The clinicopathological features and treatment modalities associated with survival of neuroendocrine cervical carcinoma in a Chinese population

Neuroendocrine cervical carcinoma (NECC) is a rare but aggressive form of cervical cancer, as it accounts for less than 3% of all cervical cancer cases [1].

NECC consists of four histologic subtypes (small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, typical carcinoid tumor, and atypical carcinoid tumor) [2]. The most common type of NECC is small cell carcinoma of the cervix (SCCC), which seems to be highly aggressive and to have a worse prognosis compared with squamous cell carcinoma and adenocarcinoma of the uterine cervix [3, 4]. Although NECC can also be mixed with other histologic types, such as squamous cell and adenocarcinoma, and the presence of the NECC component defines the clinical behaviour, the tumor should be treated according to the therapeutic regimen of NECC [2].

As we know, primary surgery and primary radiation therapy result in similar survival rates for early-stage cervical cancer of common histological types [5]. However, for NECC tumors that are ≤4 cm in size, the Society of Gynaecologic Oncology (SGO) and the Gynaecologic Cancer InterGroup (GCIG) both recommend that radical hysterectomy with lymph adenectomy followed by the administration of adjuvant etoposide/platinum-based therapies should be the preferred choice of treatment [2, 3]. For NECC tumors that are > 4 cm in size, neo-adjuvant chemotherapy (NACT) is recommended, followed by comprehensive treatment including surgery, once the tumor has been limited. These recommendations are based on limited data and are instructive for the basic treatment of NECC, but the complex treatment of NECC is not uniform in many places.

The aim of the present study is to evaluate the prognostic factors of overall survival and to examine the effects of treatment on the overall survival of patients with NECC.

Currently, due to the low incidence of NECC, most studies on NECC are comprised of limited series and case reports, which often do not include large sample sizes and prospective international studies. Therefore, it is difficult to establish appropriate guidelines for patients with NECC, only a small proportion of patients benefit from the current treatment options [6]. In our study, we performed a retrospective cohort study that consisted of 89 Chinese patients with NECC to investigate the potential prognostic factors and the optimal local treatment modalities for NECC.

The majority of stage I–IV patients (82.02%) in this study were treated with surgery as the primary treatment. The univariate analyses showed that features such as advanced FIGO stage, tumor size > 4 cm, LNM and LVSI exhibited a poorer survival, which suggests that they are high-risk factors for the recurrence and metastasis of NECC. However, the multivariate analyses showed that FIGO stage, tumor size, LNM and LVSI were not independent prognostic factors. The positive rate of LNM and LVSI in our study was 31.5 and 37%, respectively. However, a previous study of 188 patients showed that the positive rate of LNM and LVSI was 49.5 and 69.4%, respectively [1].

The 5-year OS rate of our patients with stage I-IIA NECC was 47.7%, which is consistent with the 5-year OS rates of 46.4, 46.6 and 45% for patients with stage I-II SCCC reported in previous studies [7‐9]. In our study, radiation was given to 19 (27.9%) stage I–IIA patients. NACT was given to 34 out of the 68 stage I–IIA patients who underwent primary surgery. We have shown that neither RT (P = 0.129) nor NACT (P = 0.785) was prognostic factors for the survival of stage I–IIA patients with NECC. It has been demonstrated that those who received RT vs no RT had a 5-year survival of 6.4% vs 26.9%, respectively (P = 0.015), which suggests that RT resulted in no benefits on survival [1]. Another study showed that adjuvant chemoradiation did not improve survival compared with adjuvant chemotherapy alone [10]. The prognostic effects of RT and NACT according to pathological features were also examined among patients with stage I-IIA NECC. In contrary to our expectation, the patients without LNM who underwent surgery and who received postoperative RT did not have a significantly better survival rate than patients who did not receive RT. In agreement with our findings, a study by Huang et al. [11] found that patients who received RT tended to have a poorer survival rate than those who did not receive RT. Another study also reported that patients who received primary cancer-directed surgery (CDS) had a better survival rate compared with patients who received combined CDS and RT treatment or RT alone [8]. In addition, patients with LVSI, a tumor size > 4 cm or a DOI > 2/3, who received RT did not show any difference in overall survival, compared with those who did not receive RT. It indicated that RT might have little effect on disease control. The mechanism of poor survival of patients with no LNM who received postoperative RT remains to be elucidated. Perhaps the main reason is that those patients may have high-risk factors for metastasis and recurrence such as parametrial invasion and positive resection margins. Previous studies recommended NACT as the treatment of choice in patients with NECC with a tumor size > 4 cm [10, 12]. In contrast, Lee et al. [8] reported that patients who received NACT showed a poorer prognosis than those who did not receive NACT. Also, we found that patients who received NACT did not have a significantly lower risk of death compared with those who did not receive NACT. Based on these results, we suspect that NACT does not contribute to the reduced risk of metastasis and recurrence of NECC, although NACT might be useful for enhancing the resectability of bulky tumors. Moreover, patients who receive NACT usually have larger tumors, which indicate that the size of the tumor may affect patient survival. In addition, the development and prognosis of cancer is a complex and multifactor process. Genetic variants, in particular single nucleotide polymorphisms (SNPs), are associated with cancer survival. Next, we will assess the possible prognostic ability of genetic variants on NECC survival in future studies.

This study has some limitations that should be considered. First, due to the relatively small sample size of our study, other studies with larger sample size are needed to confirm our findings. Second, our study is based on a Chinese population; thus, the impact of each treatment modality on the survival outcome in different populations with NECC needs to be tested further. Third, chemotherapy is likely to enhance the survival of patients with stage IIB-IV NECC. However, we did not investigate the effects of chemotherapy because we did not have sufficient patient clinical information.

In conclusion, advanced FIGO stage, tumor size > 4 cm, LNM and LVSI were associated with a significantly worse survival for patients with NECC according to the univariate analysis, but they were not independent prognostic factors in the multivariate analysis. Neither RT nor NACT showed a favourable effect among these patients. Furthermore, for stage I–IIA NECC, RT should be carefully used in patients without LNM. NACT may not be the optimal treatment for tumor size > 4 cm.