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Annals of Surgical Oncology 9:235-242 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Sentinel Lymphadenectomy After Neoadjuvant Chemotherapy for Breast Cancer May Reliably Represent the Axilla Except for Inflammatory Breast Cancer

Vered Stearns, MD, C. Alexander Ewing, MD, Rebecca Slack, MS, Marie F. Penannen, MD, Daniel F. Hayes, MD and Theodore N. Tsangaris, MD

From the Breast Cancer Program, Department of Oncology (VS, RS, DFH), Department of Pathology (CAE), Biostatistics Unit (RS), and Department of Surgery (MFP, TNT), Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC.

Correspondence: Address correspondence and reprint requests to: Vered Stearns, MD, University of Michigan Comprehensive Cancer Center, 6303 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0942; Fax: 734-615-3942; E-mail: stearnsv{at}umich.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: After neoadjuvant chemotherapy, women with locally advanced breast cancer (LABC) undergo a modified radical mastectomy or lumpectomy with axillary lymph node dissection (ALND) and radiotherapy. Sentinel lymphadenectomy (SL) is accepted for axillary evaluation in early breast cancer. We assessed the feasibility and predictive value of SL after neoadjuvant chemotherapy.

Methods: Eligible women received neoadjuvant therapy for LABC and were scheduled to undergo a definitive surgical procedure. Vital blue dye SL was attempted followed by level I and II axillary dissection.

Results: SL was successful in 29 of 34 patients (detection rate, 85%). Thirteen patients (45%) had positive nodes, and eight (28%) had negative nodes on both SL and ALND. In five patients (17%), the sentinel node was the only positive node identified. Overall, there was a 90% concordance between SL and ALND. The false-negative rate and negative predictive value were 14% and 73%, respectively. Among the subgroup without inflammatory cancer, the detection and concordance rates were 89% and 96%, respectively. The false-negative rate was 6%, and the negative predictive value was 88%.

Conclusions: SL after neoadjuvant chemotherapy may reliably predict axillary staging except in inflammatory breast cancer. Further studies are required to assess the utility of SL as the only mode of axillary evaluation in these women.

Key Words: Locally advanced breast cancer • Inflammatory breast cancer • Neoadjuvant chemotherapy • Sentinel lymph node mapping • Sentinel lymphadenectomy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Axillary lymph node dissection (ALND) has been an integral part of breast surgery in women with primary breast cancer.1 Women with locally advanced breast cancer (LABC) generally undergo a modified radical mastectomy or a lumpectomy and ALND after preoperative chemotherapy.2 Neoadjuvant chemotherapy may also be administered to women who do not have LABC to facilitate breast-conserving surgery.3,4

ALND is performed for both therapeutic and prognostic purposes. Many patients with breast cancer, especially those with locally advanced disease, present with a clinically positive axilla and have a high chance of positive lymph node status at the time of surgery. The goal of ALND in this case is to enhance regional control. Axillary lymph node involvement is also an important determinant of tumor progression, invasion, and metastases.5 Generally, a greater number of positive lymph nodes is associated with a higher chance of developing systemic breast cancer recurrence.6 Evaluation of the presence and number of lymph nodes involved with micrometastases may assist in adjuvant treatment recommendations and decision-making. Although the survival benefit of ALND is controversial, the procedure decreases local recurrence rates and in turn may decrease distant recurrences. Thus, it is possible that ALND may enhance survival in a small subset of women.

However, ALND is not without morbidity. Although complications after axillary surgery are uncommon, they are associated with discomfort or impairment.7–9 Major, but rare, complications include injury to the main vessels or nerves in the axilla. Minor, but much more common, complications include arm lymphedema, loss of sensation, shoulder dysfunction or limitation of motion, and seroma formation.

Most women with a stage III breast cancer will have chest wall irradiation after a mastectomy or breast irradiation after lumpectomy. Breast or chest wall radiation fields involve a portion of the axilla.1 Axillary radiation after ALND further increases the morbidity rate, especially arm lymphedema.10

Over the last few decades, there has been a trend in the United States to perform more conservative breast surgeries.1 In addition, most women are diagnosed with early stages of breast cancer, when no micrometastases to axillary lymph nodes can be identified. Sentinel lymph node mapping, or sentinel lymphadenectomy (SL), has been developed to remove a limited number of lymph nodes that might represent the status of the axilla. This technique dramatically decreases the morbidity to the axilla while accurately predicting axillary nodal status.11–14

