A Decade of Sentinel Lymph Node Mapping in Breast Cancer:
A Hypothesis - Driven Journey Toward a New Paradign
Grube BJ, Hansen NM, Turner RR, Brennan MB, Krasne DL, Glass EC, Giuliano AE

Axillary lymph node dissection (ALND) has been an integral component of the surgical management of invasive breast carcinoma. For much of the 20th century, breast cancer was believed to spread in an orderly process. Radical en bloc resection of the breast, adjacent tissues and its draining lymphatics was the standard of surgical therapy. During the 1970's, this concept was challenged by Fisher, who suggested that breast cancer was a systemic disease from inception and that the surgical management of this disease should be reevaluated. Out of this challenge grew the trials that confirmed breast conservation treatment of early breast cancer resulted in equivalent long term survival.

During the 1980's, Morton conducted experiments to determine if intraoperative lymphatic mapping (ILM) could replace complete lymph node dissection as a low morbidity procedure for staging of melanoma. In October of 1991, Giuliano began to test the feasibility of ILM and sentinel lymph node dissection (SLND) for patients with breast cancer to eliminate routine ALND without losing the staging accuracy derived from complete ALND. During the past decade SLND at the JWCI evolved as a technique, enhanced axillary staging, was validated as a concept, demonstrated no adverse outcome and decreased morbidity. The challenge for the next decade is validation of the concept of SLND in multi-institutional trials, determination of the clinical relevance of SLN assessment in staging and its role for directing oncologic treatment algorithms for better comprehensive treatment of breast cancer.

Can a sentinel draining lymph node be identified intraoperatively in breast cancer? In 1991, there was no established protocol for ILM for breast cancer. The purpose of the pilot study was to establish the methodology of ILM and SLND in breast cancer and to determine the feasibility, safety and accuracy of ILM for early stage breast cancer (1).

Between October 1991 and February 1, 1994, 174 patients underwent planned ILM and SLND followed by a Level I, II and some III ALND. This study was designed to determine the quantity of isosulfan blue dye (0.5-10 cc), the appropriate site of injection (tumor vs parenchyma vs biopsy site) and the length of time to allow for lymphatic flow from injection to axillary incision (1 to 20 minutes) necessary for identification of putative lymphatics and SLN.

Figure 1

This first developmental study established the guidelines of 3-5 cc isosulfan blue, injected peritumorally in breast parenchyma or in the wall of the biopsy cavity and a standard time interval of 5 minutes. Figure 1 demonstrates the typical appearance of blue lymphatic channel tracking to sentinel blue nodes (Figure 1).

During Phase 1 (Developmental Phase), the ability to identify the SLN was 58.6% with an accuracy of 94.3%. As the technical variables were refined and the method evolved (Phase 2), the ability to identify the SLN improved. The last 50 test cases demonstrated a 78% ability to identify the SLN with 100% accuracy. Data shown in Figure 2A and B.

• Intraoperative lymphatic mapping and sentinel node identification in breast cancer was technically feasible, safe and without added complications
  
  
• Injection of 3-5 cc 1% isosulfan blue followed by surgery ILM in 5 minutes resulted in identification of the SLN
  
  
• SLND identifies the first ("sentinel") axillary lymph node draining the primary tumor and most likely node to harbor metastases
  
  
• Sentinel lymph nodes were found in Level I or II, not Level III
  
  
• The SLN is an accurate predictor of the status of the axilla

• Further refinements in the procedure are likely to improve accuracy
  
  
• Future role of ALND may be modified by status of SLN

Does routine histologic evaluation of ALN provide adequate information of the status of the axilla? The next study hypothesized that focused histopathologic analysis of the SLN could enhance staging by thorough examination of 1-2 lymph nodes likely to contain metastases (2) .

In 1995, axillary staging in 134 patients with ALND was compared to 162 patients with SLND followed by completion ALND. One to two sections of all nonsentinel lymph nodes were evaluated with H&E. Multiple sections of the SLN were evaluated with H&E and anticytokeratin IHC.

The number of patients with axillary metastases was 29.1% in the ALND group and 42.0% in the SLND followed by ALND group (p<0.03). The results are shown in Table 1.

• SLND with multiple sectioning and IHC staining of the SLN increases accuracy of axillary staging
  
  
• Histopathologic evaluation of the SLN identifies more patients with axillary metastases which could be missed on routine H&E examination
  
  
• Micrometastases are easier to identify in the SLN with multiple sections and IHC

Could the refinement of SLND and histopathologic evaluation improve the ability to identify a SLN and accurately stage the axilla over what was originally determined in the pilot study? By 1994, the experience with ILM and SLND for breast cancer had grown, the technique had been refined and the pathologic handling of the SLN was more sophisticated with increased detection of metastases. From the inception of the SLND in 1991, the number of patients with clinically negative axillae who were treated with SLND followed by completion ALND increased (Figure 3).

The purpose of this study was to validate SLND with the mature surgical and pathologic techniques as accurate and sufficient to stage the axilla in breast cancer (3).

From July 1994 to October 1995, 107 patients with potentially curable breast cancer underwent SLND with the mature method. SLND was followed by Level I, II and part III ALND in conjunction with breast-conserving surgery or mastectomy. The SLN was evaluated with H&E and IHC. Nonsentinel nodes were evaluated by H&E.

The median age of the patients was 56.6 years. The mean tumor size was 2.11 + 1.38 cm. SLN was identified in 100 of 107 patients (93.5%). There were 42 patients with (+) SLN and 28 (66.7%) had no other positive ALN. The method of detection is shown in Table 2. The status of the axilla relative to the tumor size is shown in Table 3. In the seven patients with no SLN identified, 6 had a tumor free axilla.

