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Keywords:

  • sentinel lymph node;
  • indocyanine green;
  • lymphedema;
  • free flaps;
  • axillary reverse mapping;
  • sentinel lymph node biopsy

Abstract

  1. Top of page
  2. Abstract
  3. Intraoperative SLN Mapping and Biopsy Using ICG
  4. SLNB Using ICG: Benefits
  5. SLNB Using ICG: Challenges and Future
  6. Lymphedema
  7. Free Flaps
  8. Conclusions
  9. FUNDING SOURCES
  10. REFERENCES

Ever since Kitai first performed fluorescent navigation of sentinel lymph nodes (SLNs) using indocyanine green (ICG) dye with a charge-couple device and light emitting diodes, the intraoperative use of near infrared fluorescence has served a critical role in increasing our understanding in various fields of surgical oncology. Here the authors review the emerging role of the ICG fluorophore in the development of our comprehension of the lymphatic system and its use in SLN mapping and biopsy in various cancers. In addition, they introduce the novel role of ICG-guided video angiography as a new intraoperative method of assessing microvascular circulation. The authors attempt to discuss the promising potential in addition to assessing several challenges and limitations in the context of specific surgical procedures and ICG as a whole. PubMed and Medline literature databases were searched for ICG use in clinical surgical settings. Despite ICG's significant impact in various fields of surgical oncology, ICG is still in its nascent stages, and more in-depth studies need to be carried out to fully evaluate its potential and limitations. Cancer 2011;. © 2011 American Cancer Society.

Near infrared (NIR; emission spectra of ∼700-850 nm)1 fluorophores are probes that have gained immense interest in various fields of biomedicine because of their minimal interfering absorption and fluorescence from biological samples, inexpensive laser diode excitation, reduced scattering, and enhanced tissue penetration depth.2 However, to date, only 1 NIR probe, indocyanine green (ICG) has been approved by the US Food and Drug Administration (FDA); methylene blue is another FDA-approved probe that displays NIR properties, however, it is not considered a pure NIR probe. The former, ICG, is a water-soluble, anionic, amphiphilic tricarbocyanine probe3 with a hydrodynamic diameter of 1.2 nm, and excitation and emission wavelengths in serum at 778 and 830, respectively.4, 5 For several years, it has been used in ophthalmic angiography6 and for determining cardiac output7 and hepatic function.8 However, it has only recently shown real practicability and feasibility in the field of surgical oncology. Three major domains where NIR-guided ICG fluorophores have appeared most promising are: 1) sentinel lymph node (SLN) detection, 2) evaluation of lymphedema, and 3) assessment of microvascular circulation of free flaps in reconstructive surgery. Although several reviews have discussed the importance of NIR fluorophores (including ICG),9-13 in this review we limit our discussion specifically to ICG in an attempt to attain a better understanding of its impact and challenges it presents in the field of surgical oncology.

Intraoperative SLN Mapping and Biopsy Using ICG

  1. Top of page
  2. Abstract
  3. Intraoperative SLN Mapping and Biopsy Using ICG
  4. SLNB Using ICG: Benefits
  5. SLNB Using ICG: Challenges and Future
  6. Lymphedema
  7. Free Flaps
  8. Conclusions
  9. FUNDING SOURCES
  10. REFERENCES

The significance of cancer treatment management in relation to first lymphatic drainage from the tumor site, the SLN, was first proposed by Cabanas.14 Reiterated by Morton et al, evaluation of the SLN through biopsy has become a crucial factor in determining the status and management of patients with various solid tumors.15 At present, 2 methods are predominantly used in the detection of the SLN: injection of vital dye and/or injection of a radioactive colloid with gamma probe. Although a combination of the 2 has been shown to possibly yield better results,16, 17 as reviewed by Tuttle et al, no single method has yet been determined optimal.18 Recently, ICG with the use of charge-coupled device (CCD) cameras and light-emitting diodes (LEDs) has emerged as an alternative modality in SLN biopsy. To date, use of NIR ICG-guided SLN biopsy has been performed in breast,17, 19-25 skin,26, 27 gastric,28-35 colorectal,36 anal,37 and lung cancers.38 Although studies of the aforementioned cancers have shown promising results, these studies are still in their initial stages.

