Abstract
Sentinel
lymph node (SLN) refers to the initial site of the lymphatic drainage
from a primary tumor area. Accordingly,
sentinel
lymph node mapping (SLNM) has been brought up and widely applied to
cancer therapy for its
illuminating
role in clinical lymph node resection.
Furthermore,
sufficient
information to guide surgical pathological staging and adjuvant
treatment in endometrial cancer can be rendered by SLNM, hence
minimizing surgery injury and
reducing
the incidence of complications.
This
review aims to systematically summarize the advances and application
prospects of SLNM in endometrial cancer, with an expectation of
furnishing
reference for the clinical application.
Keywords:sentinel
lymph node,
endometrial
cancer, sentinel lymph node mapping
Introduction
Initially
put forward in 1960, sentinel lymph node (SLN) is defined as the first
site of lymphatic pathway passing lymphatic metastasis from a primary
malignant tumor,
which
can forecast
the
involvement of lymph nodes across the
drainage
area[1].
And
it has been widely acknowledged that
in
the
lymphatic
system,
lymph
drains away from the primary tumor site in an orderly manner, thus
suggesting that
the
metastatic state of SLN (negative or positive) can indicate the state of
subsequent lymph nodes and the metastasis of tumor[2].
Based
on the notion stated above,
sentinel
lymph node mapping
(SLNM)
as
an image-guided
procedure
to provide ideas for clinical decision of lymph node resection, has been
brought
up and widely applied to cancer therapy, such as penile carcinoma[3], breast cancer[4]and melanoma[5].
As
for
endometrial
cancer, although the application of SLNM was raised as early as in 1996[6], it has only been given unprecedented
attention in recent years.
Endometrial
cancer is one of the most common malignant tumors of the female
reproductive system with rapidly increasing incidence these years[7].
According
to the National Cancer Institute (NIH), there will be an estimated
65,950 new cases of the uterine cancer diagnosed and more than 12,550
deaths in 2022, making uterine cancer the ninth most prevalent cancer in
the United States
(https://seer.cancer.gov).
Currently,
the standard surgical management (NCCN guidelines version 1.2022 -
uterine neoplasms) is still the mainstay of endometrial cancer
treatment, basically covering total hysterectomy,
bilateral
salpingo-oophorectomy (BSO) and pelvic lymphadenectomy (LAD),
occasionally coupled with para-aortic lymphadenectomy (PALAD).
However,
two large randomized controlled clinical studies all revealed that
despite its statistically outstanding efficacy,
it
turned out that LAD not beneficial to ameliorate progression free
survival (PFS) and overall survival (OS) for patients with early-stage
endometrial cancer [8, 9].
Therefore,
selective lymphadenectomy
(SLAD),
generally guided by SLNM, provides an alternative to LAD by precisely
removing a small number of high-quality lymph nodes and
minimizing
surgical injury without affecting patient prognosis[2,
10].
Conclusively,
this review aims to systematically introduce the advances of SLNM in
endometrial cancer and discuss potential application, looking forward to
its future development.
2.
Thetechnique
advances of SLNM
The
most primary objective of
SLNM
is to directly demonstrate the metastatic status of lymph nodes during
surgeries in a visible way, hence precisely limiting the dissection of
lymph nodes and avoiding systemic lymphadenectomy to the maximum extent[11].
Whether
this objective can be achieved or not in
endometrial
cancer largely depends on the selection of tracer and its injection
methods.
2.1
Injection tracer
Currently,
common
tracers
of SLNM include fluorescent
dyes,
blue dyes, radioactive dyes and
carbon
nanoparticles [12, 13].
These
dyes can be used alone or in combination [14].
Fluorescent
dye indocyanine green (ICG), a safe and effective agent for SLNM, has
emerged as the most recommended tracer for intraoperative detection of
SLN in
endometrial
cancer owing to its higher sensitivity and specificity compared with
conventional tracers (blue dye and radiotracer) [15,
16, 17].
In
fact, Backes et al. found that in contrast with ISB, ICG was
conspicuously more effective in detecting SLN (ICG’s detection rate is
83% while ISB’s is 64%) [18].
Under
the stimulation of near-infrared ray (700-900 nm), fluorescence can be
emitted from lymphatic drainage vessels and lymph nodes due to
the
presence of ICG[19].
And thanks to its low
autofluorescence
and high tissue
penetration,
ICG possesses superior signal-to-noise ratio and can show deep-lying
lymph nodes, hence making it particularly appropriate for obese patients[20]. Furthermore, Papadia et al. reported
that in the application of SLNM in high-risk endometrial cancer
patients, ICG had acceptable sensitivity, false-negative rate, and
negative predictive value as well [21].
