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Ann Surg. 2004 Jan; 239(1): 61–66.
PMCID: PMC1356193

Intraoperative Imprint Cytologic Evaluation of Sentinel Lymph Nodes for Lobular Carcinoma of the Breast

Abstract

Background:

The evaluation of sentinel lymph nodes (SLNs) from a woman with lobular cancer of the breast is frequently challenging. Intraoperative imprint cytology (IIC) is equivalent to frozen sectioning for rapid SLN evaluation and is advantageous because it is rapid, reliable, cost-effective, and conserves tissue. Metastatic lobular carcinoma is difficult to identify in SLN because of its low-grade cytomorphology, its tendency to infiltrate lymph nodes in a single cell pattern, and because individual cells can resemble lymphocytes. We are unaware of any large published studies, using any technique, to evaluate SLN for lobular carcinoma.

Methods:

A retrospective review of the intraoperative imprint cytology results of 678 SLN mapping procedures for breast carcinoma was performed. From this cohort, we studied SLN from cases of lobular carcinoma. These SLN were evaluated intraoperatively by either bisecting or slicing the SLN into 4-mm sections. Imprints were made of each cut surface and stained with hematoxylin and eosin and/or Diff-Quik. Permanent sections were evaluated with up to 4 hematoxylin and eosin-stained levels and cytokeratin immunohistochemistry. IIC results were compared with final histologic results.

Results:

Sixty-one cases of pure invasive lobular carcinoma were identified. Sensitivity was 52%, specificity was 100%, accuracy was 82%, negative predictive value was 78%. No statistically significant differences in sensitivity, specificity or accuracy were identified for the intraoperative detection of lobular carcinoma versus ductal carcinoma. The sensitivity for detecting macrometastases (more than 2 mm) was better than for detecting micrometastases, 73 versus 25%, respectively (P = 0.059).

Conclusions:

The sensitivity and specificity of IIC are similar to that of intraoperative frozen section evaluation. Therefore, IIC is a viable alternative to frozen sectioning when intraoperative evaluation is required. If SLN micrometastasis is used to determine the need for further lymphadenectomy, more sensitive intraoperative methods will be needed to avoid a second operation.

The single most important predictor of outcome for women with breast carcinoma is the status of the ipsilateral lymph nodes.1–5 Traditionally, axillary lymph node status has been evaluated by routine axillary lymph node dissection (ALND) accompanying a lumpectomy or mastectomy. ALND is used to obtain precise staging data, provide local control for patients with metastatic breast carcinoma, and for the selection of adjuvant therapy.5–11 Unfortunately, the only patients that may truly derive therapeutic benefit from ALND are those patients with positive nodes, which corresponds to approximately 40% of those undergoing ALND.12–16 ALND is associated with considerable postoperative chronic morbidity, including lymphedema, neurologic injury, joint stiffness and, rarely, angiosarcoma.17–20 SLN biopsy is a highly accurate predictor of the overall axillary nodal status and has both a high sensitivity and specificity, especially when primary tumors are small.1,13,21–24 SLN mapping is attractive because it may identify a population of breast cancer patients that may benefit from ALND. More importantly, it may identify those patients in whom ALND and its associated morbidity may be avoided.1,13,21–24

The ability to stage patients intraoperatively via SLN biopsy is clearly desirable. This allows a single operative procedure to include ALND if the SLN contains metastatic carcinoma. Currently, intraoperative evaluation is performed using imprint cytology,25–32 frozen sectioning,33–42 or a combination of these techniques.44–46 The accuracy of frozen sectioning versus imprint cytologic evaluation are equivalent.47

The use of intraoperative imprint cytology (IIC) to evaluate the SLN for metastatic lobular carcinoma has not been reported in a large series. In a small series, the sensitivity of detecting lobular carcinoma in the SLN by a combined frozen section and imprint cytologic approach was discouraging.44 Because lobular carcinoma has low-grade cytologic features and tends to infiltrate lymph nodes in a single cell pattern, the distinction between lobular carcinoma and lymphoid cells can be extremely challenging. Because of this difficulty, the use of cytokeratin immunohistochemistry has become more or less standard for permanent section evaluation of metastatic lobular carcinoma. Although some groups have added cytokeratin immunohistochemistry to their intraoperative analysis, it increases turnaround time and cost.43 Therefore, in the present study, we analyze the utility of imprint cytology (without intraoperative immunohistochemistry) in the evaluation of SLN for lobular carcinoma in 61 consecutive lymph node mapping procedures performed at both an academic medical center and a community hospital.

