Endometriosis: Under the Lens – Criteria, Pitfalls and Mimics

Ectopic endometrial glands and stroma are the hallmark of endometriosis; however, its histopathologic diagnosis can be modest and is often overlooked. Hemorrhage, hemosiderin-laden macrophages, and stromal CD10 positivity are frequently used by pathologists to support their identification of both glandular and stromal components. Diagnostic problems include small or fragmented biopsies, aberrant histologic variations such as, clear cell, intestinal, or decidualized stroma, and unusual anatomic locations. Endosalpingiosis, mesothelial proliferations, and early neoplastic lesions are common mimickers of endometriosis that require careful morphologic assessment and selective immunohistochemistry. Colocalization of glands and stroma, knowledge of stromal-only lesions, and identification of characteristics suggestive of malignancy are important diagnostic pearls. To prevent overdiagnosis or underdiagnosis, histology findings must be integrated with clinical and imaging data. This study provides a pathologist-oriented paradigm for precise and repeatable histopathologic diagnosis of endometriosis by consolidating current microscopic criteria, highlighting practical problems, and outlining significant mimickers.

- ectopic endometrial tissue - microscopic diagnostic criteria - histologic variants - differential diagnosis - endometriosis mimickers 1. Introduction Endometriosis is a persistent and benign, but clinically aggressive, gynecological illness. Its hallmarks are functional endometrial glands and stroma located outside the uterine cavity. These ectopic endometrial tissues exhibit a cyclical hormonal response, just like the eutopic endometrium, which results in fibrosis, chronic inflammation, recurrent bleeding, and progressive tissue deterioration. Endometriosis is histologically benign, but it shares biological traits with neoplastic processes, including angiogenesis, resistance to apoptosis, local invasion, and a predisposition for recurrence. These traits contribute to the disease’s significant morbidity and complex clinical history [1, 2]. The condition is highly estrogen-dependent and primarily affects women who are of reproductive age. A wide range of clinical symptoms, including severe pelvic pain, dysmenorrhea, dyspareunia, infertility, and a diminished quality of life, can result from ectopic endometrial tissue, which can be found inside the pelvis or at distant extra-pelvic sites. Endometriosis is recognized as a systemic illness rather than a localized pelvic pathology due to its chronicity, heterogeneity, and unexpected course [3]. Identification of ectopic endometrial glands and/or stroma, frequently accompanied by signs of recurrent hemorrhage, such as hemosiderin-laden macrophages, is necessary for the histological diagnosis of endometriosis. However, significant morphological variation, site-specific changes, and hormonal effects sometimes make diagnosis difficult, particularly when biopsy samples are scarce. Delays in conclusive diagnosis and an underestimation of illness frequency across populations have been caused by this diagnostic complexity [4]. 2. Historical perspective Over the course of centuries, our understanding of endometriosis has gradually changed to reflect advances in pathology procedures, societal views on women’s health, and medical knowledge. Old medical manuscripts from more than 4,000 years ago describe symptoms that resemble endometriosis, especially dysmenorrhea and chronic pelvic discomfort. Indirectly implying the existence of a chronic gynecological illness affecting menstruating women, early doctors, notably those from the Hippocratic school, linked such symptoms to delayed childbirth and uterine malfunction [5]. Due to the lack of histological techniques, endometriosis remained poorly defined for centuries despite these early clinical observations. Women who presented with persistent pelvic discomfort in the middle ages and early modern times were frequently misdiagnosed as having psychiatric problems or hysteria, which resulted in a widespread disregard for their physical complaints. In addition to causing protracted pain and stigmatizing afflicted women, this historical bias considerably postponed the acceptance of endometriosis as an organic disease [6]. Karl von Rokitansky, who discovered endometrial glands and stroma within ectopic regions during microscopic examination, is credited with providing the first conclusive pathological diagnosis of endometriosis in 1860. Even though Rokitansky first reported these lesions in relation to ovarian neoplasms, his findings helped establish endometriosis as a separate pathological entity [7]. The late nineteenth and early twentieth centuries saw significant advancements, especially thanks to Thomas Cullen, who used histological criteria to define peritoneal endometriosis and methodically describe adenomyomas. Cullen’s study established the pathological basis for the diagnosis of endometriosis and highlighted the significance of microscopic investigation in distinguishing it from other gynecological disorders [8]. John A. Sampson’s work in the 1920s, when he had put forth the hypothesis of retrograde menstruation, was a significant turning point in the historical understanding of endometriosis. According to Sampson’s theory, during menstruation, endometrial tissue spreads into the peritoneal cavity through the fallopian tubes, where it implants and multiplies at ectopic locations. This theory is still one of the most important ideas in the pathophysiology of endometriosis and continues to guide current research, despite not being a uniform explanation [9]. The conceptual framework of endometriosis developed during the following decades, going beyond basic conceptions of implantation. The disease’s complex nature was made clear by developments in immunology, molecular biology, and genetics, which also highlighted the roles of environmental factors, genetic vulnerability, hormonal dysregulation, and altered immune surveillance. Endometriosis is no longer seen as solely a mechanical disease of retrograde menstruation but rather as a complicated systemic disorder with developmental, immunological, and epigenetic features [10]. Endometriosis’s historical growth reflects broader progress in gynecological pathology and women’s health advocacy. The acceptance of endometriosis as a real, crippling illness has led to advancements in patient-centered care, treatment methods, and diagnostic techniques. However, ongoing research and increased clinician awareness are necessary, given the recurrence of therapeutic obstacles and diagnostic delays. 