Japanese Journal of Clinical Oncology 31:1-6 (2001)
© 2001 Foundation for Promotion of Cancer Research
Comparison of Intraoperative Frozen Section Analysis of Sentinel Node with Preoperative Positron Emission Tomography in the Diagnosis of Axillary Lymph Node Status in Breast Cancer Patients
Departments of 1Surgery and 4Nuclear Medicine, Sungkyunkwan University, 2Samsung Medical Center, School of Medicine, Seoul National University Hospital and 3Chonbuk National University, Seoul, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Although axillary lymph node status is an important prognostic factor and axillary dissection is regarded as the gold standard for staging, it requires radical surgery which is accompanied by considerable postoperative problems such as lymphedema. This study was carried out to evaluate the diagnostic accuracy of preoperative positron emission tomography (PET) and intraoperative frozen biopsy of sentinel lymphadenectomy (SLND) in detecting axillary lymph node metastasis.
Methods: We studied 18 patients who had preoperative PET and SLND for breast cancer in the Department of Surgery at Samsung Medical Center. They all had preoperative PET with a radiolabeled glucose analogue ([18F]FDG) to visualize primary tumors and metastatic nodes. Isosulphan blue dye was used for intraoperative SLND. Frozen and permanent biopsies were then compared after full axillary dissection.
Results: In 18 cases, six had positive metastatic nodes in the permanent biopsy of full axillary dissection but were negative in three cases by preoperative PET. There was one false negative result by frozen biopsy of SLND which was later shown to be positive by permanent biopsy. The sensitivity and specificity of SLND and PET for detecting axillary node metastasis were 83, 100% and 50, 100%, respectively.
Conclusion: Although both methods are good for axillary nodal status, the intraoperative frozen biopsy result of SLND was superior to preoperative PET in our preliminary study.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The extent of axillary lymph node dissection (ALND) has become controversial because of breast conservative surgery and increased detection of breast cancer in the early stages (1–4). The significance of ALND is decreased by the following: (1) ALND does not affect survival rate, although axillary lymph node status is related to the determination of stage and adjuvant treatment method; (2) ALND is unnecessary because the rate of axillary lymph node metastasis occurs in 50% of all breast cancers; (3) adjuvant treatment is used more frequently; and (4) the complication rate of ALND is reported to be about 20% and lymphedema of the upper arm was observed in 2–27% of ALND patients (5,6). Many studies have attempted to determine the axillary lymph node status without ALND. The prognostic score was calculated by the size of the primary tumor (>2 cm), high-grade nuclear differentiation, expression of c-erb-B2 gene and expression of laminin receptor; the score was related to the survival rates but axillary lymph node status could not be accurately predicted (7).
The sentinel node is the first node draining lymph from a primary tumor. Recently, sentinel node lymphadenectomy (SLND) was introduced in melanoma and breast cancer studies to determine nodal status easily. SLND is a highly accurate, minimally invasive method to evaluate axillary lymph node involvement. Positron emission tomography (PET), by which the metabolic states of cancer cells are measured, was introduced and used to determine the stage of breast cancer. The advantage of PET is the ability to determine the malignancy and the activity of the tumor, but a decreased anatomical accuracy is a drawback.
The aim of this study was to investigate whether preoperative PET or intraoperative frozen biopsy analysis of SLND is a more accurate and useful indicator of axillary lymph node status. We compared the results of preoperative PET, the intraoperative frozen section results of SLND and the pathological stages of the permanent sections of the entire axillary node specimen.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
We reviewed 18 patients with breast cancer who underwent ALND. They were patients with clinically impalpable axillary node except one case which was only suspicious. All patients had received preoperative PET and had had successful intraoperative SLND for staging in the Department of Surgery at Samsung Medical Center from March 1996 to July 1998. The mean age was 44.7 years. Modified radical mastectomy was performed in 14 cases, and breast conservative surgery was performed in four cases. The clinical stages (according to AJCC, 5th ed.) were classified as stage I, T1N0 in five cases, stage IIA, T2N0 in six cases, stage IIB, T3N0 in four cases and stage III, T3N1 in one case, except two cases of DCIS in final pathology (Table 1).