To date, SL seems reproducible, feasible, and accurate in patients with stage I or II breast cancer. Indeed, when performed by experienced surgeons, SL is successful in up to 90% of women, and the accuracy may exceed 95%.15 Although SL seems to be highly predictive of nodal status in women with small primary breast cancer, it is not known whether LABC or primary chemotherapy will change the ability to identify the sentinel node or its predictive value. We conducted an evaluation to assess the feasibility and predictive value of SL after neoadjuvant therapy for LABC.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Women, 18 years or older, who received primary chemotherapy or endocrine therapy for histologically proven infiltrating carcinoma of the breast and who underwent an SL during the definitive surgical procedure, were included. Any woman with a T3 or T4 breast cancer who was treated by one of two surgeons at the Georgetown University Medical Center and who received her primary therapy at the Lombardi Cancer Center was eligible and was included in the analysis. The women then underwent either a modified radical mastectomy or a lumpectomy and ALND.

Sentinel Lymphadenectomy
Before the operative procedure was started, 3 to 5 ml of 1% isosulfan blue dye was injected around the primary breast tumor. If no palpable tumor was identified at the time of the procedure, the dye was injected around the area where tumor was previously palpated. A separate incision was made in the axilla, and the lymphatic vessels were identified and followed to the first (sentinel) node that drained the blue dye. The sentinel node or nodes were collected and immediately sent to surgical pathology. If palpable nodes were appreciated at the time of surgery, they were removed but were not considered sentinel nodes unless the nodes were also picked up by the blue dye. After the sentinel node was excised, a full level I and II axillary dissection was performed. The patient then underwent lumpectomy or mastectomy as previously planned. The axillary contents and breast tissues were sent for standard histopathological evaluation.

Histological Evaluation of Sentinel Lymph Nodes
Sentinel lymph nodes were bivalved along the long axis in the fresh state. One half of each sentinel node was initially examined via two levels of hematoxylin and eosin (H&E)–stained frozen sections at the time of surgery. After analysis of the frozen sections was complete, all sentinel node tissues were fixed in formalin, embedded in paraffin, and processed for permanent sectioning with routine H&E staining. If metastatic disease was identified in a sentinel node, or if the sentinel node and remaining axillary contents were free of disease, no further evaluation was performed.

In contrast, false-negative sentinel nodes were further evaluated for the presence of micrometastases by use of cytokeratin immunohistochemistry (IHC) and serial step sectioning. Paraffin tissue blocks of false-negative sentinel nodes were evaluated with four additional levels. Levels 2, 3, and 4 were stained with H&E. Level 1 was stained with a cytokeratin antibody. Avidin-biotin-peroxidase method was performed on the paraffin-embedded sections with use of a commercially available pan-keratin antibody cocktail (ChemMateTM Primary Antibody Pan Keratin Clones AE1, AE3, CAM 5.2, and 35ßH11; Ventana, Tuscon, AZ). The keratin IHC stain was considered positive if it showed keratin-positive clusters of atypical cells or multiple single atypical cells in a lymph node.

Statistical Methods
One primary end point of the study was to evaluate the sentinel node detection rate after neoadjuvant chemotherapy. A second end point was to evaluate whether the status of the permanent section of the sentinel node (positive or negative for the presence of cancer) accurately predicted cancer presence or absence as determined by H&E staining of the axillary lymph node obtained through the full level I and II dissection. The proportion of patients with a sentinel node detected was reported with an exact binomial 95% confidence interval (CI).16 Similarly, we reported the concordance between the frozen section and the permanent section with a 95% CI. Sensitivity, the false-negative rate (FNR), and the negative predictive value (NPV) are reported for SL, by using ALND as the gold standard, for those patients whose sentinel node was detected.17 Ninety-five percent CIs were calculated according to the method for risks in a 2 x 2 table as implemented in SASTM (SAS Institute, Cary, NC).18 A positive sentinel node was considered a true positive even when the remaining nodes were negative. Therefore, specificity and positive predictive value were 100% by definition.17 No further discussion of these measures will be included except to describe comparison of the sentinel node frozen section and the sentinel node permanent section.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
From November 1997 to July 2000, 34 women were included in this investigation. The patients’ characteristics are listed in Table 1. Median age at the time of the definitive surgery was 46 years (range, 29–79 years). Twenty-five women (74%) had a T3 lesion. Eight women (24%) had inflammatory breast cancer. Seven patients (20%) received preoperative combination doxorubicin and cyclophosphamide, and 24 (71%) received doxorubicin and paclitaxel with or without cyclophosphamide. One woman (3%) received AC followed by weekly paclitaxel and trastuzumab. Two women (6%) received neoadjuvant endocrine therapy. Only five women had gross nodal disease before the surgical procedure. One of the main goals of primary chemotherapy is to allow for breast conservation. Indeed, of the 25 women with a T3 lesion, 14 women (56%) had successful breast-conserving therapy.


