{"paper_id":"206d5049-667f-45ad-a46b-af54f36ad621","body_text":"75\nAnnals of Research in Oncology\nVol. 5(2), 75-94, 2025\n© 2025 Annals of Research in Oncology - ARO. Published by EDRA SpA. All rights reserved.\n75\nRESEARCH ARTICLE\nENDOMETRIOSIS: A CANCER-MIMICKING DISEASE  \nAND THE NEED FOR A TRANSLATIONAL PERSPECTIVE\nCanio Martinelli 1, 2, #, *, Andrea Vidali 1, #, Francesco Di Chiara 3, Giulio Mazzarotti 1, 4, \nSara El Messaoudi 4, Luigi Alfano 5, Alfredo Ercoli 1, 2, Antonio Giordano 1, 4\n1 Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, College of Science and \nTechnology, Temple University, Philadelphia, USA\n2 Gynecology and Obstetrics Unit, Department of Human Pathology in Adulthood and Childhood ‘‘G. Barresi”, \nUniversity of Messina, Messina, Italy\n3 John Radcliffe Hospital, Oxford, UK\n4 Department of Medical Biotechnology, University of Siena, Siena, Italy\n5 Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) \n- Fondazione G. Pascale, Napoli, Italy\n# Contributed equally\n* Correspondence to:  caniomartinelli.md@gmail.com, https://orcid.org/0000-0002-0587-8467\nABSTRACT: Endometriosis, defined by the presence of endometrial-like tissue beyond the uterine cavity, afflicts over 190 million \nyoung women worldwide and often significantly reduces quality of life. Despite being historically classified as a benign gynecologic \ndisorder, endometriosis can mimic cancer in imaging findings, serum tumor markers, and molecular signature. Increasing evidence \nsuggests endometriosis encompasses multiple biologic subtypes rather than representing a single uniform disease, which may \nexplain divergent presentations, from extensive lesions in some patients with minimal pain to smaller implants in others with severe \nsymptoms. Current management relies heavily on empirical hormonal therapies, repeated surgeries, and symptomatic treatment. \nInadequate diagnostic tools and incomplete mechanistic understanding contribute to misdiagnosis, delayed intervention, and \nsuboptimal outcomes. Without deeper elucidation of its complex biology, especially at the molecular level, substantial therapeutic \nbreakthroughs will likely remain elusive. Notably, pathways commonly implicated in malignancy are aberrantly activated in \nectopic endometrial tissue, driving proliferation, angiogenesis, and immune evasion. To address heterogeneous endometriosis \nphenotypes, a rigorous translational framework is essential. Through such structured investigation, novel data and non-hormonal \ntherapies targeting core molecular events could emerge, reducing both protracted diagnostic timelines and lowering the incidence \nof overtreatment. In recognizing endometriosis as potentially comprising distinct pathologies under one umbrella, the field may \nadvance truly individualized, biology-guided interventions.\nDoi: 10.48286/aro.2025.107\nImpact statement:  Endometriosis, affecting over 190 mil -\nlion people worldwide, displays clinical and molecular profiles \nthat closely resemble malignancies. Framing endometriosis as a \n“cancer-mimicking” disease highlights why current models, diag-\nnostic tools, and empirical therapies fail to adequately address \nprolonged diagnostic delays, high recurrence rates, and incon -\nsistent treatment outcomes. This perspective advocates a struc-\ntured translational approach, integrating meticulous preclinical \nvalidation, phase-appropriate clinical trials, and rigorous safe -\nguards in artificial intelligence and biomarker development, to \nbridge critical gaps in understanding disease biology. Such a \nbidirectional pipeline, guided by real-world clinical feedback and \nclear mechanistic insights, aims to optimize pain management, \nfertility preservation, and overall disease control. Reconceptu -\nalizing endometriosis as a systemic condition with cancer-mim-\nicking features underscores the urgency and the opportunity to \ndevelop targeted therapies beyond traditional hormonal sup -\npression and empirical surgeries, ultimately enhancing patient \nquality of life worldwide.\nKey words: endometriosis; cancer-mimicking; molecular \nmedicine; translational research.\nReceived: Apr 25, 2025/Accepted: May 27, 2025\nPublished: Jun 30, 2025\n\nVol. 5(2), 75-94, 2025\n76\nINTRODUCTION\nEndometriosis, broadly defined as the presence of \nendometrial glands and stroma outside the uterine \ncavity, affects over 190 million young women world-\nwide and severely compromises the quality of their \nlives (1-3). Historically considered predominantly gyne-\ncological, current evidence positions endometrio-\nsis as a multisystem disorder driven by inflamma-\ntory, hormonal, genetic, and neurobiological drivers \n(2-5). Notably, its capacity for tissue invasion, recur-\nrence, and resistance to standard therapies has led \nmany experts to characterize it as “cancer-mimick-\ning,” reflecting both its clinical severity and complex \nunderlying biology. However, despite sharing several \nmolecular and clinical features with malignant condi-\ntions, endometriosis itself is not classified as cancer. \nNevertheless, endometriosis does carry a recognized, \nalbeit relatively low, risk of malignant transformation, \nto endometriosis-associated ovarian cancer (EAOC) (6) \nwith recent studies indicating approximately a two-\nfold increase in lifetime risk (from about 1% in the gen-\neral population to roughly 2% in women with endo-\nmetriosis) (7-9). Critically, it remains uncertain which \npatients with endometriosis are at risk of progress-\ning to ovarian cancer. Endometriosis imposes a sub-\nstantial lifelong burden on women, primarily because \nprolonged diagnostic delays, often exceeding seven \nyears due to nonspecific symptoms and overlap with \nother conditions, mean that many affected individu-\nals live for years unaware of their underlying disease \n(10). Furthermore, the absence of a unifying theory \n(spanning retrograde menstruation, stem-cell hypoth-\neses, or coelomic metaplasia) limits our understand-\ning of why endometriosis emerges in some individ-\nuals, or why disease trajectories are heterogeneous \n(10-17). Treatment remains largely empirical, involv-\ning hormonal suppression, analgesics, and repeated \nsurgeries, offering only transient or partial relief (18). \nIn parallel, emergent technologies, refined imaging, \nartificial intelligence diagnostics, and novel molecular \nbiomarkers, offer potential (4, 18). Nevertheless, pre-\nmature implementation of these technologies, espe-\ncially AI-driven diagnostics, without sufficient biologi-\ncal understanding, risks embedding biases, exacerbat-\ning inequalities, or restricting accessibility for margin-\nalized populations (19, 20). Therefore, a patient-cen-\ntered translational framework becomes paramount, \nallowing rigorous biologic characterization to shape \nearly-phase validations, rather than deploying large-\nscale AI-driven strategies that might misdirect care. \nIndeed, parallels between endometriosis and malig-\nnancy, including shared molecular pathways and inva-\nsive properties, highlight the necessity for strategic, \nstepwise integration of laboratory findings and clinical \nobservations. Leveraging the concept of endometri-\nosis as “cancer-mimicking,” we illustrate how ambig-\nuous pathogenesis, diagnostic uncertainty, and non-\nspecific treatments hinder patient outcomes. First \nexamine immunologic and molecular mechanisms \nunderlying these cancer-mimicking traits, emphasiz-\ning the importance of elucidating these pathways for \ntargeted intervention development. Next, we propose \na bidirectional translational framework, anchored by \nphase 0/preclinical studies and informed clinical tri-\nals, aiming to advance diagnostics, management, and, \npotentially, preventive strategies.