Original Investigation
Indocyanine Green–Guided Sentinel Lymph Node Biopsy for Periocular Tumors Tal J. Rubinstein, M.D.*, Julian D. Perry, M.D.*, Jason M. Korn, M.D.†, Bryan R. Costin, M.D.*, Brian R. Gastman, M.D.†, and Arun D. Singh, M.D.* *Department of Ophthalmology and †Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.
Purpose: To compare the accuracy of indocyanine green (ICG)–guided sentinel lymph node biopsy to sentinel lymph node biopsy performed with technetium-99m in eyelid and in conjunctival malignancies. Methods: Review of a consecutive series of adult patients undergoing sentinel lymph node biopsy for eyelid and conjunctival malignancies between 2009 and 2013. Only patients undergoing both ICG-guided and technetium-99m– guided sentinel lymph node biopsies were included. Results: Five patients were identified: 3 women and 2 men. Four had conjunctival melanoma and 1 had eyelid melanoma. ICG aided in localization and confirmation of the sentinel nodes identified by technetium-99m, and all sentinel lymph nodes identified by technetium-99m were identified by ICG. All patients who underwent both sentinel lymph node modalities had negative lymph node biopsies for micrometastasis, but metastatic disease eventually developed in 1 patient. No safety concerns were identified with the use of ICG in the ocular adnexal region. Conclusions: For certain periocular malignancies, ICGguided sentinel lymph node biopsy safely identifies sentinel lymph nodes intraoperatively possibly to a similar extent compared with technetium-99m–guided methods. (Ophthal Plast Reconstr Surg 2014;30:301–304)
T
he sentinel lymph node is the first lymph node to drain a tumor, and it is often the first involved lymph node in lymphatic metastasis. Positive histology for micrometastasis within this lymph node offers accurate staging and may influence further therapy decisions such as extensive lymph node dissection or adjuvant medical therapy.1 Sentinel lymph node biopsy (SLNB) typically uses radioactive technetium-99m sulfur or albumin colloid injected into the tumor site preoperatively, with single photon emission CT (SPECT)/CT to image the location of the sentinel lymph nodes.2 A γ probe further identifies specific sentinel lymph nodes intraoperatively for dissection. Adjunctive intraoperative methylene blue or other blue dyes may assist in localization.
Although a survival benefit of SLNB in the periocular region is yet unknown, SLNB is performed in eyelid and conjunctival malignancies based on the findings that it provides a survival benefit in cutaneous melanoma.2–6 In eyelid and ocular surface malignancies, which have a 10% to 60% risk of regional lymph node metastasis, technetium-99m–guided SLNB accurately identifies the sentinel lymph node, often in the parotid, mandibular, and deep cervical regions.1,7,8 However, many limitations exist. Technetium-99m–guided SLNB of melanomas of the head and neck, including conjunctival and eyelid melanoma, has higher false-negative rates compared with truncal or extremity melanoma, and lymph node and lymphatic visualization with blue dye are poorer in the head and neck region.2,9,10 In addition, the identification of sentinel lymph nodes in the cervical region is poorer (85%) compared with other areas such as groin (99%) or axilla (95%).4 These worse outcomes in the head and neck region may be due to complex lymphatic drainage, smaller lymph nodes, steeper learning curves of performance within the head and neck region, prior surgical scarring, complex dissection sites, or in-transit metastasis not detected by SLNB.2,9,10 Indocyanine green (ICG)–guided SLNB is a newer modality used to identify sentinel lymph nodes in many types of cancers such as breast, lung, colon, head and neck, and skin.11– 16 ICG is a fluorescent dye with a spectral absorption of 750 to 810 nm and, therefore, detectable with near-infrared (NIR) light.16 ICG’s small particle size, propensity to flow through lymphatic vessels, stability within the body, and ability to be visualized in real time may circumvent the shortcoming associated with technetium-99m and blue dyes in the head and neck region.11,12,16,17 Compared with the gold standard SLNB with technetium-99m and blue dyes, ICG with NIR light accurately identifies sentinel lymph nodes in cutaneous melanoma.12,18 Furthermore, ICG-guided SLNB may identify more sentinel lymph nodes and more lymph node basins than t echnetium-99m or blue dye for a variety of cutaneous malignancies and in the neck region.10,17,18 To the authors’ knowledge, ICG-guided SLNB has not been specifically studied in ocular surface or eyelid malignancies. The authors sought to determine the efficacy of this modality in identifying sentinel lymph nodes in such malignancies.
