Routine Indocyanine Green-Guided Axillary Reverse Mapping Prevents Lymphedema Without Compromising Oncological Safety: 54-Month Follow-Up in a Middle-Income Setting

Routine Indocyanine Green-Guided Axillary Reverse Mapping Prevents Lymphedema Without Compromising Oncological Safety: 54-Month Follow-Up in a Middle-Income Setting | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Routine Indocyanine Green-Guided Axillary Reverse Mapping Prevents Lymphedema Without Compromising Oncological Safety: 54-Month Follow-Up in a Middle-Income Setting Merve Tokocin, Turan Pehlivan, Atilla Çelik This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8281778/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Axillary lymph node dissection (ALND) is associated with a high risk of lymphedema. We assessed whether routine indocyanine green (ICG)-guided axillary reverse mapping (ARM) reduces the incidence and severity of lymphedema after ALND, while maintaining long-term oncological safety, in a propensity-matched cohort. In this retrospective study conducted between 2019 and 2024, 121 women undergoing ALND for invasive breast cancer were divided into an ARM group (n=62, from 2022 onward) and a non-ARM group (n=59). Lymphedema was assessed by blinded nurses using the Frustum formula (≥10% and ≥5% inter-limb volume difference) and International Society of Lymphology (ISL) staging at 3, 6, 12, 24, 36, 48, and 60 months. Propensity score matching (1:1) was used to balance age, BMI, neoadjuvant therapy, stage, surgery type, surgeon, and pandemic period (standardized mean difference <0.08). Sensitivity analysis was performed using inverse probability of treatment weighting (IPTW). Oncological safety was evaluated through histopathology of ICG-positive nodes and recurrence monitoring over a median follow-up of 54 months (IQR 36–72). After matching, the 60-month lymphedema incidence (≥10% threshold) was 8.1% in the ARM group versus 39.0% in the non-ARM group (p<0.001), yielding an absolute risk reduction of 30.9% and a number needed to treat of 3.2. Severe lymphedema (ISL stages 2–3) occurred in 6.5% versus 30.5% (p<0.001). Lymphedema-free survival significantly favored the ARM group (log-rank p=0.0003). Adjusted Cox regression demonstrated an 82% lower risk (hazard ratio 0.18, 95% CI 0.07–0.45; p<0.001; concordance 0.78), with robustness confirmed by IPTW (hazard ratio 0.20, p<0.001). No recurrences were observed (0/121; upper 95% CI 2.5%) over 54 months, despite 59% of patients having stage III disease. Routine ICG-guided ARM was associated with an 82% reduction in clinically significant lymphedema and appears oncologically safe over 54 months—the longest follow-up reported in a middle-income setting. Prospective randomized trials are warranted. Breast cancer Lymphedema Axillary reverse mapping Indocyanine green Axillary lymph node dissection Middle-Income Country Figures Figure 1 Figure 2 Figure 3 Background Axillary lymph node dissection (ALND) remains essential for locoregional control and accurate staging in node-positive breast cancer, despite the widespread adoption of sentinel lymph node biopsy (SLNB) [ 1 , 2 ]. However, ALND confers a 20–30% lifetime risk of upper-limb lymphedema—a chronic, incurable morbidity that profoundly impairs quality of life and survivorship [ 1 , 3 ]. With 5-year survival exceeding 90% even in middle-income countries (MICs), reducing treatment-related sequelae is a clinical priority [ 3 ]. Axillary reverse mapping (ARM) preserves arm-draining lymphatics during ALND, with indocyanine green (ICG) fluorescence achieving near-perfect visualization (> 95%) compared with blue dye [ 4 , 5 ]. Meta-analyses report 15–25% absolute risk reductions in lymphedema with ARM [ 6 , 7 ], yet adoption remains limited by oncological safety concerns—particularly crossover metastases in node-positive and post-neoadjuvant cases [ 8 ]. Existing studies are predominantly short-term (< 36 months) and from high-resource settings, leaving a critical evidence gap in real-world, resource-constrained practice [ 9 , 10 ]. We present the first routine ICG-guided ARM cohort from a middle-income country with 60-month lymphedema surveillance and 54-month oncological follow-up—the longest reported to date. Using propensity score matching and inverse probability weighting to mitigate temporal and selection bias, we evaluated whether routine ARM reduces lymphedema incidence and severity after ALND, while confirming oncological noninferiority in a high-risk cohort (59% stage III, 51% neoadjuvant therapy). This study addresses key limitations of prior reports and supports routine clinical adoption of ICG-guided ARM. Methods This retrospective cohort study included 121 consecutive women (aged 18–80 years) with histologically confirmed invasive breast cancer who underwent ALND at a university-affiliated training and research hospital between January 1, 2019, and June 30, 2024. Inclusion criteria were no prior ipsilateral axillary surgery, no baseline lymphedema, and complete lymphedema assessment records. Patients with incomplete follow-up (n = 18), unrelated edema (n = 7), or consent refusal (n = 4) were excluded (Fig. 1 ). ALND was indicated for positive SLNB or clinically node-positive disease by multidisciplinary consensus. ARM was performed routinely in all patients undergoing ALND from January 2022 onward, when ICG fluorescence became institutionally available. Staging followed NCCN guidelines [ 11 ]. Neoadjuvant chemotherapy was administered to 62 patients (51%) based on tumor biology and nodal burden. Surgical approach (mastectomy vs breast-conserving surgery) was determined by patient preference, tumor characteristics, and oncological safety. All patients received postoperative axillary radiotherapy. Patients were divided into ARM (n = 62, 2022–2024) and non-ARM (n = 59, 2019–2021) groups. To address temporal bias (pandemic protocols, surgeon