Abstract
Sentinel lymph node (SLN) biopsy for cutaneous melanoma is a critical part of designing therapy for the skin malignancy. A retrospective review of 54 patients with cutaneous melanoma who underwent SLN biopsy guided by both radiotracer injection and indocyanine green (ICG) fluorescent dye compared the accuracy of identifying the SLN using each method. Patients were injected preoperatively with radiotracer at the site of the primary melanoma and intraoperatively with 2.5 mg of ICG. The detection of the SLN was compared between the two methods. Patients were followed to determine local recurrence and survival from 5 months to 4 years. ICG and radiotracer identified the SLN in 52 of 54 patients. In those patients who mapped, 52 of 52 showed mapping to the same node or nodes. The rate of cancer involvement in the identified node was 19.2% for both techniques. There was no difference in recurrence or survival between the two methods of SLN identification in short follow-up. In conclusion, ICG injection and mapping to identify SLN in cutaneous melanoma is confirmatory for radiotracer mapping and in the future may be an accurate and less costly method for SLN biopsy in cutaneous melanoma.
Keywords: Indocyanine green, melanoma, near infrared, radiotracer, sentinel lymph node biopsy
The quality and reliability of sentinel lymph node (SLN) biopsy is critical to the initial staging of patients with cutaneous melanoma.1 A local or regional recurrence in the first 2 years after SLN biopsy is considered a false-negative lymph node biopsy. We report our pilot study on the use of the near-infrared fluorescent dye indocyanine green (ICG) to confirm successful SLN biopsy in patients with melanoma. In this single center series, ICG SLN identification confirmed radiotracer SLN location in 100% of cases where mapping occurred. The technique and lessons learned are discussed.
The SLN is the first site where metastatic cancers drain and an important site where metastasis of cancer can be identified. The MSLT-1 study demonstrated that the status of the SLN had prognostic significance for disease recurrence and survival.2 The Sunbelt, MSLT-1, and MSLT-2 all demonstrated the importance of SLN biopsies in staging, prognostication, and regional node control of melanoma.
ICG dye is a fluorescent molecule that has a peak spectral absorption at 800 to 810 nm in plasma or blood. It is a sterile, water-soluble, tricarbocyanine dye. ICG contains not more than 5.0% sodium iodide. It is taken up from the plasma almost exclusively by the hepatic parenchymal cells and is secreted entirely into the bile. ICG does not undergo significant enterohepatic recirculation. It has a normal biological half-life time of 2.5 to 3.0 minutes.3
In the mid 1950s, ICG dye was predominantly used to measure liver and cardiac function. With more research on the fluorescent properties of ICG, its use was expanded to ophthalmology in the measurement of blood flow in the choroid (a layer of blood vessels below the retina). With lack of technological advancement or machinery in the 1970s, the medical imaging use of ICG in angiography was not accepted until the 1990s, and further development of its use occurred in the early 2000s.4 With ICG fluorescent properties gaining popularity and further traction in research, it has recently been used in oncology, specifically in breast and melanoma cases to detect and treat cancer through SLN biopsies.5,6
To make the SLN biopsy more efficient and reduce the false-negative rates of radiotracer SLN biopsy, the use of fluorescent dyes to improve intraoperative identification of SLN has been considered. Cloyd et al, using the Spy Elite camera in SLN biopsy, reported SLN detection rates of 88.5% with ICG compared to 96.2% using technetium-99.7 ICG showed additional lymph nodes that were not originally identified by technetium-99. A learning curve is needed to improve the identification of lymph nodes. Recently, in head and neck melanoma cases, Knackstedt et al reported a 100% SLN identification using a combination of radioisotope probe and ICG.8 Use of the fluorescent dye found and confirmed additional nodes not identified by the radioisotope probe in the head and neck region.
