Interpretation
We found that among patients with metastases, 95.65% had SLN
metastases, suggesting that SLN is a rather sensitive assessment
indicator of metastatic lymph nodes. Among methods of assessing the PLN
status, SLNB is more suitable than imaging
techniques16. Moreover, compared with PLND, SLNB
reduces complications of PLND17, and no difference was
observed in the recurrence-free survival rates of PLND and SLNB by a
prospective trial18. Therefore, SLNB may be used as an
alternative to PLND to prevent unnecessary and harmful interventions.
In this study, we explored the new
application value of CNS as a promising SLN tracer for SLNB in
early-stage cervical cancer. CNS is an advanced nanotechnology that
consists of small molecules with lymphatic tropism. CNS with
nanoparticles measuring 150 nm in diameter can pass readily through
lymphatic vessels (diameter: 120–500 nm), but not through capillaries
(diameter: 20–50 nm). Then, the CNS is identified, engulfed by
macrophages, and brought to lymphatic vessels, such that it accumulates
in the lymphatic system; therefore, CNS effortlessly stains lymph nodes.
No patient exhibited anaphylactic reactions or serious adverse events in
this study; this may be because CNS does not enter the bloodstream.
Accordingly, SLNB with CNS should be considered safe. In recent years,
CNS has proven to be beneficial as a lymph node tracer that allows lymph
nodes to be explored during surgery for breast cancer, thyroid cancer,
and gastric cancer19-21. For cervical cancer, the
application of CNS was attempted with SLNB in a limited sample size of
40 patients in 2017, with DR of 95% (38/40), sensitivity of 100%
(5/5), and NPV of 100%22. Therefore, our study was
the first prospective study with a large sample size; it demonstrated a
promising overall DR (91.29%), sensitivity (92.86%), and high NPV
(99.29%), especially for patients with tumours smaller than 20 mm
(97.75%, 100%, and 100%, respectively), thereby indicating its
clinical value for SLNB in early-stage cervical cancer.
These indicators mentioned above in the first prospective multi-centre
study that enrolled 590 patients, using technetium
(99mTc) and patent blue were 88.6%, 77.4%, and
94.3%23. In a recent systematic review, indocyanine
green (ICG) used in SLNB had a reported DR of 78% to 100% and
sensitivity of 50% to 100%24. However, the tracers
reportedly had some limitations. Their dependence on special expensive
imaging technology could deter their use in developing
countries25, additionally, its use is technically and
logistically challenging. The 99mTc is expensive and
produces radioactive contaminants; The blue dye is associated with
allergic reactions, blue discoloration of body fluids, and rare
cardiovascular reactions26-27. Therefore,
compared with the traditional
agents mentioned, CNS in SLNB for early-stage cervical cancer not only
has good diagnostic accuracy but is also safer, more economical, easier
to use, and not dependent on imaging technology.
According to our data, 85.71% of detected 1456 SLNs were in expected
locations (i.e., iliac vessels and obturator). Less common locations
were the aortic (6.94%), presacral (4.33%), and parametrial (3.02%)
regions. This is consistent with the results of a review of 3012 SLNs
(blue dye and 99mTc) 28. Therefore,
SLNB helps surgeons not only during direct SLN resection with less
disruption of the lymphatic architecture, thus making the procedure
easier and faster18, but also in identifying occult
SLNs outside the traditional dissection boundaries.
When trying to determine which subgroup of patients can obtain more
benefits from SLNB, we found that the DR of patients with <20
mm tumours was significantly higher than that of patients with ≥20 mm
tumours. Moreover, the sensitivity,
specificity, and NPV of SLNB also improved in patients with
<20 mm tumours. Similar
outcomes were reported in a prospective multi-centre
study22 and a review that assessed more than 600 cases
(blue dye and radio-colloid)29. Therefore, SLNB with
CNS is a promising procedure for well-selected early-stage cervical
cancer patients, such as patients with tumour size <20 mm.
The FNR in our study is 7.14% (two false-negative cases
with negative pathologic
ultrastaging results), and it ranged from 0% to 50% in previous
studies30. We implemented an ideal pathologic
ultrastaging method to detect micro-metastasis, to further explore the
causes of the two false-negative cases31; negative
results were obtained, that have appeared in previous
report32. Furthermore, the common characteristics of
these two patients were summarised: tumour diameters larger than 20 mm
with presence of DSI and LVSI (Table S3). These findings are consistent
with those of previous studies that reported that FNR was higher for
larger tumours (>20 mm), those with DSI (≥50%), and those
with LVSI (blue dye, radio-colloid, and ICG)16,33-34.
The prevalence can be attributed to the hypothesis that metastatic
disease can alter the lymphatic drainage pattern35.
Cancer cells spreading from the primary cancer mass may block the
lymphatic path to the first lymph node or nodes. This may explain why
there were few cases with failed SLN detection or false-negative
results. Regarding the false-negative results, the lymphatic drainage
and tracer may bypass the true SLN, which may be falsely recognised as
an alternative node (a true non-SLN)36-37. This
situation may result in false-negative cases.
Previous studies demonstrated that DSI, LVSI, large tumour size, and
positive PLNs were prognostic factors for clinical
outcomes38-39, and
that tumours larger than 20 mm and
positive LVSI and DSI were significant risk factors for pelvic nodal
metastasis40-41. We also found that tumours size,
stage, and LVSI are independent risk factors for lymph node metastasis.
The results of our study (CNS) are consistent with those of previous
studies (blue dye, radio-colloid and ICG), which showed that FNR was
higher for larger tumours (>20 mm), those with DSI (≥50%)
and those with LVSI16,33-354. Therefore, to avoid the
risk of false-negative cases and improve clinical outcomes, SLNB is more
suitable for well-selected early-stage cervical cancer patients,
especially in patients with tumours smaller than 20 mm, without DSI and
LVSI, which are more likely benefit from SLNB. More clinical studies are
required to confirm it.