State of the Art Oncology in EuropeFont: aaa

Melanoma

1. GENERAL INFORMATION

1.1 Incidence

1.1.1 Incidence and mortality

About 63,000 new cases a year of cutaneous melanoma were diagnosed in Europe, some 2% of the all cancers. Incidence rates are higher in northern Europe than eastern of Europe. In North-America, Australia and New Zealand incidence of cutaneous melanoma is even higher, at 14 and 34 respectively (Figure 1). More than 50% of patients with cutaneous melanoma are between 20 and 59 years of age and is extremely rare prior to puberty. In Europe, incidence is slightly higher in women than men: about 8 and 6 per 100,000 per year, respectively. By contrast in Northern America, Australia and New Zealand male are at least 1.5 times more likely to develop melanoma than females (Ferlay 2004).

Figure 1 Cancer incidence rate for skin melanoma in the world (Ferlay 2004)

melanoma_figura 1
Age-adjusted rates of melanoma skin cancers is increasing. Rates have doubled since the mid-1950s in many high-income countries, particularly those that already had high rates. This trend is restricted to countries where a high proportion of the population is fairskinned. Melanoma of the skin has been increasing rapidly in the UK since the 1960s, as in many other countries (Coleman 1999). Incidence has been rising by 30-50% every five years, more rapidly in women than in men; the number of patients more than doubled between 1971 and 1990. The increases affect people in all age groups, and they are not due to changes in diagnostic criteria (Van der Esh 1991). In the United States , the incidence of malignant cancer from 1973 to 2002 increased by 270% (Markovic 2007). In Italy during 1988-2002, melanoma incidence have almost doubled, while mortality is rather stable (Figure 2) (AWG 2007). The difference between incidence and mortality trends suggests substantial and long-term improvements in survival (Coleman 1999). Incidence of cutaneous melanoma is three times higher among more affluent groups (MacKie 1996).

Figure 2 Skin melanoma incidence trend for skin melanoma in Italy, men (AWG 2007)

melanoma_figura 2

1.1.2 Survival

In Europe for patients diagnosed during 2000-2002, 5-year survival was 86%. There have been a slight improvements in 5- and 10-year survival over the period 1991-2002. The profiles of 5-year and 10-year survival were similar, although 10-year survival was lower. The 10-year survival was very close the 5-year survival indicating that death generally occurred within 5 years of diagnosis (Verdecchia 2007). Five-year relative survival decreased with age from 88% to 74% from the youngest (15-45 years) to the oldest age group of patients (75 years and over). There are major between-country differences in survival among European countries: survival is higher in most Northern and Western European countries, where incidence is also high. This may be due to the diagnosis of more superficial spreading melanomas. Survival is significantly above the European average for both men and women in Scotland, where there is an active programme of early diagnosis (MacKie 2003), and lower than the European average in several Mediterranean countries, where less attention has been paid to early diagnosis. Melanomas located in the skin of the limbs tend to carry a better prognosis (5-year relative survival 85%) than those in the skin of the head and neck or trunk (5-year relative survival 81% for both). The 5-year survival for the other subsites is much lower (61%) (Dickman 1999). An association between deprivation and survival has been found for cutaneous melanoma (Coleman 1999). In England and Wales, the gap between the most affluent and most deprived groups was about 13% for survival at five years. Earlier diagnosis contributed to socio-economic differences in survival. In a population study in the West of Scotland, thin melanomas were more common in the affluent, although survival was still worse in the deprived group after adjustment for tumour thickness (MacKie 1992).

1.1.3 Prevalence

Prevalence of skin melanoma, is the number of people living with a diagnosis of skin melanoma. In Europe for both sexes skin melanoma account for 4% of the total cancer prevalence (Micheli 2002). The proportion of prevalent persons was 81 per 100,000. There were large differences between European countries in the prevalence of skin melanoma; estimates ranged from 31 in Poland to 230 per 100,000 in Sweden.

1.2 Aetiological and risk factors

Sunlight
It is estimated that 80% of melanoma is caused by ultraviolet radiation damage to sensitive skin (IARC 1992). Several studies have shown that episodic skin exposure involving severe sunburn, especially in fair-skinned white people is the major determinant or risk for melanoma. The risk of melanoma developing in people who have had sunburns is double that in people who have never had a sunburn. Moreover, the age at which sunburns occur appears to be important: sunburns in childhood are associated with the highest risk. Also evidence for the role of UVR comes from studies of immigrant populations in Australia, which have shown that the risk is proportional to the length of stay and inversely to the age at arrival (Markovic 2007; Veierød 2003). The use of psoralen–UV-A radiation photochemotherapy for psoriasis has also been associated with an increased risk of melanoma (Stern 2001). A recent meta-analysis of 13 studies suggested that sunbed and sunlamp exposure might lead to a slightly higher risk of melanoma and that the risk was higher with longer duration of exposure and earlier age at exposure (Gallagher 2005). The use of sunscreens with broad-spectrum sun protection has been shown to reduce the number of acquired nevi that develop in children by 30% to 40%. Since acquired nevi are markers for sun exposure a proper sunscreen use may have a role in melanoma prevention (Gallagher 2000).
Occupation
There are several publications that have reported association between occupational exposure and skin melanoma. A large cohort study among Nordic airline pilots showed a significant increased risk to develop melanoma (SIR 2.3) (Pukkala 2003). A meta-analysis among flight personnel (flight attendants, civil and military pilots) has confirmed the increased risk to develop melanoma (Buja 2005). The use of carbamate pesticide in agriculture and commercial setting was analyzed in the large cohort study (Agricultural Health Study). Relative to never used subjects, melanoma risk was from 4 to 5.5 times elevated, depending of the lifetime exposure. Risk remained after adjusting for sunlight exposure (Mahajan 2007). Recent studies have shown an increased risk to develop skin melanoma among nurses (Lie 2007), pulp and papers workers (Band 2001) employees in the manufacture of semiconductors (Nichols 2005), and in petroleum industry workers (Gun 2006; Sorahan 2007).
Reproductive factors
A recent pooled analysis of 10 case-control studies suggested that women with both earlier age at first birth (<20 years) and higher parity (=5 live births) had a lower risk than women with later age at first birth and lower parity (odds ratio, 0.33) (Karagas 2002). Estrogen and progesteron have been postulated to increased the risk of melanoma by stimulating melanocyte proliferation (Markovic 2007). Pregnancy and oral contraceptive use do not affect the risk of malignant melanoma (Wiggins 2005; Karagas 2002).
Diet and obesity
Obesity has been hypothesized to increase the risk of melanoma, probably because of a larger body surface area exposed to sun or differential hormonal profiles (Markovic 2007). A recent large meta-analysis has shown a weak positive association (RR< 1.2) between BMI and malignant melanoma in men (Renehan 2008). The World Cancer Research Fund and the American Institute for Cancer Research (AICR) (WCRF 2007) in their extensive report on the scientific literature on diet, physical activity and prevention of cancer, published important conclusions after a review of 167 specific publications. The panel of experts concluded that:
– there is a convincing evidence that arsenic in drinking water is probably cause of skin cancer
– there is limited evidence suggesting that selenium is a cause
Other diet related factors like potatoes, non-starchy vegetables, fruits, fish, eggs, milk, coffee, tea, alcohol, total fat, cholesterol, protein, vitamin A, retinol (foods), beta-carotene, alpha-carotene, carotenes, lycopene, folate, vitamin C, vitamin D, vitamin E, multivitamins, physical activity, energy intake were evaluated and the data were either of too low quality, too inconsistent, or the number of studies too few to allow conclusions to be reached.
Host factors
Melanocitic nevi. The risk of melanoma has been directly correlated to the total number of benign nevi (both dysplastic and nondysplastic) on the body. The risk is approximately 1.5-times higher in people with 11 to 25 nevi (compared with =10 nevi) and appears to be doubled with every increase of 25 nevi (Markovic 2007). Similarly, larger nevi (particularly >5 mm) are associated with a higher risk of melanoma. Giant nevi (>20 cm) are associated with a significantly higher risk of melanoma. Melanomas that develop in the setting of previous nevi are more likely to be on the trunk, occur in younger patients, and belong to the superficial spreading variety.
Family history
Patients with a history of melanoma in a first-degree relative have approximately a 2-times higher risk of developing melanoma than those without a family history; the risk increases in the presence of other risk factors (Cho 2005). Familial melanoma is thought to account for 10% of all melanoma cases. Furthermore, melanoma is known to cluster in families with family cancer syndromes such as familial retinoblastoma, Li-Fraumeni cancer syndrome, and Lynch syndrome type II. Immunosoppression. Patients receiving immunosuppressive agents after organ transplantation, those with acquired immunodeficiency syndrome or haematological tumours have an high risk of melanoma (Hollenbeak 2005; Euvrard 2003; Markovic 2007).

1.3 Screening and case finding

1.3.1 Screening programme

Current data do not support widespread population-based screening for melanoma. Both the US and Canadian task forces concluded that the evidence to recommend total body skin examination for the early detection of skin melanoma is insufficient (Berg 2001; Feightner 1994). The Australian National Health and Medical Research Council does not recommend mass screening or screening of high-risk people for melanoma (NHMRC 1996).

1.3.2 Primary prevention (risk reduction)

Ongoing public education is the major tool in achieving primary prevention of melanoma. It is recommended on a type R basis that public education especially targets individuals at increased risk. These individuals should be taught to be alert to the warning signs of melanoma (ABCDE signs, Table 1), and should be strongly encouraged to reduce exposure to (intermittent) UVB-radiation, including sunlamps and sunbeds.

Table 1 ABCDE Signs

A ———–> Lesion asymmetry
B ———–> Border irregularity
C ———–> Colour variegation
D ———–> Diameter > 6 mm
E ———–> Enlargement

1.3.3 Secondary prevention (early detection)

Although secondary prevention (early detection) in the form of screening (Vasen 1989) seems attractive in this easily recognisable and – at least in the early stages – simply treatable disease, randomized trials of screening versus no screening are lacking. Recently a population-based case-controlled study (Berwick 1996) of 1199 Caucasians resident in the United States has shown that skin self-examination was associated with a reduced incidence of melanoma and may reduce the risk of advanced disease. A report of mass screening of the general population from the American Academy of Dermatologist (AAD) revealed that most of the melanomas detected were localised, with median thickness of 0.3 mm, and that nearly half of the patients with a detected melanoma would not have seen a physician spontaneously (Koh 1996). Nevertheless the evidence of an advantage for surveillance and screening programmes is stronger in high-risk populations, where a number of studies have confirmed that primary melanomas were diagnosed at a stage where they were smaller and thinner (Wolfe 1999). So screening is suitable for individual clinical use on a type R basis and it is recommended on a type C basis (Wolfe 1999) for individuals at higher risk. High-risk individuals should be identified and encouraged to perform skin self-examination as a screening and preventive measure.

1.4 Referral

1.4.1 Specialised institutions

Referral of cutaneous melanoma patients to specialised institutions is generally not recommended. However, for patients who meet the eligibility criteria for prospective trials as defined by the following conditions, this option should be discussed:

a) Operable primary melanoma studies on excision margins or sentinel node biopsy.
b) Individuals at high risk of primary melanoma and patients with lymph node metastases when an adjuvant treatment has to be considered.
c) Patients with distant spread: who may be suitable for studies to elucidate the role of new systemic therapeutic options.

Referral to specialised centres has to be recommended for patients who, after resection of the primary lesion, need sentinel node biopsy, have to undergo lymph node dissection of the neck or groin, or need operations that require special expertise. The same applies to the procedure of isolated regional perfusion of the limbs or rare locations, such as vulvar or rectal melanoma, or when patients express the will of entering experimental clinical trials (i.e. vaccines). In the palliative setting referral has to be considered in cases where radiotherapy has to be given or when resection of metastases from sites such as lung or brain has to be performed.

1.5 Recent reviews and books

Balch CM, Houghton AN, Sober AJ, Soong S-J, editors. Cutaneous melanoma. 4th ed, St. Louis: Quality Medical Publishing; 2003.

Balch CM. Surgical management of melanoma: results of prospective randomized trials. Ann Surg Oncol 1999; 5: 301-9.

Eggermont AMM, Kirkwood JM. Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years? Eur J Cancer 2004; 40: 1825-1836.

Kroon BBR, Bergman W, Coebergh JWW, Ruiter DJ, on behalf of the Dutch Melanoma Working Party. Consensus on the management of melanoma of the skin in the Netherlands. Melanoma Research 1999; 9: 207-12.

Thompson JF, Scalyer RA, Kefford RF. Cutaneous melanoma. Lancet 2005; 365: 687-701.

Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med 2004; 351: 998-1012

Rosso S, Budroni M. Skin cancers: melanoma, non-melanoma cancers and Kaposi’s sarcoma. In Crocetti E et al Cancer trends in Italy: figures from the Cancer registries (1986-97). Epidemiologia e Prevenzione, Marzo-aprile, 2004.

2. PATHOLOGY and BIOLOGY

2.1 Biological data

Melanomas are malignant tumours deriving from the transformation and proliferation of melanocytes which normally reside in the basal cell layer of the epidermis. Primary cutaneous melanoma can arise on a precursor lesion (i.e. lentigo maligna, dysplastic nevus and congenital nevus) or directly on normal skin (Reed 1985). Melanoma cells are characterised by relative growth autonomy in culture. So an autocrine mechanism of growth stimulation has been suggested, which functions through the secretion of endogenous peptide growth factors such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGF-a), TGF-b or interleukin -1 (IL-1) (Herlyn 1992).

2.1.1 Tumour growth

Tumour growth can be biphasic or monophasic (Reed 1985). The biphasic pattern consists of a horizontal or radial initial growth phase (intraepidermal) followed by a subsequent vertical growth phase corresponding to the infiltration of the dermis and hypodermis. Those melanomas having such biphasic growth pattern are the so-called superficial spreading melanoma (SSM) and the lentigo maligna melanoma (LMM). Very often, acral lentiginous melanoma also has such a biphasic growth pattern. The monophasic growth pattern of melanoma consists of tumours having a pure vertical growth which includes mainly the so-called nodular melanoma (NM). The vertical growth phase can include the desmoplastic variant and minimal deviation variant.

2.1.2 Genetic abnormalities

There is evidence that familial melanoma is genetically heterogeneous (Greene 1999), and loci for familial melanoma susceptibility have been identified on the chromosome arms 1p and 9p by means of studies for homozygous deletions. Multiple genetic events have been related to the pathogenesis of melanoma (Halachmi 2001). Indeed there are families of proteins inhibiting CDK: p16INK4a and its homologues and the families of CIP and KIP proteins. While the linkage with a gene on chromosome 9 is clear, the role of chromosome 1 is still uncertain. Certain 9p21 markers are deleted in more than half of the melanoma lines studied. The gene named multiple tumour suppressor 1 (CDKN2A/MTS1) encoding p16INK4a – a low-molecular weight protein of 148 residues and a previously identified inhibitor of cyclin-dependent protein kinases (CDKs) – has been localised to the p21 region of human chromosome 9 and found to be within the critical deleted region. It consists of 3 coding exons: exon 1 containing 125 bp, exon 2 containing 307 bp and exon 3 just 12 bp. Homozygous deletions of the 9p21 region were found in 56% of melanoma tumour lines tested (84 melanoma cell lines were studied). The p16 INK4a locus overlaps an alternating reading frame (ARF) of p14 and familial mutation of the entire cistronic unit p16 INK4a /p14ARF has been reported. It was shown that there are three genes homologous to p16INK4a: p15 INK4b(CDKN2B/MTS2) on 9p21; p18INK4con 1p32; p19INK4d on 19p13. Based on DNA sequence and deletion analysis, a minimum of 75% of melanoma lines contained mutant MTS1 or had lost the gene from both homologues. Mutations of the p16INK4a coding region and adjoining splice junction sequences were identified in 33/36 melanoma cases in 9 families, whereas 2 were detected in normal controls and are not disease-related. Analysis of these mutations showed that 92% of melanoma cases, 30% of dysplastic nevus cases, and 15% of unaffected individuals carried one of the mutations. Of the 48 individuals identified as carrying a p16 mutation only 15 (31%) did not have melanoma. The nonsense mutation (Arg50Ter), splice donor site mutation (IVS2+1 [G-T]), and 3 of the melanoma-specific missense mutations (Val118Asp, Gly93Trp, and Arg79Pro) are highly correlated with melanoma in these families, and were not found in control analyses. With some exceptions, the distribution of disease-specific mutations in several families is consistent with p16 being a familial melanoma gene in 9p21 (Goldstein 1998; Pollock 1996).

2.2 Precancerous lesions

Despite the still present controversy regarding the nature of the lesions potentially associated with melanoma, their identification is very important in order to understand the biology of this disease and to identify individuals at risk (Barnhill 1992).

2.2.1 Lentigo maligna

Lentigo maligna is the precursor lesion of lentigo maligna melanoma. Pleiomorphic melanocytes are spread along the dermoepidermal junction. The epidermis is often atrophic as such lesions usually occur in elderly people or sun-damaged skin.

2.2.2 Dysplastic nevus

One of their most characteristic features of dysplastic nevus is the presence of lentiginous melanocytic hyperplasia, with cytologic atypia of the nevomelanocytes. These cells, lying along the dermoepidermal junction, are very often surrounded by collagenous changes, lymphocytic infiltrates and prominent vascularity. Individuals with many “dysplastic” (and non-dysplastic) naevi may be at higher risk of developing a melanoma, which does not necessarily arise in the dysplastic lesion but can also appear on normal skin. The incidence of melanoma in a dysplastic nevus is 1:3000 per year. So dysplastic nevi should not be considered as precursors of melanoma, but they are markers that allow identification of individuals at increased risk for melanoma.

2.2.3 Congenital nevus

Congenital nevus can be clinically diagnosed just by size because virtually all nevi greater than 2-3 cm are congenital. Smaller congenital nevi are reliably diagnosed by their history. Nevertheless there are some histological findings that suggest a congenital origin, such as the presence of nevus cells in a single cell array in the lower reticular dermis and subcutaneous fat or in nests in sebaceous glands, hair follicles, eccrine ducts and hair papillae. The estimated risk of melanoma associated with lesions smaller than 10 cm is still controversial.

2.3 Histological types

Melanomas are conveniently categorised by growth pattern. Four major types can be distinguished: superficial spreading melanoma (65%), nodular melanoma (25%), lentigo maligna melanoma (5%) and acral lentiginous melanoma (5%). Superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma are classified as radial “growth phase patterns” and nodular melanoma as “pure vertical growth phase melanoma”. Other variants of vertical growth phase of melanoma are desmoplastic melanoma and minimal-deviation melanoma (Barnhill 1992).

2.3.1 ICD-O classification

The following histotypes are considered “typical” melanomas. The ICD-O (International Classification of Diseases for Oncology) morphology code is provided in brackets (ICD-O 2000).

[M-8720/3] NOS
[M-8744/3] acral lentiginous, malignant
[M-8730/3] amelanotic
[M-8722/3] balloon cell
[M-8745/3] desmoplastic, malignant
[M-8771/3] epithelioid cell
[M-8770/3] epithelioid and spindle cell, mixed
[M-8720/2] in situ
[M-8770/0] juvenile
[M-8742/3] lentigo maligna
[M-8720/3] malignant, NOS
[M-8761/3] malignant, in giant pigmented nevus
[M-8742/3] malignant, in Hutchinson’s melanotic freckle
[M-8740/3] malignant, in junctional nevus
[M-8741/3] malignant, in precancerous melanosis
[M-8745/3] malignant, neurotropic
[M-9044/3] malignant, of soft parts
[M-8723/3] malignant, regressing
[M-8721/3] nodular
[M-8772/3] spindle cell, NOS
[M-8773/3] spindle cell, type A
[M-8774/3] spindle cell, type B
[M-8743/3] superficial spreading

2.3.2 Superficial spreading melanoma

Superficial spreading melanoma is the most frequent histological type of melanoma. It is mostly characterised by a prominent intra-epidermal proliferation, usually in single array. This initial phase of the tumour growth may last for months or years, the malignant cells invading either solely the epidermis (in situ or Clark’s level I) or more frequently the superficial part of the dermis (level II). However, in the radial phase of the tumour, malignant cells in the dermis are found only as small clusters or even as single isolated tumour cells. The prognosis at this stage is still very good. In the latter phase of the tumour growth, malignant melanocytes start invading the deeper part of the dermis (level, III, IV and V).

