The status of axillary lymph nodes is the most important prognostic factor in patients with early invasive breast cancer and may guide the need for systemic therapy and radiotherapy. long-term follow-up results from the NSABP B-32 trial have shown that further axillary lymph node dissection does not improve survival in patients with negative biopsies of anterior lymph nodes. In this group of patients, avoidance of axillary lymph node dissection has become the standard of care. Sentinel lymph node biopsy, which reduces many complications associated with axillary lymph node dissection and improves patients’ quality of life, has a tendency to gradually replace conventional axillary lymph node dissection in the assessment of axillary lymph node status as technology advances and develops.
I. Number of anterior lymph nodes and techniques and methods of detection
The anterior lymph nodes are the first lymph nodes to receive lymphatic drainage from the tumor bed, which can be one or several. It was found that the false-negative rate in the axilla is high when only one anterior lymph node is removed during biopsy, and 98-99% of axillary lymph node metastases can be detected when 3-4 nodes are taken, while getting more than 5 lymph nodes does not further reduce the false-negative rate, but increases the risk of surgical complications. Therefore, the ideal number of biopsies is 3-4.
It is now accepted that the combined application of the nuclide tracer method and the blue dye method is superior to either one of them alone. Most studies have concluded that the former is more efficient than the latter when applied to the detection of anterior lymph nodes. To ensure that the sentinel lymph nodes are visualized in a short time and can be sustained for a longer period of time for detection, the optimal size of the nuclide colloid particles is 100C200 nm.
It is generally accepted that combined superficial (subcutaneous, subareolar or periareolar) injection of blue dye and deep (perineural) injection of nuclide tracer may be the best method for sentinel lymph node biopsy. The former is simple and easy to perform, with a high detection rate of sentinel lymph nodes and less interference with lymphography, especially when the tumor is located in the outer upper quadrant, while the latter has special application for lymph node visualization outside the axilla, including the internal breast lymph nodes.
Indications for sentinel lymph node biopsy
1.Positive clinical examination
In the early years of sentinel lymph node biopsy practice, clinically palpable axillary lymph node enlargement was once considered inappropriate for further sentinel lymph node biopsy. However, since the 2010 NCCN guidelines, this is no longer considered a contraindication. This is because the inconsistency rate between lymph nodes palpable on clinical physical examination and positive pathological findings can be as high as 41% [5]. The assessment of the clinical physical examination should not be used as a criterion for suitability for anterior lymph node biopsy. Unless cytologic or histologic puncture performed under imaging guidance confirms the presence of axillary lymph node metastasis, the opportunity for sentinel lymph node biopsy should not be easily passed up.
2.After preoperative neoadjuvant chemotherapy
For locally advanced breast cancer, neoadjuvant chemotherapy can reduce the tumor stage and decrease the number of positive axillary lymph nodes, and is increasingly used in operable breast cancer. Studies have shown that chemotherapy can change the axillary lymph nodes from positive to negative in nearly 1/3 of patients. Are patients with non-palpable axillary lymph nodes after chemotherapy suitable for anterior lymph node biopsy? There have been concerns about whether chemotherapy changes the drainage of axillary lymph nodes, resulting in a decrease in the detection rate of anterior lymph nodes and an increase in the false-negative rate. It has indeed been confirmed that positive axillary lymph node status prior to chemotherapy is a major factor affecting the accuracy of sentinel lymph node biopsy, but tumor responsiveness to chemotherapy does not correlate with the false-negative rate of sentinel lymph node biopsy.
A meta-analysis showed that after preoperative chemotherapy, the accuracy and false-negative rates of sentinel lymph node biopsy were close to those of those without chemotherapy, with more satisfactory results. kelly et al. retrospectively analyzed 24 sentinel lymph node biopsy biopsy studies that included 1799 patients on neoadjuvant chemotherapy, in which lymph node involvement was found in 37% of patients. With an overall sentinel lymph node biopsy detection rate of 89.6% and a false-negative rate of 8.4%, it is believed that money less lymph node biopsy is still of clinical value in patients undergoing neoadjuvant chemotherapy. However, there is still some controversy about this area. The goal of the ongoing large-scale prospective ACOSOG Z1071 trial is to evaluate the use of anterior lymph node biopsy in patients beyond neoadjuvant chemotherapy.
3. Multifocal and multicentric lesions
A multifocal or multicentric lesion is called a multifocal or multicentric lesion if it is located more than 2 cm apart in the same quadrant of the breast or in different quadrants [8]. It was once thought that in such cases, true sentinel lymph nodes are difficult to detect, and even if the biopsy result of the sentinel lymph node is negative, the possibility of positive draining lymph nodes from other areas of the breast cannot be excluded. It is now well recognized that the breast as a whole organ has lymphatic fluid draining to only a few specific lymph nodes in the axilla. In patients with multiple lesions, the rate of metastasis of the sentinel lymph nodes and the chance of obtaining non-sentinel lymph nodes on biopsy are higher, but the overall detection and accuracy rates do not differ compared to patients with single lesion breast cancer. in a review of the literature by Mascaro Table et al, 11 clinical studies reported in the literature since 2001, in which a total of 698 patients with multiple breast cancers were biopsied for sentinel lymph nodes, were analyzed. The mean rate of sentinel lymph node detection was 95%, with more than half of the studies reporting a 100% detection rate, while all reported false-negative rates were less than 10% and a significant number of studies did not find the presence of false negatives.
