Charles M. Balch, MD
Department of Surgery
University of Texas Southwestern Medical Center
John F. Thompson, MD
Melanoma Institute Australia
Sydney, NSW Australia
Mark B. Faries, MD
John Wayne Cancer Institute
Santa Monica, CA
The regional lymph nodes are commonly the first site of melanoma metastasis. Even within a nodal basin, there may be regional spread to surrounding lymph nodes before progression to distant sites. Therefore, surgical excision of regional lymph nodes has been a focus of melanoma treatment for decades. There are three potential goals of surgery, any one of which may justify the procedure for an individual patient when the benefits of treatment are judged to outweigh the risks and morbidity:
- staging (where information about lymph node status provides an accurate prognosis and guides subsequent treatment);
- regional disease control (to prevent symptomatic growth of regional metastases); and
- improved patient survival (because tumor burden is reduced or eliminated so that the metastatic process is interrupted or delayed).1
The Role of Surgical Lympha-denectomy in Stage III Patients
The benefits of surgical lymphadenectomy (whether sentinel lymph node biopsy and completion lymphadenectomy or therapeutic lymphadenectomy) in Stage III melanoma patients have been debated for decades. However, even if some questions remain, the issue of its utility can now be put to rest with the publication of the seminal Multicenter Selective Lymphadenectomy Trial I (MSLT-1), the largest and longest-running melanoma surgical trial ever conducted, led by the late Dr. Donald L. Morton.2 The results of this 20-year prospective randomized clinical trial clearly demonstrate the staging value of the sentinel lymph node biopsy (SLNB) procedure, and in a predetermined cohort of microscopically node-positive patients with a primary melanoma thickness of 1.2—3.5 mm (a subset of intermediate thickness melanomas), also demonstrate the disease-free and disease-specific survival advantage of early surgical intervention involving complete excision of regional node metastases.2
After 35 years of uncertainty and controversy, the results of MSLT-1 provide important new insights into the value of surgical excision of regional lymph nodes in melanoma patients.1,2 Balch and colleagues proposed in 1979 that tumor thickness could guide surgical management and partitioning of patients based on their relative risk for regional and distant metastases.3,4 Thus, patients with thin melanomas (defined at that time as those less than 0.75 mm in thickness) would have a low risk for regional or distant metastases and, therefore, would not benefit from regional lymphadenectomy. Nor, at the other extreme, would patients with thick melanomas (defined in 1979 as > 4.0 mm in thickness), who would have such a high risk of distant metastases that they would receive no therapeutic benefit from lymphadenectomy (but would still derive staging value).
At that time, Balch, et al hypothesized that patients with intermediate-thickness melanomas (those ranging from 0.76 to 4.0 mm) might benefit from lymphadenectomy because they would have a high enough risk of regional node metastasis to justify the operation but a low enough risk of initial distant metastases to benefit from regional treatment and prevention of further dissemination to distant sites. They concluded, “The rationale of elective RND is improved survival in patients with intermediate-thickness lesions (0.76 to 3.99 mm), while it is [also] justifiable as a staging procedure for lesions exceeding 4.0 mm thickness.”4
This hypothesis was the scientific underpinning for the subsequent randomized Intergroup Melanoma study of elective lymphadenectomy, begun in 1983 and first reported in 1996;5,6 the randomized surgical trial conducted by the World Health Organization Melanoma Program on trunk melanomas (Trial #14);7and the first Multicenter Selective Lymphadenectomy Trial known as MSLT-1, which began in 1994, culminating in the final report 20 years later in the New England Journal of Medicine.2
Sentinel Lymph Node Biopsy
In 1992, the management of melanoma changed forever, with the landmark publication by Morton, Cochran and colleagues detailing the sentinel lymph node biopsy (SLNB) technique. This procedure enabled surgeons to remove just one or two key lymph nodes (the “sentinel nodes”) to determine whether micrometastases from a primary melanoma had reached the regional lymph node basin; if the sentinel nodes proved negative for metastases, the rest of the nodes in the basin could be spared, and if the sentinel nodes proved positive, the patient could elect to have the rest of the nodes in the basin removed.1,8 Others confirmed these findings, further demonstrating its staging value and its reproducibility across institutions.9-14 Morton, Cochran, and colleagues worldwide then embarked on a monumental project to determine the overall value of this surgical procedure in a randomized prospective study, MSLT-1.
