1. 徐慧萍1 羅竹君1,2 郭耀隆1 李國鼎1 國立成功大學醫學院附設醫院外科部1 國立成功大學醫學院臨床醫學研究所2
Predictors for False-Negative Frozen Section of Sentinel Lymph Node Biopsy in Breast Cancer Patients
徐慧萍1 羅竹君1,2 郭耀隆1 李國鼎1
國立成功大學醫學院附設醫院外科部1
國立成功大學醫學院臨床醫學研究所2

2. Background:
Sentinel lymph node biopsy (SLNB) is an surgical technique to avoid morbidity after axillary lymph node dissection.
The patients with advanced tumor stage tend to have axillary lymph node metastases.
Intraoperative frozen section help to identify metastasis in sentinel lymph nodes.
Ann Surg 2008;247:143.
Clin Breast Cancer 2013;13:140.

3. Nodal staging based on sentinel node biopsy may underestimate the extent of nodal disease.
Independent predictors of a false-negative frozen section of sentinel lymph nodes:
Invasive lobular carcinoma, lymphovascular invasion, poorly differentiated carcinoma, hormone receptor negative, multifocal tumors, or resected LN = 1.
Completing axillary lymph node dissection after sentinel lymph node biopsy in previous study:
Undiagnosed SLN metastases in 9 of 50 (18%) false-negative SLN and 12 of 107 (11%) true-negative SLN.
Clin Breast Cancer 2013;13:140.
Clin Breast Cancer 2014;14:280.
Br J Surg 2013;100:775.
Arch Surg 2010;145:161.

4. Aim of this study: Significance:
Identify specific characters of the patients tend to have false-negative sentinel lymph node in frozen section.
Long-term outcomes after second operation with axillary lymph node dissection.
Significance:
Avoid second operation in the patients with false-negative sentinel lymph node in frozen section.

5. Materials and Methods:
From 2005 to 2009, National Cheng Kung University Hospital.
Breast cancer patients with clinically node-negative disease underwent sentinel lymph node biopsy.
Preoperative injection with Tc-99m for lymphoscintigraphy and perioperative injection with methyl blue.
Surgical principles:
Positive frozen section of sentinel lymph nodes  converted to ALND immediately.
Negative frozen section of sentinel lymph nodes  wait for permanent pathological report  positive  secondary operation with ALND.

6. Research Protocol – Retrospective Chart Reviewing
Axillary lymph node dissection
Frozen section(+)
Clinical node-negative patients
Sentinel lymph node biopsy
FSLN: false-negative sentinel lymph node
Frozen section(-)
Permanent pathology
Negative
Positive
From 2005 ~ 2009
Match: age, diagnostic date, OP procedure.
Predictors: pathological factors, lumnial type.
Control
Case (FSLN)
3 : 1

7. Age, year, median (range) 47 (37-71) 48 (35-73) NS
Table 1(1). Demographics of patients with false-negative sentinel lymph nodes and control group. The patients in two groups have similar characteristics, except factors associated with lymph node metastases.
FSLN
Control
P-value
Patient, number
21 (25%)
63 (75%)
Age, year, median (range)
47 (37-71)
48 (35-73) NS
Histological type
IDC
20 (25%)
60 (75%)
ILC
1 (25%)
3 (75%)
Operative method
TM + SLNB
10 (32%)
21 (68%)
BCS + SLNB
11 (21%)
42 (79%)
Tumor stage T1
14 (24%)
45 (76%) T2
7 (28%)
18 (72%)
FSLN, false-negative sentinel lymph node; NS, non-significant.

8. Tumor size, cm, median (range) 1.8 (1.0-4.5) 1.6 (0.3-3.5) NS
Table 1(2). Demographics of patients with false-negative sentinel lymph nodes and control group. The patients in two groups have similar characteristics, except factors associated with lymph node metastases.
FSLN
Control
P-value
Patient, number
21 (25%)
63 (75%)
Tumor size, cm, median (range)
1.8 ( )
1.6 ( ) NS
Nuclear grade
(0.276)
Grade I
3 (13%)
20 (87%)
Grade II
8 (27%)
22 (73%)
Grade III
9 (31%)
20 (69%)
Extensive intraductal components
5 (20%)
20 (80%)
Positive resection margin
2 (33%)
4 (67%)
Nipple invasion
2 (100%)
FSLN, false-negative sentinel lymph node; NS, non-significant.