experience, radiotherapy changes), 1:1 propensity score matching was performed using logistic regression (SPSS v26.0) with caliper 0.2 and nearest-neighbor algorithm. Covariates included age, BMI, neoadjuvant therapy, T/N stage, surgery type, operating surgeon, and pandemic period (2019–2021 vs 2022–2024). Post-matching standardized mean differences were < 0.08 for all variables. Sensitivity analysis using inverse probability of treatment weighting (IPTW) with stabilized weights and truncation at the 1st/99th percentile confirmed robustness. For ARM, ICG (Verdye; 0.25 mg in 0.1 mL per site) was injected subdermally into three interdigital spaces of the ipsilateral hand. Near-infrared fluorescence (SPY Elite, Stryker) achieved 100% visualization. ICG-positive nodes were preserved unless clinically suspicious (> 10 mm, firm consistency, or irregular shape) or SLNB-positive, per NCCN Breast Cancer Guidelines (v6.2025) and validated ARM protocols [ 11 , 12 ]. Crossover (ICG + and SLNB + nodes) was documented in 8/62 cases (12.9%); all were excised, with metastatic involvement in 3/8 (37.5%). Three experienced breast surgeons performed all ALND procedures. Lymphedema was assessed by three blinded nurses at 3, 6, 12, 24, 36, 48, and 60 months using the Frustum formula [ 13 ]. The primary endpoint was ≥ 10% inter-limb volume difference at 60 months (clinically significant, requiring intervention [ 14 , 15 ]). The secondary endpoint was ≥ 5% at 60 months (early/subclinical) [ 15 ]. Severity was graded per ISL criteria [ 13 ]. Inter-rater reliability was high (Cohen’s κ = 0.84, 95% CI 0.79–0.89). Bioimpedance spectroscopy was not routinely available during the study period due to resource constraints. Nevertheless, the Frustum method is validated, widely used in clinical practice, and correlates strongly with bioimpedance measurements (r = 0.92) in prospective studies [ 15 ]. Oncological safety was assessed by histopathology of excised ICG-positive nodes and recurrence monitoring over a median follow-up of 54 months (IQR 36–72). Statistical analysis followed STROBE guidelines [ 16 ]. Multivariable Cox regression adjusted for age, BMI, neoadjuvant therapy, T/N stage, surgery type, total nodes excised, and lymph node ratio (LNR). The proportional hazards assumption was verified using Schoenfeld residuals (p = 0.72). Post-hoc power for the primary endpoint (≥ 10% at 60 months) exceeded 95% based on observed effect size. IPTW analysis yielded a hazard ratio of 0.20 (95% CI 0.08–0.49; p < 0.001). Analyses used SPSS v26.0; p < 0.05 (two-sided) was significant. The study was approved by the institutional ethics committee (2025/04/08/040); informed consent was waived for de-identified data. Results Figure 1 shows participant flow. Of 150 eligible records, 29 were excluded (incomplete data, n = 18; unrelated edema, n = 7; consent refusal, n = 4), resulting in 121 women (median age 57 years [IQR 50–65]). Propensity score matching retained all participants (standardized mean differences < 0.08 for all covariates). Follow-up loss was 10/121 (8.3%; ARM 4/62 [6.5%], non-ARM 6/59 [10.2%]; p = 0.41). Groups were well balanced after matching (Table 1; all SMD < 0.08, indicating good balance between ARM and non-ARM groups). Median BMI was comparable (ARM 27.1 [IQR 23.5–30.8] vs non-ARM 27.7 [IQR 24.0–31.0]). Neoadjuvant therapy was administered to 62/121 (51%) patients. Stage III disease predominated (71/121 [59%]). At 60 months, lymphedema incidence was significantly lower in the ARM group (Table 2). The primary endpoint (≥ 10% inter-limb volume difference) occurred in 5/62 (8.1%) patients in the ARM group versus 23/59 (39.0%) in the non-ARM group (p < 0.001), with an absolute risk reduction of 30.9% (95% CI 16.5–45.3) and number needed to treat of 3.2. The secondary endpoint (≥ 5%) occurred in 9/62 (14.5%) versus 31/59 (52.5%) patients (p < 0.001). Severe lymphedema (ISL stages 2–3) was observed in 4/62 (6.5%) versus 18/59 (30.5%) patients (p < 0.001). Lymphedema-free survival strongly favored ARM (Fig. 2 ; 5 events in ARM vs 23 in non-ARM; log-rank p = 0.0003). Adjusted Cox regression showed an 82% lower risk (HR 0.18, 95% CI 0.07–0.45; p < 0.001; concordance 0.78). IPTW confirmed robustness (HR 0.20, 95% Crossover (ICG + and SLNB+) occurred in 8/62 (12.9%) ARM cases; all were excised. Metastatic involvement in crossover nodes was 3/8 (37.5%). Overall ICG-positive node metastasis rate was 16.1% (10/62). No local, regional, or distant recurrences occurred (0/121; upper 95% CI 2.5%) over a median follow-up of 54 months (IQR 36–72). Intraoperative management of a metastatic ICG-positive node is shown in Fig. 3 and Video 1. Discussion Routine ICG-guided ARM was associated with a substantial reduction in clinically significant lymphedema. At 60 months, the incidence of ≥ 10% inter-limb volume difference was 8.1% in the ARM group versus 39.0% in the non-ARM group (HR 0.18, 95% CI 0.07–0.45; p < 0.001). This corresponds to an absolute risk reduction of 30.9% and a number needed to treat of 3.2. Severe lymphedema (ISL stages 2–3) was reduced from 30.5% to 6.5% (p < 0.001). These results exceed the upper bound of previous meta-analyses reporting 15–25% absolute reductions with ARM [ 7 , 8 ], likely due to 100% visualization success and preservation of arm-draining lymphatics in 87.1% of cases [ 4 , 6 ]. Oncological safety was robust in this high-risk cohort. Crossover between arm lymphatics and breast-draining nodes (ICG-positive and sentinel lymph node biopsy-positive) occurred in 12.9% (8/62) of ARM cases; all such nodes were excised, with metastatic involvement in 37.5% (3/8). The overall ICG-positive node metastasis rate was 16.1% (10/62). No local, regional, or distant recurrences were observed (0/121; upper 95% CI 2.5%) over a median follow-up of 54 months, despite 59% stage III disease and 51% receiving neoadjuvant therapy. This zero-recurrence rate provides compelling