MSLT-1 accrued 2,001 patients, of whom 1,560 with melanomas ≥1.2mm in thickness were evaluable.2 (An additional 232 patients with melanomas <1.2 mm thick were separately randomized, but the results of this cohort have not been reported because to date too few metastatic events have occurred to make a valid comparison.) The primary objective of the study was to compare overall survival for all patients randomly assigned to either 1) SLNB and, if positive for metastases, a completion lymphadenectomy, or 2) clinical observation (watch-and-wait), with lymphadenectomy only if the patient later developed clinical evidence of nodal metastases. A predetermined secondary objective of MSLT-1 was to compare survival for those patients who had completion lymphadenectomy for nodal metastases diagnosed by SLNB with that of patients who had a delayed lymphadenectomy for palpable metastases. The latter took an average 19.3 months to become clinically apparent (M. Faries, personal communication). Such a delay was, at least theoretically, a critical time period during which the metastatic process may have further disseminated and eventually caused the demise of a greater proportion of patients in this cohort with clinically detectable nodal metastases compared to those whose regional metastases were removed when the tumor burden was subclinical. It is also notable that in the delayed lymphadenectomy patients, there was regional spread within the nodal basin, since the number of metastatic nodes increased during this time as well—from an average of 1.4 metastatic nodes in the immediate completion lymph node dissection (CLND) group compared to 3.3 metastatic nodes in the delayed CLND group (p<0.001). Biopsy-based management improved 10-year melanoma-specific survival by 44 percent (p=0.006) for patients with intermediate thickness melanomas and nodal metastases, but not for those with melanomas >3.5mm thick (Figure 1). A sophisticated latent subgroup statistical analysis also demonstrated a significant treatment benefit in the intermediate thickness cohort.2,15,16
The staging information provided by SLNB is of particular value because it reliably identifies patients with nodal micrometastases.1,17 In MSLT-1 as in several previous large studies, SLN status was the most important and statistically powerful predictor of survival outcome (Table 1).2 Used in conjunction with Breslow thickness, ulceration, and other prognostic features of the primary melanoma, it allows for accurate predictions of metastatic risk and survival outcome. Information based on SLN status is also valuable for counseling SLN-positive patients about the need for completion lymphadenectomy to improve regional disease control, reduce operative morbidity (as compared with the morbidity associated with later, possibly more radical, regional surgery and often radiation therapy for palpable nodal recurrence), reduce the relative risk of recurrence by 26 percent, and potentially improve survival if nodal metastases are present.17-19 In addition, the information about their SLN status can be used to counsel patients regarding enrollment into melanoma clinical trials, and can serve as the basis for discussing a screening and follow-up regimen based on risk for subsequent development of metastases. Patients who are SLN-negative can be reassured that their prognosis is relatively improved; these patients are less likely to require adjuvant treatments and/or frequent follow-up.1,10,17
The results of MSLT-1 clearly demonstrate the important staging role of SLNB in a defined group of patients (those with intermediate thickness and thick melanomas), as well as a survival benefit in those with intermediate thickness melanomas. Just as importantly, it partitions the majority of melanoma patients with T2 to T4 melanomas who have negative sentinel nodes into a better prognostic group who can safely be spared more aggressive treatments, including potentially toxic systemic therapies.
These results reinforce guideline recommendations for SLNB made by the American Society of Clinical Oncology, the Society of Surgical Oncology, the American Joint Committee on Cancer, and other organizations (Table 2).1,17,20 MSLT-1 demonstrates that there is a role for surgical removal of regional metastases, both for its staging value and, by intercepting the metastatic process, potentially increasing survival rates in some patients. Knowing the pathological status of the regional lymph nodes is also an essential eligibility criterion for entry into adjuvant therapy clinical trials.
Should Patients with Thin (T1) Melanomas Ever Be Considered for SLNB?
