Review

Paediatric melanoma: clinical update, genetic basis, and advances in diagnosis

Emily A Merkel, Lauren S Mohan, Katherine Shi, Elnaz Panah, Bin Zhang, Pedram Gerami

Paediatric melanoma is rare and challenging to diagnose. The three subtypes are Spitzoid melanoma, melanoma Lancet Child Adolesc Health 2019 arising in a congenital melanocytic nevus, and conventional (also known as adult-type) melanoma. Spitzoid Published Online melanomas have characteristic histopathological and genomic aberrations. Despite frequent involvement of the June 13, 2019 sentinel lymph nodes, most cases have an uneventful clinical course. Among congenital nevi, the risk of melanoma http://dx.doi.org/10.1016/ S2352-4642(19)30116-6 varies by projected size in adulthood, with the greatest risk in large or giant nevi. The clinical course is generally Department of Dermatology, aggressive and accounts for most melanoma-related deaths in childhood. In conventional melanoma, superficial Feinberg School of Medicine, spreading and nodular melanoma account for most cases, with risk factors and presentation largely similar to adult Northwestern University, disease. In this Review, we discuss advances in histological diagnosis using adjunctive molecular assays, and Chicago, IL, USA summarise the genetic basis of paediatric melanoma. (E A Merkel MD, L S Mohan MSc, K Shi BS, E Panah MD, B Zhang MS, P Gerami MD) Introduction whereas melanoma arising in a congenital nevus occurs Correspondence to: 5 Paediatric melanoma is a rare entity, accounting for less much less often. Conventioanl melanomas rarely occur, Dr Pedram Gerami, Department than 1% of all melanoma diagnoses. The annual incidence but when they do, most are nodular type. Superficial of Dermatology, Northwestern is estimated at four cases per million in the USA, with spreading melanoma is uncommon in childhood. In our University, Chicago, IL 60611, USA most diagnoses occurring in children aged 10 years or experience, many lesions reported as [email protected] older.1 However, the true incidence is difficult to spreading melanomas in childhood are more accurately determine because the diagnosis of paediatric melanoma described as atypical Spitz nevi. In adolescence is challenging and there are many conditions that mimic (11–19 years), the spitzoid subtype still accounts for half of it, including Spitz nevi, Spitz tumours, and other atypical all melanomas, whereas the remainder are considered nevi. Furthermore, diagnostic standards have changed conventional.5 Among conventional melanomas in over time, particularly for Spitzoid melanoma. For adolescents, superficial spreading is the most common example, the presence of tumour deposits within a pattern, with nodular being less common. Melanoma sentinel lymph node was previously considered to be a arising in giant congenital nevi is less common in diagnostic feature. However, in the past decade, several adolescents than in children. studies2,3 have described cohorts of patients with Spitzoid Trends from the 1970s to early 2000s suggested melanoma or atypical Spitz tumours with associated increasing rates of paediatric melanoma in the USA, with sentinel lymph node involvement who remain free of an average annual increase of 2–3% per year.6–9 However, subsequent metastases. Similarly, the presence of any in the past decade, short-term trends suggest a decreasing clonal segmental karyotypical or copy number aberration incidence.10 This change might reflect a decrease in the (excluding copying number gains in chromosome 11p, number of older adolescents with thin melanomas, and HRAS) detected by fluorescence in-situ hybridisation (FISH) or comparative genomic hybridisation had, in the past, been interpreted as diagnostic of melanoma. Key messages 3,4 However, several studies have reported the presence of • Paediatric melanoma is rare, with an annual incidence of small numbers of clonal segmental copy number four per million in individuals younger than 20 years in aberrations in benign atypical Spitz tumours, suggesting the USA that chromosomal abnorm­alities vary in diagnostic and • The three most common subtypes are Spitzoid prognostic importance. Therefore, older literature on melanoma, melanoma arising in a congenital melanocytic paediatric melanoma is sometimes problematic to nevus, and conventional (so-called adult-type) melanoma interpret in light of current understanding. • In diagnostically challenging cases, an experienced There are three subtypes of melanomas that are dermatopathologist familiar with ancillary and molecular prevalent in the paediatric population: Spitzoid tests should be consulted melanoma, melanoma arising in congenital melanocytic • In childhood, Spitzoid melanoma represents most cases nevi, and conventional (so-called adult-type) melanoma, and is considered a low-grade type of melanoma; which is usually of the superficial spreading or nodular melanoma arising in a congenital melanocytic nevus is type (table 1). Acral lentiginous melanoma and lentigo less common, but has a more aggressive disease course maligna types are exceedingly rare, with lentigo maligna • In adolescence, Spitzoid melanoma still accounts for reported almost exclusively in patients with deficiencies approximately half of all cases; the remainder are in DNA repair (ie, xeroderma pigmentosa). The frequency considered conventional, which share many similarities to of each subtype varies by age group. In childhood melanoma diagnosed in adulthood (<11 years), most reported melanomas are Spitzoid, www.thelancet.com/child-adolescent Published online June 13, 2019 http://dx.doi.org/10.1016/S2352-4642(19)30116-6 1 Review

