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Use of Indocyanine Green for Sentinel Lymph Node Biopsy: Case Series and Methods Comparison

Introduction: Sentinel lymph node biopsy is indicated for patients with biopsy-proven thickness melanoma greater than 1.0 mm. Use of lymphoscintigraphy along with vital blue dyes is the gold standard for identifying sentinel lymph nodes intraoperatively. Indocyanine green (ICG) has recently been used as a method of identifying sentinel lymph nodes. We herein describe a case series of patients who have successfully undergone ICG-assisted sentinel lymph node biopsy for melanoma. We compare 2 imaging systems that are used for ICG-assisted sentinel lymph node biopsy. Methods: Fourteen patients underwent ICG-assisted sentinel lymph node biopsy for melanoma using the SPY Elite system (Novadaq, Mississigua, Canada) and the Hamamatsu PDE-Neo probe system (Mitaka USA, Park City, Utah). We analyzed costs for 2 systems that utilize ICG for sentinel lymph node biopsies. Results: Intraoperative use of ICG for sentinel lymph node biopsies was successful in correctly identifying sentinel lymph nodes. There was no difference between the Hamamatsu PDE-Neo probe and SPY Elite systems in the ability to detect sentinel lymph nodes; however, the former was associated with a lower operating cost and ease of use compared with the latter. Conclusion: ICG-assisted sentinel lymph biopsy using the SPY Elite or the Hamamatsu PDE-Neo probe systems for melanoma are comparable in terms of sentinel node detection. The Neo probe system delivers pertinent clinical data with the advantages of lower cost and ease of operation.


INTRODUCTION
The Breslow depth is one of the most important prognostic factors with regard to the 5-year survival rate in melanoma. Staging of melanoma requires sentinel lymph node biopsy (SLNB), which is indicated for intermediate thickness melanomas defined as a Breslow depth greater than 1.0 mm. 1 However, this recommendation is in an evolution as studies have demonstrated in high-risk lesions that SLNB should be performed for Breslow depth greater than 0.75 mm, especially those with adverse features such as positive deep margins, ulceration, mitosis, lymphovascular invasion or young age. 2,3 SLNB with completion lymph node dissection for intermediate thickness melanomas has not been demonstrated to improve 10-year disease-specific survival rates compared with observation; however, it has shown to be statistically significant in increasing disease-free survival. 4,5 The evolution of the SLNB has grown from the use of vital blue dyes such as methylene blue (MB), isosulfan blue (Lymphazurin) and Patent Blue V dye, to lymphoscintigraphy using technetium-99m (Tc-99m) as a marker of the sentinel lymph node. Often, a combined technique using radioisotopes and blue dye are used. Anaphylactic reactions and serotonin syndrome associated with the use of vital blue dyes have been reported in the literature. [6][7][8][9] Lymphoscintigraphy remains the gold standard in the identification of sentinel lymph nodes in melanoma. Although this method leads to accurate sentinel lymph node identification, the cost and burden to patients undergoing preoperative lymphoscintigraphy can be a challenge, and SLNB positivity can depend on hospital quality. 10 For patients undergoing lymphoscintigraphy, the patient must undergo a preoperative injection of Tc-99m before the localization procedure. In addition to this prior injection, patients may face long wait times, delays, and additional emotional stress.
The use of indocyanine green (ICG) has emerged as a powerful tool in the assessment of sentinel lymph nodes. 11,12 ICG is a small substance near-infrared fluorophore (774.96 Da), which can be visualized transcutaneously to 1.0 cm. However, it contains sodium iodide, which limits its use in patients with iodine or shellfish allergies. ICG can be used in conjunction with intraoperative imaging modalities such as the SPY Elite system (Novadaq, Mississigua, Canada) and Hamamatsu PDE-Neo probe (Mitaka USA, Park City, Utah). The use of these systems has expanded from their use in flap viability assessment to identification of sentinel lymph nodes. [13][14][15][16] We aim to show that the use of these systems is a valuable tool as a clinically safe and effective means of sentinel lymph node identification and compare the clinical efficacy and costs of the 2 systems.

METHODS
This study was exempt from Institutional Review Board review. This case series included 14 patients who underwent SLNB at our institution without the use of preoperative injection of Tc-99m. An intraoperative injection of ICG was performed around the tumor bed. Intraoperative injection of Tc-99m was used to control for the identification of the sentinel lymph nodes by using a standard gamma probe detection device. ICG-assisted SLNB was performed using either the SPY elite system (Novadaq) or the Hamamatsu PDE-Neo probe (Mitaka USA). Then, we performed a financial analysis to compare the costs of each operating system, which were obtained from the manufacturer.

