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10.1245/s10434-006-9270-y
Annals of Surgical Oncology 14:1024-1030 (2007)
© 2007 Society of Surgical Oncology
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Original Article

The Utility of Intraoperative Evaluation of Sentinel Lymph Nodes in Breast Cancer

Matthew S. Pugliese, MD1, Ronald Tickman, MD2, Nan Ping Wang, MD, PhD2, Mary Atwood, CTR3 and J David Beatty, MD1

1 Department of Surgery, Comprehensive Breast Cancer Program, Swedish Cancer Institute, 1221 Madison Street, Suite, 400 Seattle, Washington
2 Department of Pathology, Comprehensive Breast Cancer Program, Swedish Cancer Institute, 1221 Madison Street, Suite, 400 Seattle, Washington
3 Department of Research, Comprehensive Breast Cancer Program, Swedish Cancer Institute, 1221 Madison Street, Suite, 400 Seattle, Washington

Correspondence: Address correspondence and reprint requests to: J David Beatty, MD; E-mail: david.beatty{at}swedish.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: In breast cancer treatment, intraoperative sentinel lymph node (SLN) evaluation is used to identify patients who may potentially benefit from immediate completion of axillary lymph node dissection.

Methods: Prospectively collected breast cancer registry data identified 516 SLN biopsies between January 2003 and December 2005. Intraoperative evaluation (IE) of the SLNs was performed in 479 axillae. Final pathology by hematoxylin and eosin and, for negative nodes, by immunohistochemical stains was compared with the IE result. The effect of IE and final pathology on surgical treatment was examined.

Results: The sensitivities for IE of N0(i+) (n = 39), N1mi (n = 41), and N1a–3a (n = 89) metastases were 0%, 5%, and 63%, respectively. The specificity was 99.7%. IE identified 57 (44%) of SLN-positive (N1mi and N1a–3a) axillae, thus resulting in synchronous axillary lymph node dissection for those patients. Reoperation for false-negative IEs (N1mi or N1a–3a with negative IE) occurred in only 27 axillae (39%).

Conclusions: IE of SLNs has adequate sensitivity and excellent specificity. In addition to allowing patients to benefit from synchronous surgery, IE helped patients to receive care in concordance with recommended practice guidelines. The false-negative IE of SLNs highlights uncertainty with the clinical significance of axillary nodal staging when only small amounts of metastatic disease are identified in the axilla.

Key Words: Breast cancer • Axillary lymph node dissection • Sentinel lymph node • Intraoperative evaluation • Imprint cytology • Frozen section


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
The accurate identification of axillary lymph node metastases is important for patients with breast cancer.1,2 In addition to providing prognostic information, lymph node dissection is therapeutically used to provide local control and to guide decisions involving adjuvant therapy. Routine complete level I and II axillary lymph node dissection (ALND) was previously the standard way of obtaining this information in early-stage breast cancer. However, lymphatic mapping and sentinel lymph node (SLN) biopsy was introduced to help avoid the morbidity associated with routine ALND. Studies have shown that SLN biopsy reasonably stages the axilla3–5 and that the incidence of complications after SLN biopsy is lower than the incidence of complications after ALND.6,7

Currently, ALND is indicated for patients with pathologically documented axillary metastases or for early-stage breast cancer patients without preoperative documentation of axillary node metastasis, but with positive SLN biopsies. ALND can be performed as a synchronous procedure after the positive intraoperative evaluation (IE) of an SLN biopsy. It can also be performed as a second, delayed operation, on the basis of final pathology results. A synchronous operation is often preferred because it can avoid the additional morbidity, cost, inconvenience, and psychological effect of a second procedure.

Both frozen section (FS) and imprint cytology (IC) are techniques used for the IE of SLNs. Several prospective studies have shown that FS and IC have relatively equivalent sensitivities.8–10 However, important differences exist. FS is a more commonly performed pathologic procedure. It is more time consuming, can be subject to freezing artifacts, and wastes a small amount of tissue when facing into the frozen tissue block. IC can be performed rapidly and does not waste tissue that may contain small metastases.

