Clinical Features and Establishment of a Recurrence Prediction Model in Early Ovarian Clear Cell Carcinoma Patients

doi:10.21203/rs.3.rs-4942865/v1

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Research Article

Clinical Features and Establishment of a Recurrence Prediction Model in Early Ovarian Clear Cell Carcinoma Patients

https://doi.org/10.21203/rs.3.rs-4942865/v1

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Purpose This study aims to summarize the clinical characteristics of early-stage ovarian clear cell carcinoma (OCCC) patients and establish a predictive model for recurrence.

Methods A retrospective analysis was conducted on clinical, pathological, and prognostic data of 129 early-stage OCCC patients treated at Peking University Third Hospital from January 2010 to June 2023. Clinical and pathological features of these patients were compared and summarized. Prognostic factors related to recurrence were explored, and a recurrence prediction model was established through nomogram.

Results The average age of patients was 54.38±8.66 years, with 110 cases (85.2%) in Stage I. The majority underwent comprehensive staging surgery (124 cases). Most patients exhibited positive expressions of NapsinA (92%) and HNF1β (98.9%). Immunohistochemical features were consistent with OCCC diagnosis, with negative expressions of ER (81.3%), PR (86%), and WT1 (94.2%). Among the 129 patients, 18 experienced recurrence, and 5 were lost to follow-up. The median progression-free survival (PFS) for recurrent patients was 16.5 months (range: 3-59 months). Significant prognostic factors associated with PFS were identified through univariate and multivariate analyses, including tumor FIGO stage, preoperative lower limb thrombosis, comprehensive staging surgery, age at diagnosis, parity, and menopausal status. A nomogram was constructed based on these variables to establish a recurrence prediction model. The AUC values for predicting the 1-year, 3-year, and 5-year recurrence were 0.831, 0.765, and 0.759, respectively, all exceeding 0.5.

Conclusion This study provides a comprehensive summary of the clinical and pathological characteristics of early-stage OCCC patients, explores prognostic factors related to recurrence and establishes a reliable recurrence prediction model. The model may serve as a reference for clinical counseling, treatment decision-making, and follow-up of early-stage patients who desire fertility sparing.

ovarian clear cell carcinoma

early stage

prognostic factor

recurrence

nomogram

Ovarian Clear Cell Carcinoma (OCCC) is a distinct histological subtype of ovarian epithelial cancer, accounting for approximately 10% of all ovarian cancers ^[1]. OCCC patients are relatively young when diagnosed, and often presenting at early stages with a generally favorable prognosis. However, the prognosis for late-stage and recurrent patients is worse when compared to other ovarian epithelial cancers ^[2]. The 5-year progression-free survival (PFS) of early-stage patients (FIGO I-II) ranges from 57–84%. Among stage IA patients, recurrence is infrequent, while stage IC patients may experience a recurrence rate as high as 37% ^[3].

Due to the unique biological behavior of OCCC, even in early-stage patients, fertility-sparing surgery is not recommended ^[4]. However, some studies suggest that in stage I OCCC patients, whether undergoing fertility-sparing or comprehensive staging surgery, there is no significant impact on recurrence and survival outcomes ^[5]. OCCC has a higher incidence in the Asian population ^[6], with patients being younger at onset and a substantial number expressing a desire for fertility preservation. Nevertheless, there is no consensus on whether fertility preservation is advisable among early-stage patients.

Previous predictive model studies ^[7–10] have suggested that factors such as patient age at diagnosis, FIGO stage, lymph node and distant metastasis status, chemotherapy administration, presence of ascites, thrombosis, plasma fibrinogen levels > 5.36g/L, and plasma D-dimer levels > 3.27mg/L are associated with recurrence. However, few studies have specifically focused on predictive models for recurrence in early-stage (I-II) OCCC patients.

Therefore, our objective is to systematically summarize the clinical characteristics of early-stage OCCC patients, explore prognostic factors associated with recurrence, and establish a clinical recurrence prediction model for early-stage OCCC. This research aims to provide evidences for the fertility preservation in early-stage OCCC patients.

