Efficiency of imaging and frozen section in analysis of sentinel lymph node biopsy in early breast cancer

INTRODUCTION

Axillary lymph node dissection (ALND) has long been a cornerstone for determining the stage, prognosis, and appropriate treatment strategy in patients with invasive breast cancer. However, the management of axillary lymph nodes has evolved with the advent of lymphatic mapping, leading to the adoption of sentinel lymph node biopsy (SLNB) as the preferred method for axillary evaluation in early-stage, clinically node-negative breast cancer. SLNB is now considered the standard technique for detecting micro metastases and isolated tumor cells. The use of intra-operative frozen section analysis allows for rapid pathological assessment of the sentinel node, enabling immediate identification of metastatic disease and minimizing the likelihood of a second surgical intervention for axillary lymph node dissection.

When evaluating axillary lymph nodes in early breast cancer, multiple modalities such as positron emission tomography-computed tomography (PET/CT), ultrasonography (USG) of the axilla, and SLNB are employed, each offering distinct advantages. PET/CT is particularly effective at identifying larger metastatic deposits due to its high specificity, but its sensitivity is limited for smaller lesions. This suggests that PET/CT could be useful in selecting patients who may require closer assessment for micro metastasis during frozen section analysis. The present study aims to assess the effectiveness of a multimodal approach in detecting nodal metastases among breast cancer patients.

MATERIALS AND METHODS

Data collected from patients with breast cancer who underwent SLNB +/- ALND in our institution from JAN 2020 to December 2025. The patient group included early breast cancer with stage T1 or T2 and clinically node-negative. A total of 518 cases were identified. Patients with incomplete details and who underwent ALND based on the staging system were excluded.

For SLNB, patients underwent lymphoscintigraphy a day prior to surgery. The procedure includes injecting technetium 99(Tc) Sulphur colloid and blue patent dye in peri areolar region. During surgery, the sentinel lymph node is identified using a gamma probe, which shows the increased radioactivity. Nodes identified positively by the gamma probe or stained blue were excised and sent in a container as a fresh specimen without formalin.

Once received in the histopathology laboratory, the specimen is measured and sectioned. Excess fat should be removed as it may hinder the sectioning process. The largest node is measured, and the number of nodes is noted. The nodes are sectioned perpendicular to the long axis, and these Parallel sections are taken at every 2.0mm intervals before embedding all sections and proceeding for frozen section. This method helps us to locate the metastases more accurately, and the initial subcapsular invasions can be detected more accurately.

Definitions: Macro metastases are defined as tumor deposits larger than 2.0mm. Micro metastases are defined as tumor deposits larger than 0.2mm(more than 200 cancer cells) but no larger than 2.0mm. ITC(Isolated tumor cells) are defined as cell clusters or single cells less than 0.2mm.

After reporting, the nodes are removed from the cassettes and processed for regular histopathological workup. The frozen reports are compared with the final histopathology report.

We correlated the two results and analyzed for any upgrade or downgrade of the report. Upgrade results are those that showed negative nodes in frozen section, but ITC or micro metastasis in final histopathology examination (HPE); similarly, micro metastasis upgraded to macro metastasis, or negative nodes upgraded to macro metastases. The discordant nodes were then retrospectively reviewed with imaging findings and features on USG and PET imaging.

RESULTS

Intraoperative frozen section accurately identified 17% of patients with macro metastasis in their sentinel lymph node, allowing them to proceed immediately to ALND. None of the patients who had a false negative frozen section result required further intervention, as the majority were micro metastasis and isolated tumor cells, therefore would not have required further intervention. We were able to accurately identify 112 cases, of which 86 cases required ALND and proceeded further. Out of 512 cases, 406 cases were sentinel lymph nodes negative, and we were able to prevent ALND and lymphedema complications due to the procedure.

Discordance between the frozen report and the final histopathology report was found in 23 cases. Retrospectively , we did a PET CT and USG imaging of axilla correlation for false negative cases.

The results of USG axilla are as follows. Figure 1 shows no cortical thickening, Figure 2 shows eccentric cortical thickening, Figure 3 shows no cortical thickening, Figures 4 and 5 shows eccentric cortical thickening, Figures 6, 7, and 8 shows no cortical thickening, Figure 9 shows eccentric cortical thickening and Figure 10 shows no cortical cortical thickening. Patients with no cortical thickening did not undergo needle core biopsy and the seven patients with eccentric cortical thickening on USG underwent needle core biopsy. The HPE results of the needle core biopsy showed 2 metastatic carcinomatous deposit and 5 reactive hyperplasia. PET CT revealed fluoro deoxy glucose (FDG) uptake in 4 cases [Figure 11], faint uptake in 5 cases and 13 cases were non- FDG avid.

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Figure 1: A case of hormone-positive, HER2-negative early breast carcinomas. USG shows uniform cortical thickening. Needle core biopsy is not done. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 2: A case of hormone-positive, HER2-positive early breast carcinoma, adjuvant chemotherapy. USG shows eccentric cortical thickening pre-chemo. Needle core biopsy was done and proved metastatic. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 3: A case of hormone-positive, HER2-negative early breast carcinomas. USG shows uniform cortical thickening. Needle core biopsy is not done. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 4: A case of triple-negative early breast carcinoma. USG shows eccentric cortical thickening. Needle core biopsy is done and reported as reactive. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 5: A case of triple-negative early breast carcinoma. USG shows eccentric cortical thickening. Needle core biopsy is done and reported as reactive. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 6: A case of hormone-positive, HER2-negative early breast cancer. USG-Left axillary lymph node shows uniform cortical thickening. Needle core biopsy not done. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 7: A case of hormone-positive, HER2-negative early breast carcinomas. USG shows uniform cortical thickening. Needle core biopsy not done. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 8: A case of hormone-positive, HER2-negative early breast carcinomas. USG shows uniform cortical thickening. Needle core biopsy not done. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 9: A case of hormone-positive, HER2-negative early breast carcinomas. USG shows eccentric cortical thickening. Needle core biopsy has not been done since the patient was uncooperative. The final HPE turned out to be a micro metastasis, and further surgical management was not required. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography, HPE: Histopathology examination.

