Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Abstract

Key MessageThis ESMO Clinical Practice Guidelines provide updated recommendations on management of cutaneous melanoma (diagnosis, treatment and follow-up), compiled by a multidisciplinary author panel and accompanied by level of evidence and grade of recommendation, depending on the strength of supporting data and magnitude of benefit from particular interventions. This ESMO Clinical Practice Guidelines provide updated recommendations on management of cutaneous melanoma (diagnosis, treatment and follow-up), compiled by a multidisciplinary author panel and accompanied by level of evidence and grade of recommendation, depending on the strength of supporting data and magnitude of benefit from particular interventions. The European annual incidence of malignant melanoma varies from 3–5/100 000 in Mediterranean countries to 12–35/100 000 in Nordic countries, whereas it can reach over 50/100 000 in Australia or New Zealand. The incidence of melanoma has been rising steadily over the last 40 years, with a trend towards stabilisation of mortality, except in elderly males [1.Hollestein L.M. van den Akker S.A.W. Nijsten T. et al.Trends of cutaneous melanoma in The Netherlands: increasing incidence rates among all Breslow thickness categories and rising mortality rates since 1989.Ann Oncol. 2012; 23: 524-530Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. Melanoma incidence peaks at 65 years, though any age can be affected [2.National Cancer Registration and Analysis Service, Public Health England, https://www.cancerresearchuk.org (15 October 2019, date last accessed).Google Scholar]. There is an increase in the mortality-to-incidence ratios in Eastern compared with Western European countries, suggesting a need to improve prevention and early detection in Eastern Europe [3.Forsea A.M. Del Marmol V. Stratigos A. Geller A.C. Melanoma prognosis in Europe: far from equal.Br J Dermatol. 2014; 171: 179-182Crossref PubMed Scopus (37) Google Scholar]. Ultraviolet (UV) irradiation was identified as a major carcinogen involved in melanoma genesis. UV irradiation is associated with a distinct DNA damage signature and a high rate of mutations per megabase (Mb) [4.Alexandrov L.B. Nik-Zainal S. Wedge D.C. et al.Signatures of mutational processes in human cancer.Nature. 2013; 500: 415Crossref PubMed Scopus (6221) Google Scholar]. The best prevention is physical protection with adapted garments. In a randomised trial, prevention of UV exposure including the regular use of sunscreen has been shown to diminish the incidence of primary cutaneous melanomas in an Australian population [5.Green A.C. Williams G.M. Logan V. Strutton G.M. Reduced melanoma after regular sunscreen use: randomized trial follow-up.J Clin Oncol. 2011; 29: 257-263Crossref PubMed Scopus (542) Google Scholar]. Suspicious pigmented lesions are usually clinically analysed with the ‘ugly duckling’ concept and the ‘ABCD’ rule [6.Dummer R. Guggenheim M. Arnold A.W. et al.Updated Swiss guidelines for the treatment and follow-up of cutaneous melanoma.Swiss Med Wkly. 2011; 141: w13320PubMed Google Scholar]: Asymmetry, Border irregularities, Colour heterogeneity, Dynamics, (Dynamics or evolution in colours, elevation or size). Today, many primary melanomas have a diameter of <5 mm [7.Bono A. Tolomio E. Trincone S. et al.Micro-melanoma detection: a clinical study on 206 consecutive cases of pigmented skin lesions with a diameter < or = 3 mm.Br J Dermatol. 2006; 155: 570-573Crossref PubMed Scopus (64) Google Scholar]. Dynamics (or evolution) is a very important criterion because it can also help to identify rapidly growing amelanotic melanomas in educated patients. The ‘ugly duckling’ concept helps to identify melanomas, because naevi in the same individual tend to resemble one another and melanomas often do not fit the individuals naevus pattern [8.Grob J.J. Bonerandi J.J. The ‘ugly duckling’ sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening.Arch Dermatol. 1998; 134: 103-104Crossref PubMed Google Scholar]. Dermoscopy by an experienced physician enhances the diagnostic accuracy [II, B] [9.Kittler H. Pehamberger H. Wolff K. Binder M. Diagnostic accuracy of dermoscopy.Lancet Oncol. 2002; 3: 159-165Abstract Full Text Full Text PDF PubMed Scopus (930) Google Scholar]. An automated videodermoscopy system can provide improved diagnostic accuracy for patients with multiple atypical naevi in the follow-up. Full body imaging with high-resolution pictures has also shown to improve early detection [10.Salerni G. Carrera C. Lovatto L. et al.Benefits of total body photography and digital dermatoscopy (“two-step method of digital follow”) in the early diagnosis of melanoma in patients at high risk for melanoma.J Am Acad Dermatol. 