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Update on near infrared imaging technology: indocyanine green and near infrared technology in the treatment of gynecologic cancers
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  1. Beryl Manning-Geist1,
  2. Andreas Obermair2,
  3. Vance A Broach1,
  4. Mario M Leitao1,
  5. Oliver Zivanovic1 and
  6. Nadeem R Abu-Rustum1
    1. 1 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    2. 2 University of Queensland Queensland Centre for Gynaecological Cancer Research, Herston, Queensland, Australia
    1. Correspondence to Dr Nadeem R Abu-Rustum, Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; abu-rusn{at}mskcc.org

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    Introduction

    In 2020, we published a comprehensive update on the use of fluorescence imaging systems in gynecologic cancer surgery.1 The objective of the current review is to present recent advances in the use of near-infrared (NIR) imaging with indocyanine green (ICG) specific to ureter visualization, vulvar sentinel lymph node (SLN) mapping, and wound perfusion.

    Intra-vascular ICG injection has been in use for more than 50 years, with few adverse reactions reported. Hope-Ross et al evaluated the adverse events related to ICG administration during ophthalmic angiography.2 Among 1923 ICG video angiography tests performed, there were three mild reactions (0.15%), four moderate reactions (0.2%), and one severe reaction (0.05%)—a vasovagal reaction. Subsequent clinical experience determined ICG was safe at doses of 50–80 mg/kg provided the patient did not have a severe life-threatening iodide allergy, while doses used for perfusion assessment range from 0.2 to 0.5 mg/kg, or 5 mL of a 2.5 mg/mL concentration (approximately 0.2 mg/kg in a 70 kg person).3 4 ICG has no effect on blood constituents or the hemostatic system, and the incidence of adverse events with the use of ICG is one in 42 000 patients.4 In a recent case series on approximately 1400 patients with endometrial cancer who underwent SLN mapping, no patients experienced an anaphylactic response or surgical adverse event related to ICG.5

    In addition to its safety profile, the depth of visualization of ICG is another advantage. In general, ICG is optimally excited with 805 nm light and emits an approximate wavelength range of 810–875 nm (Figure 1). These NIR wavelengths, invisible to the naked eye, pass through tissue particularly well due to the low adsorption of light by the various structures of tissue such as hemoglobin and water. As a result, the tissue is relatively transparent to this light, and images of structures as much as 5 mm below the tissue surface can be formed. By comparison, fluorescence imaging with fluorescein captures images only 2–3 mm below the tissue surface,6 so sub-surface structures cannot be imaged using visible fluorophores. In general, the plasma half-life of ICG is 3–4 min, and it is hepatically metabolized. This relatively fast half-life also allows for repeat dosing.5

    Figure 1

    Near-infrared wavelengths.

    Update on retrograde injection of ICG into the ureters

    The ureters are paired organs arising from the renal pelvis and tracking towards the bladder. Their proximity on the lateral pelvic wall to important vascular structures (aorta and inferior vena cava; common, external, and internal iliac vessels) and pelvic organs make them vulnerable to intra-operative injury. The risk of ureteric injury has been reported to vary between 0.5% and 5%, depending on risk factors.

    When intra-operative ureteric injuries are not diagnosed intra-operatively, the potential sequelae of delayed diagnosis—including sepsis, fistula formation, renal impairment and failure, or death—are significant.7 Prevention or early diagnosis of intra-operative injury is an important strategy to reduce the extent of harm caused by ureteric injury.

    The distal (pelvic) ureter is the part most vulnerable to iatrogenic injury. The risk of injury increases with the complexity of the planned surgical procedure, distorted anatomy, and surgical technique/skill (eg, learning curve during robotic surgery). Injuries occur through direct force (diversion, sutures) or through thermal effects. In most cases the operating surgeon is unaware of the proximity of the ureter(s), which leads to intra-operative misjudgement.

    This section discusses the prevention of injury to the ureters through NIR medical imaging and the intra-operative use of ICG. The use of ICG for injection is currently licensed for determining cardiac output, hepatic function and liver blood flow, for ophthalmic angiography, and intra-cervical injection for gynecologic malignancies. Intra-operative injection into ureters is off-label and unconventional.

