Special Feature
Sentinel Lymph Node Dissection in Breast Cancer: A More Rational Approach to Staging?
By Arden Morris, MD, and John T. Vetto, MD
Determination of the presence or absence of axillary metastases remains the most important factor in breast cancer staging, defining prognosis, and guiding adjuvant therapy decisions. Traditionally, axillary node dissection (AND) has been the gold standard operation for obtaining this information. Axillary levels I, II, and III are bounded by the latissimus dorsi laterally and the pectoralis minor medially, the lateral and medial borders of the pectoralis minor, and the medial border of the pectoralis minor laterally and extending up to the axillary apex medially, respectively. The appropriate extent of dissection, however, has been hotly debated, with some authors urging aggressive pursuit of all three node levels,1 while others believe that the highly questionable practice of node "sampling," which involves the removal of an unspecified number of nodes (usually from level I), remains adequate.2
Investigators promoting a more complete node dissection refer to the variability of breast lymphatic anatomy, which contradicts the traditional Halstedian concept of orderly drainage. These data indicate that approximately 25% of women with breast cancer may have "skip lesions" (i.e., metastatic nodes found at higher axillary levels when lower levels are tumor-free).3,4 These authors also promote more extensive axillary dissections because current adjuvant therapy decisions are often based on the total number of involved nodes, not the level of node involvement. They also cite the potential therapeutic value of AND to local control and prevention of local recurrence and voice doubts regarding the sample size in the NSABP B-04 study, which found local control benefit but no survival benefit to AND, largely relegating it to staging procedure status.5
Proponents of a more conservative dissection cite the high morbidity rate associated with axillary dissection, including risks of postoperative arm edema, nerve damage, arm and shoulder stiffness, seroma formation, and wound infection. Those who favor "sampling" procedures cite studies in which staging and treatment based upon random excision of as few as four nodes did not lead to a significantly different outcome compared to patients undergoing traditional axillary dissection.6
The American College of Surgeons, in agreement with the 1992 NIH Consensus conference, generally recommends a "two-level" lymph node dissection (levels I and II) to strike a balance between the risks of inadequate staging with smaller operations and the risk of permanent arm lymphodema with complete node removal ("three-level dissection").7 A two-level node dissection, yielding approximately 15-20 nodes, avoids the higher postoperative morbidity associated with level III dissection, provides adequate resection (the incidence of level III skip lesions, when levels I and II are negative, is only 2%), and has a near 0% axillary recurrence rate at 50 months.
T1 Disease and Micrometastases
The management of T1 (< 2 cm) lesions is also controversial. Some surgeons support a conservative surgical approach referring to recent literature which suggests abandoning AND for T1a (£ 0.5 cm) lesions because positive nodes are found in as few as 3% of patients.8 Others favor a more aggressive nodal dissection because new techniques show that LN involvement with T1a lesions is higher than previously reported3,4 and that lymph node dissection for T1a and T1b lesions is an independent prognostic factor.5
The importance of selecting the best method to evaluate the axillary nodes of patients with T1 carcinomas has been increasingly important because of the progressive downward trend in the stage of breast cancer at diagnosis in the United States. Cady et al examined a large breast cancer database and noted a statistically significant decrease in both average tumor size and the number of positive axillary nodes in women diagnosed between 1969 and 1993. There was a full centimeter reduction in mean tumor diameter; there was a 20% increase in the number of women diagnosed with T1a (< 0.5 cm) or T1b (> 0.5 cm but < 1 cm) disease.9 Furthermore, the percentage of patients with greater than three axillary node metastases at operation declined from 17% between 1969 and 1973 to 10% between 1989 and 1993. Among patients with T1a or T1b disease and axillary node metastases diagnosed between 1989 and 1993, 70% had only one or two positive nodes, many of which contained only micrometastases. The authors predicted that, if these trends continue, most breast cancers diagnosed in the near future will be 1 cm or less in size, the axillary nodes will be involved in only 10% of cases, and when involved there will only be 1 or 2 positive lymph nodes. Accordingly, advocates of both aggressive and conservative approaches to the clinically N0 axilla may be appeased if surgery could be targeted to the shrinking number of patients with positive lymph nodes who might benefit.
