Internal Mammary Sentinel Lymph Node Biopsy in Clinically Axillary Lymph Node-Positive Breast Cancer: Diagnosis and Implications for Patient Management

The single-institution, prospective study was designed to determine the clinical relevance for IM-SLNB performed in clinically ALN-positive patients. The protocol and consent forms were approved by our Institutional Ethics Committee (No. SDTHEC20110324).

A total of 352 clinically ALN-positive patients were enrolled in this prospective study, among whom 171 received initial surgery and 181 received NST according to disease stage and patients’ preference. The clinicopathologic characteristics of these enrolled patients are presented in Table  1.

The IMLN is a common first-echelon nodal site for metastases and that IMLN metastasis is of prognostic significance in breast cancer. IMLN dissection was part of the standard surgical treatment in the 1950s and 1960s and is the main information source of IMLN metastasis to date. This radical surgical procedure was abandoned in the 1970s, because patient outcome studies showed that radical dissection did not improve survival at that time, when systemic therapy was not used. 10 For most breast cancer patients, improvement of systemic therapy has significantly decreased the risk of death from distant metastasis, after which the optimized local therapy could, eventually, contribute more to improving survival in the era of molecular subtypes guided adjuvant/neoadjuvant systemic therapy. Therefore, the diagnosis and management of IMLN have attracted more and more attention in recent years. 1, 2, 11

In recent years, the evidence supporting delivery of IMLN-RT in high-risk patients with IMLN metastasis is increasing, 12 ^– 14 and NCCN Breast Cancer Clinical Practice Guidelines updated in 2016 has raised the level of IMLN-RT recommendation, 15 IMLN-RT has attracted more and more attention to clinicians. With a median follow-up of 8.9 years, the DBCG-IMN ( N = 3089) result showed that IMLN-RT could significantly improve OS (75.9% vs. 72.2%, HR 0.82, 95% CI 0.72–0.94, P = 0.005), reduce the mortality rate (20.9% vs. 23.4%, HR 0.85, 95% CI 0.73–0.98, P = 0.03), and the distant recurrence risk (27.4% vs. 29.7%, HR 0.89, 95% CI 0.78–1.01, P = 0.07). 16 A meta-analysis of the three large clinical trials of EORTC 22922/10925 ( N = 4004), MA 20 ( N = 1832), and French trial ( N = 1334) showed that radiotherapy of internal mammary and inner supraclavicular area for high-risk breast cancer patients (ALN positive and/or tumor located in central/inner quadrant of breast) could significantly improve OS (HR 0.85, 95% CI 0.75–0.96) (absolute benefit was 1.6%, 1.6%, 3.3% respectively), DFS (HR 0.85, 95% CI 0.77–0.94) and DMFS (HR 0.82, 95% CI 0.73–0.92). 17 Subsequent to these results of the IMLN-RT trials, since 2016, NCCN Guidelines have updated recommendation of IMLN-RT for patients with ≥ 4 positive ALNs as category 1 and strongly consider IMLN-RT for patients with 1–3 positive ALNs (category 2A), both after mastectomy and lumpectomy. 15

However, controversies persist regarding recommendation of IMLN-RT in all patients at high-risk of IMLN metastasis (ALN positive and/or medial tumor) even if the NCCN guideline has upgraded its recommendation. Cong et al. reviewed the extended radical mastectomy data and showed that the IMLN metastasis rate was 9.2% (4.4–16.8%), 19.6% (18.8–6.7%), and 38.3% (36.8–46.2%) for patients with 0, 1 ~ 3, and ≥ 4 positive ALN, respectively. 18 Positive IMLN was found in approximately 9% patients with negative ALN and negative IMLN was found in approximately 60% of patients with ≥ 4 positive ALN. Therefore, current IMLN-RT indication (high-risk patients/no histopathological confirmation of IMLN) might result in over- and undertreatment, because high-risk does not represent IMLN metastasis and low-risk cannot exclude IMLN metastasis. Considering the short- and long-term cardiotoxicity of IMLN-RT, an effective and accurate method is needed to individualize the indication of IMLN-RT so that the benefit of IMLN-RT can be performed in patients with involvement of IMLN. 19, 20

Advances in sentinel lymph node biopsy of breast cancer enable IM-SLNB to provide a less invasive method for assessing IMLN than surgical dissection and may guide accurate nodal staging and individualized IMLN-RT. 9 Although the 2009 American Joint Committee on Cancer incorporated the IM-SLNB concept, routine performance of the IM-SLNB in breast cancer patients remains a subject of debate due to the low IMSLN visualization rate and unclear clinical relevance. On the one hand, the internal mammary hotspots were only detected in a small proportion of patients (visualization rate 15%; range 13–37%) with traditional radiotracer injection technique, which has been the restriction for the IM-SLNB to date. 6, 21 ^– 23 In our earlier study, we tried injecting radiotracer with a modified technique (periareolar intraparenchymal, high volume, and ultrasound guidance) and got a high IMSLN visualization rate at 71.1%, which laid a technical feasibility for the further study and clinical application of IM-SLNB. 9 On the other hand, previous studies of IM-SLNB showed that the IMSLN metastasis rate was only 8–15%, and most were accompanied by ALN metastasis. Only a small number of patients (2–8%) had positive IMSLN without ALN metastasis, which changed the lymph node staging from N0 to N + . 6, 21 ^– 23 Our center also reported a similar IMSLN metastasis rate of 8.1% in previous studies, of which five patients had lymph node staging changes from N0 to N + . 9 In summary, based on the previous IM-SLNB indications (only in clinically ALN-negative patients), the clinical benefit of IM-SLNB was greatly reduced because of the low IMSLN metastasis rate. Therefore, the indications of IM-SLNB needs to be reconsidered.