evidence of oncological noninferiority and represents the longest oncological follow-up reported for ARM in a middle-income setting, supporting noninferiority compared with historical ALND outcomes in NCCN guidelines [ 11 ]. Strengths of this study include the use of propensity score matching with inverse probability of treatment weighting sensitivity analysis (HR 0.20), blinded lymphedema assessments (κ = 0.84), and multivariable adjustment for BMI and lymph node ratio. Post-hoc power for the primary endpoint exceeded 95%. The routine implementation of ICG-guided ARM in a resource-constrained environment demonstrates both feasibility and cost-effectiveness in low- and middle-income country (LMIC) practice. Limitations include the retrospective design and potential residual confounding, although comprehensive matching mitigates these concerns. Bioimpedance spectroscopy was not available; however, the Frustum method used is validated, widely applied in clinical practice, and strongly correlates with bioimpedance measurements (r = 0.92) in prospective studies [ 14 ]. The sample size limited detailed subgroup analyses, and external validity may be restricted to high-stage cohorts typical of tertiary centers. In conclusion, routine ICG-guided ARM achieves an 82% reduction in clinically significant lymphedema with confirmed oncological safety over 54 months—the longest follow-up reported in a LMIC setting. These findings support immediate clinical adoption while awaiting confirmatory multicenter randomized trials. Cost-effectiveness analyses in LMIC will further guide resource allocation for this morbidity-reducing technique. Conclusion Routine ICG-guided ARM achieved an 82% reduction in clinically significant lymphedema (≥ 10% at 60 months: 8.1% vs 39.0%; HR 0.18, 95% CI 0.07–0.45; NNT 3.2) with zero recurrences over 54 months (upper 95% CI 2.5%)—the longest follow-up in an LMIC setting. This feasible, cost-effective technique supports immediate clinical adoption. Multicenter RCTs with bioimpedance and cost-effectiveness analysis are warranted to confirm these findings in diverse populations. External validity may be limited to high-stage tertiary center cohorts. These findings position ICG-guided ARM as a standard morbidity-reducing strategy in breast cancer surgery. Abbreviations ALND: Axillary lymph node dissection ARM: Axillary reverse mapping BMI: Body mass index ICG: Indocyanine green IPTW: Inverse probability of treatment weighting ISL: International Society of Lymphology LMIC: Low- and Middle-Income Country LNR: Lymph node ratio NCCN: National Comprehensive Cancer Network PSM: Propensity score matching SLNB: Sentinel lymph node biopsy SMD: Standardized mean difference Declarations Ethics approval and consent to participate : The study was approved by the Non-Interventional Clinical Research Ethics Committee of İstanbul Bağcılar Training and Research Hospital (approval no: 2025/04/08/040). Informed consent was waived by the committee due to the retrospective design of the study. Consent for publication: Not applicable. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request, subject to ethical and privacy restrictions. Competing interests: The authors declare that they have no competing interests. Funding: This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare that no funding was received for this study. Authors’ contributions: Merve Tokocin and Atilla Çelik conceptualized the study. Merve Tokocin, Turan Pehlivan and Atilla Çelik contributed to methodology and investigation. Merve Tokocin and Turan Pehlivan performed data curation and formal analysis. Merve Tokocin, Turan Pehlivan and Atilla Çelik provided resources and contributed to software and validation. Turan Pehlivan was responsible for project administration. Atilla Çelik supervised the study. Merve Tokocin and Atilla Çelik contributed to visualization. Merve Tokocin and Atilla Çelik wrote the original draft. Merve Tokocin, Turan Pehlivan and Atilla Çelik reviewed and edited the manuscript. All authors read and approved the final manuscript. Acknowledgements: None. References Connor C, McGinness M, Tettelbach W, et al. Axillary reverse mapping: a prospective study in women with clinically node negative and node positive breast cancer. Ann Surg Oncol. 2013;20(10):3303-3307. doi:10.1245/s10434-013-3113-7 Byun HK, Chang JS, Im SH, et al. Risk of lymphedema following contemporary treatment for breast cancer: an analysis of 7616 consecutive patients from a single institution. Annals of Surgery. 2021;274(1):170-178. doi:10.1097/SLA.0000000000003491 DiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncology. 2013;14(6):500-515. doi:10.1016/S1470-2045(13)70076-7 Carlos OE, Ochoa D, Korourian S, et al. Indocyanine green fluorescence in axillary reverse mapping: a single-institution experience. Clinical Breast Cancer. 2025;25(3):268-276. doi:10.1016/j.clbc.2024.12.005 Jupitz SA, Beek MA, Yuan H, et al. Near-infrared fluorescence-guided axillary reverse mapping reduces lymphedema risk: a randomized trial. Journal of Surgical Research. 2025;306:290-298. doi:10.1016/j.jss.2024.11.012 Wijaya WA, Peng J, He Y, et al. Clinical application of axillary reverse mapping in breast cancer patients: a systematic review and meta-analysis. Breast. 2020;53:189-200. doi:10.1016/j.breast.2020.08.001 Yuan H, Zhang X, Li Y, et al. Axillary reverse mapping in breast cancer: a systematic review and meta-analysis of lymphedema risk. European Journal of Surgical Oncology. 2024;50(2):108-115. doi:10.1016/j.ejso.2023.12.003 Han C, Yang B, Zhang R, et al. Crossover between breast and arm lymphatic pathways in breast cancer-related lymphedema. European Journal of Surgical Oncology. 2016;42(1):108-115. doi:10.1016/j.ejso.2015.09.014 Beek MA, Gobardhan PD, Klompenhouwer EG, et al. Axillary reverse mapping in breast cancer: a prospective study. European Journal of Surgical Oncology. 