Low-grade serous ovarian carcinoma (LGSOC) is a rare, indolent ovarian cancer subtype with limited effective therapies. Approximately 40% of cases lack canonical MAPK/ERK or PI3K/AKT/mTOR pathway alterations and are classified as having no specific molecular profile (NSMP). These patients have poor responses to chemotherapy, MEK inhibitors, and hormonal therapies, highlighting the need for alternative strategies. This study aimed to identify novel therapeutic targets in NSMP LGSOC. A high-throughput drug screen of 3,436 compounds (including FDA-approved, clinically tested, and investigational agents) was conducted across 12 LGSOC and one control ovarian epithelial cell line. EGFR inhibitors emerged as selective hits in NSMP cell lines and were further tested in two NSMP and two MAPK-mutant lines in combination with standard-of-care chemotherapy agents, carboplatin and paclitaxel. EGFR expression was assessed using RNA sequencing, DNA methylation profiling, and immunohistochemistry in primary tumors, followed by survival analysis based on expression levels. Unsupervised clustering of drug response data revealed subtype-specific vulnerabilities, with EGFR inhibitors showing marked cytotoxicity in all five NSMP lines (robust Z-score ≤ -2), and minimal activity in MAPK- and USP9X-mutant lines. EGFR inhibitors (avitinib, AV-412) showed selective, low-dose synergy with standard-of-care chemotherapy in NSMP models, with minimal and inconsistent effects in MAPK-mutant lines. NSMP tumors showed elevated EGFR mRNA and EGFR protein expression, associated with poor survival, advanced disease stage, and peritoneal involvement, and inversely correlated with MAPK mutations. These findings position EGFR overexpression as a defining and targetable feature of NSMP LGSOC and support further preclinical validation of EGFR inhibitors as a treatment strategy for this understudied cancer subtype. © 2026 The Pathological Society of Great Britain and Ireland.

The combination of avutometinib (a rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase [RAF/MEK] inhibitor) and defactinib (a focal adhesion kinase [FAK] inhibitor) demonstrated meaningful efficacy and tolerability in recurrent KRAS-mutated low-grade serous ovarian carcinoma, as evidenced by clinically meaningful response rates and manageable adverse events. Avutometinib plus defactinib is a new, individualized treatment option for recurrent KRAS-mutated low-grade serous ovarian carcinoma. The evidence supporting these agents highlights their potential to address the unique therapeutic needs of this patient population, offering an option tailored to molecular characteristics and disease recurrence. Avutometinib plus defactinib represents a significant advancement in the management of recurrent KRAS-mutated low-grade serous ovarian carcinoma, leading to US Food and Drug Administration accelerated approval and inclusion in the National Comprehensive Cancer Network guidelines as a Category 2A recommendation for this patient population. This literature review summarizes the pharmacology of avutometinib and defactinib and the clinical trial data supporting the combination's approval. The authors discuss adverse event management and the implications for integration into routine clinical practice. Clinicians caring for patients with low-grade serous ovarian carcinoma can use the drug knowledge and evidence outlined in this review to assist with implementing avutometinib and defactinib therapy.

Despite advancements in maintenance therapies, recurrent epithelial ovarian cancer remains a clinical challenge with varying outcomes. This study aimed to evaluate the clinicopathological status and prognostic factors of patients with recurrent epithelial ovarian cancer. We conducted a retrospective survey through the Committee on Gynecologic Oncology of the Japan Society of Gynecology and Obstetrics across 16 institutions. Histological subtypes included high-grade serous (HGS; n = 304), clear-cell (CC; n = 83), endometrioid (EM; n = 35), mucinous (n = 12), and low-grade serous (n = 9) carcinomas. At recurrence, the median age was 61 years, 74.0% of patients had a platinum-free interval (PFI) ≥ 6 months, and 78.8% maintained a performance status (PS) of 0. Genetic testing identified 42 BRCA1/2 mutations and 52 cases of homologous recombination deficiency positivity. Recurrence occurred primarily in the peritoneum, lymph nodes, and liver. For PFI ≥ 6 months, paclitaxel/carboplatin ± bevacizumab was the primary treatment; for PFI < 6 months, pegylated liposomal doxorubicin ± bevacizumab predominated. The overall response rate was 69.9% for PFI ≥ 6 months versus 17.7% for PFI < 6 months. Median overall survival was 27.9 months. Multivariate analysis confirmed histological subtype (CC/EM vs. HGS), PS, CA125 (≥ 100 U/mL), and PFI as significant independent prognostic factors, while first-line molecularly targeted therapy use showed no significant impact. PFI, histological subtype, PS, and CA125 levels are important prognostic factors for the use of molecular-targeted agents for recurrent epithelial ovarian cancer. Patients with CC and EM subtypes experience worse outcomes than those with HGS, highlighting the need for subtype-specific management in recurrent ovarian cancer.