    While NIR fluorescent agents administered intra-venously are under pre-clinical development, a very practical solution is the intra-operative injection of ICG into the ureter through cystoscopy and retrograde ureteric injection of ICG.8 ICG is prepared for injection in a similar way as for SLN biopsy. In brief, 20 mL sterile water is mixed with 25 mg lyophilized ICG, creating a 1.25 mg/mL concentration. The vial is inverted multiple times for complete mixing of the ICG powder with the sterile water and 5 mL of the ICG mixture is drawn into a 5 mL syringe. A cystoscopy with normal saline is performed. For the cystoscopy, we use a secondary laparoscopic stack so that the pelvis and the urinary bladder can be visualized simultaneously. The bladder is checked for intactness, and both ureteric orifices are located. A ureteric catheter (eg, 7 Fr), with or without a 10–15 cm guidewire, is advanced into one or both ureters and the ICG is injected (5 mL each side). The ureteric catheter(s) is removed and an indwelling catheter is placed. During laparoscopy, the injected ureter can be visualized immediately through NIR medical imaging (Figure 2).

    Figure 2

    Identification of the pelvic ureter with indocyanine green near-infrared imaging.

    Previously, the technique has been described in urological surgery9 to identify a proximally transected ureter10; in colorectal surgery to identify the course of the distal ureter11 12; and in radical cystectomies and complex minimally invasive gynecological surgical procedures.13 A video article is currently under review to describe the case of a patient who had a radical trachelectomy for stage 1b cervical adenocarcinoma (Int J Gynecol Cancer, in print). Five years after initial surgery, and after returning abnormal cervical cancer screening tests, the patient opted for a laparoscopic hysterectomy. The retroperitoneum was highly scarred and fibrosed. White light laparoscopic surgical assessment failed to identify the ureters reliably. Injection of ICG into both ureteric orifices at cystoscopy allowed for the identification of both ureters clearly so that they could be lateralized and ureteric injury avoided.

    In summary, ureteric illumination by retrograde injection of ICG is a feasible and safe method to identify ureters intra-operatively that cannot otherwise be reliably identified by white light laparoscopic surgery. This technique may be of value to surgeons and patients in order to prevent intra-operative ureteric injury when resecting severe endometriosis, a very large uterus (>14–16 weeks size), or in any other circumstances of distorted or fibrosed retroperitoneum where identification of the ureters is essential.

    Update on the use of NIR imaging for the detection of inguinofemoral sentinel lymph nodes in patients with vulvar cancer

    SLN biopsy for patients with vulvar squamous cell carcinoma, melanoma, and other vulvar malignancies has become the standard of care since the publication of the findings of the GOG-173 study and the GROINSS-V study.14 15 These studies established the oncologic safety of this technique and set standards for the identification of the inguinofemoral SLN. Since it was initially described for this indication in 2010, the use of NIR imaging with ICG injection has become more widely adopted due to its ease of use and superior visualization. In this section we will review the techniques available for SLN detection of the vulva and discuss new frontiers in optimizing SLN detection for vulvar cancer.

    Sentinel Lympn Node Identification Techniques

    The GOG-173 and GROINSS-V studies relied on white light and radiocolloid lymphoscintigraphy for SLN detection. In the GOG-173 trial, all patients were required to undergo mapping with isosulfan blue dye, with optional inclusion of radiocolloid lymphoscintigraphy. However, 2 years after the study was opened, retrospective evidence demonstrated that pre-operative lymphoscintigraphy improved SLN detection rates. Consequently, pre-operative lymphoscintigraphy and intra-operative radiolocalization were required. The study also permitted the use of other blue dyes, such as methylene blue (in 2007) due to a nationwide shortage of isosulfan blue. In this study, 92.5% of patients had at least one SLN identified at surgery: 61% of patients had nodes that were both blue and ‘hot’ (identified using intra-operative radiolocalization); 24% of patients had nodes that were blue only; and 15% had nodes that were identified with radiolocalization only. False-negative rates were 7.8% for radiocolloid alone, 2.0% for blue dye alone, and 1.6% for radiocolloid plus blue dye.14 A meta-analysis in 2014 by Meads et al reviewed mapping techniques by radiocolloid lymphoscintigraphy, as well as blue dye. They reported SLN detection rates of 94.0% (95% CI 90% to 96%) for radiocolloid lymphoscintigraphy alone and 68.7% (95% CI 63% to 74%) for blue dye alone.16 The standard of radiocolloid localization plus colored dye was set by this study and remains the surgical standard today. While detection rates are high with this combined technique, the approach causes considerable dissatisfaction for both patients and clinicians. Lymphoscintigraphy is painful, requires an additional procedure and, intra-operatively, localization with a gamma counter necessitates multiple disruptions of the dissection in order to detect the radiolabeled lymph node. Blue dye is similarly unsatisfactory. While the blue dye does allow for the visual localization of the lymph node, the localization is useful when the surgeon can see the lymphatic channels and node clearly, with no visual feedback as to the location of the node when there is even a small amount of adipose tissue surrounding it. Therefore, the blue dye can only be seen clearly when the node is nearly completely identified. Given these challenges, surgeons have turned to NIR imaging as an alternative to blue dye.