Yet
notably, ICG can result in more interstitial fluid to enter lymphatic
channels since it is albumin-bound and causes oncotic pressure. In a
consequence, lymphatics can probably and sometimes easily be mistaken
for lymph nodes because of their seemingly bigger and swollen appearance[22], suggesting that surgeons ought to be alert
of this pitfall in the application of ICG.
Blue dyes encompass methylene blue,
patent
blue
and
isosulfan
blue.
These
dyes can bind to serum proteins following interstitial administration,
which
can reach
peritumoral
lymphatic vessels and lymph nodes through
lymphatic
drainage[12].
With
no need for advanced imaging system equipment, it merely relies on
visual identification of SLNs, which promotes its feasibility[23].
Nonetheless,
blue dyes’ slow diffusion in lymphatic vessels possibly leads to a lower
detection rate [24].
What’s
more, the possibility of anaphylactic reactions to patent blue and
isosulfan blue during SLN biopsy has been reported[25, 26], together with the negative effects of
intradermal isosulfan dye injection on declined pulse oximetry[27].
Radioactive
tracers, such as technetium-99 ((99m)Tc) can reach the peritumoral lymph
nodes through lymphatic drainage and emits gamma rays with a high
concentration in the SLN [28].
And
its rays can be detected by gamma detector and single-photon emission
computed tomography (SPECT-CT) during the operation.
It
has been reported that the combinative use of technetium-99m and dyes
(ICG or blue dyes) has a remarkable detection rate[29].
Despite
the reality that Tc(99m) can penetrate into deep tissue, it still has
several drawbacks that cannot be neglected.
In
particular,
its
detection depends on special imaging equipment, which results in a
higher cost and inconvenience. Moreover, radioactive contamination can
potentially
occur.
All these shortcomings collectively limit its clinical use. But
surprisingly, evidence has confirmed that based on
Nanotop
compound ((99m)Tc Nanotop),
the
combination of radiocolloid and ICG is feasible and safe[30, 14].
Carbon
nanoparticles (CNPs), a sort of nanosized polymeric carbon granules with
an average diameter of 150 nm, are a novel injected suspension[31].
Previously,
it was mostly used in superficial tumors such as
breast
cancer [32] and thyroid cancer[33].
As
an emerging tracer, it has been applied in
tracing
lymph
nodes and sentinel lymph node detection of endometrial cancer[34]. Having been injected into the submucosal
layer around the tumor, CNPs can selectively enter lymphatic system due
to the interstitial-lymphatic fluid transport effect[31]. And since there is a difference in
respective permeabilities between lymph and blood systems, CNPs would
not permeate into the blood capillaries for its overlarge size, thus
implying that CNPs lead to few toxic side effects[35].
2.2
Injection method
While
direct peritumoral injection uniformly applies to
melanoma,
vulvar
cancer, and cervical cancer,
controversies
remain over selecting injection
methods
for SLNM in endometrial cancer due to the complex lymphatic drainage
pattern [36, 37, 38].
At
present,
main
injection techniques have been evaluated for SLNM in endometrial cancer,
including
cervical
injection,
hysteroscopic
or
transvaginal
ultrasound-guided
injection
and
sub-serosal
or myometrial injection.
Cervical
injection has been accepted and
recognized
by most surgeons for its
simple
operation without hysteroscopic surgery and high pelvic detection rate[38]. In
cervical
injection, superficial injection can penetrate uterine vessels, isthmus,
parametrial, and uterine body,
while
deep injection can reach para-aortic lymph nodes through pelvic funnel
ligament [28].
Therefore,
a combined superficial (1–3 mm) and deep (1–2 cm) cervical injection
is
adequate[2]. The different options for cervical injection
include a 2-sided option (3- and 9-o’clock) and 4-quadrant options
(3-,6-, 9-, and 12- o’clock; 2-, 4-, 8- and
10-o’clock).
Niikura et al.considered
that if
lymphatic
flow from the uterine cervix was comparable to that from the uterine
body in the same patient, then the injection into the cervix would
theoretically be more
precise[39].
Additionally,
cervical
injection is stable because of the rarity of
cervical
deformation
caused by
anatomic
variations (such as
myomas)
and cervical scar from prior procedures (such as conization history or
bulky
tumor infiltration) [2]. However, the probability
of missing occult para-aortic lymph nodes is the main argument against
the cervical injection[39].