2012; 67: e17-e27Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar]. Machine-learning algorithms trained on either standard or dermatoscopic images have been shown to correctly diagnose pigmented skin lesions, with a success rate comparable to that of a panel of 21 board-certified dermatologists; though early results are very promising, their use in clinical practice remains to be evaluated [11.Esteva A. Kuprel B. Novoa R.A. et al.Dermatologist-level classification of skin cancer with deep neural networks.Nature. 2017; 542: 115-118Crossref PubMed Scopus (54) Google Scholar]. The use of patient-operated diagnostic devices without medical supervision is presently not recommended. Diagnosis should be based on a full thickness excisional biopsy with a minimal side margin [V, A]. Processing of the primary tumour according to international guidelines and by an experienced pathology institute is mandatory. The histology report should follow the eighth edition of the American Joint Committee on Cancer (AJCC) tumour, node, metastasis (TNM) classification and include: the maximum thickness in millimetres (Breslow) reported to the nearest 0.1 mm (rounding up starting at 0.05), presence of ulceration and clearance of the surgical margins [II, A] [12.Gershenwald 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 (1206) Google Scholar]. Although no longer included in the eighth edition of the AJCC classification, mitotic rate and regression assessment and recording is recommended for all tumour thickness categories due to its important prognostic determinant when evaluated using its dynamic range across all melanomas [12.Gershenwald 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 (1206) Google Scholar]. Information on anatomical site (including extra-cutaneous sites, such as mucosa, conjunctiva) and degree of sun damage of the surrounding skin is necessary. It should also include the melanoma type [superficial spreading melanoma, lentigo maligna melanoma (LMM), acral lentiginous melanoma, nodular melanoma, and others]. In rare situations, melanomas may derive from dermal melanocytes (melanoma arising from giant congenital naevus, malignant blue naevus and spitzoid lesions), which should be reported as well [13.Whiteman D.C. Pavan W.J. Bastian B.C. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin.Pigment Cell Melanoma Res. 2011; 24: 879-897Crossref PubMed Scopus (201) Google Scholar]. Atypical spitzoid tumours should be distinguished from spitzoid melanoma as they do not have a metastatic potential. In these melanomas, the prognostic relevance of tumour thickness and sentinel lymph node (SN) involvement is questionable. Mutation testing for actionable mutations is mandatory in patients with resectable or unresectable stage III or stage IV [I, A], and is highly recommended in high-risk resected disease stage IIC but not for stage I or stage IIA–IIB. BRAF testing is mandatory [I, A]. If the tumour is BRAF wild-type (WT) at the V600 locus (class I BRAF mutant) sequencing the loci of the other known minor BRAF mutations (class II and class III BRAF mutant) to confirm WT status and testing for NRAS and c-kit mutations are recommended [II, C] [14.Yao Z. Yaeger R. Rodrik-Outmezguine V.S. et al.Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.Nature. 2017; 548: 234-238Crossref PubMed Scopus (294) Google Scholar]. Although no good targeted therapies options exist for these drivers at the moment, they are important to identify for future opportunities and to select patients for clinical trials. Alternatively, a clinically validated next-generation sequencing panel covering all key oncogenic drivers is increasingly being carried out. As drivers are actionable and can impact clinical decision, mutation analysis must be carried out in accredited (certified) institutes that have careful quality controls. The main melanoma subtypes are associated with different mutational landscapes: frequently mutated genes include [15.Hayward N.K. Wilmott J.S. Waddell N. et al.Whole-genome landscapes of major melanoma subtypes.Nature. 