SLND: Concept, Techniques, and Results
In the 1980s, Morton et al introduced the concept of mapping dermal lymphatic flow patterns using vital blue dye to identify the first lymph node draining a specific dermal region, the "sentinel" lymph node (SLN), in patients with melanoma.10,11 Based on Morton’s high accuracy of SLN identification (< 1% false-negative rate in > 500 cases) in melanoma, Giuliano et al performed a pilot study in women with breast cancer.12
One-hundred-seventy-four patients with operable breast cancer underwent SLND after peritumoral injection of isosulfan dye. Subsequent definitive surgery included a three-level axillary node dissection. The authors identified the SLN in 65.5% of patients. There was a definite learning curve, as identification rates improved to 78% in the last 50 cases. Routine histopathologic processing of excised SLNs predicted the overall axillary status accurately in 95.6% of cases; the positive and negative predictive values were both 100% in the last 100 cases. On closer examination, including immunohistochemical staining, only one of the five (total 114) SLNs that were falsely negative proved to be a genuinely falsely negative node. Three SLNs were actually fat globules and one was positive for breast cancer using immunohistochemical techniques. Interestingly, in 38% of cases, the only positive node was the SLN and, in 23% of cases, the SLN "skipped" level I and was located only in level II and, thus, would likely have been missed by a level I dissection or sampling procedure. Taken together, these data argue for an intermediate approach between sampling and complete AND: The SLN should be sampled in every patient and followed by selective 2-level AND if it is positive.
Giuliano et al compared the ability of SLND vs. traditional AND to stage the axilla, reasoning that a more focused but more extensive histopathologic examination of a single node would improve the accuracy of staging.13 Two comparable groups, including 296 patients, underwent either AND or SLND followed by AND (all had either a lumpectomy or mastectomy). AND specimens were processed routinely, while SLND specimens underwent extensive sectioning after hematoxylin and eosin (H & E) staining, followed by cytokeratin immunohistochemical staining if H & E examinations were negative. Significantly fewer (29%) axillary metastases were found in the AND group vs. the SLND group (42%). Furthermore, micrometastases (£ 2 mm) were diagnosed in 10% of the AND group vs. 38% in the SLND group. Just as in melanoma, routine H & E stains and limited sectioning failed to detect cancer metastatic to lymph nodes in a significant percentage of patients. The SLN technique permits more extensive pathologic staging by decreasing the number of samples to be analyzed from 15 or 20 lymph nodes to one. These authors indicate that SLND leads to more accurate staging of the axilla, and that the increased costs of more extensive histopathology would be offset by the smaller number of nodes that need to be examined and from selected application of two-level AND to only those cases in whom the sentinel node is positive.
Previous Halstedian notions of orderly lymphatic drainage from the breast have been refuted by more recent radiologic mapping, revealing highly variable lymphatic anatomy. This explains the 1.3-42.0% incidence of skip lesions reported in the literature. In a representative study, Van Lacker et al reviewed 377 AND cases and discovered that, in cases of axillary involvement, 25% contained skip lesions above level I, while 4% contained skip lesions above level II.14 Reliable statistics regarding local recurrence and distant metastases after SLND are not yet available since all SLN resections to date have been followed by two-level AND, but the very low incidence of false negative SLND described above (currently 2/352 genuinely false negative nodes in Giuliano’s series) is encouraging in this regard.
Lymphoscintigraphy can also be used for lymphatic mapping and SLN identification in breast cancer. In 1993, Krag et al reported a pilot study in which 22 consecutive breast cancer patients underwent peritumoral injection of technetium-labeled sulfur colloid, followed by localization of the axillary SLN via a hand-held gamma counter.15 Patients underwent SLND followed by a three-level AND and definitive cancer operation. Eighteen patients (82%) had identifiable sentinel nodes, seven were positive for metastases, and in three, the sentinel node was the only involved node in the axillary basin. The 11 axillae with negative sentinel nodes proved negative on AND. The authors concluded that radiolocalization of the sentinel node in a nuclear medicine suite followed by SLND is a highly sensitive staging procedure that is not technically difficult to perform and has the potential to reduce the costs and morbidity of axillary staging.
