Primary synchronous cancers of the endometrium and ovary: 10-year treatment experience
Yi-Ting Hwang1
, Gin-Den Chen2, Ying-Hsiang Chou3, Hsien-Chun Tseng3, Hsin-Lin Chen3, Bo-Jiun Chang3, Yueh-Chun Lee3, Shih-Tsung Chang3,4
Contributions: (I) Conception and design: ST Chang, YT Hwang; (II) Administrative support: YH Chou, HC Tseng, YC Lee; (III) Provision of study materials or patients: GD Chen, YC Lee, ST Chang; (IV) Collection and assembly of data: YT Hwang, HL Chen, BJ Chang; (V) Data analysis and interpretation: ST Chang, YT Hwang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Background: Primary synchronous endometrial and ovarian cancer (SEOC) is a rare, complex malignancy, representing about 10% of endometrial cancer cases and 5% of ovarian cancer cases. This study showcases a 10-year treatment experience of SEOC patients at Chung Shan Medical University Hospital.
Methods: From 2010 to 2020, we retrospectively included patients diagnosed post-surgery with SEOC and confirmed by pathology, excluding metastatic diagnoses. Dual pathologist confirmations were obtained for all pathology reports. Clinical and follow-up data were sourced from the hospital’s medical records and cancer database.
Results: A total of 19 patients were diagnosed with primary SEOC with an average age of 54.58 years [standard deviation (SD) =12.33 years]. All underwent comprehensive surgical treatment: 14 received only adjuvant chemotherapy while 2 had adjuvant concurrent chemo-radiotherapy. From the time of diagnosis to December 2022, 9 recurrences and 6 deaths were observed. The 5- and 10-year overall survival (OS) rates stood at 69.86% and 55.89%, respectively. Among various stratification variables, only the International Federation of Gynecology and Obstetrics (FIGO) stage of ovarian cancer at initial diagnosis (FIGO I–II vs. III–IV) significantly impacted survival (P=0.002).
Conclusions: Literature suggests that SEOC survival outcomes hinge on tumor stage and extent. This aligns with our findings, albeit with a smaller patient cohort. We determined that the FIGO staging of ovarian cancer plays a critical role in patient prognosis.
Keywords: Synchronous endometrial and ovarian cancer (SEOC); stage-dependent survival outcomes; dual primary gynecologic malignancies
Received: 05 January 2024; Accepted: 12 October 2024; Published online: 06 November 2024.
doi: 10.21037/tro-24-1
Highlight box
Key findings
• A total of 19 patients with primary synchronous endometrial and ovarian cancer (SEOC) were studied over 10 years.
• The International Federation of Gynecology and Obstetrics (FIGO) stage of ovarian cancer at diagnosis significantly impacted survival outcomes.
What is known and what is new?
• SEOC generally has a favorable prognosis, especially when limited to the uterus and ovary.
• This study confirms the prognostic importance of ovarian cancer stage in a Taiwanese cohort.
What is the implication, and what should change now?
• More research is needed on molecular profiling and targeted therapies for high-risk SEOC patients.
• The new FIGO staging system for endometrial cancer should be implemented to guide treatment decisions.
Introduction
Synchronous endometrial and ovarian cancer (SEOC) refers to a patient’s simultaneous presence of both endometrial and ovarian cancer. To diagnose SEOC, Ulbright and Roth (1) delineated a set of pathologic criteria in 1985, then Scully and Young described a list of clinicopathological features in 1998 (2). Primary SEOC is relatively uncommon in gynecologic oncology. According to data from the M.D. Anderson Cancer Center, these neoplasms account for approximately 10% of ovarian cancers and 5% of endometrial cancers (3).
They also summarize possible characteristics of patients with SEOC, including young age, obesity, premenopausal status, and nulliparity.
In general, complete surgery is necessary for the diagnosis and treatment of SEOC. Additionally, preoperative imaging examinations, such as computed tomography (CT) or magnetic resonance imaging (MRI), can be used to aid in the diagnostic process. The need for adjuvant treatment is usually determined based on postoperative pathology reports (4). A 5-year survival rate of 86% and a 10-year survival rate of 80% in patients with SEOC were reported by the Gynecologic Oncology Group (GOG) (5). Previous studies believed that patients with SEOC had a better prognosis than those with metastatic endometrial cancer or ovarian cancer (3,5,6).
This retrospective study is the 10-year treatment experience of patients with primary SEOC at Chung Shan Medical University Hospital. This study aims to present the clinicopathological features and the survival status of patients. Additionally, we focus to explore potential risk factors that could impact the disease control rate and patient survival rate. We present this article in accordance with the STROBE reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-24-1/rc).