METHODS Accepted for publication December 2, 2013. J.D.P. is a consultant for Merz Pharmaceuticals and B.R.G. is a consultant for LifeCell. The remaining authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Arun D. Singh, M.D., Cole Eye Institute, 2022 East 105th Street, Cleveland, OH 44195. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000096
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The authors retrospectively reviewed the charts of all patients evaluated at the Cole Eye Institute who underwent SLNB between 2009 and 2013. Charts were reviewed for patient age; gender; type of primary malignancy, location, and histologic features; type of SLNB performed; SLNB operative details; SLNB complications; and SLNB histologic results. Only data from initial biopsies were included. Cleveland Clinic Institutional Review Board approval was granted to perform this chart
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review, and the authors were compliant with the Health Insurance Portability and Accountability Act. Patients who underwent SLNB with technetium-99m alone were excluded. The remaining patients underwent SLNB with both technetium-99m and ICG. One of 2 physicians from the Department of Plastic Surgery performed the SLNB. All patients underwent tumor excision by one of the authors (A.D.S.) at the time of the SLNB. For technetium-99m–guided SLNB, technetium-99m sulfur colloid (between 208 and 479 microcuries) was injected into the tumor site, and SPECT/CT imaging was used to identify the sentinel lymph nodes preoperatively. Subsequent use of the intraoperative γ probe identified the precise surgical site and distinguished the sentinel lymph nodes from background radiation when the lymph node γ counts were more than 10 times higher than background. For ICG-guided SLNB, 25 mg of ICG was reconstituted with sterile water to produce 10 ml of ICG solution. The ICG solution was administered through intralesional infiltration at doses between 0.5 and 1.5 ml. NIR light provided by the SPY Elite system (LifeCell, Bridgewater, NJ) was used intraoperatively to identify draining lymphatic vessels when possible (Figs. 1 and 2A). In addition, after skin incisions were made based on technetium-99m localization, ICG dye and NIR light were used to confirm lymph nodes with elevated γ counts on the γ probe (Fig. 2B). All lymph nodes that fluoresced were identified as sentinel lymph nodes. Blue dyes were not used because the surgeons essentially used ICG in lieu of blue dyes.
FIG. 2. Example of patient undergoing indocyanine green (ICG)–guided sentinel lymph node biopsy of conjunctival melanoma. A, Fluorescence of eye (*) as seen by the SPY Elite system after instillation of ICG into the conjunctiva. Note lymphatic migration of ICG (arrow). Image contrast has been adjusted. B, Intraoperative utilization of the SPY Elite system identifying fluorescence of a draining lymph node. Image contrast has been adjusted.
RESULTS
FIG. 1. The SPY Elite system (courtesy of LifeCell). A, The imaging head, which aims the infrared light onto desired location. B, Articulating arm. C, Imaging monitor.