4.Ductal carcinoma in situ (DCIS)
In clinical practice, it is not uncommon to see preoperative or intraoperative diagnosis of ductal carcinoma in situ and postoperative paraffin pathology report suggesting invasive carcinoma. A meta-analysis of 22 relevant studies found that 7.4% of patients with a preoperative diagnosis of DCIS had metastasis in the anterior sentinel lymph nodes, compared with 3.7% of patients with a postoperative diagnosis of DCIS. Given the potential benefit to DCIS patients, it is currently recommended that patients with DCIS who have high-risk factors such as extensive lesions, high histologic grade, and are ready for mastectomy or primary reconstruction undergo sentinel lymph node biopsy in order to reduce the potential threat posed by underestimation of the disease.
5.Male breast cancer
Male breast cancer patients account for about 1% of all breast cancer cases. The use of sentinel lymph node biopsy in male breast cancer patients has achieved good results similar to those in female patients, with a success rate of detection between 97% and 100%. Because of the relatively advanced stage of disease in male patients, the chance of detecting positive sentinel lymph nodes is relatively increased. The Memorial Sloan-Kettering Cancer Center [13] reported a 10-year experience of 78 male breast cancer patients who underwent sentinel lymph node biopsy, with an accuracy rate of 97%. Of these patients, 51% had negative sentinel lymph nodes, thus avoiding axillary lymph node dissection. At a median follow-up of 28 months, there was no case of breast cancer recurrence due to axillary lymph node metastasis.
6. Breast cancer in pregnancy
The dose of radionuclide 99u injected in the anterior lymph node biopsy is about 4% of the dose of a conventional bone scan, which is safe and effective as it has little effect on the fetus. Urine testing of the patient shows very low levels of radioactive material. Therefore, in patients with breast cancer in pregnancy, anterior lymph node biopsy should also not be easily abandoned and unnecessary axillary lymph node dissection should be added. However, the safety of blue dye tracer is not known due to its hypersensitivity reaction, so it should not be used in pregnant patients.
7. History of previous breast or axillary surgery
For patients who have undergone breast-cancer preserving surgery, breast augmentation or reduction surgery, and sentinel lymph node biopsy, it is technically feasible and effective to perform sentinel lymph node biopsy again. It is important to note that a history of previous sentinel lymph node biopsy biopsy can lead to lymphatic drainage to sites other than the ipsilateral axilla, such as the contralateral axilla, supraclavicular, internal breast, and interstitial pectoral muscles, thus requiring preoperative lymphatic imaging in this group of patients. Some studies have shown that patients with less than 10 lymph nodes removed during previous surgery have a higher success rate of re-biopsy.
Advances in pathological examination of sentinel lymph nodes in breast cancer
Since the number of lymph nodes obtained from sentinel lymph node biopsy is smaller, a more careful pathological examination can be performed. Breast pathology has evolved from dividing lymph nodes in two, to multi-layer sections spaced 2-3 mm apart, to serial sections of 200-500 um, and staining methods from simple HE staining to immunohistochemical staining (IHC) and even molecular level reverse transcription-polymerase chain reaction (RT-PCR) testing. The current consensus is at least multilayer sectioning + HE staining, and the NCCN 2011 guidelines for positive anterior lymph nodes are based on multilayer sectioning + HE staining. Routine use of IHC keratin staining to determine the presence or absence of metastases is not recommended and should only be used when HE staining is inconclusive.The results of the Z-0010 trial also suggest that sentinel lymph node metastases detected by IHC do not have prognostic predictive value.
A newly reported multicenter prospective study (MIMS trial), was the first to report the use of real-time quantitative RT-PCR in the detection of anterior lymph nodes. Seven genes (mam, mamB, PIP, CK19, muc1, PSE, CEA) were tested in 348 patients in the study with negative T1-T3 multilayer sections + HE-stained lymph nodes, of which 27% (n=94) had overexpression of the molecule, but none of the genes or combinations of genes had a predictive value for relapse.
IV. Treatment and prognosis of micro-metastases after anterior lymph node biopsy
In the 7th edition of AJCC pathological staging of breast cancer lymph nodes, micrometastases of less than 2 mm are classified as micrometastases (pN1mi) and isolated cell clusters (ITC, pN0[i+]). pN1mi refers to metastases with maximum diameter > 0.2 mm or metastatic cell count more than 200, while ITC refers to small metastatic clusters with diameter ≤ 0.2 mm and individual tissue cross-sectional cell count less than Small clusters of metastases with less than 200 cells in a single cross-section of tissue.
