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10.1245/ASO.2003.04.023
Annals of Surgical Oncology 10:1166-1170 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Touch Preparation or Frozen Section for Intraoperative Detection of Sentinel Lymph Node Metastases From Breast Cancer

Tehillah S. Menes, MD, Paul Ian Tartter, MD, FACS, Howard Mizrachi, MD, Sharon Rosenbaum Smith, MD, FACS and Alison Estabrook, MD, FACS

From the Departments of Surgery (TSM, PIT, SRS, AE) and Pathology (HM), St. Luke’s-Roosevelt Hospital Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Paul Ian Tartter, MD, FACS, Comprehensive Breast Center, 425 West 59th Street, New York, NY 10019; Fax: 212-523-7012; E-mail: paul_tartter{at}slrhc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The preferred technique for intraoperative evaluation of the sentinel lymph node has not been determined. The purpose of this study was to compare the sensitivity and accuracy of intraoperative evaluation of the sentinel lymph node by touch preparation cytology and frozen section.

Methods: A total of 117 patients with clinically node-negative breast cancer or ductal carcinoma-in-situ undergoing sentinel lymph node biopsy had intraoperative evaluation of the sentinel node by touch preparation, frozen section, or both. The results of the intraoperative evaluation were compared with the final histological results of hematoxylin and eosin (H&E) paraffin section and immunohistochemistry (IHC).

Results: Twenty-six (57%) of the 46 patients with nodal involvement had metastases detected during surgery. The sensitivity of touch preparation for detecting macrometastases was 78%; for detecting all H&E metastases, including micrometastases, was 57%; and for detecting all metastases, including those seen on IHC, was 40%. The sensitivity of frozen section for detecting macrometastases was 83%; for detecting all H&E metastases, including micrometastases, was 78%; and for detecting all metastases, including those seen on IHC, was 64%. Both have a low sensitivity for micrometastases seen by H&E paraffin section: 57% and 78%, respectively. Neither detected micrometastases diagnosed by IHC only.

Conclusions: Both touch preparation and frozen section seem to be accurate in detecting macrometastases, but not micrometastases. Intraoperative evaluation of the sentinel lymph node by touch preparation allows for a quick evaluation of the node without wasting significant tissue and without detecting occult microscopic metastases, which may be beneficial because the clinical importance of these has yet to be elucidated.

Key Words: Sentinel lymph node • Breast cancer • Touch preparation cytology • Frozen section


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel lymph node biopsy is gaining acceptance as the preferred procedure for the evaluation of axillary node status in breast cancer patients. Conventional axillary lymph node dissection provides precise staging with local disease control but carries a considerable morbidity, including pain, paresthesia, and lymphedema. Sentinel lymph node biopsy identifies patients who do not need axillary dissection, reducing morbidity in most patients with clinically node-negative breast cancer. Ideally, patients with metastases to the sentinel node can be identified during surgery and undergo completion axillary dissection without having to return to the operating room at a later date. Without intraoperative evaluation of the sentinel node, approximately 25% of patients will have to return to the operating room. This can be technically difficult in patients who have had mastectomy with immediate breast reconstruction at the time of sentinel node excision.

Frozen section and touch preparation are commonly used for intraoperative evaluation of the sentinel node. With frozen section, thin sections are cut from a frozen block of tissue and stained with hematoxylin and eosin (H&E). Frozen section is time consuming, creates artifacts due to freezing, and consumes a significant amount of tissue.1 With touch preparation cytology, the cut surfaces of the node are imprinted and fixed on a glass slide for cytological examination. This procedure takes less time than frozen section because there is no need to freeze the tissue, no freezing artifacts are created, and minimal amounts of the node are used.2 If one is to rely on touch preparation or frozen section when selecting candidates for immediate completion of axillary dissection, their accuracy must be compared with the standard method, which is H&E permanent paraffin sectioning of the specimen.

We conducted a retrospective study of all early-stage breast cancer patients who had a sentinel node biopsy, to determine whether touch preparation or frozen section was superior for detecting metastases to the sentinel node. These patients had sentinel node biopsy and intraoperative analysis of the node by touch preparation or frozen section. We examined the sensitivity and accuracy of these methods and calculated the rates of detection of micrometastases and immunohistochemistry (IHC)-detected micrometastases.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All patients at the Comprehensive Breast Center at St. Luke’s-Roosevelt Hospital Center and the Mount Sinai Medical Center in New York who were treated by one of the authors for clinically node-negative breast cancer from 1998 to September 2002 were candidates for sentinel node biopsy. During this period, more than 600 breast cancer patients had a sentinel node biopsy by using radioisotope, blue dye, or both to visualize the node. A total of 118 cases had intraoperative evaluation of the node by touch preparation, frozen section, or both, at the discretion of the pathologist. These constitute the study group. All the excised sentinel lymph nodes for each patient were considered as a unit, and calculations were performed per patient.