    The era of NIR imaging

    In 2010, Crane and colleagues described their experience using a custom-built NIR light source and camera for the intra-operative detection of ICG-labeled sentinel inguinofemoral lymph nodes in patients with vulvar carcinoma. The authors appropriately concluded that this technique might eventually replace the conventional use of blue dye and radiocolloid injection in gynecologic cancers, breast cancer, and melanoma.17 In a publication the following year, the authors reported their results of NIR imaging in 16 groins from 10 patients. In these patients, a total of 29 SLNs were identified by radiocolloid, 26 of which were detected with NIR imaging and 21 with blue dye. The authors also noted that transcutaneous mapping was possible in five of 16 groins.18 Over the next 2 years, three other groups published small retrospective experiences using NIR imaging with ICG-labeled inguinofemoral SLNs. In vivo SLN detection rates ranged from 95.7% to 100% in these studies compared with in vivo detection rates of 64.9–78.6% using blue dye alone.19–21

    In 2017, Soergel and colleagues published their findings comparing detection modalities including radiocolloid, ICG, and blue dye. In their series of 27 patients, representing 52 at-risk groins, 91 SLNs were detected, and all were positive for ICG. Furthermore, eight SLNs that were not detected by intra-operative radio localization or blue dye were identified by ICG alone.22 The Memorial Sloan Kettering Cancer Center experience was published in 2019 and reviewed 106 patients, representing 265 at-risk groins undergoing inguinofemoral SLN biopsy. In this series, only one groin failed mapping when ICG was used alone, and 100% of groins had an SLN detected when ICG and technetium-99m were used together.23 Similar studies published in a contemporary time period demonstrated detection rates of 89.7–100% when ICG was used alone.24–26

    Future of NIR imaging in vulvar cancer

    The use of NIR for the detection of inguinofemoral SLNs in patients with vulvar cancer has steadily increased over time. As more evidence emerges that NIR localization of SLNs in vulvar cancer is as effective (or more effective) than conventional techniques, this method will continue to replace the use of radiocolloid and blue dye. NIR light sources and cameras continue to evolve, and their use is more appropriately tailored to this surgery. Ongoing prospective studies will definitively compare NIR with standard-of-care technetium-99m and colored dye, and this imaging modality may well become the new standard in SLN detection in vulvar cancer (Figure 3).

    Figure 3

    Right groin sentinel lymph node using indocyanine green and color-segmented fluorescence.

    NIR angiography in wound perfusion assessment

    Radical gynecologic surgery for invasive cancers, including pelvic exenteration, vaginectomy, and vulvectomy, often results in large cutaneous and visceral defects requiring flap-based closure. Current standard surgical options for closure include vertical rectus abdominis myocutaneous, fasciocutaneous, and gracilis flaps. Complications of flap-based abdominopelvic reconstruction, such as necrosis, wound separation, and infection, occur in 19.6–44.4% of cases.27–29 These complications increase patient morbidity and can lead to delayed wound healing, re-operation, infection, and re-admission. There are many etiologies of flap failure, such as infection, hematoma/seroma, and poor tissue integrity from prior radiation therapy. An important process underlying many surgical complications of flap-based reconstruction is impaired perfusion. Previously identified risk factors for perfusion compromise are frequently encountered in patients with gynecologic cancers, and include smoking history, diabetes mellitus, hypertension, vascular disease, kidney disease, pulmonary disease, nutritional status, body mass index >30 kg/m2, pre-operative steroid use, exposure to radiotherapy, and exposure to chemotherapy.

    To limit flap complications following reconstruction, there is a need for intra-operative assessment tools that allow surgeons to intervene when tissue perfusion is compromised. The standard approach for intra-operative assessment of skin and myocutaneous flap perfusion after abdominopelvic defect repair is based on unaided visual clinical judgment and subjective surgeon evaluation of features such as turgor, tissue color, and capillary refill. A variety of tools have been developed to improve intra-operative assessment of perfusion. Handheld Doppler, Duplex ultrasound, infrared thermography, venous pressure, combined laser Doppler spectrophotometry, and fluorescence imaging have been used to assess perfusion of flaps, most prominently in breast reconstruction.30 Subsequent evaluations of these modalities have found that fluorescence imaging, such as NIR angiography, is the most accurate method for assessing flap perfusion (Figure 4).30

    Figure 4

    Skin perfusion of right abdominal wall vertical rectus abdominis myocutaneous flap with indocyanine green. Note the decreased perfusion in the cranial edge of the flap (left corner).