Methods
From 2010 to 2020, we conducted a retrospective study at Chung Shan Medical University Hospital, including patients who were diagnosed with pathologically confirmed SEOC after undergoing surgery. The clinical data and follow-up information of these patients were collected from the hospital’s medical records and cancer database.
To ensure the accuracy of our study, we sought the expertise of two experienced obstetrical and gynecological pathologists who carefully reviewed the pathology reports of all SEOC patients in our hospital. Patients with pathologically confirmed uterine or ovarian metastases were excluded from the study, allowing us to focus specifically on primary SEOC cases.
Among the cohort of patients who underwent surgery, a total of 24 individuals were diagnosed with synchronous endometrial cancer and ovarian cancer. After excluding patients with metastatic disease, a subgroup of 19 patients with primary SEOC was included for subsequent follow-up and statistical analysis.
The staging of endometrial and ovarian cancer in this study adhered to internationally recognized guidelines established by the International Federation of Gynecology and Obstetrics (FIGO 2009, 2018 edition) and the American Joint Committee on Cancer (AJCC 6th, 7th, 8th edition). The study incorporated comprehensive data on several critical clinical parameters, including age at diagnosis, histology, grade, depth of myometrium invasion, lymph node involvement, disease recurrence, and patient survival.
Statistical analysis
The distribution of patients’ clinical characteristics was presented as mean for continuous variables (e.g., age at cancer diagnosis) and frequency (proportion) for nominal variables [e.g., histological type, grade, pathological tumor-node-metastasis (TNM) stage, FIGO stage, and cancer treatment]. The Kaplan-Meier (KM) procedures were utilized to estimate the cumulative probabilities (95% confidence interval) of mortality and cancer recurrence at 1-, 3-, and 10-year intervals following cancer diagnosis (7). The KM curves were stratified based on age, histological type of endometrial cancer or ovarian cancer, and FIGO stage of endometrial cancer or ovarian cancer. The log-rank test was used to evaluate the differences in KM curves among the stratified characteristics. The type 1 error was set at 0.05, and statistical analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) software.
Ethical considerations
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and approved by the Institutional Review Board of the Chung Shan Medical University Hospital (CSMUH Number: CS1-23150). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Results
A total of 19 patients were diagnosed with primary SEOC, with ages at initial diagnosis ranging from 38 to 83 years, and a mean age of 54.58 years. Among them, 12 individuals (63.2%) were below the age of 55 years, while 7 individuals (36.8%) were aged 55 years or above. Table 1 presents the pathological characteristics and stages of endometrial cancer, while Table 2 provides the corresponding information for ovarian cancer.
Table 1
| Characteristics | N (%) |
|---|---|
| Histological type | |
| Endometroid adenocarcinoma | 18 (94.7) |
| Adenocarcinoma† | 1 (5.3) |
| Grade | |
| 1 | 2 (10.5) |
| 2 | 15 (78.9) |
| 3 | 2 (10.5) |
| T stage | |
| 1a | 12 (63.2) |
| 1b | 1 (5.3) |
| 2 | 4 (21.1) |
| 3a | 2 (10.5) |
| N stage | |
| 0 | 14 (73.7) |
| 1a | 1 (5.3) |
| 2a | 1 (5.3) |
| Unknown | 3 (15.8) |
| M stage | |
| 0 | 19 (100.0) |
| FIGO stage | |
| I–II | 16 (84.2) |
| III–IV | 3 (15.8) |
†, the pathology report provided a description ‘adenocarcinoma’ with no precise histotype. FIGO, International Federation of Gynecology and Obstetrics.
Table 2
| Characteristics | N (%) |
|---|---|
| Histological type | |
| Endometroid adenocarcinoma | 11 (57.9) |
| Other types† | 8 (42.1) |
| Grade | |
| I | 12 (63.2) |
| II | 4 (21.1) |
| III | 1 (5.3) |
| Unknown | 2 (10.5) |
| T stage | |
| 1a | 8 (42.1) |
| 1b | 1 (5.3) |
| 1c | 3 (15.8) |
| 2b | 1 (5.3) |
| 3b | 2 (10.5) |
| 3c | 4 (21.1) |
| N stage | |
| 0 | 15 (78.9) |
| 1 | 1 (5.3) |
| Unknown | 3 (15.8) |
| M stage | |
| 0 | 19 (100.0) |
| FIGO stage | |
| I–II | 11 (57.9) |
| III–IV | 8 (42.1) |
†, including undifferentiable carcinoma, serous adenocarcinoma, granulosa cell tumor, carcinosarcoma, mucinous carcinoma, thecoma and endometroid adenocarcinoma, serous mucinous broadline tumor with micro invasion. FIGO, International Federation of Gynecology and Obstetrics.
