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M. R. Freund et al.
The last type shows no uorescence in the lesion itself but
rather surrounding uorescence. In addition, the uorescent type
depended on the histopathological entity of the cancer. Welldifferentiated hepatocellular carcinomas (HCC) showed a total
uorescence, while poorly differentiated HCCs and all 28 analyzed CRLMs showed a rim uorescence [63].
This characteristic rim is a consequence of the biliary drainage obstruction due to the metastasis in the surrounding hepatocytes. On the other hand, well-differentiated HCCs show a
dysfunction of biliary excretion [63, 64]. The uorescence in the
surrounding hepatocytes could be detected using a uorescence
microscope [65].
Dosage andTiming ofAdministration
ICG may be administered via a central or peripheral venous catheter; there is no need for a bolus prior to liver surgery. Different
approaches regarding the administration timing of ICG range
from 14days to 24 h before the operation as the optimal timing
remains unclear. The dosage recommendations also vary between
a body weight-adapted dose of 0.1mg/kg up to individual doses
of 50mg of ICG [46]. Van der Vorst etal. investigated different
dosages and timings for the detection of CRLM with ICG- FI.They
were not able to report a statistically signicant difference
between a dosage of 10 and 20mg. There was also no signicant
difference between application 24 and 48h prior to surgery [64].
We prefer the administration of 0.1mg/kg 24h prior to surgery
via a peripheral venous catheter. This also has organizational rea-
Fig. 3.7 Liver metastasis of colorectal cancer with typical uorescent rim.
Application of 0.02mg/kg was performed 12h before surgery
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sons since most patients are admitted 1day prior to surgery. The
administration of the dye should take place at least 24h prior to
surgery to avoid interferences due to the biliary secretion of
ICG.If the dye is applicated less than 24h, we chose a dosage of
0.02mg/kg 24 (Fig.3.7).
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Detection ofAdditional Metastatic Lesions
A lesion <10mm is currently difcult to detect using preoperative
diagnostics. Thus, additional diagnostic modalities, e.g., IOUS
and ICG-FI, are becoming increasingly important in the surgical
treatment of metastatic CRC.
Liberale and colleagues reviewed the available literature
regarding ICG-FI for the intraoperative detection of CRLM.Ten
publications published between 2009 and 2016 were included.
Their results showed the smallest detectable lesions ranged from
1 to 5mm in diameter. In 20 of the 130 patients, additional CRLM
could be identied that were not detected preoperatively.
The detection sensitivity ranged between 69% and 100%.
However, the sensitivity is limited by the depth, ranging from 5 to
10mm below the liver capsule. The authors concluded that ICG-FI
could be used as a diagnostic tool to detect additional lesions,
especially combined with IOUS for lesions located deeper within
the liver parenchyma [46].
Determination ofResection Margins Using ICG-FI
The resection margin is one of the most important factors inuencing local recurrence and disease-free survival. Several studies
have investigated ways to improve resection technique using
ICG-FI.New systems, including robotic devices, enable real-time
intraoperative navigation through combined ICG and white light
images.
In a retrospective analysis of 86 patients undergoing ICG-FIassisted surgery for CRLM compared to a control group of 87
patients, the ICG-FI group showed a 4-year liver-specic relapsefree survival of 47%, while the control group showed 39%.
However, these results were not statistically signicant due to an
underpowered cohort size [66].
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Nevertheless, in a pilot study on real-time surgical margin
assessment using the previously described uorescent rim as
guidance, whole resection including the uorescent area resulted
in an improved rate of negative resection margins [67]. Aoki and
colleagues also presented similar results. Twenty-ve patients
undergoing laparoscopic liver resection received ICG with a dose
of 0.5mg/kg of body weight 2–14days before surgery. Seventeen
of the 25 patients had CRLM.In comparison to the control group
(72 patients from retrospective data), there were no R1 resection
margins in the ICG group, indicating an advantage [68].
The reliability of the uorescence resection margin was also
investigated using a uorescence microscope. In 72 cases of
CRLM, the uorescent rim could be microscopically identied in
50% of all cases. There were no malignant ndings in the uorescent rim. In conclusion, the uorescent rim represents a reliable
oncologic CRLM resection border [69].
M. R. Freund et al.
Pulmonary Metastasis
The second most common CRC metastasis location is the lung
[54, 55]. Limited pulmonary colorectal metastasis resection is a
widely accepted surgical approach. However, the detection of pulmonary metastatic lesions remains challenging, especially during
video-assisted thoracoscopic surgery (VATS).
There are very limited data on ICG-FI for pulmonary CRC
metastasis. In a case series of eight patients, Keating and colleagues transferred results from previous experiments on mice to
an invivo study. A dose of 5mg of ICG per kg of body weight
was administered 24 h before surgery via a peripheral vein.
Previously described pulmonary metastases presented as hyperuorescent lesions. Furthermore, additional lesions could be
identied in some cases [70]. As a limitation of the technology in
terms of detectability, lesions deeper than 2cm could not be displayed [65].
