Utilization of Indocyanine Green for Augmentation of Pulmonary Metastases Resection in Adolescent and Young Adult Sarcoma Patients

Utilization of Indocyanine Green for Augmentation of Pulmonary Metastases Resection in Adolescent and Young Adult Sarcoma Patients | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 19 September 2025 V1 Latest version Share on Utilization of Indocyanine Green for Augmentation of Pulmonary Metastases Resection in Adolescent and Young Adult Sarcoma Patients Authors : Sophia Schermerhorn MV , Emily Vore , Alexander Bondoc , Todd Jenkins , and Roshni Dasgupta [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175827979.99889188/v1 400 views 219 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Complete pulmonary metastasectomy is central to curative-intent therapy for sarcoma, but lesion localization can be challenging. Indocyanine green (ICG) near-infrared fluorescence offers real-time intraoperative guidance, though data in pediatric and adolescent/young adult sarcoma patients is limited. Methods: A retrospective review of patients with metastatic sarcoma who underwent pulmonary metastasectomy was performed. Patients were dosed preoperative ICG (dose: 4mg/kg, 24 hours before surgery) between April 2019 and November 2022. Demographics, tumor histology, operative details, lesions characteristics and ICG status were analyzed. Sensitivity, positive predictive value (PPV) and the proportion of lesions identified solely by ICG were calculated. Results: 31 patients aged 6-42 years underwent 51 pulmonary metastasectomy. Overall sensitivity of ICG for detecting metastatic lesions was 81% with a PPV of 39%. ICG identified 17% of metastases not palpable or visible on inspection. Patients with prior lung radiation demonstrated lower sensitivity at 64% than the overall cohort. No adverse reactions to ICG were observed. Conclusion : ICG fluorescence imaging is a safe adjunct to pulmonary metastasectomy in pediatric, adolescent and young adult sarcoma patients. It facilitates more complete resection by identifying additional lesions not detected with standard techniques without significant adverse effects. These findings support use of ICG as a complement to meticulous surgical exploration. Further multicenter studies are needed to assess its impact on oncologic outcomes. Utilization of Indocyanine Green for Augmentation of Pulmonary Metastases Resection in Adolescent and Young Adult Sarcoma Patients Sophia MV Schermerhorn 1 , Emily Vore 1 , Alexander J Bondoc 1 , Todd Jenkins 1 , Roshni Dasgupta 1 1 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH Word count: Abstract: 216/250 Main Text: 2260/3500 Keywords: Indocyanine green, pulmonary metastasectomy, fluorescent guided surgery, pediatric patients, sarcoma Short Running Title: ICG for Pulmonary Metastasectomy in Pediatric Sarcomas Tables: 3 Figures: 0 Abbreviations Key: ICG- Indocyanine Green PPV- Positive Predictive Value CT- Computed Tomography EPR- Enhanced Permeability and Retention NRSTS- Non-rhabdomyosarcoma soft tissue sarcomasMIP – Maximum Intesnsity Projection Corresponding Author Roshni Dasgupta, MD, MPH Division of Pediatric General and Thoracic Surgery Cincinnati Children’s Hospital Medical Center University of Cincinnati 3333 Burnet Avenue Cincinnati, Ohio 45229 513-636-4371 [email protected] Background: Complete pulmonary metastasectomy is central to curative-intent therapy for sarcoma, but lesion localization can be challenging. Indocyanine green (ICG) near-infrared fluorescence offers real-time intraoperative guidance, though data in pediatric and adolescent/young adult sarcoma patients is limited. Methods: A retrospective review of patients with metastatic sarcoma who underwent pulmonary metastasectomy was performed. Patients were dosed preoperative ICG (dose: 4mg/kg, 24 hours before surgery) between April 2019 and November 2022. Demographics, tumor histology, operative details, lesions characteristics and ICG status were analyzed. Sensitivity, positive predictive value (PPV) and the proportion of lesions identified solely by ICG were calculated. Results: 31 patients aged 6-42 years underwent 51 pulmonary