Spitzoid melanoma Melanoma arising in CMN Conventional melanoma

Clinical Papule or nodule; frequently amelanotic, but can be New, rapidly growing nodule arising in the deep • Children: typically papules or nodules of any colour, but any colour (eg, pink-red to blue-black); distribution is dermis or subcutaneous tissues of a CMN; commonly often amelanotic; most do not follow ABCD criteria; not limited to sun-exposed skin solitary and ulcerated; by comparison, proliferative nodular subtype most common nodules commonly occur in multiples and are not • Adolescents: similar to presentation in adults with lesions ulcerated having ABCD criteria Histological Primary differential diagnosis is Spitz nevus vs The primary differential diagnosis is benign Nodular melanoma: similar to adult nodular melanoma; atypical Spitz tumour; most cells have abundant proliferative nodules arising in congenital nevi; no horizontal growth phase present; superficial spreading eosinophilic cytoplasm and characteristic Spitzoid compared with benign proliferative nodules, melanoma: similar to superficial spreading melanoma in cytomorphology; nuclear atypia is typically high melanomas typically have epithelioid or small blue adults with a preceding horizontal growth phase, pagetosis, grade; expansile growth in the form of expansile cell tumour-like morphology, with sheets of lentiginous growth, and junctional confluence with nodules or sheets; ulceration, epidermal melanocytes with high-grade nuclear atypia; mitotic frequent alteration of the epidermal contour; precursor consumption, brisk deep mitotic activity, and poor activity is high (often >3/mm2); zones of necrosis or nevus is common maturation are often seen; epidermal hyperplasia ulceration can be helpful in establishing a diagnosis might be seen on the surface, but Kamino bodies are relatively uncommon

CMN=congenital melanocytic nevi. ABCD=asymmetry, border irregularity, colour variegation, diameter >6 mm.

Table 1: Summary of clinical and histological features by subtypes of paediatric melanoma

and positive sentinel lymph node biopsies, whereas other Panel: Summary of genomic alterations by subtype of studies report the opposite.8,13–16 Meaningful conclusions paediatric melanoma from large databases are limited by several factors, most Spitzoid melanoma notably the incomplete recording of important features • Fusion events involving ROS1, NTRK1, NTRK3, ALK, BRAF, such as histological subtype or a coexisting congenital MAPK, MET, and RET genes melano­cytic nevus. As more is known about the genetic • Clonal segmental chromosomal copy number aberrations and molecular underpinning of melanoma, reporting of identified with fluorescence in-situ hybridisation analysis various mutations or chromosomal aberrations will be • Homozygous deletions in chromosome 9p21 and TERT increasingly important (panel). promoter mutations are considered high risk Spitzoid melanoma Melanoma arising in congenital melanocytic nevi Clinical presentation • Amplification of mutated NRASQ61K, NRASQ61R, and NRAS In 1948, Sophie Spitz introduced the term melanomas codons 12 and 13 of childhood to describe melanocytic lesions arising • Multiple segmental clonal chromosomal aberrations; rare early in life with histological similarities to conventional cases with chimeric gene fusions melanomas, but with seemingly less aggressive clinical • TERT promoter hypermethylation behaviour.17 Since then, lesions with similar features Conventional melanoma have been categorised into a spectrum of histological • Similar to melanomas in adults from intermittently diagnoses, including Spitz nevi, atypical Spitz tumours, sun-damaged skin and Spitzoid melanomas. Spitzoid melanoma can be • BRAFV600E and TERT promoter mutations common seen both in childhood and in adolescence, but • Segmental chromosomal copy number aberrations also constitutes a larger proportion of childhood melanoma. common Patients typically do not have traditional melanoma risk factors, although increased numbers of melanocytic nevi in these patients have been observed.18 Morpho­logically, suggests the effectiveness of public health initiatives, lesions usually present as pink or reddish nodules on the increased sunscreen use, decreased time spent outdoors, extremities or head and neck. Although they more earlier detection through dermoscopy, or improved access commonly display modified ABCD (asymmetry, border to dermatological services.10,11 Additionally, some of the irregularity, colour variegation, diameter >6 mm) criteria decrease could be because of improved histological than non-Spitzoid lesions do, the ABCD criteria are met classification of more atypical nevi that can mimic in only 40% of cases.19 Dermoscopy improves the clinical melanoma (eg, Spitz nevi). For younger patients, who detection of Spitzoid lesions. Spitz nevi are characterised have a higher proportion of tumours with poor prognostic by six main patterns: starburst, globular, multicomponent features and different genomic aberrations, the same or atypical, homogeneous, reticular, and dot vessels. might not be true.8,10,12 In paediatric melanoma, the Additional secondary features can include reticular relationship between patient age, tumour characteristics, depigmentation, superficial black network, or a blue- and mortality is complex. Some studies have shown white veil. Because there can be considerable overlap in decreased mortality in young patients despite having the dermoscopic features of benign and malignant thicker melanomas with ulceration, high mitotic rates, Spitzoid lesions, the current consensus is that any

