Historical perspective

The incidence of melanoma is increasing faster than that of any other cancer.⁷ As with most malignancies, patient outcome is determined by a combination of clinical and pathologic factors that ultimately determine the stage of disease. The factors that affect outcome in melanoma include BRESLOW TUMOR THICKNESS, CLARK'S LEVEL OF INVASION (for melanomas 1 mm), primary tumor ulceration, lymph-node metastases, and distant metastasis.⁸ In fact, with the exception of metastatic status, these same factors have been shown to predict SLN metastasis.⁹ Indeed, nodal status is the single most important determinant of patient survival in early-stage melanoma.^{3, 8}

When melanomas metastasize, regional lymph nodes are usually the first-detected sites of spread. Furthermore, it is relatively rare for patients who develop distant metastatic melanoma to never manifest nodal metastasis at some point in time, although nodal metastasis is not always the first-detected site of metastatic disease. Of course, many patients with nodal metastasis will subsequently develop distant metastatic disease. Not long ago, patients with intermediate or thick melanomas and clinically negative (non-palpable) regional nodes were offered either elective lymph-node dissection or nodal observation. The lack of survival benefit and the risk of significant morbidity from elective lymph-node dissection led investigators to pursue SLN biopsy.

Current management

SLN biopsy is widely accepted as an accurate method of staging regional lymph-node basins, and has been shown to reflect accurately the true metastatic status of the entire basin.^{10, 11, 12} No other clinical or pathologic factor provides the same degree of prognostic information as SLN biopsy.³ Despite the accuracy of SLN biopsy in documenting the nodal-basin status, up to 15% of patients will develop metastatic disease and die without histologic evidence of nodal metastasis.^{13, 14, 15} This is poorly understood; however, it is known that some patients' melanoma will metastasize beyond the regional lymph nodes without detectable nodal metastases. The most common site of failure following a negative SLN biopsy is within the nodal basin itself; this pattern of recurrence is found in approximately 6–9% of patients whose results were negative after undergoing SLN biopsy.^{13, 14}

Some authors have suggested that SLN biopsy might not be valuable, since it has not been shown to improve survival.^{16, 17} However, SLN biopsy is an accurate staging tool that provides significant prognostic information. No other staging modality is scrutinized for therapeutic benefit, including CT, chest radiography, and MRI. SLN biopsy is an accurate and minimally invasive staging test; it should not be expected to provide a survival benefit in order to be considered valid and clinically useful.

Technical issues

Most surgeons use the combination of radioisotope localization and vital blue dye mapping to ensure accurate identification of the SLN (Table 1). This combination can be especially useful in identifying SLN at unusual sites (sometimes outside traditional cervical, axillary, and inguinal nodal basins) and in patients with multiple draining basins. Truncal and distal extremity melanomas may drain to multiple basins, and multiple-basin drainage patterns appear to negatively impact survival¹⁸ (Figure 1). For these reasons, it is useful to obtain a preoperative LYMPHOSCINTIGRAM (nuclear medicine scan) to identify the lymphatic drainage patterns prior to SLN biopsy.

Figure 1 Preoperative lymphoscintigram on a midline truncal melanoma demonstrating bilateral axillary nodal drainage.

 

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Table 1 Selected series investigating identification of the sentinel lymph node in melanoma.

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Approximately 5% of patients with thin melanomas (<1 mm) will have a positive SLN.^{3, 19} The rate of SLN positivity increases to about 20% for patients with intermediate thickness (1–4 mm) melanomas.³ For patients with thick (4 mm) melanomas, the rate of SLN positivity is approximately 32–39%,^{3, 4, 20} and, as for thinner melanomas, SLN status remains the strongest predictor of survival.^{4, 20}

Standard lymph-node analysis involves cutting the node in half, or 'bivalving' the node, and obtaining one or two thin sections from the center of the lymph node. This technique results in a very small volume of nodal tissue examined, thus introducing the possibility of a false-negative result, especially in the setting of MICROMETASTATIC DISEASE. Since traditional lymph-node processing limits the volume of tissue actually analyzed by the pathologist, many patients could potentially harbor a small focus of disease that was missed, within the node. One of the fundamental concepts of SLN biopsy is that the pathologist has much fewer nodes to process (usually 1–3 nodes) and therefore can invest more resources and time in thorough analysis. Actual processing of the SLN itself differs significantly from traditional lymph-node analysis in that it includes serial sectioning of the SLN (usually every 4 m, for a total of 50 sections per node) and staining with hematoxylin and eosin, as well as immunohistochemistry (IHC), most commonly for the S100 protein and/or HMB-45 antigen^{21, 22}(Figure 2). By combining hematoxylin and eosin and IHC with serial sectioning of the node, which significantly increases the volume of nodal tissue examined, the sensitivity for detection of nodal micrometastasis is increased.²³ IHC is useful in detecting micrometastatic disease, especially as a single cell or tiny clusters of metastatic cells.

Figure 2 Pathologic analysis of a sentinel lymph node containing metastatic melanoma.