3. Epidemiology One of the most common gynecological conditions affecting women of reproductive age is endometriosis, but because of diagnostic limitations and variation in disease presentation, it is still challenging to determine the full epidemiological impact of this condition. Significant underestimation of illness prevalence across communities has resulted from the lack of trustworthy noninvasive diagnostic indicators and the reliance on surgical vision for conclusive diagnosis. As a result, rather than population-based screening studies, the majority of epidemiological data on endometriosis come from surgical cohorts, infertility clinics, and women who present with pelvic pain [11, 12]. According to global prevalence estimates, between 6% and 10% of women in the overall reproductive age population suffer from endometriosis. Nonetheless, among some clinical populations, its frequency increases significantly. According to studies, nearly 35% to 50% of women assessed for persistent pelvic discomfort and 30% to 50% of women presenting with infertility have endometriosis. These numbers demonstrate the substantial correlation between endometriosis, pain syndromes, and reproductive dysfunction, highlighting the disease’s significant global contribution to gynecological morbidity [13, 14]. Variations in diagnostic procedures, healthcare availability, clinician awareness, and sociocultural variables influencing symptom reporting all have an impact on epidemiological variation. Endometriosis is still notably underdiagnosed in many low and middle-income nations, and women may experience symptoms for years before receiving the proper diagnosis. Persistent gaps in clinical recognition and referral routes are reflected in the typical delay of 7 to 10 years between the onset of symptoms and a conclusive diagnosis, even in developed healthcare systems [15]. With a peak diagnosis between the ages of 25 and 40, age-specific prevalence patterns show that endometriosis is largely a disease of the reproductive years. However, there is growing evidence suggesting that the disease may start considerably earlier, possibly in adolescence or even before menarche. A significant proportion of modest and early-stage endometriotic lesions has been observed during laparoscopic examinations in teenagers with severe dysmenorrhea, indicating that the disease may be present long before a clinical diagnosis is confirmed [16]. A significant frequency of asymptomatic endometriosis has also been found in epidemiological research. Up to 4–10% of women have been reported to have endometriotic lesions accidentally discovered during laparoscopic procedures carried out for unrelated causes, such as tubal ligation. Although it raises significant questions about disease progression, symptom development, and the point at which intervention becomes necessary, the clinical relevance of such an asymptomatic condition is yet unknown [17]. The identification of several endometriosis phenotypes, such as, superficial peritoneal lesions, ovarian endometriomas, and deep infiltrating endometriosis (DIE), further complicates epidemiological interpretation from a pathological standpoint. Every phenotype has a unique anatomical distribution, clinical behavior, and effects on quality of life and fertility. In recent decades, DIE has become more well-recognized, which has led to apparent increases in prevalence that are more likely to be the result of greater diagnostic awareness than a real increase in the incidence of the illness [18]. Epidemiological complexity is increased by extra-pelvic endometriosis, in addition to pelvic illness. The gastrointestinal tract, urinary system, abdominal wall scars, lungs, pleura, and even distant locations such as, lymph nodes and skeletal muscle have all been reported to develop endometriotic lesions. Despite being uncommon, these symptoms broaden endometriosis’ epidemiological range and support its description as a systemic illness with multifocal potential [19]. All things considered, the epidemiology of endometriosis shows that the illness is widespread, poorly understood, and unevenly distributed among different demographics. Standardized classification methods, early diagnostic techniques, and increased knowledge are crucial for improving epidemiological estimates and directing public health campaigns that aim to lower the burden of disease and diagnostic delays. 4. Etiology and theories of pathogenesis The precise cause of endometriosis is still unknown despite decades of research, and no single theory adequately accounts for all of the disease’s clinical, pathological, and epidemiological features. As a result, endometriosis is considered a multifactorial condition that results from the intricate interaction of anatomical, hormonal, immunological, genetic, and environmental factors. To recognize the heterogeneity of disease presentation, variability in development, and variations in response to therapy found among affected women, one must have a thorough understanding of the suggested pathogenetic pathways [20, 21]. Sampson’s idea of retrograde menstruation is one of the most frequently recognized theories. It postulates that during menstruation, viable endometrial fragments reflux via the fallopian tubes into the peritoneal cavity, where they implant and multiply at ectopic locations. Even though most women who menstruate experience