosphorylation (phosphorylated AKT (pAKT)). Moreover, differential expression of components in the mammalian target of rapamycin (mTOR) pathway appears to link endometriosis with ovarian cancer development [53]. A less frequent mutation found in approximately 16–19% of EOAC and ovarian clear-cell carcinoma (OCCC) cases affects the oncogene PPP2R1A (serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform), which encodes a regulatory subunit of serine/threonine phosphatase 2 (PP2A), a negative regulator of cell growth [55]. Overall, the PI3K/protein kinase B (AKT)/mTOR pathway plays a critical role in cell cycle regulation, and mutations that alter gene regulation within this pathway contribute to the development and progression of ovarian cancer, as well as the transformation of healthy endometrial tissue into endometriosis and EAOC [56]. In contrast, the activity of the phosphatase and tensin homolog (PTEN), which counteracts the PI3K/AKT pathway, is diminished due to PTEN silencing in EAOC, thus reducing PTEN’s inhibitory effect on cell growth and division [57]. Er et al. identified additional mutated genes in the Wnt pathway, the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2) pathway, the Notch signaling pathway, cell cycle regulation, and the mismatch repair system through targeted next-generation sequencing [58]. Notably, the Notch signaling pathway is also disrupted in endometriosis and has been implicated in its pathogenesis [53]. 3.2 Epigenetic mechanisms Beyond genetic mutations, epigenetic mechanisms also play a crucial role in the malignant transformation of endometriosis into EAOC. For example, promoter hypermethylation can lead to the transcriptional inactivation of the MutL protein homolog 1 (MLH1) gene, which encodes a DNA mismatch repair (MMR) protein. This inactivation results in microsatellite instability and the accumulation of spontaneous mutations, thereby advancing the progression towards EAOC [59]. Additionally, other differentially methylated genes, such as Ras association domain family member 2 (RASSF2), which encodes the Kirsten rat sarcoma viral oncogene homolog (KRAS)- specific effector protein Ras association domain-containing protein 2, and Runt-related transcription factor 3 (RUNX3), which encodes the tumor- suppressing Runt-related transcription factor 3, have been identified as potential contributors to this malignant transformation [60]. 3.3 The tumor microenvironment The tumor microenvironment is crucial in shaping EAOCs, with estrogen concentration being a significant factor. High estrogen levels, whether from external sources like hormone replacement therapy or produced endogenously by the ovaries, promote the proliferation of endometriotic cells. Estrogen signaling in EAOC is complex and influenced by factors, such as nutritional status, oxidative stress, and surrounding cells, which in turn affect cellular metabolism, epithelial-to-mesenchymal transition (EMT), angiogenesis, and invasiveness [53]. microRNAs (miRNAs) are emerging as important posttranscriptional regulators of gene expression and potential biomarkers in endometriosis and EAOC. These small non-coding RNA (ncRNA) molecules can silence genes by binding to complementary sequences in messenger RNA (mRNA), leading to RNA degradation or translational repression. Dysregulation of miRNAs, such as those in the microRNA-200 (miR-200) and lethal-7 (let-7) families, has been observed in ovarian cancer and is involved in processes like the epithelial-to-mesenchymal transition and tumor progression [53]. Of note, microRNA-200b (miR-200b) also plays a role in the development of endometriosis, targeting zinc finger E-box-binding homeobox 1 (ZEB1), zinc finger E-box-binding homeobox 2 (ZEB2), and Kruppel-like factor 4 (KLF4), in order to regulate the stem cell phenotype, the proliferation, invasiveness, and the growth of invasive protrusions of endometriotic cells [61]. Szubert et al. found that the expression levels of microRNA-31-3p (miR-31-3p) and miR-200b were reduced in cancerous lesions compared to normal ovarian tissue and endometriosis tissue [62]. microRNA 31 (miR-31) activates hypoxia-inducible factor (HIF) under normoxic conditions by targeting the 3′ untranslated region (3′ UTR) of factor-inhibiting hypoxia-inducible factor (HIF), which leads to increased production of vascular endothelial growth factor (VEGF). VEGF overexpression is linked to both endometriosis and the progression to EAOC [53]. Furthermore, reduced levels of other microRNAs, including microRNA-17-5p (miR-17-5p), microRNA 20a (miR-20a), microRNA 222 (miR-222), and microRNA 125a (miR-125a), have been associated with angiogenesis in endometriosis by regulating factors, such as Runt-related transcription factor 1 (RUNX1), connective tissue growth factor (CTGF), thrombospondin-1 (TSP-1), and vascular endothelial growth factor-A (VEGF-A) [53]. Oxidative stress is another key factor in the malignant transformation of endometriosis to EAOC. microRNAs regulate oxidative stress by controlling the expression of reactive oxygen species (ROS)-related enzymes. Persistent oxidative stress in endometriotic cysts, possibly due to the release of free iron during menstruation, may contribute to their carcinogenic transformation [53]. Inflammation plays a significant role in EAOC carcinogenesis by creating a pro-tumorigenic environment that promotes DNA damage, tissue remodeling, immune suppression, and angiogenesis. Several inflammatory cytokines, complement factors, and inflammasome-related genes have been identified as contributors to the development of EAOC [53]. The tumor’s ability to adapt to local nutrient availability through metabolic reprogramming is another emerging hallmark of cancer. Endometriotic cells often prefer aerobic glycolysis to generate energy, even in the presence of oxygen, which helps them survive in the extrauterine environment. Ovarian cancer cells exhibit metabolic heterogeneity and flexibility, allowing cancer cells to adapt to varying levels of glucose, lipids, and amino acids, thus contributing to their proliferation and survival [53]. It is considered that 2% of ovarian endometriotic lesions will undergo malignant transformation [63]. The exact etiopathology remains unclear, but both intrinsic factors within the endometrial tissue and microenvironmental factors are considered contributors to its survival in the peritoneum and potential malignant transformation [64]. For example, the increased frequency of chromosomal abnormalities in ovarian endometriosis, as opposed to extragonadal endometriosis, suggests that the ovarian stromal environment may play a role in initiating genetic alterations, possibly leading to invasive cancer [53]. In summary, the genetic profiles of benign ovaries and ovarian endometriosis differ significantly from those of EAOC and ovarian cancer [65]. The endometriosis-associated ovarian clear-cell carcinoma harbors mutations in ARID1A, PIK3CA, CTNNB1, and PTEN, while endometriosis-associated ovarian endometrioid carcinoma harbors mutations in PTEN, CTNNB1, KRAS, ARID1A, PPP2R1A, and PIK3CA [50]. Inactivating ARID1A mutations are the most common molecular genetic alterations reported in EAOC [66], resulting in loss of expression of the protein encoded by ARID1A (BAF250a). When expressed, this protein normally suppresses cellular proliferation through a p53-dependent transcription regulation of several tumor suppressors including CDKN1A (cyclin-dependent kinase inhibitor 1A) (encoding p21) and SMAD3 (mothers against decapentaplegic homolog 3) [67]. 4. Pathological characteristics of ovarian endometriosis, atypical endometriosis, and EAOC 4.1 Endometriosis On gross examination, endometriomas or ovarian endometriotic cysts present fibrotic walls, with smooth lining and characteristic dark brown content (chocolate cyst) [68]. If endometriosis has a polypoid aspect, it leads to the differential diagnosis of a neoplasm both on grossing and frozen sections [69]. Sometimes, the cyst can display red-brown or white plaques, with a gelatinous consistency [70, 71]. For the histopathological diagnosis of endometriosis, at least two of three criteria are needed: endometrial-type glands, lined by Müllerian-type epithelium, sometimes with degenerative atypia (enlarged faded nuclei) or metaplasia, included in an endometrial-type stroma. Sometimes, smooth muscle metaplasia, osseous metaplasia, decidual change, or myxoid aspects are found [72, 73]. Another rare and particular aspect is the presence of epithelial metaplastic changes or metaplasia in ovarian endometriosis, which should not be considered neoplastic features. A study conducted by Fukunaga on 315 cases of ovarian endometriosis found 162 cases with metaplastic changes, all of them being associated with atypical endometriosis or malignant ovarian epithelial tumor. Although no significant relationship was identified between the type of metaplasia in endometriosis and the type of carcinoma, mucinous metaplasia was correlated with cases of Müllerian mucinous borderline tumors, and thus there could be an association between this type of metaplasia and hyperplasia encountered in ovarian endometriosis and Müllerian mucinous borderline ovarian tumors [74]. Moreover, there are cases when the histopathological diagnosis is made only on the presence of endometrial stroma (stromal endometriosis) or indirectly, due to the chronic hemorrhage, with foamy or hemosiderin-laden macrophages. Rarely, Liesegang rings, defined as eosinophilic noncellular rings embedded in necrotic tissue or necrotic pseudoxanthomatous nodules, with central necrosis bounded by histiocytes and an outer fibrous tissue are encountered [72]. Somewhat similar morphological aspects as mentioned above, suggestive of endometriosis, define the so-called “burnt out endometriosis.” 4.2 Atypical endometriosis Atypical endometriosis was reported in 1.74.4% of endometriotic ovarian cysts, being considered as the precursor lesion for EAOC, mainly endometrioid or clear-cell type. Atypical endometriotic lesions were found in association with these tumors in 25% of cases, presenting the same genomic alterations as EAOC [75]. Histopathological landscape is characterized by crowded endometrial-type glands, with complex architecture, lined by atypical epithelial cells as those observed in atypical endometrial hyperplasia (AEH) [75, 76, 77]. Atypical endometriosis (AE) has been historically described as having histological characteristics that are intermediary between benign and malignant states, including enlarged atypical hyperchromatic nuclei, an elevated nuclear-to-cytoplasm ratio, and cellular overcrowding, sometimes with hobnail features [75, 76, 77, 78, 79]. This type of lesion has been found to sometimes coexist with endometriosis and more frequently with EAOC, and it involves changes in the epithelial lining of endometriotic cysts marked by varying levels of cellular stratification, disorganization, inflammation, and cytological atypia [8, 77]. AE has been proposed as a precancerous lesion, as studies have shown that it can be considered as a transitional state between endometriosis and EAOC. In this regard, Ogawa et al. have reevaluated microscopic slides from 127 patients with primary ovarian carcinoma and concluded that 37 patients also had endometriosis, from which 29 cases had atypical endometriosis. The study reported the transition from typical endometriosis to AE in 22 cases, and the transition from AE to carcinoma in 23 cases, suggesting an AE could be considered a precancerous lesion, even though it is not encountered in all cases [80]. In order to further refine the risk of EAOC in the AE cases, Stamp et al. suggested that BAF250a expression may be a biomarker of cancer risk in patients diagnosed with atypical endometriosis. In their study, which included 35 cases of EAOC and 8 cases of non-cancerous AE, the immunohistochemical (IHC) expression of BAF250a was lost in most of the cases of AE associated with EAOC, but not in non-cancerous AE [81]. 