2017; 545: 175-180Crossref PubMed Scopus (729) Google Scholar]:•BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma,•BRAF, NRAS, NF1 and KIT in acral melanoma (though with lower frequencies than in cutaneous melanoma),•SF3B1 in mucosal melanoma. In addition to the mutational status, programmed death-ligand 1 (PD-L1) expression, reported as the percentage of positive tumour cells, can be useful to assess and record for all resectable or unresectable stage III and IV [I, B], though its clinical use is very limited at this time (see below). Tumour mutational burden (TMB) computed on full exome sequencing or on a large full length panel and expressed as the number of mutations per Mb can be assessed and recorded [IV, C], though its clinical use is not warranted at this time [16.Snyder A. Makarov V. Merghoub T. et al.Genetic basis for clinical response to CTLA-4 blockade in melanoma.N Engl J Med. 2014; 371: 2189-2199Crossref PubMed Scopus (3028) Google Scholar]. Staging and risk assessment procedures are determined by disease presentation at diagnosis. Physical examination with special attention to any suspicious pigmented lesions, tumour satellites, in-transit metastases (ITM), regional lymph node (LN) and systemic metastases is mandatory. In low-risk melanomas (pT1a), no additional investigations are necessary. In the other T stages, pT1b-pT4b, ultrasound (US) for locoregional LN metastasis, and/or computed tomography (CT) or positron emission tomography (PET) scans as well as brain magnetic resonance imaging (MRI), represent options for tumour extension assessment before surgical treatment and SN biopsy (SNB). Brain MRI and PET-CT/CT scan should be applied only for very high-risk patients (pT3b and higher [III, C]). The eighth version of the AJCC staging and classification system, which includes SN staging, is the preferred classification system (Table 1) [12.Gershenwald 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 (1206) Google Scholar].Table 1AJCC TNM eighth edition staging system of melanoma [12.Gershenwald 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 (1206) Google Scholar]T—primary tumourT categoryThicknessUlceration statusTXPrimary tumour thickness cannot be assessed (e.g. diagnosis by curettage)Not applicableNot applicableT0No evidence of primary tumour (e.g. unknown primary or completely regressed melanoma)Not applicableNot applicableTis (melanoma in situ)Not applicableNot applicableT1≤1.0 mmUnknown or unspecified T1a<0.8 mmWithout ulceration T1b<0.8 mmWith ulceration0.8–1.0 mmWith or without ulcerationT2>1.0–2.0 mmUnknown or unspecified T2a>1.0–2.0 mmWithout ulceration T2b>1.0–2.0 mmWith ulcerationT3>2.0–4.0 mmUnknown or unspecified T3a>2.0–4.0 mmWithout ulceration T3b>2.0–4.0 mmWith ulcerationT4>4.0 mmUnknown or unspecified T4a>4.0 mmWithout ulceration T4b>4.0 mmWith ulcerationM—metastasisM categoryaSuffixes for M category: (0) LDH not elevated, (1) LDH elevated. No suffix is used if LDH is not recorded or is unspecified.Anatomic siteLDH levelM0No evidence of distant metastasisNot applicableM1Evidence of distant metastasisSee below M1aDistant metastasis to skin, soft tissue including muscle and/or nonregional lymph nodeNot recorded or unspecified M1a(0)Not elevated M1a(1)Elevated M1bDistant metastasis to lung with or without M1a sites of diseaseNot recorded or unspecified M1b(0)Not elevated M1b(1)Elevated M1cDistant metastasis to non‐CNS visceral sites with or without M1a or M1b sites of diseaseNot recorded or unspecified M1c(0)Not elevated M1c(1)Elevated M1dDistant metastasis to CNS with or without M1a, M1b or M1c sites of diseaseNot recorded or unspecified M1d(0)Not elevated M1d(1)ElevatedTNMPathological stage groupTisN0bPathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to complete pathological staging; use clinical N information to assign their pathological stage.M00T1aN0M0IAT1bN0M0IAT2aN0M0IBT2bN0M0IIAT3aN0M0IIAT3bN0M0IIBT4aN0M0IIBT4bN0M0IICT0N1b, N1cM0IIIBT0N2b, N2c, N3b or N3cM0IIICT1a/b–T2aN1a or N2aM0IIIAT1a/b–T2aN1b/c or N2bM0IIIBT2b/T3aN1a–N2bM0IIIBT1a–T3aN2c or N3a/b/cM0IIICT3b/T4aAny N ≥N1M0IIICT4bN1a–N2cM0IIICT4bN3a/b/cM0IIIDAny T, TisAny NM1IVAJCC, American Joint Committee on Cancer; CNS, central nervous system; LDH, lactate dehydrogenase; TNM, tumour, node, metastasis.Reprinted from [12.Gershenwald 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 (1206) Google Scholar] with permission.a Suffixes for M category: (0) LDH not elevated, (1) LDH elevated. No suffix is used if LDH is not recorded or is unspecified.b Pathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to complete pathological staging; use clinical N information to assign their pathological stage. Open table in a new tab AJCC, American Joint Committee on Cancer; CNS, central nervous system; LDH, lactate dehydrogenase; TNM, tumour, node, metastasis. Reprinted from [12.Gershenwald 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 (1206) Google Scholar] with permission. Wide local excision (WLE) of primary tumours with safety margins of 0.5 cm for in situ melanomas, 1 cm for tumours with a thickness of up to 2 mm and 2 cm for thicker tumours, is recommended [II, B] (Table 2) [17.Thompson J.F. Scolyer R.A. Kefford R.F. Cutaneous melanoma.Lancet. 