retrograde menstruation, only a small percentage develop to endometriosis, suggesting that other factors such as, altered immune clearance, increased cellular adhesion, and a permissive hormonal milieu are necessary for the disease to establish [22]. Another explanation is offered by the notion of coelomic metaplasia, which postulates that, under some conditions, peritoneal mesothelial cells can still develop into tissue that resembles endometrium. The fact that endometriosis occurs in premenarchal girls, in women who have Müllerian agenesis, and at remote extra-pelvic locations that are difficult to account for by retrograde menstruation alone lends credence to this theory. Coelomic metaplasia emphasizes the peritoneal tissues’ developmental flexibility and the possible contribution of local microenvironmental factors to the onset of illness [23]. The Müllerian remnant theory, which postulates that embryonic remnants of Müllerian ducts persist in ectopic places and then develop into functional endometrial tissue under hormonal control, is another significant pathogenetic idea. Deep infiltrating endometriosis and lesions at anatomically fixed places, such as, the rectovaginal septum and uterosacral ligaments, are especially well-explained by this idea. This theory highlights the developmental origins of endometriosis in conjunction with metaplastic mechanisms [24]. The role of stem and progenitor cells in the pathophysiology of endometriosis is further supported by new data. It has been proposed that bone marrow-derived progenitor cells and endometrial stem cells, secreted during menstruation, contribute to the development and maintenance of ectopic lesions. Even after surgical excision, lesion persistence and recurrence may be facilitated by these cells, increasing the potential for proliferation and migration [25]. Immunological dysfunction represents a central component of disease pathogenesis. Women with endometriosis demonstrate impaired immune surveillance within the peritoneal cavity, characterized by reduced clearance of ectopic endometrial cells, altered macrophage activity, increased proinflammatory cytokine production, and aberrant natural killer cell function. This chronic inflammatory microenvironment promotes angiogenesis, fibrosis, and neuronal infiltration, contributing to lesion survival and pain generation [26]. The maintenance of endometriotic lesions is significantly influenced by hormonal variables. Progesterone resistance, increased expression of hormone receptors within ectopic tissue, and local estrogen production are characteristics of endometriosis. These hormonal abnormalities lengthen the lesion duration by preventing apoptosis and sustaining inflammation. The disease’s chronic and recurrent nature is further supported by the interaction between hormonal and inflammatory pathways [27]. Genetic and epigenetic influences have gained increasing attention in recent years. Higher concordance rates among monozygotic twins and familial clustering of endometriosis point toward a heritable component. Epigenetic modifications affecting genes involved in steroid metabolism, immune regulation, and cellular adhesion have been implicated in disease susceptibility and progression, offering insight into interindividual variability [28]. The development of endometriosis has also been linked to environmental factors, specifically exposure to chemicals that disrupt hormones. Dioxins, polychlorinated biphenyls, and bisphenol A are some examples of substances that might disrupt immunological function and estrogen signaling, making genetically predisposed people more vulnerable. These findings demonstrate the possible impact of environmental exposures on illness risk, even if conclusive causal linkages are still being studied [29]. When considered collectively, the etiopathogenesis of endometriosis represents a complex process that includes immunological dysregulation, hormonal imbalance, developmental abnormalities, mechanical spread, genetic susceptibility, and environmental modulation. This intricate pathogenetic environment highlights the difficulties in creating universally successful treatment approaches and explains the diversity of clinical presentations. 5. Age group Because endometriosis is heavily dependent on ovarian steroid hormones, it primarily affects women throughout their reproductive years. Although endometriosis is typically diagnosed between the ages of 25 and 40, growing awareness and better diagnostic methods have shown that the condition can appear much earlier in life. Teenagers who experience severe dysmenorrhea that does not improve with traditional treatment often show laparoscopic signs of endometriosis, indicating that the disease often starts years before it is diagnosed [30]. 6. Distribution and anatomical sites Although it most frequently affects pelvic structures, endometriosis can impact a wide range of extra-pelvic sites, demonstrating its extraordinary anatomical diversity. With frequent involvement of the ovaries, pelvic peritoneum, uterosacral ligaments, pouch of Douglas, and rectovaginal septum, the pelvis continues to be the most common site. Because it is linked to pain, infertility, and recurrence risk, ovarian endometriosis, which frequently manifests as endometriomas, represents one of the most clinically relevant types of this condition [31]. Despite being less frequent, extra-pelvic endometriosis broadens the disease’s anatomical scope. The gastrointestinal tract, bladder, ureters, abdominal wall scars, and inguinal area have all been reported to have endometriotic lesions. Scar endometriosis is an example of iatrogenic dissemination and highlights the ability of endometrial tissue to implant and persist in ectopic settings, especially after cesarean sections or other pelvic procedures [32]. From a pathological perspective, lesion morphology ranges from gland-rich lesions with active stroma to fibrotic, gland-poor foci containing hemosiderin-laden macrophages, depending on the location, duration, and hormonal effect. Because of this heterogeneity, diagnosis is made more difficult, and extensive histological investigation is required, especially in extra-pelvic regions [33]. 