2.3.3 Lentigo maligna melanoma

Lentigo maligna melanoma is a much less common type of melanoma. It corresponds to a degenerated lentigo maligna. The vertical growth phase is usually composed of spindle-like cells which often invade the reticular dermis surrounded by fibrotic stroma (dermoplastic) or may form fascicles displaying neural features and infiltrate the perineural structures of the skin.

2.3.4 Acral lentiginous melanoma

Acral lentiginous melanoma occurs on the palms of the hands or soles of the feet. In these locations both superficial spreading melanoma and nodular melanoma can be found.

2.3.5 Nodular melanoma

Nodular melanomas represent about one third of the melanomas diagnosed every year in the Caucasian population. Nodular melanoma is a tumour which right from the initial phase, starts its progression vertically, invading the deeper layers of the skin. Usually, few or no intra-epidermal components surrounding the nodule are seen. Polypoid melanoma is a variant of nodular melanoma, histologically characterised by an accumulation of melanoma cells in a large volume above the skin surface. The increase in the tumour volume encourages dislodgement of melanoma cells that are carried to the superficial lymphatic vessels, resulting in a poor prognosis.

2.4 Accuracy and reliability of pathological diagnosis

2.4.1 The pathological report

It is recommended on a type C basis that pathological reports should include the patient’s age, sex, the anatomical location of the melanoma and the size of the resected area. It is also recommended that signs of regression, if any, and mitotic rate are reported. The pathological report of a melanoma, in order to define the patient’s risk and the appropriateness of his follow-up and/or treatment, should always include: histologic type, presence of ulceration, presence of infiltrative lymphocytes, regression, microsatellite lesions, radicality (margins), microstaging (maximum vertical tumour thickness according to Breslow and level of invasion according to Clark).

2.4.2 Histopathologic examination

Histopathologic examination of a suspected melanoma should always be performed by pathologists who have specific experience in melanoma and who are trained to recognise differential diagnoses such as Spitz nevus, pigmented spindle-cell nevus, dysplastic nevus, halo nevus, combined nevus, recurrent nevus and cellular blue nevus. Immuno-histochemical techniques are helpful. Other diagnoses, such as carcinomas, can be excluded by the absence of reaction to certain specific antigens (cytokeratin, vimentin, leucocyte common antigen) and the diagnosis of melanoma can be supported by the positivity of two reactions: HMB45 and S-100 protein, the former being the more specific to melanoma.

2.5 Microstaging (the Clark and Breslow’s microstaging)

2.5.1 The Clark microstaging

The Clark microstaging is based on the depth of infiltration of the melanoma into the skin (Clark 1969a). The various levels of tumour penetration include:

  • level I: in-situ melanoma, not infiltrating through the basal cell layer;
  • level II: infiltration into the papillary dermis;
  • level III: infiltration as far as, but not into the reticular dermis;
  • level IV: infiltration into the reticular dermis;
  • level V: infiltration into the subcutaneous tissue.
2.5.2 The Breslow microstaging

The Breslow microstaging method measures the actual thickness of the tumour using an ocular micrometer (Breslow 1970). The measuring of the Breslow thickness requires a number of precautions to be taken by the surgeon and the pathologist regarding excision, primary handling of the specimen, and excision and cutting of representative sections. Measurement of Breslow thickness is highly accurate: intra- and inter-observer variability are low. Several studies have demonstrated that tumour thickness is a more reliable prognostic parameter than Clark’s microstaging. Recently (Balch 2001a) ulceration has been proved as the most relevant prognostic factor for lesions thicker than 1 mm, while Clark’s levels IV and V are still relevant only for lesions of less than 1 mm.

2.6 Particular histological types

2.6.1 Desmoplastic melanoma

Desmoplastic melanoma is a rare type of melanoma which may be associated with lentigo maligna and is localised to sun-exposed sites, especially the face, where 41% of cases occur. Variants of this tumour include neural-transforming melanoma and neurotropic melanoma. This tumour is notorious for its tendency to infiltrate adventitia of blood vessels and spread by perineural invasion and for its very high rates of local recurrence; approximately 50% (ranging from 25-82%). Therefore a careful examination of the margins of the specimens is mandatory.

2.6.2 Malignant blue nevus

Malignant blue nevus lesions arise mainly on the scalp and may be associated with a pre-existing cellular blue nevus. It is very rare, in fact only 11 well-documented cases have been reported, so metastatic melanoma should always be ruled out.

2.6.3 Mucous membranes, iris and clear cell sarcoma

Melanoma may occur in any anatomical location of the body where melanocytic cells could be present. This explains the possibility, though very rare, of developing such tumours in sites such as the mucous membranes (oral cavity, nasopharynx, anal canal, vagina and urethra), the choroid and the iris in the eye or clear cell sarcoma. These tumours raise specific problems in terms of diagnosis and treatment and they will be the focus of specific chapters.

3. DIAGNOSIS

3.1 Signs and symptoms

The principal sign of a skin lesion proven to be a melanoma is some change over a period of months. A shorter period (days or weeks) is usually more related to inflammatory conditions. The main initially observed changes of an increase in size and colour changes occur in about 70% of patients (Wick 1980). Increase in height, itching and ulceration or bleeding usually occur in more advanced lesions (Milton 1968). When melanomas grow thicker, ulceration can occur and bleeding is an ominous sign. Itching may be a subjective complaint. Around the lesion a reddish discoloration may be seen, while in case of superficial spreading melanoma there sometimes is an unpigmented halo. The ABCDE concept of early recognition, introduced in the sixties, is widely disseminated and is recommended.

A ———–> Lesion asymmetry
B ———–> Border irregularity
C ———–> Colour variegation
D ———–> Diameter > 6 mm
E ———–> Enlargement

Through the application of the ABCDE guidelines, thinner, lower-risk melanomas can be identified. However it must be stressed that these characteristics cannot be taken as a full standard: many subjects have a large number of nevi each of which is ABCD positive. For this reason it is stressed that a nevus with characteristcs different from all the other ones has to be considered suspicious.

3.1.1 Superficial spreading melanoma

Superficial spreading melanoma usually appears as a deeply pigmented area in a junctional naevus. It is generally flat at first and develops an asymmetric irregular surface as it enlarges. Patches of regression resulting in an amelanotic area are frequently seen. Later on it becomes an asymmetrically raised patch with a sculpted edge, irregularly pigmented with colours varying from paleish-blue and pink to a mottled brown-black variegation, sometimes completely black. It may be growing slowly over a number of years.

3.1.2 Nodular melanoma

Nodular melanoma presents as a nodule with sharply demarcated borders on the skin, often shiny with a slightly infiltrated base. The colour, generally darker and more uniform than that of superficial spreading melanoma, may vary from black to unpigmented. These lesions are characterised by a relatively rapid vertical growth phase. Compared to superficial spreading melanoma, nodular melanomas are more common in men, occur more often on the trunk and head and neck region, arise more often de novo, and are biologically more aggressive, particularly those that have a stalk or are polypoid.

3.1.3 Lentigo maligna melanoma

Lentigo maligna melanoma develops in 5% of lentigo maligna lesions (melanosis praecancerosa of Dubreuilh or Hutchinson’s melanotic freckle). This type of lesion is typically located in sun-exposed areas such as the face and forearms in an elderly person. This tumour is estimated to comprise 15% of all the head and neck melanomas. It begins as a tan macule with irregular edges (Clark 1969b). Later on the colour becomes darker, the lesion grows larger and the appearance changes to brown-black variegation. After a horizontal not-invasive growth phase of up to 20 years, vertical growth may develop, clinically presenting as a pigmented nodule: the lentigo maligna melanoma. A recent study estimated a 2.2% lifetime risk of invasive melanoma for lentigo maligna patients whose life expectancy is 11 years, or a 4.7% lifetime risk with a life expectancy of 33 years (Weinstock 1987). Long-term follow-up studies of lentigo maligna patients are as yet lacking.

3.1.4 Acral lentiginous melanoma

Acral lentiginous melanoma can be found on the non-hairy skin of the acra (palm, sole, nailbed). The clinical picture may be variable due to the thick skin at these sites and diagnostic (patients’ and doctors’) delay, which is a common phenomenon in these lesions. Acral lentiginous melanomas occur rarely in whites, but comprise 35% of the melanomas that develop in black races, Hispanics, or Asians.

3.2 Diagnostic strategy

A thorough physical examination must be performed when a patient presents with a lesion arousing suspicions of melanoma. The skin and subcutaneous tissue around the primary lesion and between it and the regional nodal basin have to be examined for satellite and in-transit metastases. The regional nodal basin must be evaluated. The skin of the entire body must be examined for concurrent primary melanomas as they occur in 1% of cases. Physical examination must be performed by an expert physician or dermatologist (Whited 1997). Dermoscopy (epiluminescence microscopy) is a diagnostic technique that can be used to examine in vivo skin lesions with 10- to 20-fold enlargement. This type of instrument employs oil applied to the surface of the lesion (making the dermis more transparent), a glass plate pressed against the oil (to enhance the in vivo evaluation of structures at the dermo-epidermal junction), a light source and magnification. The clinician is able to see structures not discernible to the naked eye. The in vivo diagnostic accuracy of discriminating between benign versus malignant pigmented lesions may be increased with this technique. It has been estimated that epiluminescence increases diagnostic accuracy for smaller, clinically borderline lesions by about 20%. More recently, digital imaging systems with and without epiluminescence have been studied to determine whether, and to what extent, these devices may augment and/or automate diagnosis (Kenet 1993; Rajadhyaksha 1995). Nevertheless, dermoscopy is recommended to be utilised only by experienced physicians. An excisional biopsy is the standard option on a type C basis as it is the appropriate diagnostic procedure for a skin lesion suspected of being a melanoma, provided it is anatomically, functionally, and cosmetically feasible (NIH 1992). Punch biopsy, incisional or shave biopsy, excochleation, whether or not followed by electrocoagulation or cryotherapy, are discouraged. Reliable histology requires examination of the whole lesion. The diagnostic procedure should not be mutilating in the functional or cosmetic sense. Fine needle aspiration for a cytological diagnosis of a primary lesion is unreliable and is not recommended on a type C basis (NIH 1992).

3.3 Pathological diagnosis

3.3.1 Biopsy

An excisional biopsy is the standard option on a type C basis as the appropriate diagnostic procedure for a skin lesion suspected of being a melanoma, provided it is anatomically, functionally, and cosmetically feasible (NIH 1992). Punch biopsy, incisional or shave biopsy, excochleation, whether or not followed by electrocoagulation or cryotherapy, are discouraged. Reliable histology requires examination of the whole lesion. The diagnostic procedure should not be mutilating in the functional or cosmetic sense. Fine needle aspiration for a cytological diagnosis of a primary lesion is unreliable and is not recommended on a type C basis (NIH 1992). Accurate measurement of melanoma thickness, at the moment the most important prognostic parameter, is only possible when the entire lesion is excised. Partial specimens bear the risk of not being representative. Moreover, microstaging may be hampered due to the risk of tangential embedding of the specimen. Apart from Breslow thickness, accurate assessment of other histological features may also be hindered by partial biopsy, such as the histogenetic type of melanoma, the presence or absence of ulceration and the Clark level of invasion. Measurement of the Breslow thickness and the Clark level by frozen section examination is unreliable (Nield 1988) and is not recommended on a type C basis.

3.3.2 Margin for diagnostic excision

As a resection margin for the diagnostic excision, a distance of 2 mm from the border of the lesion and into the subcutaneous tissue is recommended. Undermining of the surgical resection edges should be avoided, because if the excision is not radical, an extra wide re-excision might be necessary. The orientation of the biopsy wound should be planned with the definitive excision in mind. Preference is given to anaesthesia at a distance from the tumour (“field block”). Local anaesthesia directly around the lesion is discouraged.

3.3.3 Incisional diagnostic biopsy

When an excisional biopsy is not feasible, for example when the lesion is very large and/or is so anatomically situated that total excision would be mutilating or disfiguring, especially in the head and neck region, incisional diagnostic biopsy is unavoidable. In these cases a representative biopsy at a peripheral suspicious site of the lesion is advocated. If the lesion proves to be a melanoma, the entire growth can be excised by subsequent radical surgery, which then still allows proper microstaging for prognosis (Nield 1988). The advantages of excisional biopsy are obvious. First only total excision will establish a satisfactory diagnosis in certain instances. Is the lesion a melanoma or not? A variety of naevocytic lesions may pose diagnostic problems, especially if only part of the lesion is taken for histopathological examination. Moreover, many melanomas show histological evidence of a pre-existing naevus. If an incisional biopsy has been erroneously taken from such a pre-existing naevus part, an incorrect diagnosis will be given. Second, only excisional biopsy will enable proper microstaging and prognosis.

4. STAGING

4.1 Staging classification

4.1.1 Staging system

The formerly used staging system for melanoma was a simple classification scheme dividing patients into three categories: stage I for localised disease, stage II for regional metastatic disease and stage III for distant metastases. However, because 80% of newly diagnosed melanoma patients now present with stage I, a new four-stage system of classification to divide patients more evenly has been recommended by the American Joint Committee on Cancer (AJCC), and Union Internationale Contre le Cancer (UICC) (UICC 1997). Such a classification has been recently modified further and it became official with the publication of the 6th edition of the AJCC Cancer Staging Manual in 2002 (Balch 2001a; UICC 2002). New staging includes thickness and ulceration, determine the T-classification, the number of metastatic lymph nodes and the delineation of occult vs. palpable nodal metastases, the N-classification and the site of distant metastases and the presence of elevated serum LDH in the M-classification.

4.1.2 AJCC New staging system (Balch 2001a)*
AJCC New staging system
Primary tumour
T1 Tumour up to 1.0 mm thick A: Without ulceration and Clark’s level II /III
B: With ulceration or Clark’s level IV / V
T2 Tumour 1.01-2.0 mm thick A: Without ulceration
B: With ulceration
T3 Tumour 2.01-4.00 mm thick A: Without ulceration
B: With ulceration
T4 Tumour >4.00 mm thick A: Without ulceration
B: With ulceration
Regional lymph nodes
N1 1 node A: Micrometastasis
B: Macrometastasis
N2 2-3 nodes A: Micrometastasis
B: Macrometastasis
C: In-transit metastases/satellite(s) without
metastatic nodes
N3 4 or more metastatic nodes or matted nodes
or in-transit metastases satellite(s) with metastatic nodes
Distant metastasis
M1a Distant skin, subcutaneous or nodal metastases LDH = Normal
M1b Lung metastases LDH = Normal
M1c Visceral metastases
Any distant metastases
LDH = Elevated
Stages
Clinical Staging Pathologic Staging
0 Tis N0 M0 Tis N0 M0
IA T1a N0 M0 T1a N0 M0
IB T1b N0 M0 T1b N0 M0
T2a N0 M0 T2a N0 M0
IIA T2b N0 M0 T2b N0 M0
T3a N0 M0 T3a N0 M0
IIB T3b N0 M0 T3b N0 M0
T4a N0 M0 T4a N0 M0
IIC T4b N0 M0 T4b N0 M0
III Any T N1 M0
N2
N3
IIIA T1-4a N1-2a M0
IIIB T1-4b N1-2a M0
T1-4a N1-2b M0
T1-4a/b N2c M0
IIIC T1-4b N1-2b M0
T1-4b N2b M0
Any T N3 M0
IV Any T, any N, M1

 

4.1.3 Changes in Melanoma Staging comparing previous (1997) and new (2002) versions
Changes in Melanoma Staging comparing previous (1997) and new (2002) versions
FACTOR OLD SYSTEM NEW SYSTEM COMMENTS
Level of invasion Primary determinant of T staging Used only for defining T1 melanomas Correlation only significant for thin lesions
Thickness Second prognostic factor of T staging, thresholds of 0.75, 1.50, 4.0 mm Primary determinant of T staging; thresholds of 1.0, 2.0, 4.0 mm Correlation of metastatic risk is a continuous variable
Ulceration Not included Included as a second determinant of T and N staging category Signifies a locally advanced lesion; dominant prognostic factor for grouping stage I, II and III
Satellite metastases In T category In N category Merged with in-transit lesions
Thick melanomas, > 4.0 mm In stage IIIA In stage IIC Stage III defined as regional metastasis
Dimensions of nodal metastases Primary determinant of N staging Not used No evidence of significant prognostic correlation
No. Of nodal metastases Not included Primary determinant of N staging Thresholds of 1 v 2-3 v ³ 4 metastatic nodes
Metastatic tumour burden Not included Icluded as second determinant of N staging Clinically occult (microscopic) v clinically apparent (macroscopic) burden of nodal metastases
Lung metastases Merged with all other visceral metastases Separate category as M1b Has a somewhat better prognosis than other visceral metastases
Clinical v Pathologic staging Not accounted for due to lack of sentinel node technology Sentinel node results incorporated into definition of pathologic staging Large variability in outcome between clinical and pathologic staging

 

4.1.4 M.D. Anderson system

To compare results obtained in regional isolated perfusion, use is made of the M.D. Anderson staging system, focusing especially on local-regional recurrent disease.

M.D. Anderson system
IA Primary intact
IB Primary excised
IIA* Local recurrence in contact with scar/skin graft
IIB* Satellites Normal 0 14 false false false MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:”Tabella normale”; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:””; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:”Times New Roman”; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;} = 3 cm from primary/skin graft
IIIA Satellites/in-transit metastases > 3 cm from primary/skin graft
IIIB Regional lymph node metastases
IIIAB Satellites/in-transit metastases with regional lymph node metastases
IV Distant metastasis
* The original M.D. Anderson staging system is adopted according to Klaase (Klaase 1994) by splitting up stage II into stage IIA and IIB.

 

4.2 Staging procedures

4.2.1 Physical examination

A thorough physical examination must be performed when a patient presents with a lesion arousing suspicions of melanoma. The skin and subcutaneous tissue around the primary lesion and between it and the regional nodal basin have to be examined for satellite and in-transit metastases. The regional nodal basin must be evaluated. The skin of the entire body must be examined for concurrent primary melanomas as they occur in 1% of cases.

4.2.2 Radiographic and/or laboratory studies

In superficial lesions, radiographic and/or laboratory studies are not needed, although chest radiography, liver ultrasound and serum lactodehydrogenase are frequently obtained. Preoperative CT, MRI or PET scans to screen for lymph node or distant metastases have a low yield and are not recommended. Ultrasound of the regional lymphnodes is the simplest and more cost-effective approach. Fine needle aspiration for a cytological diagnosis under ultrasound guidance of lymph nodes is standard procedure. As a diagnostic strategy, radio-immunoscanning is not recommended.

4.2.3 Pathological staging (microstaging)

Pathological staging is important to determine prognosis and treatment. Two methods of microstaging are used world-wide. The Clark microstaging (Clark 1969a) is based on the depth of infiltration of the melanoma into the skin. The various levels of tumour penetration include:
level I, in-situ melanoma, not infiltrating through the basal cell layer;
level II, infiltration into the papillary dermis;
level III, infiltration as far as, but not into the reticular dermis;
level IV, infiltration into the reticular dermis;
level V, infiltration into the subcutaneous tissue.
The Breslow microstaging (Breslow 1970) method measures the actual thickness of the tumour using an ocular micrometer. Measurement of the Breslow thickness requires a number of precautions to be taken by the surgeon and the pathologist regarding excision, primarily handling of the specimen, and excision and cutting of representative sections.