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  		TABLE 1. Patient characteristics
 
Identification of Sentinel Nodes
Sentinel lymph nodes were identified in 29 patients, for a detection rate of 85%, with a 95% CI of 73% to 97%. The median number of sentinel lymph nodes was 2 (range, 1–7). For the five women whose sentinel nodes were not identified, 0, 1, 2, 5, and 10 positive nodes were identified in the subsequent node dissection (Table 2). Two of these patients had inflammatory breast cancer, one woman had an upper inner quadrant lesion and known internal mammary involvement, and two additional patients had a central lesion. All five women received preoperative dose-dense single-agent sequential chemotherapy with doxorubicin and paclitaxel and had a negative axilla before the surgical procedure.


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  		TABLE 2. Characteristics of patients with nondetectable sentinel nodes
 
Identification of Sentinel Node and Tumor Location
Of the 26 women with noninflammatory breast cancer, 16 tumors (62%) were located in the upper outer quadrant of the affected breast. Five tumors (19%) were central. Three tumors (11%) were in the upper inner quadrant, one (4%) was in the lower outer quadrant, and one (4%) was in the lower inner quadrant. As we noted previously, of the five patients with unsuccessful SL, two had inflammatory breast cancer, two had a central lesion, and one had an upper inner quadrant lesion and a known positive internal mammary lymph node. Of the five women with a central lesion, SL was successful in only three, for an identification rate of 60% and a 95% CI of 7% to 100%. The detection rate among the four women with inner quadrant breast tumors was 75%, with a 95% CI of 20% to 100%.

Concordance Between SL and ALND
Of the 29 patients whose sentinel node was identified, 13 (45%) had positive nodes on SL and ALND, and 8 (28%) had negative nodes on SL and ALND (Table 3). In five women (17%), the sentinel node was the only positive node identified. The sensitivity and NPV of SL in our cohort were 86% and 73%, respectively. SL accurately represented the axillary status in 90% of the patients (Table 3).


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  		TABLE 3. Concordance between sentinel nodal status and axillary lymph nodes
 
Lymph node micrometastases were identified in the ALND in three patients in whom SL was negative (Table 4). Thus, the procedure was not accurate in 10% of patients (FNR, 14%). All three patients had a negative axilla before the surgical procedure. Two of the three patients with a false-negative SL had inflammatory breast cancer. Of those, one patient had multifocal residual disease and had four lymph nodes involved with micrometastases on ALND. A second patient had a pathologic complete response in the breast and only a few cells identified in two positive nodes on ALND, with marked nodal fibrosis and xanthomatous reaction. In addition, the same woman had one intramammary node removed; it contained micrometastatic disease on H&E evaluation. A third patient, who did not have a clinical diagnosis of inflammatory breast cancer, had a reactive sentinel lymph node with fibrosis, focal calcification, and histiocytic and giant cell reaction with cholesterol clefts. A retrospective review of the surgical specimen revealed extensive lymphatic involvement. Sentinel node tissues from the three false-negative cases were re-evaluated via serial step sectioning and IHC for cytokeratin in an attempt to detect micrometastases. In one of the three, IHC cytokeratin staining was positive in the sentinel node. The metastatic focus consisted of scattered single cells in an otherwise fibrotic area of the node.


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  		TABLE 4. Characteristics of patients with false-negative sentinel lymphadenectomy
 
Inflammatory Breast Cancer Subgroup
Eight patients in our cohort had inflammatory breast cancer. Of those, three (38%) had positive nodes on SL and ALND, and one (13%) had negative nodes on SL and ALND. In two patients (25%), a sentinel node was not identified, and in two additional patients (25%), SL was false negative. The identification rate was 75%, with a 95% CI of 35% to 92%. Thus, the successful SL rate in women with inflammatory breast cancer was 75%, compared with 89% in women with locally advanced, noninflammatory breast cancer. The sensitivity and NPV of successful SL in the 23 patients with a T3 lesion were 94% and 88%, respectively. The accuracy rate for noninflammatory breast cancer was 96%, with an FNR of 6% (Table 3).