4.3 Endometriosis-associated ovarian cancers The main epithelial ovarian cancer histotypes are classified as types I and II, according to the dualistic pathogenic model proposed by Kurman et al. [48]. The first category comprises the so-called endometriosis-associated tumors and it includes the endometrioid, clear-cell, and seromucinous carcinomas. Type II tumors are mainly composed of high-grade serous carcinomas, which represent almost the majority (70%) of ovarian carcinomas [48]. Among the EAOC, the seromucinous histotype is rare, while the most frequent histotypes associated with endometriosis are the endometrioid ovarian carcinomas and the clear-cell ovarian carcinomas. One essential difference between the two categories resides in their pathogenic models and their subsequent prognosis. It is now considered that most high-grade serous carcinomas originate from undetectable atypical lesions within the fallopian tubes [82], with subsequent exfoliation and implantation on the ovaries, peritoneum, omentum and on abdominopelvic organs, resulting in the development of late-stage cancers from inception. In contrast, most of the type I tumors originate from ovarian endometriotic cysts that are easily detected, and they are confined to the ovary for a variable period of time, making therapeutic approaches more efficient and improving the prognosis [48]. To conclude, EAOC typically manifests as endometrioid and clear-cell carcinomas, and less frequently by seromucinous borderline tumors, squamous cell carcinoma, carcinosarcoma, adenosarcoma, or endometrial stromal sarcoma. 4.3.1 Endometrioid carcinomas Endometrioid carcinomas represent 25% of ovarian carcinomas [83]. Regardless of the disease stage or response to platinum-based therapies, the prognosis is favorable. It has been found that patients diagnosed with endometrioid ovarian carcinoma often have a clinical history and microscopic foci of endometriosis (10–20%) [84]. Squamous differentiation, a pathognomonic element for ovarian endometrioid tumors, is found in about half of the cases associated with endometriosis. Morphologically, ovarian endometrioid carcinomas exhibit an endometrioid-like epithelium, similar to uterine endometrioid carcinomas, characterized by stratified columnar, non-mucinous, with a villoglandular pattern. Most tumor glands present luminal margins, oriented back-to-back, separated by an abundant fibrocellular stroma. Ovarian endometrioid carcinoma exhibits the following architectural patterns: papillary, cribriform, glandular, microglandular, spindle cell, secretory, ciliated cell, sertoliform, and sex cord-like [85]. Based on nuclear grade and the percentage of solid area, ovarian endometrioid carcinomas are classified as: well, moderately, or poorly differentiated. If the well-differentiated type presents a villoglandular architecture, the moderately and poorly differentiated types are most frequently solid, glandular, or microglandular. Cellular atypia and mitotic figures are rarely encountered in poorly differentiated carcinomas, while high-grade tumors exhibit marked nuclear pleomorphism, associated with an increased mitotic index. In the situation of an undifferentiated pattern of ovarian carcinoma, the following criteria favor a diagnosis of endometrioid carcinoma: (i) metaplastic structural elements, such as squamous, morular, mucinous, or “hobnail,” (ii) cellular phenotype (eosinophilic cells or secretory changes), (iii) foci of endometriosis, and (iv) fibrous stroma [85]. 4.3.2 Clear-cell carcinomas Clear-cell carcinomas represent approximately 5% of ovarian carcinomas [83]. The characteristic feature of these tumors is that, regardless of the grading type used, they have an unfavorable progression, often recur compared to other histological types, and have a reduced response rate to chemotherapy (CHT) [84]. Thus, compared to other tumor types, although they are included in the category of type I tumors, these are high-grade, with a reserved prognosis. The latest trends according to the specialized literature suggest including ovarian clear-cell carcinomas in the category of type II tumors. The etiopathogenesis of this category is closely related to endometriosis, similar to ovarian endometrioid tumors. Morphologically, ovarian clear-cell carcinomas have three essential features to be followed: (i) cytoplasmic changes, (ii) nuclear appearance, and (iii) architectural pattern. Due to the “clear” appearance of the cellular cytoplasm (resulting from the accumulation of glycogen) or the eosinophilic appearance (oxyphil cells), clear-cell carcinomas are easily recognized. It should be noted that, for histopathologists, just the clear cytoplasmic appearance is not sufficient for diagnosis, as this appearance can occur not only as a result of glycogen accumulation but also of lipids or as a result of cellular injury with a hydropic-vacuolar cytoplasmic appearance. The particular nuclear appearance gives the cell a “target” shape, “hobnail,” characterized by hyperchromatic nuclei that protrude into the glandular lumen. The most frequently encountered architectural phenotypes in clear-cell carcinomas are: tubulocystic/cystic (dilated cystic glands lined by flattened epithelium), papillary (small round papillary axes lined by epithelium with a maximum of two layers of polygonal or cuboidal cells), and the solid pattern, with mucin-containing cytoplasm (rarely described). Characteristically, all described patterns are located in a hyalinized, eosinophilic, fibroblastic, myxoid, rarely colloid stroma. The increased mitotic index, stratification, and cellular detachment are not characteristic of ovarian clear-cell carcinomas [86]. Occasionally, cellular features such as “signet ring” cells can be identified [86]. Additionally, morphological features, such as open tumor rings, hyaline globules, and targetoid bodies, have been described [86]. 