Melanoma in children

INTRODUCTION — Pediatric melanoma, usually defined as melanoma occurring in patients younger than 20 years, is rare, accounting for approximately 1 percent of all melanomas [1,2]. Because of its rarity, the biology, clinical behavior, and histopathologic features of pediatric melanoma are not well characterized. The diagnosis is often difficult to establish, especially in prepubertal children in whom melanoma may present as a nonspecific, amelanotic lesion with a morphology resembling a benign growth, resulting in frequent misdiagnosis and delays in diagnosis. Delay in diagnosis and tumor biology probably both account for thicker melanomas found in children [3,4].

This topic will discuss the clinical presentation, diagnosis, and management of melanoma in children. Melanoma in adults is discussed separately. Spitz nevi and atypical Spitz tumors are also discussed separately.

●(See "Melanoma: Clinical features and diagnosis".)

●(See "Pathologic characteristics of melanoma".)

●(See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

●(See "Spitz nevus and atypical Spitz tumors".)

EPIDEMIOLOGY

Incidence — Melanoma is rare in individuals younger than 20 years. In the United States, the estimated annual incidence rate was nine per million in those aged 15 to 19 years according to the 1975 through 2014 Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review [5]. Melanoma is even rarer in younger children, with estimated annual incidence rates of one, two, and three per million in the age groups 1 to 4, 5 to 9, and 10 to 14 years, respectively [5]. Lower incidence rates of pediatric melanoma have been reported among Hispanic and American Indian children <19 years (2.1 and 3.3 per million individuals, respectively) [6]. Melanoma in non-White children is more likely to present at an earlier age compared with White children [7].

Progressive increases in melanoma incidence in children have been reported in the United States and other countries over the last few decades, with approximately 90 percent of cases occurring among children older than 10 years [1,8,9]. However, an analysis of data from the National Program of Cancer Registries-SEER combined database for the period 2001 to 2015 showed a decline in incidence rates of melanoma in adolescents and young adults in the United States [10]. This finding is consistent with trends in Australia, Sweden, and the Netherlands, where reductions in pediatric melanoma incidence have also been reported [11-13].

Risk factors — Risk factors for adult melanoma are also significant for pediatric patients. They include genetic factors (eg, family history of melanoma, light skin phenotype, inherited deoxyribonucleic acid [DNA] repair defects, variants in genes associated with cancer predisposition syndromes), environmental factors (eg, excessive exposure to sunlight, history of sunburns, indoor tanning), and iatrogenic or acquired immunosuppression.

In a cohort of 70 pediatric patients with melanoma, 40 percent had high nevus counts, 27 percent had a positive family history of melanoma, and 25 percent reported a history of sunburn [14-16].

Variants of the melanocortin-1 receptor (MC1R) gene, a key regulator of skin pigmentation, are likely genetic risk factors for melanoma in children and adolescents.

●In a multicenter case-control study including 233 children/adolescents (≤20 years) and 932 adults with melanoma and 932 controls, children and adolescents with melanoma had higher frequencies of any MC1R variants, r variants, V60L variants, and D294H variants than adults with melanoma and unaffected controls [17].

●In an Italian cohort of 123 patients younger than 21 years with histologically confirmed melanoma (116 conventional melanomas, 4 spitzoid, and 3 of other types), MC1R pathogenic variants were found in 67 percent of patients, whereas pathogenic variants affecting CDKN2A were extremely rare in sporadic cases (2 percent) [18].

Other risk factors include germline variants in RB1 (associated with hereditary retinoblastoma) and in WRN (associated with Werner syndrome) [15,19]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis" and "Werner syndrome".)

PATHOGENESIS — Pediatric melanoma is considered to be biologically distinct from adult melanoma due to several distinctive features: greater thickness at presentation, higher frequency of amelanotic lesions, greater rate of sentinel node positivity, and overall less aggressive clinical course [3,20]. Whether the greater thickness at presentation is due to delayed diagnosis or more rapid growth of these tumors in children has not been determined.

Molecular testing has provided insights in the molecular pathogenesis of pediatric melanoma [21]. As in adults, activating BRAF mutations are the predominant genetic alteration of conventional melanoma in children. The term "conventional melanoma" refers to melanoma subtypes typically seen in adults, including superficial spreading, nodular, acral lentiginous, and desmoplastic melanoma.