metastasectomy. Overall sensitivity of ICG for detecting metastatic lesions was 81% with a PPV of 39%. ICG identified 17% of metastases not palpable or visible on inspection. Patients with prior lung radiation demonstrated lower sensitivity at 64% than the overall cohort. No adverse reactions to ICG were observed. Conclusion: ICG fluorescence imaging is a safe adjunct to pulmonary metastasectomy in pediatric, adolescent and young adult sarcoma patients. It facilitates more complete resection by identifying additional lesions not detected with standard techniques without significant adverse effects. These findings support use of ICG as a complement to meticulous surgical exploration. Further multicenter studies are needed to assess its impact on oncologic outcomes. Introduction Most children who succumb to solid malignancies do so secondary to metastatic disease or the complications of treatment of metastatic disease.[1] The lungs are the most common site of metastasis in sarcoma patients.[1–4] Pulmonary metastasectomy has been associated with survival benefit across most histologic subtypes and therefore clearance of all pulmonary disease is therefore critical for achieving long term survival.[2, 3, 5–9] The rate of pulmonary metastasis and the survival benefit of metastasectomy vary across sarcoma subtypes. Osteosarcoma, the most common pediatric sarcoma, demonstrates pulmonary spread in up to one-third of patients and has long-standing evidence supporting survival benefit with complete resection. Non-rhabdomyosarcoma soft tissue sarcomas also show high rates of pulmonary metastasis, with studies suggesting improved outcomes following complete metastasectomy. In contrast, rhabdomyosarcoma is associated with a lower incidence of pulmonary metastasis but poor overall prognosis, with benefits from surgery less clearly deliniated. Ewing sarcoma is unique in its chemo- and radiosensitivity, and while metastasectomy is frequently performed, contemporary data have yielded mixed results regarding survival benefit. Thus, while pulmonary metastasectomy has a role in pediatric sarcoma care, its utility is nuanced and histology-dependent. The goal of pulmonary metastasectomy is complete removal of metastatic lesions with maximal preservation of normal lung tissue. 3 Computed Tomography (CT) is the preoperative modality of choice for metastasis identification, however, intraoperative localization has traditionally relied on surgeon visualization and tactile feedback.[1] Sole reliance on these methods can be technically challenging as smaller, softer and deeper lesions may be missed. Adjuncts such as preoperative wire or coil placement and intraoperative ultrasound have been employed to increase the completeness of resection, with varying success.[1, 2, 10, 11] Limitations of these methods include logistical challenges in coordination with radiology, risk of dislodgement and pneumothorax with coil or wire placement, and surgeon error of ultrasound interpretation.[5, 11] CT-guided intralesional methylene blue injection is yet another technique, but diffuse pleural staining can obscure localization and limit its utility.[11] Fluorescence-guided surgery utilizing near-infrared (NIR) imaging has emerged as a valuable intraoperative adjunct, enhancing a surgeon’s visual field with numerous applications in the modern-day operating environment.[11–15] In pediatric oncologic surgery, indocyanine green (ICG) fluorescence has been used to identify tumor margins, localize metastases, differentiate peritumoral critical structures and guide reconstruction.[5, 10, 11, 13, 15–17] ICG has been used as an intra-operative adjunct in pulmonary metastasectomy in both adult[14, 18, 19] and pediatric[5, 20–24] populations. In pediatric patients, most studies have focused on hepatoblastoma. This is because ICG is metabolized by hepatocytes and therefore hepatic tumors have increased affinity for ICG. Conversely, far less is known about its performance in other metastatic solid tumors such as sarcomas. 