Serous tumors of the testis and paratestis are rare neoplasms originating from Müllerian duct epithelium, exhibiting histological features analogous to their ovarian counterparts, predominantly manifesting as serous borderline tumors and low-grade serous carcinomas. Definitive diagnosis of these tumors requires histopathological examination and immunohistochemical profiles to confirm Müllerian differentiation. This study reports the first documented NRAS p.Q61R mutation as a likely pathogenic variant (Class II) and a BRCA2 variant of uncertain significance (Class III) in a tunica vaginalis micropapillary serous borderline tumor with microinvasive low-grade serous carcinoma. While NRAS mutations are infrequently observed in ovarian serous tumors, their presence in this context suggested potential shared oncogenic pathways between male and female Müllerian-type neoplasms. Notably, the NRAS p.Q61R variant was classified as Class II and may be associated with malignant progression from borderline tumors to invasive carcinoma. These findings underscore the need for long-term surveillance and molecular investigations to clarify tumor behavior, recurrence risks, and therapeutic targets in such rare entities.

Borderline ovarian tumors and low-grade serous carcinoma: A retrospective analysis from argentine and Uruguayan oncology centers.

High-Grade Serous Ovarian Carcinoma (HGSOC) and Low-Grade Serous Ovarian Carcinoma (LGSOC) are distinct subtypes of epithelial ovarian cancer with significant differences in pathogenesis and prognosis, posing challenges for precise diagnosis. Identifying reliable biomarkers is crucial for improving differential diagnosis and clinical management. Transcriptome RNA-seq data of HGSOC and LGSOC were obtained from the GEO database (GSE27651, GSE126132). Differentially expressed immune-related genes (DIRGs) were identified. Functional enrichment analysis and protein-protein interaction (PPI) network construction were performed. The Least Absolute Shrinkage and Selection Operator (LASSO) regression and multiple Support Vector Machine Recursive Feature Elimination (mSVM-RFE) algorithms were used to select predictive genes. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curves, and a nomogram was developed. Findings were validated in an independent dataset and via immunohistochemistry (IHC). The CIBERSORT algorithm assessed correlations between key DIRGs and tumor-infiltrating immune cells, with false discovery rate (FDR) correction applied for multiple testing. Seventy-one DIRGs were identified in HGSOC versus LGSOC, predominantly enriched in cytokine-mediated signaling, cytokine-cytokine receptor interaction, and JAK-STAT pathways. STAT1 and IL-7 were selected as diagnostic biomarkers, with area under the curve (AUC) values of 0.908 and 0.842 in the train group. Respectively, validation in an independent merged cohort (GSE14001, GSE73168, GSE146965; 55 HGSOC, 13 LGSOC) yielded AUCs of 0.703 (95% CI: 0.517-0.889) for STAT1 and 0.706 (95% CI: 0.501-0.912) for IL-7. IHC confirmed significantly higher STAT1 and lower IL-7 protein expression in HGSOC tissues (P < 0.05). Immune microenvironment analysis revealed that HGSOC exhibited significantly higher fractions of naïve B cells, M2 macrophages, and neutrophils, and lower fractions of resting memory CD4+ T cells and eosinophils after FDR correction (all q < 0.05). STAT1 expression was strongly positively correlated with M1 macrophages (ρ = 0.688, q = 9.9×10- 8), and showed correlation trends with other immune cell types that did not remain significant after FDR correction. IL-7 expression exhibited a negative correlation trend with neutrophils (ρ = -0.372, raw P=0.0048, q = 0.100). STAT1 and IL-7 are consistently differentially expressed between HGSOC and LGSOC and may serve as ancillary diagnostic biomarkers in histologically ambiguous cases. However, their clinical utility-particularly in multi-gene combinations-requires prospective validation.