NRAS mutations in pediatric cases are primarily seen in melanomas arising in large and giant congenital melanocytic nevi (the congenital nevi also harbor NRAS mutations regardless of melanoma), while kinase fusions characterize Spitz melanomas [21].

●A whole genome or whole exome sequencing and targeted sequencing of 23 pediatric melanoma samples, including 15 conventional (superficial spreading and nodular) melanomas, 3 associated with congenital nevi, and 5 spitzoid melanomas, revealed [22]:

•Conventional melanomas (ie, superficial spreading and nodular) from 15 patients aged 10 to 20 years were histologically similar to adult melanoma and showed a high burden of somatic single nucleotide mutations, in most cases consistent with ultraviolet (UV) radiation damage. The activating BRAF V600 mutation was found in 13 of 15 patients, and TERT promoter mutations were found in 12 of 13 patients. Inactivating mutations or biallelic deletions in CDKN2A and PTEN were found with low frequency.

•All three melanomas associated with congenital nevi had NRAS (but not BRAF or TERT promoter) mutations, which is not surprising based on the known NRAS mutant status of most large and giant congenital nevi [23]. Although the sizes of the three congenital nevi were not reported, their mutation profile and the fact that all children were <5 years of age and had a fatal outcome suggest that the congenital nevi were likely large lesions.

•Two of the five spitzoid melanomas demonstrated kinase fusions but not BRAF/NRAS mutations.

●In another study of 26 pediatric melanomas, whole exome sequencing revealed that 6 of 10 conventional melanomas harbored the somatic BRAF V600E mutation, a biallelic deletion of CDKN2A was detected in two melanomas, a monoallelic deletion of CDKN2A was detected in one advanced melanoma, and TERT promoter mutations were detected in three cases [24]. Among the 12 spitzoid melanomas, none had TERT promoter mutations; four had a heterozygous deletion of CDKN2A; and three had ALK, ROS1, and MROH5 fusions. In both groups, most mutations were ultraviolet B (UVB) signature mutations.

In other reports, kinase fusions that include MAP3K8, ALK, NTRK1, NTRK3, MET, RET, ROS1, and BRAF have been found with variable frequency [25-29]. Of note, kinase fusions have also been identified in a significant number of Spitz nevi and atypical Spitz tumors [27,30-32]. (See "Spitz nevus and atypical Spitz tumors", section on 'Mutational analysis'.)

Another whole genome sequencing study of tumor samples from 50 adolescent and young adults (median age 20 years, range 10 to 30 years) with stage III/IV melanoma (superficial spreading in 43 of 50 patients) demonstrated BRAF mutations in 96 percent of cases (82 percent p.V600E) [33]. TERT was the second most frequently mutated gene, with promoter hotspot mutations present in 80 percent of cases, followed by PTEN (36 percent), CDKN2A (24 percent), TP53 (24 percent), and RBI (12 percent). Ninety percent of the mutations found were UV radiation signature mutations [34]. Germline MC1R risk alleles were identified in 8 of 10 patients with conventional melanoma.

These findings support the hypothesis that conventional melanoma in adolescents is similar to BRAF-mutant adult melanoma and confirm that UV radiation is likely a major mutagenic factor in melanomas occurring in adolescence.

Melanomas associated with congenital nevi and Spitz melanomas are instead distinct entities with a different genetic profile, clinical course, and prognosis. (See 'Spitzoid melanoma' below.)

CLINICOPATHOLOGIC SUBTYPES — Data on the frequency of histologic subtypes of pediatric melanoma have not been collected systematically, but it is estimated that approximately 40 to 50 percent of pediatric melanomas are of the conventional subtype (adult melanoma type), which shares similar morphologic features with adult cutaneous melanoma (ie, superficial spreading and nodular) [35].

