Neuroendocrine tumors (NETs) of the gynecological tract are rare, constituting only 2% of all gynecologic cancers and roughly 1.2%–2.4% of all neuroendocrine tumors [1]. NETs are primarily found in the cervix among gynecologic organs, with about 0.9%–1.5% of cervical cancers having a neuroendocrine origin, followed by the ovaries, vulva, and endometrium in terms of frequency [2, 3]. Uterine cervical NETs can be categorized as carcinoid tumors, atypical carcinoid tumors, small cell carcinomas, or large cell neuroendocrine carcinomas. The latter two types are referred to as high-grade neuroendocrine carcinomas (HGNECs), known for their extreme aggressiveness, are associated with decreased survival rates, even among patients diagnosed in the early stages of the disease [4, 5, 6]. Therefore, HGNECs demand management strategy that is distinct from other histological types. However, owing to the lack of prospective studies on management approaches for HGNECs, standard treatment guidelines have not been established [7].

A recent meta-analysis investigating the response rates and long-term results of various cervical cancer histologies treated with neoadjuvant chemotherapy (NACT) followed by surgery indicated that squamous cell carcinomas achieved complete and partial clinical response rates of 21% and 59.2%, respectively, while nonsquamous cancers achieved rates of 32.2% and 42.9%, respectively. Interestingly, neither these differences in response nor long-term outcomes were found to be statistically significant when stratified by chemotherapy regimen or histology. Furthermore, none of these studies have evaluated the impact of NACT on HGNECs [8].

All published studies have included only a few cases of locally advanced-stage squamous or adenocarcinoma of the cervix underwent with NACT and surgery [9]. This study aimed to determine the survival and recurrence in 60 patients with histologically diagnosed HGNEC by comparing patients who received radical surgery after NACT with those who only underwent primary radical surgery.

Neuroendocrine neoplasms are rare malignancies and are among the most aggressive types of gynecological cancers with limited therapeutic options [11]. Because patients are sometimes diagnosed in advanced stages with distant metastasis, curative surgery is not always the first treatment option. Instead, neoadjuvant therapy may be administered beforehand to reduce tumor burden [12]. A prior examination of six randomized trials, involving individuals with locally advanced cervical cancer who underwent NACT before undergoing surgery, found that NACT significantly reduced tumor size, invasion depth, and nodal metastasis [8]. However, studies on the effectiveness of NACT in patients with HGNECs of cervical cancer are lacking. Therefore, we aimed to share our single-center experience of treating patients with HGNEC who underwent NACT before radical surgery.

We found that the median tumor size decreased slightly in both groups, but the change was not statistically significant (Table 2). Furthermore, there were no significant differences in pathological risk factors between the two groups. However, we noted that the NACT group had a higher intraoperative transfusion rate (p = 0.052) because this group had some tissue changes caused by NACT, which resulted in a bleeding tendency during the operation (Table 4). In addition, since patients undergoing surgery after NACT are at risk of perioperative anemia due to myelosuppressive chemotherapy [13], they are more likely to receive transfusions during the operation.

Clinicians chose additional treatments depending on their decisions, and we found that the adjuvant treatment modality was not a significant prognostic factor for survival. Some retrospective studies comparing NACT followed by surgery with concurrent chemotherapy have shown improved survival outcomes; however, as these studies were retrospective or non-randomized, they cannot be suggested as a standard therapy for cervical cancer [14, 15, 16]. Another individual patient meta-analysis showed that there was an absolute benefit in overall survival in NACT followed by surgery; however, all of these groups received either chemotherapy or radiotherapy afterward, making it unclear which adjuvant treatment was superior [14]. Tumor size is another prognostic factor, with maximum benefits reported in patients with stages IB2 and IIB [17]. In our study, we found no significant difference in the overall survival rates between the two study groups, indicating that NACT followed by surgery did not yield favorable survival outcomes.

Data on the effect of NACT on HGNEC remains undetermined [18, 19]. Lee et al. [18] reported that patients with stage IB-IIA small cell neuroendocrine carcinoma (NEC) who underwent NACT followed by surgery had worse survival outcomes. This multicenter study included 11 patients who received neoadjuvant chemotherapy [18]. According to a study by Wang et al. [19], patients who received NACT tended to have worse failure-free survival (41.2% vs. 60.5%, p = 0.086) than those who underwent primary surgery, regardless of adjuvant therapy. This study included all disease stages. Six patients (16.7%) underwent neoadjuvant chemotherapy followed by surgery, while five patients underwent perioperative chemotherapy plus surgery [19].

According to a recent reviewer, the implementation of immunotherapy and targeted therapy has demonstrated advantages for individuals diagnosed with cervical cancer [20]. Research has indicated that human papillomavirus (HPV)-related cervical cancer demonstrates heightened expression of programmed cell death ligand 1 (PD-L1) [21], with HPV16 E7, in particular, possessing the capability to directly stimulate PD-L1 expression [22]. There have been reports suggesting that the majority of small cell neuroendocrine cervical carcinomas, a subtype of HGNEC, are associated with HPV infection [23, 24, 25]. Considering this, suggesting that the introduction of immunotherapy, such as pembrolizumab, may lead to favorable outcomes in patients with HGNEC. Further studies are required to validate these hypotheses.

This study has some limitations. First, although the current standard is the FIGO 2018 staging system, we used the FIGO 2009 staging system to stage all patients because the data were collected from 1993 to 2017. In the FIGO 2018 system, the stage is classified as IIIC if there is lymph node metastasis, which recommends concurrent chemoradiation therapy as the standard treatment. Fortunately, our study population did not show any lymph node metastases on preoperative images. Additionally, the treatment recommendation for FIGO staging is limited to cervical cancer of common cell types [26], which may not be applicable to neuroendocrine carcinomas. Secondly, although all NACT regimens were platinum-based, the lack of uniformity could be a potential limitation. Another limitation of our study is its small sample size, which was due to the rarity of neuroendocrine carcinoma in cervical cancer. However, it is evident that the groups receiving neoadjuvant chemotherapy were very small in previous studies [18, 19], and our study is among the larger ones.

Although neoadjuvant chemotherapy followed by surgery was feasible, it failed to improve survival outcomes. Further studies investigating more effective therapies are required to improve the DFS of patients with cervical HGNEC.

DFS, disease-free survival; HGNEC, high-grade neuroendocrine carcinomas; NACT, neoadjuvant chemotherapy; OS, overall survival; PD-L1, programmed cell death ligand 1; PSM, propensity score matching.

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

HE and JuHK had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: HE, JuHK, YKS. Acquisition, analysis, or interpretation of data: HE, YKS, JuHK, YMK, JongHK, DSS, DYK, JYP. Drafting of the manuscript: HE, JuHK, YKS. Critical revision of the manuscript for important intellectual content: HE, JuHK, YKS. Statistical analysis: HE, YKS. Administrative, technical, or material support: HE, YKS, JuHK, YMK, JongHK, DSS, DYK, JYP. Supervision: JuHK. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study was approved by the institutional review board of Asan Medical Center (approval number: 2022-1406; approval date: June 28, 2022). The requirement of informed consent was waived because of the retrospective study design.

We express our gratitude to all those who helped us write this manuscript. We thank all peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflicts of interest. Jeong-Yeol Park serves as an Editorial Board member of this journal. Jeong-Yeol Park was not involved in the peer review of this article and had no access to information regarding peer review. Full responsibility for the editorial process of this article was delegated to Yasuhiko Ebina.