Background/Objectives: Since non-invasive implants and invasive implants (metastases) are a key point of differentiation between serous borderline tumors (SBTs) and low-grade serous carcinoma (LGSC), the correct diagnosis of these two types of extraovarian lesions is crucial for patient treatment and prognosis. However, accurate diagnosis can be challenging even for experienced pathologists. The aim of this study was to evaluate interobserver agreement in the classification of these extraovarian lesions. Methods: Twenty-four cases of ovarian SBT and LGSC with 33 samples of non-invasive implants of SBT and metastasis of LGSC were independently reviewed by three gynecologic pathologists and three general pathologists. Diagnostic criteria included destructive invasion, micropapillary architecture, and retraction clefts. To measure interobserver agreement, Fleiss' kappa and Cohen's kappa were calculated, with consensus diagnoses determined by the majority of gynecologic pathologists. Results: According to the consensus, diagnosis 42.4% biopsies were classified as metastases of LGSC and 57.6% as non-invasive implants of SBT. Overall reproducibility was substantial (κ = 0.61). The agreement among gynecologic pathologists, as well as between gynecologic pathologists and the consensus (using leave-one-out reference), was substantial to near-perfect (κ = 0.745-0.821). General pathologists' agreement with the consensus was moderate (κ = 0.467-0.698). Agreement between general pathologists was also moderate, with κ values ranging from 0.413 to 0.518. The difference in pairwise agreement between the two groups was statistically significant, confirming that gynecologic pathologists outperformed general pathologists in classifying extraovarian lesions. Conclusions: The results showed that current diagnostic reproducibility remains suboptimal, particularly among general pathologists, underscoring the need for improved training and standardized criteria. Ultimately, a multidisciplinary approach combining morphological expertise, immunohistochemical validation and molecular stratification will be essential for optimizing diagnosis and treatment.

Folate receptor 1 (FOLR1) has recently become a well-accepted therapeutic target in advanced-stage cancers. In this study, the prevalence of FOLR1 expression across all types of gynecologic tumors was investigated and correlated with selected clinicopathologic features. A total of 306 gynecologic tumors from 304 patients were evaluated for FOLR1 expression by immunohistochemistry (IHC). A positive FOLR1 is defined as ≥75% of viable tumor cells with moderate to strong membrane staining. Of 306 tumors, 31 (10.1%) had positive FOLR1 tests; a large majority of these FOLR1-positive tumors were HGSCs (64.5%), followed by uterine serous carcinoma, poorly differentiated/high-grade carcinoma, ovarian endometrioid carcinoma, ovarian mixed carcinoma, ovarian low-grade serous carcinoma, and serous borderline tumor with cribriform and micropapillary features. FOLR1 overexpression correlated with positive PD-L1 expression (P=0.012), intact mismatch repair protein (MMR) expression (P=0.024), and positive ER expression (P=0.040). In endometrial tumors, positive FOLR1 expression was associated with poor histologic grade (P=0.019), larger tumor size (P=0.048), mutant p53 expression (P<0.001), and lower PR expression (P=0.015). Endometrial tumors with FOLR1 overexpression had a significantly higher rate of TP53 mutations (P=0.013), while all endometrial tumors with PTEN alterations were negative for FOLR1 (P=0.037). Overall, FOLR1 overexpression was associated with poor prognostic factors, such as advanced clinical stage, increased recurrence rate, higher pathologic T and N stage, poor histologic grade, larger tumor size, lymphovascular invasion, uterine serosa involvement, and shorter progression-free survival.

