Department of Breast Surgery, Cancer Institute Hospital, Tokyo, Japan
Department of Cytology, Cancer Institute Hospital, Tokyo, Japan
Department of Radiology, Cancer Institute Hospital, Tokyo, Japan
Abstract
Background
A standard intra-operative procedure for assessing sentinel lymph node metastasis in breast cancer patients has not yet been established.
Patients and methods
One hundred and thirty-eight patients with stage I breast cancer who underwent sentinel node biopsy using both imprint cytology and frozen section were analyzed.
Results
Seventeen of the 138 patients had sentinel node involvement. Results of imprint cytology included nine false negative cases (sensitivity, 47.1%). In contrast, only two cases of false negatives were found on frozen section (sensitivity, 88.2%). There were two false positive cases identified by imprint cytology (specificity, 98.3%). On the other hand, frozen section had 100% specificity.
Conclusion
These findings suggest that frozen section is superior to imprint cytology for the intra-operative determination of sentinel lymph node metastasis in stage I breast cancer patients.
Background
Sentinel node biopsy has become a common surgical procedure in the treatment of breast cancer.
Patients and methods
From April 2000 to September 2003, we performed sentinel node mapping (SNM) in 138 breast cancer patients. Candidates for SNM had to meet pre-specified criteria, which included: a tumor size less than 2 cm; a node-negative tumor based on palpation and ultrasonography, and no evidence of distant metastasis.
The technique of sentinel node biopsy has been described previously.
Sentinel nodes were evaluated by both imprint cytology and frozen section. In general, removed sentinel nodes were divided into three sections. Furthermore, we tried to section the tissue such that the sectioned plane was parallel to the plane in which the maximal section area could be obtained. When the sentinel lymph nodes were too small for trisection, they were bisected. The sectioned surface of the sentinel node was imprinted onto the surface of a slide, which was immediately immersed into a 90% alcohol solution. The slides were then stained using the Papanicolaou method. They were examined by specialized cytologists and cytopathologists. Next, the sectioned sentinel lymph nodes were sent to the laboratory, and frozen sections were made with the use of Coldtome (Sakura Fine Technical Co. Ltd., Tokyo Japan). Each frozen section was cut from one level and stained with hematoxylin and eosin (H&E). The frozen sections were studied intra-operatively by a trained pathologist. The remaining tissue specimen from the frozen section was thawed, fixed in formalin, and embedded in paraffin. This permanent specimen, stained with H & E, was sectioned from one level and was examined by a pathologist postoperatively. The final diagnosis of lymph node metastasis was based on histopathological evaluation. No immunohistological staining technique was used routinely.
Results
A total of 231 lymph nodes from 138 cases were evaluated by both imprint cytology and frozen section. Among these 138 patients, a total of 17 had axillary lymph node metastasis. The concordance between imprint cytology and the absolute diagnosis is shown in Table
Comparison between intraoperative imprint cytology and final histological diagnosis
Node-positive cases at final diagnosis
Node-negative cases at final diagnosis
Node-positive cases at final diagnosis
Node-negative cases at final diagnosis
Positive introperative imprint cytology
8
2
10
Negative introperative imprint cytology
9
119
128
17
121
Sensitivity
47.1%
Specificity
98.3%
Positive Predictive Value
80.0%
Negative Predictive Value
93.0%
The agreement between frozen section and final diagnosis is shown in Table
Comparison between intraoperative frozen section and final histological diagnosis
Node-positive cases at final diagnosis
Node-negative cases at final diagnosis
Positive in introperative frozen section
15
0
15
Negative in introperative frozen section
2
121
123
17
121
Sensitivity
88.2%
Specificity
100%
Positive Predictive Value
100%
Negative Predictive Value
98.4%
Discussion
Our study demonstrates that frozen section is superior to imprint cytology for the intra-operative diagnosis of sentinel node metastasis. Frozen section had a higher sensitivity than imprint cytology, while its high specificity was comparable to that of imprint cytology.
Several reports in the literature have compared frozen section with imprint cytology, and most of these reports have recommended imprint cytology for intra-operative sentinel lymph node determination.
Reported results of intraoperative imprint cytology and frozen section
imprint cytology
frozen section
number of cases
sensitivity
specificity
sensitivity
specificity
Present study
47.1
98.3
88.2
100
138
Leidenius et al. (2003)
68
99
83
99
375
Beach et al. (2003)
69
100
54
100
32
Liang et al. (2003)
62.5
100
62.5
100
20
Nagashima et al. (2003)
70.3
99.6
83.8
100
§ 303
Sauer et al. (2003)
58
100
77
100
§ 429
Motomura et al. (2000)
96
90.8
52
100
101
van Diest et al. (1999)
62
100
87
100
54
Fisher et al. (1993)
98
100
90.2
100
50
§ These numbers are based on the number of examnined lymph nodes
The characteristic feature of our study is that we compared imprint cytology and frozen section in an equal manner, because we studied the same sectioned surfaces using both methods. As a result, our data showed that the discrepancy in the sensitivities between these methods could be attributed mainly to sampling error associated with the imprint technique.
The evaluation of specificities in imprint cytology is also a complex issue. Generally, it is difficult to achieve a specificity of 100% using imprint cytology. There are at least two possible explanations for this difficulty. First, it is possible that benign specimens may be judged as containing malignant cells. In particular, the lobular type of breast cancer is believed to generate a false positive on imprint cytology due to the small and bland morphology of the cells. This means that some patients may undergo unnecessary axillary dissection. Unwarranted axillary clearance is clearly more problematic than a second operation for axillary dissection. The second reason is associated with micro-metastases. In cases of micro-metastases, it is possible that only imprint cytology can detect metastatic cells. However, when histopathological evaluation is required to define sentinel lymph node metastasis, the role of imprint cytology is limited.
For these reasons, we recommend frozen section rather than imprint cytology for the intra-operative diagnosis of sentinel lymph node metastasis.
We initially attempted to use imprint cytology as a modality complementary to frozen section for the intra-operative diagnosis of sentinel lymph node metastasis. Therefore, we used the Papanicolaou method for intra-operative cytological evaluation. Although this technique is time-consuming compared with other staining methods, we believe this procedure is greatly advantageous because it results in accurate evaluations.
The rate of positive sentinel node detection in patients with a sentinel node biopsy in our cohort is likely to be lower than that reported in other studies. The use of trisecting, which is nowadays inappropriate for the analysis of sentinel nodes, may be responsible for this result. However, we believe that ultrasonography, which was used in addition to physical examination to evaluate preoperative nodal status at our institution, contributed significantly to this consequence by allowing us to obtain more accurate nodal evaluations. The rate of positive sentinel node detection in patients who received a sentinel node biopsy should be low, because a high positive rate increases the possibility of missing axillary node metastases, both in sentinel and non-sentinel nodes. This, then, increases the likelihood of a subsequent salvage operation after swollen axillary lymph nodes become clinically apparent.
In the intra-operative diagnosis of lymph node metastasis, the management of micro-metastases is a difficult problem to solve.
Conclusion
This study demonstrates that frozen section is superior to imprint cytology for the intra-operative diagnosis of sentinel node metastasis with respect to both sensitivity and specificity. We currently recommend using frozen section rather than imprint cytology for detecting intra-operative lymph node metastasis.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
KT produced the study design, conducted literature searches and drafted the manuscript. MM analyzed all data and searched the literature. MI contributed to the cytological analysis. SN, KT, MM, TI and FK contributed to surgical interventions and collected patient data. MK contributed to the analysis of nuclear medicine and collected data. All authors read and approved the final manuscript