Prognostic factors and clinic-pathologic characteristics of ovarian tumor with different histologic subtypes—a SEER database population study of 41,376 cases

Introduction

With an estimated 313,959 cases and 207,252 deaths worldwide in 2020, ovarian cancer (OVC) is considered the leading cause of cancer-related deaths among all gynecological malignancies and a significant reason for mortality in women (1). Given the lack of disease-specific symptoms, most patients are diagnosed at advanced stage, which substantially increases the risk of metastasis and early death. Although the advances in OVC treatment led to an improvement in the 5-year survival from 34.8% in 1975 to 44.6% in 2011, there are several challenges in the diagnosis and treatment of OVC (2).

In 2020, the World Health Organization (WHO) established a classification for tumors of the female reproductive tract. Malignant ovarian tumors (MOTs) are mainly classified into the following subtypes: epithelial ovarian carcinoma (EOC), malignant ovarian germ cell tumors (MOGCT), malignant ovarian sex cord-stromal tumors (MOSCSTs) and ovarian neuroendocrine tumors (ONTs) (3). EOC takes up the majority of MOT patients, comprising several histotypes with distinct clinical features, epidemiologic, developmental origins and chemosensitivity as a heterogeneous disease (4). MOGCTs are rare tumors accounting for 2% to 3% of MOTs, usually develop in girls, adolescents, women of reproductive age and represent a group of MOTs for which effective surgical and chemotherapeutic management has resulted in ideal overall survival (OS) (5). The most common MOSCST is granulosa cell tumor (GCT), which derives from the cortical sex cord (6). Gynecologic neuroendocrine tumors are uncommon to rare, ONTs are mainly divided into carcinoid tumor, small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) (7).

Cancer antigen 125 (CA125) is a protein which is encoded by the MUC16 gene, and CA125 serum marker is widely used for clinical evaluation of OVC (8). MOTs vary greatly in terms of CA125 level, median age, clinical features, prognosis, prediction, etc. Specific risk factors and mortality estimates are extremely important in clinical practice as well as early diagnosis to help design more specific surveillance and survival strategies (9). However, previous studies on OVC prognosis were not comprehensive, and most of them mainly focused on subgroups of a certain disease, without a population-level investigation (10-12). The Surveillance, Epidemiology, and End Results (SEER) system covers one-third of the United States population, it is a publicly available cancer database recording data on patient characteristics including age, race, marital status, tumor size, grade, CA125, year of diagnosis, surgery, lymph node resection, SEER stage, Federation of Gynecology and Obstetrics (FIGO) stage, chemotherapy, and radiation. We aimed to verify the significant predictors of survival and survival trends associated with the MOT patients, and defined the prognostic role of CA125 level in the diagnosis of MOT, from January 2005 to December 2014. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-58/rc).

Methods

Clinical dataset

Ovarian tumor (primary site: C56.9-Ovary) cases diagnosed between January 2005 and December 2014 were extracted from the SEER program of the National Cancer Institute. We have signed the SEER Research Data Agreement for access to the SEER data using the reference number 15129-Nov2016. The histological classifications of MOTs include EOC, MOGCT, MOSCST and ONT. EOCs were categorized as serous [ICD-O-3 (International Classification of Disease for oncology, fifth edition) numbers include 8441/3, 8442/3, 8460/3, 8461/3, 8462/3, 8463/3, 9014/3], endometrioid (8380/3, 8381/3, 8382/3, 8383/3), mucinous (8470/3, 8471/3, 8472/3, 8480/3, 8482/3, 9015/3), clear cell (8310/3, 8313/3, 8443/3, 8444/3), Brenner (9000/3), undifferentiated carcinoma (8020/3), mixed (8255/3, 8323/3) and carcinosarcoma (8980/3, 8981/3). MOGCTs were recorded as dysgerminoma (9060/3), embryonal carcinoma (EC) (9070/3), yolk sac tumor (9071/3), malignant teratoma (9080/3, 9082/3, 9083/3, 9084/3) and mixed germ cell tumor (MGCT) (9085/3). MOSCSTs were classified as GCT (8620/3, 8621/3, 8622/3) and poorly-differentiated Sertoli-Leydig cell tumor (PDSLCT) (8634/3, 8631/3). ONTs were characterized as carcinoid tumor (8240/3, 8249/3), LCNEC (8013/3) and SCNEC (8046/3, 8041/3). A total of 41,411 ovarian tumor cases were identified, while 35 patients with no survival time were excluded from this analysis. A total of 41,376 ovarian cancer cases were finally identified using the SEER database (shown in Figure 1). This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Figure 1 Flow-chart for patient selection. EOC, epithelial ovarian carcinoma; MOGCT, malignant ovarian germ cell tumor; MOSCST, malignant ovarian sex cord-stromal tumor; ONT, ovarian neuroendocrine tumor; LCNEC, large cell neuroendocrine carcinoma; SCNEC, small cell neuroendocrine carcinoma.