The current classification of ovarian seromucinous tumors is somewhat complex and may present challenges in routine diagnostic practice. In the fifth edition of the WHO classification, seromucinous carcinoma (SMC) is generally regarded as a subtype of endometrioid carcinoma (EC) because of its limited diagnostic reproducibility and evidence that most tumors meeting the morphologic criteria for SMC can be reassigned to EC or low-grade serous carcinoma (LGSC) with mucinous differentiation based on integrated morphologic, immunophenotypic, and genotypic analyses. However, SMC-like tumors reassigned to LGSC remain unaddressed in the current classification systems. Although seromucinous borderline tumor (SMBT) is generally regarded as a reproducible entity, diagnostic difficulties may arise in certain cases. We report the case of an 80-yr-old woman with a large multicystic ovarian tumor predominantly composed of serous cells with micropapillary architecture characteristic of a serous borderline tumor (SBT), admixed with Müllerian-type mucinous cells. The serous component showed diffuse and strong WT1 positivity, whereas the mucinous cells exhibited variable WT1 expression. Under the current WHO classification, this tumor is diagnosed as an SMBT because it fulfills the morphology-based criteria. However, the predominance of the serous component showing diffuse WT1 expression is unusual for this entity and raises the possibility that the tumor represents SBT with mucinous differentiation, a potential borderline malignant counterpart of LGSC with mucinous differentiation. This case suggests a potential diagnostic overlap between SMBT and SBT, underscoring the need for further accumulation of similar cases and integrated analyses to clarify whether such tumors may warrant distinction from typical SMBT.

Endometrioid borderline tumors (EBTs) and seromucinous borderline tumors (SMBTs) are rare ovarian neoplasms with distinct histologic features. However, the molecular profiles of EBTs and SMBTs remain incompletely characterized. We performed histologic evaluation and DNA/RNA next-generation sequencing (NGS) using a 1425-gene pan-cancer panel on 11 EBTs and 10 SMBTs to define their mutational landscapes, conduct cross-comparisons between EBTs and SMBTs, and evaluate both against established profiles of endometrioid carcinoma and low-grade serous carcinoma. Histologically, EBTs showed adenofibromatous (64%) or intracystic (36%) growth patterns, with morule formation in 36% of cases. Aberrant nuclear β-catenin expression was observed in 73% of EBTs, significantly higher than in SMBTs (0%, P=0.001). β-catenin abnormalities and morules were absent in SMBTs. 73% EBT and 60% SMBT were associated with endometriosis. Genetically, most EBTs harbored CTNNB1 mutations (73%) with additional alterations in KRAS (36%), ARID1A (27%), ATR (27%), KMT2D (27%), PIK3CA (18%), PIK3R1 (18%), PTEN (18%), AKT1 (18%), TP53 (18%), and several others (≤18%). In contrast, SMBTs lacked CTNNB1 mutations but frequently had KRAS (60%), BRAF (30%), PIK3CA (20%), PIK3R1(20%), PTEN (20%), ATM (20%), ZFHX3 (20%), AUTS2(20%), CIC (20%), FAT1(20%), and PLAT (20%) mutations, with 20% showing concurrent KRAS/PIK3CA mutations. Pathway analysis revealed predominant WNT/β-catenin signaling in EBTs versus RAS-MEK-ERK pathway alterations in SMBTs resembling the seromucinous variant of ovarian endometrioid carcinoma, with additional involvement of PI3K-PTEN-AKT-mTOR and SWI/SNF chromatin remodeling pathways in both. These findings demonstrate that EBTs and SMBTs possess distinct morphologic and molecular profiles, expanding the molecular characterization of early ovarian endometrioid-type neoplasms.