In the cohort of 19 patients diagnosed with endometrial cancer, the majority (18 cases) were identified as having endometrioid adenocarcinoma. Among these cases, 15 demonstrated a differentiation grade of 2. Lymph node involvement was detected in two cases, while the lymph node status remained unclear for three cases. Based on the FIGO staging system, 16 patients were classified as stage I–II, while 3 patients were categorized as stage III–IV.
Regarding patients with ovarian cancer, endometrioid adenocarcinoma also constituted the predominant histological subtype, accounting for 11 cases. Among these cases, 12 exhibited a differentiation grade of 1. Lymph node involvement was observed in one case, while the lymph node status remained unclear for three cases. According to the FIGO staging system, 11 patients were categorized as stage I–II, while 8 patients fell into stage III–IV.
All patients underwent complete surgical resection as the primary treatment modality, and their postoperative diagnoses were confirmed by two dedicated pathologists. Following the surgery, 16 patients received adjuvant chemotherapy as part of their postoperative treatment plan, while only two patients received additional adjuvant pelvic radiation therapy to target the pelvic region.
The 19 study subjects were followed up from the time of cancer diagnosis until December 2022. During the follow-up period, 9 cases experienced disease recurrence, and 6 cases resulted in mortality. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 58.2% and 69.86%, respectively. The 10-year PFS and OS rates were 41.18% and 55.89%, respectively (Figure 1).
In further exploring potential factors that may influence patient outcomes, we conducted subgroup analyses based on several variables. These variables included the patient’s age at diagnosis, histological subtypes (specifically endometrioid adenocarcinoma type and other types), grade type, FIGO stage at diagnosis for endometrial cancer, FIGO stage at diagnosis for ovarian cancer, lymph node involvement status, postoperative adjuvant chemotherapy, and postoperative adjuvant radiation therapy. These analyses aimed to examine the impact of these factors on patient prognosis and identify any associations or correlations.
In our analysis of these factors, we found that among the variables examined, only the FIGO stage at diagnosis for ovarian cancer showed statistically significant differences in patient outcomes. Our study observed that among the 19 patients with SEOC, those in FIGO stage I–II (11 patients) had significantly better OS compared to those in FIGO stage III–IV (8 patients), with a P value of 0.002. This indicates that the FIGO stage at diagnosis for ovarian cancer is a significant prognostic factor for patient outcomes in our study cohort (Figure 2).
Discussion
Prognosis
Despite SEOC’s established diagnostic criteria, there remains a lack of comprehensive treatment guidelines akin to other cancers. Most current research involves retrospective studies (8). A notable analysis by the GOG study in 2001 evaluated 74 patients from 1985 to 1991 (5). These patients primarily underwent surgical procedures, with radiation and chemotherapy decisions based on physician and patient preferences. The study showed a 5-year survival rate of 85.9% and a 10-year rate of 80.3%. It highlighted a favorable prognosis, especially when the disease was limited to the uterus and ovary or had milder histological grades.
In 2004, researchers from the M.D. Anderson Cancer Center analyzed 84 synchronous cases (3). It found that younger, premenopausal, obese, and nulliparous patients frequently had concurrent endometrioid histology in both the endometrium and ovary, hinting at a hormonal link to synchronous endometrioid malignancies. The research also indicated that these patients had a better prognosis and survival rates than those with different histological profiles. Furthermore, an early-stage ovarian malignancy diagnosis led to better outcomes compared to advanced stages, an observation consistent with our clinical experiences. Several retrospective studies with over 50 participants each consistently report similar therapeutic outcomes (9-11).
Adjuvant radiotherapy or chemotherapy
A 2007 study by Signorelli (9), involving 93 patients, highlighted a 5-year disease-free survival rate of 83% and an OS rate of 96%. The data emphasized the significance of detecting SEOC in younger women, attributed to their favorable pathology, resulting in outstanding oncological outcomes. Of these patients, 44 underwent postoperative mono-therapy, 15 had combination chemotherapy, and 12 received adjuvant radiotherapy. The study stressed the role of thorough postoperative evaluation in directing subsequent therapeutic choices.