Clinical characteristics

Age, race, marital status, CA125, grade, year of diagnosis, tumor size, SEER stage, FIGO stage, surgery, lymph node resection, chemotherapy, and radiation were included in patient characteristics. Age was classified into eight groups: <20, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79 and ≥80 years. Marital status was recorded as married, single/separated/widow, and unknown. CA125 level was recorded as negative/normal, borderline, positive/elevated and unknown. Tumor grade was characterized into five groups: grade I (well differentiated), grade II (moderately differentiated), grade III (poorly differentiated), grade IV (undifferentiated; anaplastic), and unknown. The year of diagnosis was categorized as follows: 2005–2009 and 2010–2014. Tumor size was classified into <5, 5–10, and >10 cm. SEER stages were classified as localized, regional, distant, and unknown. FIGO stages were classified as stage I (T1N0M0), stage II (T2N0M0), stage III (T3N0M0, T3N1M0, T2/T1N1M0), stage IV (TXNXM1), and unknown (MX). The number of lymph node resection was classified as 0, 1–3, ≥4 and unknown.

Statistical analysis

The chi-squared test was used to analyze the distributions of clinicopathological characteristics in different histological types, and Pearson’s correlation tests were used to analyze trends in groups. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were estimated for each multivariate and univariate OS analysis using Cox proportional hazards models adjusted for patient and clinical information. Univariate logistic regression was employed to predict potential risk factors for patients. The factors that were significant in the univariate analysis were subsequently incorporated into a multivariate analysis. OS and disease-specific survival (DS) were estimated by Kaplan-Meier curves, and the log-rank test was applied to calculate differences between the curves. In different histological groups, DS was estimated by the Kaplan-Meier method. Analyses were performed using SPSS, Version 22.0. Statistical significance was defined as P<0.05.

Results

Clinicopathological characteristics of patients with MOT

The demographic and clinical characteristics of the five histological groups are shown in Table 1. A total of 41,376 patients were included in this study, of which 38,649 had EOC, 1,391 had MOGCT, 952 had MOSCST, and 384 had ONT. The majority of patients with EOC were diagnosed between the ages of 50 and 79 years. Age at diagnosis of most MOSCSTs and ONTs were in their fifties. MOGCTs were diagnosed predominantly at young ages of ≤29 years, and 73.0% of the patients were single. Most EOCs were diagnosed at advanced SEER stage, while most MOSCSTs, GNTs and MOGCTs were diagnosed at localized SEER stage. Over half of the cases (68.1%) had positive/elevated CA125 level, while a few cases (8.8%) were negative/normal among patients with EOC. The proportions of patients with positive/elevated CA125 level were similar to patients with negative/normal CA125 level in MOSCSTs and ONTs, 21.0% and 25.4%, 25.5% and 20.8%, respectively.

CA125 level according to the histological subtypes of MOT

The distribution of CA125 level among the histological subtypes are shown in Figure 2. CA125 level was more likely to be positive/elevated than negative/normal in most histological subtypes, including all EOC (serous, endometrioid, mucinous, clear cell, Brenner, undifferentiated carcinoma, mixed, carcinosarcoma), all MOGCT (dysgerminoma, embryonal carcinoma, yolk sac tumor, malignant teratoma, mixed germ cell tumor) and the majority of ONTs (LCNEC, SCNEC). Among patients with GCT and carcinoid tumor, there were more cases with negative/normal CA125 level than with positive/elevated CA125 level. The highest positive/elevated rate was found in serous carcinoma patients, at 73.5%, while the highest negative/normal rate was found in patients with PDSLCT, at 27.3%.

Figure 2 CA125 level of malignant ovarian tumor by histological subtypes. CA125, cancer antigen 125; PDSLCT, poorly-differentiated Sertoli-Leydig cell tumor; LCNEC, large cell neuroendocrine carcinoma; SCNEC, small cell neuroendocrine carcinoma.

Independent risk factors and prognostic factors for OS in patients with MOT

In this study, age, grade, FIGO stage, SEER stage, CA125, histological classification, surgery, lymph node resection, chemotherapy were significantly associated with the OS outcome according to the univariate and multivariate analyses (shown in Table 2). Significant predictors for improved OS were younger age, low grade, early FIGO stage, and localized SEER stage. In contrast, positive/elevated CA125 level [HR =1.478 (95% CI: 1.375–1.589)] was a risk factor for OS versus negative/normal CA125 level. There was a significant difference in prognosis among the different histological classifications in terms of OS, while patients with EOC showed the worst outcome. Surgery [HR =0.414 (95% CI: 0.393–0.436)], lymph node resection [HR =0.664 (95% CI: 0.641–0.688)] and chemotherapy [HR =0.624 (95% CI: 0.603–0.646)] contributed to better prognosis.