Most experienced melanoma surgeons would also offer SLNB to patients who have T1 melanomas (i.e., not thicker than 1.0 mm) if the tumors have characteristics that substantially increase the likelihood of regional node micrometastasis.1 This would include patients with T1 melanomas with primary tumor ulceration, a mitotic rate > 1/mm2 and/or Clark level IV/V invasion—especially if tumor thickness exceeds 0.75 mm. Ulceration, mitotic rate and Clark level are considered to be especially relevant in patients who have no significant comorbidity, who are younger than 40-45 years, or whose primary tumor depth is uncertain because of a tumor-positive deep margin in the biopsy specimen.21
What the Critics Say
Some still question the value of SLNB, and the MSLT-1 findings have not dissuaded them. Some, for example, maintain that SLN status is not a useful enough prognostic indicator, and that similar prognostic information can be obtained with less morbidity by
examining the features of the primary melanoma.22-25 This proposal ignores evidence from two large multicenter clinical trials (the Sunbelt Trial and MSLT-1) which specifically examined this question.26.27 In both these trials, sentinel node status provided the best prediction of outcome, with hazard ratios of 2.8 (p<0.0001) and 2.4 (p<0.01) respectively compared to the prognostic value of Breslow thickness and ulceration.26,27 The latter parameters, of course, can only indicate the likelihood that metastatic disease is present in regional nodes, whereas SLNB determines whether metastatic disease in the regional nodes is actually present. Both sources of information, the primary tumor and the lymph node, provide independent prognostic information, and both are valuable.
Others assert that the improvements in disease-free survival and (for those with intermediate thickness melanomas) disease-specific survival associated with management based on SLN status are of no clinical significance, since they are not definitively proven to lead to increased overall survival. But most clinicians and patients would disagree strongly. Detractors make much of SLNB’s morbidity, but in the modern era it is associated with much lower morbidity than occurred in early studies, and any morbidity is generally mild and transient. What cannot be disputed is that early CLND, performed when a positive SLN is identified, is a much less morbid procedure than delayed complete lymph node dissection for palpable or bulky nodal metastases, performed therapeutically only when nodal disease becomes clinically apparent. In the latter circumstance the surgical morbidity is much greater, the volume of nodal disease has more than doubled, and so too has the risk of postoperative lymphedema.19
Another suggestion made by those who oppose SLNB is that some “false-positive” sentinel nodes (with micrometastases that would never actually advance to clinical metastases) might lead to unnecessary radical surgery and morbidity.24 However, the comprehensive data collected in MSLT-1 provide no statistical support whatsoever for this theory.27
There is now convincing, irrefutable evidence demonstrating the staging value of SLNB for specific cohorts of melanoma patients. This evidence is derived from multiple prospective studies, especially the randomized MSLT-1 trial. The SLN biopsy technique (including preoperative lymphoscintigraphy and intraoperative lymphatic mapping) has enabled clinicians to identify patients with occult nodal metastases that would otherwise take months or years to become clinically palpable.1,17,21
In particular, pathologic evaluation of the SLN allows for detection of micrometastatic disease through a combination of serial sectioning and immunohistochemical staining. The latter technique has been incorporated into the 7th edition of the AJCC melanoma staging system, with the presence of micrometastases defined not only by H&E positivity but also by evidence of immunohistochemical positivity in cells with malignant morphologic features.1,13,17 In addition, the MSLT-1 trial provides evidence that a cohort of patients with intermediate thickness melanomas reaps a treatment benefit through early removal of metastatic lymph nodes, gaining a disease-specific survival advantage compared to patients receiving a delayed lymphadenectomy for clinically palpable nodal metastases.1,2 This latter conclusion has remained the subject of debate, but even if survival benefits are discounted, the staging value is compelling, and regional disease control is substantially improved.
The minimally invasive SLNB procedure should be discussed with and recommended to patients when at least one of the following indications is present: (1) the risk of clinically occult nodal metastasis is considered sufficient (approximately 10 percent or greater) to justify the procedure; (2) the prognostic information provided by SLNB would be of value to the patient and the treating physicians; (3) the tumor status of the SLN would be useful in guiding decisions regarding completion lymphadenectomy and adjuvant therapy; and/or (4) nodal staging information is required for entry into clinical trials in which the patient is interested.1,17,20,21
Thus, the SLNB procedure should be discussed with and offered to all patients with primary melanomas ≥1.0 mm in thickness and clinically normal regional lymph nodes when the criteria described above are met, and when the morbidity and risks of SLNB are considered acceptable to the physician and the patient. It may also be offered to patients with primary melanomas <1.0 mm (but preferably >0.75 mm) in thickness if there are adverse pathologic features such as ulceration or a high mitotic rate.1,17,20,21
Currently the second MSLT (MSLT-2) is ongoing. This Phase III trial examines the value of completion lymph node dissection vs. SLNB alone in patients found to have SLN metastases, since nodal metastases in 80-90 percent of such patients are limited to the sentinel node(s). The primary outcome measure will be melanoma-specific survival, and secondary outcome measures will be both disease-free survival and recurrence over 10 years of follow-up. MSLT-2 has completed accrual of nearly 2,000 subjects, and results will be available with additional follow-up, clarifying one of the last significant questions in the initial management of this disease.
