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10.1245/ASO.2005.03.067
Annals of Surgical Oncology 12:173-180 (2005)
© 2005 Society of Surgical Oncology
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Original Article

The Results of Frozen Section, Touch Preparation, and Cytological Smear Are Comparable for Intraoperative Examination of Sentinel Lymph Nodes: A Study in 133 Breast Cancer Patients

Edi Brogi, MD, PhD1, Elba Torres-Matundan, MD1, Lee K. Tan, MD1 and Hiram S. Cody, III, MD1

1 Department of Pathology, Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021

Correspondence: Address correspondence and reprint requests to: Edi Brogi, MD, PhD; E-mail: brogie{at}mskcc.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The goal of intraoperative sentinel lymph node (SLN) examination is to avoid reoperation for a positive SLN, but the ideal method of intraoperative SLN examination remains unclear, and published results vary widely.

Methods: We evaluated the sensitivity of intraoperative frozen section (FS), touch preparation (TP), and cytological smear (CS) in 305 SLNs from 133 breast cancer patients. Each SLN was received fresh and cut into 2- to 3-mm slices; TP and CS from each cut surface and an FS of the entire SLN were obtained. Postoperative evaluation of the SLN consisted of 1 hematoxylin and eosin–stained section and of one hematoxylin and eosin–stained and one immunohistochemically stained section for cytokeratin from each of two levels 50 µm apart. Tumor cells found by any method, including immunohistochemistry, identified a positive SLN. Three pathologists blinded to the final SLN diagnosis reviewed all TP, CS, and FS; the consensus diagnosis (concordance of two or more) was used for the study.

Results: FS, TP, and CS had comparable sensitivities (59%, 57%, and 59%, respectively). Each method was more sensitive in detecting macrometastases (> 2 mm; 96%, 93%, and 93%, respectively) than micrometastases (≤2 mm; 27%, 27%, and 30%, respectively). The combination of methods only marginally improved the intraoperative sensitivity. TP and CS were each responsible for a single false-positive result.

Conclusions: FS, TP, and CS are comparable for the intraoperative detection of SLN metastases, and each method is substantially better at detecting micrometastases than micrometastases. The combination of two or more techniques only marginally improves the sensitivity over that achieved by a single method.

Key Words: Imprint cytology • Micrometastases • Macrometastases • DCIS • Invasive breast carcinoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Since the initial reports by Krag et al.1 and Giuliano et al.,2 sentinel lymph node (SLN) biopsy has emerged as a new standard of care for axillary nodal staging in patients with breast cancer. Although an extensive literature has validated the SLN concept and resolved many technical issues,3 significant controversy still surrounds the role of intraoperative SLN examination. The outstanding advantage of intraoperative SLN evaluation is that SLN-positive patients can have an immediate axillary lymph node dissection and thereby avoid reoperation. The disadvantage of intraoperative examination is that it will fail to detect metastases in some patients who prove to be SLN positive as a result of postoperative evaluation of the SLN, thus necessitating reoperation. The reported sensitivity of each of the available methods—frozen section (FS), imprint cytology/touch preparation (TP), and cytological smear (CS)—varies widely, and the only two studies4,5 that have directly compared FS and TP reported contradictory results. Here we report the results of a prospective study of 133 SLN biopsy procedures in which we directly compared the sensitivity of intraoperative FS, TP, and CS, both alone and in combination.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Starting on July 1, 2002, and using our mature technique of SLN biopsy, previously described in detail,6 we performed intraoperative SLN examination in 133 consecutive patients with unilateral breast cancer according to a standardized protocol. Patients treated with preoperative chemotherapy were excluded from the study.