Inspiringly,
patients
with any site lymph node metastases will receive adjuvant therapy, which
theoretically eliminates potential metastatic lesions in para-aortic
region [40].
Conceptually,
hysteroscopic or transvaginal ultrasound-guided peritumoral injection
can directly visualize the tumor and reflect the lymphatic drainage
pathway, making them reasonable approaches to detect SLN. Comparing
hysteroscopic injection with cervical injection, Ditto et al.have revealed that detection rate of SLN in the
para-aortic
area was slightly higher in patients receiving hysteroscopic injection
(29% vs. 19.5, p=0.18), however, this difference did not reach
statistical significance [41].
Transvaginal
ultrasound-guided myometrial injection of radiotracer exhibited a
detection rate of para-aortic SLNs (greater than 45%), together with a
high sensitivity (87.5%) and negative predictive value (97.0%) for
para-aortic metastases in women with intermediate and high-risk
endometrial cancer [42]. Both hysteroscopic and
transvaginal ultrasound-guided injections were complicated,
time-consuming, and technically challenging, hence setting a limitation
for a wide acceptance and utilization in real clinical routine. Besides,
the potential risk that hysteroscopic injection can cause
intraperitoneal dissemination of tumor cells through fallopian tubes has
been brought into focus [43].
In 1996, Burke et al. firstly used sub-serosal injection of blue dye
into the uterine fundus to perform SLNM [6]. And
the detection rate of sub-serosal injection varies from 73% to 95% in
recent year’s reports [28]. Though this technique
is relatively easy to perform, sub-serosal injection has lower
sensitivity and overall detection rate.
Apart
from those mentioned above, researchers have proposed novel injection
methods.
Mückeet al. evaluated the clinical feasibility of
transcervical
subepithelial injection into the isthmocervical region of the myometrium
for sentinel detection in endometrial cancer [44].
The
outcome demonstrated that injection of 10 MBq Technetium-99m-nanocolloid
via isthmocervical myometrium led to high intra-operative detection
rates (90.3%), bilateral pelvic detection rates (57%), and para-aortic
detection rates (25%). A 5-year single-center prospective study
uncovered that the detection rates of dual cervical and fundal
indocyanine green injection in endometrial cancer were 93.5 % overall
for SLNs, 90.7 % overall for pelvic SLN, 68.0 % for bilateral SLN,
66.9 % for paraaortic SLN, and 2.9 % for isolated paraaortic SLN[45].
3.
SLN mappingalgorithm
The
main goal of SLNM is to identify the state of SLN,
thereby
limiting the need for comprehensive lymphadenectomy[38].
To
achieve this, it’s a necessity for SLNM to have a high bilateral SLN
detection rate and a high sensitivity for detection of metastatic lymph
nodes, coupled with a low false negative rate. In order to enhance the
detection rate and accordingly lower false negative rate,
strictly
hewing to an appropriate SLN algorithm is of significance[46].
The development of SLN algorithm is based upon the
lymph
drainage pathways of SLNs in pelvic cavity of endometrial carcinoma
patients.
Notably,
the lymphatic drainage of uterus is considerably complicated[47]. This drainage is presumed to be bilateral
since uterus is considered a midline structure[48].
There are three channels for pelvic SLN drainage in endometrial
cancer:
the upper paracervical pathway (UPP),
which
drains
medial external iliac and/or
obturator
lymph nodes; the lower paracervical pathway (LPP), which drains the
internal
iliac
and/or
presacral
lymph nodes along the uterine vein; the infundibulo-pelvic pathway
(IPP), which drains the para-aortic lymph nodes along the
infundibulo-pelvic
ligament [49].
It
has been reported that the
lymph
drainage
imaging
mostly
focuses
on the UPP
pathway.
Yet taking the fact that some high-risk patients may have presacral
lymph node metastasis into account, the SLN detection of the LPP pathway
should not be ignored. In addition, generally, UPP and LPP pathways
continuously drain pelvic lymph nodes to the
para-aortic
lymph node region. Therefore, according to Geppert and his collogues,
tracer-imaging lymph nodes in IPP pathway ought to be regarded as SLN
only under the premise that neither in UPP pathway nor LPP pathway can
tracer-imaging lymph nodes be found, which helps ensure that the
para-aortic lymph nodes taken during surgery are SLN rather than
secondary lymph
nodes[47]. In 2017, Persson et al.[50] proposed an SLN algorithm to achieve
bilateral
visualization in UPP and LPP pathways.