4.2.4 Sentinel node biopsy

An important development in the last decade regarding the clinical detection and early treatment of occult lymph node involvement is the intra-operative biopsy of the sentinel node, the nearest draining lymph node to the primary melanoma. These lymph nodes can be identified by preoperative lymphoscintigraphy and intraoperative tracing using a coloured dye and a hand held gamma-detection probe. The radiopharmaceutical and the dye are injected intradermally around the excisional biopsy wound of the primary melanoma. Micrometastases in the sentinel nodes are discovered in about 20% of cases, when this sentinel node biopsy is performed in melanomas thicker than 1 mm. Formal lymph node dissection should follow. In experienced hands a high accuracy rate can be achieved by this lymphatic mapping and sentinel node biopsy, but this approach is still considered investigational since the biological significance of involved sentinel nodes is unknown. Although the group of patients with positive sentinel node is not homogeneous (Cascinelli 2002). Sentinel node biopsy has become a wide spread procedure and it is recommended on a type C basis since it holds significance in assigning patients to a better defined risk group (Balch 2001b). A randomised study to determine whether lymphatic mapping and sentinel node biopsy improves regional tumour control and survival is in progress. Sentinel lymph node status has emerged as the most important prognostic factor in clinical stage I and II patients and is a useful selection criterion for entry of patients to randomized trials on adjuvant treatments (Edwards 1998; Jansen 2000; Morton 1992; Morton 1999; Nieweg 1997; Testori 1999).
In a study conducted on 472 patients, at mean follow-up of 42 months, multivariate analysis showed that sentinel node status was independent of tumour thickness and ulceration, and it is a highly significant predictor of prognosis in melanoma (Kettlewell 2006). A study carried out on 1108 stage IB, II patients submitted to sentinel node biopsy with a mean follow up period of 60 months has shown that the prognosis of these patients can be defined not only by the status of sentinel node(s): the status of non sentinel nodes was of paramount importance. Four groups of patients were identified: a) sentinel node negative patients who never developed regional node metastases (5 year survival rate 92.6%), b) sentinel node positive patients with non sentinel nodes negative (5 y. Survival 82.0%), c) sentinel positive node and secondary deposits in non sentinel node at complete node dissection (5 y. Survival 41.7%), d) patients with negative sentinel node who developed clinically detectable node metastasis in the same basin (5y. Survival 61.7%). These differences in survival were statistically significant. The Author concluded that sentinel node biopsy is a two step procedure that allows to identify patients to be submitted to complete node dissection this procdure is essential to define the prognosis of these patients (Cascinelli 2006). A study conducted on 1269 patientients with intermediate-thickness (1.2 to 3.5 mm) primary melanomas randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy showed no difference in overall survival in the two groups, but, among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3±4.6% vs. 52.4±5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P = 0.004) (Morton 2006). A randomized study to determine whether lymphoadenectomy following positive sentinel node biopsy is necessary to improve regional tumour control and survival is in progress. A meta-analysis of 22 studies enrolling 4,019 patients who underwent SLN biopsy for clinical stage I to II cutaneous melanoma corretating polymerase chain reaction (PCR) –based detection of melanoma cells in sentinel lymph nodes (SLN) of patients with TNM stage, disease recurrence rates, and survival suggested that PCR status correlated with both TNM stage (stage I to II v III; PCR positivity, 95.1% v 46.6%; P < .0001) and disease recurrence (PCR positive v negative; relapse rate, 16.8% v 8.7%; P < .0001). PCR positivity was also associated with worse overall (hazard ratio [HR], 5.08; 95% CI, 1.83 to 14.08; P < .002) and disease-free (HR, 3.41; 95% CI, 1.86 to 6.24; P < .0001) survival (Mocellin 2007). Although statistical heterogeneity was significant, the findings strongly support additional investigation in this field.

5. PROGNOSIS

5.1 General considerations

5.1.0 Gender

Male gender is associated with a greater incidence of unfavorable primary tumor characteristics without an increased risk for nodal metastasis. Nonetheless, gender is an independent factor.

5.1.1 Natural history

The clinical course of melanoma is determined by its dissemination and depends on type, thickness, localisation, growth rate and histology of the primary tumour. Locally melanoma grows wider in diameter and especially thicker resulting in ulcerating lesions. The pattern of dissemination is unpredictable with periods of rapid growth, while spontaneous regression may also occur. Local regional dissemination takes place in the form of satellites and in-transit metastases and metastases to lymph nodes.

5.1.2 Satellites and in-transit metastases

Satellites and in-transit metastases are typical of melanoma and develop between the site of the primary tumour and regional lymph nodes in the lymphatics of skin and subcutaneous tissue. They may become very numerous and sometimes remain confined to the region for a long time. Within 3 cm from the primary tumour they are called satellites. Satellites and in-transit metastases are seen in about 2 and 3% of patients respectively and are rarely less than 2 mm thick. They can be responsible for the tendency of thicker melanomas to show local recurrence. Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity and gruoped into stage III disease in the 6th edition of the AJCC Cancer Staging Manual in 2002 (Balch 2001a; UICC 2002).

5.1.3 Lymph node metastasis

Lymph node metastasis occurs in about 20% of melanoma patients and frequently precedes haematogenic metastasis. In 5% of cases overt metastatic nodes are present at the time of initial diagnosis. Lymph node metastases are mostly confined within the glandular capsule. Growth through the capsule and particularly spread in lymphatics are unfavourable prognostic features.

5.1.4 Distant metastasis

Haematogenic dissemination of metastases occurs, unlike the usual pattern seen with epithelial tumours (liver and lung), relatively frequently in brain, intestinal tract and nonregional cutaneous and subcutaneous areas. Systemic dissemination of tumour occurs in 20% of patients at some time during the course of the disease. Cerebral metastasis and liver metastasis are a frequent cause of death. Metastasis without a known primary site (usually in lymph nodes) is encountered in 2.6- 5% of melanoma patients (Jonk 1990; Katz 2005).

5.2 Prognostic factors

5.2.1 Clinical prognostic factors

To validate the new AJCC staging system the survival data of 17600 melanoma patients were collected and analyzed (Balch 2001b). Stage of disease at diagnosis is still the most important prognostic factor; the 10-year overall survival is 71% for patients with AJCC stages I and II disease and between 20-30% for stage III disease (Balch 1992b). Other prognostic factors for primary melanoma include ulceration, tumour thickness, level of invasion, primary site (extremity melanomas responding better than axial lesions) and sex (females faring better than males). For lesions thinner than 1 mm, the level of invasion seems to be more predictive of survival than ulceration, whereas ulceration is clearly the most predictive additive parameter for lesions thicker than 1.0 mm (Balch 2001b). In a large series (Balch 1992c) of stages I and II disease the most important prognostic factors were ulceration, tumour thickness, age, primary site, level of invasion and sex. Among these prognostic factors ulceration, tumour thickness, and age, are also claimed to be valid for stage III disease, however the number of metastatic nodes and the tumor burden are the most dominant predictors of survival (Balch 1992c; Balch 2004).

5.2.2 Histological prognostic factors

At present it is generally accepted that the maximal tumour thickness according to Breslow is the best predictor of prognosis. Several studies have demonstrated that tumour thickness is a more reliable prognostic parameter than Clark’s microstaging. There is an almost linear correlation between maximal tumour thickness and survival. The second histological predictor of prognosis is the depth of infiltration of the tumour (Clark microstaging). Clark levels I and II are associated with an excellent prognosis, Clark level V (infiltration down into the subcutaneous fat) with a poor prognosis. In the intermediate group, level IIIs and IV, there is considerable variation, making Breslow thickness a superior diagnostic parameter. Recently (Balch 2001a) ulceration has been proved as the most relevant prognostic factor for lesions thicker than 1 mm, while Clark’s levels IV and V are still relevant only for lesions of less than 1 mm. Also histological type has been reported to have some prognostic influence, LMM having the best prognosis and nodular melanoma the worst. Particular histological types as desmoplastic melanoma and polypoid melanoma are reported below. Other histological prognostic criteria are the number of mitoses, lymphatic infiltration (TIL cells), vascular invasion, the presence of micrometastasis and amelanosis.

5.3 Prognosis of operable disease

5.3.1 Life expectancy

After proper surgical treatment of stage I and II melanoma the 5-year life expectancy in Western Europe is presently above 80%, due to the awareness of the public of the implications of changes in moles, resulting in early diagnosis. Ten year-survival is in the range of 82-90% for melanomas not thicker than 1 mm, 85-65% for those between 1 and 2 mm, 73-60% for those between 2 and 4 mm, and 60-40 % for those thicker than 4 mm, depending on the presence or absence of ulceration (Balch 2001b; Balch 2004). Local recurrences, satellites and in-transit metastases reduce the 5 year-survival for melanoma to about 54-52% and lymph node metastases to about 67-24%, depending on the degree of nodal involvement (microscopically or macroscopically), the presence or absence of ulceration in the primary lesion and the concomitant occurrence of satellite or in-transit metastases and number of affected nodes (Cascinelli 1984; Coit 1991; Day 1981; Jonk 1990; Balch 2004).

5.4 Prognosis of particular histological types

5.4.1 Desmoplastic melanoma

Desmoplastic melanoma is a rare type of melanoma which may be associated with lentigo maligna and is localised to sun-exposed sites, especially the face, where 41% of cases occur. Variants of this tumour include neural-transforming melanoma and neurotropic melanoma. This tumour is notorious for its tendency to spread by perineural invasion and for its very high rates of local recurrence, approximately 50% (ranging from 25-82%). Extensive excision with a 2 to 3 cm margin, when feasible, is therefore recommended on a type C basis, followed by meticulous microscopic examination of the specimen margins for any evidence of perineural or perivascular invasion. A close follow-up policy should be adopted. The frightening aspect of these tumours is that, if present on the face, infiltration along nerves into the central nervous system may occur. Partial removal of bone in these cases may therefore also be necessary (Bruijn 1992).

5.4.2 Polypoid melanoma

Polypoid melanoma is a variant of nodular melanoma, histologically characterised by an accumulation of melanoma cells in a large volume above the skin surface. The increase in the tumour volume encourages dislodgement of melanoma cells that are carried to superficial lymphatic vessels, resulting in a poor prognosis (Plotnick 1990).

5.5 Pregnancy, oral contraceptives, oestrogen replacement therapy and prognosis

According to the results of several large case comparative studies pregnancy does not alter the prognosis for women with melanoma (O’Meara 2005) whether the woman is pregnant at the time of diagnosis or becomes so after apparently successful treatment (MacKie 1999). Nevertheless some of those reports have also shown that median thickness of melanomas diagnosed in pregnancy is higher than those found in non-pregnant women matched for site of melanoma. An explanation of this observation is the belief that melanocytic nevi enlarge or new nevi appear during pregnancy leading to a misdiagnosis of early melanoma. Although there are no large studies of this hypothesis, Pennoyer et al (Pennoyer 1997) described only 6.2% change among nevi distribution and size in a small population of pregnant women. It is recommended on a type C basis that the advice to women who wish to embark on pregnancy after treatment for primary melanoma be based on the well-known prognostic criteria, among which thickness and stage of disease are the most important (MacKie 1991; O’Meara 2005). The influence of oral contraceptives, even for prolonged duration, on the incidence and outcome of melanoma appears, at present, to be minimal or absent (Slingluff 1993a). The same holds true for oestrogen replacement therapy (Armstrong 1992).

5.6 Locally advanced and metastatic disease

5.6.1 Locally advanced disease

Five-year survival after regional lymph node metastasis (locally advanced disease) is 20-50% (Balch 1992b). Most patients with metastatic disease confined to skin, subcutis and lymph nodes will survive for 12 months (Balch 2001b).

5.6.2 Metastatic disease

Survival from the time of distant metastases in melanoma is usually limited: patients with visceral involvement or an elevated concentration of LDH in serum have a median survival of 4-6 months (Balch 2001b). Two-year survival after distant visceral metastasis is about 1 to 2% only. The best survivals after haematogenic metastasis are usually achieved in the case of lymph nodes, subcutaneous or intradermal and lung metastases. However, the most significant differences are between visceral and non-visceral metastases (Balch 2001b). The survival of patients with cerebral and/or liver metastasis rarely exceeds 6 to 8 months. The availability of active chemo-immunotherapeutic or polychemotherapeutic regimens may have improved, although to a very limited extent, such a prognosis. Adopting some aggressive options, including the surgical removal of lung, (sub-)cutaneous, lymph node or cerebral metastasis, total brain irradiation, “gamma knife” radiotherapy, polychemotherapy and chemo-immunotherapy, may lead to the possibility of a small but significant number of long-term survivors. The factors, influencing treatment response and therefore determining the legitimacy of such attitudes, are usually based on the performance status of the patients and the tumour burden as defined by the number of metastatic sites, the number and the size of metastases and the speed of the tumour growth (Presant 1982).

6. TREATMENT

6.1 Treatment strategy at clinical diagnosis

6.1.1 General statements

Surgery is the standard option on a type C basis for localised primary melanoma. Margins of resection must be wider according to the depth of the lesion up to a maximum of 2 cm for lesions deeper than 2 mm. Lesions not thicker than 2 mm can be excised with a margin of 1 cm. The trend towards narrower excision margins does not apply to desmoplastic melanoma, a tumour generally located on the face and notorious for its tendency to recur locally. Lentigo maligna melanoma also needs different treatment tailoring because of the frequently large dimensions of the surrounding pre-invasive lentigo maligna component. The standard treatment on a type R basis is to excise the invasive part of this growth with margins according to its thickness, thereby ensuring that, if possible, the non-invasive lentigo maligna component is totally removed. These neoplasms can be well controlled by irradiation with soft X-ray or 30-250 key orthovoltage using high dose per fraction (Farshad 2002). Nevertheless, the use of radiotherapy must be considered investigational. For patients clinically node negative, elective node dissection (ELND) is still controversial and it is not recommended on a type 1 level of evidence (Balch 2000; Balch 1988). Sentinel node biopsy is a promising experimental approach that is possibly the solution to this controversy (Balch 1999a; Cascinelli 1998). There is no evidence of any benefit from adjuvant chemotherapy. Adjuvant Alpha Interferon (IFN-a) has given controversial results depending on the stage of disease, the dose and the subset of patients. Its use must be considered inappropriate on a type 1 level of evidence for patients with stage II melanoma (Creagan 1995; Grob 1998; Kirkwood 1996; Pehamberger 1998) and suitable for individual clinical use on a type 2 level of evidence only in stage III disease. The only benefit was seen from high dose IFN-a (20 MU/m2 iv daily x 5 of 7 days for 4 weeks followed by 10 MU/m2 three times a week for 48 weeks) in a subset of selected patients, but at the expense of significant toxicity, even if there are recent reports on survival advantages from high-dose IFN-a (Kirkwood 2000; Kirkwood 2001; Kirkwood 1996; Ravaud 1999). On the other hand systematic review of the adjuvant IFN trials (Lens and Dawes) and a metanalysis of all adjuvant IFN trials demonstrated a consistent impact on DFS but now significant impact on survival and failed to show a dose-effect (Wheatlet 2003). The analysis of the pooled data of the high dose IFN trials also showed a consistent impactg on DFS, but again no significant impact on overall survival (Kirkwood 2004). Sentinel node biopsy is an important selection criterion for the entry of patients to adjuvant trials. Only stage III patients, including those “upstaged” from stage I and II patients by positive sentinel node biopsy, should be eligible. Systemic chemotherapy is the treatment of choice for metastatic non-operable disease on a type R basis, but there is no regimen that could be claimed as standard. Radiation therapy (RT) is effective in the palliative treatment of brain and bone lesions as well as nodal metastases and spinal cord compression (Cooper 1998; Ewend 1996; Geara 1996; Perchel 1994; Sause 1991). The role of RT as adjuvant treatment after therapeutic lymph node dissection, and after surgical excision of brain metastases is considered suitable for individual clinical use in selected patients on a type 3 level of evidence (Ang 1994; Cooper 1998; Creagan 1978; Elsmann 1991; Ewend 1996; Geara 1996; Hansson 1993; Storper 1993; Ballo 2003).

6.2 In situ or non invasive melanoma

6.2.1 Treatment strategy

For in situ or non invasive melanoma, therapeutic excision with a margin of 0.5 cm is the standard treatment on a type C basis, because these tumours, notwithstanding their inability to metastasise, may recur locally due to horizontal growth.

6.2.2 Therapeutic excision

Excision down to the fascia is usually performed perpendicular to the surface (Kenady 1982). It is standard treatment on a type C basis to leave the fascia intact. Primary closure of the defect is standard treatment on a type C basis. Therapeutic excisions, like diagnostic ones, can be done on an outpatient basis.

6.3 Stage I (AJCC) disease (IA: pT1a, N0, M0; IB: pT1b, T2a, N0, M0)

6.3.1 Treatment strategy

Surgery is the standard option on a type C basis for localised primary melanoma. For clinically node-negative patients, elective node dissection (ELND) is still controversial but it is not recommended on a type 1 level of evidence (Balch 2000; Balch 1988). Sentinel node biopsy is a promising experimental approach, that will possibly provide the solution to this controversy (Balch 1999a; Cascinelli 1998).

6.3.2 Therapeutic excision of primary melanoma

There is a continuing trend towards narrower excision margins in primary melanoma. Based on recently published results of prospective randomised trials, a 1 cm excision margin now is the standard treatment on a type 1 level of evidence for melanomas not thicker than 2 mm (Veronesi 1988). The trend towards narrower excision margins does not apply to desmoplastic melanoma, a tumour generally located on the face and notorious for its tendency to recur locally. Lentigo maligna melanoma also needs different treatment tailoring because of the frequently large dimensions of the surrounding pre-invasive lentigo maligna component. The standard treatment on a type R basis is to excise the invasive part of this growth with margins according to its thickness, thereby ensuring that, if possible, the non-invasive lentigo maligna component is totally removed. These neoplasms can be well controlled by irradiation with soft X-ray or 30-250 key orthovoltage using high dose per fraction but the use of radiotherapy must be considered investigational and applicable only on rare occasions such when the patient is medically inoperable or refuses surgery (Cooper 1998). Nevertheless, the use of radiotherapy must be considered investigational. To perform therapeutic excision the skin must be cut, according to the Breslow thickness, 1 or 2 cm from the visible margin of the primary melanoma or the wound of the excisional biopsy. Excision down to the fascia is usually performed perpendicular to the surface. It is standard treatment on a type C basis to leave the fascia intact (Kenady 1982), except when there is only a thin subcutaneous fat layer, especially in the case of a thick melanoma or when it is necessary not to “re-open” the previous excision scar (for instance when the biopsy proved not to be radical). If possible, primary closure of the defect is standard treatment on a type C basis. Undermining of the skin edges is a tempting possibility to facilitate this and is permitted, since the supposition that this jeopardises oncological principles is exaggerated. In the rare instances that primary closure is not possible the wound can be closed by a local skin flap, or by skin grafting. A donor site away from the region involved is generally preferred in order to make the skin graft. The therapeutic excision, like the diagnostic one, can usually be done on an outpatient basis. Hospitalisation is needed when it is anticipated that the defect will need closing by a skin graft or by an extensive local skin flap. Particular sites such as head and neck, fingers and toes as well as mucosal melanoma may require different treatment tailoring.

6.3.3 Elective lymph node dissection

Elective regional lymph node dissection is the removal of a lymph node area, in the absence of clinically suspect nodes, in the lymphatic drainage region of a tumour. The place of elective lymph node dissection in patients with melanomas between 1 and 4 mm thick has been controversial for many years, but recent evidence points in the direction that in this subgroup the side effects of the procedure outweigh possible survival benefit. According to a retrospective study of 4682 patients at Breslow depths of less than 0.76 mm and between 0.76 to 1.5 mm, the regional nodes and the nodal basin were positive in 0%, and 5% of cases respectively (Slingluff 1994). No significant advantage in survival has been reported from prospective randomised trials (Balch 2000; Lens 2002; Sim 1986; Veronesi 1982) and the outcome of retrospective studies is contradictory. In one prospective study, however, advantage of ELND has been claimed for non-ulcerating limb melanomas with a thickness between 1 to 2 mm (Balch 2000). Because subgroup analysis, in principle, is considered to be statistically invalid, the treatment option on a type 2 level of evidence is not to perform elective lymph node dissection. If the wait-and-see option is decided upon, careful follow-up is recommended on a type R basis (Berwick 1996) to detect any nodal metastatic spread at the earliest possible stage. This has to be stressed the more since metastases of melanoma sometimes have an explosive growth. Besides regular follow-up visits, the patient therefore should be instructed to check the regional lymph node station personally, for example once a month.