\nMATERIALS AND METHODS\nThis manuscript is a perspective rather than a sys-\ntematic review. We conducted a structured litera -\nture search using PubMed to address three thematic \nqueries: (i) clinical manifestations of cancer-mimick-\ning features in endometriosis (Section Clinical Paral-\nlels), (ii) molecular pathways shared with malignancy \n(Section Molecular Parallels), and (iii) translational \nresearch gaps and unmet clinical needs (Section Gaps \nin Understanding). The search strategy included origi-\nnal research articles and comprehensive reviews pub-\nlished in English, French, Spanish and Italian, identified \nusing combinations of predefined keywords (“endo-\nmetriosis,” “cancer mimicry,” “molecular pathway,” \n“translational research”). Identified articles under-\nwent initial screening based on title and abstract. Sub-\nsequently, selected publications were reviewed and \nrefined by author consensus, considering direct rel-\nevance to the specified thematic areas. This process \nresulted in the selection of 35 articles for Sections \nClinical Parallels and Molecular Parallels each, and \neight articles for Section Gaps in Understanding. The \nselected references were not intended to represent \nan exhaustive review but rather to illustrate critical \nclinical observations, molecular insights, and trans-\nlational opportunities pertinent to this perspective.\nCANCER MIMICRY\nClinical Parallels\nClinical evidence consistently indicates that endo -\nmetriosis, particularly in complex or atypical pre -\n\nVol. 5(2), 75-94, 2025\n77\nsentations, closely mimics malignancy in clinical, \nbiochemical, radiological, and pathological findings. \nThis resemblance includes elevated tumor markers, \ninvasive imaging characteristics, and lesions at atyp-\nical anatomical sites, complicating diagnostic accu-\nracy and often leading to overtreatment.\nElevated Tumor Markers\nA frequent diagnostic pitfall arises when markedly \nelevated tumor markers, such as CA-125 or CA-19.9, \nwhich ordinarily raise suspicions of gynecologic or \ngastrointestinal malignancies, occur in endometri-\nosis patients. Numerous reports document signifi-\ncantly elevated CA-125 levels, sometimes surpass -\ning 1000 U/mL, prompting urgent oncologic evalu -\nations (21-25). For example, an extremely elevated \nCA-125 level of 1386.50 U/mL, coupled with a large \novarian mass, led directly to surgery under suspicion \nof ovarian cancer (25). Similar elevations of CA-125 \nor CA-19.9 are also observed in extrapelvic lesions, \nincluding subcutaneous and abdominal wall endo-\nmetriosis (26, 27). Although indicative of malignancy, \nthese elevations lack specificity, underscoring the \nneed for cautious interpretation.\nImaging Findings Suggestive of Invasive Disease\nAdvanced imaging modalities, including ultrasound, \ncomputed tomography (CT), magnetic resonance \nimaging (MRI), and even positron emission tomog-\nraphy (PET), frequently detect masses with irreg -\nular margins, heterogeneous enhancement, and \nrestricted diffusion, hallmarks of malignancy (28-30). \nReports describe “ill-defined,” “stellate,” or “irregular” \nsoft-tissue masses with enhancement patterns indis-\ntinguishable from malignancies (31-33). For instance, \nbladder-infiltrating endometriosis has appeared on \nMRI as a heterogeneous, solid mass with restricted \ndiffusion, closely resembling bladder carcinoma \n(34). Similarly, ovarian polypoid endometriosis has \nbeen misdiagnosed preoperatively as advanced \ncarcinoma due to papillary structures, solid com -\nponents, or extensive “peritoneal” disease (25, 30). \nAlso lesions in atypical locations, such as beyond \nthe pelvis, because of discrete enhancing lesions \nin the lumbar plexus (35) or renal parenchyma (36-\n38) have led radiologists to suspect nerve sheath or \nrenal cell tumors, respectively.\n“Metastatic” or Disseminated Disease Patterns\nBeyond local invasion, endometriosis may present \nas multifocal implants throughout the peritoneum, \nbowel serosa, and omentum, mimicking peritoneal \ncarcinomatosis (23, 24). Some cases include exten-\nsive nodularity, ascites, and pleural effusions, fea -\ntures characteristic of advanced intra-abdominal or \nthoracic malignancies (32, 39). Widespread perito -\nneal dissemination, as observed in polypoid endo-\nmetriosis (26, 30, 34, 40, 41), can be mistaken for \nmetastatic dissemination. Even endometriotic lymph \nnode involvement has been reported, raising sus -\npicion of metastatic carcinoma (30, 42). One report \ndetailed extrapelvic endometriosis with progres -\nsive abdominal distension and cachexia, two clin -\nical indicators that triggered an oncology referral \nfor presumed metastatic cancer (24).\nOverlapping Symptom Profiles\nEndometriosis frequently manifests with alarming \nsymptoms classically linked to malignancy, such as \nrectal bleeding, hematuria, or large bowel obstruc-\ntion (36, 40, 43). Rectal bleeding and weight loss in \nconjunction with a rectal mass have led clinicians to \nsuspect colorectal cancer (43). Likewise, recurrent \nhematuria and flank pain associated with ureteral \nor bladder involvement have initially suggested uro-\nlogical malignancies (34, 36, 37). Similarly, uterine \nbleeding and pelvic masses often suggest gyneco -\nlogical cancers; however, polypoid endometriosis \ncan produce an indistinguishable clinical picture (25).\nExtensive Surgical Intervention due to Suspected \nMalignancy\nCancer-mimicking presentations sometimes prompt \nsurgeons to undertake aggressive interventions, \nincluding radical hysterectomy, bilateral salpingo-oo-\nphorectomy, bowel resection, or omentectomy (38, \n39, 44). In one striking example, a patient was sched-\nuled for hyperthermic intraperitoneal chemother -\napy to address presumed pseudomyxoma peritonei, \nonly for intraoperative findings to reveal endome -\ntriosis (24). Such extensive procedures carry consid-\nerable morbidity, particularly if a benign process is \novertreated (27). Frozen-section biopsies may also \nfail to definitively exclude malignancy, reinforcing \ndiagnostic confusion (24, 32, 42).\nHistopathological Pitfalls\nPathologists also face challenges, particularly with \natypical variants such as polypoid endometriosis, \ndecidualized endometriosis, or Müllerianosis in \nlymph nodes (31, 43-47). These entities may demon-\nstrate glandular crowding, papillary architectures, \nor cytologic atypia, making intraoperative differen-\ntiation from malignancy difficult (30-32, 46). Immu-\n\nVol. 5(2), 75-94, 2025\n78\nnohistochemistry is frequently indispensable to \nconfirm endometrial derivation and rule out high -\ner-grade carcinomas or metastatic lesions (31, 35, \n43, 48, 49). Thoracic endometriosis, in particular, \nposes diagnostic challenges distinct from pelvic \nlesions. Unlike pelvic endometriosis, which has \nbeen more extensively studied and characterized, \nthoracic endometriosis demonstrates unique clini-\ncal and histological features that set it apart. These \ndifferences include variations in lesion appearance, \nbehavior, and tissue composition. In particular, \nthere is growing recognition of the importance of \nstromal endometriosis, lesions composed predom-\ninantly of endometrial-type stromal cells without \naccompanying glands, in the thoracic cavity. This \nform of endometriosis may be underdiagnosed or \nmisclassified due to its subtle histological presen -\ntation, contributing to inconsistencies in diagno -\nsis and classification across different anatomical \nsites. Understanding the distinct nature of thoracic \nendometriosis, especially the role of stromal com -\nponents, is essential for improving diagnostic accu-\nracy, guiding treatment strategies, and advancing \na more comprehensive understanding of the dis -\nease’s pathophysiology (50).