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asymmetrical, raised, or nodular lesions warrant a biopsy A B to rule out atypia or malignancy.20 Environmental exposures and ultraviolet radiation are likely to have a small role in the development of these tumours, because chromosomal structural rearrangements are the initiating genomic event in most cases.

Histology A diagnosis of Spitzoid melanoma is supported by typical Spitzoid cytomorphological features, such as the presence of cells with abundant eosinophilic cytoplasm and a high degree of nuclear atypia. Additional diagnostic features can include ulceration, epidermal consumption, C D brisk deep mitotic activity, atypical mitosis, and poor maturation (figure 1).21 Compared with other subtypes of paediatric melanoma, Spitzoid melanoma can be quite deep. In two case series,18,19 the mean Breslow depth of Spitzoid melanoma at diagnosis ranged from 2·6 mm to 2·98 mm, compared with 1·2–1·93 mm in non-Spitzoid melanomas. Spitzoid melanomas are associated with a precursor lesion in only a few cases.18,19 In difficult cases, ancillary studies can provide additional diagnostic information. Immuno­histochemical assays for BRAFV600E and NRASQ61R are now readily available, and the presence of either pathogenic mutation should exclude a diagnosis Figure 1: Spitzoid melanoma of a Spitzoid neoplasm. Therefore, if a diagnosis of (A) A multicoloured (light brown, dark brown, and blue-grey) thin papule on the back of a 12-year-old white male. The papule had been present for 4 years but was gradually growing. (B) Histological examination revealed a wedge-shaped melanoma is truly supported by morphological and proliferation of Spitzoid melanocytes. Low-power micrograph (40 magnification) showed hyperchromatic, atypical genetic studies, the presence of a BRAF or NRAS cells. (C) High-power micrograph (100 magnification) showed multiple cells with mitotic activity, high-grade atypia, mutation would indicate a conventional melanoma pleomorphism, and hyperchromasia at all levels of the dermis. (D) Fluorescence in-situ hybridisation analysis showed diagnosis rather than a low-grade Spitzoid melanoma. A clonal chromosomal copy number gains at chromosome 6p25 in more than half of the cells. negative immunohistochemistry result is less helpful. parenchyma, and can also have few clonal segmental Genetics chromosomal copy number aberrations. In a cohort Most Spitzoid neoplasms arise from structural study27 of 24 patients who have Spitzoid neoplasms with chromosomal rearrangements—such as translocations, isolated deletions in chromosome 6q23, no distant chromosomal inversions, or interstitial deletions—that metastatic events were documented. result in the creation of a chimeric fusion protein. By contrast, in patients of all ages with a diagnosis of Mutations in HRAS also have a role.22 The most common Spitzoid neoplasms, homozygous deletions in chromo­ fusion events involve the kinase genes ROS1, NTRK1, some 9p21 have been linked to an increased risk of NTRK3, ALK, BRAF, MAPK, MET, and RET and have developing advanced locoregional disease, distant meta­ been observed in more than half of Spitzoid stases, and death.4 In a cohort study28 of 246 children with neoplasms.23–25 The resulting chimeric proteins are Spitzoid neoplasms, FISH analysis was found to be constitutively active and stimulate oncogenic signalling positive in 32 (13%) of patients, with 19 (8%) positive for pathways. These genomic fusions are observed across chromo­some 9p21 homozygous deletions. Although the spectrum of Spitz nevi, Spitz tumours, and Spitzoid outcomes were generally favourable, a subset of patients melanoma, highlighting that they are not indicative of (n=4) had more aggressive disease, three of whom benign or malignant behaviour.23 had homozygous deletions in chromosome 9p21. No In addition to these characteristic fusion proteins, recurrence was documented among patients with a clonal segmental chromosomal copy number aberrations negative FISH result. Although patients with Spitzoid and TERT promoter mutations can also support the neoplasms with homozygous­ deletions in chromosome diagnosis of Spitzoid lesions. FISH assays targeting 9p21 have a substantially worse prognosis than do patients chromosome 6p25 (RREB1), 6q23 (MYB), Cep6 without it, this cohort still has a substantially better (ie, centromere region of chromosome 6), 11q13 prognosis than patients with similarly staged conventional (CCND1), 9p21 (CDKN2A), Cep9, and 8q24 (c-MYC) have melanomas do. Furthermore, some of the patients been used to characterise Spitzoid lesions and their developed bulky lymph node metastases and in-transit behaviour.4,21,26 Spitz tumours can show involvement of disease without distant metastasis after 3 years. Therefore, sentinel lymph nodes, including the lymph node although homozygous deletions in chromo­some 9p21 www.thelancet.com/child-adolescent Published online June 13, 2019 http://dx.doi.org/10.1016/S2352-4642(19)30116-6 3 Review

