Interpretation
In our study, we identified possible tumor-related factors to analyze the prognostic impact of NECC. We found that mixed pathology was a positive prognostic factor for patients with NECC. In NECC, SCNEC is the most common subtype, followed by LCNEC, and most patients seldom show well-differentiated NECC [11]. All patients in this study showed SCNEC and LCNEC histological subtypes. Some of these patients also showed a combination of these subtypes with other types of cervical cancers, such as SCC and AC. Among them, 27 patients (46.6%) showed a mixed subtype, and seven of them had three histological subtypes. Compared to those of squamous cell carcinoma (SCC) and adenocarcinoma (AC), the five-year cancer-specific survival rate of NECC was lower (48.4% vs. 54.7% vs. 60%),[12] and a population-based cohort study included in the SEER database conducted from 1973 to 2002 also showed that patients with SCNEC and AC had lower chances of survival.[13] Meanwhile, another study found that the survival rate for NECC was lower than that for SCC in stages IB–IIA (P <0.001) and stages IIB–IVA (P <0.001).[14] Hence, the presence of other common subtypes may result in better outcomes. As a result, we hypothesize that the proportion of histological subtype has a particular role in the prognosis of the disease, and hence, paying attention to pathological results and a correct pathological diagnosis are crucial. In addition to the typical pathological features, immunohistochemistry is frequently used to identify the pathological type. The most common immunohistochemical evaluations for NECC include the examination of neuroendocrine markers chromogranin, CD56, synaptophysin (Syn), and thyroid transcription factor (TTF1).[15] In our study, 38, 34, 16, and 32 patients were positive for Syn, CD56, TTF1, and P16, respectively. The diagnosis of the disease was aided by all immunohistochemical markers. However, we did not analyze the proportion of different histological subtypes.
Surgery is typically used to treat patients with NECC in the early stages, whereas chemotherapy and/or radiotherapy are used to treat NECC in the advanced stages. Upon restaging all patients based on the 2018 FIGO stages, 17 patients showed the IIIC stage. According to the NCCN guideline, all patients underwent radical hysterectomy and received postoperative adjuvant treatment based on the pathological findings. Numerous retrospective studies showed that patients with NECC treated with adjuvant chemotherapy and radiotherapy could show better outcomes compared to those who were not treated with the aforementioned therapies. Multivariable analysis showed that early-stage NECC and the use of chemotherapy or chemoradiation were independent prognostic factors for improving survival. [16] Another systematic review presented that multimodality treatment with radical surgery and adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy are primary treatments for early-stage NECC.[17] According to Pei et al., the EP regimen administered for at least five cycles after radical surgery improved long-term recurrence-free survival over other treatments (67.6% versus 20.9%, P 0.001).[18] Our results were consistent with these findings. We found that radical hysterectomy plus adjuvant EP chemotherapy showed better survival outcomes. Furthermore, patients who did not receive adjuvant chemotherapy showed better outcomes than those who received adjuvant non-EP chemotherapy. However, another retrospective analysis examining the postoperative adjuvant therapy postulated that postoperative chemotherapy with carboplatin plus paclitaxel (TC) may improve the OS (P=0.016) and disease-free survival (P=0.018) in women with early-stage SCNEC.[18]Furthermore, Zhang et al. also presented the same conclusions for advanced-stage NECC.[8] Besides, other contrasting opinions have also been published. A recent study reported that adjuvant therapy did not significantly impact survival in LCNEC.[19] In addition, with median survival durations of 84.7 and 89.1 months, Lan-Fang et al. showed no statistically significant differences in survival between patients treated with postoperative adjuvant chemotherapy and adjuvant chemoradiotherapy (P= 0.671), respectively. [20]Their findings did not demonstrate the correlation between adjuvant therapy and survival rates. According to a systematic analysis, adjuvant radiotherapy did not appear to significantly enhance prognosis, and preoperative chemotherapy combined with adjuvant chemotherapy may be a superior approach.[21] Although numerous studies have been conducted examining the impact of adjuvant treatment on NECC, no consensus has been established. Hence, more studies are still required.
Clinicopathological factors, such as tumor size, staging, surgical margins, uterus invasion, parametrium invasion, LVSI, depth of stromal invasion, lymph node metastasis, and histological subtypes are used to evaluate the prognosis of cervical cancer.[22-23]Via Kaplan-Maier survival analysis, we showed that uterus invasion, parametrium invasion, and surgical margins were prognostic factors affecting survival. However, COX multivariable analysis showed that only uterus invasion was a poor prognostic factor related to the OS. Even the tumor size was not correlated with the prognosis. This may be attributed to the limitations of this study conducted in a small number of patients owing to the rarity of NECC. A retrospective analysis of 172 patients with NECC showed that larger tumor size (<4 vs. ≥4 cm: 80.1% vs. 49.0%, P= 0.02) was an important prognostic factor for OS, along with lymph node metastasis. Patients without pelvic lymph node metastasis exhibited higher five-year OS and five-year PFS (68.0% vs. 41.6%, P = 0.0028 and 62.6% vs. 29.3%, P = 0.019, respectively).[24] Another retrospective cohort study examining outcomes of minimally invasive surgery in patients with early-stage NECC also reached the same conclusion with respect to lymph node metastasis. Their study showed that lymph node metastasis and resection margin were adverse prognostic factors for survival; however, the authors did not find any relevance of the OS with respect to LVSI, depth of stromal invasion, and tumor size.[25] The results of these studies are inconsistent, which may be attributed to differences in the sample size and data sources.
NECC is a rare and highly aggressive type of cervical cancer and metastasizes mainly via lymph and blood. Hence, distant metastasis is a common event in NECC. In our study, most patients were diagnosed at early stages; however, 23 patients (39.7%) showed distant metastasis. The most common organs of metastasis were the lungs, followed by bones and livers. Another study reported approximately 50% of disease recurrence rate, which was consistent with our statistical results. They presented that distant organs, including the liver (13/31, 41.9%), lungs (11/31, 35.5%), bone marrow (4/31, 12.9%), and brain (3/31, 9.7%), were typical sites of metastasis. [18]Since NECC is prone to recurrence, other treatment options should be considered. Tangjitgamol S et al. presented that HER-2 expression was substantially related to survival; patients with negative HER-2 expression tumors had shorter survival duration than those with positive HER-2 expression tumors(p=0.03).[26] Another clinical study supported this finding. The authors presented that over-expression of VEGF and HER-2 is linked with poor prognosis in common cervical cancer.[27] These findings may demonstrate other possibilities for the clinical treatment of NECC, such as targeted therapy. Moreover, immune checkpoint inhibitors may also be beneficial for survival. Upon examining 20 patients with advanced NECC who did not undergo surgery, Ji et al. showed that the PD-L1 and PARP1 positivity rates were 70% and 75%, respectively. These findings implied that immunotarget therapy may be used to treat NECC.[28] In extensive-stage small-cell lung cancer, atezolizumab (a PD-L1 inhibitor) plus chemotherapy is the first line of treatment.[29] Therefore, PD-L1 inhibitors may show great potential for NECC treatment. However, evidence of their efficacy is lacking.