7. Diagnostic criteria The definitive diagnosis of endometriosis relies on the microscopic identification of endometrial glands surrounded by endometrial stroma outside the uterine cavity. Three primary histopathological features are needed for the diagnosis of endometriosis. First is the presence of endometrial glands, which are lined by cuboidal to columnar epithelium. The endometrial glands may exhibit cyclical proliferative or secretory changes, or even decidualization under hormonal influence. Second is the identification of a compact, cellular stroma morphologically identical to ectopic endometrial stroma, particularly in fibrotic or gland-poor lesions where glandular tissue may be sparse. The stroma consists of small, spindle-shaped cells with inconspicuous cytoplasm. A key diagnostic feature is a delicate reticulin network investing the individual stromal cells, which can be visualized using silver impregnation staining and is much finer than the collagen of native ovarian stroma or cervix. Third, evidence of chronic or recurrent hemorrhage, indicated by the presence of hemosiderin-laden macrophages or iron deposition, serves as a key marker in long-standing or deeply infiltrative cases [34]. At least two of these three elements must be present for a diagnosis to be made, with the most common diagnostic requirement being the presence of both stroma and endometrial glands. An immunohistochemical marker called CD10 reactivity can be used to confirm the existence of endometrial stroma, especially in cases where the epithelium is absent or atrophic. In situations that are unclear or complex, CD10 is very helpful. It is especially helpful in chronic instances where the amount of endometrial stroma is limited and difficult to differentiate from ovarian or non-specific fibrous stroma due to secondary alterations such as bleeding and scarring (fibrous obliteration). There may be ectopic endometrial stroma without any associated endometrial glands in stromal endometriosis. Using CD10 immunohistochemistry can assist a pathologist in identifying the cells and making the diagnosis in cases where they are uncertain if endometrial-type stroma is truly present in a tissue sample [35]. In addition to the primary diagnostic criteria, several histopathological findings strongly support a diagnosis of endometriosis by reflecting the tissue’s chronic reactive state. Often, ectopic foci are surrounded by thick scarring and fibrosis, as well as a persistent inflammatory infiltration made up of macrophages and lymphocytes. Particularly in deep infiltrating lesions, structural alterations such as, smooth muscle hyperplasia or hypertrophy are frequent, yet the presence of thick-walled blood vessels and active angiogenesis suggests a strong local blood supply. Furthermore, cystic hemorrhagic spaces – classically referred to as “chocolate cysts” when occurring in the ovaries – provide significant evidence of the cyclical bleeding and sequestered blood characteristic of the disease [34]. While these features are not independently diagnostic, their presence alongside glandular or stromal components provides a more comprehensive and definitive pathological picture. The tissue frequently contains macrophages that are laden with hemosiderin, ranging from slightly to heavily pigmented. This pigmentation results from the breakdown of blood products due to cyclic bleeding. The histopathological appearance of endometriosis can vary significantly based on the hormonal environment and cellular adaptations. In postmenopausal women, lesions may become atrophic, making it difficult to discern between the stroma and epithelium. In contrast, the stromal cells frequently experience a decidual response under the effect of pregnancy or progestin medication, changing into larger, polygonal cells. Additionally, tubal (serous) metaplasia, which is characterized by ciliated and secretory cells, is the most prevalent kind of epithelial metaplasia seen in endometriotic lesions, while clear cell, mucinous, and squamous variations can also occur. A biopsy may occasionally show “stromal endometriosis,” in which there are no discernible glands and only endometrial-type stroma. Although both elements are typically sought, many pathologists believe that the presence of stroma alone is sufficient for a conclusive diagnosis, especially when it is accompanied by hemorrhage or hemosiderin and supported by clinical symptoms [34]. 7.1 Site-specific histologic criteria 7.1.1 Ovary Endometrial glands and stroma normally line ovarian endometriomas, but the combined effects of pressure atrophy and recurrent hemorrhage often cause this lining to flatten or disappear entirely. Identification of an underlying band of endometrial stroma or the presence of hemosiderin-laden macrophages embedded within a dense, fibrotic wall is frequently used to make the diagnosis in cases where the epithelium has been eroded. A thorough histological search for “protected crevices” or invaginations – regions where the distinctive columnar epithelium is protected from pressure and thus preserved – is frequently required as a result. A characteristic that sets these cysts apart from simple ovarian cysts is their morphologically defined wall and base, which are usually made of inverted ovarian cortex [34]. Ovarian endometriomas and epithelial neoplasms, such as, serous and mucinous cystadenomas, can be distinguished clinically and pathologically using a combination of histological, macroscopic, and imaging features [34]. Histologically, the presence of endometrial-type stroma – often confirmed by CD10 reactivity – is the definitive feature of an endometrioma, even when its epithelial lining is atrophic or displays tubal (serous) metaplasia. This helps differentiate it from serous cystadenomas, which may also feature ciliated epithelium, and mucinous cystadenomas, which are lined by mucin-secreting cells. 