Leila J. Mady, MD PhD MPH and Jason G. Newman, MD
The Great Debate
The word lymph derives from the Latin lympha, which means pure water; a stream.1 The term has a pseudo-etymological association with the Greek word νύμϕη (nymph).2 In classical mythology, a nymph represents a semi-divine spirit, taking the form of a maiden inhabiting the seas, rivers, mountains, woods, and trees.1,2 Surgical oncology visionary, Dr. Donald L. Morton, the son of an Appalachian coal miner and one of the last physicians to treat John Wayne for stomach cancer, was a pioneer in mapping these “water” drainage patterns. Together with dermatopathologist Dr. Alistair J. Cochran, Morton developed the sentinel lymph node biopsy (SLNB) technique, now regarded as one of the most influential innovations in surgical oncology. The procedure was first described at the Society of Surgical Oncology in 1990 and discussed in the seminal report, “Technical details of intraoperative lymphatic mapping for early stage melanoma” published in the Archives of Surgery in 1992.
Since then, three landmark, randomized controlled trials evaluating the role of SLNB have framed the debate regarding the value of nodal intervention: the Multicenter Selective Lymphadenectomy Trial I (MSLT-I)3–5, the German Dermatologic Cooperative Oncology Group-Selective Lymphadenectomy Trial (DeCOG-SLT)6, and the Multicenter Selective Lymphadenectomy Trial II (MSLT-II)7. Yes, we recognize this is a blog for the American Head and Neck Society. But reader beware: primary cutaneous melanoma of the head and neck (excluding ear) represented only 17% of the MSLT-I 5, 0% of the DeCOG-SLT6, 14% of the MSLT-II7 patient populations. How we manage regional lymph nodes in patients with melanoma remains a tug-of-war between therapeutic intent and prognostic decision making.
To address the metastatic potential of melanoma to spread to regional lymph nodes, elective complete regional lymphadenectomy was considered the standard of care in the century before SLNB.8 Significant short-term complications (hematoma, seroma, wound break-down, wound infection) and long-term sequelae (nerve dysfunction/pain, functional deficit, edema) are often cited morbidities of regional lymphadenectomy that give clinical equipoise to complete lymph node dissection (CLND).9,10 These morbidities, however, are mostly in the context of axillary or inguinal lymph node dissection. Since the days of Crile and Martin11,12, the selective neck dissection has evolved dramatically from the routine and radical sacrifice of the sternocleidomastoid, spinal accessory nerve, and internal jugular vein. It is no surprise that with this evolution we have seen dramatic improvements in the historical morbidities associated with neck dissection.13,14
Several randomized clinical trials have been conducted to determine if the benefits of CLND outweighed the risks.15–18 The Melanoma Intergroup Committee trial15,19 compared elective lymph node dissection with clinical observation in patients with stage I and II melanoma of intermediate thickness (1.0 to 4.0 mm). Among patients with trunk (39%), arm (24%), leg (28%) and head and neck (9%) melanomas, there was no difference in overall 10-year survival for those who received elective node dissection or nodal observation.15 However, among stratified subgroups including patients with nonulcerated melanomas, those with tumor thickness of 1.0 to 2.0 mm, and those with limb tumors, there was a significant reduction in the mortality rate for patients who underwent elective lymphadenectomy. In a trial performed by the WHO Melanoma Programme16, patients with a localized trunk melanoma of 1.5 mm or more in thickness without evidence of regional or distant metastases underwent wide excision and were randomized to either immediate node dissection or node dissection delayed until clinical diagnosis of regional node metastases. Among patients who had immediate node dissection, 22% had occult node metastases; for those who received wide excision only, 31% developed regional node metastases during follow-up, among which 7% had synchronous distant metastases. In survival analysis, there was no difference in patients who never developed node metastases and patients who had no disease detected during elective lymphadenectomy. But there was a survival advantage for patients who were found to have occult disease during elective node dissection compared to patients who developed regional disease and underwent delayed dissection during follow-up.
The results of the Melanoma Intergroup Committee and the WHO Melanoma Programme trials provided support for procedures aimed at early detection and removal of regional micrometastases. The MSLT-I trial leveraged the advantages of SLNB and compared patients who underwent wide excision and nodal observation with lymphadenectomy for nodal relapse, versus wide excision and SLNB with immediate lymphadenectomy for nodal metastases detected on biopsy.3–5 The results of MSLT-I confirmed that for patients with intermediate-thickness melanomas (1.2 to 3.5 mm) who have clinically occult nodal metastases, early intervention (SLNB with immediate lymphadenectomy) decreases the risk of nodal recurrence, distant metastases, and death from melanoma.3 What MSLT-I and preceding trials teach us is that essentially all nodal metastases detected by SLNB would have become clinically evident if not removed.