4.3.3 Borderline seromucinous tumors Borderline seromucinous tumors were historically designated as borderline Müllerian mucinous or borderline endocervical-type or mixed epithelial papillary borderline tumor of Müllerian type or atypical proliferative tumors, and these terms are not currently being used. They constitute a small proportion of ovarian mucinous borderline tumors (10–15%) [7, 8] and are associated, in about one-third to half of cases, with endometriosis [8, 45]. Cytologically, these tumors exhibit a stratified epithelium containing a combination of endocervical-type mucosecretory cells, ciliated cells, and occasional acidophilic cells with abundant cytoplasm [7, 45], alongside a wide range of possible differentiations (endometrioid, serous, clear cell, and squamous) [8], most commonly presenting a low degree of atypia [8]. These tumors are often bilateral [8], are associated with stromal microinvasion [8] and although most of them are detected at an early stage, some may present peritoneal implants, as in the case of borderline serous tumors [7], and even lymph node involvement [45]. In terms of potential pathogenic mechanisms, the hypothesis of a mucinous metaplasia within endometriosis followed by progression to a cystadenoma and borderline tumor has been proposed [45]. This type of tumor shares the genetic profile of endometrioid tumor [8] and has a favorable prognosis [7]. Rarely, the malignant character associated with the borderline nature is observed, suggestive of tumor progression and having negative implications for the prognosis [8]. Due to the low degree of diagnostic concordance among gynecological pathologists and the immunohistochemical pattern of low-grade endometrioid or serous tumors, this diagnostic category remains controversial, suggesting its classification as a subtype of another type of ovarian tumor [8]. 4.3.4 Carcinosarcoma Carcinosarcoma, also known as malignant mixed Müllerian tumor or malignant mixed mesodermal tumor, morphologically represents a combination of malignant epithelial components, often high-grade (typically serous or endometrioid, and rarely undifferentiated) and mesenchymal components, either homologous or heterologous (such as osteosarcoma, rhabdomyosarcoma, chondrosarcoma, angiosarcoma, or liposarcoma) [7, 45]. These tumors frequently associate with serous tubal intraepithelial carcinoma [8] and, in about 50% of cases, with endometriosis [7]. Patients are most commonly over 50 years old, and the diagnosis is typically made in advanced stages [7]. Generally, the tumors are predominantly solid, large, with areas of cystic degeneration [45], and often exhibit extraovarian extension as they progress [7]. According to recent studies on the immunohistochemical and molecular profile, carcinosarcomas are included in the category of carcinomas that undergo stromal differentiation [8]. 4.3.5 Adenosarcoma Adenosarcoma is a neoplasm characterized by the association of a benign epithelial component with a malignant mesenchymal component, typically low-grade [7]. This biphasic tumor typically exhibits a morphology where glands are seen associated with periglandular stromal hypercellularity, displaying a papillary or polypoid appearance, with mild-to-moderate cytologic atypia, analogous to a phyllodes tumor [7]. Within this tumor, elements of sex cord development and the development of a high-grade sarcomatous component, typically with rhabdomyosarcomatous differentiation, can be associated [8, 45]. From a clinical progression standpoint, about 50% of patients exhibit extraovarian tumor extension [7]. Due to easy peritoneal dissemination, the possibility of tumor rupture, and overdevelopment of high-grade stroma, this type of tumor presents a reserved prognosis, particularly in younger patients [7, 8, 45]. Recent data from molecular studies have demonstrated that these tumors belong to the category of mesenchymal neoplasms [8]. 4.3.6 Endometrioid stromal sarcoma Morphologically, endometrioid stromal sarcoma is a frequently bilateral ovarian tumor that exhibits a morphology similar to that of endometrial stroma [7], with high-grade cytologic atypia associated with marked mitotic activity [45]. It has been observed that about 50% of patients with this tumor have it in the context of endometriosis [7]. Microscopically, endometrioid stromal sarcoma associated with endometriosis consists of large spindle cells with an increased nuclear to cytoplasm ratio, associated with spiral-like arterioles, and is more often low-grade than high-grade [7, 45]. In the literature, there is a reported possibility of association between ovarian endometrioid stromal sarcoma and synchronous or preexisting endometrial sarcoma, sharing a common cytogenetic profile [7, 8]. Ovarian endometrioid stromal sarcoma is often diagnosed at advanced stages and has a reserved prognosis [45]. 4.3.7 Squamous cell carcinoma Rarely, primary ovarian squamous cell carcinoma, possibly associated with squamous metaplasia, can occur in a context of endometriosis [7]. Although cases of non-invasive squamous neoplasia with a flat or papillary appearance within ovarian cysts, associated with cervical intraepithelial neoplasia, have been described, the suspicion of the role of human papillomavirus (HPV) has been ruled out in the etiopathogenesis of ovarian involvement due to HPV negativity at the ovarian level [7]. 5. Evaluation of a suspicious endometriotic lesion 5.1 Clinical evaluation Given that 90% of ovarian masses in premenopausal women and 60% of those in postmenopausal women prove to be benign [87], assessing the neoplastic risk is crucial in guiding diagnostic and therapeutic techniques. The suspicion of malignant transformation is difficult to determine before surgical exploration, as ovarian carcinoma is known as a “silent killer,” typically diagnosed in advanced stages. However, some symptoms and clinical signs can raise an alarm several months before diagnosis, even from the early stages [88], indicating the necessity for additional preoperative investigations that can facilitate an optimal diagnostic and therapeutic approach. Before initiating surgical treatment, obtaining a complete medical history, including significant familial and genetic risk assessments, is mandatory. Physical examination may reveal an abdominopelvic mass with characteristics suggestive of tumor transformation: solid, firm, nodular, fixed to surrounding anatomical structures. It should be noted that a very large tumor mass often proves to be a benign or borderline tumor. Rectovaginal examination is important in planning surgical intervention, as if infiltration of the rectovaginal septum is observed, a low anterior resection (of the rectosigmoid) may be necessary. If the clinical examination reveals ascitic fluid associated with a pelvic mass, an ovarian neoplasm diagnosis should be considered, until proven otherwise. Evidently, if there is a suspicion of neoplasia, pulmonary auscultation is mandatory, which might identify pleurisy, as well as examination of the superficial lymph node groups. 