7.1.2 Peritoneal endometriosis Peritoneal endometriotic lesions present a spectrum of histologic profiles that correspond with their macroscopic appearance and clinical activity. Active (red) lesions are highly vascularized and resemble the proliferative stage of the ectopic endometrium. They are frequently referred to as flame-like or polypoid implants. Typical (black) lesions, sometimes known as “powder-burn” implants, are made up of stroma and glands encircled by fibrosis and macrophages loaded with hemosiderin, which give them their distinctive dark coloring from previous hemorrhages. Healed (white) lesions show extensive scarring and minimal tissue. However, the surrounding fibrosis often protects the remaining endometrial cells from macrophage degradation, sometimes making histological confirmation easier than in more active sites [4]. 7.1.3 Deep infiltrating endometriosis Deep infiltrating endometriosis is defined by lesions that penetrate more than 5 mm beneath the peritoneal surface. Unlike superficial implants, these deep nodules consist of sparse endometrial glands and stroma embedded within dense fibrous tissue and hypertrophic smooth muscle, a structural arrangement so similar to uterine adenomyosis that it is often termed “adenomyosis externa.” A critical diagnostic and clinical feature of DIE is its close association with nerve fibers; the high density of these fibers within the lesions directly correlates with the severity of the patient’s pain [4]. 7.1.4 Gastrointestinal tract Bowel endometriosis typically infiltrates from the serosal surface, primarily involving the muscularis propria and submucosa, while seldom penetrating the mucosa. This inward progression explains why rectal bleeding is uncommon. In such cases, endoscopic biopsies often yield false-negative results, as they generally fail to sample the deeper layers where the disease is present. Rectal hemorrhage is also rare. Morphologically, the lesion can induce significant muscular hypertrophy and fibrosis, resulting in a “mushroom cap” appearance, where the intact mucosa is pushed intraluminally, resembling a polypoid tumor. Bowel endometriosis can produce constricting strictures, sometimes known as the “napkin ring” sign, which visually and radiologically resemble cancer, even when it lacks features of irregular invasion and desmoplastic grittiness [34]. 7.1.5 Fallopian tube Two different forms of endometriosis of the fallopian tubes are superficial implantation and mucosal replacement. Endometrialization, which can result in tubal occlusion, is the process by which endometrial tissue replaces the native tubal mucosa. This process is usually localized in the proximal isthmic segment. Surface implants are more prevalent, though, and they form as serosal or subserosal lesions on the outside of the tube. Unlike endometrialization, these implants do not affect the interior mucosal lining and remain separate from the tubal lumen [34]. 7.1.6 Cutaneous and scar endometriosis Scars from C-sections or episiotomies show the presence of endometrial glands and stroma embedded inside dense fibrous scar tissue or nearby skeletal muscle, which is a characteristic of endometriosis that occurs in surgical sites. To differentiate these lesions from suture granulomas, which can appear as similar palpable masses, histological examination is necessary. Although suture granulomas contain giant foreign body cells reacting to surgical material, they do not have the glandular and stromal components that are indicative of endometriosis [34]. 7.1.7 Lymph nodes Endometriosis can occasionally be found in pelvic or para-aortic lymph nodes. The diagnosis requires the presence of endometrial glands and stroma within the node architecture [34]. While imaging cannot replace histological confirmation, it is essential for treatment planning and preoperative staging. Ultrasound, more specifically transvaginal ultrasound (TVUS), has a high sensitivity and specificity for identifying ovarian endometriomas and is better at identifying which layers of the intestinal wall are impacted by deep infiltrating lesions. Thus, it is used as the first-line imaging modality. Magnetic resonance imaging (MRI) is utilized as a second-line, problem-solving technique and is considered the best method for preoperative staging and mapping, as it provides a comprehensive assessment of all pelvic compartments simultaneously. The MRI examination is more reliable than both physical examination and TVUS for mapping DIE. It relies on T 2-weighted sequences for detecting fibrotic lesions and fat-suppressed T1-weighted sequences for identifying old blood and hemorrhagic foci [36]. To reduce the need for diagnostic surgery, extensive research is being conducted on noninvasive or minimally invasive tests. Testing endometrial biomarkers – specific proteins, genes, or nerve fibers present in the menstrual fluid that can be retrieved during an in-office biopsy – is one of the main areas of focus. A comprehensive review of 95 potential endometrial biomarkers found the following: Protein gene product (PGP 9.5) (a neural nerve fiber marker): This is currently the most promising marker. It meets the criteria for a test accurate enough to potentially replace diagnostic surgery. However, because results vary significantly between different studies, it requires further high-quality research before it can be used reliably. Aromatase Cytochrome P450 (CYP19) (a hormonal marker): Despite being extensively studied, data show this marker is neither sensitive nor specific enough to be clinically useful as a diagnostic tool. Other promising markers: Biomarkers such as, the endometrial proteome, caldesmon, IL-1R2, 17βHSD2, and other neural markers (Vasoactive Intestinal Polypeptide (VIP), Calcitonin gene related protein (CGRP), Substance P (SP), and Neuropeptide Y (NPY)) show early promise for detecting the disease, but there are currently too few studies to confirm their diagnostic value [37]. 