Research progress in endometriosis-associated ovarian cancer

Ling Tang, Lin Tang, Tang L, Bian C, Ce Bian
Frontiers in oncology · 2024 · vol. 14 , pp. 1381244 · doi:10.3389/fonc.2024.1381244 · PMID:38725626 · PMC11079782 · W4395455012
review OA: gold CC0 ⤵ 8 in-corpus citations
📄 Open PDF Full text JSON View on OpenAlex View on PubMed View at publisher
⚙ AI-generated summary by claude@2026-06, 2026-06-25 ⓘ

This review examines endometriosis-associated ovarian cancer's epidemiology, pathogenesis, diagnosis, treatment, and prognosis, highlighting challenges and future research directions for stratified management.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

⚙ AI-generated deep summary by claude@2026-07, 2026-07-08 · read from full text ⓘ

This paper is a comprehensive review of endometriosis-associated ovarian cancer (EAOC), covering epidemiology, proposed mechanisms of malignant transformation (including genetic alterations such as frequent ARID1A, PTEN, and PIK3CA changes), tumor microenvironment influences, and roles for hormones, epigenetics, iron/oxidative stress, and inflammation. It reports that women with endometriosis have elevated ovarian cancer risk compared with the general population, with increased incidence of ovarian clear cell carcinoma and endometrioid carcinoma, and summarizes evidence from large studies and mechanistic models, including findings that ARID1A loss alone is insufficient for cancer in mice but combined hits (e.g., with PTEN or PIK3CA activation) can drive disease. A key caveat is that the review repeatedly notes ongoing uncertainty and the need for more robust mechanistic evidence, particularly around immune components and the precise carcinogenic steps from endometriosis to cancer. This paper is centrally about endometriosis — it focuses on research progress in endometriosis-associated ovarian cancer, including the transformation pathways linking endometriosis to ovarian clear cell and endometrioid carcinomas.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Abstract

Endometriosis-associated ovarian cancer (EAOC) is a unique subtype of ovarian malignant tumor originating from endometriosis (EMS) malignant transformation, which has gradually become one of the hot topics in clinical and basic research in recent years. According to clinicopathological and epidemiological findings, precancerous lesions of ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) are considered as EMS. Given the large number of patients with endometriosis and its long time window for malignant transformation, sufficient attention should be paid to EAOC. At present, the pathogenesis of EAOC has not been clarified, no reliable biomarkers have been found in the diagnosis, and there is still a lack of basis and targets for stratified management and precise treatment in the treatment. At the same time, due to the long medical history of patients, the fast growth rate of cancer cells, and the possibility of eliminating the earliest endometriosis-associated ovarian cancer, it is difficult to find the corresponding histological evidence. As a result, few patients are finally diagnosed with EAOC, which increases the difficulty of in-depth study of EAOC. This article reviews the epidemiology, pathogenesis, risk factors, clinical diagnosis, new treatment strategies and prognosis of endometriosis-associated ovarian cancer, and prospects the future direction of basic research and clinical transformation, in order to achieve stratified management and personalized treatment of ovarian cancer patients.
Full text 29,667 characters · extracted from pmc-nxml · 7 sections · click to expand