9. Table 2. Pathological factors in patients with false-negative sentinel lymph nodes and control group. The factors associated with lymph node metastases are distinct between two groups.
FSLN
Control
P-value
Patient, number
21 (25%)
63 (75%)
Lymph node metastasis
<0.001
Negative
63 (100%)
Positive
21 (100%)
Lymphatic tumor emboli
18 (67%)
9 (33%)
< 0.001
Resected lymph nodes
22 (9-39)
3 (1-13)
Positive lymph nodes
2 (1-7)
Nodal stage N0 N1
18 (100%) N2
3 (100%)
AJCC TNM Stage
Stage I
45 (100%)
Stage II
18 (50%)
Stage III
0 (100%)
FSLN, false-negative sentinel lymph node.

10. Table 3. IHC staining of hormone and Her-2/Neu receptors in patients with false-negative sentinel lymph nodes and control group. Intrinsic subtypes are not associated with false-negative results of frozen sections.
FSLN
Control
P-value
Patient, number
21 (25%)
63 (75%)
Estrogen receptor-positive
17 (26%)
49 (74%) NS
Progesterone receptor-positive
14 (29%)
34 (71%)
Her-2/Neu receptor-positive
2 (22%)
7 (78%)
IHC staining of Her-2/Neu
14 (26%)
41 (74%) 1+
5 (25%)
15 (75%) 2+
1 (20%)
4 (80%) 3+
1 (25%)
3 (75%)
Intrinsic subtypes
Luminal A
14 (30%)
32 (70%)
Luminal B without Her-2/Neu overexpression
2 (13%)
14 (87%)
Luminal B with Her-2/Neu overexpression
Her-2/Neu overexpression
Triple negative breast cancer
3 (23%)
10 (77%)
FSLN, false-negative sentinel lymph node; NS, non-significant.

11. Tumor size in breast echo 1.5 (1.0-2.9) n = 19 1.5 (0.7-3.2) n = 46 NS
Table 4. Preoperative assessment of patients with false-negative sentinel lymph nodes and control group. The patients in two groups have similar characteristics, except factors associated with lymph node metastases.
FSLN
Control
P-value
Patient, number
21 (25%)
63 (75%)
Tumor size in breast echo
1.5 ( )
n = 19
1.5 ( )
n = 46 NS
Tumor size in mammography
2.5 ( )
n = 18
2.0 ( )
n = 47
0.031
Sample size of core biopsy
1.0 ( )
n = 13
0.9 ( )
n = 44
Sentinel nodes for frozen section
2 (1-4)
2 (1-5)
Total resected sentinel nodes
3 (1-7)
2 (1-7)
(Some nodes were not sent for frozen section)
Lymphoscintigraphy detected nodes
1 (1-4)
1 (1-5)
FSLN, false-negative sentinel lymph node; NS, non-significant.

12. total sentinel nodes/lymphoscintigraphy detected nodes
Detected SN ratio =
total sentinel nodes/lymphoscintigraphy detected nodes
FSLN, false-negative sentinel lymph node; SN, sentinel lymph nodes.

13. Summary of Results:
The patients with FSLN tends to have higher nuclear grade and more lymphatic tumor emboli.
Expression of hormone receptor or intrinsic subtypes fails to predict FSLN.
These 21 cases received second operation with ALND. Two patients have residual metastasis in level I/II axillary lymph nodes and one in Rotter’s nodes.
Postoperative adjuvant therapy is followed by standard guideline.

14. Recurrence-free survival rate is similar between patients with FSLN and control patients.
FSLN, false-negative sentinel lymph node.

15. JAMA 2017; 318(10): 918.

16. Conclusion:
Predictors of false-negative sentinel lymph node in frozen section.
Larger tumor size in preoperative mammography.
Plenty of resected nodes with radioactivity during operation.
Higher nuclear grade.
Positive lymphatic tumor emboli.
Adjuvant therapy may replace ALND in those with FSLN.