8. Pitfalls Diagnosing and managing endometriosis involves several significant clinical, histological, and imaging pitfalls due to the disease’s highly variable presentation and its ability to mimic other conditions. The histological diagnosis of endometriosis is typically straightforward when both endometrioid glands and stroma are present, but pathologists frequently encounter significant diagnostic pitfalls when these components are altered, absent, or located in unusual sites. 8.1 Clinical and diagnostic delays There is often a significant delay in diagnosis – averaging 8 to 12 years – because severe dysmenorrhea is frequently dismissed as “physiological,” particularly in adolescents. A major pitfall in clinical evaluation is the tendency to assess women with chronic pelvic pain in psychological terms. Patients’ physical complaints are sometimes ignored, questioned, or attributed to psychological conflicts (a phenomenon described as “blaming the victim”), leading to inappropriate psychiatric referrals rather than gynecological assessment [11]. 8.2 Histological and pathological pitfalls Confusion with normal ovarian structures: Endometriosis can be erroneously diagnosed when normal morphologic appearances are misinterpreted. A highly mature ovarian follicle lacking cytoplasmic maturation can resemble endometrial stroma, and an end-stage resolving corpus luteum containing hemosiderin-laden macrophages is frequently misdiagnosed as endometriosis [34]. Other cystic mimics: Under a microscope, mature cystic teratomas, mesothelial cysts, serosal inclusion cysts, and parovarian remnants can all appear to be endometriotic foci [34]. Overlooking the epithelium: In large ovarian endometriomas, the internal pressure often causes the epithelial lining to atrophy or shed. A major pitfall is failing to thoroughly examine the specimen for a “protected crevice” where a tiny amount of diagnostic epithelium might be preserved. On the other hand, clinically evident cases of the disease may be excluded if diagnostic criteria are very strict in the absence of epithelium [34]. According to the current standard definition, endometriosis requires the histologic presence of both endometrial stroma and epithelium (glands). This poses a significant risk of false-negative diagnosis because these components are often entirely absent and comprise only a small part of the lesions. For instance, in 40% of ovarian endometriomas, the cyst wall is covered in fibrotic tissue with no visible epithelium [38]. Several prominent research groups have proposed that fibrosis should be included in the histopathologic description, since fibrosis and its primary extracellular matrix-producing cells (myofibroblasts) are believed to be the underlying source of endometriosis-related symptoms, such as pain [39]. Sometimes, when endometriotic glands are rare or entirely absent, the lesion consists only of stroma. These small nodules are frequently overlooked or misinterpreted as lymphoid aggregates, nonendometrioid stromal cells, Kaposi’s sarcoma, or metastatic low-grade endometrial stromal sarcoma. Conversely, in postmenopausal women or long-standing cysts, the stroma can become severely atrophic, fibrotic, or completely absent. It is easy to misdiagnose the remaining isolated endometrioid glands as simple epithelial inclusion cysts or endosalpingiosis [40]. Deceptive changes in the stroma: In endometriosis, the stroma may experience a number of alterations that mask its true character. A lot of acellular mucin can build up in the stroma, resulting in myxoid change. When widespread, this resembles myxoid sarcomas, metastatic mucinous adenocarcinomas, or pseudomyxoma peritonei. Decidual change is also often observed during pregnancy or progestin medication. Decidualized stromal cells can mimic metastatic signet-ring cell carcinoma by developing cytoplasmic vacuoles that displace the nucleus. Furthermore, the surrounding glands frequently flatten to the point that the tissue is mistakenly identified as ectopic decidua rather than endometriosis. Endometriosis can cause necrotic pseudoxanthomatous nodules (NPNs), which are characterized by a significant infiltrate of foamy histiocytes (pseudoxanthoma cells) surrounding central necrosis. Clinically and histologically, these so-called “burned-out” nodules can be misinterpreted as necrotic malignant tumors such as, carcinoma or melanoma, or as necrotizing infections such as, malakoplakia or Tuberculosis (TB) [40]. Cervical endometriosis: Densely packed glands with mitotic activity may be a sign of superficial endometriosis of the cervix. If the surrounding endometriotic stroma is subtle or inflamed, it can easily be misdiagnosed as cervical glandular intraepithelial neoplasia (CGIN) or adenocarcinoma in situ (AIS) [40]. Elastosis and smooth muscle metaplasia: Brightly eosinophilic elastic tissue, which resembles a corpus albicans, may replace the endometriotic stroma. On the other hand, it may develop smooth muscle metaplasia (endomyometriosis), which can occasionally result in enormous “uterus-like” masses that resemble normal leiomyomas [41]. Polypoid endometriosis: Endometriosis can occasionally result in large, mass-like polyps, up to 14 cm in size, in the vagina, colon, or ovary. Because of their dense mixture of hyperplastic glands and stroma, these polyps are quite similar to extrauterine Müllerian adenosarcomas. There is a significant risk of misdiagnosis unless the pathologist closely examines the absence of severe stromal atypia and periglandular stromal hypercellularity [40]. Atypical endometriosis is generally regarded as a preneoplastic lesion with a 0.5–1% chance of developing into epithelial ovarian carcinomas, including endometrioid or clear cell carcinomas. Since atypical endometriosis represents an early stage of dysplastic tissue with considerable genetic abnormalities, a major clinical pitfall is the failure to appropriately identify and monitor patients who display these atypical changes. Patients with recurrent endometriomas greater than 7 cm, as well as those who