6.3.4 The sentinel node biopsy

An important development in the last decade in the clinical detection and early treatment of occult lymph node involvement is the investigational method of intra-operative biopsy of the sentinel node, the nearest draining lymph node to the primary melanoma (Morton 1992). These lymph nodes can be identified by preoperative lymphoscintigraphy and intraoperative tracing using dye and a hand-held gamma-detection probe (Jansen 2000). The radiopharmaceutical and the dye are injected intradermally around the excisional biopsy wound of the primary melanoma. Micrometastases in the sentinel nodes are discovered in about 20% of cases, when this sentinel node biopsy is performed in melanomas thicker than 1 mm. Formal lymph node dissection should follow. In experienced hands a high accuracy rate can be achieved by this lymphatic mapping and sentinel node biopsy, but this approach is still considered investigational, since the biological significance of involved sentinel nodes is unknown. A randomised study to determine whether lymphatic mapping and sentinel node biopsy improves regional tumour control and survival showed that the procedure improves relapse-free survival, but not overall survival (Morton 2006). Sentinel lymph node status has emerged as the most important prognostic factor in clinical stage I and II patients, and is an important selection criterion for the entry of patients to adjuvant trials (Balch 1999a; Edwards 1998; Jansen 2000; Morton 1992; Morton 1999; Nieweg 1997; Testori 1999; Kettlewell 2006).

6.3.5 Postsurgical adjuvant treatment

There is no evidence of a role for systemic chemotherapy, immunotherapy or radiotherapy in the adjuvant setting for stage I melanoma (Nathan 1995). This kind of approach is not recommended. Clinical stage I patients, who are “upstaged” by sentinel node biopsy to stage III, are elegible for entry to adjuvant trials testing the value of IFN, vaccines etc.. The role of radiation therapy after lymph node dissection is currently undergoing reappraisal. Post-operative irradiation can be administered as suitable for individual clinical use on a type R basis in order to maximise local control when micro- or macroscopic residual disease is left in situ and a reintervention is not feasible for medical reasons, for unacceptable morbidity, or for cosmetic limitations (Bastiaannet 2005).

6.4 Stage II (AJCC) disease (IIA: pT2b, T3a, N0, M0; IIB: pT3b, T4a, N0, M0; IIC: T4b, N0, M0)

6.4.1 Treatment strategy

Surgery is the standard option on a type C basis for localised primary melanoma. For melanomas 2 to 4 mm thick, a 2 cm resection margin is the standard treatment on a type 1 level of evidence (Balch 1993). For excision margins in desmoplastic melanoma and lentigo maligna melanoma see sections 5.4.1 and 6.3.2. For patients clinically node negative, elective node dissection (ELND) is still controversial but it is not recommended on a type 1 level of evidence (Balch 2000; Balch 1988). Sentinel node biopsy is a promising experimental approach, that will possibly provide the solution to this controversy. There is no clear evidence of any benefit from adjuvant chemotherapy or postoperative lymphatic basin irradiation. The latter has some evidence of benefit in head and neck or to improve loco-regional control (Bastiaannet 2005) and it is considered suitable for individual clinical use on a type R basis. Adjuvant IFN-a has been proven as effective in increasing the disease free interval and improving survival in patients with stage IIC disease in only two randomized study (Kirkwood 1996; Kirkwood 2001), despite an advantage for disease free survival being reported by four other randomised studies (Creagan 1995; Grob 1998; Kirkwood 1996; Pehamberger 1998). The effectiveness of IFN-as reported in the ECOG 1964 study with high dose treatment, however, was not reproduced in the subsequent Intergroup study (Kirkwood 2000). In stage II melanoma adjuvant treatment with IFN-a, therefore, must be considered inappropriate on a type 1 level of evidence. Clinical stage II patients, who are “upstaged” by sentinel node biopsy to stage III, are eligible for entry to adjuvant trials testing the value of IFN, vaccines etc.

6.4.2 Therapeutic excision of primary melanoma

For melanomas 2 to 4 mm thick, a 2 cm excision margin is the standard treatment on a type 1 level of evidence (Balch 1993). There is no information from randomised trials concerning patients with melanomas thicker than 4 mm. However, since it is likely that haematogenic micrometastases already exist in the majority of these patients, the width of the local resection margin is less relevant. Excision with a 2 cm margin may therefore prove to be an adequate procedure in these patients as well. This assumption has recently been substantiated through a retrospective study (Heaton 1998). For excision margins in desmoplastic melanoma and lentigo maligna melanoma see sections 5.4.1 and 6.3.2. Particular sites as head and neck, fingers and toes as well as mucosal melanoma may require different treatment tailoring. In order to perform a therapeutic excision the skin must be cut, according to the Breslow thickness, 1 or 2 cm from the visible margin of the primary melanoma or the wound of the excisional biopsy. (see also section 6.3.2 for more details).

6.4.3 Elective lymph node dissection

Elective regional lymph node dissection is the removal of a lymph node area in the lymphatic drainage region of a tumour in the absence of clinically suspect nodes. The place of elective lymph node dissection in patients with melanomas between 1 and 4 mm thick has been controversial for many years, but recent evidence points in the direction that in this subgroup the side effects of the procedure outweigh possible survival benefit. At Breslow depths of 1.5 to 2.5 mm, 2.5 to 4.0 mm, and greater than 4 mm, the regional nodal basin was positive in, 16%, 24%, and 36% of cases, respectively (Slingluff 1994). No significant advantage in survival has been reported from prospective randomised trials (Lens 2002; Sim 1986; Veronesi 1982) and the outcome of retrospective studies is contradictory. In one prospective study, however, an advantage of ELND has been claimed for patients with 1 to 2 mm non-ulcerating disease, when it is localised on limbs (Balch 2000). In another trial, conducted by the WHO in patients with melanoma of the trunk, a survival benefit was shown for patients whose involved lymph nodes were removed electively compared with those who underwent delayed lymph node dissection (Cascinelli 1998). Because subgroup analysis, in principle, is considered to be statistically invalid, the treatment option is not to perform elective lymph node dissection on a type 2 level of evidence. If the wait-and-see option is decided upon, careful follow-up is recommended on a type R basis (Berwick 1996) to detect any nodal metastatic spread at the earliest possible stage. This has to be stressed the more since metastases of melanoma sometimes have an explosive growth. Besides regular follow-up visits, the patient therefore should be instructed to check the regional lymph node station personally, for example once a month.

6.4.4 The sentinel node biopsy

An important development in the last decade in the clinical detection and early treatment of occult lymph node involvement is the investigational method of intra-operative biopsy of the sentinel node, the nearest draining lymph node to the primary melanoma (Morton 1992). A randomised study to determine whether lymphatic mapping and sentinel node biopsy improves regional tumour control and survival showed that the procedure improves relapse-free survival, but not overall survival (Morton 2006). Sentinel lymph node status has emerged as the most important prognostic factor in clinical stage II patients (Balch 1999a; Edwards 1998; Jansen 2000; Morton 1992; Morton 1999; Nieweg 1997; Testori 1999; Kettlewell 2006), and is an important selection criterion for the entry of patients to adjuvant trials. Micrometastases in the sentinel nodes are discovered in about 20% of cases when this sentinel node biopsy is performed in melanomas thicker than 1 mm. Formal lymph node dissection should follow. In experienced hands a high accuracy rate can be achieved by this lymphatic mapping and sentinel node biopsy, but this approach is still considered investigational, since the biological significance of involved sentinel nodes is unknown. Particularly for stage IIC patients an accurate staging with CT of the chest and abdomen is recommended on a type R basis to rule out distant metastases before proceeding to the sentinel node biopsy.

6.4.5 Prophylactic isolated limb perfusion

Adjuvant regional perfusion in primary melanoma is of no benefit. Results of the large EORTC/WHO trial on this subject are negative with regard to overall survival, despite a reduction of local recurrence in the treated limbs (Koops 1998).

6.4.6 Post-surgical adjuvant treatment

There is no evidence for a role of chemotherapy in the adjuvant setting for stage II melanoma. The role of alpha-Interferon (IFN-a) has been investigated in few randomised trials. Among them the only study reporting a survival advantage was the ECOG 1964 study of high dose a-2b IFN (Kirkwood 1996); these results were not reproduced in the subsequent Intergroup study comparing high vs low dose IFN vs observation (Kirkwood 2000). Furthermore about 50% of patients experienced toxicities with high dose IFN and this schedule is more expensive (Kirkwood 1996; Ravaud 1999). Adjuvant IFN-a has been proven as effective in increasing the disease free interval and improving survival in patients with stage IIC disease in only two randomized study (Kirkwood 1996; Kirkwood 2001), despite an advantage for disease free survival being reported by four other randomised studies (Creagan 1995; Grob 1998; Kirkwood 2000; Pehamberger 1998). The effectiveness of IFN-as reported in the ECOG 1964 study with high dose treatment, however, was not reproduced in the subsequent Intergroup study (Kirkwood 2000). In stage II melanoma adjuvant treatment with IFN-a, therefore, must be considered inappropriate on a type 1 level of evidence. In stage IIC patients there is no evidence of a role of low-dose IFN in the adjuvant setting on a type 1 level of evidence, while high-dose IFN must be considered as suitable for individual clinical use on a type 2 level of evidence. Clinical stage II patients, who are “upstaged” by sentinel node biopsy to stage III, are eligible for entry to adjuvant trials testing the value of IFN, vaccines etc. A recent review of all randomized studies on adjuvant IFN-a either at low dose or intermediate or high dose concluded that according to the trials with mature data on DFS and OS there is no benefit for low-dose IFN-a and a possible advantage on DFS from high dose IFN-a but with relevant toxicity (Punt 2001). A pooled analysis of trials at median follow up times of 2.1-12.6 years showed significant improvement in relapse-free survival for patients treated with high-dose a-IFN of about 10% at 5 years, but no clear benefit in terms of overall survival, compared with patients randomly allocated to observation or vaccine therapy (Kirkwood 2004). The toxicity of a-IFN is high (Kirkwood 2002), and in view of the absence of evidencefor an overall survival benefit, it cannot be regarded as standard adjuvant therapy. Adjuvant regional perfusion in primary melanoma is of no benefit. Results of the large EORTC/WHO trial on this subject are negative with regard to overall survival, despite a reduction of local recurrence in the treated limbs (Koops 1998).
Clinical or serological autoimmunity developed during high-dose inteferon treatment seems to be correlated with a better survival rate, but, since it can occurr even after 1 year of treatment, it is a useless tool to select patients whom might benefit from the treatment (Gogas 2006). The prognostic value of the presence or emergence of autoimmune antibodies could not be confirmed as an independent prognostic factor in the EORTC 18952 trial evaluating intermediate doses of IFN vs observation in stage IIB-III melanoma (Eggermont 2005), nor in the EORTC 18991 trial evaluating adjuvant long term therapy with Pegylated IFNa2b (Eggermont 2008) as demonstrated by studies reported by Bouwhuis and coworkers at the ASCO and ECCO meetings in 2007 respectively (Bouwhuis 2007a; Bouwhuis 2007b).

6.4.7 Irradiation

Irradiation of deep primary lesions after surgery is considered investigational or suitable for individual clinical use on a type R basis (Cooper 1998; Geara 1996; Storper 1993). The role of radiation therapy after surgical procedures is currently undergoing reappraisal. Post-operative irradiation can be administered in order to maximise local control in the following clinical situations:
a) when micro – or macroscopic residual disease is left in situ and a reintervention is not feasible for medical reasons, for unacceptable morbidity, or for cosmetic limitations (Garbe 2008);
b) in head and neck lesions where there is a high risk of recurrence because of the depth of invasion, it is appropriate to treat the surgical bed and/or regional lymph-node areas (Ang 1994);
c) features associated with a high risk of primary tumor recurrence including desmoplastic subtype, positive microscopic margins, recurrent disease, and thick primary lesions with ulceration or satellitosis (Ballo 2004a).
For head and neck cases, where melanoma can be considered a separate entity with a different biological behaviour, elective, postoperative and adjuvant radiation may be employed (Cooper 1998; Geara 1996; Storper 1993). Elective irradiation is a viable alternative to elective lymph-node dissection and it may also serve as an alternative to sentinel node biopsy (Bonnen 2004). Radiotherapy can be considered suitable for individual clinical use on a type 3 level of evidence. Different hypofractionated schedules such as 3 Gy x 18, 4.5 Gy x 10, 6 Gy x 5, 7-8 Gy x 3 (0-7-21 scheme) can be appropriate, depending on the extent of disease, site of lesions, and the risk of late side effects.

6.5 Stage III (AJCC) disease (any T, N1-3, M0)

6.5.1 Treatment strategy

Surgery is the standard option on a type C basis for advanced primary melanoma. Margins of resection must be wider, according to the depth of the lesion, up to a maximum of 2 cm for lesions deeper than 2 mm (see sections 6.3.1 and 6.4.1). Therapeutic lymph node dissection is the standard treatment on a type C basis; solitary lymph node removal is inappropriate. There is no evidence for a role of chemotherapy in the adjuvant setting for stage III melanoma (Nathan 1995). The role of Interferon alpha (IFN-a) has been investigated in few randomised trials (Cascinelli 2001; Nathanson 1996) and the only proven benefit was obtained from high dose IFN-a (20 MU/m2 iv daily x 5 of 7 days for 4 weeks followed by 10 MU/m2 three times a week for 48 weeks) in a subset of selected patients, but at the expense of significant toxicity (Kirkwood 2000; Kirkwood 2001; Kirkwood 1996). A recent review of all randomized studies on adjuvant IFN-a either at low dose or intermediate or high dose concluded that according to the trials with mature data on DFS and OS there is no benefit for low-dose IFN-a and a possible advantage on DFS from high dose IFN-a but with relevant toxicity (Punt 2001). Even the reported survival advantage from ECOG 1694 is apparently weakening with longer follow-up (data unpublished). Therefore, in patient with stage III disease there no evidence for a role of low dose Interferon in the adjuvant setting on a type 1 level of evidence while HDIFN must be considered as suitable for individual clinical use on a type 2 level of evidence.
A total of 444 stage III melanoma patients from 42 centers of the German Dermatologic Cooperative Oncology Group, who had received a complete lymph node dissection, were randomized to receive either 3 MU s.c. of IFNa2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNa2a plus DTIC 850 mg/m2 every 4–8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC to adiuvant interferon resulted detrimental (Garbe 2008). The result claims the benefit of a treatment with low dose interferon for 2 years in stage III melanoma patients over observation, but does not tell us how these results compare with high-dose interferon. Studies comparing the e.v. induction phase of high dose IFN with the high-dose IFN for one year are in progress in Greece, Germany and Italy, but they all lack a control arm, therefore their results are unlikely to be definitive. The toxicity of the repeated induction regimen compared to the classical Kirkwood regimen has been published by the iatalian group and found to be comparable (Chiarion-Sileni 2006).
Gogas and collegues reported on the Hellenic Melanoma group trial at ASCO 2007, demonstrating that one month of induction phase of high dose IFN was just as good as a full year of the high dose IFN schedule, and was clearly less toxic (Gogas 2007).
The most recently reported trial in Stage III melanoma has been the EORTC 18991 trial in1256 patients, comparing long term (5 years) therapy with Pegylated IFNa2b to observation. There was a significant and sustained impact of RFS in the ITT population. The impact on DMFS and OS were not significant in the ITT population. However in the patients with stage III-N1, defined as the sentinel node positive patients, both RFS and DMFS were significantly improved in the treatment arm (Eggermont 2008).
The latest results of a meta-analysis carried out on data of 13 clinical trials were reported at 2007 ASCO meeting on behalf of the International Malignant Melanoma Collaborative Group by Wheatley et al. Data of more than 6000 patients were analyzed with more than 3700 and 3000 events for disease free survival and overall survival respectively. Individual Patients Data were provided for 11 of the 13 reported trials of IFN versus no IFN (87% of the total case series) and published data were used for the remaining two. There was a statistically significant benefit for IFN treated patients (P=0.00004) for disease free survival: this benefit was not affected either by the dose of IFN administered (test for trend P=0.2) or by the duration of treatment (test for trend P=0.5). The meta-analysis showed a statistically significant benefit on overall survival (P=0.008): there was no evidence of benefit related with the administered dose of IFN (test for trend P=0.8) or duration of IFN treatment (test for trend P=0.9). The benefit on survival was of about 3% for IFN treated patients with a Confidence Interval from 1% to 5%. The effect of IFN was not related with age, gender, tumor site, Breslow thickness, stage of the disease and number of involved nodes. Patients with ulcerated melanoma had greater benefit from IFN treatment. The Authors concluded: “This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse and improves overall survival, although the absolute survival benefit is relatively small” (Wheatley 2007). The question is that the benefit is significant on a mathematical basis only because a benefit of 1% -5% does not justify the administration of an adjuvant treatment with a consistent toxicity such the one associated with HDI. If an adjuvant treatment with interferon has to be taken into consideration this should be given at a very low dose, which toxicity is very small.

6.5.2 Therapeutic excision of primary melanoma

Refer to sections 6.3.1 and 6.4.1.

6.5.3 Therapeutic lymph node dissection

In the presence of involved regional lymph nodes, therapeutic lymph node dissection is the standard treatment on a type C basis; solitary lymph node removal is inappropriate. Clinically dubious findings can necessitate fine needle aspiration of the suspect lymph node. A negative outcome may justify a policy of waiting under strict follow-up conditions (Morton 1991; Plukker 1993). Even in the presence of distant metastases palliative resection of the involved lymph node area will often be carried out to avoid local complications such as ulceration, haemorrhage or neural invasion. It is suitable for individual clinical use on a type R basis. When the primary melanoma has been located in the vicinity of the suspicious lymph node station, it is standard treatment on a type R basis to re-excise the scar of the primary melanoma in continuity (en-block) with the lymph node dissection. In the groin, it is standard option to perform a femoro-inguinal (superficial groin) and iliacal-obturator (deep groin) dissection to the bifurcation of the iliac artery (Karakousis 1994; Karakousis 1981; Strobbe 1999).
In the axilla the standard treatment on a type C basis is to perform a complete lymph node clearance. The minor pectoral muscle is excised en-block with the lymph node specimen, if necessary. In the neck usually a complete therapeutic neck dissection is carried out as standard treatment option on a type C basis. This may be a radical neck dissection, sacrificing the sternocleidomastoid muscle, the internal jugular vein and the accessory nerve, or a modified radical dissection sparing one or more of these structures. The rationale for preservation of these structures is often arbitrary and indicated by the proximity of the lymph node metastases to one of these structures. In judging these two procedures, factors such as survival, regional tumour control and functional and cosmetic results should be considered. The parotid gland is situated in the lymph drainage area of a melanoma of the temple/forehead, ear and anterior scalp. Therefore, in these cases a superficial parotidectomy should be performed in continuity with the neck dissection. Involvement of the retroauricular and occipital lymph nodes requires removal of the lymph node-bearing tissue of the retroauricular and suboccipital region in continuity with the contents of the posterior triangle of the neck and internal jugular chain (Plukker 1993; Shah 1991).