increase risk, whether all patients with these deletions substantial effects on the expected prognosis and should be diagnosed as melanoma requires further disease management. The distinction between diagnosis investigation. In separate studies29,30 of Spitzoid neoplasms of a low-grade Spitzoid melanoma and a conventional in childhood, TERT promoter mutations have been melanoma is just as, if not more, important than correlated with the development­ of distant metastatic­ making the distinction between Spitz tumour and disease. Spitzoid melanoma.

Diagnosis and clinical course Melanomas arising in congenital nevi There is unlikely to be a single marker or feature that can Clinical presentation definitively diagnose a lesion as Spitzoid melanoma Congenital melanocytic nevi affect approximately 1% of rather than a benign spitzoid neoplasm. In difficult newborn babies33 and are classified according to their cases, this distinction should be made by an expert projected diameter in adulthood: small (<1·5 cm), dermatopathologist using clinical, morphological, and medium (1·5–19·9 cm), and large or giant (≥20 cm).34,35 molecular criteria, including multiple segmental clonal These nevi are slightly more common in females, but chromosomal aberrations, homozygous deletions in more likely to be associated with complications in chromosome 9p21, and TERT promoter mutations. Most males.36 Recently, the term congenital melanocytic nevus patients diagnosed with Spitzoid melanoma will have an syndrome has been coined to describe facial similarities uneventful clinical course. In our experience, a small among children with nevi, including a wide or prominent proportion of patients will show locoregional metastatic forehead, broad or round face, full cheeks, and other disease with bulky lymph node and in-transit metastasis, characteristic features.37 but only rarely will this lead to distant metastases and The overall risk of malignant transformation is death. Therefore, we favour the term Spitzoid melanoma estimated to be less than 1%, but this risk varies of childhood for this subtype of melanoma, with some substantially depending on nevus size.38 The risk in qualifying sentences in the pathological report that this small congenital nevi is very low, and is likely to be subtype of melanoma can be considered low grade and slightly higher than it is for only similarly sized acquired often has a better prognosis than do similarly staged nevi, whereas giant congenital melanocytic nevi with conventional melanomas. satellite lesions have a lifetime risk of 10–15%.39 In After a diagnosis is made, the decision to do a sentinel paediatric cases, approximately 70% of melanomas are lymph node biopsy should be considered carefully. In diagnosed before puberty, and up to 50% before the age atypical Spitz tumours, sentinel lymph node biopsy does of 5 years.40,41 Dermoscopically, small and medium not have the same prognostic value that has been shown congenital nevi are fairly homogeneous, with most for conventional melanoma. In a systematic review31 of lesions showing either a reticular or a globular pattern. more than 500 patients with atypical Spitz tumours, a Melanoma arising in such lesions can be identified as a positive sentinel lymph node biopsy was described in 119 disruption of these benign patterns or by identification (39%) of 303 patients undergoing sentinel lymph node of melanoma-specific structures. By contrast, melanoma biopsy, yet 118 (99%) of these patients survived after a arising in large or giant congenital nevi often occurs as a mean follow-up of 5 years.31 Therefore, we do not rapidly growing nodule arising in the deep dermis or recommend sentinel lymph node biopsy for patients subcutaneous tissues (figure 2), and dermoscopic with atypical Spitz tumours. The percentage of patients evaluation might not be as helpful.42 The biggest with Spitzoid melanoma showing tumour deposits on challenge in these cases is distinguishing melanoma sentinel lymph nodes might be higher than in those from benign proliferative nodules, and multiple biopsies with conventional melanoma, yet mortality rate remains might be necessary to establish a diagnosis.39 Because of low.18,32 Because the term Spitzoid melanoma is often the broad anatomical distribution and depth at which applied without well defined and reproducible criteria, most melanomas originate in congenital melanocytic patients generally undergo a sentinel lymph node biopsy. nevi, ultraviolet radiation is likely to have little or no role It could be reasonable, particularly in a child or if there in these cases. is genetic evidence of a fusion-driven process, to perform serial ultrasound in lieu of a sentinel lymph node biopsy. Histology However, more data are needed to clarify the role of The histological distinction of melanoma arising in giant biopsy. congenital nevi from proliferative nodules is also Conventional nodular melanomas in childhood are challenging. Proliferative nodules occur much more sometimes incorrectly diagnosed as Spitzoid melanoma, frequently than does melanoma, particularly in medium probably because of its occurrence in childhood and and large congenital melanocytic nevi, and can show histological depth of invasion. However, the prognosis some level of cytological atypia and brisk mitotic activity.43 of conventional nodular melanoma in childhood is Generally, the nodules are better circumscribed and likely not substantially different from that in adulthood. smaller in size, with most measuring less than 2 cm. The Therefore, such an error in interpretation can have presence of high-grade nuclear atypia, high mitotic

