Annals of Oncology 19 (Supplement 2): ii86–ii88, 2008
Cutaneous malignant melanoma: ESMO Clinical
Recommendations for diagnosis, treatment and follow-
R. Dummer1, A. Hauschild2& L. Jost3
On behalf of the ESMO Guidelines Working Group*
1Department of Dermatology, University of Kiel, Kiel, Germany;2Department of Dermatology, University of Kiel, Germany;3Department of Oncology, Kantonsspital,
The incidence of malignant melanoma varies from 3–5/100
000/year in Mediterranean countries to 12–20/100 000 in
Nordic countries. The mortality rate is 2/100 000 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. Increased ultraviolet-B ray exposure of
a genetically predisposed population seems responsible for an
ongoing increase in incidence over recent decades.
Suspicious lesions are characterized by asymmetry, border
irregularities, color heterogeneity, dynamics (evolution of
color, elevation or size) (‘ABCDE rule’). Diagnosis should be
based on a full-thickness excisional biopsy with a small side
margin [B]. Processing by an experienced pathology institute is
mandatory. The histology report should follow the 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.
Physical examination with special attention to other suspicious
pigmented skin lesions including head and genitalia, tumor
satellites, in-transit metastases, regional lymph node and
systemic metastases is mandatory. Today, many primary
melanomas have a diameter of <5 mm. In low-risk melanomas
(tumor thickness <1 mm) no other investigations are necessary.
In higher stages imaging is recommended in order to exclude
regional or distant metastatic disease. The refined version of the
ASCC staging and classification system, which includes the
staging of microscopically positive lymph nodes, is the
classification system of choice (Table 1).
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 [II, B]. Modifications may be needed for
preservation of function in melanomas of the fingers and toes
or those of the face and the ear.
Routine elective lymphadenectomy or irradiation to the
regional lymph nodes is not recommended [II, B].
Sentinel lymph node biopsy in melanoma with a tumor
thickness of >1 mm is necessary for precise staging and is
followed by complete clearance of regional lymph nodes, if the
sentinel node was positive for micro-metastases [C]. This
procedure should be performed only by skilled teams in
There is no generally accepted adjuvant therapy to date for
patients with high-risk primary melanoma or completely
resected lymph node metastases (stage III). Adjuvant
immunotherapy with interferon-a (IFN-a) leads to
a significant prolongation of disease-free survival in some but
not all randomized trials. Positive effects of high-dose IFN-a on
overall survival have been demonstrated in two out of three
randomized trials [C]. The optimal timing and dosing
schedules and the best type of interferon (pegylated versus
conventional) are not yet defined. Therefore, adjuvant
interferon treatment is preferentially applied in the context of
randomized clinical trials in specialized centers.
Adjuvant chemotherapies, mistletoe extracts, viscum album
and hormone therapies are not beneficial. 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 or R1 resections of melanoma metastases when
re-excision is not feasible [B].
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland
Approved by the ESMO Guidelines Working Group: August 2002, last update
September 2007. This publication supercedes the previously published version—Ann
Oncol 2007; 18 (Suppl 2): ii71–ii73.
Conflict of interest: Dr Dummer has reported no conflicts of interest. Dr Hauschild has
reported that he is member of the advisory board for Schering-Plough, Synta, Pfizer,
BMS, Bayer and that he receives study grants from Bayer, Essex Pharma, Roche,
ª 2008 European Society for Medical Oncology
treatment for locoregional metastatic
In the case of isolated loco-regional lymph node metastases,
surgical removal, including the surrounding lymph node
region, is indicated; removal of the tumor-bearing lymph node
alone is insufficient. 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 CT or positron emission tomography (PET) scans, are
necessary to exclude the presence of further metastases [B].
Non-resectable in-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 centers. 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
treatment for systemic metastatic
disease (stage IV ASCC)
Palliative therapy for advanced disease with several metastases
in different anatomical regions should initially use cytostatics
such as dacarbazine, vinca alkaloids, nitrosurea or
temozolomide alone or in combination with cytokines like
IFN-a or, in the case of aggressive metastastic disease,
polychemotherapy [C]. Since the overall impact of systemic
therapy on survival in advanced melanoma patients is
questionable, these patients should be treated preferentially in
controlled clinical trials evaluating new approaches. Surgery of
visceral metastases may be appropriate for selected cases with
good performance status and isolated tumor manifestation.
In all surgically treated patients R0 resections must be the goal.
Palliative radiotherapy should be considered especially for
symptomatic brain or localized bone metastases.
patient information and follow-up
The patient and his/her family, in particular small children,
should be instructed in avoidance of sunburn, extended
unprotected solar or artificial ultraviolet exposure and in
lifelong regular self-examination of the skin and peripheral
lymph nodes. The patient must be aware that her/his family
members have an increased risk of melanoma [B]. A secondary
melanoma develops in 8% of all melanoma patients within 2
years of their initial diagnosis. Melanoma patients also have
increased risks for other skin tumors. In patients with lentigo
maligna melanomas, 35% of the patients developed another
cutaneous malignancy within 5 years.
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 [B].
