A 2018 systematic review and meta-analysis investigated the feasibility and accuracy of using methylene blue dye (MBD) alone for sentinel lymph node biopsy (SNB) in breast cancer patients. This comprehensive analysis included 18 studies covering a total of 1,559 patients. The authors aimed to evaluate critical outcomes such as the identification rate (IR) and false negative rate (FNR) to determine the efficacy of MBD in comparison to the standard combined technique involving radioisotopes and blue dye. Findings from the meta-analysis revealed that the combined IR of SNBs mapped with MBD alone was 91% (95% CI: 88%-94%). However, the false negative rate was found to be 13%, indicating an excessive rate according to the American Society of Breast Surgeons' recommendations. The pooled sensitivity, negative predictive value, and accuracy rate were calculated as 87% (95% CI: 82%-91%), 91% (95% CI: 87%-93%), and 94% (95% CI: 92%-96%) respectively. The results suggest that while the use of MBD for sentinel lymph node mapping in breast cancer shows an acceptable identification rate, the higher false negative rate warrants caution in clinical practice. [1]
Efficacy has been evaluated in a 2024 systematic review compared efficacy for sentinel lymph node (SLN) detection between various unique dyes, dye combinations, or other tracers. Data were compiled from 37 studies. Several dye combinations were found to have 100% accuracy, all of these using either indocyanine green or Tc-99. Isosulfan blue was found to be the least accurate dye, detecting 69.8% of SLNs based on data from 3 studies. Conversely, methylene blue had higher detection accuracy, 90.8%, based on data from 7 studies. Dye combinations were found to be more accurate than individual agents. A full comparison of reviewed dyes and their corresponding accuracy is presented in Table 4. [2]
Mechanistically, isosulfan blue contains two sulfonate groups that strongly bind to plasma proteins, while its size allows it to travel in the lymphatic vessel but become trapped, eventually resulting in delineation. This compound is slowly excreted via the renal system. While allergic reactions are uncommon, they can be serious, with approximately 1% of patients experiencing anaphylaxis. Methylene blue is a thiazine dye of a smaller size than isosulfan blue that does not bind plasma proteins. Its mechanism is unclear, but may involve nondiscriminatory actions such as diffusion and anionic binding. Adverse effects related to its use may include skin staining and injection site necrosis. [2]
Additionally, a 2021 meta-analysis reviewed the risk of anaphylaxis and adverse events associated with blue dyes used in sentinel lymph node biopsy (SLNB), focusing on dyes such as isosulfan blue, methylene blue, patent blue, and indigo carmine. Data from 109 studies, encompassing 61,951 procedures, reported 94 cases of anaphylaxis, resulting in a weighted incidence of 0.061%. Among the dyes analyzed, isosulfan blue exhibited the highest anaphylaxis rate at 0.16%, compared to patent blue at 0.05% and methylene blue at 0.0006%. Differences in cancer type and procedural methods influenced outcomes, with breast cancer surgeries demonstrating a higher anaphylaxis rate of 0.083% compared to 0.0043% in melanoma surgeries. This discrepancy aligns with the use of larger dye volumes (>2 mL associated with a 0.083% rate versus <2 mL at 0.031%) and injection methods, where parenchymal injections dominated in breast cancer versus intradermal injections in melanoma (associated with a 0.0068% rate). Methylene blue, while having the lowest anaphylaxis rate, was linked to adverse effects such as tissue necrosis. Importantly, no mortalities associated with blue dye use were documented across nearly 62,000 procedures. Overall, these findings provide quantitative insights into the relative risks of different blue dyes and injection techniques used in SLNB, which may aid in risk assessment and clinical decision-making. [3]
Date for adverse reactions associated with isosulfan blue and methylene blue dyes during SLNB in breast cancer patients were compiled in a 2005 review, which investigated a total of 24 reports evaluating allergic and anaphylactic responses to these dyes. Isosulfan blue, a triphenylmethane-based compound traditionally used for SLNB, displayed an allergic reaction incidence of 1% to 3%, with severe reactions such as hypotension, angioedema, and cardiovascular collapse documented in multiple cases. These reactions necessitated immediate interventions, including epinephrine, corticosteroids, and fluid resuscitation. In contrast, methylene blue demonstrated comparable sentinel lymph node identification efficacy (93% versus 94% with isosulfan blue) but lacked reports of life-threatening allergic events. While methylene blue occasionally caused localized skin reactions such as erythema and superficial ulcerations, these were attributed to injection technique and were resolved with conservative management. Compared to the link of isosulfan blue to critical allergic incidents requiring prolonged hospital stays, methylene blue’s adverse effects were limited to transient, non-severe localized reactions, observed in one article which reported the injection of methylene blue intradermally rather than within breast parenchyma as intended. Additionally, a 2003 trial referenced within the analysis involving 112 patients receiving methylene blue for SLNB reported no allergic or systemic complications, further supporting previous studies citing methylene blue's efficacy in treating anaphylaxis and shock and emphasizing its safety profile. Based on these findings, methylene blue may be an equally effective, cost-efficient, and safer alternative to isosulfan blue for use in SLNB, particularly given its minimal risk of systemic allergic reactions. [4], [5]
A 2004 comparative case-control study evaluated the efficacy and safety of methylene blue dye versus isosulfan blue dye as tracers for sentinel lymph node biopsy in breast cancer patients. Among 164 cases, no significant differences were found in success rates (p= 0.22), number of sentinel nodes harvested (p= 0.46), concordance with radioactive nodes (p= 0.92), or incidence of metastases (p= 0.87). No adverse reactions were reported with either dye. The study concluded that methylene blue appears to be a reliable, safe, and cost-effective alternative to isosulfan blue for sentinel node mapping. [6]
In a 2008 letter to the editor, the authors discuss additional adverse events reported in literature caused by blue dyes when used in SLNB. A reported case from 2004 described capsular contraction as an adverse event linked to methylene blue dye administration following immediate reconstructive surgery for breast cancer. Conversely, isosulfan blue has been observed to alter oxygen saturation, specifically mimicking pulse oximeter desaturations due to alteration of light absorbency of the blood; fewer reports of oxygen saturation changes have been reported with methylene blue. The authors expressed a preference for methylene blue but emphasized cautious monitoring of oxygen saturation should blue dyes be used. [7], [8], [9]