302
The authors identified 5 patients who underwent SLNB using both technetium-99m and ICG. Three patients were women and 2 were men. Mean age was 72 years (range, 56–82 years). Four were diagnosed with conjunctival melanoma and 1 with eyelid melanoma. Average length of follow up was 6.6 months (range, 3–12 months). Tables 1 and 2 summarize the patient cases and results of the SLNB, respectively. Both SLNB modalities identified a range of 1 to 3 sentinel lymph nodes in the 5 patients. All lymph nodes identified by the γ probe were also identified by ICG fluorescence using NIR light, and in 1 case (Case 4), NIR light identified an additional sentinel lymph node not identified by γ probe. All sentinel lymph nodes were negative for micrometastasis. In Case 4, an 82-year-old woman with conjunctival melanoma of the OS who underwent both SLNB modalities, the γ probe initially identified readings of 400 to 1,000 counts per minute within the left parotid gland without areas that were definitively positive. During a subsequent subtotal superficial parotidectomy, NIR light identified a lymph node that correlated with γ reading of 1,200 counts per minute. An additional area in zone IIA of the neck, which was not identified on preoperative SPECT/CT imaging, was identified with the γ probe with readings of 2,000 counts per minute, and NIR light was used to identify 1 major and 1 minor sentinel nodes within this region. Pathologic analysis
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Ophthal Plast Reconstr Surg, Vol. 30, No. 4, 2014
ICG Sentinel Lymph Node Biopsy for Periocular Malignancies
TABLE 1. Demographic and initial tumor biopsy data of the study patients
Case
Age
Sex
1
76
M
2
79
M
3
56
F
4
82
F
5
68
F
Malignancy
Ulceration
Mitotic figures per mm2
Lymphatic invasion
2
No
2
No
Epithelioid
4.4
Yes
1–2
Suspicious
No
Epithelioid
4.4
Yes
1
No
L
No
4.4
Yes
3
No
R
No
Superficial spreading Epithelioid
3.43
*
*
*
Side
Limbal involvement
Histology
L
Yes
Epithelioid
R
Yes
L
Conjunctival melanoma Conjunctival melanoma Eyelid melanoma Conjunctival melanoma Conjunctival melanoma
TT (mm)
F, female; L, left-sided lesion; M, male; R, right-sided lesion; TT, tumor thickness. *Information was not included in initial biopsy report.
TABLE 2. Sentinel lymph node biopsy results of the study patients
Case 1 2 3 4 5
Location of SLN
Nodes identified by GP
Nodes identified by NIR
Nodes biopsied
Positive nodes
Follow-up time (months)
Status
Cervical Cervical Cervical Parotid, cervical Cervical
2 1 1 2 3
2 1 1 3 3
2 1 1 16 3
0 0 0 0 0
12 11 1.5 3 5.5
Alive Alive Alive Dead Alive
Follow-up time is time in months after sentinel lymph node biopsy. GP, γ probe; NIR, near-infrared light; SLN, sentinel lymph node.
actually identified 4 lymph nodes within the parotid contents and 12 lymph nodes within the neck contents. All lymph nodes were negative for malignancy, yet the patient developed metastatic disease to the axial skeleton and expired about 7 months after the surgery.
DISCUSSION This case series introduces ICG-guided SLNB as a method of identifying sentinel lymph nodes in conjunctival and eyelid malignancies. The use of ICG dye with intraoperative NIR light was as effective as technetium-99m in identifying the sentinel lymph nodes in patients who received both tracers. ICG with NIR light was used to trace lymphatic drainage in real time and to confirm the lymph nodes with elevated radiation counts on the γ probe. In 1 case (Case 4), ICG helped delineate more distinct pockets of lymph nodes within an area of high, but poorly distinguished, radiation counts. ICG-guided SLNB was deemed safe. In this patient series, there were no immediate complications noted with ICG. Although ICG may rarely cause anaphylactic shock, the risk of this complication is noted to be less than blue tracers.19,20 Furthermore, ICG offers a theoretical safety benefit compared with technetium-99m because the former is a commonly used dye in fields such as ophthalmology and is nonradioactive. The authors did not observe permanent staining of the ocular surface or skin with ICG, which can be seen with methylene blue.21 ICG-guided SLNB for malignancies, especially of the ocular surface and eyelid, is still a procedure in its infancy. While studies evaluating dosage of ICG and signal-to-background ratio suggest that increasing dosage may increase signal-to-background ratio up until very high doses, the acceptable signal-to-background ratio that best identifies a sentinel lymph node from background tissue is undetermined.12,18 In addition, while its rapid transit through the lymphatics offers