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Lymphatic Mapping inColorectal Cancer
Regional and distant lymph node status is one of the most important prognostic factors in malignant disease.
Sentinel lymph node (SLN) mapping is an important validated
diagnostic marker for breast cancer and melanoma [71]. The diagnostic reliability in gastrointestinal cancers is still unclear and
controversially discussed. Analogous to the total mesorectal excision (TME) for rectal cancers, the complete mesocolic excision
(CME) technique for colonic cancers has become an increasingly
popular practice in colorectal surgery. A key part of this technique
is central vascular ligation with consecutive radical lymphadenectomy. Thus, the usefulness of SLN mapping in CRC remains
unclear.
Morton et al. dened the sentinel lymph node as “the rst
lymph node that receives afferent lymphatic drainage from a primary tumor” [72]. The rst benet of SLN detection in CRC is to
recognize aberrant lymphatic drainage, which has been reported
in 2–29% of cases [71]. Second, complex lymphatic drainages
may be mapped in exure cancers, most likely leading to better
surgical and oncological outcomes. Various methods have been
reported for intraoperative SLN mapping. Methylene blue is the
most common agent used to detect the SLN.
A randomized controlled trial highlighted that using indocyanine green instead of methylene blue in endometrial cancer signicantly increased the lymph node detection rate per hemipelvis
after intracervical injection of 2ml ICG (1.25mg/ml) [73]. This
gave way to the rst international guideline recommending the
use of ICG for SLN mapping, in this case for endometrial cancer
(Level II, A) [74].
Few studies exist describing an SLN mapping technique for
CRC.Most studies are prospective case series with a low number
of included patients. Currently, there is one level V meta-analysis
published by Emile etal. in 2017 which discusses the topic in a
well-founded manner.
They included 12 level VI case studies with a total of 248 patients
[75]. The technical aspects of ICG administration in the included
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M. R. Freund et al.
studies were found to be heterogenous. The authors of the underlying case studies used different ICG concentrations (0.5, 2.5, 5mg/
ml), doses (0.2–5 ml), injection sites (intravenous, submucosal,
subserosal, a combination), and injection times (preoperative, intraoperative, preoperative, and intraoperative). Moreover, the time of
detection differed from study to study (intraoperative, ex vivo,
intraoperative and exvivo). To determine the sensitivity, specicity,
and accuracy of ICG-guided lymph node mapping, Emile et al.
included the 1175 lymph nodes which were found to be metastatic.
Of those included, 73% were uorescent positive (n= 895) and
26% uorescent negative (n=315). This resulted in a median sen-
sitivity of 73.7% and specicity of 100%. The positive predictive
value was 100%, while the negative predictive value was 96.7%.
The accuracy was found to be 75.7% (range 0–100%) [75]. Due to
the variability of the underlying studies, these results must be interpretated carefully. To minimize the publication bias, the authors
worked out pooled parameters. Pooled sensitivity was 71% (95%
CI: 68.3–73.3%), while specicity was 84.6% (95% CI: 83.2–
86%). A subgroup analysis by Emile etal. found that a weightbased dosage of 0.25mg/kg had the highest sensitivity (89%) and
accuracy rates (88%). Combined injection into the submucosa and
subserosa achieved 100% rates of sensitivity, specicity, and accuracy. The optimal dosage timing is still unclear. In a second subgroup analysis, Emile and colleagues showed the characteristics of
the CRC to be an important factor in diagnostic accuracy. ICG lymphatic mapping in early-stage cancers (stages I–II) shows a better
diagnostic accuracy than in advanced stages [33]. Van der Zaag
etal. showed similar ndings in a meta-analysis discussing SLN
mapping for CRC (without ICG) [76]. These ndings are supported
by Cahill etal., where in a meta-analysis, they described that 5% of
stage T1/T2 CRCs showed false-negative SLNs, while stage T3/T4
CRCs showed 17% [77]. An explanation for this issue might be the
tumor-associated obstruction of lymphatic vessels and nodes in
advanced stages. The two included studies dealing with ICG lymphatic mapping in rectal cancers showed divergent results.
Handgraaf etal. described a sensitivity of 0% [78], while Noura
etal. had a sensitivity of 100% [79]. An explanation might be that
none of the patients in the latter study received chemoradiotherapy
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or radiotherapy, while 90% in the rst study did. This leads to the
theory that neoadjuvant therapy in rectal cancer highly affects the
diagnostic viability of ICG lymphatic mapping. Ultimately, there is
little data and further investigations are needed.
A proof-of-concept study by Liberale etal. reported a detection of lymph nodes as small as 6mm using 0.25mg per kg of
body weight intravenous ICG.The dye was injected directly after
abdominal incision [80]. The authors conrmed these results in a
retrospective study showing malignant lymph nodes to be more
uorescent than benign ones [81]. However, a sensitivity of only
63% was reached. Next, Liberale and coworkers published a feasibility study to evaluate the hypothesis that intravenous ICG
injection allows for the detection and a pathological prognosis of
metastatic lymph nodes [82].
