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)
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ABSTRACT |
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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 0.212.0 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 = 2991 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 = 0.258.5 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 = 112). The mean number of axillary lymph nodes (sentinel and non-sentinel) excised per patient was 17.6 (range = 643). 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 (3040 MBq of unfiltered Tc99 sulfur colloid in 68 mL) and/or patent blue or isosulphan blue dye (total volume = 58 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 23 mm thick, and the slices were submitted in toto for histologic examination. Five serial sections, each 35 µm thick, were taken from each tissue slice of the sentinel lymph node. Sections 1, 3, and 5 were stained with hematoxylineosin, 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 23 mm thick as above, and a single 5-µm section was taken from each slice and stained with hematoxylineosin 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 hematoxylineosin 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 nodepositive (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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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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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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