    NIR angiography has been shown to accurately predict necrosis compared with clinical judgment. For example, an early case series of 10 patients compared clinical judgment to NIR angiography and, in this study, three perfusion-related complications identified by NIR angiography were not predicted by clinical judgment.31 A prospective clinical trial that compared intra-operative evaluation of mastectomy skin flaps by clinical assessment with ICG dye angiography found that NIR angiography accurately predicted necrosis in 19 of 21 cases in which clinical judgment failed.32 Holm et al reported a sensitivity of 100.0% and specificity of 86.0% with NIR angiography for detecting microvascular thrombosis in a prospective trial of 20 patients.33 In addition to accuracy, NIR angiography has also been associated with improved outcomes in breast reconstruction. A review of 191 cases by Alstrup et al showed significantly decreased rates of major complications in immediate autologous reconstructions with the use of NIR angiography versus clinical assessment alone (0.0% vs 37.7%; p=0.039).34 Another study of 114 patients by Diep et al found that rates of severe flap necrosis were significantly decreased with NIR angiography compared with clinical assessment alone (4.9% vs 18.9%; p=0.02). For this reason, fluorescence-based imaging has been widely adopted in breast reconstruction. A systematic review found that it was used in surgical decision-making (n=11 studies) to expedite post-operative intervention (n=4) or excision (n=4) of poorly perfused areas.35 36

    Despite these data from the literature on breast reconstruction, NIR angiography is not widely used in reconstruction after radical gynecologic surgery or in perfusion assessment of wound closure after laparotomy. In a recently presented prospective non-randomized trial (Near-Infrared FluORescencE Assessment of Myocutaneous Flap Microperfusion for Gynecologic RecONstrucTion (FOREFRONT; NCT05071976)),37 patients consented to the use of NIR angiography to evaluate perfusion of pedicled flap-based reconstruction following pelvic exenteration. The primary endpoint was the percentage of cases in which intra-operative NIR angiography led to a change in flap reconstruction management, with a change in ≥13.3% of cases indicating the technology was worthy of additional investigation. Investigators found that NIR angiography altered intra-operative management in 50% of patients, meeting the primary endpoint of this study. Wound complications occurred in one patient who required bedside debridement, surgical packing, and oral antibiotics. Although surgical outcome was a secondary objective, this low rate of post-operative infection compared with historical rates was deemed worthy of future investigation.

    In addition to flap-based closure, additional efforts have been made to determine if NIR angiography may be used to evaluate wound perfusion at closure after laparotomy for gynecologic surgery. In a recently published prospective non-randomized feasibility study of patients undergoing laparotomy with a gynecologic oncology service,38 skin perfusion was recorded using an NIR imaging system after ICG injection and measured by video analysis at pre-defined points before and after skin closure, and compared between patients undergoing suture versus staple-based closure methods. This study, however, reported that objective assessment of laparotomy skin closure did not meet the pre-specified feasibility threshold. However, the ability to subjectively appreciate ICG perfusion with NIR angiography suggested a possible role for NIR angiography in the real-time intra-operative assessment of wound perfusion, particularly in high-risk patients.

    Ethics statements

    Patient consent for publication

    Ethics approval

    Not applicable.

    References

    Footnotes

    • Twitter @VanceBroach, @leitaomd

    • Contributors All authors have contributed to the conception and design; analysis and interpretation of data; drafting of the manuscript; revising the manuscript critically for important intellectual content; and final approval of the version to be published. All authors also agree to be accountable for all aspects of the work.

    • Funding This study was funded by National Cancer Institute (P30 CA008748).

    • Competing interests NRA-R reports research funding from GRAIL paid to Memorial Sloan Kettering Cancer Center (MSK). MSK also has equity in GRAIL. AO is founder and managing director of SurgicalPerformance. ML reports consulting fees from Medtronic, speaker fees from Intuitive Surgical, and advisory board fees from J&J Ethicon and Immunogen.

    • Provenance and peer review Commissioned; externally peer reviewed.

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