2005; 365: 687-701Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar]. Modifications, with reduced safety margins, are acceptable for preservation of function in acral and facial melanomas and can be carried out with Slow Mohs technique, although prospective randomised trials are missing [18.Tzellos T. Kyrgidis A. Mocellin S. et al.Interventions for melanoma in situ, including lentigo maligna.Cochrane Database Syst Rev. 2014; Crossref PubMed Scopus (30) Google Scholar, 19.Clark G.S. Pappas-Politis E.C. Cherpelis B.S. et al.Surgical management of melanoma in situ on chronically sun-damaged skin.Cancer Control. 2008; 15: 216-224Crossref PubMed Scopus (48) Google Scholar].Table 2Local excision margins [17.Thompson J.F. Scolyer R.A. Kefford R.F. Cutaneous melanoma.Lancet. 2005; 365: 687-701Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar]Wide local excision margins according to Breslow (pT1a-pT4b Nx M0)Tumour thickness (Breslow) in mmExcision margin (cm)Melanoma in situ (pTis N0 M0)0.5≤2 mm (pT1a-pT2 N0 M0)1>2 mm (pT3a-pT4b N0 M0)2Reprinted from [17.Thompson J.F. Scolyer R.A. Kefford R.F. Cutaneous melanoma.Lancet. 2005; 365: 687-701Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar] with permission from Elsevier Ltd. Open table in a new tab Reprinted from [17.Thompson J.F. Scolyer R.A. Kefford R.F. Cutaneous melanoma.Lancet. 2005; 365: 687-701Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar] with permission from Elsevier Ltd. For lentigo maligna, radiotherapy (RT) can be curative and represents an option to avoid unacceptable surgery [20.Fogarty G.B. Hong A. Scolyer R.A. et al.Radiotherapy for lentigo maligna: a literature review and recommendations for treatment.Br J Dermatol. 2014; 170: 52-58Crossref PubMed Scopus (58) Google Scholar]. Definitive RT to the primary tumour is only considered in (rare) palliative cases, when excision is not possible either due to severe comorbidities of the patient (i.e. very old age, end-stage cardiovascular disease etc.) or when the morbidity of the excision is considered too great (i.e. extreme patient delay with a huge non-resectable local disease). RT is not curative in these settings. A locoregional disease treatment algorithm is provided in Figure 1. Elective lymph node dissection or primary elective irradiation to the regional LNs should not be carried out [II, B] [21.Veronesi U. Adamus J. Bandiera D.C. et al.Inefficacy of immediate node dissection in stage 1 melanoma of the limbs.N Engl J Med. 1977; 297: 627-630Crossref PubMed Scopus (556) Google Scholar, 22.Sim F.H. Taylor W.F. Ivins J.C. et al.A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results.Cancer. 1978; 41: 948-956Crossref PubMed Scopus (327) Google Scholar, 23.Balch C.M. Soong S.J. Bartolucci A.A. 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 (discussion 263-256): 255-263Crossref PubMed Scopus (583) Google Scholar, 24.Cascinelli N. Morabito A. Santinami M. et al.Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme.Lancet. 1998; 351: 793-796Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar]. Again, definitive irradiation can be considered in (rare) palliative cases. SNB is recommended for precise staging in melanoma of AJCC eighth edition stage pT1b or higher, i.e. with a tumour thickness >0.8 mm or with a tumour thickness of <0.8 mm with ulceration [II, B] [25.Han D. Zager J.S. Shyr Y. et al.Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma.J Clin Oncol. 