5.2 Laboratory findings Facing an endometriotic lesion with atypical appearance, a comprehensive evaluation is recommended, including a complete blood count. This is necessary before any surgical intervention and can provide additional clues, considering that 20–25% of patients with ovarian neoplasia also exhibit thrombocytosis (>400x109/L) [89]. Hyponatremia is also commonly identified, generally ranging between 125 and 135 mEq/L (milliequivalents per liter). Among the tumor markers used to classify patients into risk groups are cancer antigen 125 (CA125) and human epididymis protein 4 (HE4). Additionally, two algorithms for calculating neoplastic risk, the “risk of ovarian malignancy algorithm” (ROMA) and the “risk malignancy index” (RMI), are utilized. The CA125 value is higher than the cutoff value of 35 U/mL in over 90% of cases of non-mucinous ovarian carcinoma, but interpretation must be cautious, as only 50% of stage I carcinomas exhibit this characteristic [90]. The marker also has low specificity, with elevated values also found in endometriosis, as well as in patients with benign gynecological pathology or in physiological conditions, such as menstruation, pregnancy, pelvic inflammatory disease, and also in abdominal diseases, especially liver or pancreatic conditions. HE4 has a sensitivity of 72.9% and a specificity of 95% in differentiating benign from malignant ovarian tumors, both values being higher than those of CA125 [91]. The ROMA score takes into account the values of both markers, along with the patient’s menopausal status, providing a sensitivity of 88.7% and a specificity of 74.7% [92]. As for the RMI, it additionally utilizes the ultrasonic features of the ovarian tumor, which enhances both the sensitivity and specificity of the evaluation. 5.3 Imaging techniques To differentiate benign from malignant ovarian tumors, the most commonly used imaging technique is pelvic ultrasound. When employing this method, the International Ovarian Tumor Analysis (IOTA) 2018 score is used, which considers various ultrasonographic aspects of ovarian neoplasia. Characteristics suggestive of benignity include the presence of a unilocular cyst, solid components with a maximum diameter of 7 mm, acoustic shadows, a multilocular cyst with a smooth surface and maximum diameter of 100 mm, and the absence of blood flow. Indicators of malignancy include the presence of an irregular solid tumor, ascitic fluid, at least four papillary structures, an irregular multilocular solid tumor with a maximum diameter of 100 mm, and pronounced blood flow [93]. Ultrasound examination is less significant in advanced disease, as it is more difficult to interpret and cannot specify all the details necessary for staging. In such cases, CT scanning is preferred, which also allows for the assessment of hepatic, retroperitoneal, omental, or lymph node involvement and can identify the extension of the tumor to other locations. CT is not useful in differentiating benign from malignant ovarian tumor masses and is generally used to plan surgical intervention when there is a high suspicion of ovarian carcinoma. Other complementary imaging explorations include MRI and PET. Chest radiography is essential to detect pleural effusion or, less commonly, pulmonary metastases. 6. Prevention techniques Identification of those endometriomas that contain foci of AE would allow preventive measures to be taken in a useful manner. This could lead to either a timely surgery that would prevent the progression towards invasive carcinoma or even conservative treatment if the malignancy is detected in early stages, considerably reducing the morbidity, the mortality, and the treatment costs. Such measures currently include: early detection of EAOC; risk-reducing medical treatment; risk-reducing surgical treatment. 6.1 Early detection of EAOC Early detection and treatment of endometriosis-associated ovarian cancer (EAOC), which primarily includes endometrioid and clear-cell ovarian carcinomas, significantly impact long-term outcomes for patients. It plays a crucial role in improving long-term outcomes for patients by increasing survival rates, reducing recurrence, enhancing quality of life, and expanding treatment options. Integrating effective screening and monitoring strategies into clinical practice can help achieve these benefits, ultimately leading to better patient outcomes. Detecting EAOC at an early stage (I or II) significantly improves overall survival rates. Early-stage cancers are generally confined to the ovary or the pelvis, allowing for complete surgical removal, which is the cornerstone of treatment. Patients diagnosed at these stages typically have a much higher 5-year survival rate compared to those diagnosed at advanced stages (III or IV), where survival rates drop significantly. When EAOC is detected early, the likelihood of achieving optimal cytoreduction (removal of all visible tumor tissue) is much higher. Complete surgical resection is a critical factor in improving survival, as it reduces tumor burden and enhances the effectiveness of adjuvant therapies like chemotherapy or targeted therapies. In contrast, advanced-stage disease often involves widespread metastasis, making complete surgical removal more challenging and reducing the chances of achieving optimal outcomes. Also, early detection of EAOC can lead to a greater responsiveness to standard platinum-based chemotherapy, which is less effective in advanced, chemoresistant tumors, particularly