Low-grade serous ovarian cancer (LGSOC) is a rare, distinct subtype of epithelial ovarian cancer, accounting for 2-5% of all epithelial ovarian malignancies and 4-5% of serous tumors globally (1-3). LGSOC predominantly affects women at a slightly younger median age than that associated with high-grade serous ovarian cancer, with median ages at diagnosis being 54-56 years globally, compared with ~62 years in high-grade disease (3-6).

LGSOC is characterized by indolent clinical behavior, slow progression and markedly prolonged survival times compared with high-grade serous ovarian cancer, as well as minimal responsiveness to conventional cytotoxic chemotherapy (1,5,6). The hallmark histopathological features of LGSOC include mild-to-moderate nuclear atypia and low mitotic activity (<12 mitoses per 10 high-power fields). These diagnostic criteria are consistent with the 2020 World Health Organization (WHO) Classification of Female Genital Tumors (7). Microscopically, LGSOC often shows cuboidal or columnar cells with amphophilic cytoplasm and frequent psammoma bodies, and is associated with borderline serous tumors, supporting the hypothesis of a stepwise progression from benign or borderline lesions (1,2).

Despite the slower progression and distinct tumor biology compared with high-grade serous ovarian cancer, LGSOC often presents at advanced stages, and optimal cytoreductive surgery remains the cornerstone of initial treatment because the volume of residual disease is the most meaningful predictor of survival (1,2,5). Platinum-based chemotherapy is the standard adjuvant therapy but shows limited efficacy; therefore, hormonal maintenance therapy and targeted agents are increasingly used (8). Epidemiological data from Indonesia mirror global patterns, with the majority of patients with LGSOC presenting in their mid-50s, similar to trends observed in international cohorts (3-6), and a high proportion of diagnoses at advanced International Federation of Gynecology and Obstetrics (FIGO) stages (9). Survival outcomes are heavily influenced by the stage at diagnosis and surgical success, highlighting the universal need for improved early detection, refined surgical strategies and expanded access to innovative therapies (1,2,9).

Given the rarity of LGSOC, conducting robust clinical research and accumulating sufficient patient data through single-center studies presents substantial challenges. The limited patient population and geographical dispersion necessitate collaborative efforts to gain meaningful insights into the natural history, molecular characteristics and optimal treatment approaches of the disease. Therefore, multicenter studies involving multiple institutions and research groups are key to overcoming the limitations of small sample sizes inherent to rare types of cancer. Moreover, this approach allows for comprehensive analyses of clinical outcomes, identification of prognostic factors and the development of novel therapies (4). This collaborative paradigm is essential for advancing the understanding of LGSOC and ultimately improving patient care for this challenging disease.

To date, a comprehensive LGSOC profile has not been established in Indonesia. In low- and middle-income countries (LMICs), challenges such as delayed referral from primary care facilities, unequal access to advanced imaging, variability in surgical expertise and the absence of robust national cancer registries may substantially influence stage at diagnosis and treatment outcomes. Consequently, real-world data from LMIC settings are essential to understand how systemic healthcare factors interact with tumor biology and surgical management in shaping patient prognosis. To the best of our knowledge, the present study represents the first multicenter analysis of LGSOC in Indonesia and includes one of the largest cohorts reported in an LMIC setting. The present study aimed to characterize the clinicopathological features, surgical outcomes and recurrence patterns in this cohort within a diverse national referral network.

The present multicenter study reports, to the best of our knowledge, the first comprehensive overview of LGSOC in Indonesia including one of the largest cohorts reported from an LMIC. The findings confirm several established characteristics of LGSOC, including its occurrence in a relatively younger population in this setting and the substantial proportion of advanced-stage presentation. In this cohort, residual disease after surgery and advanced FIGO stage demonstrated the strongest unadjusted associations with recurrence and survival outcomes.

Compared with international cohorts, the studied Indonesian population demonstrated several distinct characteristics. The median age at diagnosis (45.5 years) was approximately a decade younger than the median of 54-56 years reported in Western and East Asian studies (3-6), suggesting potential demographic or referral differences within Indonesia, such as earlier onset or differences in health-seeking behavior. Despite the younger age, the proportion of patients diagnosed at advanced stages (III-IV; 50%) was comparable to global data, indicating that delays in presentation and diagnosis remain a universal challenge (10,11). Obesity and elevated CA-125 levels were common findings that paralleled those of other recent cohorts, highlighting their relevance as risk and prognostic factors (10,12). The overall rate of optimal cytoreduction (72.5%) was slightly higher when compared with several large single-center series (40-50%) (1,13), which may reflect differences in stage composition and the surgical focus of tertiary referral hospitals participating in the present study. Collectively, these observations illustrate how patient demographics, health-system factors and surgical centralization shape outcomes in an LMIC context. This younger median age may reflect Indonesia's population structure, which is demographically younger than the populations of several Western countries, as well as referral dynamics in which symptomatic younger patients are more likely to reach tertiary centers. Biological variation cannot be excluded; however, health-system factors likely have a substantial effect on the observed differences between the findings of the present study and those of previous reports.