Utilizing the Surveillance Epidemiology, and End Results (SEER) database, Williams et al. (12) from 1973 to 2005 assessed 56,986 cases of epithelial ovarian cancer, identifying 1,355 as SEOC. Notably, under 3% of these cases presented with coexisting ovarian and endometrial malignancies. Patients with concurrent tumors exhibited a 25% mortality risk reduction compared to isolated ovarian cancer cases. Surgical intervention was predominant at 82.2%, with an additional 15.7% incorporating radiation therapy. In 2022, Dood and co-workers further analyzed SEOC cases from the SEER database for years 2004 to 2015 (13). The investigation contrasted mortality rates between 937 patients with simultaneous stage I uterine and ovarian malignancies and those with distinct endometrial or ovarian cancers. Cohorts with coexisting stage I tumors demonstrated superior survival outcomes, with hazard ratios of 0.74 against isolated stage I uterine cancer and 0.52 against exclusive stage I ovarian cancer. Of those subjected to adjuvant therapies post-diagnosis, 54.6% underwent treatment protocols, including chemotherapy (44.1%), radiation (3.9%), or a combination thereof (6.6%). Despite the vast patient data, determining the direction of adjuvant therapy utilization remains ambiguous.
Molecular and genetic medicine
When exploring SEOC in depth, its association with Lynch Syndrome is crucial. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is a genetic predisposition that increases an individual’s susceptibility to certain cancers. While people with Lynch syndrome mainly face heightened risks for colorectal and endometrial cancers, the syndrome also boosts the likelihood of tumors in the stomach, ovaries, bladder, small intestine, liver, kidneys, and other sites (14,15).
With rapid advancements in molecular and genetic medicine, more research is focusing on using genetic anomalies to refine therapeutic strategies for SEOC. A comprehensive clinic pathological and molecular exploration utilizing next-generation sequencing (NGS) performed by Hájková et al. (16) detected several genetic perturbations affiliated with SEOC. This includes alterations in pivotal genes like PTEN, ARID1A, AKT1, PIK3CA, POLE, TP53, BRCA1, BRCA2, MLH1, MLH3, and MSH6. Such revelations emphasize that a streamlined gene panel within NGS assessments can play a pivotal role in elucidating the clonal associations amidst coexisting uterine and ovarian neoplasms. A deep understanding of these tumors’ molecular aspects gives clinicians and researchers vital insights into their origin, progression, and potential treatments.
Regarding SEOC research, Ishikawa et al. identified a notable occurrence of POLE mutations (17). If a link between POLE mutations and tumor mutation burden is established—particularly when this correlation hints at a favorable prognosis—it could enhance the effectiveness of checkpoint blockade immunotherapies. Building on this, teams of both Anglesio and Schultheis (18,19) observed that SEOC tumor evaluations often show a strong clonal similarity.
Important mention
In light of these therapeutic insights and supporting data, FIGO introduced an updated staging system for endometrial cancer in June 2023 (20). This initiative aims to provide a detailed demarcation of the prognosis landscape for endometrial carcinoma, while offering clear guidelines for tailored surgical, radiological, and systemic treatments. According to this new classification, stage IA3 describes low-grade endometrioid carcinomas confined to the uterus, which coexist with a low-grade endometrioid presentation in the ovaries. This updated system emphasizes that early stages and low-grade SEOCs typically suggest a better prognosis and might reduce the necessity for aggressive adjuvant treatments.
Limitation
This investigation employed a retrospective data analysis methodology focused on a single institution, rather than adopting a prospective study design. Despite incorporating a decade-long follow-up period, the limited sample size precluded the generation of robust conclusions and definitive treatment recommendations.
Conclusions
This retrospective study aimed to investigate the clinical-pathological features and survival status of patients with SEOC over a decade. Furthermore, it explored potential risk factors that might affect disease control rates and patient survival. Compared with other studies, although a limited number of patients is a constraint of our research, our findings remained consistent. We determined that the FIGO staging of ovarian cancer plays a critical role in patient prognosis. Patients in early stages (stage I–II) demonstrated a better OS rate compared to those in advanced stages (stage III–IV).
Molecular and genetic medical research has unveiled multiple gene mutations associated with SEOC, offering new insights into its biological characteristics and potential therapeutic targets. After confirming the treatment direction for patients at low risk based on FIGO staging, we hope that future research can assist in determining the need for adjuvant radiation therapy or systemic treatments for high-risk patients.
