Sentinel node biopsy for primary cutaneous melanoma

Abstract

For more than two decades, the technique of lymphatic mapping and sentinel lymph node (SLN) biopsy has been a standard component in the management of selected patients with primary cutaneous melanoma worldwide.1Coit D.G. Thompson J.A. Albertini M.R. et al.Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2019; 17: 367-402Crossref PubMed Scopus (180) Google Scholar, 2Michielin O. van Akkooi A. Lorigan P. et al.ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee.Ann Oncol. 2020; 31: 1449-1461Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 3Wong S.L. Faries M.B. Kennedy E.B. et al.Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update.J Clin Oncol. 2018; 36: 399-413Crossref PubMed Scopus (117) Google Scholar, 4Garbe C. Amaral T. Peris K. et al.European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics – Update 2019.Eur J Cancer. 2020; 126: 141-158Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 5Gyorki D.E. Barbour A. Mar V. et al.When is sentinel lymph node biopsy (SLNB) indicated? Cancer Council Australia.https://wiki.cancer.org.au/australia/Clinical_question:When_is_a_sentinel_node_biopsy_indicated%3FDate: 2020Google Scholar Based on pioneering work to develop and refine this technique, Morton and colleagues6Morton D. Wen D. Wong J. et al.Technical details of intraoperative lymphatic mapping for early stage melanoma.Arch Surg. 1992; 127: 392-399Crossref PubMed Scopus (3731) Google Scholar,7Morton D.L. Thompson J.F. Cochran A.J. et al.Final trial report of sentinel-node biopsy versus nodal observation in melanoma.N Engl J Med. 2014; 370: 599-609Crossref PubMed Scopus (875) Google Scholar demonstrated that regional nodes receiving direct afferent lymphatic drainage from a primary melanoma—the so-called SLNs—are the most likely lymph nodes to contain metastatic disease in a draining regional nodal basin if any are involved. The procedure has been evaluated in studies by numerous institutions and several large multicenter international clinical trials, affirming the accuracy of the procedure for staging, the prognostic significance of SLN pathological status as an important independent predictor of outcome, and evidence of its clinical value.6Morton D. Wen D. Wong J. et al.Technical details of intraoperative lymphatic mapping for early stage melanoma.Arch Surg. 1992; 127: 392-399Crossref PubMed Scopus (3731) Google Scholar, 8Gershenwald J.E. Scolyer R.A. Hess K.R. et al.Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 472-492Crossref PubMed Scopus (940) Google Scholar, 9Dessureault S. Soong S.J. Ross M.I. et al.Improved staging of node-negative patients with intermediate to thick melanomas (>1 mm) with the use of lymphatic mapping and sentinel lymph node biopsy.Ann Surg Oncol. 2001; 8: 766-770Crossref PubMed Scopus (94) Google Scholar, 10Gershenwald J.E. Thompson W. Mansfield P.F. 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: 976-983Crossref PubMed Google Scholar Data derived from the SLN is used as an important component of current melanoma staging and as a key eligibility criterion for recently completed clinical trials that have demonstrated clear clinical benefit for melanoma patients with tumor-involved SLNs, leading to recent additions to the adjuvant systemic therapy armamentarium.8Gershenwald J.E. Scolyer R.A. Hess K.R. et al.Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 472-492Crossref PubMed Scopus (940) Google Scholar,11Weber J. Mandala M. Del Vecchio M. et al.Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.N Engl J Med. 2017; 377: 1824-1835Crossref PubMed Scopus (1119) Google Scholar, 12Long G.V. Hauschild A. Santinami M. et al.Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.N Engl J Med. 2017; 377: 1813-1823Crossref PubMed Scopus (736) Google Scholar, 13Eggermont A.M.M. Blank C.U. Mandala M. et al.Adjuvant pembrolizumab versus placebo in resected stage III melanoma.N Engl J Med. 2018; 378: 1789-1801Crossref PubMed Scopus (838) Google Scholar Despite these data, a small, albeit vocal, minority in the global melanoma community opines that similar prognostic information can be obtained using clinicopathological features obtained from standard histological examination of the primary tumor. El Sharouni and colleagues examined the improvement in staging accuracy and prognostic information when knowledge of the pathological status of the SLN was added to primary tumor clinicopathological features.14El Sharouni M.A. Stodell M.D. Ahmed T. et al.Sentinel node biopsy in patients with melanoma improves the accuracy of staging when added to clinicopathological features of the primary tumor.Ann Oncol. 