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.