Cutaneous melanoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up⋆

ESMO · 2024 · Europe

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Authors: T. Amaral, M. Ottaviano, A. Arance et al.
Title: Cutaneous melanoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up⋆
Journal: Annals of oncology : official journal of the European Society for Medical Oncology, 2024
DOI: 10.1016/j.annonc.2024.11.006
Licence: CC BY 4.0
Changes: Verbatim excerpts; formatting adapted

Full text retrieved 2026-10-27 from Europe PMC · PMC7618628

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This page reproduces excerpts of the original publication; the original is authoritative. It has not been reviewed by a physician, does not state a recommendation of Medelix and does not replace medical advice. The guideline may have been updated since.

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Recommendations

Verbatim, with grade of recommendation or strength of consensus where given.

Recommendations

Dermoscopy by an experienced physician is recommended and increases the diagnostic accuracyII, A
Diagnosis should be based on a full thickness complete excision with a minimal margin of clinically uninvolved skin [II, A]. For larger lesions where complete excision is not possible without reconstructive surgery, a biopsy can be takenII, C
The histology report should include at least information on the type of melanoma, maximum vertical tumour thickness in millimetres (Breslow, measured to the nearest 0.1 mm), presence of ulceration, microsatellites, lymphovascular invasion, neurotropism/perineural invasion, tumour-infiltrating lymphocytes (TILs), presence of regression and presence or absence of tumour at the deep and peripheral edges of the biopsy [II, A]. Mitotic rate should also be reportedIII, B
A report on the wide excision should also be made available for complete pathological characterisationII, A
Testing for actionable mutations is recommended in patients with resectable or unresectable stage III or IV melanoma [I, A] and should be considered in clinical stage IIB-IIC [V, C] but not for stage I or IIA diseaseV, D
BRAF V600 testing is mandatoryI, A; ESCAT score: I-A
Staging should be according to the eighth edition of the American Joint Committee on Cancer (AJCC) TNM (tumour–node–metastasis) staging system (AJCC8)II, A
Sentinel lymph node biopsy (SLNB) is not routinely recommended for patients with a melanoma of AJCC8 stage pT1a (e.g. with a tumour thickness <0.8 mm and no ulceration)II, E
SLNB is not usually recommended but can be discussed in pT1a for special cases [e.g. 3 mitoses/mm2, a positive deep margin or when Breslow thickness cannot be reliably determined (pTx)]III, D
SLNB should be discussed with patients with a melanoma of AJCC8 stage pT1b (i.e. with a tumour thickness of 0.8-1.0 mm or with a tumour thickness of <0.8 mm with ulceration)III, B
SLNB is recommended for all patients with clinically node-negative T2a or higher tumours according to AJCC8 criteria (>1.0 mm Breslow thickness) [I, A]. Whenever possible, wide excision of the primary tumour should be carried out at the same time.
For patients with T3b, T4a and T4b melanoma who qualify for adjuvant therapy, omitting SLNB can be discussed with the patient, but the potential benefits of SLNB in terms of staging (especially in patients with a BRAF-mutated, thick primary stage IIB or IIC who could be upstaged to stage III melanoma) and locoregional control should also be discussedV, C
Whole-body physical examination with special attention to the primary tumour residual intact component and other suspicious pigmented cutaneous lesions, tumour satellites, in-transit metastases (ITMs) and regional lymph nodes (LNs) is recommended [IV, A]. In tumour stages IIB or higher, ultrasound (US), computed tomography (CT) and/or positron emission tomography (PET) scans and brain magnetic resonance imaging (MRI) are recommended to ensure proper tumour assessmentIII, B

Treatment of localised melanoma

Full depth, WLE of primary tumours with safety margins of 0.5 cm for in situ melanomas, 1 cm for tumours with a thickness ≤2 mm and 2 cm for tumours >2 mm is recommendedIII, B

Treatment of locoregional melanoma

Patients with pT1b-T4b cN0 cM0 melanoma and a positive SLNB should undergo standard follow-up [III, A] ± systemic therapy according to disease stage (see Figure 1)I, A
CLND is not recommended for patients with a positive SLNBI, E
Patients with a negative SLNB can be offered standard follow-up [III, A], clinical trial participation [V, A] or anti-PD-1 therapy for 12 months (stages IIB-IIC)I, A
Enrolment into a clinical trial wherever possible is preferredV, A