On the day before the sentinel node biopsy, .1 mL of 500-µCi unfiltered 99mTc-labeled sulfur colloid was injected intradermally over the tumor. If lymphoscintigraphy was performed on the day of the procedure, .1 mL of .2-µm-filtered 100-µCi technetium was used. The sentinel node was located by using a handheld gamma probe. The hot nodes were removed until ex vivo radioactivity level was 10:1 compared with the axillary background count. When blue dye (1% isosulfan blue; Lymphazurin; US Surgical Corp., Norwalk, CT) was used, 4 mL was injected peritumorally in the operating room. A sentinel node was defined as any blue-stained lymph node or a lymph node with a blue lymphatic leading to it. The number of sentinel nodes per patient ranged from 1 to 8 (median, 2; mean, 2.2).

The sentinel lymph nodes were sent fresh to pathology for evaluation. Frozen section, touch preparation cytology, or both were used for intraoperative evaluation of the sentinel nodes. Lymph nodes were bisected, and imprints were made of the cut surfaces. The imprints were then stained with either H&E or Diff-Quik (Richard-Allan Scientific, Kalamazoo, MI). Results were reported as positive or negative. A portion of the node was subject to frozen sectioning at the discretion of the pathologist. The sections were stained with H&E, and results were reported as positive or negative. The remaining samples of sentinel nodes and nonsentinel nodes were fixed in formaldehyde and processed to paraffin blocks, and 10 sections were taken from each embedded node. Another two paraffin sections were taken from the negative nodes and sent for IHC with epithelial membrane antigen and cytokeratin AE1/AE3.

Immediate completion axillary dissection was then performed according to the intraoperative results. Patients with metastases detected only on permanent section were taken back for completion of axillary dissection.

False-negative rates were calculated separately for macroscopic metastases, micrometastatic (<2 mm) metastases, and those that were diagnosed only by IHC. Sensitivity was calculated separately for touch preparation and frozen section. Accuracy was defined as the total number of cases in which the intraoperative result was concordant with the final permanent section result.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The 117 patients ranged in age from 22 to 81 years (average, 55 years). One patient had bilateral carcinomas. The majority (63%; n = 74) presented with palpable carcinomas, and 37% (n = 44) presented with mammographic or ultrasonographic findings. Sixty-nine (58%) had infiltrating ductal carcinoma, 25 (21%) had mixed infiltrating ductal and lobular carcinoma, 11 (9%) had infiltrating lobular carcinoma, 6 (5%) had colloid, 5 (4%) had ductal carcinoma-in-situ, 1 (1%) had tubulolobular carcinoma, and 1 (1%) had adenocystic carcinoma. The 113 invasive carcinomas ranged in size from 1 to 40 mm (mean, 17 mm). Ninety-two (78%) of the patients had breast-conservation surgery, and 26 (22%) had mastectomies. The sentinel node was found by technetium in 102 (86%) patients, by dye in 7 (6%) patients, and by both in 9 (8%) patients.

Seventy patients had intraoperative evaluation of their sentinel lymph node by touch preparation, and eight (11%) were positive (Table 1). Six negative touch preparation nodes were positive on H&E permanent section, and another six were positive by IHC only. Eleven of the 12 metastases missed by touch preparation were micrometastases: 4 were diagnosed by H&E and the other 6 by IHC. The sensitivity of touch preparation for detecting macrometastases was 78%; the sensitivity for detecting all H&E metastases, including micrometastases, was 57%; and the sensitivity for detecting all metastases, including those seen on IHC, was 40%. Touch preparation detected 1 of 11 micrometastases.