\nClinical Consequences and Need for Vigilance\nTaken together, these clinical and radiological par-\nallels have significant implications for patient care. \nSuspicion of cancer prolongs diagnostic workups, \nincreases patient anxiety, and may result in exces-\nsive therapy. Conversely, dismissing endometriosis \nprematurely may delay essential interventions and \nallow disease progression (24, 28, 37, 40, 46, 51). Con-\nsequently, clinicians should maintain a high index \nof suspicion for endometriosis in atypical presen -\ntations, extrapelvic masses, or cancer-like imaging \nprofiles, regardless of reproductive age.\nClinical observations across multiple organ systems \n(21-49, 51-56) illustrate how endometriosis can reli-\nably mimic malignancy, with raised tumor markers, \nsuspicious radiographic features, multifocal dissem-\nination, and deceptive histology ( Table 1). These \noverlapping features underline the urgent need for \nenhanced education, training, and effective dissem-\nination of existing diagnostic criteria for endometri-\nosis. Treatment strategies should consistently adopt \na multidisciplinary approach, applying current guide-\nlines appropriately yet adapting them individually to \neach patient’s specific clinical presentation, disease \nphenotype, and personal therapeutic objectives.\nTable 1. Endometriosis Mimicking Malignancy in 35 References.\nREFERENCE SUSPECTED \nMALIGNANCY\nLOCATION OF \nENDOMETRIOSIS CLINICAL CASE SCENARIO\nHu, 2021 Primary \nrectal aden\\\nocarcinoma\nDeep rectal wall/\nrectosigmoid \ncolon\nClinical: Rectal bleeding, weight loss Imaging (CT/MRI/EUS): \n4.5–5 cm rectal mass (T3/T4 suspicion), restricted diffusion \nPathology: Rectal Mucosal Biopsies showed mucosal \nhemorrhage with associated hypercellular stroma; Scattered \natypical glands were present deep in the muscularis mucosa, \nrimmed by hypercellular stroma; The deep glands and \nsurrounding stroma were strongly positive for Estrogen \nReceptor: The cellular stroma was strongly positive for CD10 \n3; These histological and immunohistochemical findings \nconfirmed the diagnosis of endometriosis\nStuparich,\n2020\nPeritoneal \ncarcinomatosis/\nGynecologic \nmalignancy\nMultiple \nperitoneal \nnodules, \nabdominal wall, \nomentum\nClinical: Postmenopausal on estrogen Imaging (CT): Multiple \nnodules suspicious for carcinomatosis\nLaparoscopy: Irregular nodules, neovascularization\nPathology: An initial CT-guided biopsy demonstrated \nendometriosis, but malignancy could not be definitively \nexcluded. Intraoperative pathology during the laparoscopic \nprocedure demonstrated only endometriosis. The final \npathology report, after the surgical removal of all disease, \nshowed polypoid endometriosis without cancer.\nGargan, \n2023\nOvarian \nmalignancy \n(multiple solid \nmasses)\nRight ovary \n(adjacent to \nendometrioma)\nClinical: Premenopausal, worsening pelvic pain\nImaging (US/MRI): Several solid, echogenic, vascular lesions \nwith homogeneous enhancement\nPathology: Polypoid endometriosis mimicking neoplastic \nmasses\n(Continued on next page)\n\nVol. 5(2), 75-94, 2025\n79\nREFERENCE SUSPECTED \nMALIGNANCY\nLOCATION OF \nENDOMETRIOSIS CLINICAL CASE SCENARIO\nKaymaz\nGezer, 2016\nMalignant \nmesothelioma \n(deciduoid) in \ndifferential\nCesarean section \nscar (abdominal \nwall)\nClinical: Mass in previous C-section scar Pathology: \nDecidualized endometriosis with large polygonal cells \nresembling deciduoid mesothelioma\nMota, 2020 Colorectal \ncancer\nUpper rectum, \nmiddle sigmoid \ncolon\nClinical: Changes in bowel habits, intermittent hematochezia\nImaging (CT): Irregular parietal thickening with contrast \nenhancement, stenosis\nColonoscopy: Concentric stenosis, friable mucosa (negative \nbiopsies) Pathology: proctosigmoidectomy specimen \nrevealed intestinal wall endometriosis, compromising \nsubmucosa and internal and external muscular layers, with \nfibrosis.\nSarofim, \n2018\nPrimary sigmoid \nmalignancy\nDistal sigmoid \ncolon, rectum, \npericolic LNs\nClinical: Acute large bowel obstruction Imaging (CT): \nThickened distal sigmoid mass causing obstruction\nOperative: Dense adherence to pelvic sidewall Pathology: \nEndometriosis in pericolic nodes mimicking metastatic \nspread\nRodrigues,\n2015\nRecurrent \nperianal \nabscess/fistula \n(non-malignant)\nPerianal region \n(episiotomy scar)\nClinical: Anal itching, pain, discharge Endorectal US: \nIrregular hypoechoic lesion Pathology: Confirmed perianal \nendometriosis\nUno, 2014 Nuck cyst/\nfemoral \nhernia (benign \ndifferential)\nRight groin \n(femoral ring)\nClinical: Painful, enlarging groin mass Imaging (MRI): Cystic \nstructure with hemorrhagic features, elevated CA-125\nHistology: Mesothelial cyst with endometrial stroma\nFoulon, \n2021\nCrohn’s disease \n(perforating)\nBowel (ileum, \ncolon), pelvis\nClinical: Diarrhea, abdominal pain, abscesses Imaging: \nIleitis, colitis, multiple abscesses, sigmoid stricture. \nMagnetic Resonance Imaging (MRI): Revealed findings \nmore characteristic of endometriosis, such as sigmoid wall \nthickening with infiltration of the perisigmoid fat, adhesions, \na retractile endometrial nodule, and a left endometrioma \n1. Computed Tomography (CT) Colonography: Confirmed \nthe sigmoid stricture but also showed nodular lesions in the \nmesorectum, compression of the left ureter by a nodule, a \nright ovarian cyst, and a small left ovarian cyst 1. Endoscopic \nSonography of the Rectum: Showed a 32 mm lesion that was \nsuggestive of rectal endometriosis\nLabs: Elevated CRP/WBC; actually, endometriosis mimicking \nCrohn’s disease Diagnosis: Based on these collective imaging \nfindings (MRI, CT colonography, Endoscopic Sonography), \nwhich revealed features highly suggestive of endometriosis \n(endometrial nodule, endometrioma, specific lesions, \novarian cysts), the clinical team changed the diagnosis from \nCrohn disease to complicated deep endometriosis\nKourouma,\n2017\nKeloid (though \nmalignancy \nsometimes \nconsidered)\nUmbilicus \n(cutaneous)\nClinical: Painful, enlarging umbilical nodule on dark skin\nInitially treated with steroids as keloid Cyclical bleeding \nindicated endometriosis Pathology: Under an ulcerated \nepidermis, the presence of endometrial glands lined by \ncylindrical epithelium was observed. Endometrial stroma \ncomposed of small round cells was also present.\nMahiou, \n2024\nInvasive \npelvic cancer \n(gynecologic or \ncolorectal)\nVaginal stump, \nrectovaginal \nseptum, \nrectum, pelvic \nperitoneum\nClinical: 68-year-old postmenopausal, infiltrating vaginal \nstump mass\nMRI: Solid + cystic lesion, hemorrhagic components\nIntraop: Cauliflower-like mass; extensive resection\nPathology: Endometriosis\nCarvalho, \n2020\nOvarian/\nperitoneal \nmalignancy\nRetroperitoneal \nmass (17x13x16 \ncm), omen tum, \niliac LN\nClinical: 31 y/o, large solid-cystic massCA-125: 641 U/mL\nLaparoscopy: Frozen pelvis, suspicious omental nodules\nPathology: Hard, irregular lesion resembling tumor; final = \nendometriosis\n(Continued on next page)\n(Continued from previous page)\n\nVol. 5(2), 75-94, 2025\n80\nREFERENCE SUSPECTED \nMALIGNANCY\nLOCATION OF \nENDOMETRIOSIS CLINICAL CASE SCENARIO\nFischer, \n2021\nInvasive \ncarcinoma \n(florid \nmesothelial \nhyperplasia)\nAbdominal wall \n(Pfannenstiel \nincision)\nClinical/Path: Endometriosis with florid mesothelial \nhyperplasia\nPathology: Florid mesothelial hyperplasia occurring within \nfibrous tissue associated with abdominal wall endometriosis. \nThe lesion exhibited an infiltrative pattern and stellate \narchitecture, mimicking an invasive carcinoma, particularly \ngiven its cytokeratin positivity 1, 2. However, the mild \ncytologic atypia and positive staining for mesothelial \nmarkers (calretinin, WT-1, CK5), along with negativity for \nmarkers typical of common adenocarcinomas, established \nthe diagnosis as a benign, reactive mesothelial proliferation.