(A) Hematoxylin and eosin staining. (B) S100 immunohistochemistry.

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Is sentinel lymph node biopsy safe?

SLN biopsy minimizes the number of patients that require full lymphadenectomy, and is associated with a complication rate of around 5% compared with 20% for full lymphadenectomy.²⁴ The most common complications include seroma or hematoma formation and minor wound infection. Recently, the question has been raised as to whether or not SLN biopsy may increase the risk of locoregional failure,²⁵ presumably from alterations in the lymphatic drainage due to the biopsy procedure itself. There is no evidence that this is true, and it has been shown that SLN biopsy for micrometastases actually decreases the number of nodal recurrences.²⁶ Nodal-basin failure following a completion lymphadenectomy (removal of the remaining lymph nodes in a basin) for a positive SLN appears to be driven by biologic factors inherent to the tumor, not by technical aspects of the SLN biopsy procedure.²⁷ On the basis of these data, SLN biopsy appears to be safe and accurately reflects tumor biology without increasing the risk of LOCOREGIONAL RECURRENCE.

Future directions for the use of sentinel lymph node biopsy for melanoma

Currently, patients with a positive SLN are advised to undergo completion lymphadenectomy. This is true even for patients with micrometastatic disease found only by IHC analysis of the sentinel node. Whether or not these patients have a better prognosis compared with patients with SLN metastases found by standard histologic methods is not clear. Approximately 80–85% of patients with a positive SLN, however, will not have any further nodal involvement,^{2, 10, 28} leading some investigators to question whether there is a subset of melanoma patients that will not experience regional nodal recurrence if a completion lymphadenectomy is not performed. To date, there are no prognostic tests that allow accurate identification of such a cohort of patients who are at low risk for non-sentinel-node disease following a positive SLN biopsy,²⁹ and in whom completion lymph-node dissection could be safely avoided.^{29, 30} Currently, the Multicenter Selective Lymphadenectomy Trial II (MSLT II), directed by Dr Morton and colleagues, is investigating the possibility of safely avoiding completion lymphadenectomy in some patients. The Sunbelt Melanoma Trial is a multicenter study that is analyzing the role of adjuvant interferon-2b for patients with minimal nodal metastasis. Another area of intense research is focused on molecular staging of melanoma. Currently, researchers are utilizing REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (RT-PCR) to detect melanoma-specific markers within SLN. This is a goal of the Sunbelt Melanoma Trial, as well as the MSLT II trial.

Historical perspective

Breast cancer is the leading malignancy, and the second leading cause of cancer-related deaths affecting women in the Western world today. It is well established that axillary lymph-node status is the most significant prognostic factor in breast cancer patients; nodal evaluation is therefore a critical part of breast cancer management.^{31, 32} Level I and II axillary lymph-node dissection, once a standard part of breast cancer treatment, is riddled with potential complications including intercostobrachial nerve paresthesias, decreased shoulder motion, and lymphedema. Building on Morton's work with SLN biopsy in melanoma,² significant strides were made by Krag, Giuliano, Reintgen and others, who introduced the technique of SLN biopsy into the breast cancer arena around the mid-1990s.^{33, 34, 35} A number of large, multicenter clinical trials, including the University of Louisville Breast Sentinel Lymph Node Study,⁵which assessed over 4,000 patients, subsequently validated this technique as a minimally invasive method of accurately staging the axilla in patients with breast cancer. As a result, SLN biopsy has become accepted as the 'state of the art' in breast cancer management.

Technical issues in current management

Lymphoscintigraphy

Lymphoscintigraphy is a technique in which a radioactive tracer is injected into the breast, and a nuclear medicine scan is performed to provide a 'road map' of lymphatic drainage from the tumor. While a preoperative nuclear medicine scan is commonly needed for SLN mapping in melanoma because the lymphatic drainage patterns are variable, the utility of lymphoscintigraphy in breast cancer is uncertain. In breast cancer, where axillary nodal drainage is almost always evident, lymphoscintigraphy increases the time and cost of SLN mapping but does not improve the SLN identification rate.³⁶ While drainage to the internal mammary nodes is sometimes evident, it is nearly always accompanied by concomitant axillary nodal drainage.³⁷ Therefore, preoperative lymphoscintigraphy might have limited utility for surgeons who decide not to remove internal mammary SLN.

Should blue dye, radioactive colloid, or both techniques be used?

Giuliano introduced the technique of SLN biopsy into breast cancer practice using a peritumoral injection of isosulfan blue dye, similar to Morton's original work in melanoma³⁴ (Figure 3). After a significant learning curve, this was found to be a simple and reliable technique for identifying the axillary SLN.³⁸ There were, however, disadvantages to this technique, including rapid transit of blue dye through the nodes, and the technical difficulty of uniformly finding SLN by tracing lymphatic channels to the node. Subsequently, Krag introduced the technique of injecting a radioactive tracer (^99mTc, technetium sulfur colloid) into the area of the breast cancer and using a hand-held gamma probe intraoperatively to identify the SLN³³ (Figure 4). The radioactive colloid remained within the SLNs for a longer period of time compared with isosulfan blue dye, and the gamma probe aided in the transdermal localization of the SLN.

