The purpose of routine axillary lymph node dissection for breast cancer is to remove metastatic lymph nodes, determine the stage, estimate the prognosis, and develop a comprehensive treatment plan. In recent years, sentinel lymph node biopsy (SLNB) has become one of the hot topics of research because it can accurately assess the status of axillary lymph nodes, maximize the function of the affected upper limb, and improve the quality of life of patients.
How to improve the accuracy of SLN and reduce the incidence of false negatives is a question that researchers are constantly considering and exploring. The so-called SLN false negative refers to the case of negative SLN but positive axillary lymph nodes. The literature reports that the false-negative rate of the combined Melan and 99TC-SC tracer method ranges from 3.2% to 9.7%, and there are still aspects of SLNB technology that need to be explored and improved, such as false-negative SLN, SLN micrometastasis, internal breast sentinel lymph node metastasis, and the feasibility of SLNB after neoadjuvant chemotherapy.
I. Causes of SLN false negativity
1. Jumping axillary lymph node metastasis: axillary lymph node metastasis does not follow the conventional way from low to high, but there is no metastasis in the low lymph nodes, while the high lymph nodes appear metastasis first. Foreign literature reports that the incidence of axillary lymph node jumping metastasis is approximately between 3% and 4%.
False negative rate related to tumor size: the smaller the tumor, the smaller the chance of false negative rate, but the higher false negative rate of larger tumors is due to the longer growth time of the tumor, which increases the chance of metastasis of the tumor cells. In this way, false negatives may occur.
When the tumor is located in the outer upper quadrant, especially near the axilla, the radiation from the injection site will interfere with the detection of SLN in the axilla, and this interference can be avoided by changing to the method of subareolar injection.
4. False negative associated with the interval between injection of nuclide and surgery: it is generally recommended to inject the nuclide 2~6h before surgery, if the time is too short, the nuclide will not be well accumulated, and if the time is too long, the nuclide will decay, both of which are unfavorable to SLN detection.
5. False negative associated with pre-surgical biopsy or radiotherapy: Because surgery or radiotherapy can cause partial interruption of lymphatic drainage pathways and change the original state of lymphatic circulation, the SLN found is not the real SLN, resulting in false negative.
6. False negative associated with pathological examination: intraoperative freezing does not reveal micrometastatic lesions in SLN. Intraoperative freezing is recommended for interrupted serial sections at 250-500 μm intervals. In addition to routine HE staining, the detection rate of metastases will be further improved if immunohistochemistry is added. Some techniques for rapid intraoperative detection of micrometastases and ITC have become new hot topics of research, such as rapid immunohistochemistry, real-time RT-PCR or nucleic acid amplification, but the sensitivity and specificity of these new methods remain to be further observed.
There are objective and subjective reasons for false negatives in SLN, but as long as the indications are strictly mastered at the beginning, standard operating procedures are strictly followed, intraoperative care is carefully taken, and the pathological examination of SLN is strengthened, even if the false negative rate is higher at the beginning, after a period of practice, the false negative rate can definitely be reduced to an acceptable level.
Second, the problem of SLN micrometastasis
Wilkinson’s large sample study concluded that lymph node micrometastasis has no significant prognostic significance. Whether the presence of micrometastases and isolated tumor cells in axillary lymph nodes in breast cancer patients has an impact on patient prognosis remains controversial. CK19 is a monoclonal antibody against epithelial cells, a marker of epithelial cells, and is expressed only in normal breast cells and breast cancer cells, but not in lymphocytes, and therefore can be used as a marker of breast cancer for the detection of micrometastases. Therefore, it can be used as a marker of breast cancer for the detection of micrometastases. The GeneSearch, Osner technique is the most recently used technique for the detection of SLN micrometastases. In general, in clinical practice, axillary lymph node dissection is performed if intraoperative rapid pathology suggests the presence of SLN micrometastases.
III. Internal breast anterior lymph node metastasis
Although internal breast sentinel lymph node biopsy is not used as a standard treatment modality, its value in terms of breast cancer staging and high-risk group for adjuvant chemotherapy deserves further investigation. Deep injection of radiopharmaceuticals in the axillary and extra-axillary regions has achieved better SLN detection rates, especially in the detection of internal breast lymph nodes, which is an important method.
IV. Non-SLN related factors
When SLN is positive, about 35% to 67% of patients have axillary lymph node metastasis limited to SLN only, and this group of patients can still avoid axillary dissection. In addition to lymph node micrometastasis, the prognostic significance of some other tumor indicators may be more important, such as tumor size, grading, and microvascular infiltration. Some prognostic models such as computed graphs, scores, and split regression models have been used to predict NSN (non-sentinel lymph node) status in SN-positive patients.
V. Whether SLNB is performed in intraductal carcinoma
SLNB is not the standard treatment for intraductal carcinoma, and is only recommended when the primary foci of intraductal carcinoma are large, the pathological grade is high, the patient is young, and local infiltration is suspected; SLNB is not necessary for DIN (ductal intraepithelial neoplasia), but only when the primary foci are infiltrated or total mastectomy is performed.
Whether SLNB is feasible after neoadjuvant chemotherapy
Some studies have shown that neoadjuvant chemotherapy can convert 20% to 40% of patients with positive axillary lymph nodes to negative, and SLNB before neoadjuvant chemotherapy will cause these patients to receive ALND (axillary lymph node dissection), so they cannot benefit from the axillary descending stage of neoadjuvant chemotherapy; for patients with SLN metastasis only, SLNB before neoadjuvant chemotherapy and ALND after neoadjuvant chemotherapy will not be able to assess the patients’ axillary descent and benefit. In patients with clinically negative axillary lymph nodes, SLNB after neoadjuvant chemotherapy is an accurate technique to guide axillary management. For larger primary lesions and more advanced breast cancers, SLNB after neoadjuvant chemotherapy is not recommended because of the increased false-negative rate.
Although there is no standardized procedure for SLNB, some preliminary consensus has been reached: most investigators agree that the combination of nuclein and dye as tracers can achieve complementary effects, not only improving the detection rate of SLN but also reducing the false-negative rate; the site of tracer injection is still controversial, with intra-skin, subcutaneous and subareolar injections on the tumor surface only identifying SLN in the axilla; deep intra-glandular injections can identify SLN in the inner breast. Breast massage after tracer injection can facilitate rapid entry of the tracer into the interstitium and lymphatic vessels of the breast, which can help to detect SLN without increasing the chance of tumor dissemination; the timing of nuclear tracer injection can be 2-6 h before surgery, and dye injection is usually done 5 min before the skin incision; the average number of SLN in breast cancer is 2-3, and 15% of patients can have 4 or more. The average number of SLNs is 2 to 3, and 15% of patients may have 4 or more.