\nPang, 2019 Advanced \novarian cancer\nUterus (posterior \nfundus), \nbilateral ovaries, \nperitoneum\nClinical: Weight loss, large pelvic massCA-125: 372.4 U/mL\nImaging: Solid/cystic tumor, 2000 mL bloody ascites\nPathology: Endometriosis\nRodriguez,\n2017\nCervical \nadenocarcinoma \n(Pap smear AGC-\nNOS)\nCervix (superficial \nendometriosis)\nClinical: Atypical glandular cells on Pap(AGC-NOS)\nConcern for endocervical neoplasia\nPathology: Microscopically, glandular formations with an \nendometrial pattern were found, surrounded by fibrous \nstroma. These findings were suggestive of an endometrioma\nYang, 2021 Cystic renal \ntumor (Bosniak \nIII)\nLower pole of \nright kidney\nClinical: Intermittent gross hematuria Imaging (CT/US): \nComplex cystic renal mass (50% chance of malignancy)\nPathology: Histopathology revealed endometriosis of the \nright renal parenchyma. Gross Examination: The resected \nmass had a diameter of approximately 1.5 cm. It contained \nseveral capsular spaces filled with brown fluid, and the cut \nsurface of the mass was yellowish. Microscopic Examination: \nConfirmed the diagnosis of renal endometriosis, \ncharacterized by the presence of endometrial glands \nand embedded stromal cells. No atypia was observed. \nIm immunohistochemical Analysis: The stromal cells and \nepithelial cells were positive for estrogen receptor (ER), \nprogestin receptor (PR), and vimentin, further supporting the \ndiagnosis of renal endometriosis.\nBasnayake,\n2020\nPossible \nmalignant \ntransformation \nof inguinal \nendometriosis\nInguinal canal Clinical: 4x4 cm cystic mass in inguinal region Imaging: \nBenign hydrocele-like, unusual site Surgery to exclude \nmalignancy; Pathology: Endometriosis\nMolina, \n2019\nCecal/colorectal \ncancer\nCecum, right \nadnexa\nClinical: Acute complete bowel obstruction, weight loss, \nmass\nImaging: 7x7x4 cm cecal lesion + adnexal mass\nHigh suspicion of malignancy Pathology: Ce cum Mass: A 4 × \n3 × 2.5 cm bluish, heterogeneous mass was identified, which \noccluded almost all the lumen of the cecum and the ileocecal \nvalve. Microscopic Examination (Cecum): Microscopy showed \nthat the colon wall was invaded by glands and endometrial \nstroma. The colonic epithelium displayed inflammatory \nchanges but was negative for malignancy. Adnexal Mass \n(Ovary and Fallopian Tube): In the ovarian parenchyma, an \nendometrial cyst covered with siderophages was found. \nGlands and endometrial stroma were also observed in the \nfallopian tube. The final diagnosis based on these findings \nwas endometriosis\nHsieh, 2023 Intra-abdominal \nmalignancy \n(gynecologic)\nWithin uterine \nleiomyoma + \nperitoneum\nClinical: Large (~10 cm) heterogeneous tumor, ascites, \nsevere pain\nCA-125: 3061, CA-19.9: 1407\nRuptured lesion with suspicious implants; Pathology: \nEndometriosis\n(Continued on next page)\n(Continued from previous page)\n\nVol. 5(2), 75-94, 2025\n81\n(Continued on next page)\n(Continued from previous page)\nREFERENCE SUSPECTED \nMALIGNANCY\nLOCATION OF \nENDOMETRIOSIS CLINICAL CASE SCENARIO\nCameron,\n2016\nMetastatic \nbreast \ncarcinoma\nUmbilicus \n(subcutaneous)\nClinical: Postmenopausal with prior invasive lobular breast \nCA\nNew umbilical lesion suspicious for metastasis Pathology: \nEndometriosis\nYazawa, \n2022\nAdvanced \novarian \ncarcinoma\nRight adnexa, \ncecum, sigmoid, \nomentum\nClinical: Rapid tumor growth, partial obstruction\nImaging (CT/PET): Multiple solid masses, high FDG uptake\nPathology: Disseminated endometriosis\nGaillard, \n2022\nPeritoneal \nsurface \nmalignancy \n(mesothelioma, \novarian CA)\nDiffuse \nintraperitoneal \ncystic lesions, \nmesentery, pelvic \nperitoneum\nClinical: Progressive abdominal distention, cachexia\nImaging: Multicystic peritoneal disease, hydronephrosis\nElevated CA-125, CA-19.9;\nPathology: Laparoscopic Appendectomy (Age 23): The \nspecimen was negative for appendicitis, endometriosis, or \nan appendiceal neoplasm. Diagnostic Laparoscopy (Age \n26): Biopsies of diffuse cystic lesions revealed abdominal \ncysts but were negative for endometriosis. Cytologic \nExamination (Age 29, from drained cyst fluid): Revealed \nneutrophil granulocytes (indicating infection/inflammation). \nCultures were positive for Staphylococcus aureus. Diagnostic \nLaparoscopy (Age 29): Biopsies of a cystic wall showed \nfibrinoid tissue and macrophages loaded with hemosiderin \n(indicating clearance of old hemorrhage). These were \nnegative for endometriosis and malignant disease. De \nbulking Surgery (Age 29): Frozen Section: Analysis of a \nsample from the wall of the largest cyst revealed numerous \nhemosiderin loaded macrophages. No malignancy was \npresent in this sample. Final Histology (Post Debulking): \nConfirmed the presence of a large cyst (32 × 16 × 5 cm) and \nmultiple smaller cysts containing endometrial epithelium \nand specialized stroma, consistent with endometriosis. \nStripping specimens showed mesothelium and the presence \nof pigmented macrophages. Cytologic analysis revealed \nligated blood cells without malignant cells.\nBuder\nBakhaya,\n2019\nMetastatic \nmelanoma\nSubcutaneous \ntissue, lower \nright abdomen\nClinical: History of melanoma, new subcutaneous lesion\nImaging (MRI): Solid lesion with enhancement\nPathology: Endometriosis\nIida, 2017 Ovarian \ncarcinoma(with \nLN metastasis)\nLeft ovary \n(polypoid \nendometriosis), \npelvic LN\nImaging (MRI): Papillary nodules, diffusion restriction\nEnlarged LN with strong enhancement Elevated CA-125, \nCA-19.9; malignancy not excluded intraop; Pathology: \nEndometriosis\nJeswani, \n2011\nNerve sheath \ntumor \n(schwannoma)\nLeft L4 neural \nforamen\nClinical: Progressive radicular pain\nImaging (MRI): Foraminal mass, suspected schwannoma\nIntraoperative: Mass involving nerve root; Pathology: \nendometriosis\nTakeda, \n2025\nGIST, \nschwannoma, \nglomus tumor, \nor metastatic \ncancer\nTerminal ileum/\nileocecal region\nClinical: Intestinal obstruction\nImaging (CT, colonoscopy): Well-enhanced submucosal \nmass, inconclusive biopsies Pathology: Endometriosis\nBadri, 2018 Renal \nmalignancy\nUpper pole of left \nkidney\nClinical: Flank pain, gross hematuria Imaging (CT/MRI): \nHeterogeneous enhancing renal mass\nPathology: Robotic partial nephrectomy: Endometriosis\nNambiar, \n2018\nMetastatic \nbreast \ncarcinoma\nAbdominal wall \n(sub cutaneous), \nsuprapubic \nregion\nClinical: Advanced breast CA; new abdominal wall mass\nPathology: Endometriosis, not metastatic disease\nAlSinan, \n2021\nInguinal hernia \nvs. Malignant \nsoft tissue \ntumor or \nlymphoma\nLeft inguinal \nregion (round \nligament)\nClinical: Painful, cyclical inguinal mass Imaging: Solid inguinal \nlesion\nDifferential: Sarcoma, lymphoma; Pathology: Endometriosis\n\nVol. 5(2), 75-94, 2025\n82\nMolecular Parallels\nClinical reports indicating that endometriosis fre -\nquently mimics cancer in its presentations have found \ncorroboration at the molecular level, where sub -\nstantial parallels have emerged. Multiple canonical \nmalignancy-associated pathways (PI3K/AKT/mTOR, \nMAPK (ERK, p38, JNK), NF-κB, Wnt/β-catenin, and JAK/\nSTAT) demonstrate aberrant activation in endome-\ntriotic lesions. These similar pathways sustain pro-\nliferation, invasive capacity, angiogenesis, and an \nanti-apoptotic state, fostering an environment in \nwhich endometriosis can behave much like a neo -\nplasm although endometriosis does not fulfill all the \nhallmarks of cancer (57). Further amplifying these \nREFERENCE SUSPECTED \nMALIGNANCY\nLOCATION OF \nENDOMETRIOSIS CLINICAL CASE SCENARIO\nWu, 2023 Colorectal \ncancer\nSigmoid colon, \nperi colic LNs\nClinical: Large-bowel obstruction, weight loss, constipation\nImaging: Mural thickening, impassable steno sis Pathology: \nMacroscopic Findings: The specimen showed localized, \nrubbery