This article appears in the following Annals of Oncology issue: ESMO Clinical Recommendations [View the issue table of contents]
ESMO clinical recommendations |
Cutaneous malignant melanoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up
1 Department of Dermatology, University of Kiel, Kiel, Germany
2 Department of Medical Oncology, Ioannina University, Ioannina, Greece
* Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations{at}esmo.org
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incidence |
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The incidence of malignant melanoma varies from 3–5/100 000/year in Mediterranean countries to 12–20/100 000/year in Nordic countries. The mortality rate is 2/100 000/year for females and 3/100 000/year for males with a lesser variation with geography. Melanoma mortality has doubled in males over the last 25 years, during which time a trend of declining incidence and mortality in high-risk Northern European countries combined with a continuing increase in Southern Europe has emerged [1]. Increased ultraviolet-B ray exposure of a genetically predisposed population seems responsible for an ongoing increase in incidence over recent decades [2].
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diagnosis |
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Suspicious lesions are characterized by asymmetry, border irregularities, color heterogeneity, dynamics (dynamics in colors, elevation or size) (the ABCD rule) [3]. Today, many primary melanomas have a diameter of <5 mm [4] [B].
Diagnosis should be based on a full thickness excisional biopsy with a small side margin. Dermoscopy performed by an experienced examiner can improve the diagnostic accuracy.
Processing by an experienced pathology institute is mandatory.
The histology report should follow the World Health Organization (WHO) classification and include maximum thickness in millimeters (Breslow), level of invasion (Clark, level I–V), presence of ulceration, presence and extent of regression and clearance of the surgical margins.
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staging |
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Physical examination with special attention to other suspicious pigmented lesions, tumor satellites, in-transit metastases, and to signs or symptoms suggestive of regional lymph node and systemic metastases is mandatory.
In low-risk melanomas (tumor thickness <1 mm) no other investigations are necessary. In higher stages imaging of nodal basin, chest/abdomen/pelvis is recommended in order to allow proper staging.
The refined version of the American Joint Comittee on Cancer (AJCC) staging and classification system, which includes the staging of microscopically positive lymph nodes, is the classification system of choice [5].
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treatment for localized disease |
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Wide excision of primary tumors with a normal skin margin of 0.5 cm for in situ melanomas, of 1 cm for tumors with a Breslow thickness up to 2 mm and 2 cm for thicker tumors is recommended [6, 7] [II, B]. Modifications may be needed for preservation of function in melanomas of the fingers and toes or those of the ear.
Routine elective lymphadenectomy or elective irradiation to the regional lymph nodes is not recommended [II, B].
Sentinel lymph node biopsy in melanoma with a tumor thickness of >1 mm provides more accurate staging information, particularly for lesions of intermediate thickness (1–4 mm) but has no therapeutic value as it did not result in overall survival benefits. It may be followed by complete clearance of regional lymph nodes if the sentinel node was positive for micro metastases [C]. However, this procedure has no proven effect on overall survival [8, 9]. Sentinel lymph node biopsy should be performed only by skilled teams in experienced centres, with appropriate balanced consideration of potential morbidity versus benefit.
There is no generally accepted adjuvant therapy to date for patients with high-risk primary melanoma or completely resected lymph node metastases (stage III). Given the absence of consistent, significant benefit in overall survival from any therapy, patient enrolment in clinical trials should be encouraged. Adjuvant immunotherapy with interferon 
leads to a significant prolongation of disease-free survival in some, but not all, randomized trials. Several large independent trials using intermediate dose (or pegylated interferon) have demonstrated a positive effect on disease-free and distant metastases-free survival in patients with micrometastases (N1a) [10]. Adjuvant treatment in patients with resected macroscopic involvement (N1b) is preferentially applied in the context of randomized clinical trials in specialized centres.
Adjuvant chemotherapy, mistletoe extracts, viscum album and hormone therapies are not beneficial [11, 12]. Adjuvant immunotherapy with other cytokines including interleukin-2, tumor vaccination, and immunochemotherapy are experimental and not to be used outside of controlled clinical trials.
Radiotherapy for local tumor control should be considered in case of inadequate resection margins of lentigo maligna melanoma [13] or R1 resections of melanoma metastases when re-excision is not feasible [B].