clear-cell ovarian carcinomas. Early-stage tumors are generally smaller, less aggressive, and more likely to be effectively treated with standard chemotherapy regimens, which can help prevent recurrence and prolong progression-free survival. Early detection can reduce the need for aggressive, multi-modal treatments often required for advanced-stage EAOC. For early-stage disease, less extensive surgery, lower doses of chemotherapy, or the use of targeted therapies may suffice, minimizing the treatment-related toxicity and improving the quality of life for patients. For younger patients diagnosed with early-stage EAOC who wish to preserve fertility, early detection allows for more conservative surgical options, such as unilateral salpingo-oophorectomy (removal of one ovary and fallopian tube) or cystectomy (removal of the cyst only). These approaches may maintain reproductive potential while still effectively treating the cancer, provided the disease is adequately staged and monitored. Patients diagnosed with early-stage EAOC also have a lower risk of cancer recurrence compared to those diagnosed at a later stage. Early detection allows for complete resection of the tumor and a more effective initial treatment, reducing the likelihood of residual disease that could lead to recurrence. Lower recurrence rates are associated with better long-term survival and quality of life. The early detection of EAOC could be obtained by a trained ultrasonographist, as this technique allows complete characterization of the location and extent of endometriotic lesions [94]. Supplementary MRI, when available, is useful in detecting all locations of endometriosis, especially when ultrasonography has limitations (for example, regarding lesions located above the rectosigmoid junction) [94]. In this context, several researchers have raised awareness towards the elements of suspicion, pointing out the signs and symptoms that might suggest malignant transformation of an endometriotic cyst. For example, Nezhat et al. point out that an increase of endometrioma size, changing of ultrasonographic characteristics, and mural node formation constitute ominous signs that require surgical excision [95]. Suspicion is also raised when the patient develops symptoms such as dysmenorrhea and dyspareunia or is facing a relapse or worsening pelvic pain symptoms [96]. Supplementary, advancing age (over 45 years) and the size of endometriomas (over 8 cm) were found to be independent predictors of development of ovarian cancer among women with ovarian endometrioma [50]. It is generally believed that when gynecologists or radiologists with specialized oncological experience evaluate all suspicious endometriomas, the effectiveness of imaging techniques in identifying cysts that need surgical removal can be significantly improved. [50]. In a recent article, Younis et al. postulate that the overall lifetime risk of a woman with endometriosis to develop EAOC remains minimal [97]. They emphasize the importance of imagistic differentiation between benign, “homogenous cystic ‘ground glass’”-appearing endometrioma and EAOC. They consider that suspicious ultrasound findings, such as large, vascularized, papillary, unilateral cysts (>9 cm) with solid intracystic projections, should be further characterized by MRI [97, 98]. In this regard, the non-invasive transvaginal ultrasound is considered a new and promising technique in early diagnosis of malignant transformed endometriosis, being able to accurately evaluate ovarian masses, the method being doubled by MRI in uncertain cases [99]. 6.2 Risk-reducing medical treatment It is already established that prolonged oral contraceptive use is associated with a major reduction in the risk of developing an endometrioma, as this medication inhibits ovulation. It can be concluded that oral contraceptives and progestogens should theoretically reduce the risk of EAOC in women with a history of endometriosis, even in those without current endometriomas [50]. It is well known that the development of endometrioid ovarian cancer is primarily driven by a hormonal environment with high levels of estrogen and low levels of progesterone. Additionally, high intracystic levels of heme and free iron lead to a state of persistent oxidative stress, which may lead to stress-resistant types like clear-cell ovarian carcinoma. In this context, Kim et al. propose that the long-term use of oral contraceptives and progestogens in women with existing endometriomas may reduce the risk of mainly receptor-positive endometrioid ovarian cancer to a greater extent than with respect to the risk of mainly receptor-negative clear-cell ovarian carcinoma [100]. Overall, the long-term use of oral contraceptives might contribute to the prevention of EAOC by limiting disease progression without detrimental effects on the reproductive potential [101]. 6.3 Risk-reducing surgical treatment Regardless of the imagistic aspect and suspicion, some clinicians suggest surgery as a method of risk reduction. Even though in younger women diagnosed with endometrioma, surgery has specific individual indications and limits, in perimenopausal women removal of ovaries with endometriotic cysts may be taken into consideration. Until now, no robust studies have provided information regarding the effect of surveillance compared with that of surgery (unilateral salpingo-oophorectomy or cystectomy/partial ovarian excision) on mortality from EAOC in patients with endometriosis/endometriomas [50]. Specialists suggest that surgery should be considered for endometriomas with a prolonged evolution, especially if they are not being hormonally treated (either with oral contraceptives or with progestogens), and also in the case of de novo detection of an endometrioma during medical treatment, as the risk of malignancy appears here to have substantially increased [102, 103]. Moreover, according to Haraguchi et al., recurrent endometriomas are at especially augmented risk of malignant transformation, as all EAOCs in their series developed in patients who experienced a cyst recurrence [104]. In most women with a history of endometriosis but without ultrasonographic evidence of endometriomas, surveillance rather than risk-reducing salpingo-oophorectomy seems advisable. 