A growing body of data is becoming available regarding the use of IC and FS for intraoperative SLN evaluation. At our institution, we previously performed a smaller retrospective study of 385 patients identified through a pathologic database.11 In that study, the sensitivities for IC detection of N0(i+) (n = 36), N1mi (n = 24), and N1a–3a (n = 65) metastases were 0%, 4%, and 74%, respectively. The goals of this study were to validate the accuracy of IE and to better characterize the overall utility of intraoperative SLN evaluation by using a prospective breast cancer registry at the Swedish Cancer Institute.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Approval for the study was obtained from the Swedish Medical Center Institutional review board. Prospectively collected data from the breast cancer registry identified 503 consecutive patients (516 axillae) with clinically node-negative breast cancer who underwent SLN biopsy between January 2003 and December 2005. IE was not performed on 32 axillae. IE was not completely documented in five axillae. Of the remaining 479 axillae, 175 overlap with the 385 patients studied previously from the pathologic database.

During surgery, SLNs were identified by using a combination of either isosulfan or methylene blue dye and 99mTc-labeled sulfur colloid. They were surgically excised and sent to pathology for IE. Each SLN was serially sectioned at 1- to 2-mm intervals perpendicular to the long axis of the node. IC was performed on the cut surface of all nodal slices. The IC was examined microscopically and interpreted by a pathologist as positive or negative for metastatic disease. Atypical-appearing cells were reported as indeterminate. The results were immediately conveyed to the surgeon in the operating room. Atypical results were considered negative by the surgeon, pending final pathology. Intraoperative FS was used selectively in situations in which additional information was requested by the surgeon or pathologist. Thirteen pathologists participate in IE of SLNs, and four have specific training in cytopathology. As part of our protocol, a pathologist can request an intraoperative second opinion from a colleague.

After IE, the SLNs were then fixed in 10% buffered formalin and processed in the usual fashion for permanent sections. Ten sequential sections at an interval of 100 to 200 µm between levels were collected from the tissue block of SLNs. This ensured complete histological examination of each 1- to 2-mm-thick nodal slice. Section levels 2, 5, and 9 were evaluated by routine hematoxylin and eosin (H&E) staining. If negative, section level 4 (or any additional level that was deemed appropriate) was then evaluated by immunohistochemical staining for pankeratin. The axillae were staged as N0(i–), N0(i+), N1mi, or N1a–3a according to the American Joint Committee on Cancer Cancer Staging Manual (6th edition). All false-negative IEs are reviewed as part of quality-assurance measures.

The breast cancer registry prospectively collects data from all patients who receive part or all of their care at the Swedish Cancer Institute. From 1990 to 2006, more than 7000 cases have been entered. Collected information includes demographics, tumor pathology (histology, immunohistochemistry, fluorescence in situ hybridization, and staging status); multidisciplinary treatment details for primary and metastatic disease; and diagnostic, recurrence, follow-up, and death dates. Because information regarding intraoperative SLN evaluation was not prospectively obtained, the medical records were reviewed, and the IE of each axilla was added to the breast cancer registry–generated database. The data were then analyzed to determine the accuracy of the intraoperative SLN evaluation and to help characterize the overall utility of the test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
The final cohort consisted of 479 axillae evaluated in 466 patients. The most common indications for axillary evaluation were invasive ductal carcinoma, ductal carcinoma-in-situ, invasive lobular carcinoma, and invasive ductal/lobular mixed (Table 1Go). The average age, tumor size, modified (Nottingham) Bloom-Richardson score, lymphovascular invasion, hormone-receptor status, and type of surgical intervention were also collected (Table 2Go).


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  		TABLE 1. Indications for axillary staging
 

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  		TABLE 2. Cohort characteristics
 
Isolated tumor cells or clusters of cells up to and including .2 mm in size [N0(i+)] were identified in 39 axillae (8%) on final pathologic analysis. Micrometastases, defined as clusters of metastatic cells >.2 mm, up to and including 2 mm (N1mi), were identified in 41 axillae (9%) on final pathologic analysis. Macrometastases, metastatic lesions >2 mm (N1a–3a), were identified in 89 axillae (19%) on final pathologic analysis. The sensitivity of IE for N0(i+), N1mi, and N1a–3a disease was 0%, 5%, and 63%, respectively. The specificity was 99.7% (Table 3Go). Of the 479 axillae evaluated, 175 were previously analyzed and presented from the pathologic database. Table 4Go compares the pathologic database subset with the patients identified only through the breast cancer registry.


