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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.037 on November 15, 2004

Annals of Surgical Oncology 11:1056-1060 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Sentinel Lymph Node Metastases Detected by Immunohistochemistry Only Do Not Mandate Complete Axillary Lymph Node Dissection in Breast Cancer

Richard J. Gray, MD, Barbara A. Pockaj, MD and Christopher R. Conley, MD

From the Section of Surgical Oncology, Departments of Surgery (RJG, BAP) and Pathology (CRC), Mayo Clinic, Scottsdale, Arizona.

Correspondence: Address correspondence to: Richard J. Gray, MD, CB Surgery, Mayo Clinic, Scottsdale, AZ 85259; Fax: 480-301-8414; e-mail: gray.richard{at}mayo.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 REFERENCES
 
Background: The significance of breast cancer sentinel lymph node (SLN) metastases detected only by immunohistochemistry staining (IHC) remains poorly understood. This study attempted to quantify the risk of non-SLN metastases.

Methods: A prospectively collected database of 750 consecutive SLN biopsy procedures in breast cancer patients was reviewed. Medical records were reviewed to supplement the database.

Results: SLNs were identified in 738 (98.4%) of these procedures in 723 patients. Of these, 151 patients (20.5%) had metastases detected by hematoxylin and eosin staining (H&E), and 33 (4.6%) of the 718 with known IHC staining results had metastases detected by IHC only. Twenty-eight (84.8%) of 33 patients with IHC-detected metastases underwent complete axillary lymph node dissection (CALND). The median primary tumor size was 2.0 cm among those undergoing CALND and 0.9 cm among the five patients treated without CALND (P = .10). Two of the 28 patients (7.1%) had additional metastases detected with CALND. These patients had a T3 or T4 invasive lobular primary tumor. Of 24 patients with T1 or T2 primary tumors and IHC-detected metastases who underwent CALND, none had additional metastases detected. Median follow-up was 14.5 months. All patients with IHC-detected SLN metastases were treated with adjuvant systemic therapy. None of the five patients with IHC-detected metastases not undergoing CALND has subsequently manifested clinical axillary disease.

Conclusions: CALND could have been or was safely omitted in 29 of 29 patients with T1 or T2 primary tumors and metastases detected by IHC. Such patients should be counseled about this low risk before CALND is recommended.

Key Words: Breast cancer • Immunohistochemistry staining • Micrometastasis • Sentinel node


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 REFERENCES
 
Lymphatic mapping and sentinel lymph node (SLN) biopsy have been rapidly adopted for the staging of patients with breast cancer. The status of the SLN has been shown to accurately reflect the status of the axillary basin,1,2 so despite the lack of a prospective randomized trial, many centers proceed with complete levels I and II axillary lymph node dissection (CALND) only when a metastasis is found within a SLN. Because the status of the regional lymph nodes remains the most important predictor of breast cancer survival,3 detailed assessment of each SLN has been believed to be paramount so as to avoid understaging the patient and undertreating the regional lymph node basin(s).

Immunohistochemical (IHC) techniques such as staining with antibodies to cytokeratin (CK) can be used to detect epithelial cells, presumed to be metastases, in SLNs. This has resulted in the detection of IHC-positive cells in up to an additional 11.6% of patients.4–7 Whether these cells are truly cancer cells and, if so, whether they have clinical significance remain unanswered. The College of American Pathologists8 and the 2001 Consensus Conference on the Role of SLN Biopsy9 each concluded that decisions on adjuvant therapy and CALND should not be made based on the results of IHC examination of SLNs. Despite this, several reports detail the frequent use of CALND in patients with IHC-positive SLNs,10–14 including one recommending that CALND be considered for all such patients.13 Pending data from a large, ongoing prospective trial, clinicians will continue to be faced with decisions about whether to use IHC techniques and if so how to manage the axillae of patients with "metastases" detected by this methodology alone. In this study, we analyze the utility of CALND in these patients.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 REFERENCES
 
The protocol was approved by our institutional review board. We reviewed the prospective database at the Mayo Clinic in Scottsdale of all patients who have undergone intraoperative lymphatic mapping and SLN biopsy for breast carcinoma at our institution. Medical records were reviewed to supplement the database information. Between 1995 and October 2003, 750 SLN biopsies were attempted in 735 patients; 15 patients underwent bilateral SLN biopsies for bilateral malignancies. At least one SLN was identified in 738 (98.4%) of these procedures in 723 patients. These 738 SLN biopsies comprise the study group.