Survival analysis according to the histological classifications

The survival curves of OS and DS in MOTs are shown in Figure 3, according to histological classifications. The restricted mean survival time (RMST) obtained up to 120 months (10 years) of ONTs and EOCs were 87.7 and 76.8 months in DS, 78.8 and 66.7 months in OS, respectively. The difference between their RMST was 10.9 months (95% CI: 5.6–16.2) in DS (P<0.001) and 12.1 months (95% CI: 6.5–17.6) in OS (P<0.001). Irrespective of the stage, MOGCT patients had high DS and OS rates for the best prognosis, which were both >90% (shown in Table 3). EOC patients had the worst survival in four histological classifications with low 10-year DS rate (47.3%) and OS rate (35.1%), as shown in Table 3.

Figure 3 DS (A) and OS (B) according to histological classifications. DS, disease-specific survival; OS, overall survival; EOC, epithelial ovarian carcinoma; MOGCT, malignant ovarian germ cell tumor; MOSCST, malignant ovarian sex cord-stromal tumor; ONT, ovarian neuroendocrine tumor.

Survival analysis of the various histological subtypes

Cumulative survivals of histological subtypes are shown in Figure 4, according to histological classification groups. In EOCs, cumulative survival remained higher in endometrioid than in other histotypes (shown in Figure 4A). Throughout the entire survival period, carcinosarcoma had worst survival among all the histological subtypes, and its 3- and 10-year DS rates were 43.0% and 25.1% (shown in Table 4). In MOGCT patients, ECs had the worst survival, and patients with dysgerminoma had a better prognosis than the other subtypes (shown in Figure 4B). GCT showed better survival rate than PDSLCT in the MOSCST group (shown in Figure 4C). In ONTs, patients with carcinoid tumor had the best prognosis, as the 3-, 5- and 10-year DS rates were >95% (shown in Table 4). However, patients with LCNEC had the worst prognosis, which was even worse than patients with SCNEC (shown in Figure 4D).

Figure 4 DS curves according to histological subtypes in EOC (A), MOGCT (B), MOSCST (C), and ONT (D). DS, disease-specific survival; EOC, epithelial ovarian carcinoma; MOGCT, malignant ovarian germ cell tumor; MOSCST, malignant ovarian sex cord-stromal tumor; ONT, ovarian neuroendocrine tumor; PDSLCT, poorly-differentiated Sertoli-Leydig cell tumor; LCNEC, large cell neuroendocrine carcinoma; SCNEC, small cell neuroendocrine carcinoma.

Discussion

This study aimed to assess the risk factors and trends in survival of MOTs based on a large population, from January 2005 to December 2014. In this study, younger age, low grade, early FIGO stage, and localized SEER stage had significant associations with improved OS. Most patients with EOC, sex cord-stromal tumors and neuroendocrine tumors were diagnosed above 50 years of age, while MOGCTs were diagnosed predominantly below 30 years of age (13-15). Patients diagnosed at different ages also had different long-term outcomes. In this study, EOC patients had the worst survival among the four histological classifications, while MOGCT patients had the most favorable outcomes, with the estimated 5-year survival rates >90%, irrespective of the stage.

For stage I tumors, a previous study showed that ovarian cancer was the leading cause of death for 6 years after diagnosis. Moreover, OVC remains the most common cause of death for 15 years after diagnosis in women with stage III–IV tumors. Patients with EOC remain at substantial risk of tumor-related death for many years after initial diagnosis (16). However, the difference in prognosis among various subtypes has been rarely studied. Although fallopian tube and peritoneal carcinomas share many similarities with EOCs, this study was designed to investigate tumors primary in the ovary of different histological types. Compared with other histological subtypes of tumor, this study found that patients with EOC are at greatest risk for death. In EOC, carcinosarcoma had the worst survival among all the epithelial subtypes, followed by serous and clear cell carcinoma, while endometrioid carcinoma had the best outcome. As a biphasic malignant tumor, carcinosarcoma is composed of high-grade carcinomatous and sarcomatous elements. Cytoreductive surgery followed by platinum-based chemotherapy is still the mainstay treatment (17). The 5- and 10-year DS rates were 32.3% and 25.1%, respectively, for patients with carcinosarcoma, the most predominant epithelial cancer in our study. High-grade serous carcinoma (HGSC) is the most common ovarian carcinoma (70%), and approximately 20% of the HGSCs have germline BRCA1/2 mutations (18,19). Some studies demonstrated that patients harboring BRCA mutations could have a higher sensitivity to platinum than BRCA wild-type cases. And poly (ADP-ribose) polymerase (PARP) inhibitor is currently indicated as maintenance therapy after front-line chemotherapy, meanwhile it is also approved as monotherapy for the treatment of patients with BRCA mutant tumors (20-22). In contrast, the response rate of platinum-based chemotherapy is only 20–50% for ovarian clear cell cancer, which may be one of the reasons for the poor prognosis (23). Primary ONTs are rare malignant neoplasms associated with unfavorable prognosis. There is limited data on the risk factors and prognosis compared to other pathological subtypes (24-26). LCNEC had the worst prognosis among ONTs in our study, with a 3-year DS rate of 21.8%. More therapeutic options should be explored to improve the survival rate. A case report showed that immunotherapy with nivolumab achieved complete response, even in the absence of PD-L1 tumor expression, emphasizing a potential role of targeted therapy in these tumors with aggressive biological behavior (27).