4,5 The aim of our study was to determine the efficacy and accuracy of ICG in identifying pulmonary metastatic lesions in pediatric, adolescent and young adult sarcoma patients, and to describe any complications related to the use of ICG dye. Materials and Methods A retrospective chart review was performed of all patients diagnosed with sarcoma who underwent open or thoracoscopic pulmonary metastasectomy with the use of pre-operative ICG at a single tertiary care institution between April 2019 – November 2022. Institutional review board approval (IRB #2022-0744) was obtained. Per institutional standard, all patients followed the same preoperative protocol. Cross sectional imaging including Maximum intensity projection imaging (MIP) were obtained to identify suspicious pulmonary nodules and guide surgical planning. Patients then received an intravenous dose of ICG (4mg/kg) 24 hours before surgery. Intraoperatively, infrared-detecting camera systems were used either thoracoscopically or with a hand-held device (Pinpoint, Stryker. Portage, Michigan). All palpable lesions and non-palpable, ICG-avid lesions were resected. Resections were performed with vascular-loaded stapling devices or hand-held cutting instruments, and all sealed margins were oversewn with suture and reinforced with hemostatic agent. Data collected included demographics, operative approach, preoperative lung radiation, previous thoracic surgery, primary pathology, length of stay, chest tube duration, development of air leak, 30-day postoperative complications and lesions characteristics (ICG status, palpability and histologic tumor presence). Categorical variables were compared using chi-squared or Fisher’s exact test as indicated. To evaluate the diagnostic performance of ICG for accurately identify metastatic lesions, sensitivity, specificity, positive predictive value and negative predictive value were calculated using histopathologic confirmation of metastatic disease as the gold standard for a true positive result. Results In total, 51 operations were performed in 31 patients, ages 6 – 42 years (median age 18 years) at the time of surgery. Of the 51 procedures, 27 (52.9%) were for metastasis from osteosarcoma, 8 (15.7%) from Ewing sarcoma, 5 (9.8%) from Leiomyosarcoma, 2 (3.9%) from Synovial sarcoma, 2 (3.9%) from Fibrosarcoma, 2 (3.9%) from Rhabdomyosarcoma and 5 (10%) from various other sarcomas (Table 1). Seven (13.7%) patients received preoperative radiation to the lung and fifteen (29.4%) procedures were reoperations in a pleural space having already undergone thoracotomy. Minimally invasive thoracoscopic surgery was only performed in 2 (3.9%) procedures, with the remaining 49 procedures performed via open thoracotomy. All patients had a chest tube placed at the conclusion of surgery. Most chest tubes were removed on postoperative day 1 (N=29, 56.9%), though 10 patients (19.6%) experienced postoperative air leak and 2 patients (3.9%) had prolonged air leak (>4 days). Length of stay on the surgical service ranged from 1–9 days (median 3 days). There were no statistically significant associations between primary pathology, preoperative radiation, surgical approach, previous thoracoscopic procedure, age at time of surgery, or number of specimens resected and the patient’s length of stay, chest tube duration or presence of chest tube air leak (Table 2). A total of 409 specimens were resected, with over half (N=221, 54.0%)were obtained during pulmonary metastasectomy for osteosarcoma. Additional specimen characteristics are detailed in Table 3. Test characteristics for ICG are detailed in Table 4. Overall, ICG had a sensitivity of 81% and a positive predictive value of 39.0%. On a subgroup analysis of patients with prior lung radiation, the sensitivity of ICG for both palpable and nonpalpable lesions was 64%. For non-palpable lesions, ICG had a positive predictive value 15.0% (26 tumor positive specimens of 173 ICG positive, non-palpable specimens). Of all lesions resected that were positive for tumor, 17% were non palpable but ICG avid. Of the specimens that were palpable during resection, only 54% (127 of 236 specimens) had tumor. For palpable lesions, the positive predictive value of ICG was 67.6% (98 tumor positive specimens of 145 ICG positive, palpable specimens). Post