The role of elective lymph node dissection in the treatment of patients with early-stage melanoma remains controversial. Some surgeons advocate the routine use of elective node dissection in patients with intermediate-thickness primary tumors, but the cost, morbidity, and low yield of tumor-positive lymph nodes associated with this approach make it less appealing than wide excision and observation. Multiple retrospective studies suggest a survival advantage as high as 25% for patients undergoing elective node dissection in the setting of clinically negative nodes, as opposed to delayed node dissection for clinically evident nodal metastases. Although two randomized prospective studies failed to demonstrate a survival advantage in patients undergoing elective node dissection, as compared with those having wide excision alone, both studies were criticized for their design [1,2].
In 1992, Morton and associates described their initial experience with a minimally invasive technique to determine the presence of occult regional lymph node metastases . This technique, intraoperative lymphatic mapping and selective lymph node dissection, was devised as an alternative to elective node dissection in patients with intermediate-thickness melanoma. The technique employs a vital blue dye to map the regional lymph nodes and identify occult lymph node metastases in the primary ("sentinel") node(s). Only those patients with occult tumor cells in the sentinel node(s) are subjected to a complete regional lymph node dissection; patients with tumor-free sentinel nodes are spared the cost and morbidity of complete node dissection.
Intraoperative lymphatic mapping is based on the hypothesis that each skin site drains via the dermal lymphatics to the adjacent lymph node basin and to one or two particular sentinel nodes. Thus, metastases to the regional nodes spread in a direct sequential fashion from the primary site. The presence of skip metastases is rare. Only when the sentinel node(s) contain(s) tumor is there a risk of disease in the other regional lymph nodes. When the sentinel node(s) is(are) free of tumor, the remaining nodes in the same lymph node basin are unlikely to contain metastases.
Steps in the Sentinel Node Technique
The sentinel node technique is performed in three steps, beginning with preoperative lymphoscintigraphy to identify the regional basin and sentinel node(s) at risk for metastases. We perform lymphoscintigraphy using a variety of radiopharmaceuticals, including technetium-labeled human serum albumin (HSA), or sulfur(Drug information on sulfur) or albumin colloid . In their review, North and Spellman recommend preoperative lymphoscintigraphy only in those patients who have primary melanomas on the torso or at sites that may be expected to have ambiguous drainage patterns. However, at the John Wayne Cancer Institute we use preoperative lympho-scintigraphy in all patients in order to determine the regional lymph node basin at risk and to map the site of the sentinel node(s). It is important to realize that the location of the sentinel node(s) often cannot be determined by strict anatomic guidelines. Moreover, the sentinel node often is not the lymph node closest to the primary lesion.
The second step in the sentinel node procedure is intraoperative lymphatic mapping. We use isosulfan blue dye (patent blue V is no longer available in the United States), injecting approximately 0.5 to 1 mL intradermally adjacent to the primary lesion or around the biopsy site. The injection can be repeated every 15 to 20 minutes if the sentinel node is not found. While larger volumes of dye can be used, as noted by North and Spellman, it is important not to use excess dye when the sentinel node is anatomically close to the primary, as permeation of dye through soft tissue can obscure mapping of the lymphatics. It is equally important that the dye not be injected into the excisional biopsy cavity. We have noted stasis of the dye when injections are made in this manner.
Following injection of the blue dye at the primary site, an incision is made overlying the regional lymph node basin and the sentinel node(s) is(are) located and dissected. We have found that preoperative lymphoscintigraphy is useful for determining not only the site of the sentinel node(s) but also the approximate time it takes the blue dye to move from the primary site to the sentinel node(s). The blue-stained lymphatics are followed from the edge of the wound and traced to the primary draining (sentinel) node(s). Each sentinel node is isolated from the adjacent tissue and excised.
The third step in the sentinel node technique is pathologic examination of the sentinel node(s). Although Morton's group originally employed frozen-section analysis using both hematoxylin and eosin (H & E) staining and immunohistochemical techniques, we have found approximately a 5% incidence of false-negative sentinel nodes with frozen-section analysis. Therefore, we now examine permanent sections, first by conventional techniques with bivalving of the sentinel node(s) and examination of both faces. We then use immunohistochemical staining when H & E staining is negative.