6.5.4 Postsurgical adjuvant treatment

There is no evidence for a role of chemotherapy in the adjuvant setting for stage III melanoma (Nathan 1995). A recent review (Punt 2001) of all randomized studies on adjuvant IFN-a either at low dose or intermediate or high dose concluded that according to the trials with mature data on DFS and OS there is no benefit for low-dose IFN-a (Cascinelli 2001; Nathanson 1996) and a possible advantage from high dose IFN-a but with relevant toxicity. The only proven benefit was obtained with high dose IFN-a (20 MU/m2 iv daily x 5 of 7 days for 4 weeks followed by 10 MU/m2 three times a week for 48 weeks) in a subset of selected patients, but at the expense of significant toxicity (Kirkwood 2000; Kirkwood 2001 ; Kirkwood 1996). The positive results obtained with high dose a-2b IFN from the ECOG study (Kirkwood 1996) were not reproduced in the subsequent Intergroup study (E1690) comparing high vs low dose IFN vs observation in 642 patients (Kirkwood 2000). Recently a third study (Intergroup E 1694) in 880 patients proved a significant improvement in overall and relapse free survival from HDI as compared to a vaccine formulated from the GM2 ganglioside antigen (Kirkwood 2001). However the short follow up of this study (< 2 years) does not allow a definitive conclusion. No definitive data are available from the EORTC 18952 study (on 1418 patients). A recent review of all randomized studies on adjuvant IFN-a either at low dose or intermediate or high dose concluded that according to the trials with mature data on DFS and OS there is no benefit for low-dose IFN-a and a possible advantage on DFS from high dose IFN-a but with relevant toxicity (Punt 2001). A pooled analysis of trials at median follow up times of 2.1-12.6 years showed significant improvement in relapse-free survival for patients treated with high-dose IFN-a of about 10% at 5 years, but no clear benefit in terms of overall survival, compared with patients randomly allocated to observation or vaccine therapy (Kirkwood 2004). The toxicity of IFN-a is high (Kirkwood 2002), and in view of the absence of evidencefor an overall survival benefit, it cannot be regarded as standard adjuvant therapy. So in patient with stage III disease there one recent study (Garbe 2008) indicating on a type 2 level of evidence a possible role of low dose Interferon for two years in the adjuvant setting, while HDIFN must be considered suitable for individual clinical use on a type 2 level of evidence. A large randomised study, EORTC study #18952, still including a control arm, evaluated intermediate doses of subcutaneous IFN-a (5 million units thrice weekly for 2 years)and showed a delay to time of distant metastasis, but this did not result in a survival advantage (Eggermont 2005). A particular caution is suggested in the concurrent use with adjuvant radiotherapy for the risk of enhancement of radiation-induced toxicity (Conill 2007).
Recent meta-analyses of 12 adjuvant IFNa trials in high-risk melanoma patients demonstrated that IFNa prolongs recurrence-free survival in a subgroup of melanoma patients. A 17% reduction in the risk of recurrence has been calculated. However, the effect on a prolongation of OS is of a lesser extent with a 7% reduction in the risk of death (Wheatley 2002; Wheatley 2003). Most of the clinical trials, which have been carried out in the adjuvant treatment of malignant melanoma were underpowered to detect such small differences at a statistically significant level. Even in a large-sized EORTC trial on 1388 patients with thick primary tumors or regional lymph node metastases only, a small increase (7.2%) in the distant metastases-free interval and a 5.4% improvement in OS have been detected after a median follow-up of 4.65 years with intermediate doses of subcutaneous IFN-a (5 million units thrice weekly for 2 years) compared to observation. The differences were not statistically significant (Eggermont 2005). A more careful selection of patients who are likely to benefit from adjuvant IFNa is mandatory, but not available yet due to the lack of predictive factors.
A total of 444 stage III melanoma patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection were randomized to receive either 3 MU s.c. of IFNa2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNa2a plus DTIC 850 mg/m2 every 4–8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC to adiuvant interferon resulted detrimental (Garbe 2008). The result claims the benefit of a treatment with low dose interferon for 2 years in stage III melanoma patients over observation, but does not tell us how these results compare with high-dose interferon.
Gogas and collegues reported on the Hellenic Melanoma group trial at ASCO 2007, demonstrating that One month of induction phase of high dose IFN was just as good as a full year of the high dose IFN schedule, and was clearly less toxic (Gogas 2007). The most recently reported trial in Stage III melanoma has been the EORTC 18991 trial in1256 patients, comparing long term (5 years) therapy with Pegylated IFNa2b to observation. There was a significant and sustained impact of RFS in the ITT population. The impact on DMFS and OS were not significant in the ITT population. However in the patients with stage III-N1, defined as the sentinel node positive patients, both RFS and DMFS were significantly improved in the treatment arm (Eggermont 2008).
Isolated regional perfusion may be investigational or suitable for individual clinical use on a type 2 level of evidence as an adjunct to excision to improve local-regional control in the presence of in-transit metastases (Hafstrom 1991; Vrouenraets 1996) although no survival advantage has been observed.

6.5.5 Radiation therapy

Irradiation of deep primary lesions after surgery is considered investigational or suitable for individual clinical use on a type R basis (Ballo 2003; Cooper 1998; Elsmann 1991; Geara 1996). The role of radiation therapy after surgical procedures is currently undergoing reappraisal. Post-operative irradiation can be administered in order to maximise local control in the following clinical situations:
a) when micro- or macroscopic residual disease is left in situ and a reintervention is not feasible for medical reasons, for unacceptable morbidity, or for cosmetic limitations (Cooper 1998; Elsmann 1991; Geara 1996);
b) in head and neck lesions where there is a high risk of recurrence because of the depth of invasion, it is appropriate to treat the surgical bed and/or regional lymph-node areas (Ang 1994; Ballo 2003; Storper 1993);
c) after a therapeutic lymph-node dissection in metastatic nodal disease when narrow margins, multiple nodes and/or extranodal spreading are present (Ballo 2002; Ballo 2003; Creagan 1978; Hansson 1993; O’Brien 1995; Ballo 2006; Mendenhall 2008; Burmeister 2006).
In-field dermal recurrences or treatment related lymphedema may sometimes occur in the treatment of inguinal nodes (Ballo 2004 b). Postoperative radiation therapy following surgery for regional lymph node metastases has been investigated in two randomised trials using hypofractionation – 7 fractions a week of 6Gy or conventional fractionation – 50 Gy in 25 fractions. No difference in overall survival or death from melanoma was noted, but reduced recurrence rate was obtained in the hypofractionated trial. This treatment can be considered suitable for individual clinical use on a type 2 level of evidence (Ballo 2002; Ballo 2003; Creagan 1978; Hansson 1993; Ross 1994; Burmeister 2006). In head and neck, where melanoma can be considered a separate entity with different biological behaviour, elective, postoperative and adjuvant radiation may be applied (Ballo 2005). Radiotherapy can be considered suitable for individual clinical use on a type 3 level of evidence. Different hypofractionated schedules such as 2.4 Gy x 20, 3 Gy x 18, 4.5 Gy x 10, 6 Gy x 5, 7-8 Gy x 3 (0-7-21 scheme) can be appropriate, depending on the extent of disease, site of lesions, risk of late side effects, presence of regional nodes, etc. (Ang 1994; Cooper 1998; Geara 1996; Storper 1993; Burmeister 2006).

6.6 Stage IV (AJCC) disease (any T, any N, M1a, b, c)

6.6.1 Treatment strategy

It is standard treatment on a type C basis to excise local recurrences, satellites and in-transit metastases when feasible (Urist 1990). Isolated regional perfusion may be investigational or suitable for individual clinical use on a type 3 level of evidence as an adjunct to excision to improve local-regional control (Hafstrom 1991; Lienard 1999; Vrouenraets 1996). Isolated lung, liver and brain metastases are suitable for surgical excision for individual clinical use on a type R basis (Balch 1999b). Metastatic disease is treated with systemic chemotherapy if it is not suitable for surgical palliation on a type R basis, but there is no regimen that could be claimed as standard. Radiation therapy is effective in the palliative treatment of brain, bone and nodal lesions as well as spinal cord compression (Cooper 1998; Ewend 1996; Geara 1996; Perchel 1994; Sause 1991).

6.6.2 Local recurrences, satellites and in-transit metastases

It is standard treatment on a type C basis to excise local recurrences, satellites and in-transit metastases when feasible (Urist 1990). Isolated regional perfusion may be investigational or suitable for individual clinical use on a type 2 level of evidence as an adjunct to excision to improve local-regional control (Hafstrom 1991; Lienard 1999; Vrouenraets 1996). The value of regional perfusion in patients with in-transit metastases or extensive tumour growth in an extremity, that cannot be resected completely, is generally accepted and is suitable for individual clinical use on a type R basis. In approximately 80% of such patients a complete remission can be achieved, which in a substantial percentage of patients (about 35%) is long standing (>3 years). By means of perfusion, amputation of the limb can usually be avoided (Kroon 1988; Lienard 1999; Vrouenraets 1996). This method consists of isolation of the blood circulation of the extremity and connection to an extra-corporeal circuit with oxygenation and temperature regulation. Subsequently the extremity is perfused with a high dose of a cytostatic drug, usually melphalan. Recent publications of large series of patients with multiple in transit metastases, bulky disease and prior failure to an ILP with melphalan alone suggest that the addition of TNF improves results significantly in patients with bulky disease and in patients who failed melphalan alone ILP (Grunhagen 2004; Grunhagen 2005). Cryosurgery, electrocoagulation, laser treatment (Strobbe 1997a), radiotherapy combined with hyperthermia (Geara 1996; Overgaard 1995) and intralesional administration of BCG or dinitrochlorobenzene (DNCB) (Strobbe 1997b) also have a place in the palliative treatment of widespread local-regional disease.

6.6.3 Metastatic disease

The prognosis of patients with distant metastases is very poor, with a median survival varying from 2 to 8 months according to the anatomical site of the metastases and the number of metastases. Surgery, when possible, should be recommended as suitable for individual clinical use any time the complete removal of all visible metastases is achievable.

6.6.3.1 Metastasectomy

In some patients with haematogenic metastases metastasectomy is suitable for individual clinical use on a type R basis (Balch 1999b). This surgery frequently results in a quick and good palliation. The indication for metastasectomy is rather strong for solitary metastases, the more so since systemic cytostatic and/or immunotherapeutic schedules have yielded almost no efficacy so far. A proper indication for metastasectomy is haematogenic cutaneous and subcutaneous metastases. Surgical intervention also has to be considered for patients with complaints and/or complications from gastro-intestinal metastatic melanoma, such as chronic or acute blood loss, ileus (invagination) or perforation (Klaase 1990). Excision of a solitary brain metastasis sometimes results in a good palliation. In a large retrospective study factors significantly associated with improved survival on a multivariate analysis were: surgical treatement, no concurrent extracerebral metastases, young age, and longer disese-free interval (Fife 2004). In cases of lung metastasis palliation is not the primary goal, however in solitary lung metastasis some prolongation of survival may be achieved.

6.6.3.2 Radiotherapy

Radiotherapy can be suitable for individual clinical use as a palliative treatment for spinal cord compression, brain metastases, nodal metastases, lung metastases, bone metastases, for brain metastases after surgery, and lastly, for pain control (Buchsbaum 2002; Cooper 1998; Ewend 1996; Geara 1996; Gerosa 2002 ; Jenrette 1996; Olivier 2007). Its role after therapeutic lymph node dissection is considered suitable for individual clinical use in selected patients on a type 3 level of evidence (Ang 1994; Cooper 1998; Creagan 1978; Elsmann 1991; Geara 1996; Hansson 1993; Storper 1993; Burmeister 2006). Radiobiological and clinical data no longer support the concept of radioresistance of melanoma (Overgaard 1995; Perchel 1994; Rounsaville 1988; Sause 1991). Intrinsic radiosensitivity appears heterogeneous but within the range of values seen in the great majority of tumour cells lines. Melanoma exhibits high response rates to irradiation using different time-dose fractionation regimens. Melanoma cells have the ability to efficiently repair both sub-lethal and potentially lethal radiation damage (Konefal 1988; Overgaard 1985; Rofstad 1994). Clinical data are consistent with the finding that high dose per fraction can achieve a higher complete response rate (Overgaard 1985), but a randomised study comparing high dose (8 Gy x 4) or low dose per fraction (2.5 Gy x 20) regimens showed similar high response rates (range 23-72%; 2 years local control: 48-82%). Both fractionation schemes can be considered as standard options on a type 2 level of evidence (Cooper 1998; Geara 1996; Sause 1991). Higher total doses are suggested as a method to offer longer palliation (Olivier 2007). Patient’s life expectancy, patient’s quality of life or the possible exhibition of late side effects can address the choice of radiation regimen: this can be regarded as suitable for individual clinical use on a type R basis.

6.6.3.3 Chemotherapy

Systemic chemotherapy treatment for melanoma has not demonstrated significant activity. The most efficient drugs are dacarbazine (DTIC), nitrosourea, cisplatinum (CDDP) and vinca-alkaloids. DTIC is considered the most active single agent, it gives a response rate of about 12 to 20%. Recentr trials however suggest a rresponse rate below 10% for DTIC alone. Responses are rare in visceral sites and they are anecdotal in cerebral metastasis (Balch 1989). Moreover, increased response rates in polychemotherapy trials never translated into survival benefits, but only in a significant increase in toxicity (Jungnelius 1998; Jelic 2002; Bafaloukos 2005). Actually polychemotherapy, addition of tamoxifen, interferon, interleukin-2 have all failed to improve survival in 27 randomized trials. Temozolomide is a prodrug of DTIC which can be administered orally and has better distribution into the cerebrospinal fluid. It is a promising new agent because of the oral route of administration and it produces responses rates similar to those obtianed with DTIC (21% CR+PR in a phase III study) (Middleton 2000b). Fotemustine, not yet available worldwide, gives a response rate of about 24% in metastatic melanoma with around 20-25% responses in brain metastases. Its toxicity profile is usually very acceptable and includes mainly neutropenia and thrombocytopenia (Jacquillat 1990). In a recent randomized clinical trial fotemustine showed a 15% overall response rate which did not translate into a survival advantage over the patients treated with DTIC (Avril 2004). For all these drugs, complete response occurs in less than 10% of cases and the median duration of response is between 4 to 6 months. Several two-, three- or four-drug regimens have been tested. The most common regimens used are CVD (CDDP, Vinblastine, DTIC) or the combination of CDDP and DTIC. All of them can achieve a response rate of about 30 to 45% with a median duration of response and complete response rates that are not significantly different from those achieved with fotemustine or dacarbazine alone (Luikart 1984). Although it is preferable to include MM patients in phase III trials, the choice between mono- or polychemotherapy is made as suitable for individual clinical use on a type R basis, because there are no data supporting a survival advantage for treatment independent from other prognostic factors. Combining DTIC with other drugs having single-agent activity and /or immunotherapeutic compounds fails to provide clinically meaningful improvement in survival, and may increase toxicity, over DTIC alone as a single administration (850-1000 mg/m2) once every 3 weeks (Eggermont 2004).
The addition of oblimersen to dacarbazine, in the attempt to overcome chemotherapy drug-resistance,significantly improved progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P < .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P < .03), among 771 patients with advanced melanoma randomly assigned to receive dacarbazine alone or the above mentioned drug combination. A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P <.02) (Bedikian 2006). Although the values reported are statistically significant, their clinical meaning is irrelevant.

6.6.3.4 Chemotherapy plus Tamoxifen

The use of tamoxifen is not recommended on a type 2 level of evidence since most of the available data from randomised prospective studies showed no advantage of adding tamoxifen to the CVD regimen, to DTIC or to the combination of CDDP + DTIC in patients with disease resistant to CDDP (Agarwala 1999; Chapman 1999; Cocconi 1992; Creagan 1999; Falkson 1998; Margolin 1998; Mc Clay 1996; Rusthoven 1996).

6.6.3.5 Cytokine_based immunotherapy with IFN-alpha and IL-2 and chemoimmunotherapy

Immunotherapy is another option for such patients. Recombinant IFN gives between 12 to 18% response rates with doses ranging between 3 and 18 million units subcutaneously three times a week. Responses in visceral sites are rare. Toxicities include mainly fatigue, myalgia, fever, leucopenia and thrombocytopenia. Adding IFN to chemotherapy did not lead to improved survival in randomized trials (Bajetta 1994; Falkson 1998; Thompson 1993; Vuoristo 2005; Young 2001). Recombinant Interleukin-2 as a single drug, gives 15 to 25% response rates with doses ranging between 9 and 18 million units, total dose or per square meter. It is given as bolus injection by the subcutaneous route, or, more usually, using continuous infusion (Keilholz 1998; Kirkwood 1995). Toxicities include flu-like syndrome, fever, hypotension, vascular leak syndrome with oliguria, ?dema, and neutropenia. High dose IL-2 produced a 7% complete response rate and 4% long-lasting CR (Atkins 2000). Although the combination of Interleukin-2 and IFN-a has been shown to be synergistic in vitro, results in humans have been rather disappointing with response rates not exceeding 30% (Atzpodien 1988). The combination of DTIC with IFN-a has been claimed as more effective than DTIC alone but the only little advantage is in terms of response rate without any advantage in survival (Huncharek 2001). The combination of rIL2 and DTIC + IFN or polychemotherapy did not demonstrate any significant benefit (Atkins 2003; Atzpodien 1998; Del Vecchio 2003; Hauschild 2001; Keilholz 1997; Keilholz 2005; Middleton 2000a; Ridolfi 2002; Rosenberg 1999; Young 2001; Vuoristo 2005). The combinations of IFN and or IL2 should not be recommended on a type 2 level of evidence in the palliative setting outside clinical studies. This is also the case for the combination of cisplatinum and a-INF which initially was associated with a high response rate (above 50%), with 10 to 20% complete responses and some long-lasting unmaintained remissions. However, these results were not reproduced in more recent randomized studies (Dorval 1999; Rosenberg 1999).

6.6.3.6 Gene therapy and vaccines

Vaccines and gene therapy should be recommended as strictly investigational (Rosenberg 2001). Randomized trials with Dentricitc Cells and peptides in combination with IL-2 thusfar have failed (Schadendorf 2004; Ernstoff 2005).

6.6.4 Bone metastases

Radiation therapy is standard treatment for symptomatic bone metastases on a type C basis. Palliative radiotherapy using either conventional or hypofractionated regimens is effective in 50-85% of patients, with total doses in the range of 20-36 Gy, dose per fraction of 3 to 6 Gy over 2-3 weeks (Cooper 1998; Ewend 1996; Rate 1988).

6.6.5 Spinal cord compression

For spinal cord compression irradiation plus corticosteroids is the standard treatment on a type R basis. Radiotherapy can be used as sole decompressive modality or as an adjuvant to laminectomy. Palliation can be achieved in 44-85% of cases (Cooper 1998; Geara 1996; Mc Clay 1996; Rate 1988). Irradiation regimens should be selected on the basis of patient long-term or short-term prognosis, and on spinal cord tolerance which limits the utilisation of high dose per fraction schedules (30 Gy at 2-3 Gy per day in 2-3 weeks).

6.6.6 Cerebral metastases

Cerebral metastases have a poor prognosis with a median survival from diagnosis of 2-5 months. Radiotherapy can provide effective, temporary palliation. Solitary brain metastases should be treated with surgical resection plus post-operative irradiation, that is standard treatment on a type 3 level of evidence (Ewend 1996; Hagen 1990). Combination therapy appears to be superior to each treatment modality alone (Buchsbaum 2002). Radiosurgery, avoiding surgical and anaesthetic risks, can be appropriate for solitary small lesions: this can be regarded as investigational or suitable for individual clinical use on a type 3 level of evidence (Choi 1985; Buchsbaum 2002; Gerosa 2002; Gonzalez-Martinez 2002; Mingione 2002; Gaudy-Marqueste 2006; Mathieu 2007). Whole brain irradiation (WBI) can be combined with radiosurgery with superior results compared with those of WBI alone and comparable with those obtained by surgery plus WBI, provided that the diameter of metastases does not exceed 3 cm (Stone 2004). In cases of multiple metastases or residual disease after surgery, palliative radiotherapy is standard treatment on a type R basis (Coffey 1991; Cooper 1998; Ewend 1996; Geara 1996; Fife 2004). Whole brain irradiation has been suggested for patients with multiple lesions at doses of 30 Gy over 2 weeks or 20 Gy over 2 weeks, the dose should be selected on the basis of prognosis, the presence of other sites of metastases, and performance status.
In a small group of patients with advanced melanoma and small brain metastasis, temozolomide as the single treatment was used: Stabilization of systemic metastasis was noted in 7 of 52 patients (13%), and there were 6 responses (5 partial responses and 1 complete response; 11%). The median time to neurologic progression was 7 months (range 2–15, months). The median survival of patients with brain metastases was 5.6 months (95% confidence interval, 4.4–6.8 months). Intracranial hemorrhagic complications were not observed (Boogerd 2007).

