Endometriosis: A Cancer-Like Phenomenon

Endometriosis is an enigmatic disease affecting approximately 10% of the population. This unique disease is often chronic and characterized by inflammation. Even though endometriosis and its related disease, adenomyosis, are benign tumors, both share several natural characteristics similar to malignant tumors, such as decreased apoptosis, higher proliferative activity, invasiveness, neuroangiogenesis, and the ability to spread to surrounding organs as well as distant sites. The pathophysiology of deep endometriosis cannot be explained solely by the classic Sampson theory of retrograde menstruation because it involves more complex mechanisms. Both endometriosis cells and cancer cells differ from normal cells, both possessing similarities and differences in cellular and genetic characteristics, growth patterns, and the ability to evade apoptosis, as well as their relationship with the immune system. By studying these characteristics profoundly, numerous clinical implications can be derived, and further research can be conducted into the approach and management of these diseases.

- endometriosis - adenomyosis - cancer - benign - malignant 1. Introduction Endometriosis is an enigmatic disease that affects around 10% of the population. This disease is often chronic and is characterized by an inflammatory condition in women, where there is tissue that resembles the endometrium (inner uterine lining) outside the uterus, especially in the pelvic area, ranging from superficial peritoneal lesions of various colors to cysts in the ovaries (endometriomas), to nodules with a depth of penetration exceeding 5 mm (deep endometriosis, often accompanied by scar tissue [fibrosis] and adhesions), to extra-pelvic lesions [1–3]. Endometriosis and its sister disease, adenomyosis, are related; both are chronic and debilitating disorders characterized by the presence of ectopic endometrial tissue, either in extrauterine locations or within the uterine myometrium [4, 5]. The prevalence of focal and diffuse adenomyosis is 17% and 15%, respectively, while the prevalence of peritoneal endometriosis, ovarian endometriosis, and deep endometriosis is 6%, 13%, and 10%, respectively. Among the infertile population, the prevalence of adenomyosis and endometriosis is 31% and 38%, respectively. Moreover, in patients presenting with gynecological symptoms, the prevalence of adenomyosis is around 45%, while endometriosis occurs in approximately 30% of cases [6]. Even though endometriosis is a benign tumor, it shares several characteristics that are somewhat similar to malignant tumors, especially in the form of deep endometriosis. Deep endometriosis was described in the early 1990s as external adenomyosis [7], with endometrial glands and stroma within fibromuscular tissue. According to pathology, endometriosis becomes more active when its depth is more than 5 mm; therefore, deep endometriosis is defined as lesions with penetration > 5 mm into the peritoneum [8]. This definition appears consistent with the concept that deep endometriosis escapes from the high steroid concentrations in peritoneal fluid [9]. Several studies have shown that many factors contribute to the growth and development of endometriosis: genetic, hormonal, and immunological factors play a role, and even intestinal permeability may be involved [10–13]. In the absence of other types of endometriosis, the isolated presence of deep infiltrating endometriosis (DIE) was observed in only 6.5% of cases. Although it may be considered a separate entity, they all may share similar pathogenic pathways [14]. Sampson’s theory of retrograde menstruation has some limitations in explaining DIE, such as the fact that endometriosis is found in only 10% of cases, whereas the physiological process of retrograde menstruation occurs in 90% of women. The pathophysiology of DIE may otherwise be explained by the role of endometrial stem/progenitor cells and coelomic epithelial and mesenchymal cells, which could be the origin of premenarcheal pelvic endometriosis. The onset of DIE in adulthood denotes that DIE could be a late stage of endometriosis [15]. On the other hand, there is a hypothesis that the endometriotic cells undergo tumor-like genetic and epigenetic modifications, and these changes influence the progression to DIE [16]. This theory could explain the existence of the three described phenotypes of endometriosis, as they could be based on different genetic mutations [12]. The more intense aggressiveness of DIE compared with the other forms seems to be caused by two main mechanisms: decreased apoptosis of endometrial cells involved in lesion sites and higher proliferation activity of those cells in response to the oxidative stress generated in these lesions [17]. Moreover, DIE is characterized by higher expression of invasive mechanisms (caused by matrix metalloproteinases [MMP] and activins) and of neuroangiogenesis (caused by nerve growth factor and vascular endothelial growth factor [VEGF]) compared with superficial and ovarian endometriosis [18]. Deep infiltrating endometriosis does not only affect pelvic organs; it can also form grafts in areas such as the digestive system, urinary tract, or even the liver, lungs, and brain [19–21]. Several neuropsychiatric comorbidities are also associated with deep endometriosis. Deep infiltrating endometriosis significantly affects mental health and is attributable to neuropsychiatric conditions such as depression, dementia, and migraines [21]. These characteristics, in turn, resemble those that occur in malignant tumors, even though endometriosis is categorized as a benign disease. This chapter mainly discusses the characteristics of endometriosis and adenomyosis related to their invasive nature, similarities and differences with malignant diseases, as well as the clinical applications of these characteristics. 