According to the NCCN guidelines, appropriate surgical staging and debulking surgery are the primary treatment for MOT patients. Adjuvant therapy is also considered in some histological subtypes. The importance of PARP inhibitors is noted in the management of ovarian cancer (28). The appropriate primary surgery should be performed based on the surgical staging and fertility concerns. For most suspected MOT patients, a hysterectomy and bilateral salpingo-oophorectomy with comprehensive staging and debulking should be performed as the initial surgery. The treatment plans are adjusted according to the histological subtypes and conditions of patients. MOSCSTs account for approximately 2–5% of all OVC, and GCT is the most common subtype (70%). Our study showed that the 10-year DS rate of GCT was 85.9%, indicating good prognosis and late recurrence. Some reports concluded that unilateral salpingo-oophorectomy can be performed in fertility-desiring patients with tumors confined to ovary, along with regular follow-up (29). MOGCT patients represent a group of uncommon tumors that comprise 2–3% of OVCs (30). MOGCT patients are primarily of reproductive age and 73% of the cases are single women. Obviously, fertility preservation is a necessity especially when the patients have not completed child-bearing. A previous study showed that 18% of MOGCT patients had nodal involvement, thereby proving the significance of lymphadenectomy (5). In our study, lymph node resection was also a positive predictor of survival, in the univariate and multivariate analyses of OS in MOT. Though comprehensive staging has been performed in adult patients, the necessity and extent of lymph node resection remain debatable. For more than two decades, cisplatin-based combination chemotherapy with bleomycin, etoposide, and cisplatin (BEP) has been the standard chemotherapy regimen, and BEP for 3–4 cycles does not typically preclude subsequent pregnancy (5). MOGCTs represent a group of ovarian cancers for which fertility-sparing surgery and effective chemotherapeutic management have resulted in excellent OS (31).

CA125 is expressed on the surface of cells as a membrane-bound protein, and plays an important role in ovarian and breast tumors (8). CA125 serum marker is widely used for clinical evaluation. As the first accepted ovarian cancer biomarker, CA125 has played a very important role in the past decades, but some reports have questioned its role. The majority of previous studies investigated the function of CA125 in ovarian cancer based on small samples, and found that CA125 is a tumor antigen that is present in 75–83% of patients with EOCs (8,32,33). According to our study, CA125 values differed in various histopathological types of ovarian tumor. CA125 is more likely to be positive in EOC. The results showed that CA125 also tends to be positive/elevated instead of negative/normal among all MOGCTs and most ONTs, which indicated that CA125 can be a sensitive clinical marker for pathogenesis of these histopathological types of ovarian tumors. In contrast, among patients with GCT, PDSLCT and carcinoid tumor, there are more cases with negative/normal CA125 level than with positive/elevated CA125 level, which means CA125 is not a good marker for these types of tumors. Taken together, CA125 is an important disease marker, and is widely used in clinical work. Human epididymis 4 (HE4) was reported as a complement to CA125 (34). Identification of more efficient biomarkers will contribute to the early diagnosis and surveillance of MOTs.

This study had several limitations, such as the lack of obesity and smoking status data. Besides, the information on targeted drugs and detailed chemotherapy regimens were not available in the SEER database. Moreover, the role of HE4 in the disease-pathogenesis and postoperative surveillance of MOT patients should also be analyzed.

Conclusions

In summary, this study was based on the SEER database to explore the risk factors, CA125 level and survival trends of MOT. Significant predictors for improved OS were younger age, low grade, early FIGO stage, and localized SEER stage. In contrast, positive/elevated CA125 level was a risk factor for OS. Epithelial and neuroendocrine tumors had the highest mortality rates. Carcinosarcoma was the most aggressive tumor in EOC, and LCNEC shared the same role among neuroendocrine tumors. Surgery, lymph node resection and chemotherapy contributed to better prognosis.

Acknowledgments

Funding: This work was supported by the Zhejiang Medical and Health Research Project (No. 2021RC102).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-58/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-58/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-58/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.This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

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/.

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