Results
We yielded a total of 1261 publications by database searches, of which
131 studies were identified after exclusion of reduplicative and
irrelevant studies. After abstracts screening, 73 unique studies
remained, and all full texts were obtained. After reviewing of the full
texts, we excluded 44 studies. The reasons for each exclusion of these
studies were listed in supplementary (p8–9). Besides, we obtained five
reports of unpublished data and two of them were eligible (supplementary
p15–16). Finally, 31 eligible studies (29 publications) were included.
Figure 1 displays the PRISMA (2009) flow diagram for study selection.
The
publication
years of the 31 identified studies were between 2002 and 2019. Most of
these studies were done in Europe, Asia, and the USA. A total of 1887
eligible patients were identified from the 31 studies. Each of them
underwent SLNB for cervical cancer, with at least one SLN detected and
examined by intraoperative FSE.
The characteristics of the 31 finally included studies were listed in
supplementary (p17). Patients with early-stage disease accounted for
66.1–100% of whole populations, with 19 out of 31 (61.3%) studies
having 100% patients at early stage. The most common histological types
were squamous cell carcinoma, followed by
adenocarcinoma. The rate of nodal metastasis
varied between 5.4–36.4% among the included studies.
The surgical approaches were affected by the FSE results in 18 studies,
of which 13 performed additional para-aortic lymphadenectomy in positive
cases. Only four studies omitted PLND in cases of negative FSE. Four
studies applied negative FSE as a prerequisite of fertility
preservation. Eight studies transferred radical surgeries to concurrent
chemoradiotherapy in positive cases. Besides, one study performed simple
hysterectomy in cases of negative FSE. Twelve studies reported follow-up
results and the oncological outcomes were generally good (supplementary
p22).
The sectioning protocols of FSE consisted of three different approaches
as following:
- SLN was bisected, one section was
taken from the maximum surface of one half SLN (9 studies);
- SLN was bisected, adjacent sections were taken from the maximum
surface of each half SLN (4
studies);
- SLN was cut into pieces at certain intervals (varied from 2 to 5 mm,
perpendicularly to their long
axis), and one or more sections were taken from each piece (13
studies).
For subgroup analysis, we defined the two “bisected” protocols
together as equatorial (E), and
the third one as latitudinal (L)
(figure 2). The next steps were similar in which the sections were
examined after staining with hematoxylin and eosin (H&E) and the rest
tissue were embedded in paraffin. For DPE, additional ultrastaging were
performed in 24 studies, while routine pathological examination was
performed alone in seven. Among the 24 studies using ultrastaging,
serial sectioning
combined
with immunohistochemistry (IHC), serial sectioning alone, and IHC alone
were performed in 18, 2 and 4, respectively.
In published pathological studies
at least four further step
sections combined with IHC examination were recommended for SLN
ultrastaging.38 We utilized this
criterion to evaluate the
stringencies of ultrastaging techniques and their potential influences.
DPEs meeting this criterion were judged as adequate, otherwise as
inadequate. The descriptions and judgements of FSE and DPE protocol for
each study were presented in supplementary (p20–21).
The process of data extraction for meta-analysis were detailed in
supplementary p10–16. Overall, there were 363 patients having SLN
metastases confirmed by DPE, of whom 115 were misdiagnosed by FSE. The
sensitivities of FSE varied over a wide range of 0%–100% among the 31
included studies (table 1).
Specificities
were 100% in all studies except two reporting false positive. Both were
due to misdiagnosis of endosalpingiosis in SLN.6,30Pooled analysis using mixed-effect model yielded an estimated rate of
0.77 (95%CI: 0.66–0.85, figure
2) for sensitivity. Heterogeneity
test for sensitivities showed
high
heterogeneity among the included studies (Q=99.09,I 2=69.73%, p<0.001).
Among 26 studies with definable pathological protocols, 19 reported FN
results. The metastatic types of FNs were available in 18 studies,
including 24 MAM, 51 MIM, and 29 ITC in 101 patients (table 2). The
metastatic types of TPs were available in nine studies, including 95
MAM, 14 MIM, and one ITC in 110 patients (table 3). The pooled
sensitivity of FSE were 0.79 (95%CI: 0.70–0.86) if ITC were not
considered, and 0.94 (95%CI: 0.85–0.98) if only MAM was considered.
Notably, only four of the 24 (16.7%) FN-MAM were missed, whereas 13 of
the 15 (86.7%) TP-MIM/ITC were detected under L-protocol.
We conducted meta-regressions to investigate the source
of heterogeneity in sensitivities.
Studies were categorized into subgroups by the study design (prospective
and retrospective), SLNB strategy (whether the surgical approaches were
affected by FSE results: yes and no),
sample
size (<60 and ≥60), overall metastatic rate (<20%
and ≥20%),
reference
standard (DPE protocol: adequate and inadequate), and index test (FSE
protocol: E and L). Five studies were excluded from meta-regression due
to undefinable methodologies. Finally, FSE protocol was found to be the
only source of heterogeneity (p<0.001, table 4).
Subgroup analysis showed decreased heterogeneities in both subgroups
stratified by FSE protocol (Q=7.59, I 2=0%,
p=0.82 for L-protocol; Q=28.90, I 2=58.47%,
p<0.001 for E-protocol). The sensitivity pooled achieved 0.86
(95%CI: 0.79–0.91) in the L-protocol subgroup (13 studies, 650
patients), whereas it was 0.59 (0.46–0.72) in the E-protocol subgroup
(13 studies, 1047 patients). The difference reached statistical
significance (P<0.001). If ITC was not considered, the pooled
sensitivities would be 0.88 (0.81–0.93) and 0.64 (0.52–0.75) for L and
E-protocol subgroup, respectively (p<0.001). If only MAM was
considered, the pooled sensitivities would be 0.97 (95%CI 0.89–0.99)
and 0.86 (0.74–0.93) for L and E-protocol subgroup, respectively
(p=0.01). In sensitivity analyses (supplementary p23–27), whatever the
alterations made in study setting or statistical model, the observation
that sectioning protocol determined the accuracy of FSE,
remained unchanged.