2013; 31: 4387-4393Crossref PubMed Scopus (178) Google Scholar]. SNB is not recommended for pT1a melanomas [26.Sondak V.K. Clinical problems in the immunotherapy surgery and radiation therapy of melanoma.American Society of Clinical Oncology 2017 Educational Book. American Society of Clinical Oncology (ASCO), 2017Google Scholar]. In the Multicentre Selective Lympadenectomy Trial I (MSLT-I), there was no significant treatment-related difference between WLE/SN versus WLE/nodal observation in the 10-year follow-up melanoma-specific survival rate in patients with intermediate-thickness melanomas and thick primary melanomas [27.Morton 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 (977) Google Scholar]. A criticised subgroup analysis seemed to show a significant benefit for the node-positive patients in the SN arm compared with the node-positive patients in the observation arm. However, any false-positive negative patients or false-positive SN results were not taken into account. Another statistical method was developed on the interim data but was not externally validated [28.Thomas J.M. Prognostic false-positivity of the sentinel node in melanoma.Nat Clin Pract Oncol. 2008; 5: 18-23Crossref PubMed Scopus (114) Google Scholar, 29.van Akkooi A. Sentinel node followed by completion lymph node dissection versus nodal observation: staging or therapeutic? Controversy continues despite final results of MSLT-1.Melanoma Res. 2014; 24: 291-294Crossref PubMed Scopus (18) Google Scholar]. In summary, the MSLT-I validated the staging potential of SNB but did not show any unequivocal survival benefit for this procedure. SNB should therefore not be considered as a therapeutic procedure. SNB should be carried out only in experienced centres [30.Nieweg O.E. False-negative sentinel node biopsy.Ann Surg Oncol. 2009; 16: 2089-2091Crossref PubMed Scopus (36) Google Scholar]. Quality criteria for centres performing SNB include the following [31.Dummer R. Ramelyte E. Levesque M. et al.Critical aspects to achieve a high-quality melanoma clinic.Curr Opin Oncol. 2017; 29: 145-150Crossref PubMed Scopus (2) Google Scholar]:•Review and comparison of primary histology with SNB is recommended in difficult cases.•Histology evaluation of the SNB according to cell morphology and immune profile of the primary.•SNB procedure carried out simultaneously with the safety margins re-excision of the primary to avoid lymph drainage modifications.•SNB and re-excision carried out by an experienced surgical team.•Marking of the scar during the consultation, preferably with photo documentation.•Single-photon emission CT (SPECT) imaging in cases of unclear sentinel LN localisation. SN tumour burden has been assessed in different ways, and all different measures conclude that it adds to the accuracy of the prognosis [32.van Akkooi A.C.J. de Wilt J.H.W. Verhoef C. et al.Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative?.Ann Oncol. 2006; 17: 1578-1585Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 33.van Akkooi A.C.J. de Wilt J.H.W. Voit C. et al.Sentinel lymph-node false positivity in melanoma.Nat Clin Pract Oncol. 2008; 5: E2Crossref PubMed Scopus (6) Google Scholar]. The most used and best reproducible method between pathologists has been the maximum diameter of the largest lesion (MDLL) according to the Rotterdam Criteria, which the European Organisation for Research and Treatment of Cancer (EORTC) has validated and adopted [34.Murali R. Desilva C. Thompson J.F. Scolyer R.A. Factors predicting recurrence and survival in sentinel lymph node-positive melanoma patients.Ann Surg. 2011; 253: 1155-1164Crossref PubMed Scopus (36) Google Scholar, 35.van der Ploeg A.P.T. van Akkooi A.C.J. Rutkowski P. et al.Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria.J Clin Oncol. 2011; 29: 2206-2214Crossref PubMed Scopus (164) Google Scholar, 36.van der Ploeg A.P.T. van Akkooi A.C.J. Haydu L.E. et al.The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients.Eur J Cancer. 2014; 50: 111-120Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. An MDLL cut-off of 1 mm has been used for adjuvant therapy trials. Therefore, though not formally part of the AJCC eighth edition evaluation, it is recommended to record the EORTC/Rotterdam criteria in the reporting of SN tumour burden. Complete lymph node dissection (CLND) for SN-positive patients was the standard of care until very recently. Following the MSLT-I trial, both the MSLT-II and the German Dermatologic Cooperative Oncology Group-selective lymphadenectomy (DeCOG-SLT) trials analysed the benefit of performing routine CLND for SN-positive disease. Both studies reported no impact on survival for early CLND compared with nodal observation with periodic US of the SN-positive basin [37.