- Balch CM, Gershenwald JE. Clinical value of the sentinel-node biopsy in primary cutaneous melanoma. N Engl J Med 2014; 370:663-4.
- Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. New Eng J Med 2014; 370:599-609.
- Balch CM, Murad TM, Soong SJ, et al. A multifactorial analysis of melanoma: prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann Surg 1978; 188:732-42.
- Balch CM, Murad TM, Soong SJ, et al. Tumor thickness as a guide to surgical management of clinical stage I melanoma patients. Cancer 1979; 43:883-8.
- Balch CM, Soong SJ, Bartolucci AA, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 1996; 224:255-63; discussion 263-6.
- Balch CM, Soong S, Ross MI, 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; 7:87-97.
- Cascinelli N, Morabito A, Santinami M. Immediate or delayed dissection of regional nodes in patients with melanomas of the trunk. A randomized study. Lancet 1998; 351:793-796.
- Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127:392-9.
- Ross MI, Reintgen D, Balch CM. Selective lymphadenectomy: Emerging role for lymphatic mapping and sentinel node biopsy in the management of early stage melanoma. Semin Surg Oncol 1993; 9:219-223.
- JF, McCarthy WH, Bosch CM, et al. Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Mel Res 1995; 5(4):255-60.
- Gershenwald JE, Colome MI, Lee JE, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998; 16:2253-60.
- Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999; 17(3):976-83.
- Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2313 patients with stage III melanoma. J Clin Oncol 2010; 28(14):2452-2459.
- Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 1999; 230:453-63; discussion 63-5.
- Altstein LL, Li G, Elashoff RM. A method to estimate treatment efficacy among latent subgroups of a randomized clinical trial. Stat Med 2011; 30(7):709-17. doi:10.1002/sim.4131.
- Altstein L, Li G. Latent subgroup analysis of a randomized clinical trial through a semiparametric accelerated failure time mixture model. Biometrics 2013; 9:52-61.
- Balch CM, Morton DL, Gershenwald JE, et al. Sentinel node biopsy and standard of care for melanoma. J Am Acad Derm 2009; 60:872-875.
- Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Eng J Med 2006; 355:1307-17.
- Faries MB, Thompson JF, Cochran AJ, et al. The impact on morbidity and length of stay of early versus delayed complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy Trial 1. Ann Surg Oncol 2010; 17:3324-9.
- Wong SL, Balch CM, Hurley P, et al. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. Ann Surg Oncol 2012; 19:3313-24.
- Gershenwald JE, Coit DG, Sondak VK, Thompson JF. The challenge of defining guidelines for sentinel lymph node biopsy in patients with thin primary cutaneous melanomas. Ann Surg Oncol 2012; 19(11):3301-3.
- Yang JC, Sherry RM, Rosenberg SA. Why is sentinel node biopsy “standard of care” for melanoma? Nat Rev Clin Oncol 2014; 11:245-246.
- Van Akkooi AC, Eggermont AMM. MSLT-1 — SNB is a biomarker, not a therapeutic intervention. Nat Rev Clin Oncol 2014; 11:248-249.
- Thomas JM, Cady B. Letters to the Editor. Sentinel node biopsy in melanoma, with reply by Thompson JF, Cochran AJ, and Faries MB. N Eng J Med 2014; 370:2148-2150.
- Coit D. Sentinel lymph node biopsy for melanoma: a plea to let the data speak. Ann Surg Oncol 2014; 21:3359-3361.
- Thompson JF, Faries MB, Cochran AJ. Sentinel node biopsy: a plea to let the data be heard. Ann Surg Oncol 2014; 21:3362-3364.
- Faries MB, Cochran AJ, Thompson JF. MSLT-1 — response of clinical trial investigators. Nat Reviews Clin Oncol 2014; 11:680.