Conventional (adult type) melanoma — Conventional pediatric melanomas (ie, melanoma subtypes typically seen in adults, including superficial spreading, nodular, acral lentiginous, and desmoplastic melanoma) occur predominantly in adolescents and less frequently in younger children. In a cohort of children and adolescents with melanoma, conventional melanoma was diagnosed in 36 of 62 children ≤11 years (58 percent) and in 392 of 452 adolescents 12 to 19 years (87 percent) [20]. Pediatric conventional melanomas are superficial spreading or nodular in most cases, while the acral lentiginous and lentigo maligna melanoma types are exceedingly rare.

In a meta-analysis of individual patient data that included 1002 patients with pediatric melanoma from 213 studies (median age 12 years, interquartile range 6 to 15 years), of 544 melanomas for which information on histologic type was available, 43 percent were superficial spreading melanomas, 27 percent nodular, and 20 percent spitzoid/spindle cell [36].

Spitzoid melanoma — "Spitzoid" melanomas (ie, melanomas with clinical and histologic features of Spitz tumors) are most often seen in children <11 years. In children, spitzoid melanoma has clinicopathologic features, biologic behavior, and prognosis distinct from adult-type spitzoid melanoma [37]. "Spitz melanoma" is a subtype of spitzoid melanomas with distinct kinase fusions and TERT mutations. There are no clinical features that distinguish adult spitzoid melanoma from pediatric spitzoid melanoma, but prepubertal lesions have reassuring clinical courses.

●A multisite investigation spanning over two decades in 12 large academic institutions did not identify any fatal cases of spitzoid melanoma in prepubertal children [38].

●Similarly, there were no fatal outcomes among the Spitz melanomas and atypical Spitz tumors reported in the 2022 prospective registry Molecular Analysis of Childhood Melanocytic Tumors, which integrates molecular analysis of pediatric melanomas [25].

Melanoma arising in congenital nevi — Melanoma develops in approximately 1 to 3 percent of patients with congenital melanocytic nevi and in up to 12 percent of those with giant congenital melanocytic nevi [39-41]. In a systematic review of melanoma risk associated with congenital melanocytic nevi, the mean age at diagnosis was 15.5 years (median 7 years) [42]. (See "Congenital melanocytic nevi", section on 'Risk of melanoma'.)

Melanomas associated with congenital melanocytic nevi may arise in the skin, the central nervous system, or other extracutaneous locations. In an analysis of a United Kingdom cohort of 448 children with congenital melanocytic nevi observed between 1988 and 2016, 12 children (2.7 percent) developed a melanoma [40]. Of these, seven were primary melanomas of the central nervous system, two were primary cutaneous, one was primarily lymph nodal, and two were melanomas with unknown primary. An abnormal screening magnetic resonance imaging (MRI) of the central nervous system in the first year of life in these patients was associated with a higher melanoma risk compared with a normal screening MRI (12 versus 2 percent, respectively). (See "Congenital melanocytic nevi", section on 'Neurocutaneous melanosis'.)

Congenital and infantile melanoma — Congenital and infantile melanoma, defined as melanoma present at birth or developing in the first year of life, is exceedingly rare, with only a few cases reported in the literature [43].

Congenital melanoma can arise de novo, in association with a congenital nevus, or from transplacental metastases from metastatic maternal melanoma. The pathophysiology of transplacental spread of melanoma is unclear. Factors involved may include the high vascularity of the placenta, placental production of angiogenic and growth factors, and impaired fetal immune response.

In a retrospective review of 87 females with placental or fetal metastases, 27 cases were attributed to melanoma [44]. The fetus was affected in six cases, and five of six infants succumbed to disease. In one report of transplacental metastasis of terminal maternal melanoma, the infant experienced spontaneous regression of all lesions and was disease free at the time of the report publication [45].

There are no long-term follow-up data on unaffected children born to mothers with metastatic melanoma to exclude the possibility of a delayed presentation of the disease. However, neonates who do not present melanoma metastases at birth should be considered at high risk and undergo close clinical monitoring. Some experts recommend repeated clinical evaluation during the first year of life and even beyond. Pathologic examination of the placenta for melanoma is also warranted in these cases.

CLINICAL PRESENTATION — The clinical presentation of pediatric melanoma is, in many cases, atypical and varies depending on the patient's age, clinical subtype, and anatomic site [4]. The atypical appearance of pediatric melanomas can cause a diagnostic challenge, leading to a delay in diagnosis and thicker lesions (picture 1).

