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Influence of the New AJCC Breast Cancer Staging System on Sentinel Lymph Node Positivity and False-Negative Rates

David R. McCready, Wei Sean Yong, Alexander K. T. Ng, Naomi Miller, Susan Done, Bruce Youngson

Affiliations of authors: Department of Surgical Oncology (DRM, WSY, AKTN) and Department of Pathology (NM, SD, BY), Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada

Correspondence to: David R. McCready, MD, MSc, Department of Surgical Oncology, Princess Margaret Hospital, University of Toronto, 610 University Ave., Toronto, Ontario M5G 2M9, Canada (e-mail: david.mccready{at}uhn.on.ca)


    ABSTRACT
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The sixth and newest edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer now defines axillary sentinel lymph nodes with micrometastatic deposits 0.2 mm in diameter or smaller as node-negative. The aim of this study was to determine how this new classification scheme would affect axillary sentinel lymph node positivity, false-negative rate, and overall accuracy of an inception cohort of 205 breast cancer patients undergoing definitive surgery that included sentinel lymph node biopsy plus level I/II axillary lymphadenectomy. Based on the previous AJCC system for staging breast cancer, in which all sentinel lymph node metastases were considered positive, the rate of nodal positivity in this cohort was 47%, the overall accuracy was 99%, and the false-negative rate was 2.1%. According to the new classification system, the rate of nodal positivity in this cohort was 39.5% and the overall accuracy was 98%. The false-negative rate rose to 4.9% because two patients with micrometastatic deposits 0.2 mm or smaller, which are considered node-negative in the new system, had macroscopically positive disease in non-sentinel lymph nodes found in the completion lymphadenectomy.


Each edition of the American Joint Committee on Cancer (AJCC) breast cancer staging system documents the evolving knowledge of cancer diagnosis, staging, and prognosis. A number of changes have been incorporated into the sixth and most recent AJCC breast cancer staging system, implemented in January 2003 (1). The major nodal categories (e.g., N1, N2) are now defined by the number of involved axillary lymph nodes, and metastases to supraclavicular nodes have been reclassified from M1 to the N3 category. With reference to nodal positivity, categorization is now also based on the maximum size of the metastasis. If techniques such as immunohistochemistry or polymerase chain reaction are used to detect tumor cells, then a descriptor for the method can be so indicated as pN0 (i+) or pN0 (mol+), respectively. Reference to changes in the more advanced stages and T categories was addressed in a recent publication by Woodward et al. (2).

On occasion, specific classification changes can substantially influence treatment decisions. One alteration relevant to current surgical practice for breast cancer relates to the definition and classification of nodal micrometastases in sentinel lymph nodes. The previous staging schema (3) counted all nodal metastases as positive regardless of the size of the metastatic deposit. In the new staging system, by contrast, nodal stage is partly defined by the size of the micrometastasis. Nodal metastases larger than 2.0 mm in diameter are now counted as pN1 or greater, depending on the number of nodes with metastases. Nodal metastatic deposits 0.21–2.0 mm in diameter are now labeled as pN1mi (micrometastases). Clusters of malignant cells 0.2 mm in diameter or smaller that are seen in nodes are now defined as pN0.

The purpose of this study was to detail the changes in staging that would occur by imposing the latest definitions on an inception cohort of patients who had intensive examination of sentinel lymph nodes and a completion axillary lymphadenectomy as part of their definitive surgery for breast cancer. Specifically, we examined the effect of defining micrometastatic (<=0.2 mm) nodal deposits as node-negative on the rate of overall axillary node positivity, the false-negative rate, and the overall accuracy of the sentinel lymph node biopsy.

An inception cohort of patients (n = 205) was gathered from 1997 to 2001. The mean age was 55.4 years (range = 29–91 years). All patients had undergone sentinel lymph node biopsy, completion level I/II axillary lymphadectomy, and breast-conserving surgery or mastectomy by one surgeon (D. R. McCready). All patients had histologically proven invasive carcinoma prior to the sentinel lymph node surgery, and all had clinical stage I or II disease without palpable axillary lymphadenopathy. The mean primary tumor diameter was 1.83 cm (range = 0.25–8.5 cm). The size distribution of the primary tumors was 70% T1, 28% T2, and 2% T3. The mean number of sentinel lymph nodes excised per patient was 2.8 (range = 1–12). The mean number of axillary lymph nodes (sentinel and non-sentinel) excised per patient was 17.6 (range = 6–43). Written informed consent was obtained from each patient, and review of the data was approved by the University Health Network Research Ethics Board.

Sentinel lymph nodes were localized by peritumoral injection of a radioactive colloid (30–40 MBq of unfiltered Tc99 sulfur colloid in 6–8 mL) and/or patent blue or isosulphan blue dye (total volume = 5–8 mL). Lymphoscintigraphy was performed for patients who underwent radioactive colloid injection. Radioactive nodes were considered sentinel nodes if the count per 10 seconds was less than or equal to 10% of that of the most radioactive node (4). Intra-operative localization of the sentinel lymph nodes was performed with the help of a handheld gamma probe (Cancer Wise Medical, Morgan Hill, CA) and also by visualizing the blue lymphatic ducts and lymph nodes. At the time of surgery, the sentinel lymph nodes and the axillary dissection specimens were labeled separately.