METHODS

All patients undergoing SLN mapping from May 1997 to May 2001 from the Moses H. Cone Hospital, Greensboro, NC, and Wake Forest University Baptist Medical Center, Winston-Salem, NC, were reviewed. This included SLN mapping procedures from 679 consecutive patients with an intraoperative imprint cytologic diagnosis of the SLN. A chart review of each patient was performed for the following data: age, sex, method of tumor detection, type of breast, and axillary surgical procedure. Primary tumor data compiled included: size, type, and histologic grade. Lymph node data gathered included: number of SLN and non-SLN obtained, number of each containing metastatic tumor and size of largest metastatic deposits. Tumor size was recorded according to the guidelines of the American Joint Committee on Cancer.48 Histopathologic grade was based on the modified Bloom-Richardson system.49

Surgical Protocol

A standard protocol was used to identify the SLN. The patient’s tumor bed was injected with filtered technetium sulfur colloid (0.5–1.0 mCi) preoperatively. A lymphoscintigram was obtained at the surgeon’s discretion in the Nuclear Medicine Department before the patient’s arrival to the operative suite. A gamma probe (Neoprobe 2000, Neoprobe Corp., Dublin, OH) was used intraoperatively to detect the SLN. In addition, in all cases perilesional injections of isosulfan blue were used intraoperatively to provide visual identification of the SLN. The SLN were then harvested and sent fresh to pathology for intraoperative and permanent section evaluation. Breast-conserving surgery was performed in 73% of patients, and the remaining 27% underwent mastectomy. Complete ALND was performed only if the SLN contained tumor cells. A few of the cases were on cooperative group protocols, which mandated lymphadenectomy regardless of the SLN result.

Pathologic Examination

Excised lymph nodes submitted for intraoperative evaluation were examined using one of 2 methods depending on which institution was performing the evaluation. In the first method, the SLN was bisected along the long axis. Care was taken to obtain complete cross sections of the maximum diameter, preferably including the hilum and the marginal sinus. For each lymph node half, a pair of imprints was made by gently touching the cut surface of the SLN to a glass slide. One imprint from each pair was air dried and stained with the Diff-Quik stain. The second imprint from each surface was immediately fixed in 95% ethanol for 3 minutes and then stained with hematoxylin and eosin (H&E). In the second method, the SLN was sliced into 4-mm slices and imprints were made of each cut surface, air-dried, and stained with Diff-Quik.

Imprints were reviewed intraoperatively by either a board-certified cytologist or a pathologist with informal cytologic training. Diagnostic categories included positive or negative for tumor or atypical cells present. Positive results prompted completion of the axillary lymphadenectomy, and a negative result no further lymphatic dissection. Completion of the lymphadenectomy was at the surgeon’s discretion with the unusual result of atypical cells present. The surgical team was subsequently notified of the result. After an interpretation was rendered, the SLN was fixed in 10% formalin, processed in the usual manner, and embedded in paraffin. A single H&E-stained section of the SLN was cut from the paraffin block and examined. If initial review of the H&E-stained section was negative, a SLN protocol consisting of an additional 3 H&E stained levels, cut at 50-μm intervals, in conjunction with immunohistochemical stains for cytokeratin (AE1/AE3, Dako, Carpinteria, CA), was performed on the first of the 3 levels. Immunohistochemical studies were conducted using the avidin-biotin-peroxidase complex method described elsewhere.50 Immunohistochemical stains for cytokeratin were considered positive if strong immunoreactivity in cell clusters or individual cells that demonstrated anatomic and cytologic features of metastatic tumor cells were identified (Fig. 1).

figure 9FF1
FIGURE 1. A, Frozen section of sentinel node involved with lobular carcinoma. Tumor cells are indistinguishable from lymphocytes at this power (H&E ×200). B, Immunohistochemical stain for cytokeratin from same lymph node as in (A). The ...

When discrepancies existed between the intraoperative and permanent section results, slides were reviewed by an independent pathologist in an attempt to determine the cause of the discrepancy. When non-SLNs were obtained, they were examined using standard pathologic techniques. If greater than 4 mm in width, non-SLNs were sectioned; if less than 4 mm, non-SLNs were submitted whole. Routinely, a single H&E-stained section of the non-SLNs was examined and in several cases multiple levels were obtained in an attempt to verify the presence of metastases.

Statistics

χ2 and Fisher exact test tests (as appropriate) were used to assess differences in clinical and pathologic factors between those with and those without SLN performed and to assess the association between pathologic factors and IIC results. Sensitivity was defined as the percentage of positive IIC results among those with positive permanent pathology. Specificity was defined as the percentage of negative IIC results among those with negative permanent pathology. The false-negative rate was defined as the number of false-negative intraoperative imprint results divided by the sum of the false-negative and true-positive results. For the purposes of this manuscript, statistical significance was defined as a P value of less than 0.05.