●Prepubertal children – In prepubertal children, the clinical presentation of melanoma often does not conform to the conventional ABCDE criteria (asymmetry, border irregularities, color variegation, diameter ≥6 mm, evolving lesion) (picture 2). Melanoma may present as:

•Symmetric, pigmented lesion with regular borders simulating a banal nevus

•Pink or reddish, symmetric, dome-shaped papule simulating a Spitz nevus (picture 3)

•Amelanotic, nodular lesion simulating a pyogenic granuloma (picture 4) or common wart

•Lesion that may be uniform in color and smaller than 6 mm

These features have been summarized in a "pediatric ABCD" criteria (amelanotic, bleeding/bump, color uniformity, de novo/any diameter) to be used in combination with the ABCDE rule in clinical settings to identify suspicious lesions in children [14]. (See 'Physical examination' below.)

In a series of 70 children with melanoma, 60 percent of lesions in children <11 years and 40 percent of lesions in adolescents lacked the conventional ABCDE criteria [14]. Lesions were more likely to be small and amelanotic in young children and frequently uniform in color in adolescents, with lesion evolution being a nearly universal finding.

●Adolescents and young adults – In adolescents and young adults, the clinical presentation of melanoma is similar to the presentation in adults. Melanomas in this age group are most often superficial spreading or nodular and fulfill the ABCDE clinical criteria in many cases. Most patients have a light phenotype and may have a family history of melanoma [46].

It should be noted that the "evolving lesion" criterion of the ABCDE rule may be overlooked in both children and adolescents, in whom the onset of new nevi as well as their increase in size (either increase in diameter and/or elevation) are common occurrences.

In an Italian series of 39 children with pediatric melanoma (median age 15 years, range 5 to 18 years), 95 percent of lesions were pigmented, and over 60 percent clinically showed the classic ABCDE features (asymmetry, irregular border, more than two colors, diameter >6 mm, evolving lesion) [47].

In a study of 52 pediatric melanoma cases, approximately 52 percent of lesions manifested the conventional ABCDE criteria [48]. However, the clinical morphology differed significantly between cases of spitzoid melanoma and nonspitzoid melanomas, with 40 percent of the spitzoid and only 13.5 percent of nonspitzoid melanoma showing the "pediatric ABCD" features.

●Melanoma in congenital nevi – The presentation of melanoma in a congenital nevus is rare, occurring in approximately 1 percent of all patients with congenital melanocytic nevi [41], 2 percent of patients with large congenital melanocytic nevi [39], and up to 15 percent of highest-risk patients with giant congenital melanocytic nevi and multiple congenital melanocytic nevi (previously termed "satellites"). Visible clinical changes may prompt concern for melanoma in a congenital melanocytic nevi, such as a new-onset, distinct-appearing, growing, bleeding papule or nodule (in contrast to proliferative nodules, which can occur gradually with multiple lesions and are not expected to grow continuously with symptoms or bleeding) [49].

Importantly, up to one-third of children who present with congenital melanocytic nevi-associated melanomas have central nervous system-associated melanoma [50], which may present with a change in neurologic symptoms or symptoms of increased intracranial pressure.

DIAGNOSIS — The diagnosis of melanoma in pediatric patients should be made through a combination of clinical, histologic, and genetic characteristics and requires insight of experienced dermatopathologists [51].

General considerations — The diagnosis of melanoma in children is challenging due to its rarity and often banal clinical presentation. The frequent "benign" appearance of melanoma in children frequently results in a delayed diagnosis and higher disease stage.

●In a study of 70 children with melanoma, the time from detection to diagnosis was ≥6 months in 82 percent of patients and >12 months in 62 percent of patients, and in keeping with the diagnostic delay, more than 90 percent of childhood cases and 50 percent of adolescent cases were diagnosed with stage IIa disease or higher [14].

●In a series of 96 primary pediatric melanomas from 86 patients, the prebiopsy clinical diagnosis was a benign lesion in 40 of 68 cases (59 percent) [46]. Pediatric melanomas that mimicked benign-appearing lesions had a fivefold higher risk of having a Breslow thickness >1 mm.

