clinical recommendations

Annals of Oncology 20 (Supplement 4): iv129iv131, 2009

doi:10.1093/annonc/mdp152

Cutaneous malignant melanoma: ESMO Clinical

Recommendations for diagnosis, treatment and
follow-up
R. Dummer1, A. Hauschild1 & G. Pentheroudakis2
1

Department of Dermatology, University of Kiel, Kiel, Germany; 2Department of Medical Oncology, Ioannina University, Ioannina, Greece

staging

The incidence of malignant melanoma varies from 35/

100 000/year in Mediterranean countries to 1220/100 000/
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].

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].

diagnosis
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 IV), presence of ulceration, presence and extent of
regression and clearance of the surgical margins.
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: August 2002, last update
September 2008. This publication supercedes the previously published versionAnn
Oncol 2008; 19 (Suppl 2): ii86ii88.
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.

treatment for localized disease

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 (14 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 a leads to a significant
prolongation of disease-free survival in some, but not all,

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incidence

clinical recommendations
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].

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 [IIIII, 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.

treatment for systemic metastatic

disease (stage IV AJCC)
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

iv130 | Dummer et al.

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 R0resections are the goal.
Palliative radiotherapy should be considered especially for
symptomatic brain or localized bone metastases.

patient information and follow-up

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 36 months during the first 3 years and every
612 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.

note
Levels of Evidence [IV] and Grades of Recommendation [AD]
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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treatment for locoregional metastatic

disease

Annals of Oncology

Annals of Oncology

clinical recommendations

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