2.1 Research Subjects

Data were collected from 129 cases of stage I-II pure ovarian clear cell carcinoma (OCCC) patients treated at Peking University Third Hospital from January 2010 to June 2023. This study was approved by the Institutional Ethics Board.

2.2 Data Collection

Clinical data from 129 OCCC patients were retrospectively collected, including age at diagnosis, FIGO stage, BMI, parity, menopausal status, dysmenorrhea status, presence of comorbid endometriosis, preoperative presence of lower limb or other site thrombosis, preoperative serum CA125 levels, preoperative blood calcium levels, tumor size, surgical approach, postoperative treatment details, postoperative recurrence status, and tumor immunohistochemistry.

2.3 Data Analysis

Statistical analysis was performed using SPSS 25.0 software. Continuous variables with a normal distribution were expressed as mean ± standard deviation (x̅ ± s), and those without a normal distribution were expressed as median (P25, P75). Categorical variables were presented as frequencies and percentages. Univariate and multivariate COX regression analyses were performed to identify risk factors for progression-free survival (PFS), with calculation of hazard ratios (HR) and 95% confidence intervals. Survival analysis employed the Kaplan-Meier curve model. A p-value of < 0.05 was considered statistically significant.

2.4 Construction of Nomogram Model

A nomogram graph was constructed using R language version 4.2.2 based on the risk factors related to PFS identified through univariate and multivariate COX regression analyses. The model was evaluated using the Receiver Operating Characteristic (ROC) curve, and the Area Under the Curve (AUC) was calculated.

3.1 Clinical Data

This study included a total of 129 patients with stage I-II pure ovarian clear cell carcinoma (OCCC) treated at Peking University Third Hospital from January 2010 to June 2023. The clinical characteristics of the patients are detailed in Table 1. The average age of onset was 54.38 ± 8.66 years (range: 36-76 years), with 37% of patients being below 50 years old. Combining preoperative imaging and postoperative pathology, a total of 111 cases were diagnosed as FIGO stage I, accounting for 86.0% of the cases. At the time of diagnosis, 66.7% of patients were already postmenopausal, 36% reported a history of dysmenorrhea, 10.1% had a nulliparous history, and 14% had never given birth. Preoperative examinations indicated an average serum CA125 level of 41.37 (17.15, 132.2) U/mL, with 44.2% of patients having a normal CA125 level. Among the 62 patients with available clinical data, the preoperative blood calcium level was 2.32 (2.22, 2.39) mmol/L, and only 2 patients had blood calcium levels exceeding the upper limit of the normal range. Preoperative imaging suggested that the maximum tumor diameter at diagnosis was 30 cm, and the minimum diameter was 2.1 cm. Preoperatively, 7.8% of patients had lower limb venous thrombosis. Patients diagnosed with endometriosis based on intraoperative findings and postoperative pathology accounted for 48%.

3.2 Surgery and Postoperative Treatment

Among the 129 OCCC patients, 95.3% underwent standard ovarian cancer comprehensive staging/cytoreductive surgery, involving the removal of the entire uterus, bilateral adnexa, systematic pelvic and para-aortic lymph node dissection, and omentectomy. Among these, 60 patients underwent laparoscopic surgery, and 63 patients underwent open surgery. One patient with stage IA opted for fertility-preserving ovarian cancer staging surgery through laparoscopy, preserving the uterus and contralateral adnexa. However, two years later, due to a "right ovarian mass," the patient underwent laparoscopic total hysterectomy and removal of the right adnexa. Postoperative pathology confirmed an ovarian chocolate cyst, and the patient did not achieve pregnancy during this two-year-period. Additionally, 5 patients underwent incomplete staging surgery.

Nine patients did not receive chemotherapy postoperatively due to early tumor staging. The majority of patients (89.1%) received chemotherapy with a regimen of paclitaxel plus carboplatin. Other patients, due to factors such as age, comorbidities, and drug allergies, received alternative chemotherapy regimens, including cisplatin plus cyclophosphamide, single-agent paclitaxel, or combination therapy with topotecan plus carboplatin. Seven patients received targeted and/or immunotherapy in addition to their initial treatment. Details are shown in Table 2.