Therefore, diagnosing melanoma in children requires a high index of suspicion based on history, clinical findings, and dermoscopic findings as well as a low threshold for the decision to perform a biopsy. The definitive diagnosis is reliant upon histopathologic evaluation and on molecular tests, where available.

History — A prominent feature in pediatric melanoma is lesion evolution over time. However, melanoma evolution in children may be misinterpreted as the expected and natural evolution of benign, pigmented lesions during childhood and adolescence. Patients or parents/caregivers may report a history of bleeding, particularly for ulcerated lesions. Additional complaints may include pain, itch, or discomfort, all of which can prompt evaluation in the clinic. Moreover, patients and parents/caregivers should be queried for recent treatments (eg, wart removal preparations) or trauma, as melanoma may have been misdiagnosed and treated as a benign entity.

Physical examination — In older adolescents and young adults, melanoma most often presents as a conventional "adult-type" melanoma that will manifest the conventional ABCDE criteria (asymmetry, border irregularity, color variegation, large diameter, evolving lesion) in most cases.

In contrast, melanomas in prepubertal and pubertal children are often of the spitzoid type, and many of these will lack the conventional features of asymmetry, border irregularity, color variegation, and large diameter included in the ABCDE rule. (See 'Clinical presentation' above.)

Thus, additional sets of pediatric criteria (the pediatric ABCD and the CUP criteria) have been proposed to be used in combination with the conventional ABCDE rule in nonspecialized care settings to identify lesions suspicious for melanoma [14,52]:

●A = Amelanotic

●B = Bleeding, bump

●C = Color uniformity

●D = De novo, any diameter

●C = Color is pink/red, changing

●U = Ulceration, upward thickening

●P = Pyogenic granuloma-like lesions, pop-up of new lesions

While these additional criteria may increase sensitivity for melanoma detection, they are not specific for melanoma. In a study of 52 pediatric melanoma cases (of which 15 were spitzoid and 37 nonspitzoid), only 40 percent of spitzoid melanomas and 13 percent of nonspitzoid melanomas fulfilled the proposed pediatric ABCD criteria [48].

If a lesion suspicious for melanoma is found on skin examination, palpation of the regional lymph nodes should be performed to evaluate for enlarged nodes.

Evaluation of congenital nevi should include palpation for new nodules or focal changes, especially in large congenital nevi, since these melanomas often develop below the dermo-epidermal junction.

Dermoscopy — Dermoscopy has emerged as a useful tool to differentiate the morphology of various pediatric skin lesions that resemble melanoma. Evaluation using a dermatoscope is painless and well tolerated by children in the clinic [53].

It must be emphasized that even in the absence of melanoma-specific structures and atypical vascular morphology, all lesions that do not manifest an unequivocal benign pattern and lesions that appear atypical should be considered for histopathologic examination. A useful approach may also include measurement, photography, and close clinical follow-up for evaluation of lesion evolution.

Ten melanoma-specific dermoscopic structures have been identified:

●Atypical network

●Negative network

●Streaks

●Shiny, white structures

●Atypical dots and globules

●Irregular blotches

●Blue-white veil

●Regression structures

●Peripheral, brown, structureless areas

●Atypical vessels

The presence of at least 1 of these 10 structures should raise suspicion of melanoma. Since a subset of pediatric melanomas are amelanotic, the examination of vascular structures and presence of shiny, white structures is of primary importance (table 1). Any nodular, pink lesion with dotted vessels; milky, red globules; serpentine vessels; shiny, white structures seen with polarized light dermoscopy; or negative (inverse) network should be considered suspicious for melanoma. (See "Dermoscopic evaluation of skin lesions", section on 'Criteria for melanoma'.)

It is important to acknowledge that many of the dermoscopic features observed in melanoma can also be seen in Spitz nevi, making the clinical differential diagnosis between Spitz nevi and melanoma challenging.