Lymphatic Mapping and SLN Biopsy Technique
Lymphatic mapping and SLN biopsy were performed with a combination technique utilizing injections of filtered 99mTc-labeled sulfur colloid and blue dye, with the exception of four patients mapped with blue dye alone. 99mTc-labeled sulfur colloid was injected either the day before operation (28%) or the day of operation (72%) in a subdermal (83.9%) or subareolar (16.1%) position. Blue dye was injected 5 minutes before making the axillary incision in either a subdermal (68.9%) or subareolar (31.1%) position. Lymph nodes were considered to be SLNs if they were stained blue, had a blue lymphatic entering the node, emitted gamma counts ≥10% of the highest gamma counts emitted by an SLN, emitted gamma counts more than four times those emitted by background nodes, or were palpably suspicious.

Pathologic Evaluation of SLNs
SLNs were cut into sections 2 to 3 mm in thickness. Following fixation and embedding in paraffin, they were sectioned serially at intervals of 50 microns for preparation of four tissue sections (levels), each measuring 4 microns in thickness. Levels one, two, and four were evaluated by hematoxylin and eosin (H&E) staining and level three was analyzed for cytokeratin by IHC with use of the pancytokeratin antibody AE1/AE3. The IHC method was performed with a Dako Autostainer (DakoCytomation, Woburn, MA) with both positive and negative controls. SLNs were considered to be positive for metastasis by only IHC staining if cells were identified as stained by antibodies to CK with no H&E correlate.

Statistical Methods
Statistical comparisons were made with {chi}2 analysis or two-sample t-test as appropriate. Significance was determined to be at P ≤ .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
REFERENCES
 
The study group included 723 patients who underwent 738 successful intraoperative mapping and SLN biopsy procedures. The patient and primary tumor data for this group are summarized in Table 1. The mean patient age was 64.1 years (range, 29–95). Most primary tumors were stage T1 (77.1%) or T2 (14.2%). The mean number of SLNs identified was 2.53 (range, 1–8). SLN metastases were identified by H&E in 151 patients (20.5%). No patient had bilateral metastases either by H&E or IHC.


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  		TABLE 1. All patients’ characteristics
 
Of the 738 SLN procedures, results of the IHC staining of the SLNs were available for 718. The other 20 patients were enrolled in the American College of Surgeons Oncology Group (ACoSOG) Z0010 trial and therefore had IHC performed at the central laboratory; these results were blinded to the patient and our institution. Thirty-three of these 718 patients (4.6%) had metastases identified by IHC only. This represents 5.7% of the 574 patients whose SLNs were negative for metastases by H&E.

The risk of H&E-detected metastases generally increased with increasing T-stage, while the risk of IHC-detected metastasis was more variable (Table 2). The rates of H&E-detected SLN metastases were consistent among tumors with ductal and lobular histology. In contrast, metastases detected only by IHC were nearly four times more likely among patients with some component of lobular histology than among those with pure ductal histology (11.9% versus 3.0%; P < .01; Table 2). The mean number of SLNs identified was 2.45 among those without metastases, 2.54 among those with H&E metastases, and 2.65 among those with IHC-detected metastases (P = .79).


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  		TABLE 2. Risk of sentinel lymph node (SLN) metastases by T stage and histology
 
In 27 of the 33 patients (81.8%) with IHC-detected metastases, the metastasis was present in a single SLN. The other six patients had IHC-detected metastases in two SLNs. The volume of disease detected in these patients included individual and small clustered cells in a subcapsular sinus (11; 33%), scattered individual cells (1; 3%), clusters of 3 to 25 cells (12; 36%), foci of 0.5 to 0.9 mm (8; 24%), and a 2-mm focus (1; 3%). Most patients had fewer than 100 cells staining positive by IHC.

Of the 151 patients with H&E SLN metastases, 133 (88.1%) underwent CALND. Five patients were randomized to no CALND in the American College of Surgeons Oncology Group Z0011 trial and 13 refused CALND. The mean number of lymph nodes in the CALND specimen was 16.8 (range, 7–31). Additional metastases were identified in 45 (33.8%) of these patients. The risk of detecting additional metastases increased with increasing T-stage (Table 3). The mean number of lymph nodes with metastases in the CALND was 1.52 (range, 0–29).