bowel wall thickening which was compressing \nand distorting the lumen. The serosa appeared mottled \nbrown, indicating previous hemorrhage and hemosiderin \ndeposition, and also showed greyish-white fibrous \npuckering. A cross section showed a rubbery, pale tan \nappearance consistent with hyperplastic smooth muscle \ncompressing the lumen. Patches of congested, mottled, \nand brown serosa overlay sites of endometriosis. No \nfeatures suggestive of malignant transformation were \nfound . Microscopic Findings: The presence of endometrial \nglands and stroma scattered throughout the bowel wall \n(submucosa and muscularis propria) confirmed the \ndiagnosis of Deep Infiltrating Endometriosis (DIE). There \nwas marked smooth muscle hyperplasia, expanding the \nbowel wall. The muscularis mucosae was seen blending \nwith the muscularis propria, and the hyperplastic smooth \nmuscle contained scattered endometrial-type glands. Ectopic \nendometrial epithelium was discovered within two pericolic \nlymph nodes. Within the affected lymph node(s), there was \na cystically dilated gland lined by endometrial epithelium, \ncontain ingblood/fibrin, surrounded by lymph node \nparenchyma showing reactive follicles.\nLedezma, \n2021\nBladder \nmalignancy\nBladder dome \n(infiltrating), \ncontacting \nremnant cervix & \nsigmoid\nClinical: Chronic pelvic pain, severe hematuria\nImaging (US/CT/MRI): Infiltrative bladder mass, restricted \ndiffusion\nCA-125: 93.9\nPathology: Endometriosis\nMedlin, \n2016\nPseudomyxoma\nperitonei \n(appendiceal/\nperitoneal CA)\nDiffuse \nperitoneal \nimplants, large \ncystic masses, \nendometriomas\nClinical: Diffuse abdominal pain, weight gain, ascites\nImaging (CT): Multi-loculated fluid, bowel centralization, \nadnexal mass\nElevated CA-125 (223)\nPathology: Endometriosis\nFan, 2025 Ovarian/ \nperitoneal \nmalignancy\nLeft ovary \n(polypoid \nendometriosis), \npelvic side wall, \nuterus, right \nadnexa\nClinical: Severe pelvic pain, recurrence Imaging (CT/\nMRI): Complex cystic-solid pelvic masses, infiltration, \nhydronephrosis CA-125: 1386.5\nPathology: Polypoid endometriosis\nZhao, 2018 Rectal cancer; \nalso suspected \ncervical cancer \nor GIST\nRectal wall (4 cm \nfrom anus)\nClinical: Postcoital bleeding, constipation, narrow stool\nImaging (US, CT, PET): Rectal mass with FDG uptake\nInitial biopsy: Mesenchymal tumor suspicion; Pathology: \nEndometriosis\nUmair, \n2020\nRenal tumor Right kidney \n(interpolar \nregion)\nClinical: Paroxysmal flank pain in pregnancy Imaging (MRI):  \n~ 6 cm heterogeneous renal mass\nRadical nephrectomy for presumed malignancy; Pathology: \nendometriosis\n(Continued from previous page)\n\nVol. 5(2), 75-94, 2025\n83\nmalignant-like behaviors are hormonal signaling dis-\nturbances (notably estrogen-dependent growth and \nprogesterone resistance), persistent inflammatory \ndrivers, and various epigenetic modifications often \nalso implicated in tumor pathogenesis (Figure 1).\nMolecular Pathways\n- PI3K/AKT/mTOR Pathway : Extensive work has \nestablished that the PI3K/AKT/mTOR axis is per -\nsistently overactive in eutopic and ectopic endome-\ntrial cells, evidenced by high levels of phosphory -\nFigure 1. This figure highlights six interrelated functional pathways that underlie the pathophysiology of endometriosis, depicted around a \ncentral image showing ectopic endometrial lesions dispersed across pelvic and intestinal structures. Each color-coded sector summarizes \nevidence-based mechanisms contributing to lesion establishment and survival:\n• Hormonal Signaling\nExaggerated estrogenic drive (elevated ERβ expression, COX-2/VEGF induction) and reduced progesterone receptor signaling jointly sustain \ninflammatory and proliferative cascades, in part through crosstalk with MAPK/ERK, p38, NF-κB, JNK, and Wnt/β-catenin (59, 70, 71, 75, 78).\n• Inflammatory Signaling\nPersistent elevation of proinflammatory cytokines (TNFα, IL-1β, IL-6, IL-8, RANTES, MCP-1) and immune cell dysregulation (macrophages, \nNK cells, T/B lymphocytes) drive lesion progression and pain. Iron overload from retrograde menstruation intensifies oxidative damage, \nwhile TLR4/MyD88 and microbiome shifts exacerbate localized and systemic inflammation (59, 69, 71, 78, 81-83).\n• Oxidative Stress\nRepeated hemorrhage into the peritoneal cavity and iron-rich debris trigger excess reactive oxygen/nitrogen species, fueling DNA damage \nand inflammation. Mitochondrial ERβ-mediated responses, along with NF-κB and MAPK activation, reinforce lesion viability; partial \namelioration is possible through antioxidant strategies in model systems (65, 67, 69, 71, 75, 78, 84).\n• Apoptosis Regulation\nAberrations in FAS and TNF-α pathways, coupled with increased Bcl-2 expression, enable endometriotic cells to evade apoptosis. Multiple \npathways, including NF-κB, PI3K/AKT, ERK, JNK, and p38, further sustain cell survival, while mitochondrial ERβ can suppress caspase 8 \n(via NCOA-1), mirroring chemoresistance observed in malignancies (59, 69, 71, 78, 85).\n• Angiogenesis\nOverexpression of VEGF, MIF, and PGE2 drives formation of new vascular networks critical for lesion nourishment. Regulation by Wnt/β-\ncatenin, ERβ, and HIF-1α converges on MAPK/ERK and PI3K/AKT/mTOR, while NF-κB signaling amplifies the production of pro-angiogenic \nmediators (69, 71, 83, 85).\n• Invasion and Epithelial–Mesenchymal Transition (EMT)\nDecreased E-cadherin and heightened markers such as N-cadherin and vimentin, together with Snail/Slug/Twist transcription factors, \npromote tissue invasion and migration. Mechanistic drivers, PI3K/AKT, MAPK/ERK, NF-κB, Wnt/β-catenin, act in concert with TGFβ and \nCOX-2/PGE2, while lncRNA HOTAIR fosters EMT through miR-519b-3p/PRRG4 (59, 60, 68-70, 76).\n\nVol. 5(2), 75-94, 2025\n84\nlated AKT (p-AKT), PI3K, AKT1, 4EBP1, and mTOR-ac-\ntivating proteins (AXL, SHC1), together with dimin -\nished PTEN-mediated inhibition (58–64). Notably, \nhotspot mutations in PIK3CA and PTEN have been \nreported in deep infiltrating variants, implicating \nthese genetic defects in advanced disease. Through \nthis pathway, endometriosis lesions gain prolifer -\native, pro-angiogenic, and pro-survival functions, \npotentially contributing to both progesterone resis-\ntance and heightened risk of EAOC (58-65). Regula-\ntory control is multifactorial: cytokines (TNFα), growth \nfactors (FGFR2, ERBB2/3), and estrogen (via PTEN \nsuppression) jointly activate PI3K/AKT. Non-cod -\ning RNAs such as miR-92a and miR-135a/b further \namplify the pathway, whereas miR-194-5p attenu -\nates it. LncRNAs, notably HOXA-AS2, interface with \nmiR-4459/IGF2BP2 to enhance cell proliferation via \nAKT, and ENPP3, commonly hypomethylated, fuels \nthe AKT/mTOR/4EBP1 axis. In addition, endosta -\ntin-expressing endometrial stem cells may counter \nangiogenic signals via miR-21-5p/TIMP3 within this \ncascade (58, 60-62, 62-64, 66).\n- MAPK Pathways (ERK, p38, JNK): Enhanced acti-\nvation of ERK, p38, and JNK MAPKs is evident in \nendometriotic lesions relative to normal endome -\ntrial tissue (59, 67, 68). These MAPKs govern prolif-\neration, survival (through Bcl-2), migration, invasion, \nangiogenesis, inflammation, and pain hypersensi -\ntivity. Their activation arises from diverse stimuli, \nTNFα, IL-1β, FGFR2, leptin, or TGFβ, and proceeds \nvia the Ras–Raf–MEK cascade (59, 62, 66). Specific \nmiRNAs (e.g., miR-340-5p) modulate MAPK activ -\nity and pharmacological inhibition of Raf, VEGFR, \np38, or JNK suppresses lesion growth in preclinical \nmodels (55, 64).\n- NF-κB Pathway: Chronic NF-κB activation occurs \nin ectopic stromal cells and peritoneal macrophages, \ndiverging from normal cyclic regulation (61, 69). This \npersistent activation drives inflammatory media -\ntors (IL-6, IL-8, RANTES, MCP-1, GM-CSF, MIF), matrix \nremodeling via metalloproteinases (MMPs), angio-\ngenesis (VEGF), and resistance to apoptosis (59, 61, \n62, 65, 66, 69, 70). NF-κB activation is triggered by \nTNFα, IL-1β, TSLP, iron overload, or TLR4/MyD88 \nsignaling, whereas miR-16 negatively regulates the \npathway by targeting IKKβ (65, 66, 69, 71).