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PET
The patients were kept in a fasting state for 12 h before checking PET. A PET Advance Scanner (General Electric, Milwaukee, WI) and a PET Tracer 200 cyclotron (General Electric, Uppsala, Sweden) were used for scanning and 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) synthesis. After transmission scanning for 20 min, 10 mCi of [18F]FDG were injected intravenously and then dynamic scanning was performed for 56 min and static scanning for 45 min. The acquired data were recombined into the image and the standardized uptake value (SUV) was calculated by computer. An SUV value >2.5 was considered as a malignancy. SUV was calculated as follows:
SUV = concentration in tissue (mCi/g)/injected dose (mCi)/body weight (g).
SLND Method
A 6 ml volume of mixed solution, made by mixing 50 mg of isosulfan blue with 5 ml of pure water, was injected into the breast parenchyme surrounding the primary tumor site and after 5 min an incision was made over the axillary area. The axillary area was then explored. Blue-stained lymphatics and lymph nodes were discovered and the most proximal lymph node was sent for a frozen section. Final permanent pathological reports of hematoxylin and eosin (H&E) stain of the sentinel lymph node and the non-sentinel axillary node specimens were compared.
Statistical Analysis
Statistical values were calculated as follows:
sensitivity = TP/TP + FN
specificity = TN/TN + FP
positive predictive value = TP/TP + FP
negative predictive value = TN/TN + FN
chance corrected agreement (kappa value) = Io – Ie/1 – Ie
where TP = true positive, TN = true negative, FP = false positive, FN = false negative, Io = overall percentage agreement and Ie = expected value on the basis of chance alone.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The preoperative serum glucose level of 18 patients was within normal limits. The operative procedures undertaken were modified radical mastectomy in 14 cases and breast conservative surgery in four cases, ALND was performed to Berg’s level III. The sizes of the tumors in pathology were Tis (in situ) two cases, T1 seven cases, T2 seven cases and T3 two cases according to the TNM classification. Axillary lymph node metastasis was present in six cases (Table 2). Primary tumor was found on PET in all cases (Figs 1 and 2). The average SUV value was 5.1 and axillary lymph nodes were discovered in three of six metastatic cases (50%) on PET. The mean size of positive nodes in PET was 1.3 cm. The size of the smallest node was 0.9 cm. The results of PET were as follows: sensitivity = 50% (3/6), specificity = 100% (12/12), agreement = 57%, positive predictive value = 100% (3/3) and negative predictive value = 80% (12/15).
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Even though the discovery rate of sentinel lymph nodes was 79.2% in our institute during the same duration (84 out of 106 cases) (Fig. 3), here we successfully found sentinel nodes in all 18 cases. The level of discovered sentinel nodes was level I in 17 cases and level II in one case. The mean number of sentinel nodes per patients was 1.2 (range 1–3). One case was not diagnosed as a positive node by frozen section intraoperatively, which had a metastatic deposit in the non-sentinel node with permanent histology postoperatively.
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There was no false-positive case. The results of frozen section analysis of SLND were as follows: sensitivity = 83% (5/6), specificity = 100% (12/12), agreement = 87%, positive predictive value = 100% (5/5) and negative predictive value = 92.3% (12/13) (Table 3). Out of 18 cases, six (33.3%) had axillary positive nodes in permanent H&E pathology.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Axillary lymph node status is the single most important prognostic variable regarding survival of breast cancer patients today. Physical examination and imaging studies such as ultrasound cannot accurately predict metastatic deposit of the axilla in breast cancer patients. Ultrasonography has been shown to be more sensitive than physical examination or mammography for the detection of positive axillary lymph nodes in women with breast cancer (8). The purposes of ALND in breast cancer were to determine the stage and prognosis, select adjuvant therapy such as radiotherapy, chemotherapy and hormonal therapy and remove regional metastatic tumor. Numerous modifications for ALND were attempted because ALND had no influence on the survival rate (2).