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  		TABLE 3. Risk of additional metastases detected in CALND
 
Twenty-eight (84.8%) of 33 patients with IHC-detected metastases underwent CALND. The median primary tumor size was 2.0 cm among those undergoing CALND and 0.9 cm among the five patients treated without CALND (P = .10). The mean number of lymph nodes in the CALND was 14.6 (range, 6–22). Two of the 28 patients (7.1%) had additional metastases detected with CALND. This risk of additional metastases detected with CALND was significantly less than the risk associated with an H&E-detected SLN metastasis (P = .007). The two patients with additional metastases both had advanced invasive lobular primary tumors (Table 3). One had a T3 primary with two of three SLNs showing IHC-detected foci of 0.3–1 mm in size, and the other had a T4 primary with one of two SLNs showing an IHC-detected focus of 0.4 mm. Of 24 patients with T1 or T2 primary tumors and IHC-detected metastases who underwent CALND, none had additional metastases detected. Median follow-up was 14.5 months. Of the five patients with IHC-detected metastases not undergoing CALND, none has subsequently manifested clinical axillary disease. All 33 patients with IHC-detected SLN metastases were treated with adjuvant systemic therapy; the tumors of 29 (87.9%) were estrogen- and/or progesterone-receptor-positive, and all 29 received adjuvant hormonal therapy. Fifteen (45.5%) were treated with cytotoxic chemotherapy.

COMMENTS
While SLN mapping and biopsy have become widely accepted for the staging of breast cancer patients, there is still much to be learned about performing these procedures in these patients. Because many institutions, including ours, perform CALND only if an SLN metastasis is identified, a premium is rightly placed on minimizing false-negative SLN biopsies. This has led to a routine of detailed pathologic examination of SLNs, including in most cases IHC staining or reverse transcriptase polymerase chain reaction. Clearly these practices have led to the detection of previously unrecognized metastases, but it is not clear if the cells thus detected represent true metastases and, if so, whether they are clinically relevant. This is certainly true for cells detected only by IHC techniques. The question of the clinical relevance of IHC-detected "metastases" will soon be answered by the ACoSOG Z0010 trial. While awaiting the data from this trial to mature, however, clinicians will continue to make treatment decisions based on limited data.

The first decision forced by IHC-detected metastases is whether a CALND should be performed. This is an important decision for several reasons. The current American Joint Committee on Cancer (AJCC) staging system classifies these patients as N0, so if an H&E-detected metastasis is present in another node, a CALND would upstage the patient to N1. In addition, if other lymph node metastases are present, a CALND could have an impact on regional control of disease or survival. Finally, additional disease detected by CALND could change adjuvant treatment recommendations. If, on the other hand, no additional metastases are detected, then the patient is unlikely to reap any benefits in exchange for the added morbidity associated with a CALND.15 Although the College of American Pathologists8 and the 2001 Consensus Conference on the Role of SLN Biopsy9 each concluded that the decision to perform a CALND should not be based on the results of IHC examination of SLNs, in practice this finding cannot be ignored.

This study demonstrates that among a limited number of patients with IHC-detected SLN metastases, the risk of H&E-detected metastases in non-SLNs was 7.1% overall and 0% in patients with T1 or T2 primary tumors. This low risk is consistent with the fact that disease burden within the SLN and primary tumor size are the strongest predictors of non-SLN metastases.14,16 Had those patients in our series with IHC-detected SLN metastases been considered to be node-negative and not undergone a CALND, our absolute false-negative rate would have been worsened by 1.3% (2 false negatives/153 true positives). This rate is comparable to the corresponding potential false-negative rates for other reported studies of IHC-detected SLN metastases: 0%,10 1.2%,11 and 2.6%.13

The risk of additional lymph node metastases being found with CALND appears lowest for patients with small primary tumors with pure ductal histology. The number of patients in our series is too small to draw a firm conclusion, however. There did appear to be a selection bias in our patients with IHC-detected metastases who underwent CALND, since the median primary tumor size was 2.0 cm versus 0.9 cm for those without CALND. This difference failed to reach statistical significance (P = .10), perhaps due to the small sample size. It is unlikely that any of these patients not undergoing CALND had metastases in non-SLNs, given the smaller median tumor size and the lack of subsequent clinical axillary disease. These patients were not included in the calculation of the risk of additional metastases, however, as the median follow-up is too short to draw this conclusion.