Pathologic evaluation of each sentinel lymph node was performed following a standard grossing protocol. Each sentinel lymph node was bisected along its longitudinal axis to yield tissues slices 2–3 mm thick, and the slices were submitted in toto for histologic examination. Five serial sections, each 3–5 µm thick, were taken from each tissue slice of the sentinel lymph node. Sections 1, 3, and 5 were stained with hematoxylin–eosin, and sections 2 and 4 were immunohistochemically stained with CAM 5.2 (Becton-Dickinson, San Jose, CA) for low-molecular-weight cytokeratin. All non-sentinel lymph nodes were sectioned to yield tissue slices 2–3 mm thick as above, and a single 5-µm section was taken from each slice and stained with hematoxylin–eosin only. All pathologic slides from the sentinel lymph nodes were subsequently reviewed by a single pathologist (B. Youngson), who was blinded to the results of the axillary dissection. The sentinel lymph nodes were reported as either positive or negative for metastatic disease, and the size of the largest focus of metastatic disease and the primary detection method (either hematoxylin–eosin or immunohistochemistry) was recorded. The number of positive nodes and the total number of nodes removed in the completion axillary lymphadenectomy were also noted.

At the time of the surgery and the original pathology reporting, the fifth edition of the AJCC cancer staging system was in use. Using those definitions, 96 patients (47%) were found to be axillary lymph node–positive (Table 1). Ninety-four patients had positive sentinel lymph nodes (true-positives) and two patients had false-negative sentinel lymph nodes, defined as such by the fact that, although no metastases were detected in the sentinel lymph node, metastases (>2.0 mm) were found in non-sentinel lymph nodes excised in the completion axillary lymphadenectomy. The accuracy was therefore 99% (203/205), and the false-negative rate was 2.1% (2/96). The remaining 109 patients had true-negative sentinel lymph nodes, defined by the fact that neither the sentinel nor the non-sentinel lymph nodes showed any evidence of metastatic disease. Among those with lymph node metastases, 54 patients had sentinel lymph nodes as the only nodes positive for metastatic disease.


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Table 1. Sentinel lymph node 2 x 2 table using AJCC (fifth edition) definitions

 
To determine whether the stage of the 94 patients with positive sentinel lymph node metastases under the previous system would change using the new staging system, we divided these patients into the three categories specified in the newest AJCC scheme (Table 2) and reclassified those with sentinel lymph node metastases 0.2 mm or smaller in diameter as pN0. In 57 patients, the largest sentinel lymph node metastasis was greater than 2.0 mm; in 20 patients, the sentinel lymph node metastases were 0.21–2.0 mm; and in 17 patients, the lymph node metastases were 0.2 mm or smaller. Because a completion axillary lymphadenectomy was performed for all patients, it was determined that the number of patients with at least one non-sentinel lymph node that was positive with hematoxylin–eosin staining in the above categories was 31, 7, and 2, respectively. Most sentinel lymph node deposits between 0.21 and 2.0 mm were primarily detected (90%) on the hematoxylin–eosin sections, but those 0.2 mm or smaller were generally detected (59%) by immunohistochemical staining. It should be noted that all of these metastatic deposits consisted of cytologically malignant cells that usually could be seen retrospectively on the adjacent hematoxylin–eosin sections once identified on the immunohistochemically stained slides and would fit the definition of isolated tumor cells in the sixth edition of the AJCC staging manual (1).


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Table 2. Sentinel and non-sentinel node positivity according to size and primary method of detection

 
Within this new category containing 17 patients with nodal metastases measuring 0.2 mm or smaller but considered pN0, two patients (12%) had macroscopic nodal disease present in the apparently normal completion axillary lymphadenectomy. They would have been falsely staged and would have had clinically relevant residual nodal disease if a completion lymphadenectomy had not been performed, because their sentinel lymph node classification was considered pN0 in the new staging schema.

A 2 x 2 table (Table 3) based on reassignment by the new staging system to include the two additional patients now classified as false-negative, shows four false-negative sentinel lymph node results (two from the original results plus two from this reclassification), 77 true-positives, and 124 true-negatives. There were no false-positives. The overall nodal positivity rate dropped to 39.5% (81/205), and the false-negative rate more than doubled to 4.9% (4/81). Overall accuracy dropped to 98% (201/205).


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Table 3. Sentinel lymph node 2 x 2 table using AJCC (sixth edition) definitions

 
Intensive evaluation of sentinel lymph nodes results in the greater detection of micrometastases, which are defined in the latest AJCC classification system as those deposits not greater than 2.0 mm (1,5). Other series support this study's finding—that maximum staging accuracy is achieved by performing a completion lymphadenectomy, even if only minute metastatic deposits are detected in sentinel lymph nodes (610).

In addition to increasing the false-negative rate, implementation of the sixth edition of the AJCC Staging Manual instructions for defining node positivity and reclassification produced a stage reduction for 17 of the 205 (8.3%) patients in this cohort. Eleven of the 205 patients (5.4%) staged as IIA in the previous system (tumor sizes 1T1a, 3T1b, and 7T1c) would now be categorized as stage I. Six patients previously staged as IIB (6T2 tumors) would now be staged as IIA.

In summary, this study supports the concept that the sentinel lymph node should be carefully and intensely examined for this procedure to be most accurate. If any evidence of disease is detected, then a completion axillary lymphadenectomy will provide maximum staging information and minimize the risk of leaving residual nodal disease in the axilla. This is important for good local regional control of disease, systemic treatment decisions, and possibly patients’ overall survival. This question is currently being addressed by the American College of Surgeons Z0011 clinical trial, which is randomly assigning patients with early-stage breast cancer and positive sentinel lymph nodes to completion axillary lymph node dissection or no further surgery.


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Manuscript received October 14, 2003; revised March 24, 2004; accepted April 2, 2004.


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