intraoperative visualization of the lymphatic tracks, this can theoretically lead to identification of higher tier nodes beyond the sentinel nodes when time between ICG injection and visualization increases.15 In this series, ICG did not definitively appear to identify higher tier nodes beyond those identified by the γ probe, but the possibility and effect of procuring higher tier, nonsentinel nodes in ICG-guided SLNB, especially within delicate lymph node dissections of the head and neck regions, is unknown. One patient succumbed to metastatic disease despite the utilization of SLNB. In this patient, the incongruence between SPECT/CT and intraoperative findings suggests that other lymph node basins may have existed. In addition, a subtotal superficial parotidectomy may have missed lymph nodes deeper within the gland. Other possibilities of this false-negative SLNB result include histologic false-negatives, in-transit metastasis, or metastasis via extralymphatic routes. Finally, because pathology identified more lymph nodes within the tissues than originally expected intraoperatively, 1 limitation of both SLNB modalities may be spatially distinguishing singular lymph nodes within certain tissues. To the authors’ knowledge, ICG-guided SLNB specifically for conjunctival and eyelid malignancies has not been previously studied. Because the SPY Elite system or other NIR systems are available in institutions that use it in breast and head and neck reconstruction for assessment of flap perfusion, the technology is accessible in these institutions for studies of ICG-guided SLNB. Further studies should determine whether ICG-guided SLNB can be used as a solitary procedure. In this study and other studies of head and neck cancer, however, the dissection sites were determined by technetium-99m and the γ probe, while other institutions have investigated ICG– technetium-99m hybrid tracers in certain malignancies.10,22,23 Furthermore, studies indicate that the use of NIR light after skin
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incision may increase the rate of sentinel lymph node identification compared with its use before incision, suggesting the importance of technetium-99m and the γ probe in identifying the dissection sites.24 Further studies should additionally assess the sensitivity and specificity of ICG-guided SLNB compared with both technetium-99m–guided SLNB and blue dyes. Finally, studying the outcomes and safety of ICG-guided SLNB in the different tumor types of the eyelid and conjunctiva should further clarify the advantages and limitations of this modality.
REFERENCES 1. Esmaeli B. Sentinel node biopsy as a tool for accurate staging of eyelid and conjunctival malignancies. Curr Opin Ophthalmol 2002;13:317–23. 2. Pfeiffer ML, Savar A, Esmaeli B. Sentinel lymph node biopsy for eyelid and conjunctival tumors: what have we learned in the past decade? Ophthal Plast Reconstr Surg 2013;29:57–62. 3. Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999;17:976–83. 4. Morton DL, Cochran AJ, Thompson JF, et al.; Multicenter Selective Lymphadenectomy Trial Group. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg 2005;242:302–11; discussion 311–3. 5. Savar A, Ross MI, Prieto VG, et al. Sentinel lymph node biopsy for ocular adnexal melanoma: experience in 30 patients. Ophthalmology 2009;116:2217–23. 6. Cohen VM, Tsimpida M, Hungerford JL, et al. Prospective study of sentinel lymph node biopsy for conjunctival melanoma. Br J Ophthalmol 2013;97:1525–9. 7. Maalouf TJ, Dolivet G, Angioi KS, et al. Sentinel lymph node biopsy in patients with conjunctival and eyelid cancers: experience in 17 patients. Ophthal Plast Reconstr Surg 2012;28:30–4. 8. Ho VH, Ross MI, Prieto VG, et al. Sentinel lymph node biopsy for sebaceous cell carcinoma and melanoma of the ocular adnexa. Arch Otolaryngol Head Neck Surg 2007;133:820–6. 9. Chao C, Wong SL, Edwards MJ, et al.; Sunbelt Melanoma Trial Group. Sentinel lymph node biopsy for head and neck melanomas. Ann Surg Oncol 2003;10:21–6. 10. Nakamura Y, Fujisawa Y, Nakamura Y, et al. Improvement of the sentinel lymph node detection rate of cervical sentinel lymph node biopsy using real-time fluorescence navigation with indocyanine green in head and neck skin cancer. J Dermatol 2013;40:453–7. 11. Murawa D, Hirche C, Dresel S, et al. Sentinel lymph node biopsy in breast cancer guided by indocyanine green fluorescence. Br J Surg 2009;96:1289–94.