Figure 3 Sentinel lymphatic mapping in a patient with invasive breast cancer demonstrating a blue stained lymphatic channel leading to a blue stained sentinel node.

 

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Figure 4 Intraoperative lymphatic mapping and sentinel lymph node biopsy in a patient with invasive breast cancer.

The handheld gamma probe is used to identify the sentinel node and to guide the dissection.

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While the techniques of using either blue dye or radioactive colloid alone result in high identification rates, a number of authors subsequently investigated the benefit of using a combination technique of both blue dye and radioactive colloid.³⁵ Although there is no significant difference in false-negative rates between the various injection techniques, the use of radioactive colloid in addition to blue dye injection allows optimal identification of SLNs.^{39, 40} Table 2 summarizes a number of large studies, each assessing over 150 patients, that demonstrate the accuracy, false-negative rate and SLN identification rates using blue dye, radioactive colloid, or both.

Table 2 Selected series investigating techniques of sentinel lymph node biopsy in breast cancer.

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Intradermal versus intraparenchymal injection

The intradermal injection technique, popularized in melanoma, has also been used in breast cancer. Some, however, have argued that an intraparenchymal injection may be more appropriate as it would necessitate mapping from the tumor itself rather than the overlying skin. While both techniques are often used, the intradermal injection technique has been associated with a higher identification rate, and is associated with higher radioactive counts in the SLN than intraparenchymal injection, thus facilitating SLN identification.⁴¹

Peritumoral versus subareolar injection

When the technique of SLN biopsy was originally introduced, the peritumoral injection technique was almost universally used. This followed from work in melanoma, the rationale being that blue dye and/or radioactive colloid injected around the primary tumor would follow the path of the lymphatic system draining to that portion of the breast, to the first draining lymph nodes. This technique, while widely used, posed a number of technical challenges. Could SLN biopsy be done in the setting of multicentric disease? Could one map the drainage of non-palpable tumors without radiologic guidance?

Early embryologic studies of the breast suggested that the lymphatic drainage of the breast stemmed from the SUBAREOLAR PLEXUS, and that subareolar injection might offer a simpler method of lymphatic mapping.⁴² This technique has now been validated in a number of large clinical studies, and for many surgeons, has become the injection method of choice for SLN mapping.⁴³

Patient issues in current management

With the emergence of SLN biopsy as an accepted method of staging for patients with breast cancer, some questioned which patients would be appropriate candidates for this technique. While originally it was felt that SLN biopsy was only appropriate for small tumors, it has now been established that this technique can also be used to stage the axilla in larger tumors.⁴⁴ The accuracy of SLN biopsy after neoadjuvant chemotherapy, however, continues to be controversial, with false-negative rates of 0–33% being reported.^{45, 46} Many have now adopted the practice of performing SLN biopsy before neoadjuvant chemotherapy.

Although it is known that preinvasive tumors do not spread to the lymph nodes, the minimally invasive technique of SLN biopsy has been used in cases of ductal carcinoma-in-situ (DCIS) as a means of assessing the nodal status of patients in whom microinvasive cancer may have been missed, especially when needle-core biopsy was used for diagnosis. While the indications for this procedure in patients with DCIS are controversial, the use of SLN biopsy in patients who choose mastectomy is clearly warranted, as it would not be possible to perform a SLN biopsy after mastectomy if invasive disease should be discovered. The pathologic assessment of SLNs in such circumstances must be considered with caution, because up to 23% of patients with DCIS and with no evidence of invasion may be found to have cytokeratin-positive cells on IHC analysis.⁴⁷ Such cytokeratin-positive cells are currently classified as 'isolated tumor cells of unknown biologic significance' and are generally thought of as simply displaced cells rather than true metastasis. It is important, therefore, that such patients should not receive aggressive therapy that may be unwarranted for their early disease.

Future directions for the use of sentinel lymph node biopsy for breast cancer

As the technique of SLN biopsy in breast cancer continues to mature, many ongoing studies are addressing the controversies that have emerged. The question of whether SLN biopsy should be accepted as the 'standard of care' continues to be an issue for some surgeons, despite the evidence provided by large validation studies. As a result, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 Trial will randomize 4,000 clinically node-negative patients to SLN biopsy alone (with completion axillary dissection for SLN-positive patients) versus SLN biopsy plus axillary dissection. While the primary endpoint of the NSABP study is survival, the European Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial seeks to determine the impact of SLN biopsy on morbidity and quality of life.

There has been much controversy surrounding the appropriate pathologic means of analyzing the SLN. The utility of IHC and the relevance of bone-marrow metastasis is the subject of the recently closed American College of Surgeons Oncology Group (ACOSOG) Study Z0010.⁴⁸ There are a number of studies that are also investigating other methods (e.g. RT-PCR) for identifying tumor cells in the SLN. In light of the multiple pathologic techniques that may be used to analyze SLNs, these data have been incorporated into the 6^th edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer.⁴⁹