6.7 Treatment of particular sites

6.7.1. Melanomas of head and foot

The tendency to use narrower excision margins is of utmost importance in the treatment of melanomas of the hand and foot. However, even with 1 or 2 cm margins, mutilation often cannot be avoided. Here, surgeons have to use their best judgement, weighing function and cosmetic appearance against the possible increased risk of local recurrence, when wishing to use an even narrower excision margin than indicated. Skin grafting in this area is seldom indicated.

6.7.2 Melanomas of the fingers and toes

For melanomas of the fingers and toes, amputation is usually considered the best treatment option. The amputation level for subungual melanoma of the toes can be taken at the metatarsophalangeal joint and for subungual melanoma of the fingers at the proximal interphalangeal joint. In cases of thin subungual melanomas, a more distal amputation level must be considered. For subungual melanoma of the thumb, amputation distal to the metacarpophalangeal joint is standard treatment on a type R basis, if possible, in order to preserve some function of the thumb stump.

6.7.3 Mucosal melanoma

Melanoma of the mucosa is an uncommon neoplasm accounting for about 4 % of all melanomas and is characterised by a poor prognosis. Head and neck, anorectal and urogenital regions are the most frequently involved sites (Kristiansen 1992; Shibuya 1993). Post-operative and palliative irradiation for anorectal and urogenital melanoma can be recommended as suitable for individual clinical use on a type R basis. Mucosal melanoma of the head and neck most frequently involves the oral cavity, nasal cavity and paranasal sinuses. When surgery is not feasible, radical radiation can be considered as standard option on a type C basis giving complete response and durable local control rates in the range of 29-75% (Cooper 1998; Elsmann 1991; Gilligan 1991; Wada 2004; Krengli 2006). Few data are available on the use of irradiation in the post-operative setting; however, it can be considered as optional treatment on a type R basis with the intent of increasing long-term local control (De Meerleer 1998; Temam 2005; Owens 2003). Inclusion of the CNS in the treatment field obviously represents a limiting factor in the utilisation of high dose per fraction regimens.

6.7.4 Head and neck melanoma

Less than 20% of patients develop melanoma in the head and neck area. Such individuals are considered as having a worse prognosis but there are no clear data to support this conclusion. Scalp melanoma probably has a poor prognosis because it is thicker at diagnosis. Surgeons have to use their best judgement, weighing function and cosmetic appearance against the possible increased risk of local recurrence when performing an even narrower excision than is usually indicated. There are no data supporting the hypothesis of an increase in local recurrences when narrower margins were utilised in this area. Skin grafting in the head and neck area, especially in the face, is seldom indicated. For treatment of some types and stages of head and neck melanoma, postoperative and adjuvant radiation may be appropriate (Ang 1994; Cooper 1998; Geara 1996; Morton 1991; Burmeister 2006). Radiotherapy can be considered suitable for individual clinical use on a type 3 level of evidence. Different hypofractionated schedules such as 3 Gy x 18, 4.5 Gy x 10, 6 Gy x 5, 7-8 Gy x 3 (0-7-21 scheme) can be employed, depending on the extent of disease, site of lesions, risk of late side effects, presence of regional nodes, etc. (Ang 1994; Storper 1993).

6.7.5 Ano-Rectal Melanoma

Rectal melanoma is rare and it is prone to rapid dissemination, its surgical management is controversial but abdominoperineal resection failed to show survival advantage over wide local excision and therefore should be reserved to tumors not amenable to local excision or for the palliative treatment of large obstructive lesions on a type C basis (Yap 2004).

6.7.6 Vaginal melanoma

In cases of surgically unresectable disease, primary radiation therapy is indicated on a type R basis (Miner 2004).

7. LATE SEQUELAE

7.1 Treatment related late effects and sequelae

Disfiguring wounds and scars are the most frequent late effects of surgical treatment of melanoma. Plastic surgery may be necessary for wound repair.

7.2 Second tumours

There are controversial data concerning second primary tumours among patients with melanoma. There is a higher incidence of tumours among patients treated for melanoma and a higher risk of a second primary melanoma, lymphomas, non-melanoma skin cancers, brain and nervous system cancers according to various reports. Age, sex and time from diagnosis of melanoma have been reported to be influential factors.

8. FOLLOW-UP

8.1 General aims

The postoperative follow-up of melanoma patients is the same irrespective of the tumour site. The major goal of follow-up is the detection of local regional recurrences and nodal recurrence, because distant metastatic disease is largely incurable and elaborate laboratory and imaging studies have not proven to be useful. The value of the (potential) tumour marker in the blood, the S-100 protein, is under investigation. It has been reported that this marker can be used to detect melanoma recurrences before they become apparent (Bonfrer 1998). Patients are required to perform self examination of the skin and of regional lymph nodes. There are no studies concerning the frequency of follow-up visits. In a large study of 602 patients with thin melanoma (< 0.75 mm) only 24 recurrences (4%) were recorded and among them there were only 5 (1%) operable recurrences within 5 years (Moloney 1996).
The only prospective study on follow up was conducted in Germany on 2008 stage I-IV consecutive melanoma patients. The follow-up protocol was carried out according to the guidelines established in 1994 by the German Society of Dermatology, that recommends follow-up examinations every 3 months in the first 5 years after resection of the primary tumor, continued every 6 months until the 10th postoperative year. The results of the study suggest that an elaborated follow-up schedule in cutaneous melanoma is suitable for the early detection of second primary melanomas and early recurrences (Garbe 2003).

8.2 Suggested protocols

A common procedure for follow-up is to review the history and perform a physical examination three / four times a year in the first two or three years. Thereafter this proceedure should be followed every 6 months for a total period of 10 years. In asymptomatic patients, laboratory and radiological studies to detect metastatic disease are not justified outside clinical trials.

INDEX

Agarwala SS, Ferri W, Gooding W, Kirkwood JM. A phase III randomized trial of dacarbazine and carboplatin with and without tamoxifen in the treatment of patients with metastatic melanoma. Cancer 1999; 85: 1979-1984 [Medline]

Ang CG, Kelly JW, Fritschi L, Dowling JP. Characteristics of familial and non-familial melanoma in Australia. Melanoma Res 1998; 8: 459-464 [Medline]

Ang KK, Peters LJ, Weber RS, Morrison WH, Frankenthaler RA, Garden, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys 1994; 30: 795-798 [Medline]

Armstrong BK, English DR. Epidemiologic studies. In: Balch CM, Houghton AN, Milton JW, Sober AJ, Soong SJ, editors. Cutaneous melanoma. 2nd ed. Philadelphia: JB Lippincott Company. 1992; 12-26 [Medline]

Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000; 6 Suppl 1:S11-4 [Medline]

Atkins MB, Lee S, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM. A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. PROC ASCO 2003; 22: 708 [Medline]

Atzpodien J, Shimazaki C, Wisniewski D, et al. Interleukin-2 und interferon-a in der adoptiven Immunotherapie des Plasmozytoms: ein experimentelles Model. In: Lutz D, Heinz R, Nowotny H, et al, editors. Leukaemien und Lymphome. Munchen-Wien-Baltimore: Urban and Schwarzenberg. 1988; 211-212 [Medline]

Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 2004; 22: 1118-1125 [Medline]

AWG. AIRT Working Group. Italian cancer figure – Report 2007 – Survival. Epidemiologia e prevenzione, anno 31 (1) 2007 Supplemento. Epidemiol Prev 2007; 1 [Medline]

Bafaloukos D, Tsoutsos D, Kalofonos H, Chalkidou S, Panagiotou P, Linardou E, et al. Temozolomide and cisplatin versus temozolomide in patients with advanced melanoma: a randomized phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol 2005; 16: 950-957 [Medline]

Bajetta E, Di Leo A, Zampino MG, Sertoli MR, Comella G, Barduagni M, et al. Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol 1994; 12: 806-811 [Medline]

Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001a; 19: 3635-3648 [Medline]

Balch CM, Houghton AN, Peters L. Cutaneous melanoma. In: DeVita V, Hellman S, Rosenberg S, editors. Cancer: principles and practice of oncology. 3rd ed. Philadelphia: JB Lippincott. 1989; 1499-1542 [Medline]

Balch CM, Ross MI. Sentinel lymphadenectomy for melanoma–is it a substitute for elective lymphadenectomy? Ann Surg Oncol 1999a; 6: 416-417 [Medline]

Balch CM, Soong S, Ross MI, Urist MM, Karakousis CP, Temple WJ, et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 2000; 7: 87-97 [Medline]

Balch CM, Soong S, Shaw HM, Urist MM, McCarthy WH. An analysis of prognostic factors in 8500 patients with cutaneous melanoma. In: Balch CM, Houghton AN, Milton GW, Sober AJ, Soong S, editors. 2nd ed. Pahiladelphia: JB Lippincott Company. 1992c. p. 165-187 [Medline]

Balch CM, Soong SJ, Atkins MB, Buzaid AC, Cascinelli N, Coit DG, et al. An evidence-based staging system for cutaneous melanoma. CA Cancer J Clin 2004; 54: 131-149 [Medline]

Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001b; 19: 3622-3634 [Medline]

Balch CM, Urist MM, Karakousis CP, Smith TJ, Temple WJ, Drzewiecki K, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Annals of Surgery 1993; 218: 262-267 [Medline]

Balch CM. Cutaneous melanoma: prognosis and treatment results worldwide. Semin Surg Oncol 1992b; 8: 400-414 [Medline]

Balch CM. Palliative surgery for stage IV melanoma: is it a primary treatment? Ann Surg Oncol 1999b; 6: 623-624 [Medline]

Balch CM. The role of elective lymph node dissection in melanoma: rationale, results, and controversies. J Clin Oncol 1988; 6: 163-172 [Medline]

Ballo MT, Ang KK. Radiotherapy for cutaneous malignant melanoma: rationale and indications. Oncology (Huntingt) 2004a; 18: 99-107 [Medline]

Ballo MT, Bonnen MD, Garden AS, Myers JN, Gershenwald JE, Zagars GK, et al. Adjuvant Irradiation for Cervical Lymph Node Metastases from Melanoma. Cancer 2003; 97: 1789-1796 [Medline]

Ballo MT, Garden AS, Myers JN, Lee JE, Diaz EM, Jr., Sturgis EM, et al. Melanoma metastatic to cervical lymph nodes: Can radiotherapy replace formal dissection after local excision of nodal disease? Head Neck 2005; 27: 718-721 [Medline]

Ballo MT, Ross MI, Cormier JN, Myers JN, Lee JE, Gershenwald JE, et al. Combined-modality therapy for patients with regional nodal metastases from melanoma. Int J Radiat Oncol Biol Phys 2006; 64: 106-113 [Medline]

Ballo MT, Strom EA, Zagars GK, Bedikian AY, Prieto VG, Mansfield PF, et al. Adjuvant irradiation for axillary metastases from malignant melanoma. Int J Radiat Oncol Biol Phys 2002; 52: 964-972 [Medline]

Ballo MT, Zagars GK, Gershenwald JE, Lee JE, Mansfield PF, Kim KB, et al. A critical assessment of adjuvant radiotherapy for inguinal lymph node metastases from melanoma. Ann Surg Oncol 2004b; 11: 1079-1084 [Medline]

Band PR, Le ND, Fang R, Astrakianakis G, Bert J, Keefe A, et al. Cohort cancer incidence among pulp and paper mill workers in British Columbia. Scand J Work Environ Health 2001; 27: 113-119 [Medline]

Barnhill R, Mihm MCJ. Histopathology of malignant melanoma and its precursor lesions. In: Balch CM, Houghton AN, Milton GW, Sober AJ, Soong S, editors. Cutaneous melanoma. 2nd ed. Philadelphia: JB Lippincott Company. 1992 [Medline]

Bastiaannet E, Beukema JC, Hoekstra HJ. Radiation therapy following lymph node dissection in melanoma patients: treatment, outcome and complications. Cancer Treat Rev 2005; 31: 18-26 [Medline]

Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006; 24: 4738-4745 [Medline]

Berg AO, Allan JD. Introducing the third US Preventive Services Task Force. Am J Prev Med 2001; 20: 3-4 [Medline]

Berrino F, Capocaccia R, Coleman MP, Esteve J, Gatta G, Hakulinen T, et al. Survival of cancer patients in Europe: the EUROCARE-3 study. Ann Oncol 2003; 14 Suppl 5 [Medline]

Berrino F, Capocaccia R, Esteve J, et al. Survival of cancer patients in Europe. The Eurocare-II Study. Lyon: IARC Press. 1999 [Medline]

Berwick M, Begg CB, Fine JA, Roush GC, Barnhill RL. Screening for cutaneous melanoma by skin self-examination. J Natl Cancer Inst 1996; 88: 17-23 [Medline]

Bonfrer JM, Korse CM, Nieweg OE, Rankin EM. The luminescence immunoassay S-100: a sensitive test to measure circulating S-100B: its prognostic value in malignant melanoma. Br J Cancer 1998; 77: 2210-2214 [Medline]

Boniol M, De Vries E, Coebergh JW, Dore JF. Seasonal variation in the occurrence of cutaneous melanoma in Europe: influence of latitude. An analysis using the EUROCARE group of registries. Eur J Cancer 2005; 41: 126-132 [Medline]

Bonnen MD, Ballo MT, Myers JN, Garden AS, Diaz EM, Jr., Gershenwald JE, et al. Elective radiotherapy provides regional control for patients with cutaneous melanoma of the head and neck. Cancer 2004; 100: 383-389 [Medline]

Boogerd W, De Gast GC, Dalesio O. Temozolomide in advanced malignant melanoma with small brain metastases: can we withhold cranial irradiation? Cancer 2007; 109: 306-312 [Medline]

Bosetti C, La Vecchia C, Naldi L, Lucchini F, Negri E, Levi F. Mortality from cutaneous malignant melanoma in Europe. Has the epidemic levelled off? Melanoma Res 2004; 14: 301-309 [Medline]

Bouwhuis M, Suciu S, Kruit W, Sales F, Patel P, Punt C, et al. Prognostic value of autoantibodies (auto-AB) in melanoma patients (pts) in the EORTC 18952 trial of adjuvant interferon (IFN) compared to observation (obs). PROC ASCO 2007a; 25, 18S: 118s [Medline]

Bouwhuis M, Suciu S, Testori A. Prognostic value of autoantibodies in melanoma stage III patients in the EORTC 18991 phase III randomized trial comparing adjuvant pegylated interferon a2b vs observation. Eur J Cancer 2007b; 5: 5 [Medline]

Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970; 172: 902-908 [Medline]

Bruijn JA, Mihm MCJ, Barnhill RL. Desmoplastic melanoma. Histopathology 1992; 20: 197-205 [Medline]

Buchsbaum JC, Suh Jh, Lee SY, Chidel MA, Greskovich JF, Barnett GH. Survival by radiation therapy oncology group recursive partitioning analysis class and treatment modality in patients with brain metastases from malignant melanoma: a retrospective study. Cancer 2002; 94: 2265-2272 [Medline]

Buettner PG, Leiter U, Eigentler TK, Garbe C. Development of prognostic factors and survival in cutaneous melanoma over 25 years: An analysis of the Central Malignant Melanoma Registry of the German Dermatological Society. Cancer 2005; 103: 616-624 [Medline]

Buja A, Lange JH, Perissinotto E, Rausa G, Grigoletto F, Canova C, et al. Cancer incidence among male military and civil pilots and flight attendants: an analysis on published data. Toxicol Ind Health 2005; 21: 273-282 [Medline]

Burmeister BH, Mark SB, Burmeister E, Baumann K, Davis S, Krawitz H, et al. A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma-Trans Tasman Radiation Oncology Group (TROG) Study 96.06. Radiother Oncol 2006; 81: 136-142 [Medline]

Burmeister BH, Smithers BM, Davis S, Spry N, Johnson C, Krawitz H, et al. Radiation therapy following nodal surgery for melanoma: an analysis of late toxicity. ANZ J Surg 2002; 72: 344-348 [Medline]

Buzaid AC, Legha SS. Combination of chemotherapy with interleukin-2 and interferon-alfa for the treatment of advanced melanoma. Semin Oncol 1994; 21: 23-28 [Medline]

Calabresi F, Aapro M, Becquart D, Dirix L, Wils J, Ardizzoni A, et al. Multicenter phase II trial of the single agent fotemustine in patients with advanced malignant melanoma. Ann Oncol 1991; 2: 377-378 [Medline]

Cascinelli N, Belli F, MacKie RM, Santinami M, Bufalino R, Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet 2001; 358: 866-869 [Medline]

Cascinelli N, Bombardieri E, Bufalino R, Camerini T, Carbone A, Clemente C, et al. Sentinel and nonsentinel node status in stage IB and II melanoma patients: two-step prognostic indicators of survival. J Clin Oncol 2006; 24: 4464-4471 [Medline]

Cascinelli N, Clemente C, Bifulco C, Tragni G, Morabito A, Santinami M, et al. Do patients with tumor-positive sentinel nodes constitute a homogeneous group? Ann Surg Oncol 2002; 8 (9 Suppl): S35-S37 [Medline]

Cascinelli N, Morabito A, Santinami M, MacKie RM, Belli F. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 1998; 351: 793-796 [Medline]

Cascinelli N, Vaglini M, Nava M, Santinami M, Marolda R, Rovini D, et al. Prognosis of skin melanoma with regional node metastases (stage II). J Surg Oncol 1984; 25: 240-247 [Medline]

Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17: 2745-2751 [Medline]

Chiarion-Sileni V, Del BP, Romanini A, Guida M, Paccagnella A, Dalla PM, et al. Tolerability of intensified intravenous interferon alfa-2b versus the ECOG 1684 schedule as adjuvant therapy for stage III melanoma: a randomized phase III Italian Melanoma Inter-group trial (IMI – Mel.A.) [ISRCTN75125874]. BMC Cancer 2006; 6:44 [Medline]

Cho E, Rosner BA, Colditz GA. Risk factors for melanoma by body site. Cancer Epidemiol Biomarkers Prev 2005; 14: 1241-1244 [Medline]

Choi KN, Withers HR, Rotman M. Intracranial metastases from melanoma. Clinical features and treatment by accelerated fractionation. Cancer 1985; 56: 1-9 [Medline]

Clark WHJ, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 1969a; 29: 705-727 [Medline]

Clark WHJ, Mihm MC, Jr. Lentigo maligna and lentigo-maligna melanoma. Am J Pathol 1969b; 55: 39-67 [Medline]

Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, et al. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med 1992; 327: 516-523 [Medline]

Coffey RJ, Flickinger JC, Bissonette DJ, Lunsford LD. Radiosurgery for solitary brain metastases using the cobalt-60 gamma unit: methods and results in 24 patients. Int J Radiat Oncol Biol Phys 1991; 20: 1287-1295 [Medline]

Coit DG, Rogatko A, Brennan MF. Prognostic factors in patients with melanoma metastatic to axillary or inguinal lymph nodes. A multivariate analysis. Ann Surg 1991; 214: 627-636 [Medline]

Cole BF, Gelber RD, Kirkwood JM, Goldhirsch A, Barylak E, Borden E. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 1996; 14: 2666-2673 [Medline]

Coleman MP, Babb P, Daniecki P, et al. Cancer survival trends in England and Wales, 1971-1995: deprivation and NHS region. Studies in medical and population subjects No. 61. London: The Stationary Office. 1999 [Medline]

Conill C, Jorcano S, Domingo-Domenech J, Marruecos J, Vilella R, Malvehy J, et al. Toxicity of combined treatment of adjuvant irradiation and interferon alpha2b in high-risk melanoma patients. Melanoma Res 2007; 17: 304-309 [Medline]

Cooper JS. The evolution of the role of radiation therapy in the management of mucocutaneous malignant melanoma. Hematol Oncol Clin North Am 1998; 12: 849-62, vii [Medline]