An analysis of 49 dermoscopic images from 52 pediatric melanoma cases (mean age 15 years, range 2 to 20 years) found that the dermoscopic patterns most frequently associated with nonspitzoid melanomas were the multicomponent pattern and nevus-like pattern (58 and 25 percent, respectively) [48]. The multicomponent pattern is the "classic" dermoscopic melanoma pattern encountered in superficial spreading-type melanoma, with most cases presenting with a disorganized distribution of dots/globules, atypical network, blue-white veil, vessels, and negative network. In most cases, spitzoid melanomas showed a "vascular, pink, Spitz-like pattern" with atypical vessels and shiny, white structures or a "pigmented, Reed-like" pattern with black, blue-gray, and dark brown colors, peripheral streaks, and dark blotches. In this study, all cases of melanoma revealed at least one of the melanoma-specific structures.

Biopsy — Biopsy is warranted when there is clinical suspicion of melanoma. An excisional biopsy including the subcutaneous fat with a small (2 mm) rim of normal-appearing skin is the preferred biopsy method. While incisional biopsy, including deep shave biopsy, is acceptable (especially if the lesion is large and/or in a cosmetically sensitive area), superficial shave biopsies should be avoided since the full depth of the lesion is required to accurately determine the degree of maturation of the melanocytes, evaluate the base of the lesion, and obtain an accurate measure of tumor thickness.

Pathology — Not only are pediatric melanomas difficult to diagnose clinically, but they may also be challenging histopathologically. Among pediatric melanomas, childhood tumors may show more aggressive histopathologic features than adolescent tumors (picture 5). In a cohort of 12 children and 20 adolescents with melanoma, the median Breslow thickness was 3.5 mm for lesions in children versus 1.5 mm in adolescents [28].

●Spitz melanoma – It can be difficult to distinguish a Spitz melanoma from an atypical Spitz tumor because they have similar architectural and cytologic features, although the number and severity of atypical features are increased for melanomas (picture 3). For example, a large lesion diameter (especially >1 cm), increased mitotic rate (especially >6 per mm²), high cellular density, and ulceration raise concern for malignancy in Spitz tumors.

Genetic analysis can be helpful to identify "spitzoid" melanomas that do not have the signature Spitz mutations (eg, ALK, ROS1, RET, NTRK, NTRK3, BRAF, MET kinase fusions). For example, presence of BRAF V600E mutation in a lesion that has morphologic spitzoid features is a concerning feature.

Unfortunately, there are no identified genetic alterations that reliably distinguish Spitz melanoma from atypical Spitz tumors. Expert dermatopathologists can recognize features to diagnose atypical Spitz tumors, but in some cases, expert consultants are not able to come to consensus on challenging lesions.

Atypical Spitz/spitzoid neoplasms are more worrisome if they are:

•Clinically large (>1 cm) [54] or with an expansile nodule [55-57].

•Arising in a patient over age 10 [27,30,38,54].

•Presenting histopathologic features that are concerning and have been reported with more aggressive disease, including mitotic index of ≥6 mitoses/mm², ulceration, extension of the tumor into subcutaneous fat [54], or high-grade nuclear atypia [37,58]. (See "Spitz nevus and atypical Spitz tumors", section on 'Histopathology'.)

●Conventional melanoma – The same criteria for the histologic diagnosis, classification, and stage grouping for adult melanoma are applied to the pediatric conventional subtypes. The affected individuals are typically adolescents or postpubertal children. (See "Pathologic characteristics of melanoma" and "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

●Lesions of uncertain malignant potential – There are pediatric melanocytic tumors of uncertain malignant potential for which even expert dermatopathologists cannot reach consensus on a diagnosis [59].

Immunohistochemistry — BRAF V600E staining can be helpful to identify and classify conventional melanomas (including those presenting with spitzoid histopathology morphology that are not true Spitz melanomas).

Homozygous deletion of CDKN2A, which can be observed on immunohistochemistry as p16 loss, is a marker for aggressive disease [25,30,37,60].

Molecular tests — Although histopathology continues to play an important role in the diagnosis of pediatric melanocytic lesions, integration of genomic findings improves the accurate pathologic classification of these lesions, which may ultimately affect the clinical management of these patients [21,25,26,30,61]. The 2018 World Health Organization (WHO) classification of melanocytic tumors identifies different patterns of genetic alterations that lead to the development of melanoma subtypes as well as benign and intermediate, melanocytic lesions (table 2) [55].