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12. Gilmore DM, Khullar OV, Gioux S, et al. Effective low-dose escalation of indocyanine green for near-infrared fluorescent sentinel lymph node mapping in melanoma. Ann Surg Oncol 2013;20:2357–63. 13. Gilmore DM, Khullar OV, Jaklitsch MT, et al. Identification of metastatic nodal disease in a phase 1 dose-escalation trial of intraoperative sentinel lymph node mapping in non-small cell lung cancer using near-infrared imaging. J Thorac Cardiovasc Surg 2013;146:562–70; discussion 569–70. 14. van der Pas MH, Ankersmit M, Stockmann HB, et al. Laparoscopic sentinel lymph node identification in patients with colon carcinoma using a near-infrared dye: description of a new technique and feasibility study. J Laparoendosc Adv Surg Tech A 2013;23:367–71. 15. van der Vorst JR, Schaafsma BE, Verbeek FP, et al. Near-infrared fluorescence sentinel lymph node mapping of the oral cavity in head and neck cancer patients. Oral Oncol 2013;49:15–9. 16. Namikawa K, Yamazaki N. Sentinel lymph node biopsy guided by indocyanine green fluorescence for cutaneous melanoma. Eur J Dermatol 2011;21:184–90. 17. Fujisawa Y, Nakamura Y, Kawachi Y, et al. Indocyanine green fluorescence-navigated sentinel node biopsy showed higher sensitivity than the radioisotope or blue dye method, which may help to reduce false-negative cases in skin cancer. J Surg Oncol 2012;106:41–5. 18. van der Vorst JR, Schaafsma BE, Verbeek FP, et al. Dose optimization for near-infrared fluorescence sentinel lymph node mapping in patients with melanoma. Br J Dermatol 2013;168:93–8. 19. Olsen TW, Lim JI, Capone A Jr, et al. Anaphylactic shock following indocyanine green angiography. Arch Ophthalmol 1996;114:97. 20. Fujiwara M, Mizukami T, Suzuki A, et al. Sentinel lymph node detection in skin cancer patients using real-time fluorescence navigation with indocyanine green: preliminary experience. J Plast Reconstr Aesthet Surg 2009;62:e373–8. 21. Reyes F, Noelck M, Valentino C, et al. Complications of methylene blue dye in breast surgery: case reports and review of the literature. J Cancer 2010;2:20–5. 22. Frontado LM, Brouwer OR, van den Berg NS, et al. Added value of the hybrid tracer indocyanine green-99mTc-nanocolloid for sentinel node biopsy in a series of patients with different lymphatic drainage patterns. Rev Esp Med Nucl Imagen Mol 2013;32:227–33. 23. Brouwer OR, Buckle T, Vermeeren L, et al. Comparing the hybrid fluorescent-radioactive tracer indocyanine g reen-99mTc-nanocolloid with 99mTc-nanocolloid for sentinel node identification: a validation study using lymphoscintigraphy and SPECT/CT. J Nucl Med 2012;53:1034–40. 24. Namikawa K, Tsutsumida A, Tanaka R, et al. Limitation of indocyanine green fluorescence in identifying sentinel lymph node prior to skin incision in cutaneous melanoma. Int J Clin Oncol 2014;19:198–203.
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Indocyanine Green–Guided Sentinel Lymph Node Biopsy for Periocular Tumors Tal J. Rubinstein, M.D.*, Julian D. Perry, M.D.*, Jason M. Korn, M.D.†, Bryan R. Costin, M.D.*, Brian R. Gastman, M.D.†, and Arun D. Singh, M.D.* *Department of Ophthalmology and †Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.
Purpose: To compare the accuracy of indocyanine green (ICG)–guided sentinel lymph node biopsy to sentinel lymph node biopsy performed with technetium-99m in eyelid and in conjunctival malignancies. Methods: Review of a consecutive series of adult patients undergoing sentinel lymph node biopsy for eyelid and conjunctival malignancies between 2009 and 2013. Only patients undergoing both ICG-guided and technetium-99m– guided sentinel lymph node biopsies were included. Results: Five patients were identified: 3 women and 2 men. Four had conjunctival melanoma and 1 had eyelid melanoma. ICG aided in localization and confirmation of the sentinel nodes identified by technetium-99m, and all sentinel lymph nodes identified by technetium-99m were identified by ICG. All patients who underwent both sentinel lymph node modalities had negative lymph node biopsies for micrometastasis, but metastatic disease eventually developed in 1 patient. No safety concerns were identified with the use of ICG in the ocular adnexal region. Conclusions: For certain periocular malignancies, ICGguided sentinel lymph node biopsy safely identifies sentinel lymph nodes intraoperatively possibly to a similar extent compared with technetium-99m–guided methods. (Ophthal Plast Reconstr Surg 2014;30:301–304)
T
he sentinel lymph node is the first lymph node to drain a tumor, and it is often the first involved lymph node in lymphatic metastasis. Positive histology for micrometastasis within this lymph node offers accurate staging and may influence further therapy decisions such as extensive lymph node dissection or adjuvant medical therapy.1 Sentinel lymph node biopsy (SLNB) typically uses radioactive technetium-99m sulfur or albumin colloid injected into the tumor site preoperatively, with single photon emission CT (SPECT)/CT to image the location of the sentinel lymph nodes.2 A γ probe further identifies specific sentinel lymph nodes intraoperatively for dissection. Adjunctive intraoperative methylene blue or other blue dyes may assist in localization.
