Blue Dye Mapping The Concept

The use of colored substances to demonstrate lymphatic vessels and lymph nodes is not a new concept. It was the technique employed by a number of the earliest anatomists who sought to map human cutaneous lymphatic drainage pathways (see Chapter 2). By injecting materials such as Prussian Blue dye and Chinese ink, they confirmed that lymphatics and blood vessels were distinctly separate entities and produced the first recorded maps of cutaneous lymphatic drainage pathways. In more recent times, blue dye was used extensively to demonstrate lymphatic channels in the foot and hand, allowing them to be cannulated for radiological lymphography (see Fig. 4 in Chapter 2). In the mid-1980s, Morton and his colleagues at the John Wayne Cancer Institute began studies using blue dye which were destined to provide new insights into the clinical relevance of lymphatic drainage pathways for malignancies such as melanoma and breast cancer. First in animal experiments and then in man, it was shown that blue dye traveled rapidly from any given injection site in the skin to a ''sentinel'' lymph node [13,14]. It was postulated that tumor cells would travel along the same lymphatic channels and lodge first in a sentinel node. If a sentinel node was found to be free of micrometastatic disease, it could therefore be assumed that the entire node field was likely to be disease-free and that full regional lymph node dissection was unnecessary. The accuracy of sentinel node status as an indicator of regional lymph node status has since been confirmed by several other histological studies involving sentinel lymphadenectomy with immediate full regional node clearance and careful examination of all the other nodes in the operative specimen [15-17].

Injection Technique

Two blue dyes are in common use for lymphatic mapping and sentinel lymphade-nectomy. The more satisfactory agent is probably patent blue dye, but this is not currently available in the United States, where isosulfan blue is normally used. The blue dye is injected intradermally at several points around the melanoma if it remains in situ, or on either side of the central part of the biopsy scar if excision-biopsy has been performed previously (Fig. 2). Great care must be taken to ensure that the injection is truly intradermal and not subcutaneous, to avoid the possibility of mapping a lymphatic pathway leading to a node that is not the true sentinel node draining the melanoma site on the skin. If lymphatic mapping using either blue dye or a radiolabeled colloid is attempted after a wide local excision of the primary melanoma, inaccurate sentinel node identification is even more likely to occur. This is because there is evidence that the originally existing lymphatic pathways draining the melanoma are disrupted by the excisional surgery [11] so that lymphatic drainage from the area may be diverted to a lymph node that is not the true sentinel node. If a simple excision-biopsy has been performed with margins of no more than a few millimeters around the melanoma, however, it is thought that subsequent lymphatic mapping will reliably indicate the true sentinel node or nodes. Most of the literature on lymphatic mapping in melanoma is from mapping after an excisional biopsy.

Systemic Effects of Blue Dye Injection

Administration of blue dye produces some effects that can cause concern if not anticipated and understood. The patient's skin can take on an ashen gray, almost cadaveric appearance, and a pulse oximeter may indicate desaturation of the

Sentinel Lymph Node Mapping
Figure 2 Intradermal patent blue dye injection at a primary melanoma site on the leg, prior to sentinel lymph node biopsy.

blood even when arterial oxygen tensions are well above normal. The urine shows blue-green discoloration for up to 24 h postoperatively. More serious side effects are rare. Very occasionally, however, an allergic reaction to the blue dye can occur, with the rapid development of widespread large, watery vesicles filled with pale blue fluid. Standard treatment for an acute allergic reaction, including parenteral antihistamines and corticosteroids, is usually effective in dealing with this potentially serious clinical situation.

Timing of Blue Dye Injection

It is normally satisfactory to inject the blue dye 5-10 min before anesthetic induction (if general anesthesia is to be used) or at a similar time before surgical incision (if local anesthesia is to be employed). This allows time for the injection site to be gently massaged and for the patient to exercise the relevant body part, when the anatomical location of the primary melanoma site makes this possible. Both of these maneuvers increase the likelihood that satisfactory passage of blue dye to the regional lymph node field will have occurred by the time of surgical exploration of that field. They are particularly important if, as frequently happens, the patient has become cold while being transferred from the ward to the operating suite, and while in a cool holding bay or anesthetic room awaiting surgery. Unless special precautions are taken, it is not uncommon for limb cutaneous temperatures of 32-33°C to be recorded when patients arrive in an operating theater. When local anesthesia is used, epinephrine (with lidocaine) is best avoided because of its potential effect on lymphatic flow.

If the preoperative lymphoscintigram has shown very slow movement of tracer from the primary melanoma site to the regional nodes [9,10], earlier injection of blue dye is desirable 10-20 min before anesthetic induction, with more prolonged exercise of the relevant body part. The temptation to more vigorously massage the injection site should be resisted because it is theoretically possible that this could redirect drainage of the dye in a nonphysiological way and could result in blue staining of nodes which are not true sentinel nodes draining the original melanoma site.

THE SURGICAL PROCEDURE Planning the Skin Incision

The position, direction, and extent of the skin incision appropriate for sentinel lymphadenectomy is primarily determined by the mark or marks made on the overlying skin by the nuclear medicine physician at the time of preoperative lymphoscintigraphy. However, the position of the incision should also be such that complete excision of it would easily be possible as part of a full regional node dissection if the sentinel node was found to contain micrometastatic disease.