Eaoc

A high estrogen state is considered a significant risk factor for the malignant transformation of EMS ( 52 ). Factors such as early menarche, infertility, or low parity keep patients in a prolonged state of endogenous high estrogen levels, increasing not only the likelihood of EMS but also the risk of EAOC. A stratified study on 66,450 women investigating 12 risk factors for epithelial ovarian cancer found that the risk of OEC gradually increases with earlier age at menarche and later age at menopause ( 53 ). Recent research exploring hormone replacement therapy (HRT) in postmenopausal women with a history of EMS found that, except for HRT using estrogen alone, other HRT regimens do not increase the risk of ovarian cancer in postmenopausal women with a history of endometriosis ( 54 ). This reflects the potential increased risk of EAOC with exogenous estrogen, highlighting different pathways in the role of endogenous and exogenous estrogen in the association between EMS and EAOC, deepening our understanding of this complex relationship. In a retrospective case-control study, Udomsinkul et al. identified menopause as a significant independent risk factor for EAOC ( 55 ). In postmenopausal women, ovarian function declines, leading to a significant decrease in estrogen levels. It is generally believed that postmenopausal patients may experience relief from symptoms of EMS due to the decline in estrogen levels. However, Giannella et al. reported an incidence of endometriosis in menopausal women to be 2-4% ( 56 ), highlighting the importance of special attention to this group. The decreased likelihood of physiological cysts and the increased risk of malignant transformation of ovarian masses in postmenopausal women make it a noteworthy consideration. Current research indicates that age and the long-term development of EMS are important risk factors for EAOC patients. It is noteworthy that EAOC patients are diagnosed at a younger age, with the average diagnosis age being 48.65 years compared to 54.39 years for non-EAOC patients ( 57 ). In a study the longest duration of ovarian endometriotic cysts in EAOC patients was 23 years, with an average duration of 10 years ( 58 ). The study suggests that the long-term development of ovarian endometriotic cysts increases the risk of malignant transformation. Murakami et al.analyzed the medical history of EAOC patients and found that the median time from the diagnosis of endometriotic cysts to the diagnosis of EAOC was 36 months, with approximately 75% of patients progressing to EAOC within 60 months ( 59 ). Given the low incidence of EAOC, the phenomenon of endometriotic cysts rapidly progressing to cancer in a short period suggests that EAOC may occur in earlier, less detectable stages, highlighting the occult nature of EAOC and emphasizing the importance of identifying the risk in early-stage EAOC patients. The relationship between hysterectomy and ovarian cancer is intricate. Previous studies suggest that hysterectomy may impede retrograde menstrual flow and the transfer of carcinogenic substances ( 60 ), thereby reducing the risk of ovarian cancer. Khoja et al. after accounting for confounding factors such as estrogen and estrogen-progestin use, as well as a history of EMS, found that the risk of ovarian cancer decreases only in women with a combination of hysterectomy and EMS ( 61 ), while there is no correlation in women without EMS. Ring et al. research also confirms that, although hysterectomy is not generally associated with the risk of ovarian epithelial cancer ( 62 ), it significantly reduces the risk of ovarian clear cell carcinoma. In patients with endometriosis, the infrequent use of oral contraceptives, comorbid depression, or pelvic inflammation may elevate the risk of ovarian cancer ( 63 ). However, for patients with EAOC, there is currently a lack of well-designed studies providing conclusive evidence regarding these risk factors.

Intro

Endometriosis (EMS) is a prevalent condition that significantly impacts the quality of life and reproductive function in women. According to statistics, the prevalence of EMS among women of childbearing age ranges from 5% to 10% ( 1 ), while it can reach as high as 20% to 60% in women experiencing pelvic pain or infertility ( 2 ). Despite its benign nature, EMS shares biological characteristics with malignant tumors, showing invasive, adhesive, and metastatic potentials, with a risk of malignant transformation. As epidemiological and molecular genetic research continues to reveal, EMS is closely related to epithelial ovarian cancer (EOC), especially ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC). Therefore, ovarian cancers closely associated with endometriosis, which may arise malignantly from endometriosis, predominantly manifest as OCCC and OEC. Collectively, these are referred to as Endometriosis-associated ovarian cancer (EAOC). Early in 1925, Sampson ( 3 ) pioneered the demonstration of the correlation between EMS and ovarian cancer and subsequently proposed the pathological diagnostic criteria for EAOC. These criteria comprise: 1) the existence of cancerous tissue in proximity to endometriotic lesions, 2) exclusion of metastasis from other tumor sources, and 3) the presence of characteristic glandular epithelium surrounding endometriotic lesions. In 1953, Scott introduced an additional criterion ( 4 ): microscopic evidence of the transformation from endometriotic lesions to malignant tissue. Compared to non-EAOC patients, those with EAOC exhibit a younger age at diagnosis, an earlier onset of the disease, lower tumor grades, and lower recurrence rates ( 5 ), suggesting that EAOC represents a distinct subtype of solid tumors. At present, the diagnosis of EAOC mainly depends on surgery and pathological examination, but the rate of missed diagnosis is often increased due to the “burnout effect” of the tumor and the doctor’s neglect of EMS lesions when reading the film. By comprehensively reviewing the epidemiology, pathogenesis, risk factors, clinical diagnosis, treatment modalities and prognosis of EAOC, this review aims to elucidate the distinctive characteristics of EAOC, facilitate early identification by clinicians and provide a valuable reference for enhancing the prognostic outcomes associated with EAOC.