Fresh SLNs submitted for intraoperative examination were cut into 2- to 3-mm slices along the major axis. One study pathologist (E.T-M.) obtained one TP slide by pressing each cut surface of a lymph node against a clean glass slide and obtained two CSs by scraping each cut surface with a clean blade and smearing the material onto two clean slides. TP and CS slides were then fixed in 95% alcoholic formalin and stained with rapid hematoxylin and eosin (H&E). TP and CS slides were not reviewed during surgery. The SLN tissue was then entirely snap-frozen in liquid nitrogen, and a single 5-µm-thick H&E-stained FS was examined by the undesignated pathologist assigned to the FS desk for that day, and the result was reported during surgery. Large lymph nodes were entirely submitted in two tissue blocks, and we obtained one TP and two CSs corresponding to each frozen tissue block. The frozen SLN tissue was then fixed in formalin and routinely processed to obtain a single 5-µm-thick H&E-stained paraffin section (FS control). If no carcinoma was identified by this point, then two adjacent sections (one stained with H&E and one with an anticytokeratin immunohistochemistry [IHC] technique) were taken from the paraffin block at each of two levels 50 µm apart. One IHC section was stained with CAM 5.2 (Becton Dickinson Immunocytometry Systems, San Jose, CA) and the other with AE1:AE3 (Ventana Medical Systems Inc., Tucson, AZ). The SLN was considered positive if metastatic carcinoma was detected by any of these methods, and metastatic foci were characterized as macrometastases (>2 mm) or micrometastases (≤2 mm).

The three study pathologists (E.T-M., L.K.T., and E.B.) independently reviewed the TP and CS slides without knowledge of the intraoperative or final diagnoses. The slides were not screened by a cytotechnologist or marked for positive findings, and the time required for review of a case was not monitored. Cases were categorized as positive only on the basis of finding unequivocally malignant cells; cases with atypical or suspicious cells were considered negative. The diagnosis agreed on by two of the three study pathologists was that reported. We also compared the intraoperative FS diagnoses by the undesignated pathologists with those obtained on review by the study pathologists.

After collection of all the data was completed, two pathologists (E.T-M. and E.B.) reviewed the slides of all cases read as positive by any of the three methods to determine false-positive and false-negative rates. Finally, one pathologist (E.T-M.) reviewed each case to determine tumor size and type and nuclear grade.

Sensitivity was defined as (method-positive)/(SLN-positive), with SLN-positive defined as a SLN that was positive on final pathology by any method (FS, TP, CS, H&E, or IHC). Specificity was defined as (method-negative)/(method-negative) + (method false-positive), with false-positive results identified by the study pathologists on the basis of morphological discordance from the primary tumor (see Results). Both sensitivity and specificity were determined on a per-node (denominator = number of SLNs) and per-patient (denominator = number of patients) basis. A waiver of authorization for this study was issued by the Memorial Sloan-Kettering Cancer Center institutional review board.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Population
A total of 305 SLNs from 133 consecutive patients (mean age, 57 years; range, 20–91 years) were examined during a period of 3 months, for a mean number of 2.3 SLNs per patient (range, 1–7). A total of 121 patients (91%) had invasive cancers, with a mean size of 1.5 cm (range, .2–4.5 cm); 3 (2%) had ductal carcinoma-in-situ (DCIS) with microinvasion; and 9 (7%) had high-grade DCIS.

Patients With Positive SLNs
Positive SLNs were found in 50 patients (38%). At least one SLN macrometastasis was found in 25 SLN-positive patients (50%); micrometastases were detected by H&E in 21 (42%) and only by IHC in 4 (8%) patients. A single positive SLN was present in 41 patients (82%), 19 of whom had macrometastases. Two positive SLNs were present in seven patients (14%), four of whom had macrometastases. Three positive SLNs were present in two patients (4%), both of whom had macrometastases. Among SLN-positive patients, the mean tumor size was 1.7 cm (range, .3–4.5 cm), and the mean size of metastatic deposits was .45 cm (range, < .1–1.8 cm).

Results of FS
We evaluated 310 FSs obtained from 305 SLNs, including one FS from each of the 2 tissue blocks obtained from 5 large SLNs. A mean of 1.01 FSs per SLN were obtained (range, 1–2). The mean number of FSs per patient was 2.3 (range, 1–7). Initial evaluation by FS identified a positive SLN in 27 (54%) of 50 patients: 24 (96%) of 25 with macrometastases, 3 (14%) of 21 with H&E-detected micrometastases, and 0 of 4 with micrometastases detected only by IHC. On re-review of the FS slides, three additional positive SLNs were found; two contained micrometastases <.1 cm, and each was found in a case initially read as negative. One was found in a patient whose other SLN had initially been reported as positive. Therefore, the sensitivity of FS was increased by re-review from 54% (27 of 50) to 58% (29 of 50).