Technique

First described by Kitai et al in breast cancer (BC) SLN biopsy (SLNB)20 and Kusano et al in gastric cancer (GC) SLNB,29 the technical aspect of using ICG with CCD cameras and LEDs has more or less remained the same, with a few notable exceptions. The general process involves 3 main steps: localization of the primary tumor, injection of ICG, and detection of the SLN by CCD with LED. First, the tumor is preoperatively localized and marked. During or before the operation, ICG is injected in the peritumoral location. The dose and the location of injection have been scrutinized and debated in both BC and GC SLNB. With regard to BC (Table 1), various depths ranging from intradermal to subcutaneous injection of ICG have been performed. Despite this inconsistency, the detection rate of the SLN has been rather consistently high. In terms of dose, 1 to 25 mg has been reported in SLNB, and microgram amounts have been reported for SLN mapping (Table 2). It has been suggested by Tagaya et al that their high detection rates of SLN in BC, compared with those obtained by Kitai et al, were partially because of the lower dosage of ICG.24 To date, the reported visualization of lymphatic vessels and the SLN using the ICG fluorophore has ranged from as little as 10 to 100 μg of ICG, used by Sevick-Muraca et al,39 to as much as 25 mg of ICG, used by Kitai et al.20 Further studies of controlled ICG dose escalation at a consistent injection site need to be performed to determine the optimal dose. Conversely, in SLNB of GC, it was determined that as long as the injection of ICG was peritumoral, submucosal, or subserosal injection did not affect the outcome of the rate of SLN detection.40

Table 1. SLNB in Breast Cancer Patients With ICG Detection
StudyNo. of PatientsAge of Patients, Mean y [range]Type and Dose of ICGInjection SiteICG-Positive SLN (%)False Negative (%)Comments
  • Abbreviations: CCD, charge-coupled device; HSA, human serum albumin; ICG, indocyanine green; SLN, sentinel lymph node.

  • a

    One true false negative lymph node; SLN was not detected.

Kitai 2005201856.9 [—]ICG, 5 mL {25 mg}Subcutaneous-periareolar17/18 (94.4)First study using CCD
Tagaya 20082425— [—]ICG, 1 mL {5 mg}Subdermal-periareaolar25/25 (100)ICG compared to blue dye
Murawa 2009213056 [27-84]ICG, 5 mg, 10 mg, 15 mgIntradermal-periareolar29/30 (96.7)2/21a (9.5)Dose-dependent study, ICG compared to radiocolloid
Troyan 200925661.2 [51-65]ICG:HSA, 1.6 mL {12.5 μg}4 deep peritumoral injections and 4 subcutaneous-peritumoral5/6 (83.3)ICG compared to radiocolloid, FLARE
Hirche 2010194358.4 [27-83]ICG, average 11 mgSubareolar region42/43 (97.7)1/18 (5.6)
Hojo 20101714157.6 [34-86]ICG, 2 mLSkin overlying the tumor and subareolar region140/141 (99.3)ICG/blue dye compared to ICG/radiocolloid
Table 2. SLNB in Gastric, Colorectal, Anal, Skin, and Lung Cancer With ICG Detection
StudyObjectiveNo. of PatientsAge of Patients, Mean y [range]Type and Dose of ICGInjection SiteICG-Positive SLNFalse Negative (%)Comments
  1. Abbreviations: ICG, indocyanine green; IREE, infrared ray electronic endoscopy; SLN, sentinel lymph node; SLNB, sentinel lymph node biopsy.

Kusano 200829Gastric cancer2267.7 [—]ICG, 2 mL4 peritumoral sites; subserosa of gastric wall20/22 (90.9)6/10 (60)
Colorectal cancer2670.0 [—]ICG, 2 mL4 peritumoral sites; subserosa of colorectal wall23/26 (88.5)4/6 (66.7)
Miyashiro 200830Gastric cancer366.3 [60-73]ICG, 2-4 mLPeritumoral site3/3 (100)
Ohdaira 200932Gastric cancer1462.2 [30-82]ICG, 0.5 mL {5 mg}4 peritumoral sites; submucosal site of gastric wall14/14 (100)IREE
Ohdaira 200934Proximal gastric cancer3062.9 [43-84]ICG, 0.5 mL {5 mg}4 peritumoral sites; submucosal site of gastric wall30/30 (100)IREE
Tajima 200935Gastric cancer5668.4 [—]ICG, 2 mL31 patients: 4 peritumoral sites; submucosa of gastric wall 25 patients: subserosa of gastric wall54/56 (96.4)6/17 (35.3)
Kelder 201028Gastric cancer21260 [35-84]ICG, 0.4 mL {5 mg}4 peritumoral sites; submucosal site of gastric wall211/212 (99.5)1/26 (3.8)IREE, early gastric cancer
Noura 201036Lower rectal cancer2558.4 [33-74]ICG, 1 mL {5 mg}4 peritumoral sites; submucosal layer via the anus23/25 (92)
Hirche 201037Anal cancer1258 [21-90]ICG, 5 mL {25 mg}Peritumoral10/12 (83.3)Compare to radiocolloid
Fujiwara 200926Skin cancer1068.1 [34-80]ICG, 3-5 mgIntradermal-peritumoral10/10 (100)Patent blue also used
Tanaka 200927Skin cancer6ICG, 1 mL {5-8 mg}Intradermal-peritumoral6/6 (100)
Yamashita 201138Nonsmall cell lung cancer3163 [54-83]ICG, 2 mL {5 mg}Peritumoral25/31 (80.6)0/24 (0)