2. Endometriosis: A cancer-like phenomenon Endometrial stem cells or progenitor cells, including endometrial mesenchymal stem cells (eMSCs) and endometrial epithelial progenitors (eEPs), are released during retrograde menstruation and can adhere to the peritoneal surface due to altered integrin profiles on endometrial stromal cells (ESCs) and smooth muscle cells (SMCs) from women with endometriosis [22]. Even though retrograde menstruation provides a mechanism for endometrial cells to enter the pelvic cavity, this mechanism alone is not sufficient to cause endometriosis [23]. The presence of abnormal stem cells in the menstrual fluid, with their inherent properties and interactions that facilitate adhesion, proliferation, and differentiation, contributes to the formation of sporadic endometriosis lesions and triggers local inflammatory responses as well as immune dysregulation [23, 24]. Endometriosis cells are not exactly the same as eutopic endometrial cells. Although eutopic endometrial cells and tissues are frequently used to represent endometriotic lesions, they have unequivocal differences at both the tissue and cellular levels [25]. Immunohistochemical comparison between eutopic and ectopic endometrium also shows significant alterations in marker expression. The immunohistochemical analysis of normal endometrial tissues and deep endometriosis samples demonstrated that fibroblast growth factors (FGFs), such as FGF-7, FGF-10, and hepatocyte growth factor (HGF), exhibited significantly higher expression levels in the epithelium and stroma of normal controls compared to endometriosis samples. Conversely, FGF-23 and interferon-τ (IFN-τ) showed significantly higher expression in the ectopic endometrial stroma of endometriosis samples relative to eutopic endometrium. The expression level of prolactin receptors (PRL-R) is higher in the epithelium of normal endometrial tissues, while the expression level of growth hormone (GH) is higher in the epithelium of endometriosis samples. Both insulin growth factors (IGF-1 and IGF-2) are more highly expressed in the epithelium and stroma of normal samples compared with endometriosis samples [26]. Cancer cells are also different from normal cells in many ways. Cancer development is a complex process requiring many mutations; their cells are genetically unstable, leading to an increase in replication and mutation rates. Some of the specific characteristics of cancer cells include the ability to avoid apoptosis, ignore antigrowth signals, and generate independent internal growth signals. Therefore, uncontrolled growth is the first real hallmark of cancer. Cancer cells also omit boundary signals and become invasive; they can develop their own blood supply (angiogenesis). Telomerase in cancer cells causes these cells to live indefinitely, meaning they live beyond the normal 50–70 reproductive cycles seen in normal cells. Cancer cells can metastasize as they spread to distant parts of the body. Loss of differentiation in cancer cells causes these cells to no longer be able to perform specific functions [27, 28]. 2.1 Cellular and genetical perspective Endometrial stem cells or progenitor cells, including endometrial mesenchymal and EPs, exuviate during retrograde menstruation and may adhere to peritoneal surfaces due to altered integrin profiles in endometrial stromal and smooth muscle cells from women with endometriosis. These cells differentiate into various cell types and are involved in the initiation and persistence of ectopic endometrial growths. They may originate from the basal layer of the endometrium and can be identified by specific markers such as CD140b +, CD146 +, SUSD2 + eMSCs (Sushi Domain Containing-2 of eMSCs), N-cadherin +, SSEA-1 (Stage-Specific Embryonic Antigen-1), and side population (SP) cells. Endometrial stromal cells and smooth muscle cells have the potential to differentiate into various cell types under the influence of altered peritoneal environments characterized by immune cells and inflammatory mediators. The exact origin and differentiation pathways of these stem/progenitor cells, whether from basal endometrial layers or coelomic epithelial transformation, remain elusive and require further research [29–33]. Even though endometriosis is defined as the presence of endometrial glandular and stromal cells, as well as histiocytes that potentially contain hemosiderin, the presence of these two components alone is sufficient to establish the diagnosis. Over time, the histiocytes convert the extravasated red blood cells into glycolipid and