Results of TP
We evaluated 310 TPs obtained from 305 SLNs, including 2 TPs for each of the 5 large SLNs that were frozen in 2 tissue blocks. A mean of 1.01 TPs per SLN were obtained (range, 1–2). The mean number of FSs per patient was 2.3 (range, 1–7). The sensitivity of TP was comparable to that of FS (Table 1Go). TP did not identify any of the four cases positive only by IHC.


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  		TABLE 1. Results of FS, TP, and CS by metastasis size
 
Results of CS
We evaluated 620 CSs obtained from 305 SLNs, including 4 CS for each of the 5 large SLNs that were frozen in 2 tissue blocks. A mean of 2.03 CSs per SLN were obtained (range, 2–4). The mean number of CSs per patient was 4.6 (range, 2–14). The sensitivity of CS was comparable to that of FS and TP (Table 1Go). CS did not identify any of the four cases positive only by IHC. On re-review, one CS slide initially read as negative was converted to positive, and this increased the sensitivity from 54% (27 of 50) to 58% (28 of 50).

Micrometastases Detected Only by TP
In a single patient, the SLN was positive only on TP, and no additional epithelial cells were found on final pathology, including multiple H&E and IHC stains through the tissue block. The epithelial cells seen on TP were morphologically comparable to those in her 1.5-cm primary invasive cancer (Fig. 1Go). This finding did not alter the patient’s treatment.



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  		FIG 1. True-positive case detected only in touch preparation (TP). (A) A cohesive cluster of epithelial cells was detected on a TP slide (original magnification, x400; stain, hematoxylin and eosin). (B) A positive immunoreaction for keratin AE1:AE3 (performed on the same TP slide) highlights the epithelial cells (original magnification, x400).

 
False-Positive Results
One case each of TP and CS was identified as a false-positive result. In the case initially read as positive on TP, no metastatic cells were found by any of the other methods. On re-review, these cell clusters differed morphologically from the patient’s primary tumor (which was DCIS) and resembled hypertrophic blood vessels admixed with atypical lymphoid cells seen on the H&E-stained sections (Fig. 2AGo). Because of this false-positive result, the specificity of TP was 99% (83 of 84 patients).



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  		FIG 2. False-positive case in touch preparation (TP). (A) Epithelioid cells with prominent nuclei and smudged chromatin present in a TP were interpreted as neoplastic by 2 out of 3 reviewers (original magnification, x400), but these cells were morphologically dissimilar to the primary carcinoma (not shown) and were not immunoreactive for cytokeratin. (B) False-positive case in smear preparation (CS). Numerous epithelial cells were present in a CS preparation but were absent in all the other preparations obtained from the same lymph node (original magnification, x400). The epithelial cells had small and bland nuclei, and a few were spindle shaped with a central nucleus. The cells were morphologically dissimilar to the primary breast carcinoma. The presence of these cells was attributed to cross-contamination from a different specimen.

 
The CS slide initially read as positive contained a large number of epithelial cells; no metastatic cells were found by any of the other methods. The cell displayed a spindled morphology with centrally located nuclei and bland cytologic features, unlike the breast primary tumor (Fig. 2BGo). We hypothesized that these cells represented contamination from another patient’s specimen processed at the same time. Because of this false-positive result, the specificity of CS was 99% (83 of 84 patients).

Marginal Benefit of Combining Methods
Although the sensitivities of FS, TP, and CS were comparable overall, there were four FS-positive patients in whom TP and CS were both negative and four FS-negative patients in whom TP was positive; CS was positive in three of the four. As a result, combining methods would have only marginally increased the sensitivity of intraoperative detection (Table 2Go) and only for patients with micrometastases.


