Sentinel Lymph Node Biopsy for Melanoma

History and Rationale

Surgical strategies for stage I and II patients have included two main components: wide excision of the primary tumor or biopsy site and regional lymph node evaluation. While recommendations for the extent of excision margins are well established and widely accepted, the approach to the clinically uninvolved regional lymph nodes has been the center of ongoing controversy. How to best manage the following clinical scenario is often called into question: A 36-year-old patient with a biopsy-proven 1.8 mm melanoma. Physical examination reveals the absence of enlarged lymph nodes in any potential regional lymph node group. The chest X-ray is normal and the patient is otherwise healthy. Traditionally, this patient would have been offered one of two options in addition to excision of the primary tumor: 1) observation of the regional lymph nodes and formal node dissection only if the patient subsequently develops clinically evident (palpable) nodal disease, an approach termed therapeutic lymph node dissection (TLND); or, 2) a formal lymph node dissection as a component of the initial surgical treatment, referred to as elective lymph node dissection (ELND). Both of these approaches have theoretical and very real disadvantages.

A significant percentage of individuals, predicted by increasing primary tumor thickness, ulceration, or other unfavorable histologic features of the primary tumor, harbor clinically undetectable regional lymph node metastases, which in most patients will progress to palpable (macroscopic) nodal disease if left untreated. Once clinical nodal involvement develops, the ability to achieve long-term survival and durable regional disease control with a TLND may be compromised compared to surgical approaches targeted at treating microscopic nodal burden. The rate of distant metastatic disease and relapse in the treated nodal basin is at least 50% and 15–50%, respectively, following TLND.

The practice of ELND was popularized for the sole intent of reducing these high rates of disease recurrence. Proponents of ELND suggested that removal of microscopically involved lymph nodes would prevent the development of clinically apparent lymph node disease, which in turn could, in a significant percentage of patients, eliminate a potential source of distant failure. Furthermore, a dissection performed when the lymph node involvement is microscopic would more completely eradicate regional metastases and prevent recurrence in the treated basin and the potential sequelae of pain, skin ulceration, blood vessel and nerve involvement, and advanced lymphedema that can be associated with this pattern of failure. In the majority of patients, however, microscopic nodal disease is absent at diagnosis and therefore they cannot benefit from an ELND and are subjected to the cost and morbidity of an unnecessary operation. It is therefore not surprising that overall survival advantage with ELND was not observed in prospective randomized trials that compared the outcome of stage I and II patients receiving either ELND or nodal observation.

For these reasons, the routine practice of ELND has been appropriately challenged. A rational compromise emerged when the technique of lymphatic mapping and SLN biopsy was introduced as a minimally invasive method for determining if occult nodal metastases are present. Patients with proven occult nodal disease in the SLN could then undergo an early TLND, and those without disease could be safely observed, an approach popularized as selective lymphadenectomy . This approach has been extensively studied worldwide.

Scientific Support for the Sentinel Node Concept

Lymphatic mapping relies on the hypothesis that the dermal lymphatic drainage from cutaneous sites to the regional lymph node basin is an orderly and definable process and that these lymphatic drainage patterns should mimic the metastatic spread of melanoma cells in the lymphatics ( Figure 55-1-1 ). In this way, the first lymph node(s) receiving lymphatic drainage (the sentinel nodes) are the most likely to contain metastatic disease. The successful identification, surgical removal, and careful histologic examination of these nodes should provide accurate nodal staging.

To test this hypothesis, clinical studies were performed using intradermal injections of blue lymphatic dyes (isosulfan blue or patent blue V) at the primary tumor site followed by the visual identification of the SLNs in the nodal basin. These studies established the following: 1) SLN identification rates, and 2) the accuracy of the SLN in determining the presence or absence of regional nodal metastases.

The first report published by Morton et al. in 1992 evaluated 237 patients and demonstrated an 82% SLN identification rate. Subsequent studies from the M. D. Anderson and Moffitt Cancer Centers and the Sydney Melanoma Unit reported similar findings. Accuracy assessment was accomplished through the use of synchronous ELND performed at the time of the SLN biopsy. These initial studies evaluated 402 patients with successful SLN localization, 86 of whom were found to have regional node metastases (81 patients with a positive SLN and 5 additional patients with disease only in a non-SLN). This low false-negative rate of 5% supported the SLN concept.

Additional evidence that regional node metastasis is an orderly and non-random event was provided from the M. D. Anderson Cancer Center reporting on the examination of 105 lymphadenectomy specimens in patients with at least one positive SLN. Investigators found that the SLN was the only node involved in 83 (79%) of the basins, with disease in additional nodes identified in 21% of the lymphadenectomy specimens. Presented in another way, 68% of all the SLNs removed from all patients with at least one involved SLN and only 1.8% of all non-SLNs were involved with metastatic disease.

Tremendous interest was generated from these initial studies, and many centers subsequently adopted the selective lymphadenectomy approach for newly diagnosed intermediate- and high-risk stage I and II melanoma patients. Improvements in SLN localization techniques, insights into the biologic relevance of the SLN (discussed below), and additional findings supporting the SLN concept emerged. In a report of nearly 250 SLN-negative patients followed for over 3 years, only 10 patients (4%) developed nodal failure within the previously mapped regional basin. Such failures represent a false-negative rate similar to the 5% determined by concomitant ELND. More careful histologic scrutiny of the negative SLNs from these same 10 patients revealed the presence of disease in 8. These data not only further supported the validity of the SLN concept, but also suggested that routine histologic examinations of SLNs may fail to detect clinically relevant disease.

Technical Advances

Initial SLN identification rates of 80% to 85% using blue dye injections provided a promising beginning. The use of high-resolution cutaneous lymphoscintigraphy and an intraoperative handheld gamma detection device to locate radiolabeled colloids that have accumulated in SLNs after being injected at the primary site have yielded higher SLN identification rates. The use of a gamma probe was first described by Krag et al., who reported a 95% SLN identification rate. Studies comparing combined modality techniques (radiocolloid plus blue dye) versus blue dye alone demonstrated a significant increase in SLN identification to 99% with the combined approach.

The intraoperative use of the gamma probe provides a method of detection that is independent of and more sensitive than visualization of blue-stained nodes and can locate SLNs that might otherwise be undetected. The number of SLNs identified was greater when both modalities were employed compared to blue dye alone (1.74 versus 1.31, respectively). This more complete removal of SLNs may further reduce the already low false-negative rate. Figure 55-1-2 summarizes the components necessary for successful identification and removal of an SLN.

These techniques can also aid in the localization of SLNs that may exist outside and/or proximal to the formal nodal basin; referred to as interval, in-transit, or ectopic SLNs ( Figure 55-1-3 ). According to published studies, the frequency of such SLN locations is in the range of 5% to 10% of patients, and the frequency of involvement with microscopic disease is the same as that of SLNs harvested from formal basins. The failure to identify these nodes risks under-staging some patients and leaving behind potential sources of clinical recurrences.