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12 Use ofFluorescence Guidance inPediatric Surgery
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intraoperatively by palpation [22]. ICG also demonstrates effec­tiveness for relapsed hepatoblastoma, including patients who pre­viously underwent liver transplantation for management of hepatoblastoma and subsequently presented with relapse in the liver graft [55].
The high sensitivity and seamless integration into robotic or laparoscopic cameras make ICG a useful adjunct during both open and laparoscopic resections in children. It is particularly useful for laparoscopic-assisted oncologic resections, during which palpation of the liver surface is less feasible [52].
ICG can also be used to evaluate hepatic perfusion and delin­eate boundaries between liver segments during hepatectomy. Terasawa etal. developed a technique that would allow for assess­ment of the boundaries of tumor-bearing hepatic segments, both to determine a line of transection and to evaluate the perfusion of the preserved hepatic parenchyma [56]. After transecting the hepatic parenchyma and clamping the portal pedicle of the tumor­bearing hepatic segments, 1.25mg of ICG is administered intra­venously. This creates a visual line of demarcation between non-uorescing tumor-bearing hepatic segments that are to be resected and surrounding uorescing hepatic parenchyma to be preserved.
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Non-hepatic Primary Tumor Resection
Until recently, most reports of uorescent-guided resection of non-hepatic primary tumors were limited to case reports and series of adult patients. However, recent series have demonstrated the successful utilization of ICG as an adjunct during oncologic resection of non-hepatic tumors in children. Furthermore, pro­spective trials assessing the feasibility of ICG-mediated near­infrared imaging for resection and identication of margins in pediatric neoplasms are currently underway.
Esposito et al. utilized ICG for laparoscopic excision of abdominal lymphoma and robot-assisted resection of ovarian tumors in pediatric patients [12]. ICG was administered intrave­nously at a dosage of 0.5mg/mL/kg for three patients with lym-
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phoma. ICG allowed for assessment of the vascularization of the lymphoma tumor, helped dene the level of resection in cases requiring mesenteric division, and was used to detect lymph nodes for biopsy or resection. Of the ve patients with ovarian tumors, three were mature teratomas and two were seromucinous cystad­enoma on pathology. Patients received an intravenous administra­tion of ICG at a dosage of 0.5 mg/mL/kg. Within 20–30s of injection, ICG allowed for delineation between the hypo­uorescent ovarian tumor and normal salpinx and ovarian paren­chyma. It also allowed for verication of perfusion to the salpinx and uterus following tumor resection.
In a large series of pediatric patients, Abdelhafeez et al. achieved uorescence in 46 out of 52 tumors: nine osteosarco­mas, six neuroblastomas, six non-rhabdomyosarcoma soft tissue sarcomas, ve rhabdomyosarcomas, three Ewing sarcomas, two germ cell tumors, one chondroblastoma, one solid pseudopapil­lary neoplasm of the pancreas, one lymphoma, and one myoepi­thelial carcinoma of the chest wall (in addition to nine hepatoblastomas and two hepatocellular carcinomas) [51]. The majority of patients received 1.5 mg/kg of ICG intravenously over 15min the day prior to surgery. Near-infrared imaging dem­onstrated an 88% sensitivity and 77% specicity rate for identi­fying tumors. Eighty- eight percent of malignant tumors demonstrated uorescence versus 23% of benign lesions. ICG was unable to identify two primary adrenocortical tumors included in this series.
Background noise from ICG uptake of surrounding organs is a common concern in uorescence-guided surgery. Abdelhafeez etal. reported that background noise was observed in 57% of pro­cedures, including 100% of trunk and extremity resections, 68% of abdominal operations, and 40% of thoracic cases [51]. Of note, although background noise from adjacent organs was noted in all open abdominal and thoracic operations, it was only seen in 45% and 15% of minimally invasive abdominal and thoracic resec­tions, respectively. This suggests that optimization of ambient light contamination may be a strategy for mitigating the effects of background noise during ICG-guided resections.