Recommendations for follow-up depend upon the risk of
relapse over time. Follow-up relies primarily on clinical
examinations every 3 months during the first 3 years and every
6–12 months thereafter. Since patients with a thin primary
melanoma have only a small risk of relapse, imaging techniques
are not necessary for this patient population. In contrast,
ultrasound of lymph nodes, CT or whole body PET/PET–CT
scans may be considered in the follow-up of high-risk patients,
i.e. those with thick primary tumors or following treatment of
metastases. However, there is currently no consensus on the use
of imaging techniques or blood tests. Rising serum S100 has
a higher specificity for disease progression than lactate
AJCC TNM stage10-year
Criteria for staging
IA T1a N0 M087.9T1a = Breslow £1 mm, no
ulceration (U–) and Clark
T1b = Breslow £1 mm with
ulceration (U+) or Clark
T2a = Breslow
1.01–2.0 mm U–
T2b = Breslow 1.01–2.0 mm,
U+/T3 = 2.01–4.0 mm U–
T3b = Breslow 2.01–4.0 mm
U+/T4 = > 4.0 mm U–
T4b = Breslow > 4.0 mm U+
U–, N1a = 1 lymph
+/N2 = 2–3 nodes
U+, N1a = 1 lymph
+/N2 = 2–3 nodes
U+, N1b = 1 lymph
+/N2 = 2–3 nodes
U– or U+, N3 = ‡4 nodes,
satellite or in transit
M1a = nodal
metastases with normal
metastases with normal
M1b = lung
metastases with normal
M1c = LDH elevated
and/or any non-
IBT1b N0 M0 83.1
T2a N0 M079.2
IIAT2b/T3a N0 M0 64.4/63.8
IIBT3b/T4a N0 M0 53.9/50.8
T4b N0 M0
Any Ta N1a/N2a M0
IIIBAny Tb N1a/N2a M0 47.7/35.9
IIIC Any Tb N1b/N2b M0 24.4/15.0
Any T N3 M0 18.4
IVAny T any N M1a 15.7
Any T any N M1b2.5
Any T any N M1c6.0
Percentage figures are median values for disease-specific survival with
a standard deviation between 1% and 7%. AJCC, American Joint
Committee on Cancer; TNM. Tumor–node–metastasis; LDH, lactate
Annals of Oncology
Volume 19|Supplement 2|May 2008 doi:10.1093/annonc/mdn100 | ii87
dehydrogenase (LDH) and therefore is the most accurate blood Download full-text
test in the follow-up of melanoma patients if any blood test is
done at all [D].
Psychosocial guidance and rehabilitation—if
needed—constitute an important task of the caring physician.
Reporting follow-up results to Clinical Cancer Registries
secures quality control of surgical and medical interventions.
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 expert authors and the
1. de Vries E, Bray FI, Coebergh JW, Parkin DM. Changing epidemiology of
malignant cutaneous melanoma in Europe 1953–1997: rising trends in
incidence and mortality but recent stabilizations in western Europe and
decreases in Scandinavia. Int J Cancer 2003; 107: 119–126.
2. 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: 570–573.
3. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet 2005; 365:
4. Eggermont AM. Critical appraisal of IFN-alpha-based adjuvant therapy in stage
II–III malignant melanoma. Expert Rev Anticancer Ther 2002; 2: 563–569.
5. Lens MB, Dawes M. Interferon alfa therapy for malignant melanoma:
a systematic review of randomized controlled trials. J Clin Oncol 2002; 20:
6. Kleeberg UR, Suciu S, Broecker EB et al. Final results of the EORTC 18871/DKG
80-1 randomised phase III trial: rIFN-alpha 2b versus rIFN-gamma versus
ISCADOR M versus observation after surgery in melanoma patients with either
high risk primary (thickness > 3 mm) or regional lymph node metastasis. Eur J
Cancer 2004; 40: 390–402.
7. Farshad A, Burg G, Panizzon R, Dummer R. A retrospective study of 150 patients
with lentigo maligna and lentigo maligna melanoma and the efficacy of
radiotherapy using Grenz or soft X-rays. Br J Dermatol 2002; 146: 1042–1046.
8. Australian Cancer Network. Guidelines for the management of cutaneous
melanoma. Sydney: Stone Press 1997.
9. Dummer R, Panizzon R, Bloch PH, Burg G. Updated Swiss guidelines for the
10. Huncharek M, Caubet JF, McGarry R. Single-agent DTIC versus combination
chemotherapy with or without immunotherapy in metastatic melanoma: a meta-
analysis of 3273 patients from 20 randomized trials. Melanoma Res 2001; 11:
11. Kaufmann R, Spieth K, Leiter U et al. Temozolomide in combination with
interferon-alfa versus temozolomide alone in patients with advanced metastatic
melanoma: a randomized, phase III, multicenter study from the Dermatologic
Cooperative Oncology Group. J Clin Oncol 2005; 23: 9001–9007.
12. Titus-Ernstoff L, Perry AE, Spencer SK et al. Multiple primary melanoma: two-
year results from a population-based study. Arch Dermatol 2006; 142:
13. Beyeler M, Waldispuhl S, Strobel K et al. Detection of melanoma relapse: first
comparative analysis on imaging techniques versus S100 protein. Dermatology
2006; 213: 187–191.
14. Kleeberg UR, Garbe C. Recommendations for follow-up of patients with
cutaneous melanoma. Dermatol Ther 1999; 10: 83–87.
Annals of Oncology
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