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activity, ulceration, and zones of necrosis can be used as A B morphological features suggestive of melanoma.

Genetics The initiating somatic mutation in giant congenital nevi involves NRASQ61K and NRASQ61R in up to 80% of lesions.44 Mutations in BRAFV600E are less common, occurring in approximately 5–15% of small congenital nevi.44 In addition to these oncogenic point mutations, there is some evidence that particular genotypes can predispose to the development and projected adult size of congenital melanocytic nevi. The presence of MC1R (encoding the melanocortin 1 receptor) variants has been associated C D with increased frequency and size of congenital melanocytic nevi.45,46 Specifically, the individuals with the V92M variant or an R allele (D84E, R151C, R160W, D294H) are more likely to have large (>60 cm) congenital melanocytic nevi, a size considered to predict an increased incidence of malignant melanoma. Amplification of mutated NRAS is one mechanism that leads to malignant progression in patients with congenital melanocytic nevi.47 Ultraviolet signature mutations have also been reported in these melanoma subtypes, although there is some evidence that these might represent passenger mutations, rather than primary drivers of E F tumour formation.30 By contrast with other melanoma subtypes, TERT promoter mutations are usually absent, but hypermethylation in the TERT promoter can be seen.30 Although whole chromosomal copy number aberrations are common in benign proliferative nodules, melanomas arising in giant congenital nevi often have multiple segmental clonal chromosomal aberrations.

Diagnosis and clinical course Melanoma arising in congenital nevi is generally considered to be highly aggressive.39 Small nevi are relatively common and affect approximately 1% of Figure 2: Melanoma arising in a congenital melanocytic nevus (A) A 3-month-old African-American girl with a growing nodule within a 13 cm thin brown plaque (denoted by livebirths, whereas the incidence of large nevi is estimated pink hair ties). (B) The nodule measured 4 cm by 3 cm and was firm, lobulated, and exophytic. (C) Histological at one in 20 000 newborn babies per year.48 This means examination (40 magnification) revealed a sheet-like proliferation of intermediate-sized melanocytes extending that nearly 200 infants are born in the USA with large nevi to the base of the specimen. (D) On higher power (100 magnification), the melanocytes showed high-grade each year. Approximately 10% of such lesions will undergo nuclear atypia and frequent mitotic figures. Apoptotic bodies were also seen. Excision and sentinel lymph node biopsy (not shown) revealed a Breslow depth of 8·0 mm and two (40%) of five lymph nodes were positive for malignant transformation and a third to two-thirds of malignant melanoma. (E) Fluorescence in-situ hybridisation analysis showed three or more copies of chromosome those cases will be fatal.38,49 This implies that as many as 6p25, compared with only one or two copies of chromosome 6q23 in the vast majority of cells, confirming the ten deaths per year are due to this subtype alone, most of presence of a clonal segmental chromosomal copy number aberration. (F) PET-CT showed increased metabolic which will occur by 10 years of age.50 Because paediatric activity in the left posterior cervical lymph nodes, consistent with metastatic disease. The patient was enrolled in a paediatric trial with pembrolizumab, a PD-11 inhibitor. melanoma accounts for only 18 deaths per year in the USA and the highest mortality rate is seen in adolescents,11 we suggest that this subtype accounts for most deaths in neurocongenital melanosis, hydro­cephalus, primary childhood melanoma. Most melanomas diagnosed in CNS tumours or malformations, developmental delay, or giant congenital nevi are deep and have an advanced behavioural abnormalities.36,52 In such cases, the term T-stage at the time of diagnosis. Among case reports of congenital melanocytic nevus syndrome has been fatal or metastasising paediatric melanoma arising in proposed. Features associated with neurocongenital congenital nevi, 28% of patients presented with T3 lesions melanosis include large nevus diameter or more than and 68% presented with T4 lesions at diagnosis.51 two medium-sized nevi and multiple satellite nevi.36,41,53 Congenital melanocytic nevi can be further complicated Location along the posterior axis has also been suggested by the presence of neurological abnormalities,­ including as a risk factor for neurological complications, but this melanosis of the brain parenchyma and leptomeninges, association can be confounded with the overall size of the www.thelancet.com/child-adolescent Published online June 13, 2019 http://dx.doi.org/10.1016/S2352-4642(19)30116-6 5 Review

