Update on near infrared imaging technology: indocyanine green and near infrared technology in the treatment of gynecologic cancers

INTRODUCTION: NEAR-INFRARED SCIENCE

In 2020, we published a comprehensive update on the utilization of fluorescence imaging systems in gynecologic cancer surgery (1). The objective of the current review is to present recent advancements 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.

Intravascular 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 3 mild reactions (0.15%), 4 moderate reactions (0.2%), and 1 severe reaction (0.05%)—a vasovagal reaction. Subsequent clinical experience determined ICG was safe at doses of 50 to 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 1 in 42,000 patients (4). In a recent case series on approximately 1,400 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 nm to 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 tissue surface (6); thus, subsurface structures cannot be imaged using visible fluorophores. In general, the plasma half-life of ICG is 3–4 minutes, 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. Its 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 it vulnerable to intraoperative injury. The risk of ureteric injury has been reported to vary between 0.5% and 5% depending on risk factors.

When intraoperative ureteric injuries are not diagnosed intraoperatively, the potential sequalae of delayed diagnosis, including sepsis, fistula formation, renal impairment and failure, or death, are significant (7) Prevention or early diagnosis of intraoperative 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 (e.g., 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 intraoperative misjudgement.

This section discusses the prevention of injury to the ureters through NIR medical imaging and the intraoperative 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 intracervical injection for gynecologic malignancies. Intraoperative injection into ureters is off-label and unconventional.

While NIR fluorescent agents administered intravenously are under pre-clinical development, a very practical solution is the intraoperative 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 it is done for SLN biopsy. In brief, 20 mL of sterile water is mixed with 25 mg of lyophilized ICG, creating a 1.25 mg/mL concentration. The vial is inverted multiple times for the complete mixing of the ICG powder with the sterile water. Five 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 visualised simultaneously. The bladder is checked for intactness, and both ureteric orifices are located. A ureteric catheter (e.g., 7FR), with or without a 10-cm to 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 visualised immediately through NIR medical imaging (Figure 2).

Figure 2:

Identification of pelvic ureter with indocyanine green near-infrared imaging

Previously, the technique has been described in urological surgery (9) to identify a proximally transected ureter (10); in colorectal surgery to identify the course of the distal ureter (11,12); and in radical cystectomies and complex minimally invasive gynaecological surgical procedures (13). Currently, a video article is under review to describe the case of a patient who had a radical trachelectomy for stage 1b cervical adenocarcinoma (in print, Int J Gynecol Cancer). 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 lateralised and ureteric injury avoided.

In summary, ureteric illumination by retrograde injection of ICG is a feasible and safe method to identify ureters intraoperatively 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 intraoperative ureteric injury when resecting severe endometriosis, a very large uterus (>14 to 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 SLNS 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.

SLN 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 preoperative lymphoscintigraphy improved SLN detection rates. Consequently, preoperative lymphoscintigraphy and intraoperative 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. Sixty-one percent of patients had nodes that were both blue and “hot” (identified using intraoperative 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% confidence interval [CI], 90%-96%) for radiocolloid lymphoscintigraphy alone and 68.7% (95% CI, 63%–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, intraoperatively, localization with a gamma counter necessitates multiple disruptions of the dissection in order to detect the radiolabeled lymph node. Blue dye is similarly dissatisfying. 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 small amounts 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 intraoperative 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 5 of 16 groins (18). Over the next 2 years, three other groups published small retrospective experiences utilizing NIR imaging with ICG-labeled inguinofemoral SLNs. In vivo SLN detection rates ranged from 95.7–100% in these studies, compared to 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, 8 SLNs that were not detected by intraoperative radio localization or blue dye were identified by ICG alone (22). The Memorial Sloan Kettering Cancer Center (MSK) 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 from 89.7–100% when ICG is 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% to 44.4% of cases (27–29). These complications increase patient morbidity and can lead to delayed wound healing, reoperation, infection, and readmission. 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, preoperative steroid use, exposure to radiotherapy, and exposure to chemotherapy.

To limit flap complications following reconstruction, there is a need for intraoperative assessment tools that allow surgeons to intervene when tissue perfusion is compromised. The standard approach for intraoperative 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 intraoperative 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 (30).

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 intraoperative evaluation of mastectomy skin flaps by clinical assessment to ICG dye angiography found that NIR angiography accurately predicted necrosis in 19 of 21 cases in which clinical judgment failed (32). Holm et al. demonstrated a sensitivity of 100.0% and specificity of 86.0% with NIR angiography for detecting microvascular thrombosis in a 20-patient prospective trial (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. revealed 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 postoperative intervention (n=4) or excision (n=4) of poorly perfused areas (35,36).

Despite these data from the breast reconstruction literature, 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 percentage of cases in which intraoperative NIR angiography led to a change in flap reconstruction management, with a change in ≥13.3% cases indicating the technology was worthy of additional investigation. Investigators found that NIR angiography altered intraoperative 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 outcomes was a secondary objective, this low rate of postoperative infection compared to 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 predefined 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 intraoperative assessment of wound perfusion, particularly in high-risk patients.

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)