In this study, we investigated treatment strategies, prognostic factors, and outcomes in the largest cohort of patients with ovarian NETs to date. The key finding of the current study is that our data reveal that age, AJCC stage, treatment method, and histological type were identified as independent prognostic factors for ovarian NET. In addition, our analysis revealed that prognosis was relatively good among patients with early-stage disease treated with surgery alone, whereas more comprehensive treatment (surgery + CTX + RT) was required to improve prognosis in patients with advanced-stage disease. Prognosis was also poor for patients with HGNEC than for those with LGNET.
Given the rarity of ovarian NETs, the literature consists mostly of case reports and small case series [8–11]. Moreover, this disease entity encompasses several tumor types, with the largest single series reporting 58 cases of ovarian large-cell carcinoma . The median survival time for patients with large-cell neuroendocrine carcinoma of the ovary is 10 months. In their analysis of 329 cases, Soga et al.  divided patients into two carcinoid groups based on the presence or absence of a related dermoid. The authors reported 5-year survival rates of 84–93.7% for these two groups. In addition, there are 11 case reports , all of which discuss patients who underwent primary surgery. Five of these patients received adjuvant CTX with platinum therapy. The median overall survival time among 11 patients was 20 months. However, no previous large-sample studies have investigated ovarian NETs, highlighting the practical clinical significance of the current study.
Establishing a diagnosis of ovarian NET can be challenging. Immunohistochemistry can help identify these tumors because they express markers of neuroendocrine differentiation, such as neuron-specific enolase (NSE), synaptophysin, chromogranin CD56, vimentin, and epithelial membrane antigen (EMA) [4, 15]. The diagnosis can be confirmed by immunohistochemistry using one or more standard neuroendocrine markers. At present, SMARCA4 [16–18] is recognized as a biological marker of hypercalcemic-type small-cell carcinoma. Unfortunately, there are currently no candidate drugs for targeted therapy in these patients.
Our multivariate analysis revealed that treatment options were related to prognosis. Patients with early-stage ovarian NETs experienced good survival outcomes after surgery alone. The 5-year OS and CSS rates were as high as 97.03% and 96.90%, respectively. For patients with advanced-stage disease, comprehensive treatment (surgery + CTX + RT) was associated with improved survival rates, regardless of the type of ovarian NET. Ovarian carcinoids were also often small and unilateral tumors confined to the ovaries. Unilateral salpingo-oophorectomy also appears to be associated with high cure rates , although other gastrointestinal metastases must be excluded. For patients with metastatic disease , it is recommended to conduct a thorough evaluation using magnetic resonance imaging (MRI) or 111-pentetide indium scanning to rule out the presence of other major sources (such as the gastrointestinal tract) , and to ensure prompt initiation of appropriate treatment. Some scholars  believe that somatostatin analogs (such as lanreotide and octreotide) should be considered if carcinoids are diagnosed, and that somatostatin analogs should be used before and during tumor resection to prevent carcinoid crisis complications . In a study by Nasioudis et al. , the authors were unable to verify that CTX can prolong survival time in patients with stage II–IV carcinoids, although another study noted that the Ki-67 proliferation index may aid in the selection of patients likely to benefit from CTX . However, reports on ACT are rare. Indeed, there were only five cases in our study. Because ACT is an extremely rare disease, little is known regarding its biological behavior . Our results indicated that treatments were carried out in accordance with the carcinoid regimen, and that large-cell carcinoma and small-cell carcinoma of the ovary were uncommon and classified as HGNEC. The literature reports that prognosis is poor and that progression is rapid among these patients. Even when discovered early, the probability of metastasis or recurrence remains high [12, 15, 20, 25–27]. Thus, CTX, RT, or adjuvant treatment is recommended even in the early stage. Harrison et al.  reported that the combination of RT and CTX provides the best chance of long-term survival for patients with HGNEC. However, even with comprehensive treatment, the prevalence of relapse within 2 years remains high among patients with advanced-stage disease [25, 26, 29].
Because ovarian NETs are rare, information regarding the safety of conservative treatment designed to preserve fertility in young women is very limited. However, if the patient recognizes the risk, fertility-preserving surgery can be considered in the early stage [1, 6].
Due to the rarity of the disease and the lack of systematic population-based research or registration data, treatment strategies for ovarian NETs have not been standardized. It is relatively unlikely that the tumor will be identified as an NET prior to surgery, meaning that the treatment will be based on surgical findings. In addition, most adjuvant treatments are based on the treatment plan for lung NETs, which consists of a combination of surgical resection and postoperative supplementation with platinum-based CTX. The most commonly used drugs include cisplatin, carboplatin, doxorubicin, epirubicin, and etoposide [25, 29]. Even in patients with relapse, the current treatment plan is still a comprehensive treatment based on platinum CTX, and postoperative adjuvant CTX is more common in patients with ovarian epithelial tumors, with relatively fewer patients receiving adjuvant RT. Surgery combined with RT and CTX plays an important role in patient prognosis, especially for those with advanced ovarian NETs. Taken together, the available evidence highlights the need to develop novel drug treatments such as molecular targeting strategies. Pembrolizumab has been used in patients with recurrent cervical and vulvar NETs and has shown promise in phase II clinical trials . Therefore, clinical trials investigating the use of pembrolizumab for ovarian NETs are warranted.
We compared the characteristics of patients with different histological subtypes of ovarian NETs (LGNET vs. HGNEC). LGNET was milder, more frequently presented as stage I disease, more often involved tumors with diameters < 5 cm, and was associated with lower rates of lymph node positivity and distant metastasis than HGNEC. Among patients with LGNET, 94.3% were treated with surgery alone, and the 5-year survival rate was as high as 93.56%. These findings indicate that prognosis is relatively better among patients with ovarian LGNET than among those with HGNEC.
The present study has some limitations. Importantly, the SEER database does not include information regarding the number of chemotherapy cycles, specific chemotherapy regimens, or neoadjuvant chemotherapy regimens. In addition, the time, location, and treatments for disease recurrence are not specified, and the SEER database does not yet provide preoperative imaging data. Nonetheless, use of the SEER database was also the major strength of our study, as it provides big data regarding cases of ovarian NETs over the past 12 years. To our knowledge, our study is the largest investigation of ovarian NET conducted to date. Moreover, our data provide valuable clinical information regarding different treatment regimens and related prognostic information for patients with ovarian NETs.
In conclusion, the current research reveals that age, AJCC stage, treatment method, and histological type are independent prognostic factors for ovarian NETs. Moreover, our results indicate that prognosis is relatively good among patients with early-stage disease treated with surgery alone. However, comprehensive treatment involving surgery, CTX, and RT is required to improve prognosis in patients with advanced disease. Future studies should focus on the development of individualized treatment strategies for prolonging survival time in patients with ovarian NETs.