RESULTS
Our case series involved 14 patients who underwent SLNB in conjunction with ICG. The SPY elite system was used for 5 cases, and the Hamamatsu PDE-Neo probe for the remaining 9 patients (Figs. 1-3). All cases correctly identified the sentinel lymph node with no complications of the procedure. This was confirmed by concomitant Tc-99m injection. In certain cases, it was possible to visualize the course of the dye beneath the skin, one involving a digital adenocarcinoma of the thumb and 2 involving cutaneous melanomas of the thigh.
Costs of each operating system used at our institution are shown in Table 1

DISCUSSION
The early use of ICG was centered around calculating liver remnant volume after hepatectomy. 17 As the use of ICG has expanded, it has most notably been used in plas-  tic surgery as a tool to assess intraoperative flap perfusion and viability. 18,19 Multiple studies have outlined the positive outcomes associated with using ICG-assisted imaging for SLNB in breast cancer and the better outcomes of decreased surgical-site occurrences. 12,[20][21][22] The use of ICG for SLNB remains an underexplored but promising area in melanomas. 23 The application of this technique to patients with melanoma was first described in an article by Korn et al. 24 This retrospective review com-pared a total of 90 cutaneous melanoma patients in 2 cohorts who either received SLNB with the traditional blue dye and radioisotope or received SLNB with a radioisotope and the ICG Spy Elite system. Results demonstrated a statistically significant difference in SLN localization using either the ICG fluorescence or the radioisotope/handheld gamma probe method (98.0% and 97.8%, respectively) compared with the localization rate of 79.4% with the blue dye method. Furthermore, there was a trend toward a reduction in surgery length in the ICG cohort. 24 Other studies have confirmed the utility of ICG for SLNB in cutaneous melanoma and the identification of lymph nodes undetected by traditional radioisotope or blue dye techniques. [14][15][16] Our study demonstrated the comparable effectiveness of using the SPY Elite or the Mitaka Hamamatsu PDE-Neo probe system with ICG in correctly identifying all sentinel lymph nodes in our cohort of patients. The lower cost and mobility offered by the Hamamatsu probe makes it the more advantageous system in SLNB. Despite the success of the ICG for SLNB, the limited data make it difficult to recommend its use in lieu of traditional, radioisotope-based lymphoscintigraphy; however, it does offer clinical benefits as an adjuvant technique to identify otherwise missed lymph nodes. The cost of the operating unit refers to the initial investment required to purchase the device. The recurring costs include the cost of the ICG and the disposable drape, which are incurred with each case. The Mitaka Hamamatsu PDE Probe requires a smaller drape, given its smaller, hand-held probe, compared with the Spy Elite system, which accounts for the lower recurring cost per case. The SPY Elite system and the Hamamatsu PDE Neo probe are systems that can utilize ICG in the identification of sentinel lymph nodes. The SPY Elite system allows surgeons to control the camera and screen intraoperatively. Images can be saved and reviewed during the case; however, limitations to this technology include its large size as well as the need to purchase the ICG/Drape exclusively from Novadaq. Conversely, the Hamamatsu PDE is a small hand-held device with an additional CPU unit, which makes it freely moveable with handheld adjustments for color versus black/white options. Additions to the device can be bought independently. Therefore, given the comparable success rates between the 2 systems in identifying sentinel lymph nodes, the mobility and cost-effectiveness offered by the Hamamatsu PDE probe make it the more advantageous system.
There are inherent limitations with our study, given the small study size and the single surgeon experience. Further studies are necessary to more clearly delineate the role of ICG in SLNB for melanoma. We cannot recommend the use of ICG alone in SLNB, but believe that it can serve as a useful adjunct to existing methods such as vital blue dyes and radiotracers. The clinical utility of ICG stems from its usefulness as an intraoperative tool in the open identification of sentinel lymph nodes. Given the visibility of the fluorescent dye in 3 cases without the use of infrared light, the degree of skin thickness in individual cases can allow for additional uses of ICG. Furthermore, Tc-99m uptake in sentinel lymph nodes was observed to occur more rapidly than uptake of ICG, suggesting that the 2 modalities used in conjunction may increase the sensitivity of localizing sentinel lymph nodes in cutaneous melanoma.

CONCLUSIONS
ICG-assisted SLNB using the SPY Elite or the Hamamatsu PDE-Neo probe systems are safe and effective methods for the identification of sentinel lymph nodes. In our experience, the Hamamatsu PDE-Neo probe system is a more user friendly and cost-effective method compared with the SPY Elite system.