It is hard to pattern the majority of our practice from the minority of head and neck patients included in these trials. Head and neck mucosal melanoma is particularly aggressive, portends poorer prognosis compared to trunk and extremity counterparts, and is characterized by unpredictable recurrence patterns.20–22 Though we are far from Crile and Martin, the morbidities associated with locoregional recurrence in the head and neck are not trivial. Despite minimal lymphedema following CLND in the head and neck compared to other sites, there are real concerns over permanent cranial nerve and carotid injuries in the salvage setting.22 In a longitudinal review of 356 patients with head and neck melanoma who underwent SLNB directed management at the University of Michigan, 25% of patients (n=13/52) who developed locoregional macrometastases experienced permanent cranial neuropathies following salvage dissection (16 total nerve injuries: 10 facial, 5 spinal accessory, and 1 hypoglossal).21 This is in stark contrast to no cranial nerve deficits in patients who underwent SLNB and immediate CLND. In another recent investigation from the University of Michigan, although neuropathy and neck impairment were associated with CLND, these deficits did not have significant impacts on quality of life.20 Although regional recurrences and related cranial nerve injuries are overall rare, immediate CLND provides a safe and effective modality for regional disease control while providing pivotal histopathologic data to aid in therapeutic risk-stratification and decision making.
Or Not Complete
The DeCOG-SLT6 and MSLT-II7 trials were designed to answer the question, “Does completion lymph node dissection improves survival for patients with SLNB positive metastases?” In DeCOG-SLT, patients with cutaneous melanoma ≥ 1 mm in thickness of the torso, arms or legs (note the absence of head and neck patients) and positive SLNB were randomized to CLND versus nodal observation with ultrasound (every 3 months). The study was closed early due to difficulties in recruiting patients and a lower than expected distant-metastases-free survival event rate. Although the trial was underpowered, there were no differences in survival outcomes between the CLND and observation groups (including distant-metastases-free survival, recurrence-free survival, and overall survival). It is prudent to note that most trial patients (66%) had low nodal burden, with SLNB metastases of 1 mm or less. Nevertheless, DeCOG-SLT showed for the first time that survival outcomes were similar regardless of sentinel node tumor burden (≤1 mm versus >1 mm) or primary tumor characteristics. Perhaps more importantly, the DeCOG-SLT results highlighted that leaving residual nodal disease did not confer a higher risk of systemic disease based upon having a positive SLNB result.
In MSLT-II, patients with primary melanoma ≥ 1.2 mm in thickness or ulcerated melanoma (regardless of thickness) of the head, neck, scalp, trunk, arms or legs and positive SLNB were randomized to CLND versus nodal observation with ultrasound (every 4 months years 1 – 2, every 6 months years 3 – 5, and then annually). Similar to the observations of DeCOG-SLT (with the added advantage of being adequately powered) most patients had low-volume nodal disease and immediate CLND did not improve melanoma-specific survival. Though larger sentinel-node tumor burden was associated with non-sentinel node metastases, there was no survival benefit from CLND in subgroup analysis of patients with greater nodal disease. Since most patients have all nodal metastases cleared by the SLNB itself, the additional therapeutic value from CLND may be limited. Despite absence of a survival advantage, immediate CLND improved the rate of regional disease control (similar to the findings of MSLT-I) and provided staging and prognostic information (derived from the pathologic status of non-sentinel nodes).
It is impossible to discuss the role of surgery in cutaneous melanoma without talking about systemic treatments. In general, there are two main categories of FDA-approved systemic therapies: 1) immune checkpoint inhibitors [e.g., anti-programmed cell death protein 1 (anti PD-1), anti-cytotoxic T lymphocyte-associated antigen 4/anti (CTLA-4)] and 2) targeted molecular inhibitors [e.g., serine/threonine-protein kinase B-Raf (BRAF), mitogen-activated extracellular signal-regulated kinase (MEK)].23 Compared to the trials discussed previously, a key difference in trials that have evaluated patients undergoing immune checkpoint or targeted molecular inhibitors (EORTC 1807124, Checkmate 23825, EORTC 132526, and COMBI-AD27) is that most had resected stage III disease, all of which required complete nodal staging for inclusion. Stage III melanoma can encompass a range of nodal disease from the smallest deposit of microscopic disease in a sentinel lymph node; bulky, clinically evidence nodal disease; to in-transit metastases.28 In these trials focused on “high-risk” patients, a benefit in recurrence-free survival was shown in the setting of adjuvant systemic therapy. While current trials are underway to examine systemic therapy for stage II disease, the National Comprehensive Cancer Network supports the adjuvant use of these therapies following SLNB, irrespective of CLND. Though CLND results in upstaging of disease (19% in N-category; 5% in AJCC 8th edition stage), adequate risk stratification is possible based on ulceration and sentinel-node tumor burden from SLNB alone.29 Herein is one of the strongest reasons to move away from CLND. Under this paradigm, SLNB, adjuvant systemic therapy, and active surveillance may supersede CLND as the new standard of care.