Newer molecular biology techniques, such as reverse transcriptase-polymerase chain reaction (RT-PCR), can be used to recognize specific melanoma gene sequences and may further enhance the sensitivity of the sentinel node technique by detecting submicroscopic metastases . However, RT-PCR is costly and labor-intensive and requires a laboratory that is specialized in handling minute samples of messenger RNA (mRNA). Even under the best conditions, mRNA contamination is still possible. Moreover, the significance of a sentinel node that is RT-PCR-positive and the rate of false-positive results with this technique are unknown.
Results With the Technique
In 1992, Morton and associates reported their initial experience with intraoperative lymphatic mapping and selective sentinel lymphadenectomy [3,6]. The sentinel node was detected in 82% of the first 237 regional lymph node basins dissected. By performing complete node dissections, Morton and colleagues were able to determine an accurate rate of false-negative sentinel nodes; less than 1% of nonsentinel nodes were the exclusive site of metastases--a false-negative rate of less than 1% for this technique.
Since Morton's original description of the sentinel node technique, a number of investigators have reported their experience with this procedure [7,8]. These studies have verified its high degree of accuracy for the detection of sentinel nodes, low incidence of false-negative sentinel nodes, and low rates of regional recurrence.
To improve the success rates for locating the sentinel node(s), several investigators have modified the mapping technique through the use of radiopharmaceuticals and a hand-held gamma probe. As mentioned by North and Spellman, a study of 106 melanoma patients reported by Albertini and associates from the University of South Florida demonstrated that the gamma probe helped find sentinel nodes that were not demonstrated by blue dye alone . A total of 16 patients had probe-identified sentinel nodes that did not stain blue; in 2 cases, these nonstained sentinel nodes contained metastases.
We have reviewed our experience in 32 patients who underwent a mapping technique in which we combined the blue dye with technetium-labeled HSA . The concordance between preoperative lymphoscintigraphy and intraoperative findings was 100%. In addition, the gamma probe helped identify additional sentinel nodes that did not absorb the dye well. However, we did not find any additional tumor-containing nodes with this technique.
An Alternative to Traditional Management
We believe that intraoperative lymphatic mapping with selective lymph node dissection represents an alternative approach to the traditional management of patients with intermediate- thickness primary melanoma. Although our initial experience demonstrated a steep learning curve for mastering this technique, other investigators have been able to quickly gain experience and achieve a high degree of accuracy by using the original guidelines that we proposed.
More-recent studies using the hand-held gamma probe suggest that this device may enhance the surgeon's ability to find the sentinel node. We typically use technetium-labeled HSA in combination with the blue dye or inject HSA immediately prior to dye injection. This technique is particularly useful when one is first learning the sentinel node procedure and in basins such as the axilla where blue-stained nodes are often difficult to locate. However, radio-pharmaceuticals can also produce ambiguous results; we see great variation in count ratios between blue-stained sentinel nodes and nonstained nodes. Even though sentinel node(s) may have a higher ratio of radioactivity, the presence of high counts in adjacent nonsentinel nodes may be misleading.
Ongoing Randomized Trial
A major international randomized trial, the Multicenter Selective Lymphadenectomy Trial, is now in progress to determine whether there is a survival advantage when selective sentinel lymphadenectomy is added to wide excision for patients with intermediate- thickness (1- to 4-mm) primary melanoma. Only those patients who have a tumor-containing sentinel node undergo complete node dissection. A secondary aim of this study is to determine whether the sentinel node technique improves the staging of patients with cutaneous melanoma. Patients with regional lymph node metastases are encouraged to receive interferon alfa-2b(Drug information on interferon alfa-2b) (Intron A).
The results of two randomized prospective studies examining the role of elective lymph node dissection will soon be available. Even if these trials fail to demonstrate a survival advantage for patients undergoing elective node dissection in addition to wide excision, sentinel lymphadenectomy will likely become the standard of care in patients with intermediate-thickness melanoma, in order to improve the staging of their disease and identify candidates for adjuvant therapy.