Albeit
that the detection effect is excellent, the procedure is cumbersome.
And
repeated tracer
injections
conducted in the study may passively affect the detection rate of SLNs
due
to the influence of adjacent lymph node imaging. Subsequently, Bollinoet al. [51] optimized the SLN
algorithm
based on histology and lymphatic
anatomy.
Specifically, detection of SLN along the UPP and LPP can be restricted
to high-risk patients and a
full
pre-sacral lymphadenectomy should be performed if the LPP pathway cannot
be
visualized.
However, the above SLN algorithm has not been widely applied in the
detection of SLN in endometrial cancer, calling for further relevant
research.
The
current research mostly follows the SLN algorithm put forward in the
NCCN guidelines, that is, if bilateral imaging cannot be achieved, the
undeveloped lateral lymph nodes should be
dissected[52].
And
suspicious lymph nodes ought to be removed during surgery.
Removing para-aortic lymph nodes
or not depends on the decision of the surgeon. Strictly following the
SLN algorithm can boost the detection rate of SLN and reduce the false
negative rate, thereby providing accurate information for clinical
decision-making.
4.Pathological
evaluation andLow-Volume
Metastasis
For
the pathological evaluation of SLN, the NCCN guidelines recommend the
use of pathological
ultra-staging[52].
Pathological
ultra-staging refers to a combinative assessment approach of both
multiple serial sectioning and immunohistochemical staining for
surgically removed lymph nodes [53].
Not
only can this method improve the detection rate of lymph node
metastasis, but also identify low volume metastatic disease (LVMD)
according to the size of the metastases. In accordance with their
diameter, metastases can be divided into macro-metastasis
(> 2 mm) and low-volume metastases
(LVM)
(< 2 mm). And LVM can be further subdivided into isolated
tumor cells (ITCs) (< 0.2 mm) and micro-metastasis (MM) (0.2-2
mm) [54].
Pathological
ultra-staging improves the detection of lymph node micro-metastases in
endometrial
cancer and can assess the staging of endometrial cancer patients[55, 56]. The NCCN guidelines also affirmed the
potential value of pathological ultra-staging to detect endometrial
cancer low-volume metastases [56]. However,
pathological ultra-staging takes a considerable consumption of time and
requires experienced pathologists to operate, which is not conducive to
guiding intraoperative decision-making. And the specific implementation
process and application indications need further study.
The
clinical significance and management of LVM remain controversial.
According
to the 2021 NCCN guidelines, LVM is not a basis for staging upgrade, but
LVM
can guide the formulation of adjuvant therapy[57,
58,
59].
Studies
have found
that
patients with
LVM
frequently received adjuvant chemotherapy and had improved oncologic
outcomes in comparison to those with macro-metastasis to the lymph
nodes,
however,
low-risk patients with LVM have limited benefit from adjuvant therapy[60]. Additionally, there is a possibility of
overtreatment in
LVM
guided adjuvant chemotherapy [60,
61].
Therefore, adjuvant therapy should be formulated based on
histopathological findings, uterine status, and the overall situation of
the
patient.
In conclusion, at present, the management of LVM patients in clinical
practice should be individualized based on the specific situation of
patients.
5.The
application ofSLNM
in endometrial cancer
5.1
SLNM in low-riskendometrial
cancer
The
lesions
of low-risk patients are mostly confined to uterine corpus, with a low
risk of lymph node
metastasis.
And
the ESMO-ESGO-ESTRO proposed that
LND
is not recommended for low-risk patients (histological grade 1 or 2,
superficial myometrial invasion <50%)[62].
In
the 2018 NCCN guidelines, that SLNM can be used for surgical staging
when
endometrial
cancer patients have no metastasis or no obvious extrauterine disease[56].
Correspondingly,
burgeoning
evidence has emerged to support
the
extraordinary potential of SLNM in
low-risk
endometrial
cancer treatment [63, 64].
For
instance, a FIRES trial investigated 385 patients with stage I
endometrial cancer, eventually concluding that the detection rate and
negative predictive value of SLN were 86% and 99.6%, respectively[10]. Furthermore, study evaluating the
cost-effectiveness of three types of lymphadenectomies (systematic
LAD,
selective LAD, SLNM) in low-risk endometrial cancer found that
SLNM
ultimately outshined other two methods [65].
In
conclusion, the advantages of low cost and high effectiveness of SLNM
make it a consensus to replace systematic LAD in patients with
early-stage and low-risk endometrial cancer.