Correlation Between Frozen and Permanent Sections of the Sentinel Node
Frozen sections of sentinel nodes are performed routinely at our institution. To determine whether the accuracy of frozen section evaluation of the sentinel node differed in this patient population compared with the standard population at our institution, the frozen section diagnosis for each patient was compared with the permanent section diagnosis. Of the 29 women in whom a sentinel node could be identified, 28 had frozen sections performed on their sentinel lymph nodes. In the one remaining patient, by the surgeon’s request the sentinel node was submitted directly for permanent processing without a frozen section.

Of the 28 cases with frozen section diagnoses, 21 (75%) were concordant. Of the seven discordant cases, five had frozen sections that were reported negative but for which permanent sections were positive. Two remaining cases were determined positive for metastatic cancer on frozen section but were subsequently negative on permanent section of the sentinel node and in ALND. Thus, the sensitivity of frozen section analysis in this group of patients compared with the gold standard (H&E of the permanent section) was 71%, and specificity was 82%. The positive predictive value and NPV were 86% and 64%, respectively.

Of the five false-negative cases, one frozen sentinel node was determined as highly suspicious, and diagnosis was deferred to permanent section. In one case, the half of the specimen that was selected for frozen section did not contain lymphoid tissue, but it was later discovered on permanent sections that the other half contained a small lymph node with metastatic tumor. In two cases, only permanent section control slides of the frozen section tissue contained metastatic tumor; in each case this involved a microscopic, adjacent, second lymph node in the sentinel node biopsy tissue that was not present on the frozen section slides. Finally, in one case, retrospective review of the actual frozen section slides demonstrated rare metastatic tumor cells. In all cases, the metastatic tumor was <1 mm in total diameter.

On review of the two false-positive cases, one sentinel lymph node was highly reactive, with marked sinus histiocytosis and many atypical histiocytes and giant cells. Subsequent IHC for keratin was negative. In the second case, exuberant reactive lymphoid hyperplasia was present.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Over the last 100 years, many attempts have been made to allow for more conservative breast surgeries. Indeed, 50% to 75% of women with a stage I or II breast cancer in the United States undergo breast-conserving therapy.18 However, in LABC, the treatment of choice remains modified radical mastectomy, and only approximately 20% to 30% of women who receive primary chemotherapy may have breast-conserving surgery and ALND instead.19 In addition, most women with LABC will receive breast or chest wall radiation. Most of these women have a very high risk of systemic recurrence.20 Thus, conservative evaluation of the axilla and minimizing the morbidity relating to this evaluation are desirable.

In this investigation, we included women with T3 or a T4 breast cancer who received neoadjuvant chemotherapy or endocrine therapy. Large randomized clinical trials demonstrated that preoperative chemotherapy enhances breast-conserving local therapy but does not affect survival in primary breast cancer.4 Indeed, among the 26 women with T3 disease in our series, breast conservation was successful in 14 (56%). In addition, administration of neoadjuvant chemotherapy allows for accurate tumor measurements and assessment of response to therapy, perhaps permitting for an individual patient’s estimate of prognosis.21,22 We demonstrated that SL in a group of women with LABC was accurate in 90% of the cases. Furthermore, serial step sectioning and IHC detected occult micrometastatic disease in one of the three false-negative sentinel nodes. When we excluded women with inflammatory breast cancer, SL was accurate in 96% of the patients evaluated.

Only a few investigators have previously reported assessment of the role of SL in women who have received primary chemotherapy. In the largest retrospective investigation, 51 women who received primary chemotherapy underwent SL with blue dye alone or in combination with 99mTc-labeled sulfur colloid.23 The procedure was successful in 84% of the women, with an accuracy rate of 93%, including 46% in which the sentinel node was the only positive node. The FNR in the investigation was 12% (3 false-negative cases of 25 women with positive axillary nodes by standard ALND). In a smaller investigation of women who received preoperative chemotherapy, an FNR of SL with use of both isosulfan blue dye and 99mTc-labeled colloid was 33% (three false negatives in nine women with positive axillary nodes on ALND).24

Our results are similar to those of the larger published report. However, we also included women with inflammatory breast cancer. Of the eight patients with inflammatory breast cancer, SL was unsuccessful in two, and in an additional two patients the sentinel node was negative and the other axillary nodes were positive. Exclusion of the inflammatory breast cancer cases increased the accuracy rate and decreased the FNR of our series substantially (to 96% and 6%, respectively). Inflammatory breast cancer represents a clinical diagnosis. The process usually presents with a diffuse infiltration of the breast, the dermis, and its lymphatics, often without a definitive mass. The underlying biology of this entity is likely to be very different from that of primary noninflammatory breast cancer. Because of cancer infiltrating the dermis and lymphatics, there may be an occlusion of lymphatic channels in the breast. In turn, it may be difficult to identify sentinel nodes or we must accept a high FNR.