Low-grade serous ovarian carcinoma is a rare subtype of epithelial ovarian cancer, accounting for less than 10% of serous malignancies. Compared to high-grade serous ovarian carcinoma, it follows an indolent course, often affects younger women, and demonstrates resistance to conventional cytotoxic chemotherapy. Low-grade serous ovarian is characterized by recurrent MAPK pathway alterations (KRAS, BRAF, NRAS) and frequent expression of functional hormone receptors, supporting the rationale for targeted and endocrine strategies. Optimal management relies on complete surgical cytoreduction. Endocrine therapy has shown promise, particularly in maintenance settings, and is being investigated in frontline strategies. MEK inhibitors, especially trametinib and avutometinib in combination with defactinib, have recently demonstrated improved outcomes in recurrent disease, while new combination strategies are under active evaluation to overcome resistance mechanisms. Immunotherapy remains of limited efficacy, though biomarker-driven combinations are explored. Ongoing biomarker-guided trials are expected to refine treatment paradigms.

Assessment of survival and clinicopathologic characteristics associated with lymph node isolated tumor cells in epithelial ovarian cancer.

Ovarian cancer is a highly lethal gynecological malignancy with poor prognosis. Early diagnosis of ovarian cancer is crucial for improving patient survival rates. Ultrasound is currently the most used imaging modality for the detection of ovarian cancer. However, its diagnostic accuracy is limited, particularly in the early stages of the disease. Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for cancer diagnosis. In this study, we aimed to investigate the clinical value of ultrasound combined with ctDNA (mutations in: TP53, KRAS, and PIK3CA) in the early diagnosis of ovarian cancer. A total of 686 participants were enrolled, comprising 186 advanced symptomatic ovarian cancer patients, 16 histologically confirmed asymptomatic ovarian cancer patients, and 484 patients with benign ovarian lesions. Of the 202 ovarian cancer cases, 57.4% were high-grade serous carcinomas, followed by endometrioid (15.8%), clear cell (9.9%), mucinous (7.9%), and low-grade serous carcinomas (6.9%). All participants underwent standardized ultrasound examination and ctDNA analysis. Ultrasound characteristics were evaluated for morphological features including mass composition, border definition, and presence of ascites. Circulating tumor DNA was analyzed for mutations in TP53, KRAS, and PIK3CA genes. Diagnostic performance was assessed through sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) calculations for individual and combined detection methods. In asymptomatic ovarian cancer patients, ultrasonography revealed complex solid-cystic masses in 50.0% of cases and ascites in 43.75%, with 87.50% sensitivity and 94.33% specificity. Molecular analysis detected ctDNA mutations in 81.25% of asymptomatic cases, predominantly in TP53 (31.25%), KRAS (25.00%), and PIK3CA (25.00%). This analysis, which focused exclusively on these three genes, demonstrated 81.25% sensitivity and 97.46% specificity. The combined diagnostic approach significantly improved detection parameters (p < 0.001), with sensitivity increasing to 93.75%, specificity to 99.25%, PPV to 75.00%, and NPV to 99.85%. False-positive results decreased from 38 (ultrasound alone) and 17 (ctDNA alone) to 5 cases with the combined approach. Distinct mutation profiles were observed between cancer and benign groups, with only 15.91% of benign cases showing detectable ctDNA mutations. Our results suggest that ctDNA is a promising biomarker for the early detection of ovarian cancer, with higher sensitivity and specificity than ultrasound. The combination of ultrasound and ctDNA may provide a more accurate diagnostic strategy for the early detection of ovarian cancer. These findings may contribute to the development of novel noninvasive biomarkers for the early diagnosis of ovarian cancer.