Uren et al also used radio-labeled colloid for lymphatic mapping in the breast, specifically looking at tumor site drainage patterns, presence of interval nodes, and whether a sentinel node could be identified in each draining basin.16 They found that lymphatic drainage, while usually ipsilateral, crossed the breast midline in 32% of cases and flowed directly to the supraclavicular or infraclavicular nodes in 20% of upper quadrant lesions, again supporting the notion of high variability in lymphatic drainage patterns. Drainage to the ipsilateral axilla did occur in 85% of cases with 100% accurate identification of a single sentinel node. These authors advocated preoperative lymphatic mapping in breast cancer and proposed combining the use of lymphoscintigraphy with isosulfan blue dye injection in order to maximize SLN identification.
Albertini et al recently reported a prospective trial in which peritumoral injections of both vital blue dye and radiolabeled colloid were employed to locate sentinel nodes, resulting in a 92% successful identification rate and a 100% positive and negative predictive value.17 In 67% of cases, the sentinel node was the only site of metastatic disease, again underscoring the value of SLN identification and excision.
Clinical Implications for SLND
As primary breast tumors get smaller, more questions regarding the necessity of routine AND arise. In 1996, Giuliano et al evaluated the incidence and predictors of axillary involvement and the use of SLND in 259 women with T1 breast cancers.4 One-hundred-fourteen such patients underwent SLND followed by a three-level AND. The only statistically significant predictor of nodal involvement by univariate analysis was tumor size, consistent with the findings of other investigators.14 Overall rates of nodal involvement by routine pathologic analysis were 10%, 13%, and 30% in T1a, T1b, and T1c disease respectively. Nodes deemed negative by H & E examination were subjected to cytokeratin immunohistochemical staining, yielding an increase in axillary metastases to 15% in T1a disease. Thus, even tumors smaller than 1 cm yielded a significant number of metastatic nodes. Sentinel lymph nodes were identified in 64% of patients and accurately predicted axillary status in 98% of all patients and in 100% of T1a and T1b tumors. Again citing a learning curve for both surgeons and pathologists, Giuliano notes that, at his institution, accurate identification of the SLN in breast cancer patients has improved to 85% since the conclusion of this study.
Given the increasing ability to detect SLNs by combining preoperative lymphoscintigraphy with vital blue dye mapping, the existence of skip lesions in some involved axillae, the 38-67% reported frequency in which the SLN is the only metastatic node present, and the possibility of a more thorough pathologic exam, proponents of SLND argue that it allows for significantly greater staging accuracy.
Recommendations and Future Directions
The presence of axillary metastases in breast cancer is the single best prognostic indicator and a key guide to therapeutic decisions. Clinical evaluation has only about a 30% diagnostic accuracy rate, thus patients continue to require a reliable diagnostic procedure. Routine AND, while highly accurate, carries significant attendant morbidity risk. Therefore, it would be a major advance to avoid this surgery in patients who are node-negative. The results of a current multi-center trial may prove that SLND is an appropriate alternative, leading to more selective application of AND and its avoidance in N0 disease. Despite the enthusiasm for SLN techniques generated by the above data, it is important to remember that these new procedures require special training and are associated with a learning curve. Accordingly, use of SLND should be restricted to trained surgeons studying the procedure in a prospective fashion. Thus, at present, routine two-level AND remains the gold standard operation for studying the clinically negative axilla.
If, as predicted by Cady et al, an increasing number of breast cancers are diagnosed at the T1a or T1b stage (with an associated 15-30% positive axillary node rate), it would be interesting to determine precisely how often the SLN is the only positive node present in the axilla. Future studies may focus on ways of identifying, without AND, the approximately 67% of node-positive T1 patients in whom the SLN is the only involved node. If this were possible, excision of the SLN, whether "positive" or "negative," could provide sufficient replacement for AND, yielding an outpatient procedure with decreased cost and reduced morbidity. In view of the fact that all current treatment regimens have been based on a possibly less accurate staging procedure (AND), adjuvant treatment would then be inherently more "targeted," perhaps leading to better overall outcome. (Dr. Morris is Resident, Department of Surgery, Oregon Health Sciences University, and Dr. Vetto Assistant Professor of Surgery, Section of Surgical Oncology, Oregon Health Sciences University.)
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