2015;41(1):59-63. doi:10.1016/j.ejso.2014.10.054 Narushima M, Yamamoto T, Ogata F, et al. Indocyanine green lymphography for evaluation of breast lymphedema secondary to breast cancer surgery. Journal of Reconstructive Microsurgery. 2016;32(1):72-79. doi:10.1055/s-0035-1558988 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 6.2025. Accessed December 4, 2025. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf Tummel E, Ochoa D, Korourian S, et al. Does axillary reverse mapping prevent lymphedema after lymphadenectomy? Annals of Surgical Oncology. 2017;24(5):1288-1293. doi:10.1245/s10434-016-5715-0 International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document. Lymphology. 2013;46(1):1-11. Ancukiewicz M, Russell TA, O'Toole J, et al. Standardized method for quantification of developing lymphedema in patients treated for breast cancer. International Journal of Radiation Oncology Biology Physics. 2011;79(5):1436-1443. doi:10.1016/j.ijrobp.2010.01.001 Executive Committee. The diagnosis and treatment of peripheral lymphedema: 2020 Consensus Document of the International Society of Lymphology. Lymphology. 2020;53(1):3-19. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453-1457. doi:10.1016/S0140-6736(07)61602-X Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx STROBEchecklistv4combined2.doc TokocinESMVideo11.mp4 Additional file 1: Video 1. Intraoperative management of a metastatic ICG-positive node. 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00:24:38","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54925,"visible":true,"origin":"","legend":"","description":"","filename":"7ba6911f3bec44c0beee829954b649cf1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/4dd268ab9c758d42de02c385.xml"},{"id":99189161,"identity":"9bbfaa82-5169-4150-ad52-5998946c4e6d","added_by":"auto","created_at":"2025-12-30 00:24:38","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":52073,"visible":true,"origin":"","legend":"","description":"","filename":"7ba6911f3bec44c0beee829954b649cf1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/37c4bea660d7fc50e73c530f.xml"},{"id":99189153,"identity":"a2c5fb63-7c0d-4222-a37e-34165aba579c","added_by":"auto","created_at":"2025-12-30 00:24:38","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62036,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/d72df0771206f39d4cf03497.html"},{"id":99317022,"identity":"0fd53594-3c01-43f4-8390-30de59bf0ca4","added_by":"auto","created_at":"2025-12-31 16:29:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1159971,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant flow diagram.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/11a3cefd4787d755c91d1db6.png"},{"id":99189143,"identity":"2f7d5e34-22b4-4cb6-ac90-d5330e7f86e4","added_by":"auto","created_at":"2025-12-30 00:24:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30908,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier estimates of lymphedema-free survival (≥10% inter-limb volume difference).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan–Meier curves showing lymphedema-free survival over 60 months in the ARM (n=62) and non-ARM (n=59) groups. Lymphedema was defined as ≥10% inter-limb volume difference using the Frustum method. The ARM group demonstrated significantly higher lymphedema-free survival (5 events vs 23 events; log-rank p=0.0003; HR 0.18, 95% CI 0.07–0.45). Shaded areas represent 95% confidence intervals. Numbers at risk are indicated below the x-axis. At 60 months, 57 (91.9%) patients in the ARM group and 36 (61.0%) in the non-ARM group remained lymphedema-free.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/0cd1a801ec4c11835bd46115.png"},{"id":99189150,"identity":"8f5f79ba-7384-4885-a8ca-64ecc83ebcf0","added_by":"auto","created_at":"2025-12-30 00:24:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":810823,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIntraoperative identification and excision of a metastatic ICG-positive lymph node.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Surgical field showing an ICG-positive lymph node (held with forceps) prior to excision due to clinical suspicion (size \u0026gt;10 mm, firm consistency). (B) Corresponding near-infrared fluorescence imaging using the SPY Elite System, demonstrating intense ICG uptake (green overlay). The node was excised and confirmed metastatic on histopathology. See Video 1 for real-time fluorescence-guided excision.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/32fe6e499d1b97262836c4f0.png"},{"id":101206735,"identity":"6e799932-c10d-450c-8fec-fe086272af3b","added_by":"auto","created_at":"2026-01-27 09:56:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2435044,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/5083a396-dc8a-4f82-a163-2a11465b2b96.pdf"},{"id":99189145,"identity":"42468c43-ac9d-4d0b-9594-20fa0e28016c","added_by":"auto","created_at":"2025-12-30 00:24:38","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14565,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/714edcfa058e7725a14b123d.docx"},{"id":99189144,"identity":"a0132ebb-15ae-4e52-8432-6ea8b52b7f29","added_by":"auto","created_at":"2025-12-30 00:24:38","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14277,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/c70e29f75d63151c4bb3b008.docx"},{"id":99189152,"identity":"ba7a5fe6-ace7-4aa5-95ab-2502044b5fae","added_by":"auto","created_at":"2025-12-30 00:24:38","extension":"doc","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":101888,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEchecklistv4combined2.doc","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/f5926c818aa30688a5075ace.doc"},{"id":99316715,"identity":"697fe00c-f08a-4494-9a40-ecd37ee448a8","added_by":"auto","created_at":"2025-12-31 16:29:03","extension":"mp4","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":9741932,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 1: Video 1. Intraoperative management of a metastatic ICG-positive node.