Clinical

Clinical symptoms and signs of EAOC are atypical, lacking specific diagnostic criteria. According to the “dualistic model of ovarian cancer”, researchers suggest that EAOC often belongs to Type I ovarian cancer, characterized by relative indolence, typically lower invasiveness, and less propensity for widespread dissemination ( 64 ). Symptoms of EAOC are often similar to those of endometriosis, mainly presenting as pelvic masses. Clinicians should be vigilant for EAOC when endometriosis patients exhibit typical cyclical pain rhythm changes, abnormal uterine bleeding, or if the mass has a maximum diameter >10 cm or shows rapid enlargement ( 65 ). Currently, there is a lack of specific and cost-effective biomarkers to identify the occurrence of EAOC. Serum carbohydrate antigen 125 (CA125) is the most commonly used ovarian tumor marker. Previous studies suggested that malignancy is likely when CA125 is >200 U/ml. However, CA125 is not highly specific, as it can be influenced by various factors such as endometriosis, inflammation, and menstruation. Its sensitivity in early-stage EAOC is also relatively low. In other study CA125 levels showed no significant statistical difference between patients with ovarian endometriotic cysts and those with EAOC ( 66 ). Compared to CA125, carbohydrate antigen 19.9 (CA19.9) and human epididymal protein 4 (HE4) have advantages in diagnosing EAOC. CA19.9 is a potential serum marker for diagnosing EAOC; in Magalhães et al. study, a serum CA19.9 >22.31 U/ml showed a sensitivity of 82.14% in distinguishing between ovarian endometriotic cysts and EAOC ( 67 ). HE4, highly expressed in ovarian cancer and unaffected by endometriosis, exhibits high specificity. Xu et al. found that a serum HE4 >59.7 pmol/L could diagnose EAOC, with a specificity of 99.4% when HE4 >140 pmol/L ( 68 ). For epithelial ovarian cancer, the combined detection of HE4 and CA125 demonstrates higher sensitivity than CA125 alone. Multiple studies suggest that the joint examination of various tumor markers is more effective in diagnosing ovarian epithelial cancer ( 69 ). In a comprehensive review, concluded that the combination of CA125 and HE4 is currently the most effective diagnostic approach for ovarian epithelial cancer, but its discriminative ability for EAOC requires further clinical research and analysis for validation ( 70 ). Ultrasound plays a crucial role in the diagnosis of epithelial ovarian cancer. Typical features include cystic and solid masses, thick septa, associated solid nodules or papillary projections, and areas of necrosis. Ovarian cancer often presents with ascites and enlarged lymph nodes, with peritoneal, mesenteric, and omental metastases. In differentiating from EAOC, ultrasound examination should focus on specific characteristics of EAOC, such as a cystic lesion diameter larger than 10 cm or showing an increasing trend, having a unilocular or multilocular solid component, and rich blood flow signals ( 71 ). The disappearance of ground glass echoes is also indicative of malignancy ( 72 ). Moreover, EAOC typically manifests as a unilateral cystic lesion with papillary projections, and ascites is less commonly observed ( 73 ). Magnetic Resonance Imaging (MRI) with its excellent soft tissue resolution and multi-planar imaging advantages offers greater accuracy in differentiating EAOC compared to Computerized Tomography (CT). A study found that Whole-Body Diffusion-Weighted Imaging/MRI (WB-DWI/MRI) achieved an accuracy of 93% in determining the benign or malignant nature of ovarian masses, significantly higher than CT’s accuracy of 82% ( 74 ). Using MRI relaxation method to measure the total iron concentration and transverse relaxation rate of cyst fluid in ovarian endometriosis cysts can predict the malignant transformation of ovarian endometriosis ( 75 ). In Zhang X et al. research, using MRI to depict the features of EAOC and non-EAOC, revealed that EAOC, especially clear cell ovarian cancer, more commonly presents as a unilocular cystic mass ( 76 ), showing statistically significant lateralization. Cystic fluid exhibits low signal intensity on T2-weighted imaging, and focal nodular growth patterns are more frequent. These findings underscore the critical role of ultrasound and MRI in the diagnosis of EAOC.