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: 757-767Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 38.Faries 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 (787) Google Scholar]. CLND provides additional staging information, as ∼15%–20% of SN-positive patients have additional non-SN involvement. However, upstaging occurs even less frequently at ∼6% of cases. Therefore, considering the morbidity of routine CLND, this practice can no longer be recommended [I, E] [39.Madu M.F. Franke V. Bruin M.M. et al.Immediate completion lymph node dissection in stage IIIA melanoma does not provide significant additional staging information beyond EORTC SN tumour burden criteria.Eur J Cancer (Oxford, England 1990). 2017; 87: 212-215Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 40.Verver D. van Klaveren D. van Akkooi A.C.J. et al.Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations.Eur J Cancer. 2018; 96: 25-33Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 41.Coit D. The enigma of regional lymph nodes in melanoma.N Engl J Med. 2017; 376: 2280-2281Crossref PubMed Scopus (30) Google Scholar]. In the case of isolated locoregional clinically detectable (macroscopic, non-SN) LN metastases, therapeutic lymph node dissection is indicated [III, C]; removal of the tumour-bearing LN alone is insufficient [42.Morton D.L. Wanek L. Nizze J.A. et al.Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Analysis of prognostic factors in 1134 patients from the John Wayne Cancer Clinic.Ann Surg. 1991; 214: 491-501Crossref PubMed Scopus (301) Google Scholar]. However, before undertaking additional aggressive local surgical treatments, a detailed staging investigation that includes high-resolution imaging techniques such as PET, CT or MRI is necessary to exclude distant metastases [III, B] [6.Dummer R. Guggenheim M. Arnold A.W. et al.Updated Swiss guidelines for the treatment and follow-up of cutaneous melanoma.Swiss Med Wkly. 2011; 141: w13320PubMed Google Scholar]. Evidence of distant metastatic spread will preclude surgery and qualify the patient for systemic therapy (see below). Resectable satellite or ITM patients can be candidates for surgery, though the advent of highly effective systemic therapies is now challenging such an approach as it is associated with the risk of rapid progression, jeopardising the chances of long-term benefit from systemic therapies. Non-resectable satellite, ITM or inoperable primary tumours of the limbs, without additional metastases, may be treated with isolated limb perfusion using melphalan and/or tumour necrosis factor alpha [III, C]. Alternatively, talimogene laherparepvec (T-VEC) has shown an improved durable response rate compared with subcutaneous granulocyte-macrophage colony-stimulating factor, especially in stage IIIB/C, IVM1a (AJCC seventh edition [43.Balch C. Buzaid A. Soong S. et al.Final Version of the American Joint Committee on cancer staging system for cutaneous melanoma.J Clin Oncol. 2001; 19: 3635-3648Crossref PubMed Scopus (2274) Google Scholar]) melanoma patients [44.Andtbacka R.H.I. Kaufman H.L. Collichio F. et al.Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma.J Clin Oncol. 2015; 33: 2780-2788Crossref PubMed Scopus (1585) Google Scholar] [I, B]. These local procedures should be carefully weighed against systemic treatment, in order not to lower their chances in providing long-term benefit. Such local treatments either require major surgery or experience using oncolytic viruses and should therefore be restricted to experienced centres. Since their efficacy data are less established, RT, electrochemotherapy, carbon dioxide (CO2) laser or other intralesional therapy may also be proposed within clinical trials [V, D] [16.Snyder A. Makarov V. Merghoub T. et al.Genetic basis for clinical response to CTLA-4 blockade in melanoma.N Engl J Med. 2014; 371: 2189-2199Crossref PubMed Scopus (3028) Google Scholar, 45.Hong A. Fogarty G. Role of radiation therapy in cutaneous melanoma.Cancer J (Sudbury, Mass.). 2012; 18: 203-207Crossref PubMed Scopus (21) Google Scholar, 46.Henderson M.A. Burmeister B.H. Ainslie J. et al.Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial.Lancet Oncol. 2015; 16: 1049-1060Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 47.Miura J.T. Kroon H.M. Beasley G.M. et al.Long-term oncologic outcomes after isolated limb infusion for locoregionally metastatic melanoma: an international multicenter analysis.Ann Surg Oncol. 2019; 26: 2486-2494Crossref PubMed Scopus (28) Google Scholar]. Adjuvant RT for local tumour control can be considered in cases of inadequate resection margins of LMM, in R1 resections (microscopic tumour at the margin) of melanoma metastases (only when second surgery is not adequate) or after resection of bulky disease [III, B] [48.Farsha