Once injected, ICG is strongly bound to serum proteins and takes ∼1 to 10 minutes to be transferred to the SLN.20 As this is happening, the operation theater's light is turned off and the CCD is used to detect the ICG drainage in the peritumoral lymphatic system. The CCD usually consists of 3 main components: an NIR-sensitive image intensifier, 16-bit dynamic-range frame transfer CCD camera, and LEDs.39 To detect the SLN, the LEDs produce 1 wavelength of the invisible NIR beam onto the ICG. In response, the ICG emits back another wavelength of an invisible NIR beam (Stokes shift),41 which is detected by the intensifier and displayed on the camera. This allows for localization and marking of lymph nodes (and sometimes lymphatic ducts). The lights are turned back on, and the biopsy can then be performed.

BC

In the context of BC, ICG was originally used as a dye marker to perform SLNB. Motomura et al42 first described this technique in 172 BC patients who received an injection of 25 mg (5 mL) ICG into the peritumoral breast parenchyma. The SLN was detected in 127 of 172 (73.8%) of the patients, with a false-negative rate of 5 of 45 (11.1%); although at the time this detection rate was viewed as acceptable, ICG as a dye marker still exhibited a high false-negative rate.42 Thus, with the intention to improve, Motomura et al later combined a radiocolloid (technetium-99m [99mTc]-radiolabeled tin colloid) with the ICG dye. In this study, the ICG dye alone was again assessed, and resulted in a similar middling detection rate of 78 of 93 (83.9%) and a high false-negative rate of 4 of 21 (19%). However, when the dye and radiocolloid were combined, both the detection and false-negative rates significantly improved to 131 of 138 (94.9%) and 0 of 41 (0%), respectively.43 Although this method seldom creates adverse reactions, a further problem is the high cost of the radiocolloids. With the advent of the CCDs, Kitai et al intraoperatively used ICG as an NIR fluorophore rather than just a dye in 18 BC patients.20 In a similar technique to that of Motomura et al,42, 43 patients received an injection of 25 mg (5mL) ICG into their subcutaneous breast tissue. Use of the dye alone resulted in a detection rate of 15 of 18 (83.3%) lymphatic channels and 9 of 18 (50%) lymph nodes. With the aid of the CCD, SLNs were detected in patients at a rate of 17 of 18 (94.4%), with a 6 of 6 (100%) detection rate of metastatic positive nodes.20 This high detection rate opened a new interest in NIR-guided SLNB, and soon several trials were performed. Tagaya et al used a subdermal injection of 5 mg (1 mL) ICG in 25 BC patients, achieving detection of the SLN in all patients and 8 of 8 (100%) metastatic involvement.24 Murawa et al used an intradermal injection of various doses (5-15 mg) of ICG in 30 BC patients, and found the SLN in 29 of 30 (96.7%) patients, 19 of 21 (90.5%) metastatic SLN involvement, and a low false-negative rate of 2 of 21 (9.5%).21 Hirche et al then produced similar results when 43 BC patients were injected with an average of 11 mg of ICG; SLNs were detected at a rate of 42 of 43 (97.7%) with 17 of 18 (94.4%) metastatic involvement, and again a low false-negative rate of 1 of 18 (5.6%).19 In all 4 experiments, a high rate of SLN detection and metastatic involvement and a low false-negative rate were observed. These results were comparable to, if not better than, the reported blue dye and/or radiocolloid methods.44, 45 Furthermore, when blue dye or radiocolloid was juxtaposed against NIR-guided SLNB, ICG in fact resulted in a higher detection rate and sensitivity.21, 24 Hojo et al compared 3 methods of SLNB: using 2 mL blue dye, using 1 mL ICG fluorophore in the guided method, and using ICG combined with 99mTc-labeled phytate.17 All 3 methods resulted in high detection of the SLN, with the blue dye method yielding 105 of 113 (92.9%), ICG fluorophore yielding 140 of 141 (99.3%), and the combined method resulting in 28 of 28 (100%).