Progress

Most ovarian cancer patients experience recurrence within approximately three years. Advanced ovarian cancer and recurrent cases often exhibit resistance to platinum-based drugs, leading to a deterioration in clinical prognosis ( 77 ), making ovarian cancer treatment a longstanding challenge in gynecologic oncology. Compared to the common high-grade serous ovarian carcinoma, EAOC has a lower incidence rate, but it shows better early prognosis, although the late-stage survival rate is significantly lower than high-grade serous ovarian carcinoma. EAOC patients generally exhibit poorer response to platinum-based chemotherapy compared to non-EAOC cases ( 78 , 79 ). Current experience in EAOC treatment primarily stems from studies on epithelial ovarian cancer. The initial standard treatment for EAOC includes surgery followed by platinum-based chemotherapy ( 77 ). Early-stage EAOC patients should undergo comprehensive staging surgery, while for intermediate to late-stage EAOC patients, consideration should be given to primary debulking surgery (PDS) upon preoperative or intraoperative assessment of extra-ovarian metastasis. Surgery should aim to remove all macroscopically visible tumors to reduce tumor burden, enhance chemotherapy efficacy, and improve prognosis. Lymph nodes serve as crucial pathways for solid tumor metastasis. Systematic lymph node dissection in early-stage ovarian cancer patients is valuable for determining tumor staging, however it is not known whether it is beneficial for prognosis. EAOC as a specific subtype of ovarian epithelial cancer, is often diagnosed in its early stages. Recent evidence from a multicenter retrospective study suggests that early-stage and low-grade endometrioid ovarian cancer patients who undergo lymph node dissection have superior 5-year disease-free survival and overall survival rates compared to those who do not undergo lymph node dissection ( 80 ), with rates of 92.0% vs. 85.6% ( p =0.016) and 97.7% vs. 92.8% ( p =0.013), respectively. Another prospective, multicenter, randomized phase III clinical trial designed by Deng et al. in 2023 is ongoing. By comparing the progression-free survival (PFS) and overall survival (OS) outcomes of patients with stage IA-IIB epithelial ovarian cancer who undergo lymph node dissection surgery versus those who do not ( 81 ), this study aims to provide more precise evidence regarding the efficacy and safety of early lymph node surgery. The benefits and drawbacks of performing lymph node dissection in advanced ovarian cancer patients have been elucidated by high-quality evidence. A multicenter, phase III randomized controlled trial published in the New England Journal of Medicine in 2019 demonstrated that systematic pelvic and para-aortic lymph node dissection did not prolong patients’ OS or PFS and was associated with a higher incidence of postoperative complications ( 82 ). Subsequently, the National Comprehensive Cancer Network (NCCN) guidelines adjusted the indications for lymph node dissection surgery. A small proportion of EAOC is diagnosed in advanced stages, where achieving complete resection through surgery is challenging. Researchers have long attempted to enhance drug efficacy through intraperitoneal chemotherapy, particularly for advanced ovarian cancer. Early clinical trials conducted by the Gynecologic Oncology Group (GOG), including GOG-104, GOG-114, GOG-172, and GOG-252, failed to establish intraperitoneal chemotherapy as a first-line treatment due to design flaws, insufficient statistical evidence, and a higher likelihood of adverse reactions. Hyperthermic intraperitoneal chemotherapy (HIPEC), which combines thermal therapy and intraperitoneal perfusion treatment with intraperitoneal chemotherapy, has become a hot topic in debulking surgery for advanced ovarian cancer in recent years. In 2018, Van Driel et al. demonstrated that adding HIPEC to stage III epithelial ovarian cancer patients led to longer recurrence-free survival and overall survival without increasing the incidence of side effects ( 83 ). The clinical trial OVHIPEC-1 reported by Aronson et al. in 2023 confirmed a 10-year survival benefit of HIPEC in primary stage III epithelial ovarian cancer patients undergoing interval cytoreduction surgery ( 84 ). The efficacy of HIPEC in patients suitable for initial cytoreduction surgery remains uncertain. The OVHIPEC-2 trial, initiated in January 2020, is expected to provide results in this regard ( 85 ). However, the statistical results of the HIPECOVA trial conducted by Villarejo Campos et al. in 2024 failed to demonstrate a significant improvement in the prognosis of ovarian cancer patients with HIPEC ( 86 ). Therefore, HIPEC treatment remains experimental rather than standard therapy. Currently, the standard first-line treatment regimen for EOC and EAOC is platinum-based combination chemotherapy, specifically carboplatin plus intravenous paclitaxel administered every 3 weeks for a total of 6 cycles. The JGOG 3016 trial previously reported significant improvements in progression-free survival and overall survival with a weekly dose-dense paclitaxel regimen and a 3-weekly carboplatin regimen, whereas the ICON8 trial did not observe this benefit. These trials have different strengths and weaknesses, and the differences may be related to pharmacogenomics or other factors such as dose intensity. The findings of Clamp et al. in 2022 confirmed that weekly dose-dense first-line chemotherapy did not improve overall survival or progression-free survival compared to standard 3-weekly chemotherapy ( 87 ). Therefore, the 3-weekly regimen chemotherapy remains the first-line approach. Late-stage EAOC carries a poor prognosis, warranting in-depth research into targeted therapy and immunotherapy. Currently, molecular targeted therapies for ovarian cancer, such as poly ADP-ribose polymerase (PARP) inhibitors and the anti-angiogenic agent bevacizumab, have shown favorable outcomes in maintenance therapy for epithelial ovarian cancer patients with BRCA mutations, thereby extending the survival of ovarian cancer patients to some extent ( 88 ). However, even with satisfactory tumor reduction achieved through surgery and standardized chemotherapy and maintenance therapy, cancer patients may still experience treatment failure due to platinum resistance or tumor recurrence, highlighting the need to enhance drug efficacy and prolong recurrence-free survival. Mirvetuximab soravtansine (MIRV), an antibody-drug conjugate targeting folate receptor (FR) alpha, has shown promising efficacy when combined with bevacizumab in platinum-resistant recurrent ovarian cancer patients. Mirvetuximab soravtansine (MIRV) is a folate receptor (FR)-targeting antibody-drug conjugate (DC). In 2020, researchers found that MIRV combined with bevacizumab demonstrated good efficacy in treating platinum-resistant recurrent ovarian cancer patients. The confirmed objective response rate (ORR) was 39%, with a particularly effective response observed in the subset of platinum-resistant ovarian cancer patients with high FRα expression, achieving an ORR of 56%. The median duration of response was 12 months, and the PFS was 9.9 months ( 89 ). Phase 2 clinical studies of MIRV in epithelial ovarian cancer patients reported in 2023 further demonstrated its anti-tumor activity, along with good tolerability and safety, providing encouraging results ( 90 ). EAOC is highly likely to originate from endometriosis-associated ovarian cysts, which are often considered complex immune-related diseases. Immunotherapy has shown great potential in the treatment of EOC and EAOC. However, previous large phase III studies exploring the addition of immunotherapy to standard first-line treatment regimens have been disappointing, including the IMagyn050/GOG 3015/ENGOT-OV39 ( 91 ) and JAVELIN Ovarian 100 ( 92 ) studies. A turning point in immunotherapy emerged in 2023 with the release of interim data from the global multicenter phase III DUO-O study, showing promising clinical efficacy, warranting continued attention. Recently, based on the establishment of animal models of endometriosis, successful reports of establishing EAOC mouse models have also emerged ( 93 ). By simulating tumor characteristics and reproducing the biological properties of tumors, these models can provide important reference for clinical precision treatment research, which is crucial for the study and development of precision treatment for EAOC.