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Figure 10: A case of hormone-positive, HER2-negative early breast carcinomas. USG shows uniform cortical thickening. Needle core biopsy not done. HER2: Human epidermal growth factor receptor 2, USG: Ultrasonography.

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Figure 11: (a) Fused PET CT image. (b) ET image. FDG avid irregular malignant lesion (SUV max 4.7) in the right breast (large red circle in the right breast) with minimal eccentric cortical thickening of the right axillary lymph node( small red circle right breast) showing minimally increased metabolic activity (SUV max 2.1). PET CT: Positron emission tomography-computed tomography, ET: Emission tomography, FDG: Fluoro deoxy glucose,SUV: Standardized uptake value.

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DISCUSSION

Axillary lymph node involvement is one of the most significant prognostic factors in breast cancer. Traditionally, ALND has been the standard surgical approach for managing the axilla. However, this procedure is associated with complications such as lymphedema and prolonged hospitalization, which can result in long-term morbidity for patients. In recent years, SLNB, with or without subsequent axillary dissection, has become widely adopted. Studies have demonstrated that SLNB, particularly when guided by lymphoscintigraphy, can reliably identify metastatic lymph nodes intraoperatively. Furthermore, intraoperative frozen section analysis of sentinel lymph nodes helps avoid unnecessary ALND in node-negative patients and prevents the need for a second surgery in node-positive cases.

In our study, 17% of patients showed metastatic involvement of sentinel lymph nodes on frozen section and subsequently underwent axillary dissection. This approach allowed us to avoid ALND and its associated complications in the remaining patients. A total of 23 false-negative cases were identified, all of which consisted of micro metastases or isolated tumor cells. These cases were further evaluated in relation to imaging findings. Comparison with PET/CT and USG results showed that 9 of the 23 cases were FDG-avid, while 14 were not. Additionally, axillary ultrasound identified 7 lymph nodes with eccentric cortical thickening. These findings suggest that a subset of cases exhibited preoperative imaging features suspicious of metastasis, although core needle biopsy (CNB) was not performed.

Similarly, a study by Riedel et al.^[1] reported that while the addition of CNB to assess sonographically suspicious lymph nodes can improve specificity, reaching up to 100% in some cases, it does not significantly enhance sensitivity, as it applies only to patients with ultrasound-positive nodes. Another study by Mahipal et al.^[2] concluded that PET/CT cannot replace SLNB for staging axillary lymph node involvement. In our study, PET/CT and ultrasound findings were used to guide more detailed frozen section analysis by increasing sampling from suspicious nodes, thereby improving diagnostic accuracy.

Over the past decade, PET/CT has become more widely available and is commonly used to assess metastatic disease. Metastatic axillary lymph nodes in breast cancer often demonstrate uptake of 18F-FDG, suggesting a potential role for PET/CT as an alternative to SLNB.^[3] However, multiple studies have shown that PET/CT has limited sensitivity in detecting micro metastases and isolated tumor cells.^[4]

A review of the literature [Table 1]^[1,2,5-9] indicates that false-negative rates for frozen section analysis of sentinel lymph nodes range from 11% to 29% across different studies. In contrast, our study demonstrated a lower false-negative rate of 4%. This may be attributed to the setting up of our institution, which is a specialized referral-based, one-stop breast center, and the relatively large sample size of 518 cases included in the analysis.

In previous studies, only a single modality was used to evaluate metastatic lymph nodes, with outcomes assessed in terms of sensitivity, specificity, accuracy, and false-negative rates. In contrast, our study retrospectively analyzes a multimodal approach combining PET/CT, USG, and frozen-section analysis for the evaluation of sentinel lymph nodes. Our findings suggest that this combined approach can reduce false-negative rates. However, micro metastases and isolated tumour cells (ITCs) may still be missed even with multimodal assessment and are more reliably detected through standard histopathological examination by an experienced pathologist.

The main limitations of this study include a relatively small sample size and a short study duration. Additionally, not all patients could afford PET scans. As this is a referral center dealing exclusively with breast cases, the observed false-negative rate was 4%, which is lower compared to other studies. Further validation of these findings requires a longitudinal prospective study with a larger cohort.

SLNB is a technically demanding procedure that requires experienced surgeons, histotechnicians, and pathologists to achieve high sensitivity and specificity. Therefore, applying these findings to peripheral centers is feasible only where SLNB is routinely practiced. Moreover, it is essential for the pathologist to have comprehensive clinical information prior to evaluating sentinel lymph nodes. This should include the histological type and grade of the primary tumor, hormonal receptor status, ultrasound findings, PET/CT results, and details of any adjuvant therapy administered.

CONCLUSION

In early breast cancer, intraoperative frozen section assessment of the sentinel lymph node biopsy facilitates timely, efficient axillary staging with a high level of diagnostic accuracy. Every procedure has its own drawbacks. False negative results occur in this procedure, though less frequently. A multimodality approach will guide us in detecting these cases. In our study, PET/CT reports and USG imaging could detect an additional 9 cases as suspicious before surgery. The rest of the 14 cases were missed even in these investigations. Even then, with the help of these two investigations, the pathologists would be more cautious while examining during frozen sections, so that extra sections can be taken.