hemosiderin, becoming the pseudoxanthoma cells that can replace the endometriotic stroma. Rare cases of endometriosis may consist solely of stromal elements, also known as “stromal endometriosis” [34]. There are some differences between normal human endometrium and endometriotic cells. The ectopic glandular epithelium in ovarian endometriosis shows short, sparse microvilli on the free surface of secretory cells. Some microvilli are detached from the surface. Short cilia of ciliated cells are rarely seen. Mitochondria are enlarged. Glandular cells contain small amounts of rough endoplasmic reticulum (RER), numerous free ribosomes, Golgi apparatus, lipofuscin, and myelinosomes. The nuclear membrane shows marked irregularities. Some ectopic epithelial cells have giant nuclei. Cytoplasmic protrusions containing small amounts of organelles are observed in some ectopic epithelial cells. The basement membrane becomes highly convoluted, and decidua-like cells containing numerous short, club-shaped RERs are observed. The number of macrophages is markedly increased as well [35]. In a rat model of endometriosis, transmission electron microscopy showed variable degrees of vacuolation in most epithelial cells. Their nuclei were highly euchromatic with active large nucleoli. Other dark cells with elongated dark nuclei are interspersed between columnar cells. Numerous mitochondria, small glycogen deposits, and vesicles with electron-dense cores are noticed. Well-defined microvilli were observed at the apical cell membrane [36]. Mitochondrial structure is associated with oxygen partial pressure, mitochondrial respiration, and energy requirements. It has been reported that mitochondria change their morphology and cristae in response to oxidative stress. When exposed to oxidative damage, mitochondria adapt by shifting to an elongated shape with expanded cristae for more metabolic bioenergetics, glycolysis, and reactive oxygen species (ROS) production [37, 38]. Mitochondria are responsible for regulating ROS production, energy metabolism, and signal transduction in endometriosis. The basal oxygen consumption rate (OCR) of ectopic ESCs is increased by 95% compared to eutopic ESCs, while ectopic ESCs have a greater proton leakage rate. Ectopic ESCs also have a 14% higher glycolysis rate than eutopic ESCs [39]. Ectopic endometrial stromal cells experience more severe hypoxia, causing mitochondria to shift from oxidative phosphorylation to glycolysis. Recent research has found that women with endometriosis have higher levels of lactate and ethanol in their peritoneal fluid [40]. Even if there are some distinctions between normal endometrial cells and those with endometriosis, the cell structure of endometriosis remains different from malignant tumor cells, as the latter often have abnormal chromosomes and DNA, making their nuclei larger and darker. They also often have different shapes than normal cells [41]. Genetic instability is also one of the main characteristics of malignant cells. It can manifest as microsatellite instability (MIN), which arises from individual mutations in the DNA chain and causes an increased mutation rate, as well as chromosomal instability (CIN), which refers to an increased rate of loss or gain of entire chromosomes or parts of chromosomes during cell division. Mutation itself includes insertions, deletions, duplications, and other “mistakes” in the genome [27]. Genetic instability also causes malignant tumor cells to avoid terminal differentiation. With further reproduction, they revert to a more undifferentiated appearance of primitive or stem cells rather than maintaining their highly specialized functions and form [27, 28]. Benign gynecologic disorders like endometriosis, adenomyosis, and leiomyoma have some key recurrent genetic mutations. The key mutations in endometriosis are KRAS, PIK3CA, PPP2R1A, ARID1A, PTEN, and p53, whereas in adenomyosis, they are KRAS, PIK3CA, PPP2R1A, as well as MED12 in leiomyoma [5, 42]. Several studies show shared genetic mechanisms between endometriosis and cancers in women; there is a well-established association between ovarian endometriosis (or endometrioma) and the development of ovarian endometrioid and clear cell carcinomas [43, 44]. Genetic alterations of KRAS, ARID1A, and PIK3CA also commonly occur in these tumors. The ideal ovarian microenvironmental conditions likely facilitate the transformation of endometriosis into endometriosis-related neoplasms [45]. Nevertheless, based on the currently available evidence, the increase in absolute risk for cancer in women with endometriosis is very small. The absolute risk escalation of ovarian, breast, and thyroid cancer in people with endometriosis relative to people without is + 1.2%, + 0.5%, and + 0.5%, respectively. Therefore, endometriosis patients may be reassured that their cancer risk is low and close to that of people without the disease [46]. Epithelial ovarian cancer (EOC) consists of five main histological subtypes: endometrioid carcinoma (10%), clear cell carcinoma (10%), mucinous carcinoma (<5%), and low-grade serous carcinoma (LGSC) (<5%), which are categorized as type I EOC and are thought to develop from the implantation of extra-ovarian tissue, including