3.3 Pathological Immunohistochemical Characteristics

The immunohistochemical characteristics of patients’ tumor tissues are summarized in Table 3. The majority of patients exhibited positive staining for NapsinA (81/88, 92%) and HNF1β (94/95, 98.9%). A significant proportion of patients demonstrated negative expression for ER (81.3%, 83/123), PR (86%, 86/100), and WT1 (94.2%, 49/52), aligning with the immunohistochemical features of OCCC. Among patients, 86% (92/107) were classified as p53 wild-type, 50% (12/24) showed loss of ARID1A expression, 4.2% (2/48) had mismatch repair deficiency (MMR-D), and 82% (15/17) were HER2 positive. There was no significant association between patient progression-free survival (PFS) and various immunohistochemical markers.

3.4 Recurrence Status and Analysis

Among the 129 patients, 18 experienced recurrence, and 5 were lost to follow-up. The median progression-free survival (PFS) of recurrent patients was 16.5 months (range: 3-59 months), including 11 stage I patients, 7 stage II patients.

In the univariate analysis of risk factors for PFS in stage I-II patients (Table 4), the results showed that advanced tumor FIGO stage (P=0.019), preoperative presence of lower limb thrombosis (P=0.006), and not undergoing comprehensive staging surgery (P=0.047) were significantly associated with patient PFS. The Kaplan-Meier curve is shown in Figure 1.

In the multivariate analysis of risk factors for PFS in stage I-II patients (Table 4), the results revealed that older age at diagnosis (P=0.023), multiparity (P=0.016), non-menopausal (P=0.034), preoperative presence of lower limb thrombosis (P=0.018), and incomplete staging surgery (P=0.044) were significantly associated with patient PFS.

3.5 Construction of Nomogram Model

The variables significantly associated with progression-free survival (PFS) in both univariate and multivariate analyses (tumor FIGO stage, preoperative presence of lower limb thrombosis, undergoing comprehensive staging surgery, age at diagnosis, number of pregnancies, and menopausal status) were incorporated into the model. After excluding missing data, a nomogram graph was constructed and obtained (Figure 2). The scale on each variable axis corresponds to the score on the score axis. Drawing a line perpendicular to the variable axis yields the corresponding score. The scores for each variable are then summed to obtain the total score, which corresponds to the predicted recurrence rates at 1, 3, and 5 years. The model achieved an area under the curve (AUC) of 0.831 for 1-year recurrence, 0.765 for 3-year recurrence, and 0.759 for 5-year recurrence (Figure 3). All AUC values are greater than 0.5, indicating good predictive performance of the model.

Ovarian clear cell carcinoma (OCCC) is a distinct histological subtype of epithelial ovarian cancer associated with a relatively poorer prognosis, especially in advanced and recurrent cases. Therefore, early identification of high-risk patients is of significant clinical value. Compared to high-grade serous ovarian cancer, OCCC tends to occur at a younger age, with a higher proportion of early-stage patients ^[11]. In our study, patients under the age of 50 accounted for 37%, nonparous patients accounted for 14% and stage I patients accounted for 85.2%, highlighting the importance of considering fertility-sparing surgery for early-stage OCCC patients. However, there are limited researches on the prognosis of PFS in early stage OCCC patients. This study aimed to explore factors related to recurrence in early stage OCCC through clinical data analysis, construct a predictive model, and provide insights into the clinical management of OCCC patients.

Between 50% and 74% of OCCC cases are associated with endometriosis, and approximately one-third of the OCCC originates directly from endometriotic lesions ^[2]. Endometriosis may contribute to a relatively favorable prognosis for OCCC, but it is not an independent prognostic factor ^[12]. In our study, 48% of patients had concurrent endometriosis, and their average PFS was shorter than that of patients without endometriosis. However, the presence of endometriosis did not significantly impact PFS. Strict follow-up is advised regarding the possibility of the recurrence of endometriosis and malignant transformation postoperatively, especially in patients desiring fertility preservation.