ICG is also used in mapping the SLN in axillary reverse mapping. This technique makes it possible to spare the local lymph nodes that collect lymph from the arm during axillary lymphadenectomy for BC. The first studies, by Thompson et al46 and Nos et al,47 describe the presence of often separate SLNs for the arm and for the breast. An attempt to save the SLNs of the arm may decrease the incidence of postoperative arm lymphedema. Noguchi et al reported axillary reverse mapping identification using subdermal ICG in the area of the medial wrist and upper medial arm. The axillary reverse mapping nodes and their lymphatic vessels were observed in 87.5% of patients undergoing axillary lymph node dissection and 75% of patients undergoing SLNB. The axillary reverse mapping lymph node was the same as the SLNB lymph node in only 14% of the cases.22 Further clinical studies using axillary reverse mapping are necessary, and the use of ICG appears to be a good addition to this technique because of its high sensitivity and the lack of staining that occurs when using blue dye.

Gastric, colorectal, and anal cancer

Similarly to its use in BC, ICG was originally used as a simple dye to perform SLNB in GC. Hiratsuka et al were the first to use this technique in this area, using 5 mL (25 mg) of ICG in 74 patients with GC. In total, 73 of 74 (98.6%) SLNs were detected, with 1 of 10 (10%) reported to be false negative. Although a high rate of detection and low false-negative rate were observed, the authors stated cautiously that all the patients were in early stages (T1 and T2) of the cancer.48 Ichikura et al similarly studied 62 patients in early stages of GC. In this study, 2 doses of ICG, 4 mL and 8 mL, were compared and in all patients, regardless of the dose, 1 or more SLN was detected, with a reported false-negative rate of 2 of 15 (13.3%). However, by using a larger dose (8 mL), a greater number and larger distribution of lymph nodes was found.49 Park et al also produced comparable results when 100 GC patients received 5 mL (25 mg) of ICG before SLNB. SLNs were found in 94 of 100 (94%) patients, with a false-negative rate of 3 of 14 (21.4%) and 4 of 14 (28.6%) as determined by hematoxylin and eosin staining and immunohistochemical staining, respectively.50 These studies indicate that ICG is a useful option in early stages of GC, with results similar to those obtained with blue dye or radiocolloids.

ICG as an NIR fluorophore was first used by Nimura et al, who performed SLNB with the aid of infrared ray electronic endoscopy on 84 patients.31 Infrared ray electronic endoscopy is similar to the device used in BC SLNB; it is composed of a CCD but in addition possesses an electronic endoscope.51 By using the dye-guided method alone, tissue contrast was poor, and visualization of stained lymph nodes was reported to be difficult.52, 53 In addition, the view using infrared ray electronic endoscopy is rather different from that of activated ICG in BC, but it nevertheless provides a higher contrast than dye alone. Nimura et al compared ICG dye against a combination of infrared ray electronic endoscopy and ICG, and both methods resulted in detection in 83 of 84 (98.8%) patients. However, a higher detection of metastatic SLNs of 11 of 11 (100%) was reported in the combined method than in ICG alone 7 of 11 (63.6%). The combined infrared ray electronic endoscopy and ICG produced a false-negative rate of 15 of 215 (7%).31 In a similar study, Kelder et al compared ICG alone to the combination of infrared ray electronic endoscopy and ICG in 212 gastric cancer patients and found a detection rate of 182 of 212 (85.8%) with ICG but 211 of 212 (99.5%) with the combination of infrared ray electronic endoscopy and ICG. Furthermore, the infrared ray electronic endoscopy and ICG combination only produced 1 false-negative node.28 Ishikawa et al were able to detect 1 or more SLNs and lymphatic basins in all 16 gastric cancer patients examined, with 1 false-negative case.54 Ohdaira et al performed SLNB in 2 different studies, resulting in 30 and 14 patients on whom they used the infrared ray electronic endoscopy and ICG combination with a detection rate of 30 of 30 (100%) and 14 of 14 (100%), respectively.32, 34 Infrared ray electronic endoscopy in combination with ICG provided a high detection rate and low false-negative rate.