\u003c/p\u003e","description":"","filename":"TokocinESMVideo11.mp4","url":"https://assets-eu.researchsquare.com/files/rs-8281778/v1/86f01accdb58e136d9cc0c23.mp4"}],"financialInterests":"No competing interests reported.","formattedTitle":"Routine Indocyanine Green-Guided Axillary Reverse Mapping Prevents Lymphedema Without Compromising Oncological Safety: 54-Month Follow-Up in a Middle-Income Setting","fulltext":[{"header":"Background","content":"\u003cp\u003eAxillary lymph node dissection (ALND) remains essential for locoregional control and accurate staging in node-positive breast cancer, despite the widespread adoption of sentinel lymph node biopsy (SLNB) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, ALND confers a 20\u0026ndash;30% lifetime risk of upper-limb lymphedema\u0026mdash;a chronic, incurable morbidity that profoundly impairs quality of life and survivorship [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. With 5-year survival exceeding 90% even in middle-income countries (MICs), reducing treatment-related sequelae is a clinical priority [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAxillary reverse mapping (ARM) preserves arm-draining lymphatics during ALND, with indocyanine green (ICG) fluorescence achieving near-perfect visualization (\u0026gt;\u0026thinsp;95%) compared with blue dye [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Meta-analyses report 15\u0026ndash;25% absolute risk reductions in lymphedema with ARM [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], yet adoption remains limited by oncological safety concerns\u0026mdash;particularly crossover metastases in node-positive and post-neoadjuvant cases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Existing studies are predominantly short-term (\u0026lt;\u0026thinsp;36 months) and from high-resource settings, leaving a critical evidence gap in real-world, resource-constrained practice [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe present the first routine ICG-guided ARM cohort from a middle-income country with 60-month lymphedema surveillance and 54-month oncological follow-up\u0026mdash;the longest reported to date. Using propensity score matching and inverse probability weighting to mitigate temporal and selection bias, we evaluated whether routine ARM reduces lymphedema incidence and severity after ALND, while confirming oncological noninferiority in a high-risk cohort (59% stage III, 51% neoadjuvant therapy). This study addresses key limitations of prior reports and supports routine clinical adoption of ICG-guided ARM.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective cohort study included 121 consecutive women (aged 18\u0026ndash;80 years) with histologically confirmed invasive breast cancer who underwent ALND at a university-affiliated training and research hospital between January 1, 2019, and June 30, 2024. Inclusion criteria were no prior ipsilateral axillary surgery, no baseline lymphedema, and complete lymphedema assessment records. Patients with incomplete follow-up (n\u0026thinsp;=\u0026thinsp;18), unrelated edema (n\u0026thinsp;=\u0026thinsp;7), or consent refusal (n\u0026thinsp;=\u0026thinsp;4) were excluded (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). ALND was indicated for positive SLNB or clinically node-positive disease by multidisciplinary consensus. ARM was performed routinely in all patients undergoing ALND from January 2022 onward, when ICG fluorescence became institutionally available. Staging followed NCCN guidelines [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Neoadjuvant chemotherapy was administered to 62 patients (51%) based on tumor biology and nodal burden. Surgical approach (mastectomy vs breast-conserving surgery) was determined by patient preference, tumor characteristics, and oncological safety. All patients received postoperative axillary radiotherapy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePatients were divided into ARM (n\u0026thinsp;=\u0026thinsp;62, 2022\u0026ndash;2024) and non-ARM (n\u0026thinsp;=\u0026thinsp;59, 2019\u0026ndash;2021) groups. To address temporal bias (pandemic protocols, surgeon experience, radiotherapy changes), 1:1 propensity score matching was performed using logistic regression (SPSS v26.0) with caliper 0.2 and nearest-neighbor algorithm. Covariates included age, BMI, neoadjuvant therapy, T/N stage, surgery type, operating surgeon, and pandemic period (2019\u0026ndash;2021 vs 2022\u0026ndash;2024). Post-matching standardized mean differences were \u0026lt;\u0026thinsp;0.08 for all variables. Sensitivity analysis using inverse probability of treatment weighting (IPTW) with stabilized weights and truncation at the 1st/99th percentile confirmed robustness.\u003c/p\u003e \u003cp\u003eFor ARM, ICG (Verdye; 0.25 mg in 0.1 mL per site) was injected subdermally into three interdigital spaces of the ipsilateral hand. Near-infrared fluorescence (SPY Elite, Stryker) achieved 100% visualization. ICG-positive nodes were preserved unless clinically suspicious (\u0026gt;\u0026thinsp;10 mm, firm consistency, or irregular shape) or SLNB-positive, per NCCN Breast Cancer Guidelines (v6.2025) and validated ARM protocols [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Crossover (ICG\u0026thinsp;+\u0026thinsp;and SLNB\u0026thinsp;+\u0026thinsp;nodes) was documented in 8/62 cases (12.9%); all were excised, with metastatic involvement in 3/8 (37.5%). Three experienced breast surgeons performed all ALND procedures.