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  		TABLE 2. Results of combined methods
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study was undertaken with two goals: (1) to conduct a controlled head-to-head comparison of FS with TP and CS and (2) to define which method or combination of methods would maximize the sensitivity of intraoperative assessment. On the basis of a literature review, the ideal method for intraoperative examination of the SLN remains unclear (Table 3Go). The sensitivity of FS (8 reports7–14) ranges from 57% to 87%, and that of TP or CS (13 reports15–27) ranges from 29% to 94%. Further confusion arises from the contradictory results of the two studies designed to compare TP and FS (Table 3Go); in one, Van Diest et al.4 observed sensitivities of 63% and 91%, respectively, whereas in the other, Motomura et al.5 found sensitivities of 92% and 51%. Veronesi et al.28 and Viale et al.29 have described a method ("exhaustive frozen section") that offers near-perfect sensitivity but imposes a workload (60 sections per node, stained with H&E and rapid IHC) that is beyond the capacity of all institutions except their own.


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  		TABLE 3. Intraoperative examination of the SLN: summary of published results for each method
 
Much of the variation noted previously is not surprising, because none of the published studies used identical methods. Sensitivity in this context is calculated as (intraoperative method+)/(SLN+). More intensive intraoperative examination (by increasing the number of sections or cut faces examined) will increase the numerator and increase the apparent sensitivity. This relationship is clear in much of Table 3Go. Among the studies of TP, Henry-Tillman et al.26 reported the highest sensitivity (94%) but seem to have used the least comprehensive postoperative examination (single-section H&E). In contrast, Creager et al.24 reported a much lower sensitivity (54%) but used a more comprehensive postoperative examination similar to our own, with similar results.

Using standardized methods and careful pathologic review, we found no difference in sensitivity among FS, TP, and CS overall. All three methods are highly effective in identifying macro metastases and far less effective in finding micrometastases. These results are quite similar to those of Turner et al.,30 who found that a combination of FS and TP identified only 28% of SLN micrometastases. Our patients with micrometastases were the only subset who might have benefited from combining methods (Table 2Go), but this potential benefit was small and increased sensitivity by only 6% to 15%. We agree with Creager and Geisinger,31 who argued that a combined approach offers little advantage over "a solitary procedure which yields good results for a single laboratory."

We also observed no difference in specificity among FS, TP, and CS (100%, 99%, and 99%, respectively). Specificity is largely a measure of false-positive results, and our own study and prior studies (Table 3Go) indicate that false-positive results are very infrequent regardless of method. Our two false-positive cases illustrate (1) the significance of morphological discordance between the features of the primary tumor and the putative SLN metastasis and (2) the importance of cytopathologic expertise for institutions that plan to use intraoperative TP or CS to examine the SLN.

Our single positive result associated with TP in a patient whose primary tumor was DCIS raises another intriguing issue. We perform SLN biopsy for DCIS in a subset of patients (approximately 20% of all DCIS and 5% of all breast cancers) believed to be a high risk of harboring occult invasive disease and have identified positive SLNs in a surprising 12% of cases (most found by IHC staining alone)32—a rate far higher than that observed historically. Youngson et al.33,34 and Carter et al.35 have demonstrated that prior instrumentation of the breast can displace tumor cells and epithelial debris into lymphatics and nodes, a phenomenon of "benign transport" biologically distinct from true metastasis, and a recent study of our own has found that the frequency of SLN micrometastases detected only by IHC is correlated with the degree of preoperative breast manipulation. Unfortunately, pending the results of a clinical trial now in progress,36,37 there is no way at present to determine the biological significance of isolated tumor cells in the SLN. The best a pathologist can do is to identify either a morphological discrepancy (suggesting a false positive) or morphological concordance with the primary tumor.

In summary, our study demonstrates (1) that FS, TP, and CS are equivalent for the intraoperative assessment of SLN in breast cancer, (2) that the added benefit of combining methods is small, and (3) that the failure of intraoperative assessment is largely due to an inability to detect micrometastatic disease.

Received for publication March 19, 2004. Accepted for publication October 18, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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