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  		TABLE 3. Accuracy of intraoperative evaluation compared with final lymph node stage
 

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  		TABLE 4. Comparison of new patients (n = 304) in the breast cancer registry with the subset of patients (n = 175) previously studied in the pathologic database11
 
The sensitivity of IE on a per-axilla basis for N1 or greater disease (N1mi and N1a–3a) was 45%. The sensitivity of IE on a per-axilla basis for all patients with identified malignant cells [N0(i+), N1mi, and N1a–3a] was 35%. The positive and negative predictive values of IE on a per-axilla basis for N1 or greater disease (N1mi and N1a–3a) were 98% and 83%, respectively. The positive and negative predictive values of IE on a per-axilla basis for all patients with identified malignant cells [N0(i+), N1mi, and N1a–3a] were 98% and 74%, respectively.

Positive IEs were obtained in 59 (12%) of 479 axillae. All of these patients had a synchronous ALND. Negative IEs were obtained in 420 (88%) of 479 axillae. On the basis of final pathologic analysis, 30 axillae with negative IEs had completion ALNDs. On the basis of high clinical suspicion on the part of the surgeon, three axillae with negative IEs had synchronous ALNDs. One of these axillae was N0(i–). Two of these axillae had N1a disease.

IE results were reported as indeterminate 21 times. Because indeterminate results were considered negative during surgery, they were also considered negative for accuracy analysis. However, if considered positive, the sensitivity for N0(i+), N1mi, and N1a–N3a disease would be 15%, 12%, and 70%, respectively. The specificity would be 97.7%. The sensitivity of IE on a per-axilla basis for N1 or greater disease (N1mi and N1a–3a) would be 52%. The sensitivity of IE on a per-axilla basis for all patients with identified malignant cells [N0(i+), N1mi, and N1a–3a] would be 43%. The positive and negative predictive values of IE on a per-axilla basis for N1 or greater disease (N1mi and N1a–3a) would be 84% and 84%, respectively. The positive and negative predictive values of IE on a per-axilla basis for all patients with identified malignant cells [N0(i+), N1mi, and N1a–3a] would be 92% and 76%, respectively.

FS was selectively used in 45 (9.4%) of 479 axillae. In the setting of a positive IC, the FS was reported as positive every time. In the setting of negative IC, the FS was reported as negative every time. However, two of these axillae had N0(i+) disease, and two of these axillae had N1 disease. In the setting of indeterminate IC, the FS was negative or atypical in five axillae and positive in one axilla. This FS-positive axilla had N1a disease. The FS data are listed in Table 5Go.


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  		TABLE 5. Intraoperative assessment compared with final lymph node stage when selective frozen section is used
 
Final pathologic analysis identified 130 positive (N1mi and N1a–3a) SLN biopsies. Of these patients, 60 (46%) had synchronous ALND. Of the remaining 70 patients with positive SLNs, 27 (39%) had delayed ALND, and 43 (61%) did not undergo ALND (Table 6Go). Nuclear grade, lymphovascular invasion, multifocality, estrogen receptor positivity, number of negative SLNs, number of positive SLNs, and tumor size were compared between the two groups. The Memorial Sloan-Kettering nomogram12 was used to calculate the predicted probabilities of a positive non-SLN, and these were compared (Table 7Go). The number of negative SLNs obtained and the Memorial Sloan-Kettering nomogram probabilities were significantly different between patients receiving delayed ALND and those receiving no ALND.