●Next-generation sequencing – Next-generation sequencing using melanoma-specific gene panels is increasingly used for the genomic characterization of melanoma, including presence or absence of BRAF mutations; TERT promoter mutations; and the presence of kinase fusions involving MAP3K8, RET, ALK, BRAF, NTRK, and ROS1 [28,29].

Although a genetic signature that distinguishes atypical Spitz tumors and Spitz melanomas has not been determined, the following findings are thought to be associated with more aggressive clinical courses:

•Homozygous deletion of CDKN2A [25,30,37,60], which can be observed as p16 loss

•Hotspot mutation of the TERT promoter [30,37]

•BRAF fusion, noted in metastatic and fatal Spitz melanomas [30,62]

•MAP3K8 fusion [27]

•CRTC1:TRIM11 fusion [63]

In a series of eight pediatric melanomas and seven atypical Spitz tumors, next-generation sequencing identified kinase gene fusions (NTRK1, ROS1, and MET) in all tumors; TERT, BRAF, and CDKN2A alterations were identified in melanomas but not in atypical Spitz tumors [64]. The overall mutational burden was higher in melanomas than in atypical Spitz tumors.

●Fluorescence in situ hybridization – The commercial fluorescence in situ hybridization (FISH) tests and those used in research settings utilize a variety of probes to identify copy number gains and losses in melanoma and Spitz tumors. Some of the probes that identify copy number alterations include chromosomes 6p25, 6q23, 11q13, 9p21, and 8q24 [60]. It is often helpful to first examine for 9p21 deletions. Since this region contains the CDKN2A gene, which encodes p16, immunohistochemistry staining for p16 can be performed to confirm expression and therefore lack of homozygous deletion. Complete absence of p16 expression can be due to homozygous deletion, inactivating mutations, or a combination of both.

●Comparative genomic hybridization – Comparative genomic hybridization (CGH) allows detection of amplifications and deletions of smaller regions of DNA along the lengths of all chromosomes. CGH analysis typically shows copy number alterations of whole chromosomes in proliferative nodules in congenital nevi, whereas copy number variations in regions or segments of chromosomes are observed in melanomas arising in association with giant congenital nevi [65].

Imaging — Imaging is typically reserved for evaluation of regional and distant disease spread for cases with deep tumor involvement. There are no standards for imaging pediatric melanoma; in many cases, adult recommendations are followed. A study of 21 patients (median age was 14 years) with conventional (n = 10) or spitzoid melanoma (n = 11) who underwent extensive pretreatment imaging with computerized tomography (CT), MRI, and positron emission tomography (PET) followed by clinical and intensive radiographic follow-up with CT and MRI suggests that children with spitzoid melanocytic lesions who lack TERT promoter mutations do not require extensive imaging at diagnosis or follow-up given the very low risk of recurrence [66].

Brain metastases are best evaluated with MRI. Lung and liver metastases are best evaluated by CT. PET imaging is not routinely utilized due to low rates of detection of metastatic disease and high false-positive rates associated with inflammation and presence of "brown fat" that is typical of younger patients.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of melanoma in children includes a variety of cutaneous lesions, including:

●Common or dysplastic nevi – These nevi present as pigmented papules and macules that may be characteristically round and symmetric (common nevi (picture 6)) or include clinically atypical features of asymmetry, border irregularity, color variegation, or large diameter (atypical nevi (picture 7)). Nevi are present in nearly all pediatric patients, and their number increases over the first three decades of life, with a peak occurring during childhood and adolescence. Histologically, these lesions lack criteria for melanoma. These lesions are expected to bleed only with trauma, and unexplained bleeding should be investigated further. (See "Acquired melanocytic nevi (moles)" and "Atypical (dysplastic) nevi".)

●Spitz nevi and atypical Spitz tumors – These pigmented (picture 8) or pink papules (picture 9) are more common among young pediatric patients. Classic Spitz nevi are typically monitored clinically without biopsy or intervention, while those with concerning features on clinical or dermoscopic examination or atypical clinical behavior (eg, asymmetric growth, bleeding) should be biopsied for histopathologic evaluation. Ancillary molecular testing may confirm whether the lesion is a true Spitz or atypical Spitz tumor versus a "spitzoid" tumor with other genetic alterations. However, there is no gold standard genetic test to distinguish an atypical Spitz tumor from a Spitz melanoma, and dermatopathology expert consultants may not come to consensus on the diagnosis. (See "Spitz nevus and atypical Spitz tumors".)