6.4 Clinical applicability of identified risk factors Identified risk factors for EAOC can be utilized in clinical practice to enhance screening, early detection, and prevention strategies. Identifying high-risk individuals, such as personal history of endometriosis or family history of ovarian or endometrial cancer, could lead to a more personalized approach in order to provide them specific screening tools. Clinicians should consider more frequent monitoring and evaluation for ovarian cancer in women with a known history of endometriosis, particularly those with long-standing or severe endometriosis, including regular pelvic examinations, transvaginal ultrasounds, and potentially advanced imaging techniques like MRI, if warranted. Regular monitoring of serum biomarkers, such as CA125 and human epididymis protein 4 (HE4) in high-risk women, could help detect early signs of malignancy, although these markers have limitations in sensitivity and specificity. Combining biomarker analysis with imaging techniques may improve early detection rates. Additionally, women with a family history of ovarian, endometrial, or breast cancer may be at increased risk, especially if there is a familial link to conditions like Lynch syndrome or BRCA mutations. Genetic counseling and testing can be offered to these patients to identify hereditary cancer syndromes and guide risk-reducing strategies, such as increased surveillance, chemoprevention, or risk-reducing surgeries. For patients with endometriosis, molecular profiling of endometriotic lesions, if excised, may help identify mutations (e.g., ARID1A, PTEN) or hormonal profiles that are associated with higher malignancy risk. Women with these profiles may benefit from closer surveillance. Clinicians could also implement some risk-reducing interventions, such as hormonal therapy or tailored surgical approaches. Long-term use of hormonal therapies, such as oral contraceptives or progestins, may reduce the risk of endometrioid ovarian cancer in women with endometriosis. Hormonal therapy can create a progesterone-dominant environment, which has been associated with a lower risk of malignant transformation of endometriotic lesions. For women with endometriosis who are considered at high risk for EAOC (e.g., due to family history or genetic mutations), risk-reducing surgeries, such as prophylactic oophorectomy (removal of the ovaries) or hysterectomy, may be discussed. Surgical removal of visible endometriotic lesions during laparoscopy can also reduce the risk of malignancy, especially for lesions that are atypical or recurrent. Last but not least, patients could benefit from lifestyle modifications, education, and awareness. Encouraging lifestyle changes, such as maintaining a healthy weight, avoiding smoking, and managing stress, can be important preventive measures. While the direct impact of these factors on EAOC is less clear, a healthy lifestyle is generally protective against many forms of cancer. Educating patients with endometriosis about their potentially increased risk of ovarian cancer, particularly if they have additional risk factors, can empower them to participate actively in surveillance and prevention strategies. Patients should be informed of symptoms that could suggest malignant transformation, such as pelvic pain, bloating, or changes in menstrual patterns, and seek medical evaluation promptly. Additionally, encouraging eligible high-risk women to participate in clinical trials aimed at identifying new screening tools, biomarkers, and preventive strategies could contribute to advancing the field and improving outcomes for EAOC. 7. Treatment The traditional therapeutic approach included debulking surgery followed by adjuvant chemotherapy, with salvage chemotherapy as an option if the initial treatment failed or if there was a recurrence. Nevertheless, due to the recent progress in deciphering the intrinsic mechanisms of endometriosis and of EAOC, the treatment approach for EAOC has also evolved. The molecular and pathological characteristics of EAOC significantly influence treatment strategies and patient outcomes. According to the current guidelines, chemotherapeutic option for ovarian drugs cancer commonly used in the treatment of ovarian cancer, including in the EAOC, includes platinum-based drugs, such as cisplatin and carboplatin, as well as taxanes, such as paclitaxel [105, 106]. However, in the advanced stages (FIGO (The International Federation of Gynecology and Obstetrics) stage III or IV) or recurrent cases, a declining effectiveness of chemotherapy was noted, leading to a poor prognosis. Consequently, there has been a shift towards enhancing the efficacy of first-line treatment. This involves prioritizing aggressive surgical cytoreduction to improve the quality of surgery and adopting newer chemotherapy agents, often combined with targeted therapy or immunotherapy, to enhance treatment outcomes. Also, hyperthermic intraperitoneal chemotherapy (HIPEC) with perfusion of intraperitoneal chemotherapy during the surgical intervention was introduced in the therapeutic arsenal. Taking into account the strong hormone dependence of endometriosis and EAOC, hormonotherapy is currently used as another adjuvant systemic treatment option [105, 107]. For example, elevated levels of progesterone receptor (PR) in endometrioid ovarian carcinoma have been linked to a better prognosis and thus could be potential targets for tumors. In this context, high PR expression is generally associated with a more favorable prognosis and may guide the use of hormone-based therapies, such as progestins or anti-estrogen agents (e.g., tamoxifen). Conversely, the loss of estrogen receptor alpha or the high expression of estrogen receptor beta and gamma have been associated with reduced overall survival in ovarian cancer [108, 109]. In this context, several recent studies have evaluated the therapeutic potential of endocrine