Although a survival benefit of SLNB in the periocular region is yet unknown, SLNB is performed in eyelid and conjunctival malignancies based on the findings that it provides a survival benefit in cutaneous melanoma.2–6 In eyelid and ocular surface malignancies, which have a 10% to 60% risk of regional lymph node metastasis, technetium-99m–guided SLNB accurately identifies the sentinel lymph node, often in the parotid, mandibular, and deep cervical regions.1,7,8 However, many limitations exist. Technetium-99m–guided SLNB of melanomas of the head and neck, including conjunctival and eyelid melanoma, has higher false-negative rates compared with truncal or extremity melanoma, and lymph node and lymphatic visualization with blue dye are poorer in the head and neck region.2,9,10 In addition, the identification of sentinel lymph nodes in the cervical region is poorer (85%) compared with other areas such as groin (99%) or axilla (95%).4 These worse outcomes in the head and neck region may be due to complex lymphatic drainage, smaller lymph nodes, steeper learning curves of performance within the head and neck region, prior surgical scarring, complex dissection sites, or in-transit metastasis not detected by SLNB.2,9,10 Indocyanine green (ICG)–guided SLNB is a newer modality used to identify sentinel lymph nodes in many types of cancers such as breast, lung, colon, head and neck, and skin.11– 16 ICG is a fluorescent dye with a spectral absorption of 750 to 810 nm and, therefore, detectable with near-infrared (NIR) light.16 ICG’s small particle size, propensity to flow through lymphatic vessels, stability within the body, and ability to be visualized in real time may circumvent the shortcoming associated with technetium-99m and blue dyes in the head and neck region.11,12,16,17 Compared with the gold standard SLNB with technetium-99m and blue dyes, ICG with NIR light accurately identifies sentinel lymph nodes in cutaneous melanoma.12,18 Furthermore, ICG-guided SLNB may identify more sentinel lymph nodes and more lymph node basins than t echnetium-99m or blue dye for a variety of cutaneous malignancies and in the neck region.10,17,18 To the authors’ knowledge, ICG-guided SLNB has not been specifically studied in ocular surface or eyelid malignancies. The authors sought to determine the efficacy of this modality in identifying sentinel lymph nodes in such malignancies.
METHODS Accepted for publication December 2, 2013. J.D.P. is a consultant for Merz Pharmaceuticals and B.R.G. is a consultant for LifeCell. The remaining authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Arun D. Singh, M.D., Cole Eye Institute, 2022 East 105th Street, Cleveland, OH 44195. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000096
Ophthal Plast Reconstr Surg, Vol. 30, No. 4, 2014
The authors retrospectively reviewed the charts of all patients evaluated at the Cole Eye Institute who underwent SLNB between 2009 and 2013. Charts were reviewed for patient age; gender; type of primary malignancy, location, and histologic features; type of SLNB performed; SLNB operative details; SLNB complications; and SLNB histologic results. Only data from initial biopsies were included. Cleveland Clinic Institutional Review Board approval was granted to perform this chart
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review, and the authors were compliant with the Health Insurance Portability and Accountability Act. Patients who underwent SLNB with technetium-99m alone were excluded. The remaining patients underwent SLNB with both technetium-99m and ICG. One of 2 physicians from the Department of Plastic Surgery performed the SLNB. All patients underwent tumor excision by one of the authors (A.D.S.) at the time of the SLNB. For technetium-99m–guided SLNB, technetium-99m sulfur colloid (between 208 and 479 microcuries) was injected into the tumor site, and SPECT/CT imaging was used to identify the sentinel lymph nodes preoperatively. Subsequent use of the intraoperative γ probe identified the precise surgical site and distinguished the sentinel lymph nodes from background radiation when the lymph node γ counts were more than 10 times higher than background. For ICG-guided SLNB, 25 mg of ICG was reconstituted with sterile water to produce 10 ml of ICG solution. The ICG solution was administered through intralesional infiltration at doses between 0.5 and 1.5 ml. NIR light provided by the SPY Elite system (LifeCell, Bridgewater, NJ) was used intraoperatively to identify draining lymphatic vessels when possible (Figs. 1 and 2A). In addition, after skin incisions were made based on technetium-99m localization, ICG dye and NIR light were used to confirm lymph nodes with elevated γ counts on the γ probe (Fig. 2B). All lymph nodes that fluoresced were identified as sentinel lymph nodes. Blue dyes were not used because the surgeons essentially used ICG in lieu of blue dyes.