RESULTS

We attempted SLN mapping procedures in 678 consecutive patients and SLN was identified in 646 (95.3%) of these. All 646 consecutive cases with intraoperative imprint cytologic diagnosis of the SLN were evaluated as per protocol. From this cohort of 646 patients, 61 cases (9.4%) of pure invasive lobular carcinoma were identified. These patients ranged in age from 21 to 87 years (mean, 60 years). Breast-conserving surgery was performed in 69% (vs. 73% for nonlobular histology) of patients and the remaining 31% underwent mastectomy. Primary invasive tumors ranged from 0.5 to 4.5 cm (mean, 1.8 cm). Tumor representation included 54 cases of classic lobular carcinoma (nuclear grade 1) and 7 cases of pleomorphic lobular carcinoma nuclear grades 2–3).

From these 61 patients, a total of 121 SLNs were evaluated by intraoperative imprint cytology (average, 2.0 SLN/patient). A separate intraoperative diagnosis was generated for each lymph node. Results are reported on a per patient basis.

The accuracy of intraoperative imprint cytology compared with permanent section evaluation of the SLN for detection of lobular carcinoma was 82% (Table 1). Twenty-three patients had positive SLNs by permanent section evaluation and of these, 11 were falsely negative by imprint cytology (sensitivity, 52%). Negative predictive value was 78%. No false-positive intraoperative diagnoses were identified (specificity 100%, positive predictive value 100%). No statistically significant differences in sensitivity, specificity, or accuracy were identified for the intraoperative detection of lobular carcinoma versus ductal carcinoma by imprint cytology (Table 1). Sensitivity of detecting metastatic disease by imprint cytology was higher for macrometastatic disease (metastases ≥0.2 cm) than for micrometastatic disease (metastases ≤ 0.2 cm; P = 0.059; Table 2). No statistically significant difference existed between accuracy of intraoperative imprint cytology and tumor size classification, although no T3 or T4 tumors were included in the study. (Table 3). The sensitivity of detecting classic lobular versus pleomorphic lobular carcinoma was 47% and 75%, respectively; however, the small numbers in these groups did not reach statistical significance (P = 0.59; Table 4).

Table thumbnail
TABLE 1. Results of Intraoperative Imprint Cytologic Evaluation Relative to Permanent Section Evaluation for Different Histologic Types of Invasive Carcinoma
Table thumbnail
TABLE 2. Sensitivity of Intraoperative Imprint Cytology Relative to the Size of the Sentinel Lymph Node Metastasis
Table thumbnail
TABLE 3. Results of Intraoperative Imprint Cytologic Evaluation Relative to Permanent Section Evaluation and Tumor Size Classification
Table thumbnail
TABLE 4. Results of Intraoperative Imprint Cytologic Evaluation Relative to Permanent Section Evaluation for Different Histologic Grades of Invasive Carcinoma

Non-Sentinel Lymph Nodes (NSLNs)

A total of 392 NSLNs were identified in 27 patients (14.5/patient). Four NSLNs from 5 patients harbored metastatic carcinoma. No patient with a negative SLN had a NSLN that harbored carcinoma. The apparent accuracy of the sentinel lymph node mapping procedure for this population of patients was 100% (61/61).

DISCUSSION

Accurate intraoperative evaluation of SLNs permit an ALND to be performed during the initial operation if the node is positive, saving the patient both the time, cost, and burden of a second operation. At present, there is no consensus on the utility of intraoperative SLN analysis or the optimal method of evaluation. Although several intraoperative techniques including imprint cytology, frozen sectioning or a combination of these techniques have been examined.47 However, in 1999, the College of American Pathologists recommended that SLNs be examined intraoperatively by cytologic methods.51 A key advantage of the imprint cytology over frozen sectioning is the avoidance of the loss of tissue attendant to the use of a cryostat. Thus, imprint cytology preserves tissue for subsequent focused pathologic analysis of the SLNs.

Several problematic areas exist in intraoperative evaluation of SLNs, whether it be by frozen sectioning or imprint cytology. The first difficult area is the detection of metastatic lobular carcinoma. Because the relative rarity of lobular carcinoma (compared with ductal carcinoma), few studies examining intraoperative evaluation of lobular carcinoma, by either frozen section or imprint cytology are available, and both the sensitivities and number patients in these studies have been quite low.33,43,44 It is for the latter reason that we attempted to evaluate the accuracy of imprint cytology in a relatively large series of patients.

