The 2016 NCCN guidelines strongly recommended irradiation of the IMNs as part of the postoperative adjuvant radiotherapy for patients with 1-3 positive ALNs, following mastectomy and lumpectomy (category 2A). However, changes to the guidelines did not eliminate the controversies regarding irradiation of the internal mammary lymphatic chain. The reason was probably that the recurrence rate was only 2% according to clinical reports, and the irradiation dose of cardiopulmonary was increased by irradiation of the internal mammary lymphatic chain[14, 15]. In this study, we retrospectively examined data from 114 patients with local and/or regional lymph node recurrence without adjuvant radiotherapy. The recurrence rates with the chest wall, supraclavicular, and axillary lymph nodes were 43%, 22.8%, and 12.3%, respectively, which is consistent with the literature. However, the recurrence rate of IMNs was 37.7%, second to the recurrence of the chest wall, and higher than the recurrence rate with the supraclavicular region, in the present study. So the recurrence rate of IMNs was underestimated probably. The reason might be that IMNs tend to be small, with a diameter ranging from 2-5 mm. As a result, routine imaging examinations easily miss IMNs, whose short diameter in excess of 6 mm qualifies as metastasis, unless a huge mass is formed at a very late stage. In addition, IMNs recurrence rarely exists in isolation, often involving systemic metastases to the liver, lung, and other organs, while presenting without specific symptoms, leading physicians to focus on other recurrences. In this study, the patients enrolled didn’t undergo postoperative adjuvant radiotherapy owing to various reasons such as lack of indications of radiation therapy, poor economic conditions and so on, but most of the previous studies enrolled patients that underwent postoperative radiotherapy which may reduce the metastatic rate; secondly, the reason is perhaps that nearly 30% of the patients studied underwent PET-CT examination which could improve the detection rate of metastatic lymph nodes probably; and thirdly, in our opinion, the internal mammary lymph node region and the anterior mediastinal lymph node region can be seen as an entirety (the reason could be explained below), so when the metastasis of the anterior mediastinal lymph node occures, we think that the internal mammary lymph node has a very high probability of metastasis even if the short diameter is less than 6mm. In the present study, the recurrence rate of IMNs was very high, which is consistent with the pathologic results reported for extended mastectomy[11, 18]. It answers the clinical problem that a discrepancy between clinical and pathologic findings, which have confused us for many years, and suggests the necessity of irradiation of the internal mammary lymphatic chain. Overall, these findings indicate that IMNs should be included in the target volume, now that the supraclavicular lymph nodes need to be irradiated.
The IMNs receive lymphatic drainage from the medial and central parts of the breast and chest wall. The output tube is connected to the supraclavicular lymph nodes, leads to the anterior mediastinal lymph nodes, and enters the vein via the thoracic duct or the right lymphatic duct. Metastasis to the anterior mediastinal lymph node is not as rare as once thought. The anterior mediastinum is a stenotic region between the sternum, pericardium, and mediastinal pleura. Anatomically, the anterior mediastinal lymph nodes include the parasternal and anterior mediastinum group, while the parasternal group corresponds to the IMNs in breast cancer. The anterior mediastinum, which receives lymphatic drainage from the adjacent pleura, is not a region of high-risk lymph node metastasis even in lung cancer, except when there is pleural involvement or reflux of the enlarged mediastinal lymph node is formed. Anatomically, the anterior mediastinal metastatic lymph nodes should be derived from the internal mammary lymphatic chain, excluding widely lung or pleural metastases. Based on these considerations, we propose a concept of the extensive internal mammary lymph node region, which captures the internal mammary lymphatic chain and anterior mediastinal lymph node area (mainly region 3A and 6). While metastatic IMNs might be easily missed at routine imaging examinations, metastatic anterior mediastinal lymph nodes are larger and easier to identify on enhanced CT images therefore reducing the risk metastases being missed. Our results suggest that the metastatic rate to the anterior mediastinal lymph node is 50.9%. When the IMN and anterior mediastinum regions are combined, the recurrence rate increases to 59.6%. As such, we propose that irradiation of the internal mammary lymphatic chain is an indispensable part of adjuvant radiotherapy for breast cancer patients treated with surgery. This proposal is consistent with the NCCN guidelines.
Traditionally, the internal mammary lymphatic chain has been defined as the region between the first and third intercostal space; however, metastatic lymph nodes could also be observed above the upper edge of the first rib. The internal mammary artery originates from the lower wall of the first segment of the subclavian artery, 1-2 cm down the lateral side of the sternum, divided into 2 branches (the superior epigastric and musculophrenic artery) until the sixth intercostal space, and accompanied by two veins. In our opinion, the internal mammary lymph node is consistent with the medial supraclavicular lymph node, once the metastases of the IMNs happened, it is easy to metastases to the medial supraclavicular region, so this is why we suggested that the upper bound of the internal mammary lymphatic chain should be up to the subclavian vein with 5mm margin, which is connected to the caudal board of the supraclavicular CTV in breast cancer patients with high risk of recurrence.
Veronesi et al. performed a follow-up study of 737 patients who had not undergone adjuvant radiotherapy and systemic therapy after radical mastectomy for thirty years. The prognosis for patients with IMNs metastases was similar to the prognosis of patients with ALNs metastases, with the 10-year disease-free survival at 59.6% and 62.4%, respectively. And both of IMNs and ALNs metastases having the worst prognosis, the 10-year disease-free survival was 37.3%. Once IMNs recurred, according to the poor prognosis of the follow-up of 6,000 breast cancer patients, IMN metastasis may indicate distant metastasis. In a separate study from 2009, Heuts et al. reported that, during a 46-month follow-up of 764 patients, the prognosis for patients with IMN metastasis was similar to the prognosis of patients with ALN metastasis, which improved due to better understanding of IMN metastasis. In the present retrospective study, 36 patients had both IMNs and distant metastases. This is likely because the output tube of IMN is located in the supraclavicular and anterior mediastinum region, entering the superior vena cava through the left and right jugular veins, thus increasing the risk of widely systemic metastases. Moreover, the metastatic rate of the extensive internal mammary lymph node exceeded 41.2%, regardless of the tumor location, molecular subtype, or tumor stage. IMNs cannot be removed during radical surgery or modified during radical mastectomy due to the abandon of the extended radical resection. As a result, active irradiation of the internal mammary lymphatic chain may reduce the risk of metastasis and recurrence of IMN, and improve the prognosis for breast cancer patients. Nevertheless, positive systemic therapy retains its important role in breast cancer treatment.
Irradiation of IMNs is problematic because it might increase the cardiac dose, as well as the risk of morbidity and mortality. Recent advances in radiotherapy technology include sophisticated imaging integrated into planning systems with techniques that shield the heart or involve deep inspiration breath holding. Such approaches allow shaping or sculpting radiation doses to suit complex cancer volumes, while reducing treatment time to protect healthy organs. These advances have the potential to further increase the added beneﬁt of radiotherapy beyond surgery and systemic therapy, increasing survival rates.