While our results demonstrate that IHC-detected SLN metastases are much less likely to indicate disease in non-SLNs than H&E-detected metastasis, this represents only circumstantial evidence regarding the overall clinical significance of IHC-detected metastases. However, there is other evidence to suggest that IHC techniques detect disease that is not clinically relevant. Metastases detected by IHC only have been reported in up to 13% of patients with pure ductal carcinoma in situ (DCIS).17,18 This is despite the fact that axillary treatment has routinely been omitted for patients with DCIS over the past 20 years without reports of widespread axillary recurrences and an overall survival exceeding 98%.19 In addition, reexamination of the lymph nodes of patients with DCIS by means of IHC techniques has demonstrated IHC-detected disease in patients who are alive without recurrence 10 to 28 years later.20 One would not expect as many as 13% of patients with DCIS to manifest clinical axillary disease if an SLN is not identified and removed. Therefore, the reported high rates of IHC-detected "disease" in DCIS patients would suggest that IHC techniques detect at least some clinically insignificant metastases. However, this is only circumstantial evidence.

There have been previous reports of the rate of non-SLN metastases in patients with invasive breast cancer and IHC-detected SLN metastases. In 1999, Chu et al.10 at the John Wayne Cancer Institute reported that none of 33 patients with IHC-detected SLN metastases were found to have additional metastases upon CALND. This included data from CALNDs in all patients with IHC-detected disease. They proposed that CALND might not be beneficial for patients with SLN micrometastases from T1 or T2 tumors.

In 2001, Wong et al.11 in The University of Louisville Breast Cancer Study Group reported that six of 58 patients (10.3%) with SLN metastases detected only by IHC were found to have additional nodal metastases upon CALND. This study also included CALND for all patients with IHC-detected disease. The authors concluded that while IHC analysis may slightly improve the false-negative rate for SLN biopsy, this tiny reduction did not constitute a compelling reason to perform IHC staining routinely. They went on to report that they would discontinue the use of routine IHC analysis of SLNs at their institution.

Jakub et al.13 at the H. Lee Moffitt Cancer Center reported in 2002 that nine of 62 patients (14.5%) undergoing CALND for an IHC-detected SLN metastasis were found to have additional metastases within the CALND specimen. In contrast to the studies cited above, 21% of their patients with IHC-detected SLN metastases did not undergo CALND, and no comment on the characteristics or follow-up of these patients was given. In their series, though, 12.2% of patients with T1 primary tumors who did undergo CALND had non-SLN H&E-detected metastases. Thus, the impact of selection bias may have been minimal. These authors, in sharp contrast to Wong et al., concluded that CALND should be considered for all patients with IHC-detected SLN metastases.

We believe that the results of our study support counseling patients with SLN metastases detected only by IHC techniques that they are at low risk for additional metastases, before CALND is offered. We base this on the low risk of additional metastases as evidenced in our study and those of others,10,11 the suggestive evidence that IHC techniques detect at least some clinically irrelevant disease, the questionable impact of axillary dissection on overall survival,21,22 and the significant morbidity associated with CALND.15 These factors argue against mandating CALND in these patients, pending available data from the ACoSOG Z0010 trial. Certainly careful individual counseling is warranted; the risks and benefits of foregoing CALND should be clearly communicated and the patient should be involved in the final decision-making. We do believe that the use of IHC techniques can be complementary, however, by aiding the identification of H&E metastases, especially in the case of lobular histology.23 We do not, therefore, recommend the widespread abandonment of this technique but recommend instead a reasoned, individualized interpretation of the results.


   FOOTNOTES
 
This study demonstrates a low prevalence of additional nodal metastases in patients with sentinel lymph node metastases detected by immunohistochemistry staining only. These patients should be counseled about this low risk before complete axillary lymph node dissection is recommended.

Received for publication March 18, 2004. Accepted for publication August 13, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 REFERENCES
 

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