CRC. Pgase II trial of Temozolamide in advanced malignant melanoma. Kenilworth (NJ, USA): Schering-Plough Research Institute. 1994 [Medline]

Creagan ET, Cupps RE, Ivins JC, Pritchard DJ, Sim FH, Soule EH, et al. Adjuvant radiation therapy for regional nodal metastases from malignant melanoma: a randomized, prospective study. Cancer 1978; 42: 2206-2210 [Medline]

Creagan ET, Dalton RJ, Ahmann DL, Jung SH, Morton RF, Langdon RM, Jr., et al. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clini Oncol 1995; 13: 2776-2783 [Medline]

Creagan ET, Suman VJ, Dalton RJ, Pitot HC, Long HJ, Veeder MH, et al. Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma. J Clin Oncol 1999; 17: 1884-1890 [Medline]

Dancuart F, Harwood AR, Fitzpatrick PJ. The radiotherapy of lentigo maligna and lentigo maligna melanoma of the head and neck. Cancer 1980; 45: 2279-2283 [Medline]

Day CLJ, Harrist TJ, Gorstein F, Sober AJ, Lew RA, Friedman RJ, et al. Malignant melanoma. Prognostic significance of “microscopic satellites” in the reticular dermis and subcutaneous fat. Ann Surg 1981; 194: 108-112 [Medline]

De Meerleer GO, Vermeersch H, van Eijkeren M, Lemmerling M, Caemaert J, De Naeyer B, et al. Primary sinonasal mucosal melanoma: three different therapeutic approaches to inoperable local disease or recurrence and a review of the literature. Melanoma Res 1998; 8: 449-457 [Medline]

De Vries E, Coebergh JW. Cutaneous malignant melanoma in Europe. Eur J Cancer 2004; 40: 2355-2366 [Medline]

Del Vecchio M, Bajetta E, Vitali M, Gattinoni L, Santinami M, Daponte A, et al. Multicenter phase III randomized trial of cisplatin, vindesine and dacarbazine (CVD) versus CVD plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-alpha-2b (IFN) in metastatic melanoma patients (pts). PROC ASCO 2003; 22: 709 [Medline]

Desmond RA, Soong SJ. Epidemiology of malignant melanoma. Surg Clin North Am 2003; 83: 1-29 [Medline]

Dickman PW, Hakulinen T, Luostarinen T, Pukkala E, Sankila R, Soderman B, et al. Survival of cancer patients in Finland 1955-1994. Acta Oncol 1999; 38 Suppl 12:1-103.: 1-103 [Medline]

Dorval T, Negrier S, Chevreau C, Avril MF, Baume D, Cupissol D, et al. Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study. Cancer 1999; 85: 1060-1066 [Medline]

Edwards MJ, Martin KD, McMasters KM. Lymphatic mapping and sentinel lymph node biopsy in the staging of melanoma. Surg Oncol 1998; 7: 51-57 [Medline]

Eggermont AM, Kirkwood JM. Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years? Eur J Cancer 2004; 40: 1825-1836 [Medline]

Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet 2005; 366: 1189-1196 [Medline]

Eggermont AM, Suciu S, Ruka W, Marsden J, Testori A, Corrie P, et al. EORTC 18961: Post-operative adjuvant ganglioside GM2-KLH21 vaccination treatment vs observation in stage II (T3-T4N0M0) melanoma: 2nd interim analysis led to an early disclosure of the results. PROC ASCO 2008; 26: 484s [Medline]

Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 2008; 372: 117-126 [Medline]

Eggermont AM. The role interferon-alpha in malignant melanoma remains to be defined. Eur J Cancer 2001; 37: 2147-2153 [Medline]

Elsmann HJ, Ernst K, Suter L. Radiotherapy of primary human melanomas–experiences and suggestions. Strahlentherapie und Onkologie 1991; 167: 387-391 [Medline]

Elwood JM, Jopson J. Melanoma and sun exposure: an overview of published studies. Int J Cancer 1997; 73: 198-203 [Medline]

Ernstoff M, Carrillo C, Urba W, Flaherty L, Clark J, Dutcher J, et al. A Cytokine Working Group (CWG) 3-arm phase II trial of gp100 (209-2M) peptide + high dose (HD) Interleukin-2 (IL-2) in HLA-A2+ (A2+) advanced melanoma patients (pts). PROC ASCO 2005; 24 [Medline]

Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003; 348: 1681-1691 [Medline]

Ewend MG, Carey LA, Brem H. Treatment of melanoma metastases in the brain. Semin Surg Oncol 1996; 12: 429-435 [Medline]

Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 1998; 16: 1743-1751 [Medline]

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 [Medline]

Feightner JW. Feightner JW. Prevention of Skin Cancer. In: Canadian Task Force on the Periodic Health Examination. Canadian guide to clinical preventative health care. Ottawa (Canada): Health Canada. 1994; 850-859 [Medline]

Ferlay J, Bray F, Pisani P, Parkin DM. Cancer incidence, mortality and prevalence worldwide, version 1.0. Lyon: IARC Press. IARC Cancer Base No. 5. 2001 [Medline]

Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5, version 2.0 IARCPress, Lyon. 2004 [Medline]

Fife KM, Colman MH, Stevens GN, Firth IC, Moon D, Shannon KF, et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 2004; 22: 1293-1300 [Medline]

Fraker DL, Alexander HR, Andrich M, Rosenberg SA. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Onco 1996; 14: 479-489 [Medline]

Gallagher RP, Rivers JK, Lee TK, Bajdik CD, McLean DI, Coldman AJ. Broad-spectrum sunscreen use and the development of new nevi in white children: A randomized controlled trial. JAMA 2000; 283: 2955-2960 [Medline]

Gallagher RP, Spinelli JJ, Lee TK. Tanning beds, sunlamps, and risk of cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prev 2005; 14: 562-566 [Medline]

Gandini S, Sera F, Cattaruzza MS, Pasquini P, Abeni D, Boyle P, et al. Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Cancer 2005; 41: 28-44 [Medline]

Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, et al. Evidence-based and interdisciplinary consensus-based German guidelines: systemic medical treatment of melanoma in the adjuvant and palliative setting. Melanoma Res 2008; 18: 152-160 [Medline]

Garbe C, Paul A, Kohler-Spath H, Ellwanger U, Stroebel W, Schwarz M, et al. Prospective evaluation of a follow-up schedule in cutaneous melanoma patients: recommendations for an effective follow-up strategy. J Clin Oncol 2003; 21: 520-529 [Medline]

Garbe C, Radny P, Linse R, Dummer R, Gutzmer R, Ulrich J, et al. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol 2008; 19: 1195-1201 [Medline]

Gaudy-Marqueste C, Regis JM, Muracciole X, Laurans R, Richard MA, Bonerandi JJ, et al. Gamma-Knife radiosurgery in the management of melanoma patients with brain metastases: a series of 106 patients without whole-brain radiotherapy. Int J Radiat Oncol Biol Phys 2006; 65: 809-816 [Medline]

Geara FB, Ang KK. Radiation therapy for malignant melanoma. Surg Clin North Am 1996; 76: 1383-1398 [Medline]

Gerosa M, Nicolato A, Foroni R, Zanotti B, Tomazzoli L, Miscusi M, et al. Gamma knife radiosurgery for brain metastases: a primari therapeutic optino. J Neurosurg 2002, 97: 515-524 [Medline]

Gilligan D, Slevin NJ. Radical radiotherapy for 28 cases of mucosal melanoma in the nasal cavity and sinuses. Br J Radiol 1991; 64: 1147-1150 [Medline]

Gogas H, Dafni U, Bafaloukos D, Kalofonos HP, Fountzilas G, Skarlos D, et al. A randomized phase III trial of 1 month versus 1 year adjuvant high-dose interferon alfa-2b in patients with resected high risk melanoma. PROC ASCO 2007; 25, No. 18S: 473s [Medline]

Gogas H, Ioannovich J, Dafni U, Stavropoulou-Giokas C, Frangia K, Tsoutsos D, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 2006; 354: 709-718 [Medline]

Goldstein AM, Falk RT, Fraser MC, Dracopoli NC, Sikorski RS, Clark WH, et al. Sun-related risk factors in melanoma-prone families with CDKN2A mutations. J Natl Cancer Inst 1998; 90: 709-711 [Medline]

Gonzalez-Martinez J, Hernandez L, Zamorano L, Sloan A, Levin K, Lo S, et al. Gamma knife radiosurgery for intracranial metastatic melanoma: a 6-year experience. J Neurosurg 2002, 97: 494-498 [Medline]

Greene MH. The genetics of hereditary melanoma and nevi: 1998 Update. Cancer 1999; 86: 2464-2477 [Medline]

Grob JJ, Dreno B, de la Salmoniere P, Delaunay M, Cupissol D, Guillot, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 1998; 351: 1905-1910 [Medline]

Grunhagen DJ, Brunstein F, Graveland WJ, van Geel AN, de Wilt JH, Eggermont AM. One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases. Ann Surg 2004; 240: 939-947 [Medline]

Grunhagen DJ, van Etten B, Brunstein F, Graveland WJ, van Geel AN, de Wilt JH, et al. Efficacy of repeat isolated limb perfusions with tumor necrosis factor alpha and melphalan for multiple in-transit metastases in patients with prior isolated limb perfusion failure. Ann Surg Oncol 2005; 12: 609-615 [Medline]

Gun RT, Pratt N, Ryan P, Roder D. Update of mortality and cancer incidence in the Australian petroleum industry cohort. Occup Environ Med 2006; 63: 476-481 [Medline]

Hafstrom L, Rudenstam CM, Blomquist E, Ingvar C, Jonsson PE, Lagerlof, et al. Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group. J Clin Oncol 1991; 9: 2091-2094 [Medline]

Hagen NA, Cirrincione C, Thaler HT, DeAngelis LM. The role of radiation therapy following resection of single brain metastasis from melanoma. Neurology 1990; 40: 158-160 [Medline]

Halachmi S, Gilchrest BA. Update on genetic events in the pathogenesis of melanoma. Curr Opin Oncol 2001; 13: 129-136 [Medline]

Hansson J, Johansson H, Ringborg U. Postoperative radiotherapy following surgery for regional lymph node metastases in malignant melanoma. Melanoma Res 1993; 3: 90-91 [Medline]

Hauschild A, Garbe C, Stolz W, Ellwanger U, Seiter S, Dummer R, et al. Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 2001; 84: 1036-1042 [Medline]

Heaton KM, Sussman JJ, Gershenwald JE, Lee JE, Reintgen DS, Mansfield PF, et al. Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 1998; 5: 322-328 [Medline]

Herbert SH, Solin LJ, Rate WR, Schultz DJ, Hanks GE. The effect of palliative radiation therapy on epidural compression due to metastatic malignant melanoma. Cancer 1991; 67: 2472-2476 [Medline]

Herlyn M, Houghton AN. Biology of melanocytes and melanoma. In: Balch CM, Houghton AN, Milton GW, Sober AJ, Soong S, editors. Cutaneous melanoma. 2nd ed. Philadelphia: JB Lippincott Company. 1992 [Medline]

Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ. Increased incidence of melanoma in renal transplantation recipients. Cancer 2005; 104: 1962-1967 [Medline]

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: 75-81 [Medline]

IARC. IARC monograph on the evaluation of carcinogenic risks to humans, solar and ultraviolet radiation. vol. 55. Lyon: IARC Press. 1992 [Medline]

ICD-O. International Classification of Diseases for Oncology. Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S, editors. 3rd ed. Geneva: World Health Organization. 2000 [Medline]

Jacquillat C, Khayat D, Banzet P, Weil M, Fumoleau P, Avril MF, et al. Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases. Cancer 1990; 66: 1873-1878 [Medline]

Jansen L, Nieweg OE, Peterse JL, Hoefnagel CA, Olmos RA, Kroon BB. Reliability of sentinel lymph node biopsy for staging melanoma. Br J Surg 2000; 87: 484-489 [Medline]

Jelic S, Babovic N, Kovcin V, Milicevic N, Milanovic N, Popov I, et al. Comparison of the efficacy of two different dosage dacarbazine-based regimens and two regimens without dacarbazine in metastatic melanoma: a single-centre randomized four-arm study. Melanoma Res 2002 Feb ;12 (1 ):91 -8 2002; 12: 91-98 [Medline]

Jenrette JM. Malignant melanoma: the role of radiation therapy revisited. Semin Oncol 1996; 23: 759-762 [Medline]

Jonk A, Kroon BB, Rumke P, Mooi WJ, Hart AA, van Dongen JA. Lymph node metastasis from melanoma with an unknown primary site. Br J Surg 1990; 77: 665-668 [Medline]

Jonk A, Kroon BB, Rumke P, van der Esch EP, Hart AA. Results of radical dissection of the groin in patients with stage II melanoma and histologically proved metastases of the iliac or obturator lymph nodes, or both. Surg Gynecol Obstetr 1988; 167: 28-32 [Medline]

Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, et al. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A randomised phase III trial. Eur J Cancer 1998; 34: 1368-1374 [Medline]

Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 1994; 8: 23-26 [Medline]

Karagas MR, Stukel TA, Dykes J, Miglionico J, Greene MA, Carey M, et al. A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use. Br J Cancer 2002; 86: 1085-1092 [Medline]

Karakousis CP, Driscoll DL, Rose B, Walsh DL. Groin dissection in malignant melanoma. Ann Surg Oncol 1994; 1: 271-277 [Medline]

Karakousis CP. Ilioinguinal lymph node dissection. Am J Surg 1981; 141: 299-303 [Medline]

Katz KA, Jonasch E, Hodi FS, Soiffer R, Kwitkiwski K, Sober AJ, et al. Melanoma of unknown primary: experience at Massachusetts General Hospital and Dana-Farber Cancer Institute. Melanoma Res 2005; 15: 77-82 [Medline]

Keilholz U, Conradt C, Legha SS, Khayat D, Scheibenbogen C, Thatcher, et al. Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients. J Clin Oncol 1998; 16: 2921-2929 [Medline]

Keilholz U, Goey SH, Punt CJ, Proebstle TM, Salzmann R, Scheibenbogen C, et al. Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 1997; 15: 2579-2588 [Medline]

Keilholz U, Punt CJ, Gore M, Kruit W, Patel P, Lienard D, et al. Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol 2005; %20;23: 6747-6755 [Medline]

Kelley JR, Duggan JM. Gastric cancer epidemiology and risk factors. J Clin Epidemiol 2003; 56: 1-9 [Medline]

Kelly JW, Sagebiel RW, Calderon W, Murillo L, Dakin RL, Blois MS. The frequency of local recurrence and microsatellites as a guide to reexcision margins for cutaneous malignant melanoma. Ann Surg 1984; 200: 759-763 [Medline]

Kenady DE, Brown BW, McBride CM. Excision of underlying fascia with a primary malignant melanoma: effect on recurrence and survival rates. Surgery 1982; 92: 615-618 [Medline]

Kenet RO, Kang S, Kenet BJ, Fitzpatrick TB, Sober AJ, Barnhill RL. Clinical diagnosis of pigmented lesions using digital epiluminescence microscopy. Grading protocol and atlas. Arch Dermatol 1993; 129: 157-174 [Medline]

Kettlewell S, Moyes C, Bray C, Soutar D, MacKay A, Byrne D, et al. Value of sentinel node status as a prognostic factor in melanoma: prospective observational study. BMJ 2006; 332: 1423 [Medline]

Kirkwood JM, Bender C, Agarwala S, Tarhini A, Shipe-Spotloe J, Smelko B, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20: 3703-3718 [Medline]

Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000; 18: 2444-2458 [Medline]

Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001; 19: 2370-2380 [Medline]

Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 2004; 10: 1670-1677 [Medline]

Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14: 7-17 [Medline]

Kirkwood JM. Melanoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Biologic therapy of cancer. 2nd ed. Philadelphia: JB Lippincott. 1995; 388-411 [Medline]

Klaase JM, Kroon BB, van Geel AN, Eggermont AM, Franklin HR, Hart AA. Prognostic factors for tumor response and limb recurrence-free interval in patients with advanced melanoma of the limbs treated with regional isolated perfusion with melphalan. Surgery 1994; 115: 39-45 [Medline]

Klaase JM, Kroon BB. Surgery for melanoma metastatic to the gastrointestinal tract. Br J Surg 1990; 77: 60-61 [Medline]

Koh HK, Norton LA, Geller AC, Sun T, Rigel DS, Miller DR, et al. Evaluation of the American Academy of Dermatology’s National Skin Cancer Early Detection and Screening Program. J Am Acad Dermatol 1996; 34: 971-978 [Medline]

Konefal JB, Emami B, Pilepich MV. Analysis of dose fractionation in the palliation of metastases from malignant melanoma. Cancer 1988; 61: 243-246 [Medline]

Koops HS, Vaglini M, Suciu S, Kroon BB, Thompson JF, Gohl J, et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 1998; 16: 2906-2912 [Medline]

Krengli M, Masini L, Kaanders JH, Maingon P, Oei SB, Zouhair A, et al. Radiotherapy in the treatment of mucosal melanoma of the upper aerodigestive tract: analysis of 74 cases. A Rare Cancer Network study. Int J Radiat Oncol Biol Phys 2006; 65: 751-759 [Medline]

Kristiansen SB, Anderson R, Cohen DM. Primary malignant melanoma of the cervix and review of the literature. Gynecol Oncol 1992; 47: 398-403 [Medline]

Kroon BB, Balm AJ, Nieweg OE, Hilgers FJ, van Dongen JA. Local excision of cutaneous melanoma with special reference to head and neck localization: how wide? Diagn Oncol 1993; 3: 253-257 [Medline]

Kroon BB, Nieweg OE, Hoekstra HJ, Lejeune FJ. Principles and guidelines for surgeons: management of cutaneous malignant melanoma. European Society of Surgical Oncology Brussels. Eur J Surg Oncol 1997; 23: 550-558 [Medline]

Kroon BB. Regional isolation perfusion in melanoma of the limbs; accomplishments, unsolved problems, future. Eur J Surg Oncol 1988; 14: 101-110 [Medline]

Lens MB, Dawes M, Goodacre T, Newton-Bishop JA. Elective Lymph Node Dissection in Patients With Melanoma: Systematic Review and Meta-analysis of Randomized Controlled Trials. Arch Surg 2002; 137: 458-461 [Medline]

Lie JA, Andersen A, Kjaerheim K. Cancer risk among 43000 Norwegian nurses. Scand J Work Environ Health 2007; 33: 66-73 [Medline]

Lienard D, Eggermont AM, Koops HS, Kroon B, Towse G, Hiemstra S, et al. Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res 1999; 9: 491-502 [Medline]

Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol 1984; 2: 164-168 [Medline]

MacKie R, Hole D. Audit of public education campaign to encourageearlier detection of malignant melanoma. BMJ 2003; 304: 1012-1015 [Medline]

MacKie R, Hunter JA, Aitchison TC, Hole D, Mclaren K, Rankin R, et al. Cutaneous malignant melanoma, Scotland, 1979-89. The Scottish Melanoma Group. Lancet 1992; 339: 971-975 [Medline]

MacKie RM, Bufalino R, Morabito A, Sutherland C, Cascinelli N. Lack of effect of pregnancy on outcome of melanoma. For The World Health Organisation Melanoma Programme. Lancet 1991; 337: 653-655 [Medline]

MacKie RM, Hole DJ. Incidence and thickness of primary tumours and survival of patients with cutaneous malignant melanoma in relation to socioeconomic status. BMJ 1996; 312: 1125-1128 [Medline]

MacKie RM. Pregnancy and exogenous hormones in patients with cutaneous malignant melanoma. Curr Opin Oncol 1999; 11: 129-131 [Medline]

Mahajan R, Blair A, Coble J, Lynch CF, Hoppin JA, Sandler DP, et al. Carbaryl exposure and incident cancer in the Agricultural Health Study. Int J Cancer 2007; 121: 1799-1805 [Medline]