Introduction. Ovarian cancer is characterized by high mortality. Despite available diagnostic and therapeutic methods, patient survival remains unsatisfactory, especially for high-grade tumors, necessitating the exploration of new molecular targets. Heat shock proteins Hsp27 and Hsp90, which regulate cellular stress and survival, are considered key factors in tumor progression. Objective. To conduct a comparative assessment of the immunohistochemical detection of Hsp27 and Hsp90 in high- and low-grade serous ovarian carcinomas with separate evaluation of the nuclear and cytoplasmic localization of the reaction. Material and methods. The prospective study (NCT04817501) included 58 patients with newly diagnosed ovarian cancer. Of these, serous cancer (FIGO stages I-IIIC) was verified in 49 patients: 36 HG cases and 13 LG cases. Paraffin-embedded tumor tissue blocks obtained before treatment were studied. The study material consisted of paraffin blocks from biopsy and surgical tumor specimens. The proportions of Hsp27- and Hsp90-positive cells in the tumor and stromal components were assessed by immunohistochemistry followed by digital analysis of scanned images (Aperio AT2, Leica; QuPath software). Results. Significant differences were revealed in the tumor component between the HG and LG groups. The proportion of Hsp27-positive tumor cells with cytoplasmic and nuclear localization of the immunohistochemical reaction was significantly higher in the HG group than in the LG group (p=0.02). No significant differences in Hsp90 were found between the groups in either the stromal or the tumor component. Conclusion. Differences in the immunohistochemical detection of Hsp27 and Hsp90 in the tumor and stromal components of ovarian carcinoma, as well as a significant increase in the proportion of Hsp27-positive tumor cells in HGSC compared with LGSC, indicate the potential diagnostic and prognostic value of Hsp27. Furthermore, the obtained results indicate the potential of chaperone-targeted therapy as a promising direction that requires further research.

Epithelial ovarian cancer is a heterogenous group, that includes histologic sub-types with distinct biologic behavior. Stage IC disease confers a higher risk of recurrence and death compared to stage IA. While adjuvant chemotherapy may improve outcomes of patients with high-grade serous ovarian carcinoma, its impact on the oncologic outcomes of other histologic sub-types that are more chemo-resistant, such as clear cell, mucinous, and low-grade serous ovarian carcinoma is not well-established. Retrospective studies have demonstrated that omission of adjuvant chemotherapy can be considered for patients with expansile mucinous, grade 1 endometrioid, and low-grade serous ovarian carcinoma and for those with stage IC1 clear cell ovarian carcinoma. However, in the absence of data from randomized clinical trials, shared decision-making, and careful counseling of patients should be considered. Future multicenter studies are required to further validate the safety of adjuvant chemotherapy omission in certain patient sub-groups with stage IC epithelial ovarian cancer.

Folate receptor alpha (FRα) is a promising therapeutic target due to its high expression in several tumor types and its rare expression in healthy tissue. Recently, the antibody-drug conjugate mirvetuximab soravtansine has been approved for treatment of advanced platinum-resistant high-grade serous carcinoma (HGSC). Immunohistochemical expression of FRα has been extensively studied in HGSC, but most studies conducted before the clinical studies targeting FRα used variable antibodies and scoring criteria, which makes comparison of older literature data with recent studies difficult. Moreover, the data regarding its expression in other types of ovarian and other female genital tract tumors are limited or absent. In our study, we focused on immunohistochemical expression in 923 tubo-ovarian and endometrial tumors (assessed on tissue microarrays), using standardized scoring criteria and the VENTANA FOLR1 CDx assay. The results of our study showed the highest FRα expression in serous carcinomas, specifically HGSC (45% positive cases), followed by low-grade serous carcinoma (25%), endometrial serous carcinoma (11%), and serous borderline tumor (10%). Endometrioid and clear cell ovarian carcinomas showed rare positivity (2% and 1%, respectively). All other tumors examined were negative, including mucinous ovarian tumors, sex cord-stromal tumors, endometrial endometrioid carcinomas, undifferentiated and dedifferentiated carcinomas, and endometrial clear cell carcinomas. In conclusion, these results confirm that FRα expression in HGSC and LGSC reaches similar values compared to published data, and is present in a minority of endometrial serous carcinomas. In other ovarian and endometrial tumors examined, FRα expression is absent or rare.

The Molecular Landscape of Ovarian Neoplasms: A Review.