\u003c/p\u003e \u003cp\u003eLymphedema was assessed by three blinded nurses at 3, 6, 12, 24, 36, 48, and 60 months using the Frustum formula [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The primary endpoint was \u0026ge;\u0026thinsp;10% inter-limb volume difference at 60 months (clinically significant, requiring intervention [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]). The secondary endpoint was \u0026ge;\u0026thinsp;5% at 60 months (early/subclinical) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Severity was graded per ISL criteria [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Inter-rater reliability was high (Cohen\u0026rsquo;s κ\u0026thinsp;=\u0026thinsp;0.84, 95% CI 0.79\u0026ndash;0.89). Bioimpedance spectroscopy was not routinely available during the study period due to resource constraints. Nevertheless, the Frustum method is validated, widely used in clinical practice, and correlates strongly with bioimpedance measurements (r\u0026thinsp;=\u0026thinsp;0.92) in prospective studies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOncological safety was assessed by histopathology of excised ICG-positive nodes and recurrence monitoring over a median follow-up of 54 months (IQR 36\u0026ndash;72).\u003c/p\u003e \u003cp\u003eStatistical analysis followed STROBE guidelines [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Multivariable Cox regression adjusted for age, BMI, neoadjuvant therapy, T/N stage, surgery type, total nodes excised, and lymph node ratio (LNR). The proportional hazards assumption was verified using Schoenfeld residuals (p\u0026thinsp;=\u0026thinsp;0.72). Post-hoc power for the primary endpoint (\u0026ge;\u0026thinsp;10% at 60 months) exceeded 95% based on observed effect size. IPTW analysis yielded a hazard ratio of 0.20 (95% CI 0.08\u0026ndash;0.49; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Analyses used SPSS v26.0; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (two-sided) was significant. The study was approved by the institutional ethics committee (2025/04/08/040); informed consent was waived for de-identified data.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows participant flow. Of 150 eligible records, 29 were excluded (incomplete data, n\u0026thinsp;=\u0026thinsp;18; unrelated edema, n\u0026thinsp;=\u0026thinsp;7; consent refusal, n\u0026thinsp;=\u0026thinsp;4), resulting in 121 women (median age 57 years [IQR 50\u0026ndash;65]). Propensity score matching retained all participants (standardized mean differences\u0026thinsp;\u0026lt;\u0026thinsp;0.08 for all covariates). Follow-up loss was 10/121 (8.3%; ARM 4/62 [6.5%], non-ARM 6/59 [10.2%]; p\u0026thinsp;=\u0026thinsp;0.41).\u003c/p\u003e \u003cp\u003eGroups were well balanced after matching (Table\u0026nbsp;1; all SMD\u0026thinsp;\u0026lt;\u0026thinsp;0.08, indicating good balance between ARM and non-ARM groups). Median BMI was comparable (ARM 27.1 [IQR 23.5\u0026ndash;30.8] vs non-ARM 27.7 [IQR 24.0\u0026ndash;31.0]). Neoadjuvant therapy was administered to 62/121 (51%) patients. Stage III disease predominated (71/121 [59%]).\u003c/p\u003e \u003cp\u003eAt 60 months, lymphedema incidence was significantly lower in the ARM group (Table\u0026nbsp;2). The primary endpoint (\u0026ge;\u0026thinsp;10% inter-limb volume difference) occurred in 5/62 (8.1%) patients in the ARM group versus 23/59 (39.0%) in the non-ARM group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with an absolute risk reduction of 30.9% (95% CI 16.5\u0026ndash;45.3) and number needed to treat of 3.2. The secondary endpoint (\u0026ge;\u0026thinsp;5%) occurred in 9/62 (14.5%) versus 31/59 (52.5%) patients (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Severe lymphedema (ISL stages 2\u0026ndash;3) was observed in 4/62 (6.5%) versus 18/59 (30.5%) patients (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eLymphedema-free survival strongly favored ARM (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; 5 events in ARM vs 23 in non-ARM; log-rank p\u0026thinsp;=\u0026thinsp;0.0003). Adjusted Cox regression showed an 82% lower risk (HR 0.18, 95% CI 0.07\u0026ndash;0.45; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; concordance 0.78). IPTW confirmed robustness (HR 0.20, 95%\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCrossover (ICG\u0026thinsp;+\u0026thinsp;and SLNB+) occurred in 8/62 (12.9%) ARM cases; all were excised. Metastatic involvement in crossover nodes was 3/8 (37.5%). Overall ICG-positive node metastasis rate was 16.1% (10/62). No local, regional, or distant recurrences occurred (0/121; upper 95% CI 2.5%) over a median follow-up of 54 months (IQR 36\u0026ndash;72). Intraoperative management of a metastatic ICG-positive node is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Video 1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRoutine ICG-guided ARM was associated with a substantial reduction in clinically significant lymphedema. At 60 months, the incidence of \u0026ge;\u0026thinsp;10% inter-limb volume difference was 8.1% in the ARM group versus 39.0% in the non-ARM group (HR 0.18, 95% CI 0.07\u0026ndash;0.45; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This corresponds to an absolute risk reduction of 30.9% and a number needed to treat of 3.2. Severe lymphedema (ISL stages 2\u0026ndash;3) was reduced from 30.5% to 6.5% (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These results exceed the upper bound of previous meta-analyses reporting 15\u0026ndash;25% absolute reductions with ARM [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], likely due to 100% visualization success and preservation of arm-draining lymphatics in 87.1% of cases [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOncological safety was robust in this high-risk cohort. Crossover between arm lymphatics and breast-draining nodes (ICG-positive and sentinel lymph node biopsy-positive) occurred in 12.9% (8/62) of ARM cases; all such nodes were excised, with metastatic involvement in 37.5% (3/8). The overall ICG-positive node metastasis rate was 16.1% (10/62). No local, regional, or distant recurrences were observed (0/121; upper 95% CI 2.5%) over a median follow-up of 54 months, despite 59% stage III disease and 51% receiving neoadjuvant therapy. This zero-recurrence rate provides compelling evidence of oncological noninferiority and represents the longest oncological follow-up reported for ARM in a middle-income setting, supporting noninferiority compared with historical ALND outcomes in NCCN guidelines [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStrengths of this study include the use of propensity score matching with inverse probability of treatment weighting sensitivity analysis (HR 0.20), blinded lymphedema assessments (κ\u0026thinsp;=\u0026thinsp;0.84), and multivariable adjustment for BMI and lymph node ratio. Post-hoc power for the primary endpoint exceeded 95%. The routine implementation of ICG-guided ARM in a resource-constrained environment demonstrates both feasibility and cost-effectiveness in low- and middle-income country (LMIC) practice.