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  		TABLE 6. Completion of axillary lymph node dissection after intraoperative evaluation according to final nodal stage
 

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  		TABLE 7. Comparison of variables and Memorial Sloan-Kettering nomogram–predicted probabilities of a non–SLN metastasis in patients with a negative IE and a positive SLN biopsy
 
Of the axillae with malignant cells identified in their SLNs [N0(i+), N1mi, and N1a–3a], 43 received axillary irradiation (AI). AI was administered to 3, 8, and 32 axillae with N0(i+), N1mi, and N1a–3a disease, respectively. AI was given 26 times after a completion ALND. Each of the axillae contained macrometastatic disease (N1a–3a). AI was given 17 times when no ALND was performed. These axilla had N0(i+), N1mi, and N1a disease in three, eight, and six cases, respectively. Of the 43 axillae receiving AI, 19 patients had partial mastectomies for their primary tumors, and 24 had mastectomies. Of the 19 axillae receiving AI after partial mastectomy, 12 patients did not have ALNDs [N1a, n = 4; N1mi, n = 6; N0(i+), n = 2]. Of the 24 axillae receiving AI after mastectomy, 5 patients did not have ALNDs [N1a, n = 2; N1mi, n = 2; N0(i+), n = 1].


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
ALND provides prognostic information and local control for patients with metastatic axillary disease. However, as operative techniques have evolved, an increasing number of patients and surgeons have elected to use SLN biopsy in hopes of avoiding the unnecessary morbidity associated with a negative ALND. Multiple trials have documented that SLN biopsy reasonably reflects the stage of the axilla. However, the extent to which SLN biopsy provides local control is currently unknown, and even with the help of nomograms, determining the need for ALND can sometimes be difficult.12,13

The minimum standard for SLN evaluation is permanent sections with H&E staining. At this institution, SLN evaluation also includes pankeratin immunohistochemical evaluation when the initial H&E levels are negative. In this series, evaluation identified 39 patients with malignant cell clusters no greater than .2 mm [N0(i+)] and 41 patients with lymph node metastases >.2 mm but no greater than 2 mm (N1mi). Controversy exists regarding the prognostic and therapeutic significance of these diagnoses.14–16 Current American Society of Clinical Oncology practice guidelines state that ALND should be recommended to patients with positive SLNs.17 They include micrometastatic disease (N1mi) in this recommendation and state that the significance of isolated malignant cells [N0(i+)] is currently unknown. National Cancer Center Network practice guidelines simply state that ALND should be recommended to patients with involvement of an SLN seen with multiple H&E sections.18 The ongoing National Surgical Adjuvant Breast and Bowel Project and the American College of Surgeons Oncology Group trials are designed to help clarify the significance of axillary microstaging.

IE of SLNs is used to identify patients who may benefit from a synchronous completion ALND, thus allowing them to avoid a second procedure. Intra-operative assessment of SLNs can be performed by FS, IC, or both. In our institution, IC is routinely used in the IE of SLNs. FS is selectively requested when the surgeon or pathologist believes that additional information is necessary.

The primary goal of this study was to validate the accuracy of our protocol for IE by using the institution’s breast cancer registry. Our previous study found that IC was 0%, 4%, and 74% sensitive in detecting N0(i+), N1mi, and N1a–3a disease, with no false-positive results in 385 patients. This study validates those results by demonstrating 0%, 5%, and 62% sensitivities for N0(i+), N1mi, and N1a–3a disease, with only 1 false-positive result in 479 axillae. This is consistent with our review of the previously published literature in Table 8Go. It is important to note that patients with clinical examinations or ultrasound studies suggestive of axillary metastasis undergo preoperative fine-needle aspiration. If the results are positive, these patients do not undergo SLN biopsy. This may artificially decrease the sensitivity of our IE protocol through selection bias.


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  		TABLE 8. Summary of the results from series evaluating the accuracy of imprint cytology for intraoperative evaluation of sentinel lymph nodes in breast cancer
 
Indeterminate IC results accounted for 4.4% of the results. This group of patients had N1 or greater disease (N1mi and N1a–3a) 43% of the time. Considering atypical IC results as positive increases the sensitivity of IE for N1 or greater disease (N1mi and N1a–3a) from 45% to 52% at the cost of six additional false-positive results. We believe that a high threshold of positivity is important to avoid potentially unnecessary synchronous ALNDs, even if this results in decreased sensitivity. Therefore, we recommend that atypical IC results continue to be considered negative during surgery.