nevus.54 For newborn babies with two or more nevi, Genetics regardless of projected adult size or site, results of a Comprehensive genomic analyses have shown that screening MRI obtained at less than 6 months of age are conventional paediatric melanomas share many the best predictors of neurodevelopmental­ abnormalities, similarities with adult melanomas from intermittently seizures, and cases requiring surgical intervention.55 sun-damaged sites. A study26 of 15 children and adolescents with conventional melanoma documented a Conventional (adult-type) melanoma high burden of single-nucleotide mutations, and more Clinical presentation than 80% of such mutations were consistent with Approximately 40–50% of paediatric melanomas are ultraviolet-induced damage. Furthermore, 87% of considered conventional. Among such cases, risk factors samples contained activating BRAFV600 mutations, and and baseline characteristics vary by age. Young patients nearly all (92%) had TERT promoter mutations. These (age <11 years) are more likely to be ethnically diverse, findings support a role for excessive sun exposure in the have a personal history of cancer, and develop lesions on development of conventional melanoma. the head, neck, and face.8 For adolescents (11–19 years), Familial melanoma susceptibility genes, CDKN2A risk factors are similar to those that are well established in and CDK4, have also been studied in relation to adult- adults, including light skin, environmental ultraviolet type melanoma. Germline mutations in CDKN2A or exposure, and increasing age. The likelihood of diagnosis CDK4 are found in up to 40% of familial melanomas, at different ages varies substantially by race. In the with most attributed to CKDN2A.57,58 Mutations in both first year of life, a similar incidence of melanoma was genes are associated with a clinical phenotype character­ found between white and non-white patients. The groups ised by numerous atypical nevi, early age at melanoma diverged by age 5–9 years, ultimately reaching a 40-fold diagnosis, and an increased frequency of multiple higher risk in white patients by age 20 years. This trend primary melanomas. Less is known about the prevalence likely reflects different inherent biological mechanisms or effect of these germline mutations in paediatric and cultural practices, including frequent sunburns and melanoma; several recent studies30,59,60 looking at indoor tanning habits in lighter-skinned individuals. CDKN2A aberrations suggest that such mutations are Clinically, melanomas arising in the paediatric population absent or exceedingly rare. However, one study61 found are often nodular and amelanotic, and atypical vascular or that, among melanoma-prone families with or without crystalline structures can be seen on dermoscopy. For CDKN2A germline mutations, there is a six to 28 times pigmented and macular lesions, failure to conform to higher proportion of paediatric melanoma cases than in recognised benign dermoscopic patterns and the presence the general population of patients with melanoma in of melanoma-specific structures can aid in diagnosis, just the USA.61 as in adults.42 MC1R is another susceptibility gene that has been investigated in relation to the development of adult-type Histology melanoma. As a G-protein-coupled receptor located on Adult cases of melanoma are catogorised into the plasma membrane of melanocytes, the melanocortin 1 four histological subtypes: superficial spreading mela­ receptor has a role in melanogenesis by influencing the noma, nodular melanoma, acral lentiginous melanoma, type and amount of melanin produced. MC1R is highly and lentigo maligna melanoma. In paediatric patients, polymorphic in humans with varying degrees of functional the superficial spreading and nodular subtypes account loss, leading to characteristic hair and skin colour for most adult-type melanoma cases, whereas acral phenotypes. Germline MC1R variants have been studied lentiginous melanoma and lentigo maligna melanoma in relation to BRAF-mutated melanoma arising from non- occur rarely. Superficial spreading melanoma is chronically sun-damaged skin. In a cohort of patients with characterised by an initial horizontal growth phase with BRAF-mutant melanomas, BRAF mutations were six to asymmetry, poor circumscription, irregular lentiginous 13 times more likely to be found in patients with at least and nested growth, and pagetoid cells. Nodular one MC1R variant allele than in those with wild-type melanomas have little or no horizontal growth phase, and MC1R. This association was strongest in younger patients are better characterised by an invasive, horizontal (aged <40 years). Most BRAF mutations in this cohort did component beyond the basement membrane. In both not show characteristic ultraviolet-signature damage, children and adolescents, a substantial proportion of suggesting that MC1R variants could be an inherited melanomas (80%) arise in association with a pre-existing susceptibility factor, predisposing to BRAF-mutated nevus, compared with a third of lesions in adults.56 melanomas after minimal sun damage in early life.62 Classic aggressive histopathological features—including pagetosis, ulceration, and Breslow depth—must be Management and prognosis interpreted with caution in paediatric cases, because Management of paediatric melanoma has been based on these features can also be seen in lesions mimicking well established guidelines for adult patients, despite melanoma, including congenital nevi, proliferative growing evidence that this disease, particularly in young nodules, or nevi of special sites. children, has a different clinical course compared with

