Interpretation
In this study we found that many pathologists examined only one
H&E-stained frozen section for each SLN
in
order to reserve more tissue for DPE.25-29 This
consideration may be more reasonable for assessing SLN of breast cancer,
in which the axillary
lymphadenectomy can be performed asynchronously and usually replaced by
chemoradiotherapy.56 Actually, the use of FSE in SLNB
for breast cancer has significantly decreased during the past
years.57 In early-stage cervical cancer, however,
recent viewpoints have begun to emphasize the avoidance of combination
of surgery and radiotherapy, since there was a significantly increased
morbidity.14 So the management will be challenging
once the FSE result was found to be false. Therefore, best efforts are
required in intraoperative diagnosis and the FSE protocol should be
given enough attention,
especially
in
fertility-preserving
surgeries.58
Generally,
FN results can be caused by technical errors in sectioning processes or
judgment errors in
reviewing
processes. Gortzak-Uzan and colleagues49 reported a
technical error on MAM with diameter of 4-mm, which was not observed in
the frozen sections but hided in the remaining tissue. Only four MAM
were missed among the 13 studies using L-protocol. However, such FN
results seemed more common in the studies using E-protocol since there
were 20 MAM omitted in total. In the study by Slama and
colleagues29 one-level section was examined for each
node and nine of 48 MAM were missed by FSE. The median diameter of these
FN-MAM was 3.94 mm and the largest one reached 8.4 mm, which could
hardly be neglected in reviewing processes. So, it is reasonable to
speculated that most of these FNs were technical errors and could have
been avoided by taking sections at short intervals.
Some may doubt that the high FN rates were due to strict ultrastaging in
which more occult metastases might be
revealed. This explanation also seems reasonable. However, in this
meta-analysis, most of the studies used both serial sectioning and IHC
examination for ultrastaging. We classified these techniques using a
recommended criterion by previous pathological
studies.38 Yet only the FSE protocol was found to be a
source of heterogeneity in meta-regression, whereas the DPE protocol
showed
minimal
impact on sensitivity. This observation was further confirmed by
sensitivity analyses (supplementary). A more reasonable explanation is
that, in E-protocol more lymph tissue was reserved for DPE, which
inevitably carried higher opportunity to have metastasis within,
regardless of the method for detection.
The clinical significance of MIM/ITC in SLN remains to be
clarified.59,60 Okamoto and colleagues found that
non-SLN were seldom involved if SLN harbored merely
MIM/ITC.61 In the SENTICOL study, only one recurrence
was observed among 16 patients having MIM/ITC in
SLN.10 Besides, three included studies showed
favorable oncological outcomes despite that PLND were omitted in FN-FSE
cases.6,15,49 Taken together, these evidences
suggested that MIM/ITC only represented the very beginning of lymphatic
spread, and their impacts might be negligible provided that metastatic
SLNs were removed. This inference was encouraged by the findings from a
breast cancer study (IBCSG 23-01) supporting the exemption of axillary
lymphadenectomy in patients presenting only MIM/ITC in
SLN.5 If MIM/ITC was not considered, the pooled
sensitivity for L-protocol would reach 0.97 (95%CI 0.89–0.99), which
is high enough for intraoperative decision-making.
In the E-protocol subgroup there remained moderate heterogeneity in
sensitivities, which may due to the remaining methodological difference.
Since our aim was to determine the optimal protocol, the heterogeneity
in this subgroup was less important. The sectioning intervals were 2–5
mm in L-protocol and the pooled sensitivity further increased when we
restricted the criterion (supplementary p18). However, shortened
sectioning intervals may increase the pressure upon pathologists and
result in loss of tissue for DPE.18 Yamashita and
colleagues examined 3 to 5 sections for each SLN and reported that the
diagnosis usually finished within 30 minutes.30 This
may be a rational workload.
The survival data of patients whose PLND were exempted for negative
FSE-SLN is still insufficient. Only three observational
studies6,15,49 and one randomized controlled trial
(SENTICOL II=NCT01639820)7 had addressed this issue
and the outcomes were generally good. However, the sample sizes of these
studies are relatively small. High-quality evidence should be expected
from several ongoing multicenter trials (SENTIX=NCT02494063,
CSEM010=NCT02642471, SENTICOL III=NCT03386734, supplementary p28) in
which patients with FSE-negative SLN are exempted from further
PLND,37 or intraoperatively randomized into arms with
or without PLND.36 The suggestion by this
meta-analysis is to adopt L-protocol to reduce
the risk of
inadequate treatment and ensure
the
applicability
of future findings.