FIG. 2. Example of patient undergoing indocyanine green (ICG)–guided sentinel lymph node biopsy of conjunctival melanoma. A, Fluorescence of eye (*) as seen by the SPY Elite system after instillation of ICG into the conjunctiva. Note lymphatic migration of ICG (arrow). Image contrast has been adjusted. B, Intraoperative utilization of the SPY Elite system identifying fluorescence of a draining lymph node. Image contrast has been adjusted.
RESULTS
FIG. 1. The SPY Elite system (courtesy of LifeCell). A, The imaging head, which aims the infrared light onto desired location. B, Articulating arm. C, Imaging monitor.
302
The authors identified 5 patients who underwent SLNB using both technetium-99m and ICG. Three patients were women and 2 were men. Mean age was 72 years (range, 56–82 years). Four were diagnosed with conjunctival melanoma and 1 with eyelid melanoma. Average length of follow up was 6.6 months (range, 3–12 months). Tables 1 and 2 summarize the patient cases and results of the SLNB, respectively. Both SLNB modalities identified a range of 1 to 3 sentinel lymph nodes in the 5 patients. All lymph nodes identified by the γ probe were also identified by ICG fluorescence using NIR light, and in 1 case (Case 4), NIR light identified an additional sentinel lymph node not identified by γ probe. All sentinel lymph nodes were negative for micrometastasis. In Case 4, an 82-year-old woman with conjunctival melanoma of the OS who underwent both SLNB modalities, the γ probe initially identified readings of 400 to 1,000 counts per minute within the left parotid gland without areas that were definitively positive. During a subsequent subtotal superficial parotidectomy, NIR light identified a lymph node that correlated with γ reading of 1,200 counts per minute. An additional area in zone IIA of the neck, which was not identified on preoperative SPECT/CT imaging, was identified with the γ probe with readings of 2,000 counts per minute, and NIR light was used to identify 1 major and 1 minor sentinel nodes within this region. Pathologic analysis
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Ophthal Plast Reconstr Surg, Vol. 30, No. 4, 2014
ICG Sentinel Lymph Node Biopsy for Periocular Malignancies
TABLE 1. Demographic and initial tumor biopsy data of the study patients
Case
Age
Sex
1
76
M
2
79
M
3
56
F
4
82
F
5
68
F
Malignancy
Ulceration
Mitotic figures per mm2
Lymphatic invasion
2
No
2
No
Epithelioid
4.4
Yes
1–2
Suspicious
No
Epithelioid
4.4
Yes
1
No
L
No
4.4
Yes
3
No
R
No
Superficial spreading Epithelioid
3.43
*
*
*
Side
Limbal involvement
Histology
L
Yes
Epithelioid
R
Yes
L
Conjunctival melanoma Conjunctival melanoma Eyelid melanoma Conjunctival melanoma Conjunctival melanoma
TT (mm)
F, female; L, left-sided lesion; M, male; R, right-sided lesion; TT, tumor thickness. *Information was not included in initial biopsy report.