endometriosis, that undergoes malignant transformation. Meanwhile, high-grade serous ovarian carcinoma (HGSC) (70%), which is categorized as type II EOC, is proposed to develop mostly from the distal end of fallopian tube epithelium and is therefore known as serous tubal intraepithelial carcinoma (STIC) [47, 48]. The genomic alterations of type I EOC include ARID1A, PTEN (endometrioid carcinoma and clear cell carcinoma), CTNNB1, dMMR (endometrioid carcinoma), APOBEC, PIK3CA (clear cell carcinoma), KRAS (LGSC and mucinous carcinoma), BRAF (LGSC), and ERBB2 (mucinous carcinoma), while the genomic alterations of type II EOC (HGSC) include p53, HRD, and CI [48]. A summary of genetic mutations in benign gynecological tumors and epithelial ovarian cancer can be observed in Figure 1. MicroRNAs (miRNAs) are short, highly conserved, approximately 21–25 nucleotides long, noncoding, single-stranded RNA molecules that regulate gene expression at the posttranscriptional level by binding to their complementary mRNA. They influence the basic functions of organisms, including cell division, proliferation, differentiation, cell apoptosis, and blood vessel formation [49, 50]. The dysregulation of miRNAs in solid tumors and hematological malignancies highlights the complicated role of these molecules in cancer growth and progression [51, 52]. These changes in miRNAs are unique; therefore, recent clinical studies have linked their function to biomarkers, prognostic factors, and therapeutic targets. In ovarian cancer, there are miRNAs that experience upregulation and downregulation, where the former are related to oncogenic miRNAs, while the latter are linked with tumor-suppressive miRNAs. The upregulated miRNAs in ovarian cancer are miR-21, miR-200a, miR-200b, let-7, miR-199a, and miR-223, whereas the downregulated miRNAs are miR-100, miR-125b, miR-145, miR-126, miR-134, and miR-377 [53]. Regarding endometriosis, there is also dysregulation of miRNAs that play an important role in endometriosis pathological pathways, such as inflammation, proliferation, apoptosis, migration, invasion, estrogen signaling, progesterone resistance, and even altered endometrial receptivity related to decreased HOXA10 expression [54]. The upregulated miRNAs include miR-125b-5p, miR-15b, miR-122, miR-18a-5p, miR-143-3p, miR-145-5p, miR-150-5p, miR-342-3p, miR-451a, miR-500a-3p, miR-185-5p, miR-424-3p, miR-29c, miR-135a, miR-135b, and miR-196a; the last four miRNAs mentioned play a role in progesterone resistance. On the other hand, the downregulated miRNAs include miR-17-5p, miR-20a-5p, miR-9-3p, miR-141-5p, miR-145-3p, miR-542-3p, miR-199a-5p, miR-141-3p, miR-200a-3p, let-7b, let-7d, let-7 f, miR-31, miR-3613-5p, and miR-6755-3p [54, 55]. The overall alterations and functions of specific miRNAs in both endometriosis and malignant diseases still require further research and evaluation. DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates gene expression by recruiting proteins entangled in gene repression or by hindering the binding of transcription factor(s) to DNA [56]. Long interspersed element-1 (LINE-1 or L1) is a non-retroviral-like retrotransposon distributed at multiple loci throughout the human genome, and these elements are typically highly methylated in normal tissues [57]. Reduced LINE-1 methylation is a common key epigenetic alteration in several cancers [58, 59], including ovarian cancer [60, 61]. A stepwise decrease in LINE-1 methylation is observed in the following order: normal endometrium, ovarian endometrioma, endometrioid adenocarcinoma, and ovarian clear cell carcinoma (P < 0.001). This fact denotes that epigenomic changes might precede the development of ovarian cancer; hence, precise measurement of LINE-1 methylation patterns may be useful in distinguishing ovarian endometrioma from endometriosis-associated ovarian cancer [62]. Runt-related transcription factor 3 (RUNX3) plays a crucial role in controlling cellular self-renewal, proliferation, and differentiation [63]. RUNX3 hypermethylation is associated with poor prognosis, and the RUNX3 gene is under expressed in EOC tissues and ovarian cancer cell lines [64]. Furthermore, it has been shown that estrogen increases DNA methyltransferase-1 (DNMT-1) expression and RUNX3 methylation levels, thus affecting cellular biology. The estrogen-DNMT1 signaling pathway can stimulate RUNX3 hypermethylation to promote endometriosis tumorigenesis [65]. 2.2 Growth pattern and avoiding apoptosis Endometriosis and cancer (specifically endometrial or ovarian cancer) share similarities in their reliance on estrogen and inflammatory growth factors, but they differ fundamentally in their growth behavior and potential for malignancy. Endometriosis is a benign, chronic disease involving endometrial-like tissue growing outside the uterus, while cancer involves the uncontrolled, destructive growth of malignant cells. Malignant tumor mass seems to follow exponential growth; therefore, the tumor volume doubling time (TVDT), that is, the time required for a tumor to reach a twofold volume, has been used in clinical practice [66]. In high-grade serous ovarian cancer, growing lesions in the ovaries and the omentum doubled in volume every 2.2 