Malignant melanoma

Definition

Malignant melanoma of skin occurs very rarely in children and adolescents; nevertheless, it is the most common type of skin cancer in young people. Patients under the age of 20 account for only 1.3 to 2.0 percent of all cases of malignant skin melanoma in the population.

Epidemiology

The rapidly growing year-on-year percentage change in the incidence rate of malignant melanoma is alarming: the increase is about 1% per year in children under the age of 15, up to 7% per year in adolescents, and more than 12% in young adults under the age of 24. In the young generation, malignant melanoma of skin is significantly more common in girls – with the exception of children under the age of 5, where malignant skin melanoma is more prevalent in boys. In most young girls, melanoma is mostly located on their arms, legs and trunk, whereas in small boys, it is mostly located in the area of head and neck.

Aetiology

The aetiology of malignant skin melanoma in childhood is not exactly known. The malignant transformation might occur either spontaneously, or in association with several predisposing factors and risk factors.

  1. Familial occurrence of malignant skin melanoma is more common in children (25.6%) than in adults (17.3%). Usually, there is a positive family history of skin melanoma, and a provable genetic mutation of the CDKN2A gene. Familial melanomas develop at a young age, multiple primary foci of melanoma can be present.
     
  2. Sunlight and lifestyle are the most notorious risk factors for the development of malignant skin melanoma. The durations and “doses” of individual suntanning sessions are more important than the cumulative dose of sunlight. Individuals with skin phototypes I and II are most at risk. The children’s skin is more sensitive to exposition to the ultraviolet light; it is thinner than the skin of adults, and can therefore be considered as a high-risk phototype. For these reasons, infants up to the age of 6 months should not be exposed to UV light at all, and toddlers until the age of 2 years should be protected by suitable clothes and should not be exposed to the midday sun.
     
  3. Pigmented naevi. In childhood, there is a variety of pigmented naevi, which undergo constant changes since birth up to the puberty. The so-called junctional naevi are moles found in the junction (border) between the epidermis and dermis layers of the skin. Such growth activity is considered to be normal in childhood. Junctional activity of a naevus at the pubescent age, however, is considered to be a pathology.
    • Spitz’s juvenile melanoma is a specific form of a pigmented naevus in children. It occurs between the ages of 3 and 13 years. It is usually hemispheric, rigid, smooth and fast-growing (2–3 months). It develops on a healthy skin. It is benign in most cases, but atypical Spitz’s naevi, transitional and malignant forms also exist.
    • Large numbers of melanocytic naevi and the development of dysplastic naevi might present a potential risk. Individuals with at least 50 melanocytic naevi and/or at least 5 atypical melanocytic naevi are considered to be at a higher risk.
  4. Genetic factors. There are several genetic conditions which are associated with a higher risk of development of malignant melanoma:
    • xeroderma pigmentosum (photodermatosis)
    • dysplastic naevus syndrome
    • Werner syndrome
    • mutation in the RB1 gene

      Neurocutaneous melanosis is characterised by large or multiple congenital naevi associated with meningeal melanosis or skin melanoma. Leptomeningeal melanoma develops in about 64% of patients, and its prognosis is usually very poor.
  5. Trauma is considered to be a causative factor for the development of malignant melanoma on the soles, palms, and under the nails. It is practically irrelevant in children.
     
  6. Immune disorders. Patients with congenital immune disorders, patients after the treatment of another malignancy (Hodgkin’s lymphoma) and patients on a long-term immunosuppressive therapy (after organ transplantation) are at a twofold to sixfold higher risk of developing melanoma than the general population.

However, most cases of malignant melanoma in pre-pubescent children and in adolescents develop de novo in healthy individuals who have none of the above-mentioned risk factors.

Clinical symptoms

Clinical symptoms of melanoma are rather unspecific, and there are many skin lesions in children which can imitate the malignant melanoma (benign melanocytic naevus, dysplastic naevus, atypical blue naevus, haemangioma, pyogenic granuloma, warts, Spitz naevus etc.).

Most melanomas in children and adolescents develop de novo. Unlike melanomas in the adult population, 50 to 70 percent of melanomas in children aged over 10 are amelanotic.

  • In pigmented naevi, the most common symptoms of developing melanoma include changes in size and shape of the naevus, irregular borders, changing colour and irregularities in the pigment (the so-called ABCDE criteria: Assymetry, Border, Color, Diameter, Evolving).
  • The feeling of itching in the current lesion, or even bleeding from the lesion. An originally flat lesion rises above the surrounding surface and becomes palpable.
  • If malignant melanoma is not diagnosed at an early stage, the fist symptoms can involve palpable regional lymph nodes, or even symptoms arising from the metastases.

Types of malignant melanoma of skin

Melanomas fall into four basic categories. Three of them begin in situ, and sometimes become invasive; the fourth (NMM, see below) is invasive from the start.

  • Lentigo maligna melanoma (LMM) is a junctional naevus. It is virtually non-existent in children.
  • Superficial spreading melanoma (SSM) is characterised by an invasive horizontal growth of cancer cells in the epidermis. It is the most common type of melanoma, occurring in about 70% of patients. The focus is usually unevenly pigmented, and of an irregular shape.
  • Acral lentiginous melanoma (ALM) develops in acral regions of the body (palms, soles, under the nails). It is extremely rare in children and adolescents.
  • Nodular malignant melanoma (NMM) is characterised by a vertical invasive growth. It occurs in 15 to 20 percent of cases. NMM is the most aggressive type of melanoma, and the most common type of melanoma among children and adolescents.