METHODS
This retrospective review involved a consecutive series of 54 melanoma patients undergoing SLN biopsy at our community-based academic hospital. Institutional review board approval was obtained for analysis of deidentified data from a prospective registry. SLN biopsy is an off-label use of ICG and near-infrared fluorescence imaging. The imaging systems used were both the first-generation Stryker Elite camera as well as the newer SPY-PHI handheld system.
Our SLN biopsy technique includes the preoperative use of radiotracer mapping as well as ICG. In the operating room, prior to preparation for surgery, 2.5 mg of ICG diluted in sterile water is injected in the dermis adjacent to the primary melanoma site using a 1 cc syringe with a 27 gauge needle. Fluorescent dermal lymphatic migration can be seen immediately. Once the dye is seen in the lymphatic basin, the near-infrared imaging system is used to visually correlate ICG and radiotracer identified nodes. Photographs are taken of the visual images (Figures 1 and 2).
Figure 1.
Intradermal injection of 2.5 mg of indocyanine green.
Figure 2.
Injection site of indocyanine green mapping in case of melanoma of the forehead skin.
RESULTS
The clinical features of our cohort where mapping occurred are demonstrated in Table 1. The average age was 63, with 26 men and 26 women. Tumor locations were distributed as follows: 11 head and neck, 20 trunk, 13 arms, 8 legs. Extremity mapping in the 8 patients revealed the dermal lymphatic pathways that led to the SLN. In many cases, it revealed the SLN transdermally (Figure 3).
Table 1.
ICG study patients
| Characteristics | N | % | Mean |
|---|---|---|---|
| Gender | 52 | ||
| Male | 26 | 50% | |
| Female | 26 | 50% | |
| Age (years) | 63 | ||
| Ulceration | |||
| Present | 12 | 24% | |
| Not present | 40 | 76% | |
| Thickness (mm) | 2.69 | ||
| 0–1.00 | 8 | 15% | |
| 1–4.0 | 32 | 62% | |
| ≥4 | 12 | 23% | |
| Mitotic rate | 3.1 | ||
| 0 | 10 | 19% | |
| ≥1 | 42 | 81% | |
| Clark level | |||
| II | 2 | 2% | |
| III | 6 | 12% | |
| IV | 38 | 75% | |
| V | 6 | 12% | |
| SLN identification rate | |||
| SLN positive | 10 | 19% | |
| SLN negative | 42 | 81% |
ICG indicates indocyanine green; SLN, sentinel lymph node.
Figure 3.
(a) Injection site on forearm. (b) Fluorescent sentinel node. (c) Transdermal visualization of dermal lymphatic in the forearm.
ICG near-infrared fluorescent dye mapping was conducted on 54 melanoma patients who underwent SLN biopsies. Two patients in head and neck sites did not map by either modality. Of the 54 patients intended to map, the combined radiotracer and ICG technique identified SLN in 52, or 96%. In two patients there was no lymphatic mapping with either the radiotracer or ICG.
At least one SLN was identified in each mapped patient, with a total of 139 SLN identified and sampled by ICG and gamma probe signaling. Ten patients had a positive SLN for melanoma metastasis on histopathology. Twenty-six of 52 patients had 2-year follow-up with no recurrence. The rate of histological positive SLN in the ICG group was 19.2%. It was the same for radiotracer SLN. Follow-up of the 52 patients ranged from 5 months to 4 years. There have been no local or regional recurrences to date.
DISCUSSION
Certain observations were made in the course of learning this technique. Even with considerable experience in SLN biopsy, there was easily a learning curve of approximately five cases to minimize the fluorescent “mess” from even a very small amount of lymph spillage. With experience, no additional time is required for use of the near-infrared fluorescence imaging and recording. The imaging system allows easy digital documentation of the node(s) removed. With current technology, ICG confirmation does not supplant the need for radiotracer mapping, but only supplements it, and will ideally lower the false-negative SLN biopsy rate further. In this surgeon’s experience, ICG confirmation is much more reliable and accurate than the use of blue dyes. Some of the patients on this study have 2 years of data, though no false-negative rate has been calculated. Thus far there have been no regional recurrences.