Open SLNB using CCD was originally performed by Miyashiro et al in 3 gastric cancer patients. Two patients received ICG intraoperatively and 1 before the surgery. In all 3 patients, 1 or more SLNs were detected. Compared with detection using infrared imaging videoscope, the authors reported detection of lymph nodes with fluorescence to be easier, even allowing for detection through adipose tissue.30 Kusano et al performed ICG fluorescence NIR imaging in 22 gastric cancer patients and 26 colorectal patients, and stated a detection rate of 20 of 22 (90.9%) and 23 of 26 (88.5%), respectively. False-negative rates in the gastric cancer patients were 6 of 10 (60%) and 4 of 6 (66.7%) in colorectal cancer. Higher false-negative rates were reported with increasingly advanced cancer stage in both cancers: in GC, false-negative rates of T1, T2, and T3 were 1 of 3 (33.3%), 2 of 3 (66.7%), and 3 of 4 (75%), respectively, and in colorectal cancer T1 and T2 were 0 of 0 (0%) and 4 of 6 (66.7%), respectively.29 Like Miyashiro et al,30 Kusano et al29 also commented on ICG fluorescence aiding the detection of SLNs, which were not stained. Tajima et al performed SLNB in 56 gastric cancer patients, with SLNs being detected in 54 of 56 (96.4%) of the patients. The false-negative rate was reported to be 6 of 17 (35.3%), which again increased in correlation with the tumor stage; the false-negative rate of T1 was reported as 1 of 7 (14.3%), and T2 and T3 combined false-negative rate was 5 of 10 (50%).35 From these results, we can summarize that ICG fluorophores are most useful in earlier tumor stages of cancer (T1 and T2).

In colorectal cancers, Noura et al55 initially mapped SLN in 25 lower rectal cancer patients using ICG as a dye. In this study, the SLN was detected in only 7 of 25 (28%) patients. The authors suggested that this may be for 3 possible reasons: advanced stage of the rectal cancer, inability to intraoperatively trace the lymph node, and macroscopic detection of SLNs.55 The desire to improve the method of SLN detection resulted in another study by Noura et al, where SLN detection was analyzed in 25 patients with lower rectal cancers, but using ICG as a fluorophore. NIR-guided SLN resulted in a detection rate of 23 of 25 (92%) patients and a false-negative rate of 0 of 6 (0%). This method made it possible to overcome the challenge of the until-now low detection rate; however, it is interesting to emphasize that this method allowed for a high detection rate of SLNs irrespective of tumor stage. T1 and T2 had detection rates of 6 of 6 (100%) and T3 17 of 19 (89.5%).36

In anal cancer, Hirche et al reported an overall SLN detection rate of 10 of 12 (83.3%) patients using ICG fluorophore, comparable to 9 of 12 (75%) patients using radiocolloid in combination with blue dye.37

Lung cancers

Before the advent of CCD, the use of ICG dye in the detection of SLNs in lung cancer (nonsmall cell) was extremely poor. As reported by Sugi et al, a 3 mL injection of ICG resulted in the lowest detection rate of 1 of 16 (6.3%) in comparison to both 99mTc-tin colloid and isosulfan blue dye, which had similar detection rates of 9 of 18 (50%) and 9 of 14 (64.3%), respectively. In all 3 methods however, no false-negative SLNs were reported. In this study, the authors indicated that the water solubility of ICG may result in it being rapidly washed out and possibly serving as the culprit for such a low detection rate. Furthermore, they stressed the need for improvement of SLNB as a whole in lung cancer patients.56 To facilitate the uptake and migration of ICG dye to the SLN, Ito et al attempted to add 400 U of hyaluronidase to 5 mL of ICG around the tumor in the detection of SLN in 38 lung cancer patients. However, this again resulted in a low intraoperative detection rate of 7 of 38 (18.4%).57 One of the major problems with dye-assisted detection of SLNs is that if the dye localizes in anthracotic lymph nodes, it is not fully visible. Therefore, to date, positron emission tomography (PET) has been the method of choice in intraoperative SLN biopsy in lung cancer.58 Nevertheless, PET is not a fully optimal technique, with problems such as high background radioactivity because of aerosolization, and shine-through effect affecting the detection rate.58, 59 Most recently, Yamashita et al were able to use 2 mL of ICG along with a CCD to surmount this problem and achieve a high detection rate of SLNs; in a study of 31 patients, SLNs were detected in 25 of 31 (80.6%) patients with a 0 of 24 (0%) false-negative rate.38 Furthermore, in addition to avoiding the problematic complications observed in PET, by not using radiocolloids, both the surgeons and the patients were devoid of radiation.38 Analogous to the use of ICG fluorophore SLN detection in many other settings, more studies are needed to confirm the feasibility in lung cancer.