Exposing and Removing the Sentinel Nodes

Dissection must proceed cautiously, taking care not to damage any blue-stained lymphatics. When a blue lymphatic vessel is encountered, it should be traced until it reaches a lymph node, which should itself be at least partly blue stained if it is to be identified confidently as a sentinel node (Fig. 3). The number of sentinel nodes in a regional lymph node field will be known from the preoperative lymphoscintigram, as well as their approximate depth below the skin surface, making location of these nodes a relatively easy matter in most instances. It is nevertheless desirable to seek and trace blue-stained afferent lymphatics, as nodes can sometimes be elusive even when their approximate position is known and the degree to which they are themselves blue-stained may not be intense. Sometimes, a sentinel node will be only partly blue stained, in that part which is immediately adjacent to the point of entry of the afferent lymphatic bringing blue dye from the skin injection site. If this blue-stained area is on the undersurface so that it is not visible on that part of the node which has been exposed, its identity as a sentinel node may be overlooked unless a blue-stained afferent lymphatic is traced right to the node.

The objective must always be to remove sentinel nodes with as little interference to surrounding tissues as possible—particularlynonsentinel lympnnodes and their afferent lymphatics. This will not only minimize the risk of causing

Sentinel Node Mapping
Figure 3 Blue-stained afferent lymphatics (thin arrows) entering a sentinel lymph node, which is itself blue stained (thick arrow).

lymphedema but will also help to ensure that if a sentinel node is determined to be positive and a full regional node dissection is therefore required, complete clearance of the sentinel lymphadenectomy site is possible without transgressing previously dissected and thus potentially contaminated areas.

When each sentinel node is found, it is removed, with care being taken to clip or ligate afferent and efferent lymphatics in order to minimize the risk of subsequent lymphocoele formation. Having ensured that hemostasis is complete, the wound is then closed, with use of a small drain if considered appropriate.

Frozen-Section Examination of Sentinel Nodes

During early experience with the sentinel lymphadenectomy technique, routine frozen-section examination of each sentinel node was performed in some centers [14,16], and immediate regional node dissection was undertaken if the sentinel node was reported to contain micrometastatic disease. However, even when experienced melanoma pathologists examined the frozen tissue sections, the results proved unreliable. There was also concern about the amount of tissue lost (and potentially containing the only deposits of micrometastatic disease) when trimming the tissue blocks for frozen-section examinations and cutting the tissue on the cryostat. In their initial clinical studies, Morton's group performed routine immediate immunohistochemistry on frozen tissue sections [14]. Although undoubtedly more accurate than standard frozen-section examination, this technique was very labor intensive, technically demanding, and time-consuming and is not a realistic proposition as part of a standard clinical protocol. For all the above reasons, frozen section is now not performed in most centers and it is generally considered preferable to await formal paraffin section histology and immunohis-tochemistry. If necessary, a full regional node clearance can then be undertaken as a separate procedure at a later date, after full discussion of the situation with the patient.

"in-Transit" Sentinel Nodes and Lymphatic Lakes

At the time of preoperative lymphoscintigraphy, a focus of intense isotope accumulation will occasionally develop on a lymphatic pathway leading from the skin injection site toward a regional lymph node field. Usually this is, by definition, a true sentinel node, even though it lies outside a recognized lymph node field, and it must be removed and examined if a sentinel lymphadenectomy procedure is to be performed. Occasionally, however, the focus of isotope uptake will simply be an area of lymphatic dilatation or a ''lake'' (Fig. 4). If there is a chain of such foci, it becomes much more likely that they are not nodes but lymphatic lakes. However, on rare occasions a chain of two, three, or even four sentinel nodes is present. Unless the area is surgically exposed, it is not feasible to differentiate between these two entities. This means that formal exploration of all such hot spots is required if missing a sentinel lymph node or nodes is to be avoided. In these cases, it makes sense to first explore the site furthest from the primary site because first exploring the proximal nodes carries the risk of disrupting channels to the more distant nodes (Fig. 5).

Picture Axillary Lymph Nodes
Figure 4 Focus of isotope uptake due to the presence of a lymphatic ''lake'' (curved arrow). On delayed scans, this focus had disappeared completely. There is a single sentinel node in the right axilla (straight arrow).
Sentinel Node Scan Pictures

Figure 5 Interval lymph node outside a recognized lymph node field. Initial scan (a) shows channels passing to an interval node on the right back (straight arrow) and to a sentinel node in the right axilla (curved arrow). Delayed scan (b) also shows the interval node on the right back (straight arrow) plus the sentinel node in the right axilla (curved arrow). Both are sentinel nodes. Second-tier nodes in the right axilla are also visualized.

Figure 5 Interval lymph node outside a recognized lymph node field. Initial scan (a) shows channels passing to an interval node on the right back (straight arrow) and to a sentinel node in the right axilla (curved arrow). Delayed scan (b) also shows the interval node on the right back (straight arrow) plus the sentinel node in the right axilla (curved arrow). Both are sentinel nodes. Second-tier nodes in the right axilla are also visualized.

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