Treatment of ITMs

Patients with resectable ITMs should undergo complete excision with clear margins [IV, B]. These patients can also be evaluated for neoadjuvant nivolumab–ipilimumab [I, A; ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1 score: A; not EMA or FDA approved] followed by adjuvant therapy based on pathological response and BRAF status, neoadjuvant plus adjuvant pembrolizumab [II, A; not EMA or FDA approved] or adjuvant therapyI, A
Patients with resectable disease but a short disease-free interval (<6 months), unresectable satellite, ITMs or inoperable primary tumours of the limbs without additional metastases should be treated with systemic therapyIII, B
Patients with unresectable satellite or ITMs may be treated with systemic therapy with anti-PD-1 based immunotherapy or BRAFi–MEKi, according to BRAF mutation statusI, A
Local therapy with T-VEC, [I, B; ESMO-MCBS v1.1 score: 3], isolated limb infusion or isolated limb perfusion [IV, C], RT [IV, C], electrochemotherapy [IV, C] or limited palliative excision [IV, C] can also be considered (no impact on OS).

Adjuvant RT

Adjuvant RT is not routinely recommendedIII, D
RT can be considered for local tumour control in cases of inadequate resection margins of lentigo malignaIII, B
Adjuvant RT to the primary excision site should be considered for patients with desmoplastic or neurotropic melanoma for whom adequate (≥8 mm) pathological resection margins cannot be achievedIV, C
RT could be discussed for patients with an R1 resection (resection with microscopic tumour at the margin) or after resection of bulky LN metastases, especially if further surgical clearance is not feasibleIII, C

Adjuvant systemic therapy in stage IIB-IIC melanoma

Adjuvant therapy with either pembrolizumab [ESMO-MCBS v1.1 score: A] or nivolumab [ESMO-MCBS v1.1 score: A] for 12 months should be considered for patients with stage IIB-IIC disease; treatment discussions with the patient should include consideration of the RFS benefit but lack of mature OS dataI, A

Adjuvant systemic therapy in resected stage III and IV NED

Adjuvant systemic therapy options are anti-PD-1 therapy (nivolumab for resected stage IIIB-IV NED [I, A; ESMO-MCBS v1.1 score: no evaluable benefit] or pembrolizumab for resected stage III [I, A; ESMO-MCBS v1.1 score: A]) or dabrafenib–trametinib for patients with resected stage III BRAF V600E-mutated melanomaI, A; ESCAT score: I-A
For anti-PD-1-based therapy, treatment discussions with the patient should consider the DMFS and RFS benefits but lack of mature OS data compared with placeboI, A
For dabrafenib–trametinib, these discussions should also consider the DMFS and RFS benefits and potential OS benefit for patients with BRAF V600E-mutated melanomaI, A
These treatments should be given within 12 weeks of complete resectionI, A
Targeted therapy should not be offered to patients with BRAF V600K-mutated melanoma in light of the potential detrimental effect on OS reported in the COMBI-AD trialII, D
For patients with AJCC8 stage IIIA and <1 mm tumour burden, adjuvant systemic treatment is generally not recommendedI, D
The use of adjuvant nivolumab–ipilimumab is not recommended for resected stage III melanomaI, D; not EMA or FDA approved
Patients with resectable stage IV melanoma can be offered systemic therapy [V, A], clinical trial [V, A] or metastasectomy or local ablative therapy [III, B] followed by adjuvant anti-PD-1 therapyI, A
The use of adjuvant nivolumab–ipilimumab according to the dosing schedule utilised in the phase II IMMUNED trial may be an option for selected patients with resected stage IV melanomaII, C; not EMA or FDA approved

General recommendations

Patients with metastatic melanoma should have metastases (preferably) or the primary tumour screened for the detection of BRAF V600 mutationIV, A; ESCAT score: I-A
If no tumour tissue is available, circulating tumour DNA may be an alternativeIII, C
In addition to the treatment options outlined below, palliative resection [IV, C] and/or RT [IV, B] and/or T-VEC [I, C] can be considered for symptomatic extracranial disease.