This study also provided information concerning the selective use of FS in combination with routine IC. Documented FS results changed the operative decision making in 1 (2.2%) of 45 patients. If the IC result was either positive or negative, FS confirmed the IC result 100% of the time (n = 39). However, the indications for FS were not necessarily the same for the different surgeons and pathologists in this series. Additionally, in an unknown percentage of cases, the results for IC and FS were reported as positive or negative on the basis of the combined impression from both procedures. This represents a significant limitation of the FS data and has implications for the IC results. When FS is used, the sensitivity for N1mi or larger disease increased to 90%. However, the negative predictive value remained the same, at 83%. When IE did not include FS, the sensitivity for N1mi or greater disease decreased to 31%. Again, the negative predictive value remained unchanged at 83%. Because only a small number of patients underwent FS, for varying reasons, limited conclusions may be drawn. In the setting of an indeterminate IC result, FS changed operative decision making one of six times. This implies that the addition of FS may be most useful in clarifying indeterminate IC results.

The second goal of this study was to help characterize the overall utility of the IE of SLN biopsies. IE allowed 58 (45%) of 130 axillae with N1 or greater disease (N1mi and N1a–3a) to benefit from a synchronous ALND. Therefore, a positive IE helped these patients to receive care in concordance with recommended guidelines. Despite a negative IE, 2 N1 patients benefited from synchronous ALND secondary to suspicion on the part of the surgeon. Three patients with N0(i+) axilla returned for ALND. This occurred early in the series and represents an evolution of our understanding of the clinical significance of N0(i+) staging.

Of the remaining 70 false-negative results (N1mi or N1a–3a axilla with negative IE), only 27 (39%) returned for delayed ALND. This is a relatively low rate of performing delayed ALNDs. However, the rate returning for ALND after a false-negative IE did improve with increasing size of the lymph node metastasis (10 [26%] of 39 N1mi vs. 17 [55%] of 31 N1a–3a). Overall, 87 (67%) of 130 of axillae identified to be N1mi or N1a–3a by SLN biopsy did have an ALND.

We theorized that several factors may influence the decision to return to the operating room for completion ALND: (1) the likelihood of positive non-SLNs and (2) the administration of AI therapy. Using nuclear grade, lymphovascular invasion, multifocality, estrogen-receptor positivity, number of negative SLNs, number of positive SLNs, tumor size, and method of detection, Van Zee et al.12 created a nomogram for predicting the likelihood of additional non-SLN metastasis after a positive SLN biopsy. When they retrospectively looked at patients with false-negative IEs, significant differences existed in the number of negative SLNs and in the predicted probability of a non-SLN metastasis between the group that chose ALND and the group that declined ALND. Most of the false-negative IE cases were discussed at a multidisciplinary Swedish Cancer Institute breast cancer conference, and many patients were counseled with information from the Memorial Sloan-Kettering nomogram. This analysis suggests that the number of negative SLNs and the predicted probability of non-SLN metastasis may have influenced treatment decisions. We recommend that patients with false-negative results and a significant amount of disease on final pathologic analysis return for completion ALNDs, as stated in current practice guidelines. We further recommend that these cases be discussed individually at a multidisciplinary breast cancer conference and that the issues be discussed carefully with the patient before a final treatment decision is made.

AI was administered to 43 axillae. Some patients had both ALND and AI, generally when there was more extensive metastatic disease in the lymph nodes. Decisions regarding AI are made by a multidisciplinary care team. Factors involved in the consideration of treating the axilla include four or more positive axillary lymph nodes; extranodal extension; lymphovascular invasion; and suspicion of periclavicular, internal mammary, or cervical lymph nodes by imaging or pathology. Overall, ALND, AI, or both were administered to 6 (15%) of 39 N0(i+) axillae, 20 (49%) of 41 N1mi axillae, and 81 (91%) of 89 N1a–3a axillae. This is a reflection of the uncertainty regarding the significance of the small amounts of disease in N0(i+) and N1mi patients and the commitment to adequately treat the more extensive axillary disease in the N1a–3a patients.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
IE of SLNs has adequate sensitivity and excellent specificity. In addition to allowing patients to benefit from synchronous surgery, IE helped patients to receive care in concordance with recommended practice guidelines. The false-negative IE of SLNs highlights uncertainty with the clinical significance of axillary nodal staging when only small amounts of metastatic disease are identified in the axilla.

Received for publication August 17, 2006. Accepted for publication October 18, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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