The intraoperative detection of lobular carcinoma is also problematic because of its low-grade cytomorphology and its tendency to infiltrate metastatic sites in a single cell pattern. Because of this difficulty, much controversy has been generated in the pathology community with regard to this issue, most of this has been the result of individual experience. In our experience, due to the architectural and cytomorphologic features of metastatic lobular carcinoma, occasional large metastases are missed by both intraoperative evaluation and on permanent H&E sections, only to be discovered, much to the surprise of the pathologist, on cytokeratin stained sections (Fig. 1). This factor contributes significantly to the controversy that exists in this area. In the present study, no significant difference was observed between the sensitivity of detecting metastatic lobular carcinoma versus ductal carcinoma (Table 1). These difficulties underscore the need for cytologic expertise when intraoperative SLN assessments are made. Clearly, such cytologists are not available at all institutions, and the pathologic support available must be kept in mind when organizing a SLN program. Additionally, the specificity of this study was 100%, supporting the notion that false-positive examinations, which would risk completion of an undesired completion ALND, are not a problem.

The rate of nodal positivity increased with increasing tumor size. However, when examined for tumor size classification, no significant differences were observed between sensitivity of intraoperative analysis for the detection of metastatic lobular carcinoma between T1 and T2 lesions. However, the number of positive cases was small and no T3 tumors were included in this study (Table 3).

Finally, a statistically significant difference existed between intraoperative imprint cytologic detection of classic lobular carcinoma (low-grade nuclei) and pleomorphic lobular carcinoma (intermediate to high grade nuclei; Table 4). This finding was expected, as higher-grade nuclei are easier to detect than lower grade nuclei, although both tumor variants tend to infiltrate lymph nodes in a single cell fashion, thereby making identification difficult.

Another problematic area is the poor sensitivity of detecting micrometastatic disease compared with macrometastatic disease intraoperatively. In the present study, the disparity between detection of micrometastatic disease versus macrometastatic disease was significant (Table 2) and parallels the discrepancy that exists for detection of metastatic ductal carcinoma by either frozen section or imprint cytology. Some have suggested that the use of intraoperative cytokeratin immunohistochemistry protocols may decrease the intraoperative false negative rate and protocols are available for this using both frozen sections and cytologic imprints.34,43,52 At present, frozen section immunohistochemical protocols are employed by at least one group and include complete intraoperative step sectioning of the SLN, a process with a reported turnaround time of 65 minutes.34 Alternatively, we are aware of one small study employing rapid immunohistochemical cytokeratin staining to cytologic imprints of SLN.34 Turnaround time for the immunohistochemical staining in this report was 16 minutes. At present, it remains to be seen whether immunohistochemical protocols are reliable and fast enough for general use. In the present study, turnaround time was approximately 20 minutes, and we are not prepared to extend this time for a more rigorous examination. Unfortunately, it is unlikely that the sensitivity of intraoperative evaluation will increase without the use of more rigorous techniques to detect micrometastatic disease. Alternatively, intraoperative evaluation by either method is a reliable detector of macrometastatic disease, which is in and of itself a strong predictor of non-SLN metastases.44

If intraoperative evaluation is to be performed, we need to determine what acceptable sensitivity and specificity levels will be. In cohorts of screened patients the SLN will be positive in approximately 40% of patients on final pathology. Even if the sensitivity of intraoperative evaluation is only around 50%, this could potentially save a considerable amount of resources and the burden of additional surgery in a significant number of patients.

The cost of IIC at our institution for 2 SLN is $131 versus $356 for frozen sectioning. The use of IIC versus frozen section would represent a savings of over $80,000 in pathology charges alone for the 646 cases in this study. A cost-benefit analysis is lacking in this area and will be critical for the future direction of intraoperative evaluation of SLN.

In summary, intraoperative detection of metastatic lobular carcinoma by imprint cytology is equivalent to that observed in ductal carcinoma, despite earlier published data to the contrary. However, its utility in detecting micrometastatic disease is limited. Imprint cytology is at least as sensitive as frozen sectioning and is as specific. Imprint cytology is cheaper and faster than frozen sectioning.47 Tissue is not wasted in the cryostat with imprint cytology and the pathologist does not have to attempt to cut lymph nodes with the cryostat that have been largely replaced by fat. Finally, freezing artifact is not introduced into the tissue when imprints are made. As a result, we believe that intraoperative imprint cytology is advantageous over frozen sectioning when intraoperative evaluation is required and is useful for patients with lobular cancer of the breast.

Footnotes

Reprints: Edward A. Levine, MD, Surgical Oncology Service Wake Forest University School of Medicine Medical Center Blvd. Winston-Salem, NC 27157. E-mail: ude.cmbufw@enivele.

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