months and 1.8 months, respectively. Moreover, the median interval between disease initiation and the onset of metastasis is 13.1 months [67]. Conversely, endometriosis nodules grow slowly, with an annual growth rate of + 0.09 mm/year [68]. Under physiological conditions, cells receive fate-determining signals from their tissue environment, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although deviation from homeostasis and malignant tumor initiation are triggered by oncogenic mutations rather than growth factors, growth factors are key regulators of all subsequent steps in tumor development, including clonal expansion, invasion across tissue barriers, angiogenesis, and colonization toward distant parts [69]. Based primarily on in vitro models, it appears that TGF-β and other growth factors (e.g., the HGF and FGFs) enhance the invasive potential of cancer cells by upregulating secreted proteases (e.g., the MMP-2 and MMP-9) and downregulating protease inhibitors [69, 70]. TGF-β ligands, consisting of TGF-β1, TGF-β2, and TGF-β3, are secreted by numerous cell types, including epithelial cells, fibroblasts, and immune cells. They are known to participate in various cellular processes such as differentiation, proliferation, migration, remodeling, apoptosis, embryogenesis, wound healing, fibrosis, inflammation, and tumor progression [71]. TGF-β is increased in the microenvironment of chronic injury/inflammation and cancer. Furthermore, it is also stimulated by oxidative stress, Toll-like receptor signaling, as well as pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 [72]. All of these are characteristic of endometriosis; hence, it is not surprising that several studies have demonstrated significantly higher levels of TGF-β in the serum, peritoneal fluid, peritoneum, and eutopic endometrial tissue of women with endometriosis, suggesting that TGF-β expression and/or signaling may contribute to the pathophysiology of endometriosis, including cell survival, attachment, invasion, proliferation, neoangiogenesis, and immune cell activity [73]. The formation and growth of ectopic lesions in endometriosis depend on nutrient support, with neovascularization playing a key role. This mechanism involves VEGF and matrix metalloproteinase (MMP). There are several pathways of VEGF upregulation in endometriosis. One of the most important pathways starts from a hypoxic microenvironment; it prevents proteasomal degradation of hypoxia-inducible factor-1α (HIF-1α), which in turn upregulates VEGF expression and promotes angiogenesis [74]. The same mechanism also occurs in cancer cells, yet cancer cells can also produce angiogenic factors such as VEGF endogenously and then secrete them into the surrounding tissue [75]. Apoptosis in endometriosis involves a dysregulated balance between proapoptotic and anti-apoptotic factors. The growth and survival of ectopic endometrial tissues are influenced by hormonal fluctuations; therefore, the signaling imbalance between estrogen as an anti-apoptotic agent and progesterone as a proapoptotic agent is a hallmark of endometriosis. Endometriosis shows decreased expression of 17β‐hydroxysteroid dehydrogenase 2 (17β-HSD2), which converts estradiol to estriol; thus, estradiol levels, which are the most potent form of estrogen, remain high [22]. Progesterone resistance in endometriosis is caused by downregulation of progesterone receptors (PRs), especially PR-B. This is mainly due to environmental toxins, increased expression of various miRNAs, overactive cell signaling pathways, overexpressed KRAS mutations, as well as the effects of cytokines under chronic inflammation [22, 76]. In endometriotic lesions, estrogen receptor β (ERβ) is significantly overexpressed compared to estrogen receptor α (ERα), which contributes to the survival and proliferation of ectopic endometrial cells, increases lesion growth by inhibiting TNF-α, which induces apoptosis, and increases IL-1β levels, which enhance cell adhesion and proliferation [22]. Meis homeobox I (MEIS1), an apoptosis-related gene that induces apoptosis by initiating the TNFR1-mediated caspase pathway, is also downregulated in endometriosis tissue [77]. Apoptosis evasion is clearly a hallmark of cancer as well, and it involves more complex processes, starting from modifications of genes such as Bcl-2, p53, and caspase genes; posttranslational modifications; metabolic changes; dormant tumor cells that are found to be resistant to apoptosis; and even the ability of cancer cells to reverse apoptosis [78]. Cancer cells are capable of living indefinitely, surpassing the normal 50–70 reproductive cycles seen in normal cells. This is due to the presence of telomerase, which can counteract the loss of telomeres during cellular replication [27]. Telomeres are repeating sequences of TTAGGG, along with shelterin proteins, that are located at the distal ends of chromosomes. They shorten with each cell division, thus limiting the lifespan of normal somatic cells and leading to apoptosis [79]. The human telomerase enzyme consists of three core subunits: (1) the telomerase RNA component (hTERC), (2) the catalytic subunit telomerase reverse transcriptase (hTERT), and (3) the dyskerin protein [80]. Reactivation