The status of your lymph nodes matter. Limitations of previous trials reveal inherent flaws in how we can interpret their results and apply them to the head and neck population.
For the timing of lymph node intervention, what does “immediate” even mean? The WHO Melanoma Programme trial defined immediate CLND as within 6 weeks of primary excision (no SLNB performed prior to CLND; survival benefit in patients with occult disease detected during elective node dissection).16 Compare this to the DeCOG-SLT and MSLT-II trials, where immediate CLND was considered up to 17 – 20 weeks after biopsy (SLNB performed prior to CLND or nodal observation; no survival benefit).6,7 Are these differences in survival based on whether or not patients received a SLNB or because the therapeutic benefit of CLND is lost the further out you get from primary treatment?
What is indisputable is that malignant melanoma is a highly aggressive tumor with the tendency to metastasize early. Patients who harbor microscopic disease of non-sentinel nodes do worse and have poorer outcomes akin to those with clinically evident nodes.30,31 In the end, the treatment benefit of surgery in patients with regional metastasis doesn’t seem to matter so much in what you do or how much you do – SLNB or CLND – but when you do it. When it comes to addressing involved lymph nodes, there is a time-dependent disease-specific survival advantage that favors early intervention. We also need to be honest with ourselves. Does it take 10,000 hours of sentinel biopsy practice to achieve mastery of the technique, as Malcom Gladwell32 would suggest? Probably not. But long-term follow-up of patients in MSLT-I demonstrates that it takes 55 or more5 SLNB procedures to gain the experience necessary to reliably reduce nodal relapse.33,5,34
Ultimately the decision to complete or not complete is one that involves candid conversations with our patients about what we know and don’t know when it comes to treating malignant melanoma. Perhaps most importantly – but less frequently considered – the crux of the decision rests in what works best for our patients. The argument to pursue CLND is strengthened in the context of specific patient characteristics. Elderly patients (> 75 years), those with immunosuppression, and pregnant/lactating women were excluded from MSLT-II (and in general, most clinical trials). Without data, maybe these are the groups we should consider most for CLND. For patients to undergo observation of the regional nodal basin as described in DeCOG-SLT and MSLT-II, routine ultrasound and frequent follow-up visits are required. For patients who can’t make these follow-ups, in settings without the processes or personnel available for high-quality nodal ultrasounds, or in circumstances of limited access or eligibility to clinical trials, completion neck dissection remains a reasonable treatment option for nodal management in cutaneous melanoma of the head and neck.
- lymph, n. In: Oxford English Dictionary. Oxford University Press. https://www.oed.com/view/Entry/111599?redirectedFrom=Lymph&p=emailA8NRW5.cGQWUw&d=111599
- nymph, n.1. In: Oxford English Dictionary. Oxford University Press. https://www.oed.com/view/Entry/129400?
- Morton DL, Thompson JF, Cochran AJ, et al. Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma. N Engl J Med. 2014;370(7):599-609. doi:10.1056/NEJMoa1310460
- Morton DL, Elashoff R, Hoekstra HJ, Coventry BJ. Sentinel-Node Biopsy or Nodal Observation in Melanoma. N Engl J Med. Published online 2006:11.
- Morton DL, Cochran AJ, Thompson JF, et al. Sentinel Node Biopsy for Early-Stage Melanoma. Ann Surg. 2005;242(3):302-313. doi:10.1097/01.sla.0000181092.50141.fa
- Leiter U, Stadler R, Mauch C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17(6):757-767. doi:10.1016/S1470-2045(16)00141-8
- Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376(23):2211-2222. doi:10.1056/NEJMoa1613210
- Snow H. Melanotic cancerous disease. Lancet. 1982;140:869-922.