• SLND is minimally invasive
  
  
• ILM with 1% isosulfan blue identifies the SLN in 93.5% cases
  
  
• SLN histopathologic analysis with cytokeratin IHC is highly accurate
  
  
• SLND was 100% accurate with no false negatives

Is the enhanced detection of metastases, especially micrometastases a reflection of the intense histopathologic evaluation of the SLN compared to nonsentinel nodes and does not represent any biologic significance? The purpose of this study was to determine whether the sentinel node is truly the axillary lymph node most likely to harbor metastatic tumor and to assess the true histologic false-negative rate of SLND at our institution (4) .

From February 1994 to October 1995, 103 patients underwent SLND followed by completion ALND. The median age was 55. The median tumor size was 1.8 cm. H&E staining identified 33 patients with (+) SLND (32%). IHC evaluation of 157 (-) SLN upstaged 10 patients (14.3%) (Table 4). In 60 patients whose SLN were negative by H&E and IHC, 1087 nonsentinel nodes were examined at 2 levels by IHC. Only 1 additional tumor positive node was identified.

The final tumor status of sentinel and nonsentinel axillary nodes demonstrates that SLND alone would be sufficient for 57.3% of patients with no evidence of axillary metastases. In addition, 24.3% had only involvement of the SLN (Table 5)

• If the SLN is tumor free by H&E and IHC, the probability of nonSLN involvement is <0.1%
  
  
• The false negative rate for nonSLN metastasis is 0.97%
  
  
• The SLN is the most likely node to harbor metastases

The standardization of SLND, the validation with completion ALND and complete histopathologic assessment of the SLN and nonSLN challenges the establish paradigm of ALND for staging in breast cancer when the SLN is negative. In 1995, the ability to identify the SLN was 93.5% and the accuracy of the SLN to predict the status of the axilla was 99%. The purpose of this study was to determine the complication rate and the local recurrence rate in women who had a tumor-free SLN who did not undergo ALND (5).

From October 1995 to July 1997, 133 consecutive women with tumors <4 cm underwent SLND for staging. SLND was the only axillary operation if the SLN (-). Completion ALND was performed when the SLN (+).

SLND identified the SLN in 132/133 patients (99% accuracy). Eight patients were excluded from analysis. Three elderly patients with SLN micrometastases refused ALND and five because of subsequent ALND. All 5 patients were SLN (-) and ALND (-). The status of the axilla is shown in Table 6.

Complications occurred in 20 patients (35%) undergoing ALND after SLND, but in only two patients (3%) undergoing SLND alone (p=0.001). There were no local recurrences at a median follow-up of 39 months.

• The ability to identify the SLN in breast cancer with intraoperative lymphatic mapping with 1% isosulfan blue is 99%.
  
  
• Minimally invasive SLND results in statistically significant reduction in axillary morbidity
  
  
• SLND alone does not demonstrate any adverse outcome for locoregional control at a median follow-up of 39 months.

At the close of the 20th century, the surgical treatment of breast cancer has turned to refined surgical assessment of locoregional disease to minimize the morbidity of breast cancer surgery without compromising locoregional control. The enrollment into multicenter national trials such as the ACoSOG Z10 and Z11 seek to further delineate the extent and type of surgical intervention appropriate for the treatment of breast cancer using ultrastaging. Intraoperative lymphatic mapping with isosulfan blue and SLND has brought us to a new series of questions regarding the most appropriate surgical intervention in the axilla, much like breast conserving surgery did 30 years ago.

Since May 1999, 207 patients at the JWCI have been enrolled in the ACoSOG Z10 Trial. There was 100% ability to identify the SLN.

• A method was defined
  
  
• Improved Staging was demonstrated with the SLN
  
  
• Complete axillary node assessment was seminal for verification of the SLN as the first tumor draining node
  
  
• Single institution validation with the refined technique confirmed the principle
  
  
• SLND for node negative patients has become a new paradigm for breast cancer treatment n SLND is undergoing multicenter validation
  
  
• The future role of SLND in breast cancer is as a fulcrum around which new clinical trials are designed to answer questions about staging and multidisciplinary treatment

1. Giuliano, A., Kirgan, DM, Guenther, JM, Morton, DL (1994) Lymphatic Mapping and Sentinel Lymphadenectomy for Breast Cancer. Ann Surg, 220, 391-401.

2. Giuliano, A., Dale, PS, Turner, RR, Morton, DL, Evans, SW, Krasne, DL (1995) Improved Axillary Staging of Breast Cancer with Sentinel Lymphadenectomy. Ann Surg, 222, 394-401.

3. Giuliano, A., Jones, RC, Brennan, M, Statman, R (1997) Sentinel Lymphadenectomy in Breast Cancer. J Clin Oncology, 15, 2345-2350.

4. Turner, R., Ollila, DW, Krasne, DL, Giuliano, AE (1997) Histopathologic Validation of the Sentinel Lymph Node Hypothesis for Breast Carcinoma. Ann Surg, 226, 271-278.

5. Giuliano, A., Haigh, PI, Brennan, MB, Hansen, NM, Kelley, MC, Ye, W, Glass, EC, Turner, RR (2000) Prospective Observational Study of Sentinel Lymphadenectomy Without Further Axillary Dissection in Patients with Sentinel Node-Negative Breast Cancer. J Clin Oncology, 18, 2553-2559.

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