How should melanoma in children be managed?
Melanoma in children and adolescents is rare. Although melanoma occurring in adults has many similar features there is enough variance in presentation and behaviour to warrant a separate guidelines section on childhood and adolescent melanoma (CAM).
Different definitions of ‘childhood’ have been used. Studies reporting the experiences of individual centres have often merged all ages of young patients, some labelling those up to 20 years of age as ‘childhood’ cases. However, for these guidelines, it was considered more appropriate to separate patients into two groups, those under and those over 10 years old, since melanoma incidence rises sharply around the time of puberty.
Melanoma remains rare in childhood and uncommon in adolescent groups, however, it is the second most common cancer in adolescents and young adults. Australian and international databases report the incidence of childhood and adolescent melanoma to be approximately 0.5–0.6 per 100,000 per year.
A systematic review indicated that paediatric melanoma (<10 years of age) represents 1–3% of all paediatric malignancies and accounts for 1–4% of melanoma cases across all ages.
There are conflicting reported data on the incidence trends for paediatric melanoma, with different studies reporting stable, increased or decreased in rates. Several factors that might contribute to these differences in incidence trends have been suggested, such as potential under-reporting in registries, and misclassification of atypical nevi in prepubertal children. From birth the incidence rate of melanoma increases with age, especially once adolescence is reached.
It has been suggested that the change in the observed incidence of childhood and adolescent melanoma, particularly the latter, may be attributable to sun-related behaviour. Countries that have established sun protection programs in recent decades, such as Sweden, the USA and Australia, are starting to report a decreased incidence.
Pathology and aetiology
There are three major subtypes of melanoma occurring in children and adolescents:
- Spitzoid subtype (see Clinical features of melanoma)
- congenital naevus-associated subtype
- conventional (adult) subtype.
Spitzoid tumours are histological subtypes of melanocytic lesions that are more commonly seen in children and young adults. These lesions can be difficult to assess in terms of their malignant potential. Spitzoid tumours can be benign, malignant or of uncertain malignant potential (see Management of melanocytic tumour of unknown malignant potential).
Most melanomas occurring in prepubescent children (less than 10 years of age) are predominantly of the Spitzoid type (also termed malignant Spitz tumour). This subtype displays much histological overlap with atypical Spitzoid tumours which can be difficult to distinguish from melanoma. Some of these melanomas are associated with chromosomal translocations involving ALK, ROS1, NTRK1/3 or MET.
An infrequently encountered subtype of melanoma occurring in prepubescent children is that associated with the presence of a large/giant congenital naevus. These melanomas tend to be aggressive and they commonly contain NRAS mutations. This subtype, although uncommon, is disproportionately observed in prepubescent children compared to adolescents or adults.
Most melanomas occurring in adolescent children are conventional or adult subtypes of melanoma. They display histological features reflecting this, share molecular features with melanomas occurring in adult patients, and are commonly associated with BRAFV600E mutations. An ultraviolet mutation signature is identified in conventional-type melanomas occurring in adolescent patients. Most paediatric melanomas develop sporadically (de novo) without a known underlying condition or genetic predisposition such as a germline mutation in the melanoma susceptibility gene Cyclin D Kinase 2 A(CDKN2A).
Ultraviolet light exposure plays a significant role the development of in a large proportion of CAM.
Melanomas in children and adolescents (CAM) as described above can present as a typical adult type melanoma, or in conjunction with a CMN or as a Spitzoid lesion.
Cordoro et al found that 60% of children aged <10 years and 40% of adolescents presenting with melanoma did not meet the traditional ABCDE criteria. This resulted in frequent delayed diagnosis. Given that CAM are more likely to present in an atypical manner, then a modified version of the ABCDE criteria can be applied. CAM often presents as amelanotic, symmetrical lesions with regular borders, uniform colour and diameters of ≤6mm. It has been proposed the following criteria be included as they are more specific to CAM:
- A = amelanotic
- B = bleeding, bump
- C = colour uniformity
- D = de novo, any diameter
- E = evolution of mole.
Using the ABCDE criteria in conjunction with dermoscopy improves diagnostic accuracy in childhood melanoma.
Patients with conditions such as xeroderma pigmentosum, familial atypical mole-melanoma syndrome, >100 melanocytic naevi, atypical melanocytic naevi and those with genetic predisposition to melanoma are more prone to developing CAM. Immunosuppressed patients may also be at increased risk.
CAM may be associated with thicker tumours and higher rates of lymph node metastasis when compared with melanoma in adults. Despite this, survival rates are similar to those seen in adults with melanoma. CAM patients have a higher risk of recurrence and melanoma deaths more than five years after initial diagnosis, hence long term follow up is necessary in these patients.
Genetic predisposition to melanoma
Most cases of melanoma are considered to be sporadic, however melanoma susceptibility is increased in individuals with inherited mutations in the CDKN2A or CDK4 gene (see Genetic determinants of high risk for new primary melanomas).
Routine genetic testing of patients is not recommended however, referral to a genetics service should be considered if there is a significant family history of melanoma or where a genetic predisposition to melanoma is suspected. It is recommended that patients thought to be at increased risk should have regular clinical examinations and optimise their sun protection.
