Sentinel Lymph Node Mapping: Promise and progress

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By Mary Sue Brady, MD, FACS

Cancer research continues to question the standard of care to find new approaches to improve survival outcomes for patients. The evolution of the surgical management of regional lymph nodes in patients with melanoma is an extraordinary lesson in the importance of humility and open-mindedness for academic surgeons.

When I began my surgical training more than 20 years ago, we believed that regional lymph node metastasis preceded distant metastasis and that removal of these nodes would interrupt the metastatic progression of melanoma. Those who questioned this concept did so at considerable risk to their reputation and professional standing!  Needless to say, there were few dissenters, but one of these was a medical oncology colleague. He suggested that the ideal surgical trial would compare the survival of patients with microscopically positive regional sentinel lymph nodes (SLNs) who had no further surgery with those who had a regional lymphadenectomy. At that time I thought he was crazy: How irresponsible it would be to randomize patients with known nodal metastasis to observation!

Decades of Melanoma Lymph Node Surgery Progress

Consider the radical changes in surgical management we have seen over the last 50 years. Prospective randomized trials began to provide strong medical evidence to guide recommendations, compared to the retrospective data and expert opinion that guided surgical care historically. The 1970’s and 80’s were the golden eras of prospective randomized trials for breast cancer (2) and melanoma. (3), (4) Melanoma surgical margin recommendations changed from 5 cms to a much less morbid 1-2 cm margin based on prospective trials that provided strong safety evidence. (5), (6) Several other prospective randomized trials addressed the question of elective lymph node dissection (ELND) in patients with varying degrees of risk for regional nodal disease. (3), (4), (7) Contrary to what we expected, none of these trials demonstrated that surgical removal of regional nodes improved survival. We argued that the benefit was obscured by the fact that 80 percent of patients had no evidence of lymph node metastasis at pathologic review. If only we could identify the 20 percent of patients with nodal metastasis!

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Recent Advances in Sentinel Lymph Node Mapping

Enter the era of sentinel lymph node (SLN) mapping, a seismic event in melanoma care, and subsequently in breast cancer care. It allowed surgeons to identify the subset of patients with positive regional nodes who would potentially benefit from complete surgical lymphadenectomy.  Confirming our experience with ELND, approximately 20 percent of patients were found to have positive SLNs.

Initially, patients with positive SLNs went on to have completion lymphadenectomy (CLND), to remove all nodes in the draining basin. But surgeons and patients began to question the need for additional nodal surgery in these patients. Retrospective studies demonstrated no difference in survival between patients who did and did not have their remaining regional nodes removed. (8), (9) These results triggered questions in the melanoma surgical community similar to when we questioned ELND. As well, recent prospective randomized trials have provided strong evidence that removal of regional nodes, while effective in identifying patients at high risk for recurrence, has no impact on melanoma-specific survival. (10)

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The MSLT-II Trial

Today, we are right back to the question by my forward thinking medical oncology colleague more than 20 years ago! The difference, though, is that we will benefit from a stronger body of evidence. A prospective randomized phase III trial, the Multicenter Selective Lymphadenectomy Trial II, MSLT-II. (1)is comparing survival in patients with positive SLNs who undergo CLND compared to patients with positive SLNs receiving close surveillance of the nodal basin with ultrasound monitoring. Memorial Sloan Kettering Cancer Center is a participating site for this study, which began in 2004 and is following 1,925 patients for ten years. The ongoing study is no longer recruiting participants and is expected to complete data collection by September 2022.

The initial promise of curing more patients with metastatic melanoma using surgery has been superseded by tremendous progress in our understanding of the role of lymph node metastasis in patients with melanoma and our ability to identify high risk patients.  This allows us to select patients for treatment with new immunotherapeutic agents, a potentially more effective approach than surgery alone.

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  1. Morton DL. Overview and update of the phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) in melanoma. Clinical & Experimental Metastasis 2012; 29(7):699-706.
  2. Fisher B, Redmond C, Fisher ER. Clinical trials and the surgical treatment of breast cancer. Surg Clin North Am 1978; 58(4):723-36.
  3. Veronesi U. Regional lymph node dissection in melanoma of the limbs Stage I — A cooperative international trial (WHO Collaborating Centers for diagnosis and treatment of melanoma). Recent Results Cancer Res 1977(62):8.
  4. Balch CM, Soong S, Ross MI, Urist MM, Karakousis CP, Temple WJ, et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 2000; 7(2):87-97.
  5. Balch CM, Soong SJ, Smith T, Ross MI, Urist MM, Karakousis CP, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 2001; 8(2):101-8.
  6. Veronesi U, Cascinelli N, Adamus J, Balch C, Bandiera D, Barchuk A, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 1988; 318(18):1159-62.
  7. Veronesi U, Adamus J, Bandiera DC, Brennhovd IO, Caceres E, Cascinelli N, et al. Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N Engl J Med 1977; 297(12):627-30.
  8. Wong SL, Morton DL, Thompson JF, Gershenwald JE, Leong SP, Reintgen DS, et al. Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol. 2006;13(6):809-16.
  9. Bamboat ZM, Konstantinidis IT, Kuk D, Ariyan CE, Brady MS, Coit DG. Observation after a positive sentinel lymph node biopsy in patients with melanoma. Ann Surg Oncol. 2014;21(9):3117-23.
  10. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.

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