1014 Low-grade Serous Carcinoma is a Persistent Diagnostic Challenge

Background and objectives Ovarian carcinoma is one of the most lethal carcinomas among females. Its high prevalence and shorter 5-year survival rate is due to the fact that most of the cases are diagnosed at later stages. This highlights the importance of early diagnosis through reliable biomarkers. We studied the diagnostic role of SOX9 protein in ovarian carcinoma and its diagnostic ability. The primary objective was to compare the level and clinical relevance of SOX9 protein in the tissues of patients with ovarian carcinoma with non-malignant ovarian tissues. Methods Tissue levels of SOX9 protein were estimated in the study and control groups (60 each group). SOX9 levels were compared between the study vs. control groups and also between high grade and low-grade ovarian cancer. SK-OV3 ovarian adenocarcinoma cell line was used as supportive evidence to prove the presence of SOX9 in malignant ovarian cells. Results Levels of SOX 9 protein (3.9±2.7 ng/mL) were high in tissue of ovarian cancer patients when compared to non-malignant (1.5 ±1.1 ng/mL) ovarian tissues. Higher levels of SOX 9 protein were found in tissues of ovarian cancer patients when compared to non-malignant ovarian tissues. The mean of SOX 9 levels in tissues of high-grade serous carcinoma was 3.5±2.5 ng/mL as compared to 1.0±0.9 ng/mL in low-grade serous carcinoma. Interpretation and conclusions SOX9 appears to be an important player in the molecular tumourigenesis of ovarian cancer, particularly in high grade tumours.

Objective: To investigate the potential value of quantitative digital pathology analysis in predicting prognosis in micropapillary serous borderline ovarian tumor (MP-SBOT). Methods: Clinical and pathological data from 366 serous borderline ovarian tumor (BOT) patients who attended the First Affiliated Hospital of Nanjing Medical University between October 2012 and November 2023 were retrospectively reviewed. Patients were classified into MP-SBOT group and non-MP-SBOT group according to their pathological subtype. Within the MP-SBOT group, patients were further classified into recurrence and non-recurrence subgroups. Digital image analysis using QuPath was performed on 83 ovarian serous tumors with adequate tissue quality, including MP-SBOT (n=48), SBOT in the non-MP-SBOT group (n=9), serous cystadenoma (n=11), low-grade serous carcinoma (n=7) and high-grade serous carcinoma (n=8). Quantitative pathological features including nuclear area, cellular area, and nuclear-to-cytoplasmic ratio (N/C ratio) of tumor cells were extracted. Univariate and multivariate Cox regression analyses were used to identify factors associated with MP-SBOT recurrence. Kaplan-Meier method was applied to estimate progression-free survival (PFS) time. Results: (1) Compared with non-MP-SBOT group, MP-SBOT group patients exhibited higher median serum carbohydrate antigen 125 level (127.9 vs 36.5 kU/L), higher D-Dimer level (0.7 vs 0.3mg/L), higher proportion of bilateral ovarian tumors (60.4% vs 15.4%), higher proportion of invasive peritoneal implants (25.0% vs 3.1%), higher proportion of International Federation of Gynecology and Obstetrics (FIGO) stage Ⅱ-Ⅲ (54.1% vs 10.0%), higher proportion of mixed cystic-solid mass detected by imaging examination (88.1% vs 70.1%) and higher proportion of recurrence (33.3% vs 13.5%) with statistically significant differences (all P<0.001). (2) Quantitative digital pathology revealed the distinct cellular morphologic characteristics in MP-SBOT. The tumor cell N/C ratio was significantly higher in MP-SBOT group than non-MP-SBOT group (0.48 vs 0.41; P<0.05). The tumor cell N/C ratio increased progressively with tumor malignancy. (3) Univariate Cox analysis identified tumor cell N/C ratio>0.50 and conservative surgery as factors associated with recurrence in MP-SBOT group. Multivariate analysis confirmed that an elevated tumor cell N/C ratio was an independent risk factor for recurrence in MP-SBOT group (HR=7.278, 95%CI:1.940-27.307, P=0.003). (4) Kaplan-Meier survival analysis showed that patients with tumor cell N/C ratio>0.50 had a significantly shorter median PFS than those with the tumor cell N/C ratio≤0.50 (164.0 vs 35.0 months, P<0.001). Conclusions: MP-SBOT display more aggressive clinical features. The elevated tumor cell N/C ratio shows potential clinical value in predicting recurrence in MP-SBOT patients.