The prognostic significance of the presence of small metastases in the anterior lymph nodes, the need for systemic therapy, including chemotherapy and endocrine therapy, and the need for axillary lymph node dissection have been controversial.
The results of a Dutch retrospective study (MIRROR trial) affirm the significance of micrometastases as well as ITC. In the study, 1032 patients with micro-metastases and 819 patients with positive lymph nodes with ITC were divided into two groups receiving adjuvant therapy (995 patients) and no adjuvant therapy (856 patients), respectively, and compared with patients in the group with negative lymph nodes and no adjuvant systemic therapy (856 patients). At a median follow-up of 5.1 years, the results showed no difference in disease-free survival (DFS) between the micrometastasis and ITC groups for patients who did not receive adjuvant systemic therapy, but both were significantly lower than the lymph node-negative group. In contrast, for patients with lymph node micrometastases or ITC, the DFS was significantly better in the group receiving adjuvant therapy than in the group not receiving adjuvant therapy. This led to the conclusion that micrometastases have prognostic value and that adjuvant systemic therapy significantly improves patient prognosis.
However, a recent study with a large sample found that even after excluding adjuvant therapy, micrometastases in the sentinel lymph nodes had no effect on the overall survival (OS) of patients.
V. Discussion of the need for axillary lymph node dissection in light of the different results of sentinel lymph node biopsy
It is now well established that removal of axillary lymph nodes in patients with negative sentinel lymph node biopsies does not provide a survival benefit. So, is axillary lymph node dissection necessary in all patients with positive sentinel lymph node biopsy results, especially in patients with micro-metastases? This question has been studied at a number of institutions and it has been concluded that not dissecting the axillary lymph nodes does not increase the risk of local recurrence. These include both large or long follow-up retrospective analyses and small prospective clinical trials.
Some of the non-randomized controlled retrospective studies have chosen not to perform further axillary lymph node dissection for relatively low risk of residual axillary tumors or because no intraoperative metastases were found, and usually radiotherapy is deliberately dosed or expanded to cover the area of the lymph nodes.
It has also been suggested that the significantly lower than expected rate of local recurrence is due to the small number of residual tumor cells in the axilla that can be eliminated by subsequent systemic therapy or radiotherapy.Karl Y et al. performed a retrospective analysis of clinical bulk cases and found that 20.8% of the 97314 patients with positive anterior lymph node biopsies did not undergo axillary lymph node dissection. Of the 79.2% of patients who underwent axillary lymph node dissection, those with minimal axillary lymph node metastases did not benefit from it.
In 2010, ASCO published the results of the Z-0011 trial with 6.2 years of follow-up, suggesting that axillary lymph node dissection also did not improve outcomes in patients with 1-2 large metastases in the anterior lymph nodes. However, selective physician bias (preferring to have patients undergo axillary lymph node dissection) caused the clinical trial to be closed early due to slow patient enrollment, and the results were not sufficiently convincing.
The prospective AMAROS trial currently being conducted by EORTCG enrolls patients with masses between 0.5 and 3.0 cm and negative clinical lymph nodes and positive anterior lymph nodes. The aim is to compare the treatment effect of lymph node dissection with radiotherapy to determine whether radiotherapy can replace axillary lymph node dissection in this group of patients.
However, the results of the retrospective MIRROR trial showed that the absence of axillary lymph node dissection in patients with micrometastases in the anterior lymph nodes significantly increased the 5-year recurrence rate in the axilla (6.2 vs. 1.2%, risk index 4.45; 95% confidence interval 1.46C13.54).
One of the larger prospective trials, Trial IBCSG-23-01, is also underway [26]. to understand the impact of axillary lymph node dissection or not on survival in patients with microscopic metastases in the presence of anterior lymph nodes.
VI. Predictive model for non-sentinel lymph node status
The analysis revealed that about half of the patients with macrometastases (metastases in the anterior lymph nodes) had metastases in non-sentinel lymph nodes, while those with micrometastases in the anterior lymph nodes or ITC had about 20% and 12% odds of having metastases in non-sentinel lymph nodes, respectively.
This shows that a significant number of patients no longer have tumor remnants in the axilla after performing sentinel lymph node biopsy. How to accurately identify these patients and thus avoid unnecessary axillary lymph node dissection has become an important issue.
In addition to the existing clinical models to assess the status of the patient’s sentinel lymph nodes in conjunction with imaging, there are also many models dedicated to predicting the presence or absence of tumor involvement in non-sentinel lymph nodes based on the known metastatic status of the sentinel lymph nodes. The main relevant factors known include the size of metastatic lesions in the sentinel lymph nodes and the presence or absence of tumor vascular infiltration. Among them, the MSKCC model (www.mskcc.org/nomograms ) and Stanford model are commonly used. as well as prediction models specifically for micro-metastases in the sentinel lymph nodes, etc.
New prediction models are still being developed. They provide a useful reference for assessing the risk of remaining axillary lymph node metastases after sentinel lymph node biopsy, but are limited in their sensitivity and specificity and do not determine which patients can avoid axillary lymph node dissection.