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  		TABLE 1. Mode of first detection of metastasis
 
Sixty-seven patients had intraoperative evaluation of their sentinel lymph node by frozen section, and 21 (31%) nodes were positive. Six frozen section–negative nodes were later found to be positive on H&E permanent section, and another six with negative nodes by frozen section and H&E were positive by IHC. Ten patients had micrometastases, and frozen section detected two of these. Eight of the 12 metastases missed by frozen section were micrometastases: 2 were detected by H&E permanent section and 6 by IHC. Frozen section did not detect four sentinel lymph nodes harboring macrometastases. In three of these six false negatives (two micrometastases and four macrometastases by H&E), the metastases were found in the half of the node that was not used for frozen section. The sensitivity of frozen section for detecting macrometastases was 83%; the sensitivity for detecting metastases seen by H&E permanent section was 78%; and the sensitivity for detecting all metastases, including those seen by IHC, was 64%. Frozen section did not detect any micrometastases seen by IHC only.

Twelve patients whose nodes were negative by intraoperative analysis (six frozen section and six touch preparation) had positive nodes by H&E. Eight additional patients were found to have a positive sentinel node on IHC after no tumor was found by H&E or frozen section. All of these were micrometastases. Four of these were described as having a small number of cells staining positive [probably consistent with isolated tumor cells, pN0(i+) in the new tumor, node, metastasis staging system]. Lobular histology was overrepresented in patients with false-negative intraoperative or permanent section results, and the sentinel node was more frequently found with dye, but these findings are not statistically significant.

Nineteen patients had both frozen section and touch preparation cytology performed on their sentinel lymph node. There was 100% consistency between the combined results and those of the permanent H&E sections.

Twenty-six (57%) of the 46 patients eventually proven to have nodal involvement had metastases detected in the sentinel node during surgery, and 25 had completion axillary dissection at that time. Another six were taken back at a later date for completion axillary dissection.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The value of intraoperative evaluation of the sentinel node is that it potentially reduces the number of patients who need to return to the operating room for completion axillary dissection. In our hands, intraoperative evaluation with touch preparation or frozen section was comparable. When nodal metastases are found with either method, the axillary dissection is completed under the same anesthesia, as occurred with 25 of our patients. Six patients with metastases missed by touch preparation or frozen section returned to the operating room at a later date for axillary dissection, and 14 patients with missed metastases received adjuvant therapy without the removal of additional nodes. The decision to return to the operating room was individualized. Generally, patients with micrometastases were not returned to the operating room unless finding additional positive nodes would influence the choice of adjuvant therapy.

The problem with both touch preparation and frozen section is that both methods miss approximately one third of patients found to have metastases by H&E or IHC. The sensitivity and false-negative rates of these methods for intraoperative evaluation of the sentinel nodes are dependent on numerous variables, which render published series incomparable. For example, some serially section nodes in 1- to 2-mm longitudinal slices and touch-prepare both sides of each slice,3 whereas others bisect nodes,4,5 serially section in 2- to 3-mm slices,6,7 or use a combination of methods.8 Serial sectioning invariably increases the sensitivity of touch preparation or frozen section over simply examining the cut sides of the bisected node.8 In addition, the rate of nodal positivity in published series is dependent on whether IHC is used on all negative nodes,3,5,9 used only selectively by the pathologist,1,10 or not used at all.4 Node positivity also depends on whether a few tumor cells detected by IHC alone are counted as metastases, whether micrometastases are counted as involved nodes or only metastases >2 mm, and whether patients with advanced cancers with palpable nodes or those who have received neoadjuvant therapy are included.10 Large numbers of patients with early breast cancers reduce the proportion of patients with nodal metastases detectable by any means and cause the specificity and accuracy to be high and the false-negative rate to be low. Because no two published series have comparable techniques, pathologists, and patients, comparison of specificities, sensitivities, and false-negative rates is meaningless.

However, it is clear from the published series that whatever method is used to evaluate the sentinel node during surgery, the more slices made and examined, the higher the yield. At one extreme is Motomura et al.,3 who reported a sensitivity of only 52% for frozen section of bisected nodes, and at the other extreme is Viale et al.,8 who obtained 96% sensitivity for frozen section by examining 15 sections of 4-µm-thick slices per node. Comparable results have been reported for serially sectioned sentinel nodes examined by touch preparation. Few institutions have the resources to examine these nodes so thoroughly while the patient is on the operating table.

The weakness of all intraoperative methods is micrometastases. Only 11% to 25% of micrometastases are detected by touch preparation5,9,10 and 23% to 82% by frozen section.8,11 The clinical significance of micrometastases is unresolved and outside the scope of this discussion, but if adjuvant systemic therapy is not being recommended for micrometastases, the issue is moot.