Margolin KA, Liu PY, Flaherty LE, Sosman JA, Walker MJ, Smith JW, et al. Phase II study of carmustine, dacarbazine, cisplatin, and tamoxifen in advanced melanoma: a Southwest Oncology Group study. J Clin Oncol 1998; 16: 664-669 [Medline]

Markovic SN, Erickson LA, Rao RD, Weening RH, Pockaj BA, Bardia A, et al. Malignant melanoma in the 21st century, Part 1:Epidemiology, Risk Factors, Screening, Prevention, and Diagnosis. Mayo Clin Proc 2007; 82: 364-380 [Medline]

Martin L, Eschwege F, Marandas P, Luboinski L. intéret de la radiothérapie dans le traitement des mélanomas malins muqueux des voies aérodigestives supérieures: à propos de 34 cas traités à l’Institut Gustave Roussy. Bull Cancer Radiother 1991; 78: 223-231 [Medline]

Mathieu D, Kondziolka D, Cooper PB, Flickinger JC, Niranjan A, Agarwala S, et al. Gamma knife radiosurgery in the management of malignant melanoma brain metastases. Neurosurgery 2007; 60: 471-481 [Medline]

Mc Clay CE, Mc Clay CM. Systemic chemotherapy for the treatment of metastatic melanoma. Semin Oncol 1996; 23: 744-753 [Medline]

Mendenhall WM, Amdur RJ, Grobmyer SR, George TJ, Jr., Werning JW, Hochwald SN, et al. Adjuvant radiotherapy for cutaneous melanoma. Cancer 2008; 112: 1189-1196 [Medline]

Micheli A, Mugno E, Krogh V, Quinn MJ, Coleman M, Hakulinen T, et al. Cancer prevalence in European registry areas. Ann Oncol 2002; 13: 840-865 [Medline]

Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000b; 18: 158-166 [Medline]

Middleton MR, Lorigan P, Owen J, Ashcroft L, Lee SM, Harper P, et al. A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer 2000a; 82: 1158-1162 [Medline]

Middleton MR. Adjuvant interferon in the treatment of melanoma. Br J Cancer 1999; 80: 1679-1680 [Medline]

Milton GW. Clinical diagnosis of malignant melanoma. Br J Surg 1968; 55: 755-757 [Medline]

Miner TJ, Delgado R, Zeisler J, Busam K, Alektiar K, Barakat R, et al. Primary vaginal melanoma: a critical analysis of therapy. Ann Surg Oncol 2004; 11: 34-39 [Medline]

Mingione V, Oliveira M, Prasad D, Steiner M, Steiner L. Gamma surgery for melanoma metastases in the brain. J Neurosurg 2002; 96: 544-551 [Medline]

Mocellin S, Hoon DS, Pilati P, Rossi CR, Nitti D. Sentinel lymph node molecular ultrastaging in patients with melanoma: a systematic review and meta-analysis of prognosis. J Clin Oncol 2007;25: 1588-1595 [Medline]

Moloney DM, Gordon DJ, Briggs JC, Rigby HS. Recurrence of thin melanoma: how effective is follow-up? Br J Plast Surg 1996; 49: 409-413 [Medline]

Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006; 355: 1307-1317 [Medline]

Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg OE, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 1999; 230: 453-463 [Medline]

Morton DL, Wanek L, Nizze JA, Elashoff RM, Wong JH. 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. Annals of Surgery 1991; 214: 491-499 [Medline]

Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127: 392-399 [Medline]

Nathan FE, Mastrangelo MJ. Adjuvant therapy for cutaneous melanoma. Semin Oncol 1995; 22: 647-661 [Medline]

Nathanson L. Interferon adjuvant therapy of melanoma. Cancer 1996; 78: 944-947 [Medline]

NHMRC. National Health and Medical Research Council. Guidelines for preventive interventions in primary health care: Cardiovascular disease and cancer. Report of the Assessment of Preventative Activities in the Health Care System Initiative. Canberra (Australia): National Health and Medical Research Council, Commonwealth of Australia. 1996 [Medline]

Nichols L, Sorahan T. Cancer incidence and cancer mortality in a cohort of UK semiconductor workers, 1970-2002. Occup Med (Lond) 2005; 55: 625-630 [Medline]

Nield DV, Saad MN, Khoo CT, Lott M, Ali MH. Tumour thickness in malignant melanoma: the limitations of frozen section. Br J Plast Surg 1988; 41: 403-407 [Medline]

Nieweg OE, Kapteijn BA, Thompson JF, Kroon BB. Lymphatic mapping and selective lymphadenectomy for melanoma: not yet standard therapy. Eur J Surg Oncol 1997; 23: 397-398 [Medline]

O’Brien CJ, Petersen-Schaefer K, Ruark D, Coates AS, Menzie SJ, Harrison RI. Radical, modified, and selective neck dissection for cutaneous malignant melanoma. Head Neck 1995; 17: 232-241 [Medline]

O’Meara AT, Cress R, Xing G, Danielsen B, Smith LH. Malignant melanoma in pregnancy. A population-based evaluation. Cancer 2005; 103: 1217-1226 [Medline]

Olivier KR, Schild SE, Morris CG, Brown PD, Markovic SN. A higher radiotherapy dose is associated with more durable palliation and longer survival in patients with metastatic melanoma. Cancer 2007; 110: 1791-1795 [Medline]

Overgaard J, Gonzalez GD, Hulshof MC, Arcangeli G, Dahl O, Mella O, et al. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet 1995; 345: 540-543 [Medline]

Overgaard J, von der Maase, Overgaard M. A randomized study comparing two high-dose per fraction radiation schedules in recurrent or metastatic malignant melanoma. Int J Radiat Oncol Biol Phys 1985; 11: 1837-1839 [Medline]

Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg 2003; 129: 864-868 [Medline]

Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, et al. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol 1998; 16: 1425-1429 [Medline]

Pennoyer JW, Grin CM, Driscoll MS, Dry SM, Walsh SJ, Gelineau JP, et al. Changes in size of melanocytic nevi during pregnancy. J Am Acad Dermatol 1997; 36: 378-382 [Medline]

Perchel RE. Radiobiology and radiation treatment of malignant melanoma: a review. Radiat Oncol Invest 1994; 1: 249-260 [Medline]

Plotnick H, Rachmaninoff N, VandenBerg HJ, Jr. Polypoid melanoma: a virulent variant of nodular melanoma. Report of three cases and literature review. J Am Acad Dermatol 1990; 23: 880-884 [Medline]

Plotnick H, Rachmaninoff N, VandenBerg HJ, Jr. Polypoid melanoma: a virulent variant of nodular melanoma. Report of three cases and literature review. J Am Acad Dermatol 1990; 23: 880-884 [Medline]

Plukker JT, Vermey A, Roodenburg JL, Oldhoff J. Posterolateral neck dissection: technique and results. Br J Surg 1993; 80: 1127-1129 [Medline]

Pollock PM, Pearson JV, Hayward NK. Compilation of somatic mutations of the CDKN2 gene in human cancers: non-random distribution of base substitutions. Genes, Chromosomes & Cancer 1996; 15: 77-88 [Medline]

Prayer L, Winkelbauer H, Gritzmann N, Winkelbauer F, Helmer M, Pehamberger H. Sonography versus palpation in the detection of regional lymph-node metastases in patients with malignant melanoma. Eur J Cancer 1990; 26: 827-830 [Medline]

Presant CA, Bartolucci AA. Prognostic factors in metastatic malignant melanoma: The Southeastern Cancer Study Group Experience. Cancer 1982; 49: 2192-2196 [Medline]

Pukkala E, Aspholm R, Auvinen A, Eliasch H, Gundestrup M, Haldorsen T, et al. Cancer incidence among 10,211 airline pilots: a Nordic study. Aviat Space Environ Med 2003; 74: 699-706 [Medline]

Punt CJ, Eggermont AM. Adjuvant interferon-alpha for melanoma revisited: news from old and new studies. Ann Oncol 2001; 12: 1663-1666 [Medline]

Rajadhyaksha M, Grossman M, Esterowitz D, Webb RH, Anderson RR. In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast. J Invest Dermatol 1995; 104: 946-952 [Medline]

Rate WR, Solin LJ, Turrisi AT. Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys 1988; 15: 859-864 [Medline]

Ravaud A, Bedane C, Geoffrois L, Lesimple T, Delaunay M. Toxicity and feasibility of adjuvant high-dose interferon alpha-2b in patients with melanoma in clinical oncologic practice. Br J Cancer 1999; 80: 1767-1769 [Medline]

Reed RJ. The histological variance of malignant melanoma: the interrelationship of histological subtype, neoplastic progression, and biological behaviour. Pathology 1985; 17: 301-312 [Medline]

Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371: 569-578 [Medline]

Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, et al. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol 2002 Mar 15 ;20 (6 ):1600 -7 2002; 20: 1600-1607 [Medline]

Riou JP, Ariyan S, Brandow KR, Fielding LP. The association between melanoma, lymphoma, and other primary neoplasms. Arch Surg 1995; 130: 1056-1061 [Medline]

Rofstad EK. Fractionation sensitivity (alpha/beta ratio) of human melanoma xenografts. Radiother Oncol 1994; 33: 133-138 [Medline]

Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 1999; 17: 968-975 [Medline]

Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature 2001; 411: 380-384 [Medline]

Ross M, Meyer JL. Management of the regional lymph nodes in malignant melanoma: surgery, radiotherapy or observation. Front Radiat Ther Oncol 1994; 28:226-34 [Medline]

Ross M. Results of randomised surgical trials for melanoma. 6th World Congress on Cancer of the Skin. Buenos Aires, Argentina. abstract 1995 [Medline]

Rossi CR, Seno A, Vecchiato A, Foletto M, Tregnaghi A, De Candia A, et al. The impact of ultrasound scanning in the staging and follow-up of patients with clinical stage I cutaneous melanoma. Eur J Cancer 1997; 33: 200-203 [Medline]

Rosso S, Budroni M. Skin cancers: melanoma, non-melanoma cancers and Kaposi’s sarcoma. In: Crocetti E, et al, Editors. Cancer trends in Italy: figures from the Cancer registries (1986-97). Epidemiologia e Prevenzione. Marzo-aprile. 2004. [Medline]

Rounsaville MC, Cantril ST, Fontanesi J, Vaeth JM, Green JP. Radiotherapy in the management of cutaneous melanoma: effect of time, dose, and fractionation. Front Radiat Ther Oncol 1988; 22:62-78: 62-78 [Medline]

Rusthoven JJ, Quirt IC, Iscoe NA, McCulloch PB, James KW, Lohmann RC, et al. Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1996; 14: 2083-2090 [Medline]

Sause WT, Cooper JS, Rush S, Ago CT, Cosmatos D, Coughlin CT, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys 1991; 20: 429-432 [Medline]

Schadendorf D, Nestle FO, Broecker EB, Enk A, Grabbe S, Ugurel S, et al. Dacarbacine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) as first-line treatment of patients with metastatic melanoma: Results of a prospective-randomized phase III study. J Clin Oncol 2004; 22: 14S [Medline]

Scoggins CR, Ross MI, Reintgen DS, Noyes RD, Goydos JS, Beitsch PD, et al. Gender-related differences in outcome for melanoma patients. Ann Surg 2006; 243: 693-698 [Medline]

Shah JP, Kraus DH, Dubner S, Sarkar S. Patterns of regional lymph node metastases from cutaneous melanomas of the head and neck. Am J Surg 1991; 162: 320-323 [Medline]

Shibuya H, Takeda M, Matsumoto S, Hoshina M, Suzuki S, Takagi M. The efficacy of radiation therapy for a malignant melanoma in the mucosa of the upper jaw: an analytic study. Int J Radiat Oncol Biol Phys 1993; 25: 35-39 [Medline]

Sim FH, Taylor WF, Pritchard DJ, Soule EH. Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study. Mayo Clinic Proceedings 1986; 61: 697-705 [Medline]

Slingluff CLJ, Reintgen D. Malignant melanoma and the prognostic implications of pregnancy, oral contraceptives, and exogenous hormones. Semin Surg Oncol 1993a; 9: 228-231 [Medline]

Slingluff CLJ, Stidham KR, Ricci WM, Stanley WE, Seigler HF. Surgical management of regional lymph nodes in patients with melanoma. Experience with 4682 patients. Ann Surg 1994; 219: 120-130 [Medline]

Slingluff CLJ, Vollmer RT, Seigler HF. Multiple primary melanoma: incidence and risk factors in 283 patients. Surgery 1993b; 113: 330-339 [Medline]

Sorahan T. Mortality of UK oil refinery and petroleum distribution workers, 1951-2003. Occup Med (Lond) 2007; 57: 177-185 [Medline]

Stern RS. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001; 44: 755-761 [Medline]

Stone A, Cooper J, Koenig KL, Golfinos JG, Oratz R. A comparison of survival rates for treatment of melanoma metastatic to the brain. Cancer Invest 2004; 22: 492-497 [Medline]

Storper IS, Lee SP, Abemayor E, Juillard G. The role of radiation therapy in the treatment of head and neck cutaneous melanoma. Am J Otolaryngol 1993; 14: 426-431 [Medline]

Strobbe LJ, Hart AA, Rumke P, Israels SP, Nieweg OE, Kroon BB. Topical dinitrochlorobenzene combined with systemic dacarbazine in the treatment of recurrent melanoma. Melanoma Res 1997b; 7: 507-512 [Medline]

Strobbe LJ, Jonk A, Hart AA, Nieweg OE, Kroon BB. Positive iliac and obturator nodes in melanoma: survival and prognostic factors. Ann Surg Oncol 1999; 6: 255-262 [Medline]

Strobbe LJ, Nieweg OE, Kroon BB. Carbon dioxide laser for cutaneous melanoma metastases: indications and limitations. Eur J Surg Oncol 1997a; 23: 435-438 [Medline]

Temam S, Mamelle G, Marandas P, Wibault P, Avril MF, Janot F, et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer 2005; 103: 313-319 [Medline]

Testori A, Bartolomei M, Grana C, Mezzetti M, Chinol M, Mazzarol G, et al. Sentinel node localization in primary melanoma: learning curve and results. Melanoma Res 1999; 9: 587-593 [Medline]

Thomson DB, Adena M, McLeod GR, Hersey P, Gill PG, Coates AS, et al. Interferon-alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial. Melanoma Res 1993; 3: 133-138 [Medline]

Trotti A, Peters LJ. Role of radiotherapy in the primary management of mucosal melanoma of the head and neck. Semin Surg Oncol 1993; 9: 246-250 [Medline]

UICC (International Union Against Cancer). TNM classification of malignant tumours. Sobin LH, Wittekind Ch, editors. 6th ed. New York, Chichester, weinheim, Brisbane, Singapore, Toronto: Wiley-Liss. 2002 [Medline]

Urist MM. The role of surgery in the management of advanced melanoma. In: Rumke Ph, editor. Therapy of advanced melanoma. Pigment cell. Basel: Karger. 1990; 1-13 [Medline]

van der Esch EP, Muir CS, Nectoux J, Macfarlane G, Maisonneuve P, Bharucha H, et al. Temporal change in diagnostic criteria as a cause of the increase of malignant melanoma over time is unlikely. Int J Cancer 1991; 47: 483-489 [Medline]

Vasen HF, Bergman W, van Haeringen A, Scheffer E, van Slooten EA. The familial dysplastic nevus syndrome. Natural history and the impact of screening on prognosis. A study of nine families in the Netherlands. European Journal of Cancer & Clinical Oncology 1989; 25: 337-341 [Medline]

Veierod MB, Weiderpass E, Thorn M, Hansson J, Lund E, Armstrong B, et al. A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst 2003; 95: 1530-1538 [Medline]

Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L, et al. Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data. Lancet Oncol 2007; 8: 784-796 [Medline]

Veronesi U, Adamus J, Bandiera DC, Brennhovd O, Caceres E, Cascinelli, et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 1982; 49: 2420-2430 [Medline]

Veronesi U, Cascinelli N, Adamus J, Balch C, Bandiera D, Barchuk A, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 1988; 318: 1159-1162 [Medline]

Vrouenraets BC, Nieweg OE, Kroon BB. Thirty-five years of isolated limb perfusion for melanoma: indications and results. Br J Surg 1996; 83: 1319-1328 [Medline]

Vuoristo MS, Hahka-Kemppinen M, Parvinen LM, Pyrhonen S, Seppa H, Korpela M, et al. Randomized trial of dacarbazine versus bleomycin, vincristine, lomustine and dacarbazine (BOLD) chemotherapy combined with natural or recombinant interferon-alpha in patients with advanced melanoma. Melanoma Res 2005; 15: 291-296 [Medline]

Wada H, Nemoto K, Ogawa Y, Hareyama M, Yoshida H, Takamura A, et al. A multi-institutional retrospective analysis of external radiotherapy for mucosal melanoma of the head and neck in Northern Japan. Int J Radiat Oncol Biol Phys 2004; 59: 495-500 [Medline]

Wassberg C, Thorn M, Yuen J, Ringborg U, Hakulinen T. Second primary cancers in patients with cutaneous malignant melanoma: a population-based study in Sweden. Br J Cancer 1996; 73: 255-259 [Medline]

WCRF’amp; AICR. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR. 2007 [Medline]

Weinstock MA, Sober AJ. The risk of progression of lentigo maligna to lentigo maligna melanoma. Br J Dermatol 1987; 116: 303-310 [Medline]

Westerdahl J, Ingvar C, Masback A, Jonsson N, Olsson H. Risk of cutaneous malignant melanoma in relation to use of sunbeds: further evidence for UV-A carcinogenicity. Br J Cancer 2000; 82: 1593-1599 [Medline]

Wheatley K, Ives N, Eggermont AM, Kirkwood J, Cascinelli N, Markovic SN, et al. Interferon-a as adjuvant therapy for melanoma: An individual patient data meta-analysis of randomised trials. PROC ASCO 2007; 25, 18S: 478s [Medline]

Wheatley K, Ives N, Hancock B, Gore M, Eggermont A, Suciu S. Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev 2003; 29: 241-252 [Medline]

Wheatley K, Ives N, Hancock B, Gore M. Interferon as adjuvant treatment for melanoma. Lancet 2002; 360: 878 [Medline]

Whited JD, Hall RP, Simel DL, Horner RD. Primary care clinicians’ performance for detecting actinic keratoses and skin cancer. Arch Intern Med 1997; 157: 985-990 [Medline]

Wick MM, Sober AJ, Fitzpatrick TB, Mihm MC, Kopf AW, Clark WH, et al. Clinical characteristics of early cutaneous melanoma. Cancer 1980; 45: 2684-2686 [Medline]

Wiggins CL, Berwick M, Bishop JA. Malignant melanoma in pregnancy. Obstet Gynecol Clin North Am 2005; 32: 559-568 [Medline]

Wolfe JT. The role of screening in the management of skin cancer. Current Opinion in Oncology 1999; 11: 123-128 [Medline]

Yap LB, Neary P. A comparison of wide local excision with abdominoperineal resection in anorectal melanoma. Melanoma Res 2004; 14: 147-150 [Medline]

Young AM, Marsden J, Goodman A, Burton A, Dunn JA. Prospective randomized comparison of dacarbazine (DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in metastatic melanoma. Clin Oncol (R Coll Radiol ) 2001; 13: 458-465 [Medline]

Dr. Maurizio Amichetti (Author)
Ospedale Oncologico A. Businco – Cagliari, Italy
mail: amichettim@yahoo.it

Dr. Natale Cascinelli (Reviewer)
Istituto Nazionale Tumori – Milan, Italy
mail: direzionescientifica@istitutotumori.mi.it

Dr. Filippo de Braud (Editor)
START Clinical Editor – European Institute of Oncology – Milan, Italy
mail: filippo.de-braud@ieo.it

Prof. Alexander M.M. Eggermont (Author)
Erasmus MC – Daniel den Hoed Cancer Center – Rotterdam, The Netherlands
mail: a.m.m.eggermont@erasmusmc.nl

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gatta@istitutotumoti.mi.it

Dr. Antonella Romanini (Author)
Ospedale Santa Chiara – Pisa, Italy
mail: a.romanini@ao-pisa.toscana.it