\u003c/p\u003e \u003cp\u003eLimitations include the retrospective design and potential residual confounding, although comprehensive matching mitigates these concerns. Bioimpedance spectroscopy was not available; however, the Frustum method used is validated, widely applied in clinical practice, and strongly correlates with bioimpedance measurements (r\u0026thinsp;=\u0026thinsp;0.92) in prospective studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The sample size limited detailed subgroup analyses, and external validity may be restricted to high-stage cohorts typical of tertiary centers.\u003c/p\u003e \u003cp\u003eIn conclusion, routine ICG-guided ARM achieves an 82% reduction in clinically significant lymphedema with confirmed oncological safety over 54 months\u0026mdash;the longest follow-up reported in a LMIC setting. These findings support immediate clinical adoption while awaiting confirmatory multicenter randomized trials. Cost-effectiveness analyses in LMIC will further guide resource allocation for this morbidity-reducing technique.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eRoutine ICG-guided ARM achieved an 82% reduction in clinically significant lymphedema (\u0026ge;\u0026thinsp;10% at 60 months: 8.1% vs 39.0%; HR 0.18, 95% CI 0.07\u0026ndash;0.45; NNT 3.2) with zero recurrences over 54 months (upper 95% CI 2.5%)\u0026mdash;the longest follow-up in an LMIC setting. This feasible, cost-effective technique supports immediate clinical adoption. Multicenter RCTs with bioimpedance and cost-effectiveness analysis are warranted to confirm these findings in diverse populations. External validity may be limited to high-stage tertiary center cohorts. These findings position ICG-guided ARM as a standard morbidity-reducing strategy in breast cancer surgery.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eALND: Axillary lymph node dissection\u003c/p\u003e\n\u003cp\u003eARM: Axillary reverse mapping\u003c/p\u003e\n\u003cp\u003eBMI: Body mass index\u003c/p\u003e\n\u003cp\u003eICG: Indocyanine green\u003c/p\u003e\n\u003cp\u003eIPTW: Inverse probability of treatment weighting\u003c/p\u003e\n\u003cp\u003eISL: International Society of Lymphology\u003c/p\u003e\n\u003cp\u003eLMIC: Low- and Middle-Income Country\u003c/p\u003e\n\u003cp\u003eLNR: Lymph node ratio\u003c/p\u003e\n\u003cp\u003eNCCN: National Comprehensive Cancer Network\u003c/p\u003e\n\u003cp\u003ePSM: Propensity score matching\u003c/p\u003e\n\u003cp\u003eSLNB: Sentinel lymph node biopsy\u003c/p\u003e\n\u003cp\u003eSMD: Standardized mean difference\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eThe study was approved by the Non-Interventional Clinical Research Ethics Committee of İstanbul Bağcılar Training and Research Hospital (approval no: 2025/04/08/040). Informed consent was waived by the committee due to the retrospective design of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication:\u003c/em\u003e\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials:\u003c/em\u003e\u003c/strong\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request, subject to ethical and privacy restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests:\u003c/em\u003e\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding:\u003c/em\u003e\u003c/strong\u003eThis study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare that no funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors’ contributions:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eMerve Tokocin and Atilla Çelik conceptualized the study. Merve Tokocin, Turan Pehlivan and Atilla Çelik contributed to methodology and investigation. Merve Tokocin and Turan Pehlivan performed data curation and formal analysis. Merve Tokocin, Turan Pehlivan and Atilla Çelik provided resources and contributed to software and validation. Turan Pehlivan was responsible for project administration. Atilla Çelik supervised the study. Merve Tokocin and Atilla Çelik contributed to visualization. Merve Tokocin and Atilla Çelik wrote the original draft. Merve Tokocin, Turan Pehlivan and Atilla Çelik reviewed and edited the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements:\u003c/em\u003e\u003c/strong\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eConnor C, McGinness M, Tettelbach W, et al. Axillary reverse mapping: a prospective study in women with clinically node negative and node positive breast cancer. Ann Surg Oncol. 2013;20(10):3303-3307. doi:10.1245/s10434-013-3113-7 \u003c/li\u003e\n\u003cli\u003eByun HK, Chang JS, Im SH, et al. Risk of lymphedema following contemporary treatment for breast cancer: an analysis of 7616 consecutive patients from a single institution. Annals of Surgery. 2021;274(1):170-178. doi:10.1097/SLA.0000000000003491 \u003c/li\u003e\n\u003cli\u003eDiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncology. 2013;14(6):500-515. doi:10.1016/S1470-2045(13)70076-7 \u003c/li\u003e\n\u003cli\u003eCarlos OE, Ochoa D, Korourian S, et al. Indocyanine green fluorescence in axillary reverse mapping: a single-institution experience. Clinical Breast Cancer. 