Notably, optimal cytoreductive surgery was achieved in 72.5% of cases, which is higher when compared with the rates reported in several single-center series (40-50%) (1). Although the definition of optimal cytoreduction required complete macroscopic clearance (no visible residual disease), the relatively high R0 rate is most plausibly explained by the inclusion of a substantial proportion of early-stage cases (50%) rather than superior surgical aggressiveness alone. Therefore, comparisons with cohorts composed predominantly of advanced-stage disease should be interpreted cautiously. Moreover, a direct comparison should consider differences in patient composition; 50% of the present cohort consisted of early-stage (I-II) disease, whereas several prior studies included predominantly advanced-stage cases (III-IV) (14,15). In addition, the definition of optimal cytoreduction required complete macroscopic clearance (no visible residual disease), compared with the <1 cm residual threshold used in several international reports (16,17). Although the present study adopted a stricter definition of optimal cytoreduction, the relatively high rate of optimal surgery (72.5%) is more plausibly explained by the inclusion of a large proportion of early-stage cases (50%) rather than by the definitional criterion itself. This emphasizes the importance of considering stage distribution when comparing surgical outcomes across studies. Schmeler and Gershenson (18) reported optimal cytoreduction in 40-50% of LGSOC cases using the <1 cm residual threshold, highlighting the uniqueness of the present findings under a strict definition. This is important because numerous studies have confirmed surgical completeness as the principal prognostic factor for LGSOC, overshadowing the modest impact of adjuvant chemotherapy owing to inherent chemoresistance in the tumor (11,13). The observed adoption of adjuvant chemotherapy (74.4%) fits with still-evolving standards; however, recent meta-analyses suggest that chemotherapy has limited benefits in LGSOC, with hormonal or targeted therapies emerging as promising alternatives (8,13). The acceptance and utilization of hormone maintenance therapy remained limited in the present cohort, suggesting an area for improvement in clinical practice according to updated global guidelines (1,13).

The most statistically significant predictors of recurrence and survival in the present cohort were residual disease after surgery and the FIGO stage at diagnosis, which mirrors the conclusions of recent global and multicenter studies (1,11,13). The present data showed that patients with advanced-stage disease were more likely to exhibit suboptimal debulking and worse survival than patients with early-stage disease, a relationship confirmed in major registries and surveillance, epidemiology and end results studies (11). These findings reinforce the interpretation that, unlike high-grade serous ovarian cancer, survival in LGSOC is more sensitive to the initial quality of surgical cytoreduction than to systemic therapy (1,13).

These findings were further supported by time-to-event analyses. KM curves demonstrated significantly worse OS among patients with advanced FIGO stage, omental metastasis, peritoneal carcinomatosis, ascites, residual disease and recurrence. In univariate Cox regression, these variables were significantly associated with an increased risk of mortality, with residual disease (HR, 7.93) and recurrence (HR, 10.06) demonstrating the strongest effects. In multivariate analysis, only residual disease remained an independent predictor of OS (adjusted HR, 5.59; 95% CI, 1.44-21.66; P=0.013), whereas FIGO stage lost statistical significance after adjustment. This finding suggests that the prognostic impact of disease stage may be partially mediated through surgical outcomes, reinforcing the key importance of complete cytoreduction in LGSOC (19).

A high CA-125 level at diagnosis, which was present in 70.6% of cases, is also a recognized independent prognostic factor of tumor burden and aggressiveness. However, its specific impact on OS may be less than that of stage or surgical success (11). Tumor size was not significantly associated with tumor stage or outcome in the present cohort, which agrees with recent reports highlighting the prognostic importance of residual mass and disease stage (1,11). Unlike some international studies that classify residual disease according to size (<1 cm vs. ≥1 cm), the present dataset only distinguished between ‘no visible disease’ and ‘any visible residual disease’. This may partially explain the high rates of optimal cytoreduction. Nevertheless, interpretation of CA-125 findings should be cautious owing to the incomplete documentation in a subset of patients, which may introduce residual selection bias.

Emerging literature from the past 5 years also highlights the relevance of molecular targeted therapies, particularly the use of MEK inhibitors for MAPK pathway mutations, as superior or adjunctive options to chemotherapy in recurrent or refractory settings (1,8,13). The incorporation of precision medicine remains rare in LMIC, including the present population, but warrants advocacy in tumor board decision making.

In the present cohort, the recurrence rate was 10, and 92.5% of patients were alive at the final follow-up point. However, the median follow-up duration of 24 months is relatively short for an indolent malignancy such as LGSOC, for which late recurrences are well documented. Consequently, the reported recurrence rate likely underestimates the true long-term recurrence burden in this population, and extended follow-up is necessary for more definitive survival assessment. Published international data have reported 5-year OS rates of 59-89%, depending on the stage and extent of cytoreduction (10,11,13). These findings collectively confirm that long-term outcomes in LGSOC are primarily driven by disease stage and surgical completeness. Patients with early-stage disease universally show good outcomes, highlighting the key importance of prompt diagnosis and aggressive surgery.