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Intervention Study design Participants Tumour type Status NCT02332668 Pembrolizumab Phase 1/2; single group Age 6 months to Advanced melanoma, other Recruiting (MK-3475–051/KEYNOTE-051) assignment; open label <18 years advanced solid tumours, or relapsed or refractory lymphoma NCT03878719 Binimetinib plus Phase 1; single group Age 12–17 years Unresectable or metastatic Recruiting encorafenib assignment; open label; BRAFV600-mutant melanoma NCT03553836 Pembrolizumab Phase 3; randomised; Age 12 and older Resected high-risk stage II Recruiting (MK-3475–716/KEYNOTE-716) parallel assignment; melanoma double-blinded; placebo controlled NCT03215511 LOXO-195 Phase 1/2; single group Age 1 month and Previously treated NTRK Recruiting assignment; open label older fusion cancers, including melanoma NCT03420963 Cyclophosphamide; Phase 1; single group Age 12 months to Recurrent or refractory solid Recruiting etoposide; natural-killer assignment; open label 40 years tumours, including cells infusion cutaneous melanoma NCT03340506 Dabrafenib, trametinib, Phase 4; single group Child; adult; older Melanoma, non-small-cell Recruiting or both assignment; open label adult lung cancer, solid tumour, (rollover study rare cancers, high-grade of a previous glioma trial)

Table 2: Ongoing therapeutic trials adults. Wide local excision with adequate margins (based subtypes (28·3%). However, the mortality rate in patients on overall tumour depth) is the initial therapy of choice. with Spitzoid melanoma was less than half of that seen in Surgical margins are based on guidelines in adults, other subtypes. This is consistent with other studies,66 which recommend 1 cm margins for melanomas that are suggesting that Spitzoid melanoma of childhood is of low thinner than 1 mm; 1–2 cm margins for melanomas that grade, which can show locoregional involvement but rarely are 1–2 mm in depth; and 2 cm surgical margins for results in distant metastasis. Further studies taking into melanomas deeper than 2 mm.63 Some question the account the histological subtypes and differences in feasibility and necessity of these margins in children, biological behaviour are needed to better understand the because of frequent anatomical or functional limitations role of sentinel lymph node biopsy in paediatric melanoma. due to smaller body surface area and evidence that For paediatric patients with advanced disease, there is paediatric melanoma can have a lower risk of local scarce evidence on the safety or efficacy of adjuvant recurrence than can adult melanoma of the same therapy. Adjuvant interferon or pegylated interferon thickness.64 have been suggested as safe and feasible options.67,68 Following excision, the indications for and decision to Newer agents, including ipilimumab, have been proceed with sentinel lymph node biopsy are less clear. evaluated in phase 2 trials69 for adolescents with stage III Most studies are based on single-institution experiences or IV malignant melanoma with promising tumour in which small cohorts limit the generalisability of data. responses and a similar safety profile to that seen in In a population-based study65 of 310 patients younger adults. Early reports from an ongoing phase 2 trial70 of than 20 years diagnosed with melanoma (Breslow depth pembrolizumab in paediatric patients with advanced >0·75 mm) between 2004 and 2011, no difference in melanoma; PD-L1–positive, advanced solid tumour; or melanoma-specific survival was seen between those who other lymphoma have shown tolerability, encouraging received a biopsy and matched controls who did not. tumour response and progression-free survival. BRAF Among those undergoing biopsy, a positive result was inhibitors, including vemurafenib, have not been well associated with substantially worse melanoma-specific studied in advanced paediatric melanoma,71 but results survival at 84 months (89%) than in those who had a from three paediatric patients with BRAFV600E-mutated negative biopsy result (100%) at 84 months, but survival high-grade gliomas suggest sustained responses to was better than in adults with a similar extent of disease combined BRAF and MEK inhibitor therapy.72 Because (66%). of the biological similarities between the disease in However, studies that further stratify paediatric adults and adolescents, we support the notion that melanoma by subtype suggest that the value of sentinel adolescents should be included in adult clinical trials lymph node biopsy can depend on the subtype. A study18 when possible (table 2).73 found that biopsy was done more frequently in Spitzoid melanomas (71·4%) than in non-Spitzoid subtypes Conclusions (49·4%), and that Spitzoid melanomas had a substantially There are several distinct clinical, morphological, and higher rate of positive biopsy results (56%) than did other genetic patterns of paediatric melanoma. Spitzoid www.thelancet.com/child-adolescent Published online June 13, 2019 http://dx.doi.org/10.1016/S2352-4642(19)30116-6 7 Review