of telomerase at very short telomeres is a critical step in the development of approximately 85% of human cancers, which can ultimately lead to chromosomal chaos [81, 82]. In the case of endometriosis, it turns out that telomerase also plays a role. Endometriosis is associated with significant increases in hTERC and telomere/telomerase-related gene alterations in eutopic endometrium, which eventually lead to sufficient genomic stability that allows benign clonal expansion of endometriosis cells for years without triggering catastrophic genomic damage [80]. Several pieces of evidence suggest that estrogen controls telomerase activity directly and indirectly in estrogen target tissues. Estrogen deficiency leads to telomere shortening, whereas its overactivity increases telomerase activity and maintains telomere length. Conversely, progesterone and some growth factors, including TGF-β, have an inhibitory effect on telomerase activity and the gene expression of hTERT [83]. Androgens also upregulate telomerase in an ovarian cancer cell line [82]. It is reported that endometriotic cysts have a higher concentration of iron than their non-endometrioid counterparts, because of periodic hemorrhage into the cyst with the accumulation of free iron [84]. Ferroptosis was originally discovered as an iron-dependent form of oxidative cell death initiated by a decrease or inhibition of glutathione peroxidase 4 (GPX4), which is a key player in the cellular antioxidant defense. Direct inhibition of GPX4 results in the accumulation of lipid peroxides, which are converted to lipid ROS by the action of reactive iron cations such as Fe2+, resulting in ferroptotic cell death [85, 86]. A significant negative correlation is observed between ferritin and GPX4 levels in ovarian endometrioma [87]. Genomic alteration, inflammation, hyperestrogenism, and oxidative stress, combined with several other factors, are thought to play a role in the transformation of endometriosis from benign to atypical (borderline) and then to hormone-dependent malignant diseases like type-I EOC [84]. Ultimately, dependence on estrogen and its receptors determines the carcinogenesis process in endometriosis-associated ovarian cancer, whether it will become estrogen-dependent endometrial carcinoma or estrogen-independent clear cell carcinoma [42]. A summary of the process can be seen in Figure 2. 2.3 Relationship with the immune system A supportive microenvironment populated by various stromal cells and immune cells, including macrophages, plays a critical role in the development of endometriosis and cancer. Macrophages guard the lesions against immunosurveillance while promoting pathological cell growth, invasion, and metastasis in both endometriosis and cancer [88]. Macrophages act as main actors with broad functional plasticity that tune the balance between pro- and anti-inflammatory responses. They are grouped into pro-inflammatory (M1) and anti-inflammatory/prorepair (M2) phenotypes based on the expression of key surface markers and the production of certain cytokines [89]. Stimuli from IFN-γ, granulocyte‒macrophage colony-stimulating factor (GM-CSF), and microbial components, including lipopolysaccharide (LPS), cause macrophages to polarize into the classical M1 phenotype, which produces pro-inflammatory factors, including tumor necrosis factor (TNF) and interleukins (ILs) such as IL-1, IL-6, IL-12, and IL-23, chemokines (CXC motif chemokine ligand 10 and 11), and costimulating proteins. On the other side, stimuli from IL-4 or IL-13 cause macrophages to polarize into the M2 phenotype, which produces profibrotic factors, such as transforming growth factor β (TGF-β) and insulin-like growth factor 1 (IGF-1), as well as induces angiogenesis and lymphangiogenesis by producing VEGF-A, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and IL-8 [89]. Macrophages not only support endometriotic cell survival but also stimulate their growth and invasion by secreting numerous factors that promote endometriotic tissue proliferation, including both pro-inflammatory cytokines of M1 (TNF-α, IL-6, IL-8) and growth factors of M2 (EGF, VEGF). While the effect of growth factors on endometriosis progression is clear, the sensitivity of endometriotic cells to the proapoptotic effects of TNF-α turns out to be reduced. On the contrary, endometriotic cells begin utilizing TNF-α as a survival and growth factor by switching from TNFR1 apoptotic signaling to TNFR2/NF-κB proliferative pathways. Additionally, IL-6 secreted by macrophages can enhance endometrial cell proliferation by interacting with the ERα signaling cascade [90]. Similar to endometriosis, chronic inflammation is a necessary consequence of cancer development. Various inflammatory conditions can lead to neoplastic transformation. However, regardless of whether inflammation is present at the genesis of carcinogenesis, most tumors develop chronic inflammatory conditions that trigger various aspects of tumor progression, including genomic and epigenomic instability, immune evasion, angiogenesis, and metastatic spread [91]. There are two strategies that tumor cells use to avoid immune attacks: avoiding immune recognition and triggering an immunosuppressive response. In