The present findings concur with the latest global evidence that achieving optimal cytoreductive surgery at the earliest stage is paramount for favorable outcomes in patients with LGSOC (20). Adjuvant chemotherapy, although common, provides limited benefits; thus, greater emphasis should be placed on potential hormone-based and targeted regimens, as supported by emerging evidence. Continued research, increased access to molecular diagnostics and adherence to consensus guidelines are required to improve the prognosis of patients with LGSOC, particularly in LMICs. Because follow-up durations varied across centers, long-term survival analysis was not feasible; nonetheless, the observed survival rate at the last follow-up supports the generally favorable prognosis of LGSOC.

Beyond reflecting global patterns, the present findings also highlight several features unique to the Indonesian population. Patients in this cohort were diagnosed nearly a decade earlier than international averages, and the study encompassed nine tertiary hospitals across seven provinces, representing a multiethnic population and variable access to oncology services. Such diversity reflects the real-world complexity of cancer care in Indonesia, an archipelagic nation where geographic distance and unequal referral systems can influence the stage at diagnosis and surgical outcomes.

Structural limitations within the healthcare system likely contribute to these disparities. The distribution of obstetricians and gynecologists remains uneven, with workforce shortages and a tendency to concentrate in densely populated regions, leaving a proportion of hospitals without adequate specialist coverage (21). Moreover, the presence of specialists alone does not ensure access to high-quality oncological care, as resource constraints, limited availability of advanced therapies and gaps in training may hinder optimal management (22). These challenges are further compounded by the scarcity and geographic concentration of gynecological oncologists, with only 139 specialists nationwide and the majority located in Java, resulting in substantial barriers to timely diagnosis and treatment, particularly in remote regions (23).

Within the national health insurance system of Indonesia, the tiered referral pathway may also contribute to delays in diagnosis and treatment, creating a cascade of care that disproportionately affects rare malignancies such as LGSOC, which may remain underdiagnosed and present at more advanced stages. Collectively, these findings underscore the importance of strengthening specialist distribution, referral systems and oncology infrastructure to improve equitable cancer care delivery in LMIC settings.

The present study has several limitations. Ethnicity and geographic distance to referral centers were not captured in this dataset; however, given the multiethnic composition and wide geographic distribution of Indonesia, these factors are expected to contribute to variations in the stage at diagnosis and treatment access. Formal analyses of OS and disease-free survival could not be performed because of variability and incompleteness in follow-up documentation across centers, a common limitation in multicenter retrospective studies. First, as a retrospective analysis relying on heterogeneous electronic medical records across multiple centers in Indonesia, certain variables such as BMI, CA-125 levels and tumor size were incompletely documented. In addition, the limited number of recurrence (n=16) and mortality events (n=12) constrained the statistical power of survival analyses and restricted the complexity of multivariate modeling.

Despite these limitations, KM survival analysis with log-rank testing and Cox proportional hazards regression were performed to explore survival patterns and estimate effect sizes. Given the small number of events, the multivariate model was intentionally restricted to a limited number of clinically relevant covariates to reduce the risk of overfitting; therefore, the findings should be interpreted as exploratory rather than definitive independent predictors.

Molecular profiling data, including KRAS, BRAF and NRAS mutation status as well as hormone receptor expression, were unavailable in this retrospective cohort. Given that 40-50% of LGSOC tumors harbor MAPK pathway alterations, the absence of molecular characterization limited the assessment of eligibility for targeted therapies such as MEK inhibitors. Future prospective registries incorporating molecular data will be essential to align national management strategies with contemporary precision oncology approaches.

Future research should prioritize improving the quality and completeness of clinical documentation and establishing a national ovarian cancer registry in Indonesia. These efforts would enable robust survival analyses, support evaluation of treatment patterns and facilitate the integration of molecular and genomic data. In addition, such infrastructure would allow meaningful collaboration with international datasets, enabling comparative analyses of surgical outcomes, referral patterns and treatment effectiveness across different healthcare settings.

From a clinical perspective, strengthening the centralization of cytoreductive surgery in high-volume gynecological oncology centers is essential to improve surgical outcomes. The development of structured referral pathways from secondary and district hospitals may reduce delays in treatment and increase the likelihood of optimal cytoreduction. Expanding access to hormonal and targeted therapies, including MEK inhibitors, should also be prioritized to improve outcomes in patients with LGSOC.

From a policy standpoint, these findings support national strategies aimed at improving early detection and timely referral. Public awareness initiatives targeting persistent abdominal symptoms may contribute to earlier diagnosis and reduce the proportion of patients presenting with advanced-stage disease. Collectively, these efforts highlight the importance of coordinated clinical, research and policy approaches to improve outcomes for patients with LGSOC in resource-limited settings.

In conclusion, the present large multicenter Indonesian cohort study revealed that the ability to achieve complete surgical cytoreduction without residual disease was the most potent predictor of favorable outcomes. The present findings advocate for national health strategies focused on improving early detection and ensuring that patients with LGSOC are managed in specialized centers with the surgical expertise required to maximize their chances of optimal surgical outcomes.