Based on the experience of A-SLNB, the indication of SLNB (both axilla and internal mammary) are defined as clinically ALN-negative patient, which is adequate for axillary staging. 26 However, the indication of IM-SLNB is still referred to axillary experience and is only performed in clinically ALN-negative patients, which is not adequate to current clinical practice. Actually, IMLN metastasis is mostly found concomitantly with ALN metastasis, Huang et al. retrospectively analyzed 2269 patients who received extended radical mastectomy and showed that the IMLN metastasis rate was 4.4%, 18.8%, 28.1%, and 41.5% for patients with 0, 1–3, 4–6, and ≥ 7 positive ALN, respectively. 7 Based on the association of IMLN and ALN metastases, we tried to perform initial surgical treatment including IM-SLNB in clinically ALN-positive breast cancer patients in this study and found that 39.8% patients had IMSLN metastasis, which lead to accurate nodal stage and individual therapeutic strategy.

For patients receiving NST, the definition of nodal pCR just included the evaluation of ALN. Because IMLN metastasis has similar prognostic importance as that of ALN, the lymphatic metastasis and downstage should involve not only ALN but also IMLN. The definition of nodal pCR would not be completed without the pathology status of IMLN. It is necessary to perform IM-SLNB after NST to make clear of the whole nodal staging, because there were still 13.3% of patients with IMSLN metastases after NST. In addition, the IMSLN visualization rate was different statistically between initial surgery group and NST group (71.9% vs. 33.1%), and we speculated that the difference might be caused by the effect of NST on the lymphatic drainage pattern. Kuerer et al. 24 reported that chemotherapy could alter the lymphatic drainage patterns by the shrinkage to and fibrosis of lymph vessels as well as by obstructing lymphatic channels with cellular material or tumor emboli. Li et al. 25 also found that the lymphatic density around the breast tumor reduced significantly after NST, whereas the density of lymphatic vessels in the breast tumor was not significantly changed. However, researches on internal mammary lymphatic pathways after NST were limited, whether lymphatic vessels that drained into the IMLN were affected by NST has not been confirmed.

Another goal of this study was to determine whether there were independent predictors for IMSLN metastasis. Previous studies of IM-SLNB have demonstrated that age, tumor size, and ALN status were associated with the risk of IMSLN metastasis. 6, 21 ^– 23 However, these studies did not add much to the existing literature of the pattern of IMLN involvement, especially, histological/molecular subtypes were not found to be independently significant. In recent years, biological markers have been playing an increasingly important role in breast cancer staging and treatment decisions, and the concept of prognostic stage has been recommended in AJCC 8th edition. It could be found in our study that 11 patients (22.4%) had prognostic stage I disease despite the presence of ALN and IMLN metastasis. Although different histological/molecular subtype means different tumor recurrence patterns for all breast cancer patients, no correlation between histological/molecular subtypes and IMSLN metastasis was observed in our study. We speculated that this result might be related to the limitation of enrollment population (all the patients was clinically ALN-positive). In these patients, the risk of IMLN metastasis was mostly due to the influence of positive ALN, whereas the influence of histological/molecular subtypes would be relatively weakened.

As a minimally invasive technique, we suggest that IM-SLNB should be routinely performed during mastectomy procedure, especially in clinically ALN-positive patients; and during lumpectomy procedure, because an additional 3-cm skin incision was required, IM-SLNB should be performed in clinically ALN-positive patients and selectively in clinically ALN-negative patients (IMLN high metastatic risk: positive ALN and medial tumor). These IM-SLNB indications above might help to make clear of the pathological nodal staging including both ALN and IMLN, improve the definition of nodal pCR, and potentially affect the therapeutic strategies. Our conclusion is driven by a growing understanding of individualized treatment strategies, which means that some patients will receive more locoregional therapy, whereas other females will receive less and still have very favorable results.

Finally, the deficiency of this study is to point out: in previous clinical practice of the axilla, a backup lymph node dissection had been performed before the clinical application to verify the accuracy of A-SLNB; the same goes for IM-SLNB: it also requires high level of validation study before clinical application in order to gain clinical acceptable accuracy and false-negative rates, which confirm that the IMSLN could accurately reflect the nodal status of internal mammary basin. Although the distribution of IMSLN in this study exactly coincides with the data of IMLN metastasis sites in previous extended radical mastectomy, a validation study involving IM-SLNB followed by IMLN dissection is still necessary for higher levels of evidence-based medicine. We are conducting a multi-center validation study, selecting ALN-positive breast cancer patients for IM-SLNB followed by 1–3 intercostal IMLN dissection, and current result (no public data) show that IMLN status could be evaluated accurately by IM-SLNB (false negative rate: 3.33%, 1/30). Furthermore, there are 41.4% (12/29) patients had additional, non-IMSLN metastasis in IMSLN-positive patients, hinting that IMLN-RT remained significant after the involved IMSLN was removed by IM-SLNB.