Current technology does not permit complete mapping with ICG in all patients. In extremity exams, we found it reliable in showing mapping of the dermal lymphatics and helpful in locating the SLN in the basin (Figure 3). ICG will not miss any nodes mapped by radiotracer. In two cases, ICG identified one node each not detected by radiotracer. These were histologically negative lymph nodes, and it is not yet possible to prove they were sentinel.
The issue of ICG replacing radiotracer in part or completely in certain sites has to do with the camera’s ability or inability to measure the intensity of the transmitted light. The SPH-PHI camera can measure a light intensity number. However, in the current system, the algorithm for these measurements is based on vascular flow and not gamma counts. Thus, it cannot currently show us a 10 to 1 reduction with light that is equivalent to the same reduction used in radiotracer-based SLN identification. This “photometric” measurement needs refinement to be able to replace gamma counting. With future developments and accurate lymphatic-based photometrics, it may be possible to perform accurate SLN biopsy with ICG alone. Future studies will be needed. However, with ICG-based near-infrared capability available in most community operating rooms, and more facile handheld camera systems now available, consideration should be given to the use of ICG to visually confirm SLNs identified with radiotracer.
The study had certain limitations. It was a single-surgeon, single-institution consecutive series and did not compare radiotracer and ICG with the blue dyes. This surgeon stopped using blue dues years ago in distal extremity and head and neck melanoma cases due to unreliability. Current photometric brightness as a measurement of lymphatic quantity cannot be compared with the 10 to 1 reduction in gamma count expected with radiotracer.
In conclusion, the use of ICG dye and near-infrared imaging is 100% reliable in visually confirming radiotracer-mapped SLN. The injection and camera usage is easy to master with about a five-case learning curve, depending on the overall experience of the operating surgeon. Future photometric analysis of the “brightness” of fluorescence will hopefully allow the determination of a similar 10 to 1 reduction that currently defines SLN identification using radiotracer and gamma counts.
Disclosure statement/Funding
The authors report no funding or conflicts of interest.
References
- 1.Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599–609. doi: 10.1056/NEJMoa1310460. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242(3):302–311. doi: 10.1097/01.sla.0000181092.50141.fa. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Alander JT, Kaartinen I, Laakso A, et al. A review of indocyanine green fluorescent imaging in surgery. Int J Biomed Imaging. 2012;2012:940585. doi: 10.1155/2012/940585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Reinhart MB, Huntington CR, Blair LJ, Heniford BT, Augenstein VA.. Indocyanine green: historical context, current applications, and future considerations. Surg Innov. 2016;23(2):166–175. doi: 10.1177/1553350615604053. [DOI] [PubMed] [Google Scholar]
- 5.Kitai T, Inomoto T, Miwa M, Shikayama T.. Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer. 2005;12(3):211–215. doi: 10.2325/jbcs.12.211. [DOI] [PubMed] [Google Scholar]
- 6.Motomura K, Inaji H, Komoike Y, Kasugai T, Noguchi S, Koyama H.. Sentinel node biopsy guided by indocyanine green dye in breast cancer patients. Jpn J Clin Oncol. 1999;29(12):604–607. doi: 10.1093/jjco/29.12.604. [DOI] [PubMed] [Google Scholar]
- 7.Cloyd JM, Wapnir IL, Read BM, Swetter S, Greco RS.. Indocyanine green and fluorescence lymphangiography for sentinel lymph node identification in cutaneous melanoma. J Surg Oncol. 2014;110(7):888–892. doi: 10.1002/jso.23745. [DOI] [PubMed] [Google Scholar]
- 8.Knacksted RW, Couto RA, Gastman B.. Abstract 49. ICG fluorescence with lymphoscintigraphy for sentinel node biopsy in head and neck cutaneous melanoma: a reproducible, reliable means to improve false negative rates. J Surg Res. 2017;288:77–83. [Google Scholar]