the first strategy, mutations and deletions may result in the downregulation of the antigen-presenting mechanism and promote resistance to T-cell effector molecules such as TNF-α and IFN-γ [92]. Downregulation of cell surface NK activators renders cancer cells invisible to natural killer (NK) cell detection as well [93]. In the second strategy, cancer cell-derived factors provoke an immune-tolerant condition by secretion of suppressive molecules such as IL-10, TGF-β, prostaglandin E2, and VEGF [94]. Natural killer cell function impairment is also a main factor in the survival of endometriosis cells. Both IL-6 and TGF-β in the peritoneal fluid of women with endometriosis have been demonstrated to reduce the cytolytic activity of NK cells. In addition, IL-15, which is highly expressed on ectopic endometrial stromal cells, has been demonstrated to inhibit NK cell function in vitro. Finally, the interaction of ectopic endometrial cells with macrophages reduces NK cell cytotoxicity as well, probably through increased release of IL-10 and TGF-β [95]. As discussed previously, macrophages play a key role in both endometriosis and cancer [88]. Key factors mediating monocyte/macrophage chemotaxis to endometriotic or cancer lesions are chemokines such as monocyte chemoattractant protein-1 (MCP-1), IL-8, regulated on activation, normal T-cell expressed and secreted (RANTES), and fractalkine (CX3CL1) [90, 91]. MCP-1, also known as CCL2, is primarily upregulated by pro-inflammatory cytokines, as well as by cellular stress, oxidative stress, injury, and pathogens. Recent research has also revealed that MCP-1 is upregulated by a 40 kDa glycoprotein called chitinase-3-like protein-1 (CHI3L1), secreted by M2a macrophages [96, 97]. Chitinase-3-like protein-1, also known as YKL-40, plays a critical role in the pathogenesis of multiple organ system diseases associated with inflammation. A positive correlation between serum CHI3L1 levels and the stage of endometriosis has been revealed, and the inflammatory process of endometriosis may result in elevated CHI3L1 levels [98, 99]. In adenomyosis, there is a positive correlation between CHI3L1 MCP-1, and MMP-9; therefore, it is possible that it could become a novel biomarker and therapeutic target [97]. Chitinase-3-like protein-1can also aggravate DNA oxidative damage, induce the cancerous phenotype, promote the development of a tumor inflammatory environment, inhibit immune cells, as well as promote cancer cell growth, angiogenesis, invasion, and migration [100]. Further research is still needed to profoundly explore this glycoprotein. 2.4 Clinical implications Unlike cancer, endometriosis nodules grow relatively slowly (annual growth rate of +0.09 mm/year); hence, early diagnosis of endometriosis is not easy. Endometriosis has an overall median delay in diagnosis of 7 years [101]. This is one of the reasons why endometriosis is frequently diagnosed in an advanced stage. Another difference between endometriosis and cancer is that cancer is a highly proliferative and catabolic state, whereas endometriosis lacks these characteristics. Clinically, pain in endometriosis is usually cyclic, while pain in ovarian cancer is dull and steady [48]. The infiltrative pattern of deep endometriosis also does not resemble the destructive invasion of cancer cells, which is typically associated with a stromal desmoplastic reaction. The tissue in endometriosis is morphologically normal, yet misplaced [45]. The clinical management of endometriosis involves medical, surgical, and adjunctive therapies tailored to individual patient needs. Prostaglandin E2 (PGE2) promotes inflammation, pain, and cell proliferation in endometriosis; therefore, prostaglandin inhibition has been used as a potential therapeutic target for managing inflammation and symptoms of endometriosis [102]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for managing dysmenorrhea and pelvic pain of endometriosis by inhibiting cyclooxygenase (COX) enzymes and reducing prostaglandin synthesis [103]. Medications such as gabapentin or amitriptyline may be utilized as adjunctive therapies for chronic neuropathic pain [104]. Hormonal therapies mainly aim to suppress ovulation and menstruation, thus reducing the ectopic endometrial tissue’s exposure to cyclic hormonal changes. Hormonal therapies that have been employed in endometriosis include combined oral contraceptives (COCs), progestins, gonadotropin-releasing hormone (GnRH) agonists and antagonists, and aromatase inhibitors [22]. Dienogest, a novel progestin, has demonstrated good therapeutic effects in reducing pain associated with endometriosis. However, its antiproliferative effect as a PR agonist is reduced by the epigenetic suppression of the PR in endometriosis and adenomyosis with KRAS mutations [105]. As explained above, KRAS mutations in both endometriosis and adenomyosis carry a risk of malignancy. Selective progesterone receptor modulators (SPRMs), such as ulipristal acetate, modulate progesterone activity selectively and reduce lesion growth while preserving endometrial receptivity; however, they are not used anymore because of the risk of fulminant hepatitis [22]. Therapies targeting inflammatory and immune pathways, such