Skin cancer

Among the most recent ICG-guided NIR fluorescence SLN mapping and biopsy studies on skin cancer were reported by Fujiwara et al26 and Tanaka et al.27 Fujiwara et al studied 10 skin cancer patients (7 melanoma and 3 squamous cell carcinoma) and reported that receiving an intradermal injection of various doses of ICG resulted in a 10 of 10 (100%) SLN detection rate.26 Similarly, Tanaka et al used 5 to 8 mg (1 mL) of ICG intradermally in 6 patients (4 with melanoma, 1 with squamous cell carcinoma, and 1 with extramammary Paget disease) and had a 6 of 6 (100%) SLN detection rate.27 In both studies, visualization of lymph passage was observed in real time.

SLNB Using ICG: Benefits

  1. Top of page
  2. Abstract
  3. Intraoperative SLN Mapping and Biopsy Using ICG
  4. SLNB Using ICG: Benefits
  5. SLNB Using ICG: Challenges and Future
  6. Lymphedema
  7. Free Flaps
  8. Conclusions
  9. FUNDING SOURCES
  10. REFERENCES

The most important benefit of ICG is its well-known safety profile; there have been very few reported cases of adverse reactions. Serious complications such as anaphylactic reactions have been estimated to occur at 0.05% of patients,60 and toxicity has only been observed at higher doses than the FDA-approved concentration.61 Although uncommon, isosulfan blue and patent blue used in SLNB still possess a higher rate of adverse reactions than ICG; isosulfan dye in SLNB has been reported to cause anaphylaxis at a rate between 0.7% and 1.1%,62, 63 whereas patent blue has a rate of 0.4%.64 Also, unlike radiocolloids, there is no radiation exposure with ICG. Although intraoperative radiocolloid use has been found to be safe,65 NIR detection eliminates radioactive exposure completely.

Clearly, an evident high detection rate and low false-negative rate, especially seen in studies with BC, can be achieved in ICG-guided SLN mapping and biopsy (Table 1). Also, ICG in these studies hints toward indiscriminatory detection rate in older age. As has previously been reported by Krag et al66 and Sato et al67 using radiocolloid, older patients' lymph nodes are replaced by fat, which in turn will decrease the retention of radiocolloids.66 Although there have been cases of ICG fluorophores failing to detect SLN in the elderly,23 most studies have found the opposite to be true. However, this still needs to be validated with a larger study. Another important benefit observed while using NIR-guided SLNB with ICG was the real time visualization of transcutaneous lymphatic vessels.19, 21, 24, 26, 27 The benefit of this is significant, as it permits minimal surgical error by tracking the lymphatic flow from the peritumoral site to the first lymph node of drainage, that is, the SLN. The study by Sevick-Muraca et al39 demonstrated this observation and determined that microgram doses of ICG are sufficient to observe lymphatic trafficking to the SLN. Interestingly, by using microgram doses, active lymphatic propulsion was observed in humans for the first time.39 The lymphatic system is sometimes dubbed the “forgotten circulation” for its complexity and our lack of understanding. However, this new modality of observing active propulsion has begun to demystify and give further insight into the lymphatic system,68, 69 in addition to enhancing the elucidation of the diseases and complications observed in lymphedema.70, 71 When examining the logistics of the surgery, the use of ICG in SLNB has the significant advantage of reducing the operative time, because unlike with radiocolloids, patient preparation is very simple. This whole procedure has been reported to take an average of 15 minutes (8-25 minutes), with ICG being injected during the surgery.24 Comparably, when radiocolloids were used, injections needed to be done 30 minutes to 29 hours before surgery.72, 73

