Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases

Abstract

Objective: Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been applied to virtually all solid neoplasms since our original description of LM/SL for melanoma. Our objectives were to determine the diagnostic and therapeutic utility of LM/SL, investigate carbon dye for mapping the microanatomy of lymphatic flow within the sentinel node (SN), and determine the prognostic accuracy of molecular assessment of the SN.

Methods: Since 1985, 1599 patients with AJCC Stage I/II melanoma have been treated by LM/SL at our institution and 4590 have been treated by wide excision (WE) without nodal staging. We examined the incidence of clinical nodal recurrence after WE alone, the incidence of subclinical nodal metastases found by LM/SL, and the incidence of nodal recurrence in basins with histopathology-negative SNs.

Results: In 1514 LM/SL patients with a primary of known Breslow thickness, the incidence of metastasis in nodes claimed to be sentinel was 7.3%, 19.7%, 33.2%, and 39.7% for primary lesions </=1.0, 1.01-2.0, 2.01-4.0, and >4.0 mm, respectively. In 3652 WE-only patients, the corresponding rates of nodal recurrence were 12.0%, 32.0%, 34.4%, and 30.1%. Thus, LM/SL detected only 60% of expected nodal metastases from primary melanomas <2.01 mm. Forty of 1599 (3.1%) patients developed recurrence in basins with immunohistochemistry (IH)-negative SNs. To determine whether nonrandom intranodal distribution of tumor cells could explain missed SN metastases, we coinjected carbon particles and blue dye during LM/SL in 166 patients: 25 (16%) patients had nodal metastases, all of which were found only in nodal subsectors containing carbon particles. When paraffin-embedded SNs from a subset of 162 IH-negative patients were re-examined by quantitative multimarker reverse-transcriptase polymerase chain reaction (qRT) assay, 49 (30%) gave positive signals. These patients had a significantly higher risk of disease recurrence and death than did patients whose IH and qRT results were negative (p < 0.0001). Comparison of 287 prognostically matched pairs of patients who underwent immediate (after LM/SL) versus delayed (after observation) dissection of nodal metastases revealed 5-, 10-, and 15-year survival rates of 73%, 69%, and 69% versus 51%, 37%, and 32%, respectively (P < or = 0.001).

Conclusions: SN assessment based on intranodal compartmentalization of lymphatic flow (carbon dye mapping) should increase the accuracy of IH and, in combination with multimarker qRT assessment, will allow confident identification of most patients for whom surgery alone is curative. Our data suggest a significant therapeutic benefit for immediate dissection based on identification of a tumor-involved SN.

FIGURE 1. Two hypotheses regarding metastatic routes in melanoma. According to the incubator hypothesis (left), primary melanoma initially metastasizes via the lymphatics to the SN, which is immunosuppressed by factors released from the primary melanoma. Metastatic foci in the SN may grow but remain latent (incubate) before spreading to distant sites. Thus, finding tumor cells in the SN indicates that the primary melanoma has the ability to metastasize; removal of the tumor-involved SN before there is further spread should prevent distant metastasis. According to the marker hypothesis (right), a primary melanoma metastasizes simultaneously via lymphatic and hematogenous routes. Thus, finding tumor cells in the SN is merely a marker of a primary melanoma that can metastasize; removal of the tumor-involved SN is unlikely to influence the growth of distant metastases and would have no therapeutic effect. The absence of melanoma cells in the SN indicates a primary melanoma that is unlikely to spread to distant sites; this has important prognostic implications.

FIGURE 2. Recurrence patterns of patients with AJCC stage I/II melanoma managed by WE + postoperative observation versus WE + LM/SL + selective CLND for tumor-involved SNs.

FIGURE 3. Compartmentalization of intranodal lymph flow as detected in the operating room by radiopharmaceutical, blue dye, and carbon dye (left) and confirmed in the pathology department by carbon dye (right).

FIGURE 4. Left, Kaplan–Meier estimates of disease-free survival (DFS) in patients with H&E/IH-positive SNs (N = 53) and IH-negative SNs (N = 162) according to SN expression of no mRNA markers or at least 1 mRNA marker (tyrosinase, MART-1, MITF, and/or TRP-2). Right, Kaplan–Meier estimates of OS according to multimarker qRT and histopathology status of SNs in 215 patients.

FIGURE 5. Kaplan–Meier estimates of OS after WE for immediate versus delayed therapeutic CLND in 287 pairs of patients matched by the criteria shown in Table 4.

FIGURE 6. Comparison of the density and area of dendritic cells, T cells and B cells in 21 matched pairs of SNs and nonsentinel nodes (NSNs) from 11 patients with AJCC stage I/II melanoma. Each SN was size-matched with a NSN from the same patient (data from Cochran et al24).