as TNF-α inhibitors or IL antagonists, are in early-stage research for treating endometriosis [106]. Given the aforementioned roles and mechanisms of CHI3L1 in chronic inflammation associated with various body systems, an increasing amount of research is verifying CHI3L1 as a promising therapeutic target [107]. Chitinase-3-like protein-1activity has been shown to be reduced by CHI3L1 inhibitors in cases of neuroinflammation [108]; however, further research in endometriosis and malignancy is still needed. Vitamin D has anti-inflammatory, antiproliferative, antioxidative, and immunomodulatory effects. Research shows that endometriosis is inversely correlated with serum 25-hydroxyvitamin D3 levels [109]. Active vitamin D (1,25(OH)2D3) also plays a role in reducing inflammation associated with endometriosis by reducing IL-32 and VEGF [110]. Other molecules currently being studied for endometriosis therapy include PKF115‐584/CGP049090, an antagonist of the Wnt/β-catenin signaling pathway; FTY720 (fingolimod), the first FDA-approved oral drug for treating relapsing–remitting multiple sclerosis, which has anti-inflammatory, anti-apoptotic, antioxidative, and anti-fibrotic roles in several pathologies; recombinant P-selectin-Fc, which has demonstrated suppression of platelet aggregation, reduced angiogenesis, and macrophage infiltration; and relaxin (RLX)-2, which may suppress collagen-I, plasminogen activator inhibitor-1 (PAI-1), and IL-8 expression. All these molecules have important roles in fibrosis formation [111]. Laparoscopy is the gold standard for diagnosing and treating endometriosis. The procedure involves excision and complete removal of endometriotic lesions, which is preferred over ablation to ensure eradication of disease lesions and prevent recurrence, surgical removal of adhesions to restore pelvic anatomy and improve organ function, and ovarian cystectomy for endometriomas in symptomatic cases to relieve pain and improve fertility outcomes [112]. Yet, ovarian cystectomy overwhelmingly demonstrates a negative impact on ovarian reserve; therefore, several techniques have been developed for patients who still require fertility function, such as drainage and ovarian endometrioma vaporization with a diode laser or CO2 laser, alcohol sclerotherapy, combined approach (three-stage technique), hemostatic techniques, etc. [113–115]. In laparoscopic endometriosis surgery, especially for advanced cases, a structured approach is essential. This does not mean rigidly following a predetermined set of steps, but rather a framework that the surgeon can use depending on the surgical scenario. The fundamentals of endometriosis surgery follow the acronym SOSURE (Survey and Sigmoid mobilization – Ovarian mobilization – Suspension of uterus and ovaries – Ureterolysis – Rectovaginal and/or pararectal space entry – Excision of all visible or palpable disease). A complete description of these systematic steps is shown in Figure 3. Having a competent team of surgeons, including urologists, colorectal surgeons, anesthesiologists, as well as a gynecologists, is essential [116]. Endometriosis-associated infertility needs a personalized approach based on the extent of the disease and reproductive goals. Controlled ovarian hyperstimulation and intrauterine insemination (IUI) may be effectively utilized for minimal-to-mild endometriosis. In vitro fertilization (IVF) offers higher success rates for moderate-to-severe cases. Early referral to fertility specialists and consideration of oocyte or embryo cryopreservation are crucial for patients at risk of diminished ovarian reserve due to surgical interventions or disease progression [117]. Removal of adenomyosis before starting IVF also requires special attention because adenomyosis increases the risk of second-trimester pregnancy loss [118]. Several adjunctive and alternative therapies have also been studied in endometriosis. Lifestyle modifications, such as regular exercise, a low-inflammatory diet (particularly a Mediterranean-diet), cognitive behavioral therapy (CBT), and proper stress management, may complement conventional treatments [119]. Evidence also supports the role of acupuncture in reducing pain and improving the quality of life in endometriosis [120]. Epigallocatechin-3-gallate (EGCG), one of the principal polyphenols present in green tea, has been demonstrated to inhibit cell proliferation and angiogenesis in endometriosis [111]. 3. Conclusion Endometriosis and its related disease, adenomyosis, are unique diseases because their morphology resembles benign lesions, but they have several characteristics similar to malignancy. This chapter discusses the similarities and differences between endometriosis and malignancy from cellular and genetic perspectives, growth patterns and ability to evade apoptosis, relationship to the immune system, as well as clinical applications built upon these characteristics. Based on the facts that have been described, hopefully, the approach and management for this disease can be more comprehensive, and further research can be conducted, considering that there are still many pathways of this disease that have not been explored.

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