First-line treatment

First-line treatment decisions must take into consideration prior neoadjuvant and/or adjuvant therapy received, timing of recurrence on/after adjuvant therapy, resectability status and suitability to receive ICI therapy, as outlined in Figure 4 [V, A]. Primary or secondary resistance must be considered as this is also an eligibility criterion for clinical trials in pretreated patientsV, A
Wide excision of the primary tumourIII, B
Neoadjuvant nivolumab–ipilimumab [I, A; ESMO-MCBS v1.1 score: A; not EMA or FDA approved] followed by adjuvant therapy based on pathological response and BRAF status.
Neoadjuvant plus adjuvant pembrolizumabII, A; not EMA or FDA approved
Adjuvant anti-PD-1 therapy [I, A] or dabrafenib–trametinib for BRAF V600E-mutated tumoursI, A
Metastasectomy or local ablative therapy [III, B] followed by adjuvant anti-PD-1 therapyI, A
Anti-PD-1 therapy aloneV, A
For patients with unresectable disease, first-line ipilimumab–nivolumab [ESMO-MCBS v1.1 score: A/4] is a preferred option for all patients regardless of BRAF status when this can be safely delivered for the first few months (i.e. when a rapid response is not required due to aggressive/symptomatic disease)I, A
First-line nivolumab [I, A; ESMO-MCBS v1.1 score: A/4] or pembrolizumab [I, A; ESMO-MCBS v1.1 score: A/4] is also recommended.
Nivolumab–relatlimab can be offered as first-line treatment but EMA approval is only for patients with tumour cell PD-L1 expression <1%I, B; ESMO-MCBS v1.1 score: 3; EMA approved for PD-L1 expression <1%, FDA approval is regardless of PD-L1 expression
If anti-PD-1-based therapy is not available or patients are considered ineligible for its use, BRAFi–MEKi combination therapy (dabrafenib–trametinib [ESMO-MCBS v1.1 score: 5]; vemurafenib–cobimetinib [ESMO-MCBS v1.1 score: A/5]; binimetinib–encorafenib [ESMO-MCBS v1.1 score: A/5]) is also an option in the first line for patients with BRAF-mutated melanoma [I; A; ESCAT score: I-A].
BRAFi–MEKi for 8-12 weeks followed by ipilimumab–nivolumab (as per SECOMBIT arm C or EBIN arm B) is also an option, especially for patients with high LDH levels and/or liver metastasesII, C; ESCAT score: I-A; induction targeted therapy is not EMA or FDA approved
For patients in whom the decision to treat with targeted therapy has been made, those who cannot receive a MEKi (e.g. due to cardiovascular comorbidities, a recent BM bleeding event, history of retinal detachment or other ophthalmological contraindications) can be offered encorafenib as monotherapyII, B; not FDA or EMA approved
BRAFi/MEKi (if >3 months after stopping adjuvant BRAFi/MEKi)V, A
First-line immunotherapy options for patients with NRAS-mutated melanoma are identical to those for patients with NRAS-WT diseaseI, A

Recommendations

Patients with melanoma should be advised to avoid sunburn or unprotected solar exposure or any artificial UV exposure; lifelong regular self-examinations of the skin and peripheral LNs is also recommendedIII, A
Patients must be made aware that family members have an increased melanoma riskIII, B
Follow-up should comprise a multidisciplinary approach, including oncologists, dermatologists and other specialties, as required by each individual patient’s prior therapy and needsV, A
During melanoma follow-up, patients should be clinically monitored with whole-body examinations, preferentially by a dermatologist, to detect relapse and to recognise additional skin tumours, especially secondary melanomas, as early as possibleIII, B
There is no consensus on the optimal follow-up schedule or the utility of imaging and blood tests for patients with resected melanoma; respective national guidelines should be consulted, with adjustment as required, considering available resources, particularly after 3 years of follow-upIV, B
The follow-up schedule should be tailored to each individual patient, considering the disease stage, individual risk and personal needs of the patient, and may include clinical–dermatological examination, LN US, laboratory examinations and imaging, as outlined in Figure 6V, B

Contents of the original publication

The section headings of the original.

Introduction
Incidence and Epidemiology
Diagnosis and Pathology/Molecular Biology
Diagnosis
Molecular characterisation
Recommendations
Staging and Risk Assessment
Recommendations
Management of Local/Locoregional Disease
Treatment of localised melanoma
Treatment of locoregional melanoma
Treatment of ITMs
Adjuvant RT
Adjuvant immunotherapy for resectable stage II-IV disease
Adjuvant targeted therapy for resectable stage II-III disease
Neoadjuvant and neoadjuvant plus adjuvant systemic therapy for resectable stage III melanoma and clinically or radiologically detectable LN metastasis
Recommendations
Neoadjuvant and neoadjuvant plus adjuvant systemic therapy in resectable stage III melanoma and clinically or radiologically detectable LN metastasis
Management of Advanced/Metastatic Disease
Treatment of unresectable stage III and IV melanoma
First-line treatment
Second-line treatment
Subsequent lines
MBMs
Predictive and prognostic biomarkers
Recommendations
Oligometastatic disease
Self-Examination, Risk Assessment and Follow-Up
Recommendations
Methodology

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