2021; 32: 375-383Scopus (5) Google Scholar The study further corroborated a large body of investigation that SLN pathological status is an independent predictor of clinical outcomes for these patients and that optimal modeling requires knowledge of the pathological status of the SLN. Their well-conducted analysis included clinicopathological and follow-up data from two datasets comprised of approximately 15 000 patients from different parts of the world, which supported a robust platform for prognostic model development and validation. The differing characteristics of these two populations, a population-based Dutch Pathology Registry (PALGA) for the development cohort (N = 9272) and a prospectively-maintained research database based at a tertiary referral center in New South Wales, Australia (N = 5644), added to the models. The robust study design and reproducibility of the results were reassuring. Echoing the results of prior analyses, the findings from this study of multiple covariate hazard ratios of 2.7 and 2.9 for overall survival and recurrence-free survival, respectively (P values < 0.0001), are not surprising. Perhaps more revealing is that this question needed to be revisited at all. Early after the introduction of SLN biopsy, there was significant debate regarding the utility and reliability of the technique. As the body of data validating its value has grown, there has been broad acceptance of the procedure within the oncology community. However, there has also been a steady undercurrent of publications, largely editorials and commentaries as alluded to in the El Sharouni et al. article, that question the prognostic value of nodal staging with SLN biopsy. Their well-conducted study should help allay remaining concerns. It has been well demonstrated that microscopic tumor burden or extent of disease detected within tumor-involved SLNs—both in terms of the number of nodes involved and the size and location of the metastases within an SLN—adds substantial prognostic information beyond the current study's dichotomous SLN stratification of ‘positive’ or ‘negative’.8Gershenwald J.E. Scolyer R.A. Hess K.R. et al.Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 472-492Crossref PubMed Scopus (940) Google Scholar,15Egger M.E. Bower M.R. Czyszczon I.A. et al.Comparison of sentinel lymph node micrometastatic tumor burden measurements in melanoma.J Am Coll Surg. 2014; 218: 519-528Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar,16Dewar D.J. Newell B. Green M.A. et al.The microanatomic location of metastatic melanoma in sentinel lymph nodes predicts nonsentinel lymph node involvement.J Clin Oncol. 2004; 22: 3345-3349Crossref PubMed Scopus (219) Google Scholar While this binary approach may ease modeling efforts, and the authors note that clinicopathological variables available from standard pathology reports were included in the analysis, it does not capture the dynamic range and overall richness that the SLN biopsy information can provide. The current analysis may therefore underestimate the importance that detailed knowledge of SLN pathological status for patients with melanoma may provide. This comprehensive information can be used to refine risk combined with other clinicopathological factors: lower risk in the setting of limited microscopic tumor burden and higher risk with more extensive burden of disease. This approach has been used as an eligibility criterion for some recent adjuvant clinical trials13Eggermont A.M.M. Blank C.U. Mandala M. et al.Adjuvant pembrolizumab versus placebo in resected stage III melanoma.N Engl J Med. 2018; 378: 1789-1801Crossref PubMed Scopus (838) Google Scholar,17Dummer R. Hauschild A. Santinami M. et al.Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma.N Engl J Med. 2020; 383: 1139-1148Crossref PubMed Scopus (75) Google Scholar [e.g. American Joint Committee on Cancer (AJCC) 7th edition stage IIIA melanoma18Balch C.M. Gershenwald J.E. Soong S.J. et al.Final version of 2009 AJCC Melanoma Staging and Classification.J Clin Oncol. 2009; 27: 6199-6206Crossref PubMed Scopus (3512) Google Scholar had SLN tumor deposit with maximum tumor diameter >1 mm], as well as for ongoing trials exploring the potential clinical benefit of adjuvant therapy in patients with negative SLNs who have high-risk primary melanoma (e.g. AJCC 8th edition stages IIB or IIC).8Gershenwald J.E. Scolyer R.A. Hess K.R. et al.Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 472-492Crossref PubMed Scopus (940) Google Scholar As such, SLN status is critically important to optimally inform clinical decision making for patients considering the option of adjuvant systemic therapy and clinical trial eligibility, stratification, and analysis of ongoing and future trials in high-risk, SLN-negative melanoma. More work in optimizing prognostication is clearly warranted. El Sharouni et al. show that primary tumor characteristics remain vital to accurate prognostic evaluation, even with the knowledge of SLN status. This principle is reflected in the AJCC 8th edition melanoma staging system, in which stage III groups are in part defined by primary tumor thickness and ulceration status. Gene expression profiling has also been investigated and holds promise; additional studies are warranted to determine its contribution relative to the ever-improving models based on standard clinicopathological variables.19Grossman D. Okwundu N. Bartlett E.K. et al.Prognostic gene expression profiling in cutaneous melanoma: identifying the knowledge gaps and assessing the clinical benefit.JAMA Dermatol. 2020; 156: 1004-1011Crossref PubMed Scopus (22) Google Scholar Indeed, the development of individualized, integrated risk models that incorporate multiple clinicopathological factors, including SLN tumor burden and mitotic rate, to ultimately be considered with molecular and immune-related factors, are under active exploration.20Keung E.Z. Gershenwald J.E. Clinicopathological features, staging, and current approaches to treatment in high-risk resectable melanoma.J Natl Cancer Inst. 2020; 112: 875-885Crossref PubMed Scopus (8) Google Scholar Prognostic assessment is not the only rationale for performing SLN biopsy. For those patients who harbor SLN metastases, most can achieve long-term regional disease control by SLN biopsy alone. In the second Multicenter Selective Lymphadenectomy Trial (MSLT-II), approximately 75% of patients with primary cutaneous melanoma and a positive SLN who were randomized to nodal observation (versus completion lymph node dissection) never had a nodal recurrence in the basin that contained the SLN metastasis and therefore never required delayed lymph node dissection.21Faries M.B. Thompson J.F. Cochran A.J. et al.Completion dissection or observation for sentinel-node metastasis in melanoma.N Engl J Med. 2017; 376: 2211-2222Crossref PubMed Scopus (663) Google Scholar Had they not undergone SLN biopsy, data from the first MSLT trial support that such patients (i.e. those with a positive SLN) would have subsequently presented with clinically detectable disease following wide excision alone, required a complete lymph node dissection, and had a higher risk for dying of melanoma.7Morton D.L. Thompson J.F. Cochran A.J. et al.Final trial report of sentinel-node biopsy versus nodal observation in melanoma.N Engl J Med. 2014; 370: 599-609Crossref PubMed Scopus (875) Google Scholar Despite these and numerous other advances, unanswered questions remain with regard to the use of SLN biopsy for patients with melanoma. What is the minimal risk threshold that justifies performing the procedure for a given patient? What factor or set of factors is optimal for estimating that risk? Based on estimates of risk and benefit for a given adjuvant systemic therapy, what risk of subsequent recurrence or melanoma-related death is sufficient to justify such an approach? These important clinical questions are currently under consideration by the global melanoma community and we look forward to answers to these and other questions in the coming months and years. The analysis by El Sharouni and colleagues further builds on an expansive evidence base that strongly supports the demonstrated clinical utility and relevance of SLN biopsy, from both a staging and potential therapeutic perspective, in melanoma patients at sufficient risk for regional metastasis. Unless and until other strategies can be developed and deployed to replace the clinical utility of SLN biopsy, studies such as that of El Sharouni and colleagues will hopefully help put to rest the question of whether there is staging value in SLN biopsy compared with clinical and primary tumor features alone. JEG—outside current work—consultant and/or advisory boards: Merck, Novartis, Bristol-Myers Squibb, Regeneron, Syndax; MBF—outside current work—advisory boards: Novartis, Merck, Bristol-Myers Squibb, Pulse Biosciences, Sanofi, Nektar; AT has declared no conflicts of interest. Sentinel node biopsy in patients with melanoma improves the accuracy of staging when added to clinicopathological features of the primary tumorAnnals of OncologyVol. 32Issue 3PreviewIt has been claimed, without supporting evidence, that knowledge of sentinel node (SN) status does not provide more accurate prognostic information than basic clinicopathological features of a primary cutaneous melanoma. We sought to investigate this claim and to quantify any additional value of SN status in predicting survival outcome. Full-Text PDF