Compared to other epithelial ovarian cancers, OCCC patients have a higher risk of developing thrombosis, which is also an independent risk factor associated with prognosis ^{[13, 14]}. Similarly, in our study, preoperative lower limb thrombosis was significantly associated with recurrence after initial treatment. Tissue factor is considered as a modulator in the thrombotic process of epithelial ovarian cancer patients, closely linked to tumor tissue growth, metastasis, and angiogenesis. Therefore, the hypothesis that thrombotic patients are more prone to metastasis and recurrence is plausible ^[15–17]. Typically, thrombotic patients have higher levels of D-dimer and fibrinogen than average ^[18]. Studies have indicated a close correlation between elevated D-dimer and fibrinogen levels and the occurrence of recurrent abortion ^[19]. Therefore, for early-stage OCCC patients desiring fertility preservation, the presence of thrombosis not only increases the risk of disease recurrence after initial treatment but may also lead to adverse pregnancy outcomes.

Some retrospective studies suggest that fertility-sparing surgery (FSS) does not affect the prognosis of early-stage OCCC patients. Comparing FSS and radical surgery in patients with IA or IC stage under 45 years old, the two groups showed no significant differences in recurrent time, 5-year PFS or overall survival (OS) rates. The recurrence rate for patients undergoing FSS for early-stage OCCC was 15.2%, with a median recurrent time of 18 months ^[5]. In our study, there was only one patient who underwent FSS. Although this patient experienced a recurrence of ovarian chocolate cyst and underwent total hysterectomy and removal of the right adnexa two years after the FSS, she has shown no signs of recurrence to date. However, our study suggests that early-stage OCCC patients who did not undergo comprehensive staging surgery have a higher recurrence rate, indicating that even with FSS, it should be implemented on the basis of comprehensive staging.

There have been some studies on predictive models for OCCC recurrence, but researches on predictive models for early-stage OCCC recurrence are still limited. Our study, by analyzing preoperative clinical characteristics and surgical methods in early-stage OCCC patients, established a recurrence risk prediction nomogram. This aims to identify high-risk individuals before surgery, select appropriate surgical and treatment modalities, and provide evidence-based support for performing FSS in early, young OCCC patients. Due to the lack of PFS-related data for OCCC patients in the SEER database and the risk of overfitting in internal validation, our study model lacks subsequent validation. Therefore, it is crucial to collaborate with other medical centers to expand the sample size or conduct prospective research.

In summary, OCCC is a distinct pathological subtype of ovarian epithelial cancer, occurring at a younger age with main pathological features including negative expression of ER and PR and wild-type p53. Factors such as FIGO stage, preoperative presence of lower limb thrombosis, comprehensive staging surgery, age at diagnosis, parity and menopausal status are closely associated with the PFS of early-stage OCCC patients. The nomogram constructed on this basis can effectively demonstrate the recurrence risk of patients, providing evidence and support for clinical consultation and decision-making.

Conflict of interest

This work was supported by the National Key R&D Program of China (Program Nos.2022YFC2704400&2022YFC2704401).

Author Contribution

Yuhan Cai, Yan Gao and Yiming Fan collected the data, wrote the main manuscript text and prepared the figures and tables. Hongyan Guo and Yu Wu revised the text. All authors reviewed the manuscript.

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Tables 1 to 4 are available in the Supplementary Files section.

No competing interests reported.

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You are reading this latest preprint version

Clinical Features and Establishment of a Recurrence Prediction Model in Early Ovarian Clear Cell Carcinoma Patients

Status:

Version 1

Abstract

Figures

Introduction

Method

2.1 Research Subjects

2.2 Data Collection

2.3 Data Analysis

2.4 Construction of Nomogram Model

Results

Discussion

Declarations

Conflict of interest

Author Contribution

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1