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treatment for locoregional metastatic disease |
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In the case of isolated locoregional lymph node metastases, surgical removal, including the surrounding lymph node region, is indicated; removal of the tumor-bearing lymph node alone is insufficient [14]. Surgical removal is also recommended in the case of an isolated metastasis in a parenchymal organ, including the central nervous system. However, before undertaking additional aggressive local surgical treatments, a detailed staging investigation, including imaging techniques such as computed tomography (CT) or positron emission tomography (PET) scans, are necessary to exclude the presence of further metastases [3] [B].
Non-resectable-transit metastases or inoperable primary tumors of the limbs without additional metastases may be treated with isolated limb perfusion using e.g. melphalan and tumor necrosis factor [II–III, C]. However, such treatment requires major surgery and should be restricted to a few experienced centres. Radiation therapy may be used instead [V, D], although there are no data showing a positive effect on any outcome measure.
Adjuvant systemic therapy after complete resection as mentioned above.
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treatment for systemic metastatic disease (stage IV AJCC) |
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Palliative therapy for advanced disease with several metastases in different anatomical regions should initially use well tolerated single-agent cytotoxic chemotherapy such as dacarbazine, temozolomide, as any systemic therapy did not result in survival prolongation but symptom palliation only [15, 16] [C]. Fit patients with high-volume visceral metastatic disease who need rapid symptom palliation may be treated with combination chemotherapy or combinations of chemotherapy with cytokines in view of the superior response rates reported in some trials. However, this activity comes at the price of increased toxicity and is not associated with survival prolongation [17]. Since there is no impact of systemic therapy on survival in advanced melanoma patients, they should be preferentially treated in controlled clinical trials evaluating new approaches (combination chemotherapy with new agents, cytokines, targeted agents, immunotherapeutic approaches). Surgery of visceral metastases may be appropriate for selected cases with good performance status and isolated tumor manifestation. In all surgically treated patients in principal R0-resections are the goal.
Palliative radiotherapy should be considered especially for symptomatic brain or localized bone metastases.
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patient information and follow-up |
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Topincidencediagnosisstagingtreatment for localized diseasetreatment for locoregional...treatment for systemic...patient information and follow...notereferences |
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The patient should be instructed to avoid sun burns, extended unprotected solar or artificial ultraviolet exposure and be advised for lifelong regular self-examination of the skin and peripheral lymph nodes. The patient must be made aware that family members are at an increased melanoma risk [B].
During melanoma follow-up, patients are clinically monitored in order to detect a relapse and to recognize additional skin tumors, especially a second melanoma, as early as possible [3] [B]. Eight per cent of all melanoma patients develop a secondary melanoma within 2 years of their initial diagnosis [18]. Melanoma patients also have increased risks for other skin tumors. In patients with lentigo maligna melanomas, 35% develop another cutaneous malignancy within 5 years [14].
However, there is currently no consensus on the frequency of follow-up and the use of imaging techniques. Typically patients will be seen every 3–6 months during the first 3 years and every 6–12 months thereafter. This recommendation is based on the relapse-risk profile over time, with less frequent visits being required for patients with thinner localised melanomas.
The follow-up should be prognosis-oriented and include psychological care for the patients. Since patients with a thin primary melanoma have only a small risk of relapse, imaging techniques are not necessary for this patient population. Ultrasound of lymph nodes, CT or whole body PET/PET-CT scans may be used in the follow-up of patients with thick primary tumors or following treatment of metastases. However, as no effective salvage therapy is available to date, these investigations rarely lead to early diagnosis and surgical salvage of occasional patients with solitary metastases, with the exception of participation in clinical trials of experimental therapies.
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note |
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Levels of Evidence [I–V] and Grades of Recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty.
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footnotes |
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Approved by the ESMO Guidelines Working Group: August 2002, last update September 2008. This publication supercedes the previously published version—Ann Oncol 2008; 19 (Suppl 2): ii86–ii88.
Conflict of interest: Prof. Dummer has reported that he has consultant and advisory board relationship with Astra Zeneca, Novartis, Cephalon, Merck Sharp & Dhome, Transgene Genta, Bayer and Schering Plough. He has also reported that he receives research funding from Astra Zeneca, Cephalon, Merck, Sharp & Dhome, Transgene and Bayer; Dr Hauschild has reported that in the last two years he has been a member of the advisory board/consultant or received speakers’ honoraria from the following companies: Bayer Schering, BMS, Essex Pharma/Schering-Plough, GSK, Onyx, Pfizer, Roche Pharma and Synta; Dr Pentheroudakis has reported no conflicts of interest.
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references |
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