operative outcomes One patient was readmitted within 30 days for post-operative pain. No other post-operative complications were identified. There were no complications related to ICG. Discussion This study sought to evaluate the efficacy of ICG as an adjunct for localization in pulmonary metastasectomy for children, adolescents, and young adults with metastatic sarcoma. We found that ICG was sensitive with a sensitivity of 81%, aided in a more complete metastasectomy—as 17% of the metastatic lesions resected were identified only due to ICG use—and was safe, with no adverse reactions observed in our cohort. A key strength of our findings lies in the high sensitivity of ICG, which is particularly important given the ultimate surgical goal is complete clearance of metastatic disease. By contrast, our PPV was lower at 39%, indicating a proportion of ICG-avid nodules resected had benign pathology. While this does result in resection of non-malignant tissue, in the context of pulmonary metastasectomy, the priority remains identification and removal all metastatic foci and a modest false-positive rate is acceptable to achieve this end. Notably, 17% of metastatic lesions in this series would have been missed without ICG, underscoring its critical role in ensuring completeness of resection. Finally, despite the additional specimens resected secondary to ICG in this study, the median number of chest tube days (1 day), the number of post operative air leaks (n=10) and the number of prolonged air leaks (n=2) are all consistent with previous reports in the literature.[25, 26] Our study’s sensitivity of 81% and PPV of 39% for all lesions is consistent with the currently available data. In the pediatric population, ICG-assisted pulmonary metastasectomy has been most thoroughly evaluated for hepatoblastoma. This is because intravenously administered ICG is taken up by hepatocytes via specific membrane transporters and excreted into bile, with malignant hepatocytes—such as in hepatoblastoma—demonstrating prolonged retention. This mechanism produces high tumor-to-background contrast and has led to reported sensitivities of 98–100% for detecting pulmonary metastases in multiple hepatoblastoma series.[20–22] Conversely, for non-hepatic tumors such as sarcomas, fluorescence relies on the enhanced permeability and retention (EPR) effect—the passive accumulation of macromolecules and dyes in tumor tissue due to leaky vasculature and impaired lymphatic drainage. Because the EPR effect is less tumor-specific than hepatocyte uptake, detection rates are generally lower, and the timing of administration is critical. For sarcoma pulmonary metastases, most groups administer ICG approximately 24 hours prior to surgery to exploit the “second window” when background signal has cleared but tumor retention persists.[5, 10, 18, 19] This approach has been associated with sensitivities of 87% (thoracotomy) and 89% (thoracoscopy) in adults with metastatic sarcoma.[19] In pediatric series, Abdelhafeez et al. reported successful intraoperative identification of pulmonary metastases in all sarcoma patients,[5] while Jeremiasse et al. found that only 56% of osteosarcoma patients had ICG-avid lesions.[23] In our study, patients all tumor types—with the exception of four patients with rhabdomyosarcoma, rhabdosarcoma, myxoid chrondrosarcoma and spindle cell sarcoma (one patient in each category) had ICG-positive metastases. In our osteosarcoma subgroup, 81% had metastases that were ICG-avid. Notably, all osteosarcoma metastases identified were palpable, consistent with the dense osseous composition of these lesions, which may make them easier to palpate.[23] Jeremiasse et al attributed non-avid lesions to high tumor necrosis, which reduces the EPR effect, and to lesions located deep within the lung parenchyma—beyond the 5–10 mm penetration depth of near-infrared light.[23] While our study did not evaluate tumor depth, we did note decreased sensitivity in the seven patients who had previously undergone lung radiation with a sensitivity of 64% compared to 81% in the total patient population. This may be due to tumor necrosis like the study by Jeremiasse et al. Harris et al. further demonstrated variable ICG avidity across tumor types, with osteosarcoma generally showing stronger uptake than Wilms tumors however that patient population did not include other sarcoma histologies.