There are increased glycolysis and other metabolic rates in tumor tissues. Therefore, we may quantify the metabolic rates of tumors by PET scan images using substrate-tagged radioisotopes. The image is made by the accumulated FDG-6PO4 in tissues and metabolite of [18F]FDG. Its uptake in tumors is quantified by a dose uptake ratio (DUR) and a standardized uptake ratio (SUV). These give precise information on the tumor by checking the total amount of uptake and by observing the changes over time. Many authors have reported that an increased uptake of [18F]FDG in various malignant tumors including breast carcinoma was observed by PET (9–12). Nieweg et al. (13) detected a metastatic axillary node in five of 11 breast carcinoma patients with PET scanning. Adler et al. (14) reported the sensitivity and specificity of PET scanning in detection of metastatic nodes as 90% and 100%, respectively. Avril et al.’s data (15) showed a 79% and 96% rate in the study of 51 patients. Especially in 23 patients with tumor size >2 cm, the sensitivity and specificity were 94% and 100%, respectively. There were three false-negative cases and no false-positive cases in this study. The sensitivity and specificity were 50% and 100%, respectively.
The three cases of false negatives were as follows: PET scan was performed in one case after a neoadjuvant chemotherapy and chemotherapy might have had an effect on the decrease of metabolic activities in the nodes. A small-sized lesion <2 cm was found in two cases. Carter et al. (16) reported that the tumor size was closely related to the nodal metastasis and, as a result, a smaller tumor has a less metastatic rate and smaller number of metastatic nodes. Also, if the node is smaller than the resolution power of PET, it could not be identified by PET scan. This is meaningful in that there were no false positives and the specificity was 100%.
In another trial, the sentinel node biopsy method was applied with a less invasive technique to predict the nodal status. It is a method that can confirm the nodal metastasis found nearest to the node of the primary lesion by tracing the lymphatics draining from the lesion. It is more reasonable and selective than the random sampling method. Morton et al. (17) designed this method in 1992 to decide whether a lymphatic dissection has to be performed in stage I of malignant melanoma. They performed the procedure to pick up the stained node after injection of a vital dye into the primary lesion site. Then lymphatic dissection was performed in the cases that were confirmed to have metastasis by the stained node. The false-negative rate was <1% in this method. In 1994, Giuliano et al. applied this method to breast cancer treatment and reported good results that predicted nodal metastasis in 95.6% of cases (18). In addition, they applied immunohistochemical staining with anticytokeratin antibody to detect micrometastasis in the sentinel nodes. In this method, they found more cases of micrometastasis (19).
In our study, we confimed the efficacy of sentinel node biopsy in 18 cases of operable breast cancer patients. We also obtained good results even though the patient group was small. It was difficult to explain the compensatory effect of the two methods because the false-negative results in the two methods overlapped and the number of cases was small. However, PET scanning and the sentinel node biopsy method can predict the axillary nodal status in breast cancer. Therefore, we believe that a less extensive dissection of the axilla may replace the routine dissection method of axillary level I and II.
In summary, preoperative PET was performed preliminarily in 18 patients; primary tumor was discovered in all cases and false-negative cases of axillary lymph node were found in three instances, but no false-positive case was observed. A false-negative result for intraoperative frozen biopsy of SLND was obtained in one case but no false-positive case was observed. SLND and PET were good methods for predicting axillary lymph node metastasis with respect to sensitivity and specificity. However, intraoperative frozen biopsy of SLND is preferred for the following reasons:
1. the sensitivity of preoperative PET is lower than that of SLND;
2. the cost of PET is greater than that of SLND;
3. special staining for detection of micrometastasis is available in SLND. Our preliminary study suggests that intraoperative frozen section analysis of SLND is a better indicator of the extent of ALND than preoperative PET.
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FOOTNOTES |
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+ For reprints and all correspondence: Jung-Hyun Yang, Department of Surgery, Samsung Medical Center, 50 Ilwon-Dong, Kangnam-Ku, Seoul, 135–710 Korea. E-mail: jhyang@smc.samsung.co.kr
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Received September 22, 2000; accepted November 8, 2000.
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