Diagnosis

Diagnosis of malignant melanoma in children and adolescents is complicated, as this type of cancer is usually not considered as a possibility due to a rare occurrence, absence of generally known risk factors, atypical presentation, and a large number of other pigmented naevi. When compared to melanomas diagnosed in the adult population, melanomas in patients under the age of 20 are usually of a larger size and thickness.

Almost 80% of paediatric patients have a localised disease at the time of diagnosis. Regional lymph nodes are affected in 10–15% of patients, and distant metastases are present in less than 5% of patients.

  • A detailed examination of the entire surface of skin, including the hairy part of the head and adnexa, is essential. Suspicious lesions should be photographed and examined by a dermatoscope.
  • Imaging examination: The whole-body 18F-FDG PET imaging (including the brain) has significantly contributed to a more precise diagnosis, often combined with a CT scan.
  • Definitive diagnosis is confirmed by a histological examination (Clark level, Breslow thickness, Ki-67, angioinvasion, neurotropism, presence of ulceration).
  • Molecular genetic testing for mutations in NRAS, KRAS, BRAF, CDKN2A, NF1 can rule out a hereditary melanoma or a wild-type melanoma.

Treatment

Due to a rare occurrence of malignant melanoma in children, there are only two specific paediatric studies. Treatment of malignant melanoma in children, adolescents and young adults is therefore currently based on the experience and trials of melanoma treatment in the adult population.

Localised disease

  • Surgery is the choice of treatment. Extirpation of the primary focus with a safe margin is essential; the margin width is determined by the melanoma thickness (melanoma less than 2 mm thick: safe margin of 1 cm; melanoma more than 2 mm thick: safe margin of 2 cm). At the same time, the sentinel lymph node is identified and resected. The surgical treatment of paediatric melanomas does not differ from that applied for melanomas in the adult population.
  • As for melanocytic lesions with spitzoid features, radical resection (excision) is recommended, without specification of the safe margin width. Surgical resection is recommended for lesions with clear signs of atypia.

Spread to regional lymph nodes

Malignant melanoma typically spreads to regional lymph nodes. If regional lymph nodes are proved to be affected, a complete removal (dissection) of those lymph nodes is indicated.

Metastatic disease

  • Malignant melanoma might metastasise via bloodstream, leading to metastases in the lungs, liver, brain, bones, or even distant subcutaneous metastases. Resection of metastases (if possible) is the choice of treatment.
  • Biological therapy might be indicated for inoperable cases of malignant melanoma: immunotherapy (ipilimumab, monoclonal antibody against CTLA4) or targeted therapy (vemurafenib, BRAFV600E inhibitor). Although numerous trials of various biological therapies have been performed in the adult population, there have been none so far in the paediatric oncology.

Prognosis

It is difficult to predict the prognosis of malignant melanoma in children and adolescents. Regardless of the patient’s age, clinical stage is the most significant prognostic factor. The ten-year survival rate is more than 90% in patients with localised melanoma, but less than 10% in patients with advanced metastatic melanoma.

Negative prognostic factors for malignant melanoma in children include:

  1. clinical factors – age (patients over the age of 10 – but also infants – are at a higher risk), sex (mortality rate is 25% higher in boys than in girls), location elsewhere than on the limbs (trunk, head and neck), and clinical stage
  2. pathological factors – type of melanoma (nodular), amelanotic melanoma, thickness (Breslow), presence of ulceration, high proliferation activity, presence of vascular invasion, positive sentinel lymph node
  3. biological factors – presence of a mutation in the BRAF gene, hereditary melanoma

Literature

  1. Neier, M., Pappo, A., Navid, F.: Management of melanomas in children and young adults. Journal of Pediatric Hematology/Oncology 2012; 34(Suppl 2): S51–S54.
  2. Paradela, S., Fonseca, E., Pita-Fernández, S., Kantrow, S.M., Diwan, A.H., Herzog, C., Prieto, V.G.: Prognostic factors for melanoma in children and adolescents: a clinicopathologic, single-center study of 137 Patients. Cancer 2010; 116(18): 4334–4344.
  3. Livestro, D.P., Kaine, E.M., Michaelson, J.S., Mihm, M.C., Haluska, F.G., Muzikansky, A., Sober, A.J., Tanabe, K.K.: Melanoma in the young: differences and similarities with adult melanoma: a case-matched controlled analysis. Cancer 2007; 110(3): 614–624.
  4. Ferrari, A., Bono, A., Baldi, M., Collini, P., Casanova, M., Pennacchioli, E., Terenziani, M., Marcon, I., Santinami, M., Bartoli, C.: Does melanoma behave differently in younger children than in adults? A retrospective study of 33 cases of childhood melanoma from a single institution. Pediatrics 2005; 115(3): 649–654.
  5. Mills, O., Messina, J.L.: Pediatric melanoma: a review. Cancer Control 2009; 16(3): 225–233.
  6. Bajčiová, V.: Maligní melanom u dětí a dospívajících. Onkologie 2013; 7(2): 69–73.