[24] These findings can be interpreted in the broader context of pulmonary metastatectomy, where histology subtype strongly influences both the incidence of metastasis and the benefits of surgical resection. In osteosarcoma, complete resection has repeatedly been shown to improve survival, from early series by Goorin et al. reporting survival of 82% with complete resection versus 0% without surgery,[6]to more contemporary data by Buddingh et al. demonstrating a 5-year survival of 23% versus 3% in patients undergoing complete versus no resection.[8, 9] Non-rhabdomyosarcoma soft tissue sarcomas also show meaningful benefit: in synovial sarcoma, Spillane et al. found that metastasectomy improved 5-year survival nearly four-fold, from 6% to 23%.[9] By contrast, rhabdomyosarcoma carries a lower incidence of pulmonary metastasis (~16%) and a poor prognosis overall. Across IRS-IV and European trials, patients with isolated pulmonary disease demonstrated no survival benefit from metastasectomy, with event-free survival rates under 20% in high-risk groups.[1, 27, 28] Ewing sarcoma presents additional complexity given its chemo- and radiosensitivity. Early case series, such as Letourneau et al., reported striking survival differences (80% vs 0% with and without metastasectomy),[29] but later cohorts that adjusted for chemotherapy response and disease burden, such as Raciborska et al., found no significant benefit.[30] These data suggest that while pulmonary metastasectomy remains a common practice, its impact may be histology-specific and influenced by other treatment modalities. A strength of the present study was the consistent dosing and timing used in the entire cohort: 4 mg/kg given 24 hours prior to surgery. While there is no universally accepted pediatric dosing standard, reported doses for sarcoma metastases range from 1 to 5 mg/kg, with most studies using 5 mg/kg in adults and 4–5 mg/kg in pediatric patients.[10, 18, 19] The FDA-recommended maximum pediatric dose is 2 mg/kg when used for cardiac output monitoring,[14] but higher doses for fluorescence-guided surgery have been widely reported without significant toxicity.[5, 10, 11] In a systematic review by Le-Nguyen et al., no adverse events were noted in a pediatric population of 664 patients undergoing ICG-guided surgery.[15] Regarding timing, there is a consensus in the literature that administration 24 hours before surgery optimizes detection for non-hepatic tumors; however, this has not been directly compared with shorter intervals in a controlled trial.[5, 10, 23] This study is limited by its retrospective design and single institution setting. While this represents the largest sample size for this patient population to date, there were insufficient numbers of each histological subtype to enable meaningful comparisons. The lack of a control group precludes direct comparison of outcomes with conventional metastasectomy without fluorescence guidance. Tumor histology, prior therapy, and degree of necrosis varied among patients, which may have influenced ICG uptake. All procedures were performed by surgeons experienced with fluorescence imaging, so results may not be generalizable to centers without similar expertise or access to near-infrared imaging systems. Finally, follow-up was insufficient to assess whether fluorescence guidance impacted recurrence-free or overall survival. Conclusion In conclusion, ICG fluorescence imaging was a safe adjunct to pulmonary metastasectomy in children, adolescents, and young adults with sarcoma, facilitating the detection of additional metastases not appreciated by palpation or inspection. While its sensitivity varied across histologic subtypes and was reduced in certain clinical contexts such as prior lung radiation, ICG contributed to a more complete resection in our cohort without adverse effects. These findings support the incorporation of ICG into pulmonary metastasectomy for