experience relapses before the age of 40, are at a higher risk of developing these unusual, potentially pre-malignant alterations [42]. Misdiagnosing metaplasia and atypia: The epithelial lining of cystic ovarian endometriosis can undergo various metaplastic, hyperplastic, and atypical changes. A major diagnostic pitfall is that these endometrial epithelial metaplasias and cellular proliferations are frequently misdiagnosed as adenocarcinomas. On the other hand, diagnosticians may incorrectly classify severe atypical changes – which actually reflect precancerous lesions – as just reactive or degenerative modifications, since mild or “reactive” atypia is frequently linked to normal stromal inflammation and cellular regeneration [42]. In some cases, endometriotic cysts can undergo mucinous metaplasia with micropapillary tufting, an appearance that overlaps significantly with early Müllerian-type mucinous borderline tumors, making the distinction highly subjective [40]. 8.3 Site-specific diagnostic pitfalls Bowel endometriosis: This is considered the most commonly misdiagnosed form of endometriosis. It is often misdiagnosed as ischemic colitis, Crohn’s disease, ulcerative colitis, irritable bowel syndrome (IBS), or even colon cancer due to its vague symptoms, which include bloating, abnormal bowel habits, and abdominal pain. Furthermore, because the disease usually infiltrates from the outside in (serosa to muscularis) and rarely breaches the mucosa, rectal bleeding is uncommon, and endoscopic mucosal biopsies are usually falsely negative [11]. The symptoms of rectal endometriosis, such as hematochezia and rectal pain, overlap significantly with hemorrhoids. When a patient has both conditions, the endometriosis can easily be overlooked, as the symptoms are entirely attributed to the more common hemorrhoids. This is especially true if the endometriotic nodule is small and located deep under the rectal mucosa [43]. Rectosigmoid endometriosis can manifest with symptoms such as, hematochezia, strictures, and wall thickening, closely resembling the clinical, colonoscopic, and radiologic profile of colorectal cancer. Additionally, during fast-frozen section examinations, endometrial glands located in the muscularis of the rectum can be mistaken for cancer cell invasion [43]. Lymph node involvement: When endometriosis is found in pericolic lymph nodes, it can be mistaken for metastatic adenocarcinoma of the intestines. Pregnancy-related changes: Decidualization of ovarian endometriomas occurs during pregnancy. On sonography, these decidualized cysts may exhibit solid portions and vascularized papillary projections that closely resemble borderline ovarian cancers or neoplasms, possibly necessitating unnecessary surgery. Abdominal scars: It is specifically mentioned as a “diagnostic pitfall” when endometriosis develops in abdominal wall scars (often after hysterotomies or cesarean sections), as it can appear as a nonspecific abdominal wall mass years after the procedure. Massive ascites and hepatic lesions: In rare instances, endometriosis can present with massive brown/bloody ascites or large hepatic lesions. These presentations create a profound diagnostic conundrum because they closely mimic disseminated malignant neoplasms [11]. Soft-tissue sarcomas: When endometriosis occurs in unusual extra-peritoneal locations, such as, the wrist or groin, it can present as a painful, infiltrative soft-tissue mass. Both conditions contain an epithelial (glandular) component and a spindle cell (stromal) component. The epithelial portion of a synovial sarcoma can form glands or cords that contain mucin, perfectly simulating endometrial glands. Thus, endometriosis can histologically mimic biphasic synovial sarcoma. Endometriosis can also grow into normal surrounding tissues in a “pseudoinfiltrative” pattern, which can be easily misinterpreted under a microscope as an invasive, malignant process, potentially leading to unnecessarily aggressive surgical management if the patient’s history of endometriosis is unknown [44]. 9. Mimickers Although histologic diagnosis is typically straightforward, a variety of conditions can mimic endometriosis, causing diagnostic confusion. These mimickers often share clinical or histopathological features with endometriosis but have distinct pathophysiological mechanisms. This chapter explores the key mimickers of endometriosis, with a focus on their histopathological features, clinical presentations, and how they can be distinguished from endometriosis. 9.1 Key mimickers 9.1.1 Stromal endometriosis Clinical presentation and diagnosis: When the glandular component of endometriosis is rare or nonexistent, and the lesion is primarily made up of endometrial stroma, this condition is known as stromal endometriosis. When only a small portion of tissue is available for analysis, this type of endometriosis frequently manifests in biopsy specimens. These lesions are frequently mistaken for other benign or reactive stromal proliferations when the glandular component is absent. Histopathological fures: When a lesion is primarily composed of stroma, it is known as stromal predominance and is challenging to differentiate from other benign lesions. The stroma contains a large number of pigmented histiocytes, which are histiocytes loaded with hemosiderin and lipofuscin, and frequently resemble a reactive inflammatory infiltrate. Small, dilated blood vessels and focal hemorrhage are examples of vascular changes that are commonly seen and aid in determining whether the lesion is endometriotic. Endometrial stroma can be confirmed by CD10 immunohistochemistry, particularly in cases where glands are not present. Vascular alterations and histiocytes loaded with hemosiderin are also crucial diagnostic indicators [1, 40]. 