5 Busam KJ, Gerami P, Scolyer RA. Pathology of Melanocytic Search strategy and selection criteria Tumors. Philadelphia: Elsevier, 2019. 6 Austin MT, Xing Y, Hayes-Jordan AA, Lally KP, Cormier JN. We searched PubMed for articles published in English or Melanoma incidence rises for children and adolescents: translated into English between Jan 1, 1948, and an epidemiologic review of pediatric melanoma in the United States. J Pediatr Surg 2013; 48: 2207–13. March 1, 2019, using the terms “pediatric”, “childhood”, 7 Hamre MR, Chuba P, Bakhshi S, Thomas R, Severson RK. “adolescent”, “melanoma”, “Spitz”, “spitzoid”, “congenital Cutaneous melanoma in childhood and adolescence. melanocytic nevus”, “incidence”, “mortality”, Pediatr Hematol Oncol 2002; 19: 309–17. “epidemiology”, “treatment”, “clinical”, “dermoscopy”, 8 Strouse JJ, Fears TR, Tucker MA, Wayne AS. Pediatric melanoma: risk factor and survival analysis of the surveillance, epidemiology “histologic”, and “molecular”. 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Although paediatric melanoma characterization of pediatric and adolescent melanomas: remains rare, advances in histopathological diagnosis multicenter study of 52 cases. J Am Acad Dermatol 2018; 78: 278–88. 20 Lallas A, Apalla Z, Ioannides D, et al. Update on dermoscopy of and adjunctive molecular tests, as well as ongoing efforts Spitz/Reed naevi and management guidelines by the International to understand the genetic underpinnings of this disease, Dermoscopy Society. Br J Dermatol 2017; 177: 645–55. will be important to more appropriately diagnose patients 21 Gammon B, Beilfuss B, Guitart J, Gerami P. Enhanced detection of spitzoid melanomas using fluorescence in situ hybridization with and inform future treatments. 9p21 as an adjunctive probe. Am J Surg Pathol 2012; 36: 81–88. Contributors 22 Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number All authors contributed equally to this manuscript. increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol 2000; 157: 967–72. Declaration of interests 23 Wiesner T, He J, Yelensky R, et al. Kinase fusions are frequent in PG has been a consultant at Castle Biosciences, Myriad Genetics, and Spitz tumours and spitzoid melanomas. Nat Commun 2014; 5: 3116. DermTech; and received honoraria for this. All other authors declare no 24 Quan VL, Zhang B, Mohan LS, et al. Activating structural competing interests. alterations in MAPK genes are distinct genetic drivers in a unique subgroup of spitzoid neoplasms. Am J Surg Pathol 2019; Acknowledgments 43: 538–48. We thank Kara Walton for providing figure 1 and Lacey Kruse for 25 VandenBoom T, Quan VL, Zhang B, et al. Genomic fusions in providing figure 2. pigmented spindle cell nevus of reed. Am J Surg Pathol 2018; References 42: 1042–51. 1 Noone AM Howlader N, Krapcho M, et al. SEER Cancer Statistics 26 Gerami P, Jewell SS, Morrison LE, et al. Fluorescence in situ Review (CSR) 1975–2015. 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