False-positive results from intraoperative evaluation of the sentinel node result in unnecessary axillary node dissections and potential medicolegal repercussions. This is far more problematic than false negatives. Although we had no false-positive results by frozen section or touch preparation, false positives have been reported. If any uncertainty about the status of the node exists, clinicians should defer to H&E and IHC.

Several of the published studies used touch preparation, frozen section, or both for examining the sentinel node. Henry-Tillman et al.1 and Motomura et al.3 both reported that touch preparation was superior in sensitivity to frozen section. In the study by Motomura et al.,3 multiple sections of the node were made, and all surfaces were imprinted for touch preparation, with one frozen section made of each node. Van Diest et al.12 found that frozen section was superior to touch preparation when all cut sections of serially sectioned nodes were subjected to both frozen section and touch preparation.

There seems to be a bias toward performing frozen section when metastases are suspected clinically and toward performing touch preparation when metastases are not suspected. In most studies, including ours, micrometastases were more frequent in nodes subjected to touch preparation, and the incidence of macrometastases was higher with frozen section.

It is impossible to determine from this study or any previous study whether touch preparation or frozen section is more sensitive, because no study has presented the results of both frozen section and touch preparation on the same lymph nodes. Because the sensitivity of touch preparation is comparable to that of frozen section and because touch preparation is more rapid and less expensive, uses less tissue, and does not create freezing artifacts, we conclude that touch preparation is the best available method for intraoperative evaluation of the sentinel node. Patients should be informed that despite negative intraoperative evaluation of the sentinel node, 10% and 20% will be found to have metastases on H&E or IHC.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the full-text version at www.annalssurgicaloncology.org. They are not available in the PDF version.

Supported by the Martin Feuer Education Fund.


   FOOTNOTES
 
Intraoperative evaluation of the sentinel node by touch preparation and frozen section was compared in 117 consecutive patients. Both methods accurately detected macrometastases, and neither detected micrometastases detected by immunohistochemistry.

Received for publication April 22, 2003. Accepted for publication August 18, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Henry-Tillman RS, Korourian S, Rubio IT, et al. Intraoperative touch preparation for sentinel lymph node biopsy: a 4-year experience. Ann Surg Oncol 2002; 9: 333–9.[Abstract/Free Full Text]
  2. Treseler PA, Tauchi PS. Pathologic analysis of the sentinel lymph node. Surg Clin North Am 2000; 80: 1695–719.[CrossRef][Medline]
  3. Motomura K, Inaji H, Komoike Y, et al. Intraoperative sentinel lymph node examination by imprint cytology and frozen sectioning during breast surgery. Br J Surg 2000; 87: 597–601.[CrossRef][Medline]
  4. Rubio IT, Korourian S, Cowan C, et al. Use of intraoperative diagnosis of sentinel lymph node metastases in breast cancer. Ann Surg Oncol 1998; 5: 689–94.[Abstract]
  5. Cserni G. The potential value of intraoperative imprint cytology of axillary sentinel lymph nodes in breast cancer patients. Am Surg 2001; 67: 86–91.[Medline]
  6. Turner RR, Hansen NM, Stern SL, Giuliano AE. Intraoperative examination of the sentinel lymph node for breast carcinoma staging. Am J Clin Pathol 1999; 112: 627–34.[Medline]
  7. Ku NNK. Pathologic examination of sentinel lymph nodes in breast cancer. Surg Oncol Clin North Am 1999; 8: 469–79.[Medline]
  8. Viale G, Bosari S, Mazzarol G, et al. Intraoperative examination of axillary sentinel lymph nodes in breast carcinoma patients. Cancer 1999; 85: 2433–8.[CrossRef][Medline]
  9. Llatjos M. Intraoperative assessment of sentinel lymph nodes in patients with breast carcinoma. Cancer Cytopathol 2002; 96: 150–6.
  10. Lee A. Intraoperative touch imprint of sentinel lymph nodes in breast carcinoma patients. Cancer Cytopathol 2002; 96: 225–31.
  11. Weiser MR, Montgomery LL, Susnik B, et al. Is routine intraoperative frozen-section examination of sentinel lymph nodes in breast cancer worthwhile? Ann Surg Oncol 2000; 7: 651–5.[Abstract]
  12. Van Diest PJ, Torrenga H, Borgstein PJ, et al. Reliability of intraoperative frozen section and imprint cytological investigation of sentinel lymph nodes in breast cancer. Histopathology 1999; 35: 14–8.[CrossRef][Medline]



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