In addition, SL was successful in all 17 women with noninflammatory breast cancer and with outer quadrant breast cancers. The procedure was less successful in women with central and inner quadrant lesions. However, the numbers in each group were small (5 and 4 for central and inner quadrant lesions, respectively). In our institution, blue dye only is used for SL; this does not allow for determination of nonaxillary sentinel nodes. It is possible that the major lymphatic drainage in women with central or inner quadrant lesions is into the internal mammary chain. Inner quadrant lesions may represent a relative contraindication to SL. Alternatively, 99mTc-labeled sulfur colloid may represent a better mode of evaluation in this group of women.

Other explanations for false-negative SL cannot be excluded. For example, gross residual disease represents a contraindication to SL in primary breast cancer and may be associated with a high FNR. However, only five women in our study had palpable adenopathy after the primary therapy, and all five women had positive sentinel nodes. Poor response to the primary therapy and a large residual tumor in the breast or good response in the breast and axilla that is associated with marked residual fibrosis may be associated with a high FNR. The sample size in our study is too small to allow for subgroup analyses. Future studies designed to answer this and other questions are therefore required.

The evaluation of the frozen and permanent sections of the sentinel node was compared with an earlier report from our institution.25 The former study reviewed 138 consecutive cases of SL for patients with breast carcinoma who had not received neoadjuvant chemotherapy. In that earlier series, 49 patients had positive sentinel nodes at final diagnosis. Of these 49 patients, 9 were initially diagnosed as having a negative sentinel node by frozen section. On retrospective review of all slides, only one discordant case had carcinoma on the actual frozen section slides. The remaining eight discordant cases showed small (all <=1 mm) metastases only on the permanent sections—essentially a sampling error of the sentinel node tissue at the time of frozen section. There were no false positives in that series.25 Other investigators have reported that in a series of 890 consecutive patients who underwent SL and for whom frozen sections were available, routine perioperative frozen sections accurately diagnosed only 58% of the true sentinel node– positive cases (sensitivity 40%–76% on the basis of tumor size).26 Only one false-positive case was reported. In our analysis, the NPV of the comparison between the frozen and permanent sections of the sentinel node was 64%, suggesting that a frozen section is not sufficiently reliable to make determinations regarding the presence or removal of additional nodes. Indeed, several centers do not perform routine intraoperative evaluation of sentinel nodes.27

In conclusion, in noninflammatory LABC, SL after neoadjuvant chemotherapy accurately predicted the axilla in 96% of the cases. On the basis of our results and those of others, SL after neoadjuvant chemotherapy should not represent an absolute contraindication to SL. As discussed in the introduction, the role of axillary evaluation is dual: therapeutic and prognostic. In women with LABC, the prognosis at diagnosis is poor, and multimodality therapy is recommended regardless of the number of lymph nodes that may be present at the time of definitive surgery. In women with a clinically positive axilla, ALND should be conducted for therapeutic and local control reasons.

One might question the prognostic nature of nodal dissection after neoadjuvant therapy in patients with LABC. If the axilla were clinically negative, would the presence of micrometastases in axillary nodes dictate subsequent systemic therapy? Over the last decade, multiple nodes at the time of surgery would often prompt a recommendation for high-dose chemotherapy and peripheral stem-cell rescue or a bone marrow transplantation. However, enthusiasm regarding this treatment modality has diminished.28

Likewise, is local therapy likely to be altered on the basis of the presence or absence of axillary lymph node micrometastases after neoadjuvant therapy and surgery? Currently, most women with LABC receive radiotherapy, regardless of the definitive surgical procedure or the nodal status. Although new approaches may be used in the future in women with large residual disease or many metastatic axillary lymph nodes, in the year 2002 it is unlikely that treatment recommendations will change on the basis of the nodal status in women with LABC. Furthermore, women with LABC are at a very high risk of a systemic recurrence. Therefore, delineation of negative nodes or a few positive nodes in LABC after neoadjuvant therapy is unlikely to substantially change further treatment recommendations. This group of women may derive great benefit from minimizing the axillary procedure. Further studies are required to assess the role of SL as the only mode of axillary evaluation in women with T3 breast cancer who have received neoadjuvant chemotherapy.


   Acknowledgments
 
Supported by grant CI-3 of the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation (V.S.) and by a grant from the Fashion Footwear Foundation/QVC Presents Shoes on Sale®.

Received for publication June 29, 2001. Accepted for publication December 5, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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