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Introduction
Breast cancer has reported an increasing incidence in the last decades, especially when it comes to the early stages of the disease, due to the wide implementation of the national screening programs, due to a higher adherence of women to these programs and due to the improvements reported in the field of imagistic methods such as ultrasound, tomosynthesis or magnetic resonance imaging(1,2). Therefore, attention was further focused on developing the concept of conservative surgery for both breast and axilla. While during the 19th century the most commonly performed surgical procedure were Halstead or Madden mastectomy, these procedures are now recognized as mutilating gestures and are exceptionally used(3-5). Therefore, they were further replaced by less radical procedures such as sectorectomies or quadranectomies. Thus, a de-escalation of the breast surgery occurred; meanwhile, a similar process was described in regard to the axillary approach, standard axillary lymph node dissection being de-escalated to sentinel lymph node identification(6-9). The method has been associated with significant improvement of the quality of life, leading to a diminished rate of postoperative complications such as wound dehiscence, infection or upper limb lymphedema. However, the initial sensitivity and specificity of the method were not as high as expected and, therefore, the attention was focused on other techniques with the aim of obtaining improved results(10).
The concept of dual method of sentinel node identification
In order to increase the chances to have a correct identification of the sentinel node, certain study groups proposed a double check of the identified node; thus, the initial method of sentinel node detection – via Technetium injection at the periareolar site followed by sentinel node identification in the same day or at 24 hours after injection – has been doubled checked by an intraoperative injection of another tracer. In this regard, the concept of a dual method of sentinel node identification developed; one of the first proposed dyes for sentinel node detection was represented by methylene blue(10). The method was associated with improved rates of lymph node detection, but also with increased risks of perioperative complications, such as cutaneous necrosis, that can significantly modify the postoperative outcome, especially in cases in which conservative breast surgery is performed. It should not be omitted the fact that in such cases methylene blue is injected in the periareolar area irrespective to the site of the tumor in order to identify the sentinel node.
Furthermore, if conservative breast surgery is planned and local complications such as skin necrosis occur after methylene blue injection, the aim of a good cosmetic result is entirely compromised. Consequently, the attention was focused on identifying other potential markers which could be injected in the periareolar area and which could provide an adequate detection of the sentinel without increasing the rates of development of local complications such as skin necrosis(11,12).
The rationale of indocyanine green injection for medical purposes
Indocyanine green was approved by the Food and Drug Administration in 1959 and has rapidly gained popularity, being used with multiple purposes. Initially used for the evaluation of hepatic, renal and cardiac functions, this molecule is now widely used for its optical properties in order to provide a real-time angiographic and/or lymphographic mapping of different regions(13). The optical properties are based on the capacity of indocyanine green to absorb between 600 nm and 900 nm, with a maximum in vivo absorption at 800 nm, and to emit fluorescence between 750 nm and 950 nm(14). Due to the fact that it presents a low degree of absorption, it is considered to have a low systemic toxicity and therefore can be widely administrated to different categories of patients, including pregnant women(15).
The rationale of indocyanine green injection for sentinel node excision
Also known as the first lymphatic node in which lymph from a certain region is drained, sentinel node seems to play a crucial role in establishing the further therapeutic strategy in different malignancies, such as breast cancer, digestive cancers or malignant melanoma. Once identified and excised, it is sent for histopathological analysis in order to establish the presence or absence of isolated tumoral cells, micrometastasis or macrometastasis; furthermore, according to the status of the sentinel node, the further therapeutic strategy remains to be established(16). Thus, a correct identification of this node is mandatory, a double check of this lymph node bringing more confidence in regard to the real stage of the disease. Due to the fast-learning curve, indocyanine green based lymphography has been widely implemented and became part of the therapeutic protocol for sentinel node identification. In this direction, the rates of unnecessary lymph node dissection decreased, conducting to a lower level of postoperative complications, such as upper limb lymphedema or chronic wound related issues(17).
The role of indocyanine green in avoiding unnecessary lymph node dissection in early-stage breast cancer patients
One of the first studies which came to demonstrate the effectiveness of indocyanine green injection for sentinel node detection, to validate the method and to investigate the possibility of avoiding the unnecessary lymph node dissection, was conducted by Chi et al., being published in 2013. The study included 22 patients with early-stage breast cancer – defined as less than 5 cm tumors and negative lymph nodes – who were submitted to sentinel lymph node detection by using indocyanine green and near infrared system of visualization. In all cases, at least one sentinel node was identified, the total number of retrieved nodes being of 59; furthermore, all cases were submitted to axillary lymph node detection, a total number of 361 lymph nodes being retrieved. The histopathological studies demonstrated that eight of the 59 retrieved sentinel nodes presented metastases and 27 of the non-sentinels retrieved nodes also showed the presence of metastatic deposits. Among these cases, there was a single case that presented metastatic deposits in the non-sentinel nodes, while the sentinel node was negative. Thus, the authors demonstrated that, by using this method, the detection rate of sentinel node reaches 100%, being therefore higher when compared to the one reported by the dual method (consisting of radioactive colloid and blue dye injection)(18,19).
Meanwhile, we should not omit the fact that indocyanine green does not only offer a very high rate of sentinel node detection rate, but also avoids the disadvantages related to radioisotope usage, such as radiation exposure, licensing, costs and special conditions of injection and detection(20).
Conclusions
Indocyanine green has proven its utility in order to provide a higher rate of sentinel node detection and to improve both oncological and cosmetic outcomes in early-stage breast cancer patients, decreasing in this way the rates of unnecessary lymph node dissection. Therefore, it seems to provide an efficient de-escalation of the axillary management from routine axillary lymph node detection to sentinel node identification and excision.
Conflicts of interests: The authors declare no conflict of interests.