Primary melanoma may also uncommonly arise in a congenital melanocytic naevus (CNM). The incidence is low, of the order of 1–2%, however it greatly varies according to the severity of the congenital phenotype. Those at increased risk include patients with giant CNM, >40cm projected adult size and accompanied by multiple smaller CNM. A substantial proportion of cases of primary melanoma develop in the central nervous system rather than the skin. The presence of congenital neurological abnormalities on screening MRI in the first 6 months of life has been shown to correlate with an overall increased incidence of melanoma of 12%.
Transplacental transmission of melanoma
Transplacental transmission of melanoma, an exceedingly rare condition, was first reported in 1949 and there had been less than a dozen recorded cases up until 2005. This rarity is due to the fact that even within the small subset of women with placental involvement of metastatic melanoma, the risk of transmission to the foetus is only about 17%. Nearly all affected infants died within 18 months.
Where a lesion is suspected of being a melanoma then an excisional biopsy with narrow margins is recommended. Partial biopsies may lead to sampling errors and misdiagnosis. Lesions with Spitzoid characteristics can be especially difficult to categorise as benign or malignant and any melanoma diagnosis should be referred to a pathologist with particular expertise in this field.
Atypical spitzoid lesions that have uncertain malignant potential are more likely to metastasise to a sentinel lymph node. However, a positive sentinel node due to an atypical Spitzoid lesion of uncertain malignant potential rarely translates into an adverse effect on an individual’s survival. Unless the lesion is a definite Spitzoid melanoma, sentinel node biopsy should avoided.
The pathology slides of all Spitz-like lesions in children suspected of being malignant should be referred to histopathologists who are highly experienced in the differential diagnosis of such lesions.
Treatment and survival
The mainstay of treatment for melanoma in children, as in adults, is surgical. There is a need to integrate recent advances in the management of adult patients into the paediatric population, recognising that the relative rarity of melanoma in childhood precludes prospective trials of treatment and survival in children. Once the diagnosis of melanoma is established, whether it has arisen in a giant naevus, a small CNM, a dysplastic naevus or de novo, surgical excision should be performed with the same excision margins recommended for adults with melanomas of similar thickness. Freemyer et al reported significantly improved survival for CAM patients who received care at a specialised melanoma treatment centres even when controlling for stage of disease at presentation.
Sentinel node biopsy should be considered in CAM using the same criteria as for adult melanoma.
Despite the higher incidence of nodal metastases, survival is equal to or better than what is reported for adults. However, long-term follow-up is necessary in this population since recurrences and deaths are often seen beyond 5 years.
Sentinel node biopsy has been shown to provide prognostic information in children but there is no evidence yet of a direct survival advantage. It is reported to be well tolerated in this group. No difference was found in overall survival (OS) in patients <10 years of age who were node-positive versus node-negative. In patients <10 years of age, sentinel node biopsy and completion lymph node dissection are not associated with increased OS. In adolescents, nodal positivity is a significant negative prognostic indicator (hazard ratio 4.82, 95% confidence interval 3.38–6.87).
Recent data from the MLST-2 study indicate that observation, rather than completion lymph node dissection, is appropriate in patients with a positive sentinel node. However, these patients require close follow-up as per stage III disease guidelines dictate. Completion lymph node dissection should be carefully evaluated in CAM patients as it is associated with significant complication rates.
Follow-up of CAM patients should follow adult guidelines. Special consideration should be given to the frequency of any investigations involving ionizing radiation. Consideration of the principles of “image gently” should be considered.
There is currently no consensus on the management of inoperable stage III or stage IV CAM patients and no studies have been undertaken in these age groups. The use of high-dose interferon alpha-2b therapy in children has been found to be well-tolerated with less associated toxicity, both after resected high-risk melanoma and after a positive sentinel node biopsy. However, interferon has been superseded with the introduction of immunotherapies and targeted therapies for melanoma in the adult population and this will most likely occur in the CAM group. This management is best delivered under the guidance of a multidisciplinary team specialised in childhood malignancy and melanoma management.
Melanoma susceptibility is increased in individuals with inherited mutations in the CDKN2A or CDK4 gene. However, most cases of melanoma are sporadic. Routine genetic testing of patients at risk is not recommended due to lack of definitive evidence. It is recommended that patients thought to be at increased risk should have regular clinical examinations and optimise their sun protection.
The impact of a malignant tumour diagnosis in paediatric patients, regardless of outcome, is psychosocially and physically profound. The family unit, patient, siblings, parents and occasionally grandparents all need to be considered when seeking to address the psychosocial functioning of the family.
Psychosocial effects can manifest as increased levels of depression, anxiety and concerns regarding mortality amongst all within the family unit. A further layer of complexity, that sets a diagnosis in paediatric patients aside from adult patients, is the need to contextualise the diagnosis within a developmental stage. A child’s cognitive development determines the extent to which the young person can process the diagnosis.
Clinicians must be sensitive and adept at dealing with the natural transition of patients developmentally from childhood, to adolescence to young adulthood as these critical timepoints will herald a time to readdress disease knowledge and understanding with the possibility of further psychosocial support being required. Therefore, like the treatment of any childhood malignancy, international data would support the inclusion of psychosocial services to prevent long term emotional and behavioural problems amongst the family unit.
Melanocytic tumour of unknown malignant potential in children
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