9.1.2 Cervical endometriosis Clinical presentation and diagnosis: Cervical endometriosis can resemble diseases such as, tuboendometrioid metaplasia or low-grade endometrial stromal sarcoma. Despite being uncommon, cervical endometriosis can be difficult to diagnose because of its superficial location and its resemblance to other cervical pathologies. Features of Histopathology: “Glandular and Stromal Components”: Similar to low-grade endometrial stromal sarcoma, cervical endometriosis usually manifests as both glands and stroma that invade the cervical stroma. “Fibrosis and Inflammation”: Inflammatory cells may infiltrate the fibrotic stroma, giving the lesion a resemblance to other benign lesions or inflammatory conditions. Diagnostic advice: Endometriotic stroma can be differentiated from other cervical lesions using immunohistochemistry for CD10 and reticulin staining. Suspecting cervical endometriosis requires a careful examination of the clinical context (e.g., prior pelvic surgeries, infertility, or pain) [1, 40]. 9.1.3 Vaginal endometriosis Clinical presentation and diagnosis: One rare type of endometriosis is vaginal endometriosis. When it is situated close to the vaginal apex, its clinical presentation may resemble that of primary vaginal neoplasms. Its clinical characteristics frequently coincide with those of cancers such as endometrial carcinoma, making diagnosis more difficult. Features of histopathology: “Polypoid Growths”: Vaginal endometriosis can mimic neoplastic lesions by presenting as nodular masses or polypoid growths. “Endometrial Glands and Stroma”: The diagnosis of vaginal endometriosis may be complicated by the glands and stroma’s mild cytologic atypia or metaplastic alterations, such as squamous or mucinous metaplasia. To differentiate primary vaginal malignancies from vaginal endometriosis, histological analysis is essential. Vaginal endometriosis can be distinguished from malignant growths using immunohistochemical markers such as cytokeratin [1, 40]. 9.1.4 Tubal endometriosis Clinical presentation and diagnosis: Tubal endometriosis can mimic other illnesses, including pelvic inflammatory disease or tubo-ovarian abscesses, especially after tubal ligation or salpingectomy. The presence of endometrial-like tissue inside the fallopian tubes, which is frequently confused with other inflammatory diseases, is the hallmark of this disorder. Features of histopathology: “Endometrial Glands and Stroma”: Endometrial tissue, which can be confused with other benign lesions or infections, may be present in the fallopian tubes. “Inflammatory Cells and Fibrosis”: These lesions frequently exhibit inflammatory infiltrates and fibrosis, which can resemble other pelvic infections or inflammatory diseases. To suspect tubal endometriosis, the clinical history, such as prior tubal surgeries, is crucial. The diagnosis of endometriosis is confirmed by CD10 immunohistochemistry and the existence of endometrial glands in the tubal tissue [40, 45]. 9.1.5 Intestinal endometriosis Clinical presentation and diagnosis: Colorectal cancer, single rectal ulcers, and inflammatory bowel disease (IBD) are among the gastrointestinal disorders that intestinal endometriosis frequently mimics. The appearance varies, as some lesions penetrate deeper layers of the intestinal wall, while others resemble cystic masses. Features of histopathology: “Infiltrative Lesions”: A neoplastic condition, DIE can manifest as thicker gut walls with both glandular and stromal components. Hemosiderin and fibrosis can be distinguished from other gastrointestinal disorders, including primary bowel cancer or inflammatory conditions such as IBD, by the presence of hemosiderin-loaded macrophages within them. It is crucial to perform a histological investigation that reveals endometrial glands and stromal elements inside the intestinal wall. Colonoscopy and MRI are two imaging procedures that can be helpful in determining the extent of the lesions and ruling out other gastrointestinal disorders [40, 45]. 9.1.6 Endometriosis with atypical features Clinical presentation and diagnosis: Atypical endometriosis, such as, mucinous or clear cell metaplasia, can occasionally resemble cancers, particularly ovarian cancer. These unusual characteristics are most frequently observed in profound endometriosis or ovarian endometriomas. Histopathological characteristics: Atypia and metaplasia, such as, mucinous or transparent cell transformations, can be seen in endometriotic lesions. The histology of early-stage cancer may be quite similar to these. When stratification of the epithelial cells takes place, cytologic atypia, especially in the epithelial cells of endometriotic cysts, may indicate malignancy. Endometriotic lesions with unusual characteristics can be distinguished from malignant tumors using immunohistochemistry for markers such as p53, estrogen receptor, and CD10. To differentiate atypical endometriosis from ovarian or endometrioid cancer, a thorough clinical correlation and imaging investigations are required [40, 45]. 10. Conclusion Numerous disorders can resemble the clinical and histological symptoms of endometriosis, making diagnosis more difficult. Diagnostic confusion can result from the overlapping features of intestinal endometriosis, tubal endometriosis, cervical endometriosis, vaginal endometriosis, stromal endometriosis, and atypical forms of endometriosis. To differentiate these mimickers from actual endometriosis, histological evaluation, clinical history, immunohistochemical markers, and sophisticated imaging are crucial. Clinicians can ensure that patients receive the proper diagnosis and treatment by identifying the mimickers and using precise diagnostic methods. Acknowledgments The authors acknowledge the use of Grammarly and Quillbot for language polishing, including assistance with grammar refinement, sentence clarity, and overall readability of the manuscript. Additionally, the author acknowledge the use of Google AI Studio to assist in the interpretation of the text. The tool was used as a supportive aid in the writing process, and all interpretations and final content were carefully reviewed and validated by the author to ensure alignment with the scientific meaning.

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