\n- Wnt/β-catenin Pathway: Aberrant Wnt/β-catenin \nsignaling in endometriosis, characterized by altered \nβ-catenin expression and SFRP2 hypomethylation, \npromotes invasive growth, fibrosis, and epithelial–\nmesenchymal transition (EMT) (65, 72, 73). Proges-\nterone usually inhibits Wnt/β-catenin, but proges -\nterone resistance diminishes this protective effect. \nDysregulated factors (estrogen, FOXP1, WEE1, MMP9) \nsustain Wnt signaling, while miRNAs (miR-33b, let-\n7a/g, miR-532-3p) and COX-2/PGE2 influence path-\nway intensity and EMT induction (58, 70, 71, 73).\n- JAK/STAT Pathway: Research focusing on the JAK2/\nSTAT3 arm identifies IL6ST (gp130) hypomethylation \nand overexpression in ectopic tissue, magnifying \nIL-6 signaling (74). Enhanced JAK2/STAT3 contributes \nto lesion proliferation, invasion, and anti-apoptotic \nphenotypes analogous to tumorigenic growth (74). \nSimultaneously, downregulation of STAT1 by miR-\n194-5p removes a moderating effect on mTOR, fur-\nther bolstering JAK2/STAT3 (58, 74).\n- Epigenetic and Non-coding RNA Regulation: The \nrole of epigenetic derangements, DNA methylation \nshifts (e.g., SFRP2 hypomethylation or aberrant IL6ST \nmethylation), histone modifications (HDAC upreg -\nulation), and dysregulated miRNA/lncRNA expres -\nsion, in driving ectopic lesion resilience (64, 65, 72, \n74–76) have been raised attention. Genes mediat -\ning steroid hormone action (ESR2, PR), inflammatory \nsignaling (IL6ST), or tumor suppression (RASSF1A, \nE-cadherin) are frequently abnormally silenced or \nexpressed. As seen in oncologic processes, such epi-\ngenetic alterations provide cellular plasticity, allow-\ning endometriotic lesions to endure fluctuations in \nhormones and cytokines. Concomitant aberrations \nin specific miRNAs (e.g., miR-135b or miR-194-5p) or \nlncRNAs (HOXA-AS2, HOTAIR) can intensify these \nadaptive capabilities (64, 65, 71, 74, 74-79).\nCritical Functional Modifications\n- Hormonal Signaling (Estrogen/Progesterone) : \nEndometriosis characteristically shows an exagger-\nated estrogenic drive and impaired progesterone \nreceptor signaling, driving persistent lesion growth \nand inflammatory responses (59, 71, 75, 77, 78, 80). \nNotably, ERβ is abundant, even within mitochon -\ndrial compartments, supporting enhanced bioener-\ngetics and oxidative stress defenses. Estrogen trig-\ngers COX-2 and prostaglandin upregulation, as well \nas angiogenic mediators (VEGF), while progesterone \nresistance, encompassing reduced PR expression, \ndisrupts physiologic tissue remodeling (59, 70, 71, \n75, 77). Hormonal crosstalk also activates MAPK/\nERK, p38, NF-κB (through PTEN attenuation), JNK \n(via TSLP), and Wnt/β-catenin, with epigenetic mod-\nifiers such as Betulinic Acid (ERβ suppression) and \nmiR-23a/b (SF-1) further refining these networks \n(59, 66, 67, 69).\n\nVol. 5(2), 75-94, 2025\n85\n- Inflammatory Signaling : Chronic inflammation \nremains a hallmark of endometriosis, reflected by \nheightened TNFα, IL-1β, IL-6, IL-8, RANTES, and MCP-1 \nin peritoneal fluid and lesions. Concomitant dysfunc-\ntion occurs in macrophages, NK cells, T and B cells, \nMDSCs, and dendritic cells (59, 69, 71, 77, 81-83). \nThis proinflammatory milieu helps establish lesions, \npromotes new vessel formation, and drives fibro -\nsis and pain. Iron overload arising from retrograde \nmenstruation can intensify inflammatory and oxi -\ndative damage, while broad molecular routes (NF-\nκB, MAPK, JAK/STAT, PI3K/AKT/mTOR) orchestrate \nextended neuroinflammatory cascades. Moreover, \ngut microbiome shifts and TLR (TLR4/MyD88) per -\nturbations appear to escalate systemic and local -\nized inflammation (59, 69, 71, 77, 81-83).\n- Oxidative Stress Pathway: Repeated episodes of \nretrograde bleeding deposit iron-rich debris, fuel -\ning reactive oxygen and nitrogen species that injure \nDNA, heighten inflammation, and potentially initiate \nprecancerous changes (65, 69, 71, 75). Mitochondrial \nERβ may modulate aspects of antioxidant responses \n(e.g., SOD2). Chronic oxidative stress reciprocally \nactivates NF-κB and MAPK, reinforcing lesion via -\nbility. Model systems demonstrate that antioxidant \ninterventions can partially mitigate these detrimen-\ntal effects (66, 69, 75, 77, 84).\n- Apoptosis Regulation: Another defining feature is \nthe ability to evade programmed cell death through \ndisrupted FAS or TNF-α–mediated pathways, bol -\nstered by elevated Bcl-2 (59, 69, 71, 85). This eva -\nsion allows ectopic tissue to persist through cycli -\ncal hormonal changes. Investigations underscore \npivotal roles for NF-κB, PI3K/AKT, ERK, JNK, and p38 \nin maintaining these cells, while estrogen (ERβ) can \nsuppress caspase 8 by means of cofactors such as \nNCOA-1 (59, 69, 71, 77). Such anti-apoptotic mech -\nanisms mirror chemoresistance in various malig -\nnancies.\n- Angiogenesis: Multiple studies reveal that VEGF, \nMIF, and PGE2 are consistently overexpressed in \nendometriosis, forming an aggressive neovascular \nnetwork critical for lesion support (69, 71, 83, 85). \nThis shift into enhanced vessel formation mirrors \ntumor biology, delivering nutrients and oxygen to \nectopic cells. Wnt/β-catenin, ERβ, and HIF-1α can \ngovern VEGF expression, whereas MIF (acting via \nCD74) and PGE2 converge on MAPK/ERK or PI3K/\nAKT/mTOR routes (69, 71, 83, 85). NF-κB likewise \ninduces pro-angiogenic mediators.\n- Cell Invasion, Migration, and EMT: Endometriotic \ntissue often manifests lowered E-cadherin, height-\nened N-cadherin and vimentin, and transcription fac-\ntors (Snail, Slug, Twist) that define EMT (67-69, 71-73, \n86). Metalloproteinases, such as MMP2 and MMP9, \nremodel extracellular matrices, fostering deeper \ntissue infiltration. These invasive traits are orches-\ntrated by pathways including PI3K/AKT, MAPK/ERK, \nNF-κB, and Wnt/β-catenin, often with TGFβ serving \nas a central pro-invasive factor. FGFR2 augments \nmigration via ERK, while COX-2/PGE2 interacts with \nβ-catenin. LncRNA HOTAIR drives EMT through miR-\n519b-3p/PRRG4, aligning with malignant-type met-\nastatic processes (59, 60, 67-70, 76).\nGAPS IN UNDERSTANDING\nDespite substantial progress in elucidating clinical \nand molecular aspects of endometriosis, signifi -\ncant uncertainties persist regarding its pathogene-\nsis, accurate diagnosis, and effective application of \nemerging insights to patient care.\nMethodological and Translational Limitations\nNumerous research teams emphasize the shortcom-\nings of existing in vitro and in vivo models, which \nfail to mirror the complexity of the human disease. \nMost rodent models insufficiently capture the varied \npain phenotypes, particularly non-evoked, chronic \ncomponents, that characterize endometriosis in \npatients. While such models remain key to preclin-\nical testing, they often focus on reflex-based end -\npoints alone, thereby underrepresenting clinically \nrelevant pain features (87). Furthermore, many pre-\nclinical and clinical studies inadequately or inconsis-\ntently address pain endpoints, limiting translational \nrelevance (88). Parallel issues exist in the validation \nand clinical translation of biomarkers. Although \nnumerous genomic, epigenomic, proteomic, and \nmetabolomic candidates have been proposed, few \nhave demonstrated sufficient sensitivity, specific -\nity, or reproducibility to enter clinical practice reli -\nably (89). Variability across studies, limited sample \nsizes, and a lack of robust validation studies prevent \nbroader implementation, leaving invasive diagnos-\ntic methods and empirical management as current \nstandards of care (90).