12 Use ofFluorescence Guidance inPediatric Surgery
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Future investigations are warranted for several areas pertaining to uorescent-guided pediatric surgical oncology, including meth­ods for mitigating background noise, evaluation of the efcacy of ICG-guided surgery for organ-sparing operations in cases such as bilateral Wilms tumors, optimizing identication of neuroblastoma and sarcoma metastases, and margin delineation inlocal control operations for neuroblastoma and sarcomas.
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Pulmonary Metastasectomy forPrimary Hepatic Tumors
Because ICG does not typically collect in normal lung tissue and metastatic lesions are commonly found in the periphery of the lung, ICG uorescence allows for detection of very small, nonpal­pable pulmonary metastases secondary to hepatic malignancies [21]. ICG is concentrated in hepatocytes and metastases from hepatic tumors, making it a benecial adjunct for metastasectomy procedures [53]. The use of ICG for pulmonary metastasectomy via thoracotomy or thoracoscopy has been documented for both hepatoblastoma and hepatocellular carcinomas in pediatric patients [17]. It can detect pulmonary lesions as small as 0.062 mm in diameter [50]. A dose of 0.5mg/kg of ICG administered approxi­mately 24h prior to surgery is generally recommended [57].
ICG is particularly helpful for thoracoscopic identication of metastatic lesions, where palpation is less feasible and the decrease in ambient light minimizes background noise compared to open resections [53]. Single lung ventilation with collapse of the affected lung should be utilized when medically feasible to enhance detection of lesions with ICG [21]. Given that ICG has less optimal penetration for lesions more than 10mm below the surface of the lung, a secondary localization technique should be considered for deeper lesions [19]. To optimize detection of nod­ules, contrast mode, which demonstrates ICG signal over a dark background, can be used initially [53]. This is followed by over­lay mode, which demonstrates ICG signal over the white light image of the lung, to guide wedge resection (Fig.12.6).
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Fig. 12.6 A 2-year-old girl with PRETEXT III metastatic hepatoblastoma to the lung s/p cycle 3 chemotherapy and 3 left and 2 right pulmonary nodules. Therapeutic goal was to reach eligibility for liver transplant. Lung mets were easily identied with ICG and thoracoscopic SPY technology and removed with clear margins by wedge resection (lower picture). Note that ICG has to be given at 0.5mg/kg 24h in advance to the procedure. SPY technology allows thoracoscopic detection and parenchymal-sparing complete resection (Images courtesy of Drs. Densmore and Mowrer, Children’s Hospital of Wisconsin)
12 Use ofFluorescence Guidance inPediatric Surgery
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Pulmonary Metastasectomy forNon-hepatic Tumors
ICG is also being increasingly used for pulmonary and pleural metastasectomy via thoracotomy or thoracoscopy for pediatric tumors of non-hepatic primary. Its use has been documented for pulmonary metastases secondary to nephroblastoma, neuroblas­toma, chondroblastoma, and numerous sarcomas, including osteosarcoma, Ewing sarcoma, non-rhabdomyosarcoma soft tis­sue sarcoma, and rhabdomyosarcoma [57]. The surgical princi­ples are similar to those for pulmonary metastasectomy for hepatic primary tumors.
In comparison to metastases secondary to hepatic primary tumors, metastases of non-hepatic primary tumors may require higher doses of ICG for optimal uorescence (e.g., 3–4mg/kg). ICG dosages up to 5 mg/kg administered approximately 24 h prior to surgery have been reported [58]. Although this is higher than the dosage currently approved by the US Food and Drug Administration (FDA), adverse events related to ICG administra­tion are rare [5]. A higher concentration of ICG can be used (i.e., 5mg/mL instead of 2.5 mg/mL) to decrease the volume of ICG injected [53].