TABLE 2. Sentinel lymph node biopsy results of the study patients
Case 1 2 3 4 5
Location of SLN
Nodes identified by GP
Nodes identified by NIR
Nodes biopsied
Positive nodes
Follow-up time (months)
Status
Cervical Cervical Cervical Parotid, cervical Cervical
2 1 1 2 3
2 1 1 3 3
2 1 1 16 3
0 0 0 0 0
12 11 1.5 3 5.5
Alive Alive Alive Dead Alive
Follow-up time is time in months after sentinel lymph node biopsy. GP, γ probe; NIR, near-infrared light; SLN, sentinel lymph node.
actually identified 4 lymph nodes within the parotid contents and 12 lymph nodes within the neck contents. All lymph nodes were negative for malignancy, yet the patient developed metastatic disease to the axial skeleton and expired about 7 months after the surgery.
DISCUSSION This case series introduces ICG-guided SLNB as a method of identifying sentinel lymph nodes in conjunctival and eyelid malignancies. The use of ICG dye with intraoperative NIR light was as effective as technetium-99m in identifying the sentinel lymph nodes in patients who received both tracers. ICG with NIR light was used to trace lymphatic drainage in real time and to confirm the lymph nodes with elevated radiation counts on the γ probe. In 1 case (Case 4), ICG helped delineate more distinct pockets of lymph nodes within an area of high, but poorly distinguished, radiation counts. ICG-guided SLNB was deemed safe. In this patient series, there were no immediate complications noted with ICG. Although ICG may rarely cause anaphylactic shock, the risk of this complication is noted to be less than blue tracers.19,20 Furthermore, ICG offers a theoretical safety benefit compared with technetium-99m because the former is a commonly used dye in fields such as ophthalmology and is nonradioactive. The authors did not observe permanent staining of the ocular surface or skin with ICG, which can be seen with methylene blue.21 ICG-guided SLNB for malignancies, especially of the ocular surface and eyelid, is still a procedure in its infancy. While studies evaluating dosage of ICG and signal-to-background ratio suggest that increasing dosage may increase signal-to-background ratio up until very high doses, the acceptable signal-to-background ratio that best identifies a sentinel lymph node from background tissue is undetermined.12,18 In addition, while its rapid transit through the lymphatics offers
intraoperative visualization of the lymphatic tracks, this can theoretically lead to identification of higher tier nodes beyond the sentinel nodes when time between ICG injection and visualization increases.15 In this series, ICG did not definitively appear to identify higher tier nodes beyond those identified by the γ probe, but the possibility and effect of procuring higher tier, nonsentinel nodes in ICG-guided SLNB, especially within delicate lymph node dissections of the head and neck regions, is unknown. One patient succumbed to metastatic disease despite the utilization of SLNB. In this patient, the incongruence between SPECT/CT and intraoperative findings suggests that other lymph node basins may have existed. In addition, a subtotal superficial parotidectomy may have missed lymph nodes deeper within the gland. Other possibilities of this false-negative SLNB result include histologic false-negatives, in-transit metastasis, or metastasis via extralymphatic routes. Finally, because pathology identified more lymph nodes within the tissues than originally expected intraoperatively, 1 limitation of both SLNB modalities may be spatially distinguishing singular lymph nodes within certain tissues. To the authors’ knowledge, ICG-guided SLNB specifically for conjunctival and eyelid malignancies has not been previously studied. Because the SPY Elite system or other NIR systems are available in institutions that use it in breast and head and neck reconstruction for assessment of flap perfusion, the technology is accessible in these institutions for studies of ICG-guided SLNB. Further studies should determine whether ICG-guided SLNB can be used as a solitary procedure. In this study and other studies of head and neck cancer, however, the dissection sites were determined by technetium-99m and the γ probe, while other institutions have investigated ICG– technetium-99m hybrid tracers in certain malignancies.10,22,23 Furthermore, studies indicate that the use of NIR light after skin
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incision may increase the rate of sentinel lymph node identification compared with its use before incision, suggesting the importance of technetium-99m and the γ probe in identifying the dissection sites.24 Further studies should additionally assess the sensitivity and specificity of ICG-guided SLNB compared with both technetium-99m–guided SLNB and blue dyes. Finally, studying the outcomes and safety of ICG-guided SLNB in the different tumor types of the eyelid and conjunctiva should further clarify the advantages and limitations of this modality.
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