Conclusions

The intricate relationship between EMS and ovarian cancer warrants in-depth investigation. Early identification of high-risk individuals for cancer among endometriosis patients is of paramount importance, necessitating the development of early detection methods and close monitoring. Future research directions in understanding the mechanisms and molecular genetics of EAOC may involve the utilization of advanced technologies, such as next-generation sequencing and whole transcriptome sequencing, as personalized diagnostic tools. The objective is to identify and confirm the driver mutations and candidate genes associated with the malignant transformation of EMS. These efforts hold the potential to provide more precise targeted therapies and immunotherapies for ovarian cancer, thereby improving patient prognosis and survival outcomes.

Epidemiology

In the investigation, we have noted a relatively low risk of ovarian cancer in the general population, standing at merely 1.31% ( 6 ). Nevertheless, for individuals affected by EMS, the risk of ovarian cancer undergoes a significant escalation, exhibiting a relative risk of 2.51-fold ( 7 ), with a lifetime risk reaching 2.5% ( 8 ). Despite the comparatively modest overall incidence risk, the heightened attention is warranted due to the elevated mortality rate of ovarian cancer within gynecological cancers and the prevalent and chronic nature of EMS. In recent years, substantial interest has been directed towards researching whether individuals with endometriosis face an elevated risk of cancer. Consistent findings in the research field underscore that EMS significantly elevates the risk of OCCC and OEC. A study in the Netherlands involving 131,450 patients with histologically confirmed cases of endometriosis revealed incidence rate ratios for OCCC and for OEC ( 9 ) with similar incidence rates from a Chinese study ( 10 ).

Author Contributions

LT: Writing – original draft. CB: Writing – review & editing.

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: pmc-nxml ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

endometriosis

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (92)

Cited by (9)

Source provenance

europepmc
last seen: 2026-08-01T06:07:04.264727+00:00
openalex
last seen: 2026-06-04T00:00:01.174412+00:00
pubmed
last seen: 2026-08-01T06:05:15.470606+00:00
License: CC0 · commercial use OK