- for the MSLT Cooperative Group, Faries MB, Thompson JF, 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 (I). Ann Surg Oncol. 2010;17(12):3324-3329. doi:10.1245/s10434-010-1203-0
- Kretschmer L, Thoms K-M, Peeters S, Haenssle H, Bertsch H-P, Emmert S. Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection. Melanoma Res. 2008;18(1):16-21. doi:10.1097/CMR.0b013e3282f2017d
- Martin H, Del Valle B, Ehrlich H, Cahan WG. Neck dissection. Cancer. 1951;4(3):441-499. doi:10.1002/1097-0142(195105)4:3<441::aid-cncr2820040303>3.0.co;2-o
- Crile G. Excision of Cancer of the Head and Neck: With Special Reference to the Plan of Dissection Based on One Hundred and Thirty-two Operations. JAMA. 1987;258(22):3286. doi:10.1001/jama.1987.03400220086043
- Dunlap Q, Gardner JR, Ederle A, et al. Comparative Morbidity Profile of Elective vs Therapeutic Neck Dissection. Otolaryngol Neck Surg. Published online April 20, 2021:019459982110089. doi:10.1177/01945998211008915
- Kerawala CJ, Heliotos M. Prevention of complications in neck dissection. Head Neck Oncol. 2009;1(1):35. doi:10.1186/1758-3284-1-35
- 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). Ann Surg Oncol. 2000;7(2):87-97. doi:10.1007/s10434-000-0087-9
- Cascinelli N, Morabito A, Santinami M, MacKie R, Belli F. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. The Lancet. 1998;351(9105):793-796. doi:10.1016/S0140-6736(97)08260-3
- Sim FH, Taylor WF, Pritchard DJ, Soule EH. Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study. Mayo Clin Proc. 1986;61(9):697-705. doi:10.1016/s0025-6196(12)62768-2
- Veronesi U, Adamus J, Bandiera DC, et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer. 1982;49(11):2420-2430. doi:10.1002/1097-0142(19820601)49:11<2420::aid-cncr2820491133>3.0.co;2-2
- 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(3):255-266.
- Farlow JL, McLean SA, Peddireddy N, et al. Impact of Completion Lymphadenectomy on Quality of Life for Head and Neck Cutaneous Melanoma. Otolaryngol Neck Surg. Published online April 20, 2021:01945998211007442. doi:10.1177/01945998211007442
- Hanks JE, Yalamanchi P, Kovatch KJ, et al. Cranial nerve outcomes in regionally recurrent head & neck melanoma after sentinel lymph node biopsy. The Laryngoscope. 2020;130(7):1707-1714. doi:10.1002/lary.28243
- Schmalbach CE, Bradford CR. Completion lymphadenectomy for sentinel node positive cutaneous head & neck melanoma. Laryngoscope Investig Otolaryngol. 2018;3(1):43-48. doi:10.1002/lio2.136
- Goepfert RP, Myers JN, Gershenwald JE. Updates in the evidence‐based management of cutaneous melanoma. Head Neck. 2020;42(11):3396-3404. doi:10.1002/hed.26398
- Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522-530. doi:10.1016/S1470-2045(15)70122-1
- Weber 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(19):1824-1835. doi:10.1056/NEJMoa1709030
- Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378(19):1789-1801. doi:10.1056/NEJMoa1802357
- Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377(19):1813-1823. doi:10.1056/NEJMoa1708539
- McKean MA, Amaria RN. Multidisciplinary treatment strategies in high-risk resectable melanoma: Role of adjuvant and neoadjuvant therapy. Cancer Treat Rev. 2018;70:144-153. doi:10.1016/j.ctrv.2018.08.011
- Verver D, van Klaveren D, van Akkooi ACJ, et al. Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations. Eur J Cancer Oxf Engl 1990. 2018;96:25-33. doi:10.1016/j.ejca.2018.02.022
- Reintgen M, Murray L, Akman K, et al. Evidence for a Better Nodal Staging System for Melanoma: The Clinical Relevance of Metastatic Disease Confined to the Sentinel Lymph Nodes. Ann Surg Oncol. 2013;20(2):668-674. doi:10.1245/s10434-012-2652-4
- Leung AM, Morton DL, Ozao-Choy J, et al. Staging of Regional Lymph Nodes in Melanoma: A Case for Including Nonsentinel Lymph Node Positivity in the American Joint Committee on Cancer Staging System. JAMA Surg. 2013;148(9):879. doi:10.1001/jamasurg.2013.3044
- Gladwell M. Outliers: The Story of Success. 1st, Back Bay paperb. ed ed. Back Bay Books; 2011.
- 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. Ann Surg. 1999;230(4):453. doi:10.1097/00000658-199910000-00001
- Morton DL, Hoon DSB, Cochran AJ, et al. 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. Ann Surg. 2003;238(4):538-550. doi:10.1097/01.sla.0000086543.45557.cb