Acknowledgments
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-24-1/rc
Data Sharing Statement: Available at https://tro.amegroups.com/article/view/10.21037/tro-24-1/dss
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-24-1/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and approved by the Institutional Review Board of the Chung Shan Medical University Hospital (CSMUH Number: CS1-23150). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Ulbright TM, Roth LM. Metastatic and independent cancers of the endometrium and ovary: a clinicopathologic study of 34 cases. Hum Pathol 1985;16:28-34. [Crossref] [PubMed]
- Scully RE, Young RH, Clement PB. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. Bethesda: American Registry of Pathology; 1998.
- Soliman PT, Slomovitz BM, Broaddus RR, et al. Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases. Gynecol Oncol 2004;94:456-62. [Crossref] [PubMed]
- Shin W, Park SY, Kang S, et al. How to manage synchronous endometrial and ovarian cancer patients? BMC Cancer 2021;21:489. [Crossref] [PubMed]
- Zaino R, Whitney C, Brady MF, et al. Simultaneously detected endometrial and ovarian carcinomas--a prospective clinicopathologic study of 74 cases: a gynecologic oncology group study. Gynecol Oncol 2001;83:355-62. [Crossref] [PubMed]
- Montoya F, Martin M, Schneider J, et al. Simultaneous appearance of ovarian and endometrial carcinoma: a therapeutic challenge. Eur J Gynaecol Oncol 1989;10:135-9. [PubMed]
- Penman AD, Johnson WD. A SAS program for calculating cumulative incidence of events (with confidence limits) and number at risk at specified time intervals with partially censored data. Comput Methods Programs Biomed 2008;89:50-5. [Crossref] [PubMed]
- Dogan A, Schultheis B, Rezniczek GA, et al. Synchronous Endometrial and Ovarian Cancer in Young Women: Case Report and Review of the Literature. Anticancer Res 2017;37:969-78. [Crossref] [PubMed]
- Signorelli M, Fruscio R, Lissoni AA, et al. Synchronous early-stage endometrial and ovarian cancer. Int J Gynaecol Obstet 2008;102:34-8. [Crossref] [PubMed]
- Oranratanaphan S, Manchana T, Sirisabya N. Clinicopathologic variables and survival comparison of patients with synchronous endometrial and ovarian cancers versus primary endometrial cancer with ovarian metastasis. Asian Pac J Cancer Prev 2008;9:403-7. [PubMed]
- Song T, Seong SJ, Bae DS, et al. Synchronous primary cancers of the endometrium and ovary in young women: a Korean Gynecologic Oncology Group Study. Gynecol Oncol 2013;131:624-8. [Crossref] [PubMed]
- Williams MG, Bandera EV, Demissie K, et al. Synchronous primary ovarian and endometrial cancers: a population-based assessment of survival. Obstet Gynecol 2009;113:783-9. [Crossref] [PubMed]
- Dood RL, Pappas LM, Collin LJ, et al. Mortality Patterns of Synchronous Uterine and Ovarian Cancers: A SEER Registry Analysis. Cancer Epidemiol Biomarkers Prev 2022;31:2038-45. [Crossref] [PubMed]
- Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919-32. [Crossref] [PubMed]
- Lynch HT, Lynch JF, Lynch PM, et al. Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management. Fam Cancer 2008;7:27-39. [Crossref] [PubMed]
- Hájková N, Tichá I, Hojný J, et al. Synchronous endometrioid endometrial and ovarian carcinomas are biologically related: A clinico-pathological and molecular (next generation sequencing) study of 22 cases. Oncol Lett 2019;17:2207-14. [PubMed]
- Ishikawa M, Nakayama K, Nakamura K, et al. High frequency of POLE mutations in synchronous endometrial and ovarian carcinoma. Hum Pathol 2019;85:92-100. [Crossref] [PubMed]
- Anglesio MS, Wang YK, Maassen M, et al. Synchronous Endometrial and Ovarian Carcinomas: Evidence of Clonality. J Natl Cancer Inst 2016;108:djv428. [Crossref] [PubMed]
- Schultheis AM, Ng CK, De Filippo MR, et al. Massively Parallel Sequencing-Based Clonality Analysis of Synchronous Endometrioid Endometrial and Ovarian Carcinomas. J Natl Cancer Inst 2016;108:djv427. [Crossref] [PubMed]
- Berek JS, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 2023;162:383-94. [Crossref] [PubMed]
Cite this article as: Hwang YT, Chen GD, Chou YH, Tseng HC, Chen HL, Chang BJ, Lee YC, Chang ST. Primary synchronous cancers of the endometrium and ovary: 10-year treatment experience. Ther Radiol Oncol 2024;8:5.