\nClinical Challenges and Unmet Needs\nPain Mechanisms: A crucial unresolved issue is the \npoor correlation between lesion burden and pain \nseverity; some patients experience minimal symp-\ntoms despite extensive disease, while others suffer \n\nVol. 5(2), 75-94, 2025\n86\nsevere, debilitating pain from minor lesions. Emerg-\ning evidence suggests that neuroinflammatory path-\nways and central sensitization mechanisms might \ndecouple pain from lesion size or anatomical stag-\ning (91). As conventional surgical or hormonal ther-\napies target primarily visible lesions, many patients \nremain undertreated for persistent or recurrent \npain. Without clearer insights into these overlap -\nping neuronal and inflammatory processes, cur -\nrent approaches may miss a substantial subset of \npatients who continue to experience pain despite \nstandard treatments.\nLesion Biology Heterogeneity: Significant variability \nin lesion morphology, invasive behavior, hormonal \nresponsiveness, and recurrence risk underscores \ninherent biological heterogeneity in endometrio -\nsis. Evidence suggests stem-like or progenitor cell \npopulations contribute substantially to lesion resil-\nience and therapeutic resistance (92). However, \ndirect identification of these stem-like cells in clini-\ncally pertinent models, particularly for deep infiltrat-\ning endometriosis, is lacking. Improved techniques \nto isolate and characterize such cells could enable \nmore precisely targeted therapies that reduce recur-\nrence without the broad side effects characteristic \nof hormonal suppression.\nFertility and Reproductive Outcomes: Fertility-re -\nlated research remains notably deficient. Emerg -\ning single-cell transcriptomic and proteomic anal -\nyses reveal disruptions in oocyte maturation path-\nways linked to oxidative stress and abnormal molec-\nular regulation, correlating with reduced reproduc-\ntive outcomes in patients with ovarian endometrio-\nsis (93). While these data highlight potential molec-\nular pathways affecting ovarian function, translation \ninto clinical practice, such as methods to restore typ-\nical oocyte function, remains largely unaddressed. \nEqually puzzling is why some endometriosis patients \nmaintain robust fertility, whereas others encounter \nsevere, treatment-refractory infertility.\nLimitations of Current Hormonal Therapies: Man -\nagement of endometriosis remains predominantly \nreliant on broad hormonal suppression, posing \nsignificant drawbacks for patients with contraindi -\ncations or fertility goals. Despite preclinical prom -\nise, therapies targeting local estrogen biosynthesis, \ninflammatory signaling pathways, or dysregulated \nneuroimmune interactions remain limited in their \nclinical adoption and validation (94). Moreover, no \nconsensus exists for targeted therapies aimed at \nlocal estrogen synthesis, inflammatory pathways, \nor dysregulated neuroimmune mechanisms with -\nout broad hormonal suppression. Novel interven -\ntions (for example, lncRNA or circRNA modulators \nand agents targeting stem-like cells) show promise \nin preclinical investigations but lack rigorous testing \nin phase I/II clinical trials (87, 90-92, 94).\nDISCUSSION\nEndometriosis displays complex cancer-mimicking \ncharacteristics that complicate biomarker devel -\nopment and clinical translation (7, 81, 91). Recent \nproteomic studies identified a promising 10-pro -\ntein plasma panel achieving high diagnostic accu -\nracy (AUC 0.997), yet its performance varies con -\nsiderably across disease stages (95). Similarly, sali-\nva-based miRNA signatures combined with artifi -\ncial intelligence (AI) algorithms achieved sensitivi -\nties of 96–97% and specificities up to 95–100% (96, \n97). Although these noninvasive tools are promis -\ning, false-negative results remain a concern, poten-\ntially extending diagnostic delays. Thus, balancing \nassay accuracy against minimally invasive surgical \ninterventions remains critical. Comparative stud -\nies quantifying risks associated with false-negative \ndiagnoses versus surgical morbidity are necessary \nto inform optimal patient management strategies \n(10). A fundamental barrier remains the lack of sys-\ntematic preclinical and early-phase validation frame-\nworks connecting bench research directly to clini -\ncal practice. Despite identifying numerous molec -\nular candidates, such as dysregulated noncoding \nRNAs, epigenetic alterations, and immune checkpoint \ndysregulation, few have successfully navigated rig-\norous, phased evaluations in clearly characterized \ndisease models (89). Biomarkers derived from pro-\nteomic or metabolomic platforms similarly require \nvalidation through large-scale confirmatory studies, \nwhich remain insufficient (90). Consequently, inva-\nsive diagnostic procedures, broad hormonal suppres-\nsion, and repeated surgical interventions persist as \nthe predominant standards of care (98). Although \nendometriosis predominantly remains a benign con-\ndition with cancer-mimicking features, a small but \nclinically important proportion can undergo genu -\nine malignant transformation, particularly to EAOC. \nRecent studies have elucidated distinct EAOC clinical \nentities, notably distinguishing between endometri-\nosis-correlated ovarian carcinoma, characterized by \ntransitional lesions such as atypical endometriosis \nor borderline tumors, and endometriosis-inciden -\ntal ovarian carcinoma, in which benign endometri-\n\nVol. 5(2), 75-94, 2025\n87\nosis occurs independently alongside ovarian can -\ncer. Patients with endometriosis-correlated ovar -\nian carcinoma tend to present at younger ages, ear-\nlier disease stages, and with different histopatho -\nlogical subtypes compared to ovarian cancers with-\nout associated endometriosis, underscoring criti -\ncal prognostic and therapeutic differences (6). At \na molecular level, the transition from benign ovar-\nian endometriosis to carcinoma is associated with \nspecific miRNA profiles, with recent analyses iden-\ntifying miRNAs, such as hsa-miR-200a-3p, hsa-miR-\n141-3p, hsa-miR-183-5p, and hsa-miR-10a-5p, that are \nsignificantly upregulated during malignant trans -\nformation. These miRNA biomarkers offer promis-\ning diagnostic potential for the early identification \nof patients at elevated risk of progression to EAOC \nbut they still need external clinical validation (99). \nFurthermore, comprehensive molecular and clini -\ncal data reinforce the need for individualized man-\nagement strategies, emphasizing precise molecular \ndiagnostics and targeted therapeutic approaches \nto optimize outcomes in ovarian cancer manage -\nment (100). To address these shortcomings, we pro-\npose adopting a structured translational approach \nwhereby new hypotheses undergo systematic vali-\ndation in robust preclinical models before advanc-\ning to carefully staged clinical trials within rigor -\nously stratified patient populations (101). Such an \napproach ensures promising molecular or immu -\nnological candidates first undergo Phase 0 trials to \ndetermine safety and biological plausibility prior to \nprogressing to larger-scale Phase II/III evaluations. \nAromatase inhibitors exemplify how structured, \nsmall-scale experimental validations can translate \ninto targeted, non-hormonal therapeutic options \n(94). Employing this structured pipeline facilitates \nefficient conversion of laboratory discoveries into \nclinically applicable tools. Structured translational \nresearch also promotes refined clinical phenotyp -\ning. By stratifying endometriosis into distinct clini -\ncal subtypes (e.g., deep infiltrating, peritoneal, ovar-\nian), novel therapies—such as immune checkpoint \nmodulators, anti-inflammatory compounds, and \nepigenetic drugs—can be more precisely