appropriately selected patients, with the understanding that it should complement rather than replace meticulous surgical exploration. Further multicenter studies are needed to define its impact on surgical outcomes and long-term disease control. In addition, the development of novel targeted fluorophores directed against tumor-specific antigens may allow for even greater precision in intra-operative detection of metastatic disease in the future. [31] Conflict of Interest Statement The authors declare that they have no conflicts of interest relevant to this manuscript. Acknowledgements The authors received no financial support for the research, authorship, or publication of this article. 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[cited 2025 Aug 31] Available from: https://pubmed.ncbi.nlm.nih.gov/26707423/ 31. Hernot S, Van Manen L, Debie P, Sven J, Mieog D, Lucas Vahrmeijer A. Review Latest developments in molecular tracers for fluorescence image-guided cancer surgery [Internet]. 2019Available from: www.thelancet.com/oncology Tables TABLE 1. Cohort Demographics, clinicopathologic characteristics, surgical approach, and complications for pulmonary metastasectomy with indocyanine green. Age at surgery, median (IQR) 18 (15 - 24.57) /= 25 years, N (%) 13 (25.5%) Pathology, N (%) Osteosarcoma 27 (52.9%) Ewing’s 8 (15.7%) Leiomyosarcoma 5 (9.8%) Synovial Sarcoma 2 (3.9%) Fibrosarcoma 2 (3.9%) Rhabdomyosarcoma 2 (3.9%) Myxoid Chondrosarcoma 1 (2.0%) NF1 1/ MPNST sarcoma 1 (2.0%) Spindle cell sarcoma 1 (2.0%) Sarcoma cic-dux4 1 (2.0%) Histocytic sarcoma 1 (2.0%) Preoperative Radiotherapy, N (%) None 37 (72.5%) Lung 7 (13.7%) Other site 7 (13.7%) Occurrence, N (%) Initial 36 (70.6%) Recurrence 15 (29.4%) Surgical approach, N (%) Open 49 (96.1%) Thoracoscopic 2 (3.9%) Surgical Specimen, median (IQR) 7 (4 - 10.5) Days Length of Stay, median (IQR) 3 (2 - 4) Days Chest Tube Duration, median (IQR) 1 (1 - 2) Prolonged air leak (>4 days), N (%) 2 (3.9%) Readmission for pain, N (%) 1 (2.0%) TABLE 2. Specimen characteristics including indocyanine green avidity, pathologically confirmed presence (tumor +) or absence (tumor -) of tumor cells, and positive predictive value (PPV) of indocyanine green. Osteosarcoma 221 63 115 18 25 77.8% Ewing’s 59 11 30 7 11 61.1% Synovial Sarcoma 44 34 8 0 2 77.7% Leiomyosarcoma 27 7 16 2 2 100% Fibrosarcoma 17 3 4 2 8 60.6% Rhabdomyosarcoma 11 0 9 0 2 0.0% Myxoid Chondrosarcoma 9 0 6 0 3 0.0% NF1 1/ MPNST sarcoma 9 4 0 0 5 100.0% Spindle cell sarcoma 6 0 3 0 3 0.0% Sarcoma cic-dux4 4 1 2 0 1 100% Histocytic sarcoma 2 1 1 0 0 100% Total 409 124 194 29 62 81.0% TABLE 3. Test accuracy of indocyanine green for palpable lesions, non-palpable lesions and overall in patients undergoing lung metastastectomy for sarcoma. Positive predictive value 67.6% Negative predictive value 68.1% Sensitivity 77.2% Specificity 56.9% Non-palpable lesion using ICG Positive predictive value 15.0% All Lesions (Palpable and Non-palpable lesions) Positive predictive value 39.0% Negative predictive value 68.1% Sensitivity 81.0% Specificity 24.2% Information & Authors Information Version history V1 Version 1 19 September 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords pediatric oncology sarcoma sarcomas soft tissue Authors Affiliations Sophia Schermerhorn MV Cincinnati Children's Hospital Medical Center View all articles by this author Emily Vore Cincinnati Children's Hospital Medical Center View all articles by this author Alexander Bondoc Cincinnati Children's Hospital Medical Center View all articles by this author Todd Jenkins Cincinnati Children's Hospital Medical Center View all articles by this author Roshni Dasgupta [email protected] Cincinnati Children's Hospital Medical Center View all articles by this author Metrics & Citations Metrics Article Usage 400 views 219 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Sophia Schermerhorn MV, Emily Vore, Alexander Bondoc, et al. Utilization of Indocyanine Green for Augmentation of Pulmonary Metastases Resection in Adolescent and Young Adult Sarcoma Patients. Authorea . 19 September 2025. 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