agents, such as letrozole, tamoxifen, aromatase inhibitors, and fulvestrant, in ovarian cancer, as reviewed by Langdon et al. [110]. Supplementary, estradiol-triazole analogs were developed, with the scope of targeting proteins involved in the epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) pathway in ovarian cancer [111]. Another innovative strategy involves incorporating the anti-angiogenic medication bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF)-A, into first-line treatment alongside chemotherapy. Additionally, bevacizumab can be utilized as monotherapy for individuals with newly diagnosed advanced ovarian cancer and platinum-resistant recurrent cases. Moreover, clear-cell ovarian carcinoma often overexpresses VEGF and anti-angiogenic agents, such as bevacizumab, can be particularly effective for these tumors. Moreover, oral VEGF receptor tyrosine kinase inhibitors like pazopanib and nintedanib have been employed for maintenance therapy in platinum-sensitive recurrent ovarian cancer, offering notable benefits [112]. The tumor microenvironment, including immune cell infiltration, can affect treatment responses. Tumors with high immune cell infiltration may be more responsive to immunotherapy, while those with a suppressed immune microenvironment might require combination treatments to enhance the immune response. In addition to that, the advancement and utilization of anticancer immunotherapies, involving immune checkpoint inhibitors like anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies, have resulted in notable enhancements in the management of diverse cancers. These therapies are particularly effective in combating the evasion of immune-mediated detection and elimination of malignant cells [112]. Regarding the genetic mutations and alterations with potential therapeutic targeting, it has been shown that EAOCs frequently exhibit mutations in genes, such as ARID1A and PTEN, which are implicated in chromatin remodeling and cell growth regulation, respectively. These mutations can help identify tumors that might respond to targeted therapies, like PI3K/AKT/mTOR inhibitors. Also, some EAOCs may show deficiencies in mismatch repair proteins, leading to microsatellite instability (MSI). These tumors are often more responsive to immune checkpoint inhibitors (e.g., pembrolizumab), making immunotherapy a viable treatment option. Insights into molecular pathways of EAOCs could also lead a way towards personalized therapy. As clear-cell ovarian carcinoma often shows activation of the PI3K/AKT/mTOR pathway, it could be a potential candidate for mTOR inhibitors (e.g., everolimus) or PI3K inhibitors. Further detailed analysis could provide insights regarding biomarkers for personalized treatment. The presence of specific biomarkers, such as hormone receptors, MSI status, and actionable mutations (e.g., BRCA, ARID1A), helps to stratify patients for personalized treatment approaches, potentially improving outcomes by tailoring therapies to the tumor’s unique molecular profile. 8. Prognosis Taking into consideration the particularities of EAOC, such as the high prevalence of endometrioid or clear-cell ovarian cancer (CCOC) histotypes, it is generally considered that it has a better prognosis than other types of ovarian cancer, with the exception of advanced stages of clear-cell ovarian cancer, which has an earlier recurrence rate and a lower overall survival rate [113]. In any case, EAOC is usually detected sooner than non-EAOC, which also contributes to the better management and prognosis of this neoplasia, but it is unclear whether the association with endometriosis actually contributes to this better prognosis, compared to endometrial cancer (EC) and CCOC, which are not associated with endometriosis [113]. Similar conclusions were reached by Li et al. [114], who concluded that in patients with EAOCs, a significantly longer overall survival was recorded compared to non-EAOC patients, probably because the association with endometriosis leads to a higher prevalence of early-stage and low-grade tumors, and thus a much better survival rate than non-EAOC. These survival analysis findings showed that stage at diagnosis seems to be more important to prognosis than association with endometriosis alone [114]. Ultimately, the molecular and pathological characteristics of EAOC significantly influence treatment strategies and outcomes. By understanding these characteristics, clinicians can better tailor therapies to individual patients, potentially improving response rates and survival outcomes. In conclusion, endometriosis-associated ovarian cancer (EAOC), encompassing primarily endometrioid and clear-cell ovarian carcinomas, represents a distinct subset of ovarian malignancies with unique molecular and pathological characteristics that directly influence patient management and outcomes. Early detection remains pivotal, as it markedly improves survival rates, enhances responsiveness to standard treatments, and allows for more conservative approaches, including fertility preservation in younger patients. Understanding the role of hormonal environments, genetic mutations, and the molecular pathways driving the transformation from endometriosis to EAOC has led to more personalized treatment strategies and improved patient care. However, significant gaps in knowledge persist. Future research should focus on developing reliable, non-invasive biomarkers and advanced imaging techniques for early detection, particularly in high-risk women. Additionally, a deeper understanding of the molecular mechanisms underlying the progression of endometriosis to malignancy is crucial to identifying new therapeutic targets. Research should also explore the role of the tumor microenvironment and the immune system’s involvement in EAOC progression to optimize the use of immunotherapies and targeted treatments. Addressing these unresolved questions will be key to advancing the field, improving early detection, and ultimately providing better outcomes for patients with EAOC.

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