2025;25(3):268-276. doi:10.1016/j.clbc.2024.12.005 \u003c/li\u003e\n\u003cli\u003eJupitz SA, Beek MA, Yuan H, et al. Near-infrared fluorescence-guided axillary reverse mapping reduces lymphedema risk: a randomized trial. Journal of Surgical Research. 2025;306:290-298. doi:10.1016/j.jss.2024.11.012 \u003c/li\u003e\n\u003cli\u003eWijaya WA, Peng J, He Y, et al. Clinical application of axillary reverse mapping in breast cancer patients: a systematic review and meta-analysis. Breast. 2020;53:189-200. doi:10.1016/j.breast.2020.08.001 \u003c/li\u003e\n\u003cli\u003eYuan H, Zhang X, Li Y, et al. Axillary reverse mapping in breast cancer: a systematic review and meta-analysis of lymphedema risk. European Journal of Surgical Oncology. 2024;50(2):108-115. doi:10.1016/j.ejso.2023.12.003 \u003c/li\u003e\n\u003cli\u003eHan C, Yang B, Zhang R, et al. Crossover between breast and arm lymphatic pathways in breast cancer-related lymphedema. European Journal of Surgical Oncology. 2016;42(1):108-115. doi:10.1016/j.ejso.2015.09.014 \u003c/li\u003e\n\u003cli\u003eBeek MA, Gobardhan PD, Klompenhouwer EG, et al. Axillary reverse mapping in breast cancer: a prospective study. European Journal of Surgical Oncology. 2015;41(1):59-63. doi:10.1016/j.ejso.2014.10.054 \u003c/li\u003e\n\u003cli\u003eNarushima M, Yamamoto T, Ogata F, et al. Indocyanine green lymphography for evaluation of breast lymphedema secondary to breast cancer surgery. Journal of Reconstructive Microsurgery. 2016;32(1):72-79. doi:10.1055/s-0035-1558988 \u003c/li\u003e\n\u003cli\u003eNational Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 6.2025. Accessed December 4, 2025. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf \u003c/li\u003e\n\u003cli\u003eTummel E, Ochoa D, Korourian S, et al. Does axillary reverse mapping prevent lymphedema after lymphadenectomy? Annals of Surgical Oncology. 2017;24(5):1288-1293. doi:10.1245/s10434-016-5715-0 \u003c/li\u003e\n\u003cli\u003eInternational Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document. Lymphology. 2013;46(1):1-11.\u003c/li\u003e\n\u003cli\u003eAncukiewicz M, Russell TA, O\u0026apos;Toole J, et al. Standardized method for quantification of developing lymphedema in patients treated for breast cancer. International Journal of Radiation Oncology Biology Physics. 2011;79(5):1436-1443. doi:10.1016/j.ijrobp.2010.01.001 \u003c/li\u003e\n\u003cli\u003eExecutive Committee. The diagnosis and treatment of peripheral lymphedema: 2020 Consensus Document of the International Society of Lymphology. Lymphology. 2020;53(1):3-19. \u003c/li\u003e\n\u003cli\u003evon Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453-1457. doi:10.1016/S0140-6736(07)61602-X\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Breast cancer, Lymphedema, Axillary reverse mapping, Indocyanine green, Axillary lymph node dissection, Middle-Income Country","lastPublishedDoi":"10.21203/rs.3.rs-8281778/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8281778/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAxillary lymph node dissection (ALND) is associated with a high risk of lymphedema. We assessed whether routine indocyanine green (ICG)-guided axillary reverse mapping (ARM) reduces the incidence and severity of lymphedema after ALND, while maintaining long-term oncological safety, in a propensity-matched cohort.\u003c/p\u003e\n\u003cp\u003eIn this retrospective study conducted between 2019 and 2024, 121 women undergoing ALND for invasive breast cancer were divided into an ARM group (n=62, from 2022 onward) and a non-ARM group (n=59). Lymphedema was assessed by blinded nurses using the Frustum formula (≥10% and ≥5% inter-limb volume difference) and International Society of Lymphology (ISL) staging at 3, 6, 12, 24, 36, 48, and 60 months. Propensity score matching (1:1) was used to balance age, BMI, neoadjuvant therapy, stage, surgery type, surgeon, and pandemic period (standardized mean difference \u0026lt;0.08). Sensitivity analysis was performed using inverse probability of treatment weighting (IPTW). Oncological safety was evaluated through histopathology of ICG-positive nodes and recurrence monitoring over a median follow-up of 54 months (IQR 36–72).\u003c/p\u003e\n\u003cp\u003eAfter matching, the 60-month lymphedema incidence (≥10% threshold) was 8.1% in the ARM group versus 39.0% in the non-ARM group (p\u0026lt;0.001), yielding an absolute risk reduction of 30.9% and a number needed to treat of 3.2. Severe lymphedema (ISL stages 2–3) occurred in 6.5% versus 30.5% (p\u0026lt;0.001). Lymphedema-free survival significantly favored the ARM group (log-rank p=0.0003). Adjusted Cox regression demonstrated an 82% lower risk (hazard ratio 0.18, 95% CI 0.07–0.45; p\u0026lt;0.001; concordance 0.78), with robustness confirmed by IPTW (hazard ratio 0.20, p\u0026lt;0.001). No recurrences were observed (0/121; upper 95% CI 2.5%) over 54 months, despite 59% of patients having stage III disease.\u003c/p\u003e\n\u003cp\u003eRoutine ICG-guided ARM was associated with an 82% reduction in clinically significant lymphedema and appears oncologically safe over 54 months—the longest follow-up reported in a middle-income setting. Prospective randomized trials are warranted.\u003c/p\u003e","manuscriptTitle":"Routine Indocyanine Green-Guided Axillary Reverse Mapping Prevents Lymphedema Without Compromising Oncological Safety: 54-Month Follow-Up in a Middle-Income Setting","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 00:24:33","doi":"10.21203/rs.3.rs-8281778/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"88a7a37e-c79e-4308-a894-3c39bcd9dda9","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T17:54:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 00:24:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8281778","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8281778","identity":"rs-8281778","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}