SLNB Using ICG: Challenges and Future

  1. Top of page
  2. Abstract
  3. Intraoperative SLN Mapping and Biopsy Using ICG
  4. SLNB Using ICG: Benefits
  5. SLNB Using ICG: Challenges and Future
  6. Lymphedema
  7. Free Flaps
  8. Conclusions
  9. FUNDING SOURCES
  10. REFERENCES

Despite the many viable features of ICG as an NIR fluorophore in SLNB, becoming the gold standard in SLNB would require further development. As mentioned by Onihishi et al,4 3 components of the NIR probe are important in SLN detection: hydrodynamic diameter, surface charge, and contrast generation. Like ICG, those probes that have a hydrodynamic diameter of <10 nm may potentially pass the SLN,57 but those that are bigger may cause a delay in labeling the SLN.4 Although its anionic properties allow a high uptake of ICG by the lymphatic system, the problem of short retention time was evident in the earlier experiments performed by both Kitai et al20 and Tagaya et al.24 In some cases, ICG alone remained around the tumor, and only a small amount migrated toward the SLN, so the addition of hyaluronidase to ICG was required to facilitate migration.57 These problems were resolved by conjugating ICG with human serum albumin (HSA) in a 1:1 ratio, which improved retention time by increasing the hydrodynamic diameter to 7.3 nm.4, 25 However, at this time more studies are needed to assess the full capabilities of ICG in SLNB. The contrast generation, or the brightness of NIR fluorophores, has been another issue of ICG. The brightness of ICG, as determined by the equation quantum yield × ϵ (molar absorption coefficient at excitation wave length),74 has been up to approximately 5× lower than its inorganic counter parts, such as the quantum dots.9 The fluorescence of ICG has been reported to be visible through approximately 0.5 to 1.0 cm of soft tissue.20, 27 The quantum yield of the current ICG may have been adequate for skin cancer,26 but there is still room for improvement, especially for cancers requiring deeper lymph node dissection. It has been reported that conjugating ICG with calcium nanoparticles,75 silver,76 and HSA25 can increase quantum yield, but only ICG-HSA has been validated in humans.

Another challenge of NIR-guided ICG in SLN detection is the assessment of patient selection criteria to minimize false-negative rates. This has been a particular problem in gastric cancer SLNB, as higher tumor stages (especially T3)29, 35 and obesity50 have been reported to be contributing factors for a higher false-negative rate. Higher tumor stages have been blamed because of the associated high number of cancerous cells blocking the uptake of ICG.

The learning curve and skill have been always been important factors in any type of SLN mapping and biopsy.49, 77 Use of the ICG fluorophore in SLNB may provide an alternative in shortening the learning curve, especially in the context of gastric SLNB by illuminated visualization of the SLNs.30, 31, 50 Although results with the ICG fluorophore are encouraging, its effectiveness in comparison to other methods of SLN mapping and biopsy and the nature by which any possible improvement may vary in different types of cancer require further scrutiny.

It is important to improve the technical aspects of SLN detection methods. Because shadowless lights in the operating theater give off their own intrinsic NIR beam, lymphatic navigation must be performed in the dark to minimize the interference with beams produced by the ICG. This restricts the surgeons from being able to map and perform SLN dissection in real time. In a recent study, Hirche et al37 reported that a new system has been developed that can be used under daylight conditions, but its implications and clinical translation in SLN detection has yet to be assessed. In addition, efforts by Troyan et al25 and Gioux et al13 have resulted in the development of the FLARE imaging system, which has allowed viewing of the surgical anatomy with 2 independent channels of NIR fluorescence. As mentioned in the report, this additional capacity of viewing 2 channels allows numerous possibilities, such as labeling the SLN 1 color and all the others a different color using 2 different NIR fluorophores. Despite its immense potential, the FLARE imaging system is extremely costly and impractical at this time. Although a more compact version is being developed, its full capability and effectiveness has not yet been assessed.25

Lymphedema

  1. Top of page
  2. Abstract
  3. Intraoperative SLN Mapping and Biopsy Using ICG
  4. SLNB Using ICG: Benefits
  5. SLNB Using ICG: Challenges and Future
  6. Lymphedema
  7. Free Flaps
  8. Conclusions
  9. FUNDING SOURCES
  10. REFERENCES