In a series of 52 adult patients with a history of sarcoma who underwent pulmonary metastasectomy, additional lesions were detected with ICG in 59% of patients in the uorescence-guided surgery cohort versus 25% of patients in the historical control cohort for whom additional lesions were detected with visual and tactile feedback alone (p < 0.05). Patients in the uorescence­guided surgery group also had signicantly improved median progression-free survival and longer time to recurrence in the lung compared to historical controls [58].
Further investigation is warranted to evaluate the effect of treatment necrosis and decreased tumor viability on ICG sensitiv­ity of pulmonary nodules. However, ICG is a promising adjunct for pulmonary metastasectomy.
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Lymph Node Identication andSentinel Lymph Node Biopsy
Sentinel lymph node biopsy (SLNB) is an important technique for staging and regional lymph node assessment of malignancy (Figs.12.7 and 12.8). Although well established for many types of
Fig. 12.7 ICG lymphangiography for sentinel lymph node biopsy for mela­noma of the left ear using the SPY Portable Handheld Imaging System. The upper image shows the overlay mode and the lower image the SPY uores­cence mode. ICG is injected into the lesion on the upper ear. Note clear visi­bility of the lymph vessels leading to the sentinel node of the lesion (Images courtesy of Dr. Marcus Malek, UPMC Children’s Hospital of Pittsburgh)
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Fig. 12.8 ICG lymphangiography for sentinel lymph node biopsy for mela­noma of the right upper thigh using the SPY Portable Handheld Imaging Sys­tem. The upper image shows the overlay mode and the lower image the SPY uorescence mode. ICG is injected into the lesion on the upper thigh. Note clear visibility of the lymph vessels leading to the sentinel node of the lesion. The right lower image shows the uorescence of the resected sentinel lymph node (Images courtesy of Dr. Marcus Malek, UPMC Children’s Hospital of Pittsburgh)
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adult cancer, the role for SLNB in pediatric cancers is less dened [59]. SLNB is currently used in pediatric cases of melanoma and various sarcomas, including rhabdomyosarcoma and certain soft tissue sarcomas [59]. Technetium lymphoscintigraphy remains the gold standard for SLNB, with blue dyes such as lymphazurin or methylene blue often used in conjunction for visual identica­tion of sentinel nodes. Valente et al. found that ICG with NIR uorescence imaging was safe and performed similarly to techne­tium 99m for SLNB in breast cancer patients [60]. ICG has also been used for SLNB and lymph node harvest in other adult cancer types, including melanoma, gynecologic cancers, and colorectal cancers [6163]. It is currently unknown whether uorescent or ICG lymphoscintigraphy is noninferior for SLNB or lymph node identication in pediatric patients. However, it can be used an adjunct for lymph node identication [12].
In pediatric patients, reports of ICG use for lymph node identi­cation and SLNB have been more limited. Esposito etal. utilized ICG to detect a thoracic hilar lymph node for biopsy for suspected lymphoma [14]. A 0.5mg/mL/kg of ICG was injected into the lung parenchyma intraoperatively to assist with lymph node iden­tication [12]. In a series of pediatric patients with paratesticular rhabdomyosarcoma, Manseld etal. injected 10mg of ICG into the spermatic cord under either direct visualization or ultrasound guidance to facilitate retroperitoneal lymph node dissection [64]. Injection of ICG into the spermatic cord led to iliac lymph node avidity using near-infrared spectroscopy, with sequential spread along the ipsilateral para-aortic or para-caval lymph node chain. Recently, a case report described the use of ICG to increase lymph node harvest during laparoscopic Wilms nephroureterectomy [65]. Despite International Society of Pediatric Oncology (SIOP) and Children’s Oncology Group (COG) protocols requesting more than six lymph nodes during Wilms nephroureterectomy, the median number of nodes obtained during both open and mini­mally invasive resections is approximately four. In this case report, 2mL of 2.5mg/mL ICG was injected into the normal renal parenchyma near the tumor in 0.5mL aliquots. Seven hilar, supra­hilar, pre-aortic, and para-aortic nodes subsequently demonstrated uorescence, including several that would have gone undetected
12 Use ofFluorescence Guidance inPediatric Surgery
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without ICG.However, further investigation is warranted evaluat­ing injection sites other than the renal parenchyma so as to pre­vent violation of COG guidelines and potential upstaging of the tumor.