Although local injection yields the best results according to the
meta-analysis by Emile etal. [75], intravenous injection seems to
be a more viable option. Accurate local injection requires experience and expertise, and the targeted structure might be missed.
These two application techniques are principally different. Local
administration gives an accurate picture of the lymphatic route.
Intravenous injection works by ICG accumulation in tumor tissues due to the compromised endothelial barriers, which most
likely leads to a better detection of malignant lymph nodes [80].
Based on these results, Cao and associates recently published a
study using ICG-FI to evaluate the localization of and determine
the tumor margin, map lymph nodes, and detect malignant lymph
nodes [83]. They intravenously injected a bolus of 25mg of ICG
and took measurements at different points in time (0.5, 1, 2, 4, and
24h). The tumor boundaries were found to be apparent 1h after
injection, but clearest after 2–4h. According to the tumor signalto-background ratio (SBR), optimal visualization occurred 2 h
after injection. In the same study, the authors mapped a total of 40
lymph nodes. All lymph nodes were detected by ICG from 0.5 up
to 5h after injection. A minimum SBR of 1.13 showed a detection
rate of 95% for any lymph node (38/40). The optimal SBR threshold for metastatic lymph nodes was found to be 2.5 according to
the Youden Index (sensitivity 80.0%, specicity 48.6%). They
concluded that it was not possible to differentiate between meta-
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Fig. 3.8 (a) Sentinel lymph node after submucosal application of 1mg indo-
cyanine green (ICG) in a case of colonic cancer. Injection is performed endoscopically 24 h before surgery If the tumor can be passed, four spots are
injected around the tumor (two oral, two aboral). (b) ICG application used for
tumor and sentinel lymph node detection
M. R. Freund et al.
static and nonmetastatic lymph nodes using the SBR technique.
Unfortunately, the authors did not further investigate the correlation between injection timing and lymph node detection accuracy.
According to these studies, using this technique accurately detects
the tumor as well as most of the lymph nodes.
All in all, the existing studies are too inhomogeneous with few
cases and low evidence, leading to a low reliability. Thus, the results
must be interpreted carefully. Data suggests that a dosage of 0.25mg/
kg of body weight results in the highest sensitivity, specicity, and
accuracy. Preoperative injection into both the subserosa and submucosa showed the best detection rates (Fig.3.8), followed by intravenous injection [75]. However, intravenous injection prior to surgery
is more easily standardized and reliable. The data also suggest that
after intravenous ICG injection, the uorescence may be used for
tumor detection and lymphatic mapping without additional doses.
The timing of injection remains unclear and depends strongly on
which form of application is used. Further studies are needed to conrm these preliminary data and to establish a standardized technique
for CRC lymphatic mapping. To that extent, in a recently published
intercontinental Delphi survey, no consensus was reached on the
value of ICG use for mapping of sentinel node, and the only consen-
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sus achieved for lymph node assessment was that two to four injection points are required [40].
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Future Perspectives: Fluorescence-Guided
Tumor Targeting
The current detection of sentinel or additional lymph nodes and
colorectal metastasis is based on uorescence patterns. However,
although there are data that uorescence intensity correlates with
pathologic ndings, it remains unspecic. Lately, there have been
innovative approaches to identify additional lesions in a more targeted manner. Overall, there are multiple different molecular targets that can be addressed [84].
Regarding the more specic detection of additional colorectal
lesions, SGM-101 should be mentioned. SGM- 101 is a uorescent dye-conjugated antibody against carcinoembryonic antigen
(CEA) [85]. In a recently published clinical trial on the detection
of colorectal and pancreatic liver metastasis, SGM-101 was
administered 2 to 4days prior to surgery. Nineteen lesions were
detected, 17 of which were histopathologically conrmed malignant lesions [86]. In a similar approach, Harlaar and co-authors
investigated a uorescent dye conjugated to bevacizumab in
patients with PC from CRC. The idea behind the study is the
hyperexpression of vascular epithelial growth factor (VEGF) in
PC from CRC. Bevacizumab is a monoclonal antibody against
VEGF, and therefore, after conjugation of the uorescent dye to
bevacizumab, PC uorescence may be achieved. The study
showed that lesions without uorescence were benign; however,
lesions with hyperuorescence were false-positive in 47% of
cases [87].
Conclusion
Although there is still an ongoing debate, it appears that ICG
uorescence perfusion assessment may be benecial in lowering
the risk for AL.This technology has been proven to be safe, cost-
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effective, easy to implement, readily available, and effective in
the evaluation of bowel perfusion. The data also suggest that preoperative ICG injection may be used for tumor detection and
lymphatic mapping. ICG may also be used to detect additional
CRLM and its uorescent rim represents a reliable oncologic
CRLM resection border. Targeted uorescence is a promising
approach and future goal of ICG-FI in oncological surgery.
Additional study results are necessary for further evaluation of
this technology.
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