Lymphedema is a serious and debilitating disease. It sometimes occurs as a complication secondary to oncological surgery. Numerous efforts have been made in the development of techniques to detect and surgically minimize this complication, but none has fully succeeded in doing so.78 Lymphoscintigraphy has been a method of evaluating lymphedema, but because of its cumbersome and expensive nature, there has been only limited use of this technique. As previously mentioned in the article, NIR-guided ICG has demonstrated the ability to trace the lymphatic system. On the basis of this fact, 2 independent groups were able to use and diagnose lymphedema intraoperatively. Ogata et al observed real time visualization of the lymphatic system that aided in lymphaticovenular anastomosis71 in 5 lymphedemic patients (4 secondary, 1 primary). Likewise, Unno et al performed the exploration in 12 lymphedemic patients (all secondary) and 10 healthy volunteers. In the 12 patients, 4 had abnormal fluorescence patterns, and 15 of 16 lymphedemic legs (of 12 patients) had detectible dermal backflow, which was interpreted as lymphatic flow obliteration. It was further observed that of the 16 lymphedemic legs, 8 had proximal obstruction of lymph vessels with dilated lymph vessels, and 6 had a diffuse glittering pattern of fluorescence. In all 10 healthy volunteers, normal fluorescence was observed.79 Both groups affirmed the usefulness of this technique and indicated the need for further trials. Ogata et al71 also added that, similarly to the observations during SLN detection, only superficial lymphatics can be observed, although in this case this may pose less of a problem.

Free Flaps

  1. Top of page
  2. Abstract
  3. Intraoperative SLN Mapping and Biopsy Using ICG
  4. SLNB Using ICG: Benefits
  5. SLNB Using ICG: Challenges and Future
  6. Lymphedema
  7. Free Flaps
  8. Conclusions
  9. FUNDING SOURCES
  10. REFERENCES

In reconstructive surgery using free flaps, complications arise because of microvascular blood flow.

Reconstructive surgery often requires a free flap to be harvested from a donor site. A free flap is defined as a graft of free tissue transferred from another site to cover the injured site.80 Although the success rate exceeds 90%, the serious complication of flap failure still exists.81 One way to prevent this failure is to monitor and detect abnormal blood flow after surgery. If any problem is detected, prompt reoperation can salvage the free flap with a 33% to 57% success rate.82 Although there are several ways to detect the flow in macrovascular circulation after surgery, only 2 novel methods, contrast harmonic ultrasound and ICG fluorescence angiography, have shown promising results in microvascular circulation detection. As Giunta et al showed in rat models, NIR-guided ICG was feasible in the prediction of free flap necrosis by monitoring the perfusion index, that is, a calculated parameter that indicates the rate of filling as an extent of arterial blood flow measurement.83 Lamby et al80 and Prantl et al82 further validated these findings in humans and concluded the credibility and effectiveness of the technique. Holm et al81 also used NIR-guided ICG, but taking into account the finding that more complications occur on the venous side, proposed a different parameter—intrinsic transit time—in monitoring the free flaps. This parameter describes the time for ICG to flow from the arterial to venous anastomosis in free flaps, and showed that an intrinsic transit time >50 seconds can lead to a significant risk of this complication.81

Although NIR-guided ICG monitoring of the microvascular system is in its nascent stages, it will hopefully become a useful and accessible tool in decreasing postoperative complications and further understanding the pathophysiology behind them.

Conclusions

  1. Top of page
  2. Abstract
  3. Intraoperative SLN Mapping and Biopsy Using ICG
  4. SLNB Using ICG: Benefits
  5. SLNB Using ICG: Challenges and Future
  6. Lymphedema
  7. Free Flaps
  8. Conclusions
  9. FUNDING SOURCES
  10. REFERENCES

As illustrated in this article, ICG fluorophore has played a crucial role in the advancement of various areas in surgical oncology, including SLNB, reconstructive surgery in free flaps, and postsurgical complications such as lymphedema. Although innovations in recent years with NIR-guided ICG have not been limited to the antecedent, this review accentuates the most current developments, with the hopes that improvements are made by further understanding the rapidly growing progress and the challenges it faces. Despite the finding that the current state of ICG fluorophore development still demands a great deal of research and testing for a wide adoption into everyday clinical practice, it nevertheless holds immense potential and promises.

REFERENCES

  1. Top of page
  2. Abstract
  3. Intraoperative SLN Mapping and Biopsy Using ICG
  4. SLNB Using ICG: Benefits
  5. SLNB Using ICG: Challenges and Future
  6. Lymphedema
  7. Free Flaps
  8. Conclusions
  9. FUNDING SOURCES
  10. REFERENCES
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