ICG lymphoscintigraphy can also be used for tumors of the trunk and extremities. 4mL of ICG can be injected subcutane­ously at a concentration of 1.25mg/mL in four quadrants around the tumor intraoperatively (1mL per quadrant) [53]. In smaller children, ICG is frequently visible through the skin when using a near-infrared imaging device. Sentinel lymph nodes are best visu­alized using a contrast mode, whereas other modes, such as the color-segmented uorescence mode, can be utilized for identica­tion of regions with high uorescence intensity.
Further study is needed to evaluate the sensitivity and specic­ity of ICG lymphoscintigraphy for various cancer types in pediat­ric patients.
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Pediatric Plastic Surgery Applications
There has been increasing utilization of ICG in pediatric plastic surgery for a variety of purposes, including assessment of ap perfusion, evaluation of lymphedema, and management of lym­phatic malformations. Reconstruction of congenital anomalies has given way to the use of ICG for several operations unique to pediatric patients. For instance, Hinchcliff etal. described the use of intraoperative laser-assisted ICG angiography for a one-year­old with anterior plagiocephaly [66]. The patient underwent cal­varial reconstruction for unilateral coronal synostosis, during which tension during closure was encountered. ICG was safely utilized to verify perfusion to the anterior and posterior aps prior to closure. Tomioka etal. also utilized ICG to evaluate ap perfu­sion in a one-year-old who underwent web transplantation for syndactyly [67].
In a case series of 433 pediatric free tissue transfers, Upton etal. emphasized that technical considerations are more complex in pediatric transfers given technical factors such as patients’ diminutive vessels, as well as challenges with postoperative
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immobilization [68]. Fried etal. described the use of ICG to ver­ify perfusion of a free latissimus dorsi myocutaneous ap in a six-month-old for reconstruction of a temporal fossa defect after resection of a teratoma [69]. Intraoperative use of ICG in pediatric patients may mitigate the morbidity of ap failures or vascular complications requiring a return to the operating room for anasto­motic revisions or ap repositioning [68]. Martins etal., in their case series of pediatric patients undergoing rst-stage autologous total ear reconstruction, found that patients in the intraoperative laser-assisted ICG angiography treatment group were signi­cantly less likely to undergo surgical revision in comparison to the non-ICG group [70].
ICG can also be used for real-time imaging of lymphatic anat­omy and ow in the case of lymphedema or lymphatic malforma­tions. ICG can detect lymphatic channels within one to two centimeters of the skin surface in the absence of fascia, muscle, or bone overlying the channels [33, 34]. Injection of ICG can aid in the visualization of lymphatic channels, valves, and ow, which can facilitate staging and management [71, 72]. Greives et al. injected 12.5μg of ICG in 0.05mL of saline into the dorsum of each hand and foot to evaluate lymphatic uptake in a 21-month­old with congenital lymphedema of the right hand and arm [73]. Imaging demonstrated normal lymphatic anatomy with decreased lymphatic contractile function of the right upper extremity rela­tive to the unaffected extremities, which aided in determining appropriate management.
ICG can also facilitate identication, resection, and classica­tion of lymphatic malformations. Shirota etal. used ICG to aid complete resection of a lymphatic malformation in the abdominal wall of a 15-year-old male [74]. The patient had failed manage­ment with sclerotherapy three times and MRI alone had failed to adequately determine the extent of the tumor. Kato etal. similarly used ICG lymphography to identify lymphatic malformations originating throughout the body in 20 pediatric patients ages 11months to 10years [75]. They identied four classic ow pat­terns: (1) strong detectable inow, (2) multiple small observable inows, (3) supercial lymph ow over a lesion, and (4) ow around a lymphatic malformation without connection to the
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