matched \nto patient subgroups most likely to respond. This \ntargeted approach reduces reliance on empirical \ntreatment strategies (11). Early-phase models fur -\nther help define relevant clinical endpoints, such \nas pain alleviation, fertility restoration, and lesion \nregression, while incorporating advanced imaging, \nimmunological profiling, and biomarker assess -\nments to measure therapeutic outcomes dynam -\nically. An emerging yet underappreciated concern \ninvolves reliance on large-scale data analytics and \nAI-driven methodologies for identifying molecular \nsignatures and disease subtypes. Without robust, \npatient-centered translational frameworks, indis -\ncriminate use of AI risks embedding pre-existing \nbiases, amplifying health inequalities, and gener -\nating outcomes that neither address patient-spe -\ncific clinical needs nor tangibly improve clinical care \n(20, 102). AI models developed on incomplete or \nbiased datasets may further exacerbate misdiagno-\nsis or inappropriate therapeutic decisions. To mit -\nigate these risks, AI applications should undergo \ntransparent, phase-appropriate clinical validation, \nclearly defined endpoints, and equity-focused per-\nformance assessments. Such rigor prevents the \npitfalls associated with opaque algorithmic (“black-\nbox”) decision-making. Similarly, advanced imag -\ning and machine-learning technologies must fol -\nlow carefully structured validation pathways prior-\nitizing high-quality data, equitable patient access, \nand continual monitoring. These measures ensure \nAI-enhanced strategies meaningfully advance criti-\ncal clinical outcomes such as pain relief and fertility \npreservation, thereby safeguarding both scientific \nintegrity and personalized patient care. Ultimately, \nendometriosis represents a multifaceted, systemic \ndisorder with numerous malignant-like features \n(11). Establishing a translational roadmap grounded \nin refined phenotyping, phase-focused validation, \nand methodical clinical trials is vital. By instituting \na well-defined pipeline, clinicians and researchers \ncan move beyond traditional hormonal treatments, \nultimately delivering targeted, effective interven -\ntions and significantly improving quality of life for \nwomen who currently endure the substantial bur -\ndens of endometriosis.\nACKNOWLEDGEMENTS\nWe extend our sincere gratitude to Endosummit \nand its scientific committee, including patient advo-\ncates, for their commitment to advancing knowl -\nedge and improving care in endometriosis. We par-\nticularly thank Doctor Joseph Raccuia for his excep-\ntional contributions to training and mentoring new \nsurgical specialists. We also wish to acknowledge \nthe researchers at the Sbarro Health Research Orga-\nnization (Temple University, PA, USA) for their vital \nrole in translating medical and scientific findings \ninto practical innovations.\n\nVol. 5(2), 75-94, 2025\n88\nCOMPLIANCE WITH ETHICAL \nSTANDARDS\nFundings\nNo funding was utilized for this study as it com -\nprised observational research incorporating rou -\ntine clinical practices.\nConflict of interests\nThe authors declare that there are no conflicts of \ninterest associated with this publication.\nAvailability of data and materials\nThe data supporting the findings of this study are \navailable upon reasonable request to the corre -\nsponding author.\nAuthors’ contributions\nCM: Conceptualization, Methodology, Formal anal-\nysis, Writing – Original Draft, Supervision, Project \nadministration. AV: Conceptualization, Investiga -\ntion, Resources, Writing – Review & Editing, Super-\nvision. FDC: Formal analysis, Visualization, Writing – \nOriginal Draft. GM: Validation, Formal analysis, Data \nCuration. SEM: Investigation, Data Curation, Writ -\ning – Original Draft. LA: Formal analysis, Investiga -\ntion, Validation. AE: Investigation, Resources, Vali -\ndation, Writing – Review & Editing. AG: Supervision, \nProject administration, Funding acquisition, Writing \n– Review & Editing.\nEthical approval\nThis research adhered to the ethical standards of\nthe World Medical Association’s Declaration of Hel-\nsinki and complies with the Recommendations for \nthe Conduct, Reporting, Editing, and Publication of \nScholarly Work in Medical Journals, including the \ninclusion of diverse human populations in terms of \nsex, age, and ethnicity.\nHuman studies and subjects\nN/A.\nAnimal studies\nN/A.\nPublications ethics\nThe publication ethics followed by this study align \nwith those outlined by the International Committee \nof Medical Journal Editors (ICMJE), regarding publish-\ning and editorial issues in medical journals.\nPlagiarism\nThe article provides a comprehensive review of the \nlatest studies in the field, with accurate citations.\nData falsification and fabrication\nThe writing and contents of the article are entirely \noriginal and were developed entirely by the authors.\nAbbreviations\nAI: Artificial Intelligence\nAKT: Protein Kinase B (also referred to as “PKB”)\nAXL: AXL Receptor Tyrosine Kinase\nBcl-2: B-cell lymphoma 2\nCA-125: Cancer Antigen 125\nCA-19.9: Cancer Antigen 19.9\nCD74: Cluster of Differentiation 74\ncircRNA: Circular RNA\nCOX-2: Cyclooxygenase-2\nCT: Computed Tomography\nCTLA-4: Cytotoxic T-lymphocyte-Associated Protein 4\nEAOC: Endometriosis-Associated Ovarian Cancer\nEMT: Epithelial–Mesenchymal Transition\nENPP3: Ectonucleotide Pyrophosphatase/Phospho-\ndiesterase 3\nERβ: Estrogen Receptor Beta (also written as ESR2)\nERK: Extracellular Signal-Regulated Kinase\nFGFR2: Fibroblast Growth Factor Receptor 2\nGal-9: Galectin-9\nGC–MS: Gas Chromatography–Mass Spectrometry\nGM-CSF: Granulocyte Macrophage Colony-Stimu -\nlating Factor\nHDAC: Histone Deacetylase\nHIF-1α: Hypoxia-Inducible Factor 1-Alpha\nHOXA-AS2: HOXA Cluster Antisense RNA 2\nHOTAIR: HOX Transcript Antisense RNA\nIGF2BP2: Insulin-like Growth Factor 2 mRNA-Bind -\ning Protein 2\nIKKβ: IκB Kinase Beta\nIL-1β: Interleukin 1 Beta\nIL-6: Interleukin 6\nIL-8: Interleukin 8\nIL6ST (gp130): Interleukin 6 Signal Transducer (gly -\ncoprotein 130)\nJAK: Janus Kinase\nJNK: c-Jun N-terminal Kinase\nlncRNA: Long Noncoding RNA\nMAPK: Mitogen-Activated Protein Kinase\nMCP-1: Monocyte Chemoattractant Protein 1 (also \nknown as CCL2)\nMDSCs: Myeloid-Derived Suppressor Cells\nMIF: Macrophage Migration Inhibitory Factor\nmiRNA: MicroRNA\n\nVol. 5(2), 75-94, 2025\n89\nMRI: Magnetic Resonance Imaging\nmTOR: Mechanistic Target of Rapamycin\nMyD88: Myeloid Differentiation Primary Response 88\nN-cadherin: Neural Cadherin\nNCOA-1: Nuclear Receptor Coactivator 1\nNF-κB: Nuclear Factor kappa B\np38: p38 Mitogen-Activated Protein Kinase\npAKT: Phosphorylated AKT\nPD-1: Programmed Cell Death Protein 1\nPD-L1: Programmed Death-Ligand 1\nPET: Positron Emission Tomography\nPI3K: Phosphatidylinositol 3-Kinase\nPRRG4: Proline-Rich Gla (γ-carboxyglutamic acid) \nProtein 4\nPTEN: Phosphatase and Tensin Homolog\nRaf: Rapidly Accelerated Fibrosarcoma (proto-onco-\ngene in the MAPK pathway)\nRANTES: Regulated upon Activation, Normal T Cell \nExpressed and Secreted (also known as CCL5)\nRASSF1A: Ras Association Domain Family Member 1\nSHC1: SHC Adaptor Protein 1 (Src Homology 2 \ndomain-containing)\nSFRP2: Secreted Frizzled-Related Protein 2\nSOD2: Superoxide Dismutase 2\nSTAT: Signal Transducer and Activator of Transcription\nTGFβ: Transforming Growth Factor Beta\nTIM-3: T-cell immunoglobulin and mucin-domain \ncontaining-3\nTLR4: Toll-Like Receptor 4\nTNFα: Tumor Necrosis Factor Alpha\nTSLP: Thymic Stromal Lymphopoietin\nVEGF: Vascular Endothelial Growth Factor\nVEGFR: Vascular Endothelial Growth Factor Receptor\nWEE1: WEE1 G2 Checkpoint Kinase\nWnt: Wingless/Integrated\n4EBP1: Eukaryotic Translation Initiation Factor \n4E-Binding Protein 1\nREFERENCES\n1. 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