●Blue nevi – Blue nevi are dark blue-gray papules (picture 10) and macules that may raise concern due to their characteristic dark color, corresponding to the presence of melanocytes deeper in the dermis. (See "Acquired melanocytic nevi (moles)", section on 'Blue nevi'.)

●Proliferative nodules in large congenital nevi – Proliferative nodules may appear as papules within larger congenital nevi and have atypical histology (picture 11) but reassuring genomic studies [67]. In a comparison of proliferative nodules and lethal melanomas arising in congenital nevi of children, one study reported that proliferative nodules more frequently arise from the dermis, occur in multiple sites instead of one single focus, and have infrequent ulceration (3 of 22 proliferative nodules versus 2 of 2 lethal melanomas) [68]. Histologically, proliferative nodules had lower mitotic rates (<5/mm²) than that generally seen in melanomas. Proliferative nodules more often have whole chromosomal aberrations, whereas lethal melanomas more often have copy number aberrations of 6p25 without gains of the long arm of chromosome 6 [68]. (See "Congenital melanocytic nevi".)

●Pyogenic granulomas – Pyogenic granuloma, also called lobular capillary hemangioma, is a benign vascular tumor that presents as a growing pink or red papule that can bleed, simulating an amelanotic melanoma. Histology shows a distinct vascular proliferation. (See "Pyogenic granuloma (lobular capillary hemangioma)".)

●Warts – Warts are viral papules that are often characterized by hyperkeratosis and/or visible pinpoint capillary vessels. They can arise on cutaneous or mucosal surfaces and within congenital melanocytic nevi. The presence of multiple lesions and characteristic clinical features suggests the diagnosis. Histopathology can confirm the diagnosis. (See "Cutaneous warts (common, plantar, and flat warts)".)

MANAGEMENT — The staging system and management of pediatric melanoma is the same as for adult melanoma. (See "Staging work-up and surveillance of cutaneous melanoma".)

Surgery — The management of pediatric melanoma is the same as for adult melanoma. Once the diagnosis has been confirmed, wide local excision to the deep fascia with an appropriate surgical margin of normal tissue is necessary for definitive treatment and pathologic staging (see "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites"). The recommended margin size depends on the thickness of melanoma and on whether the anatomic location permits removal with the designated/recommended margins, which are the same as for melanoma in adults [51] (see "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Resection margins'):

●0.5 to 1 cm for melanoma in situ

●1 cm for melanoma with a Breslow thickness ≤2 mm

●2 cm for a Breslow thickness >2 mm

In select cases (eg, younger children, facial location), consideration can be given to narrower margins of excision than those used in adults.

An analysis of data from the United States National Cancer Database including 2081 patients ≤20 years (median age 17 years, interquartile range 14 to 18 years) with invasive cutaneous melanoma found no statistically significant difference in overall survival for patients who underwent narrow excision (≤1 cm) compared with patients who underwent wide excision (>1 cm) after adjusting for patient age and tumor depth, site, ulceration, and stage (hazard ratio 0.57, 95% CI 0.32-1.01) [69].

Thin (<1 mm) pediatric melanomas typically do not require further treatment beyond wide excision, though the children will enter a monitoring phase with regular skin and lymph node examinations. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

Sentinel lymph node biopsy — Lymphatic mapping and sentinel lymph node biopsy (SLNB) is controversial in pediatric patients. This is a procedure that allows identification of lymph node micrometastases and pathologic staging of melanoma involving the regional lymph node basin. In adults, randomized trials have demonstrated the utility of this method in prognostication and risk stratification [70]. (See "Evaluation and management of regional nodes in primary cutaneous melanoma", section on 'SLNB timing and technique'.)

The controversy in the use of SLNB in pediatric patients stems from data indicating that younger patients, who have spitzoid melanomas (or indeterminate or borderline tumors) in most cases, have higher rates of positive sentinel lymph node (SLN) compared with adult patients and that positivity does not predict an aggressive clinical course [71].

●One study reporting on a series of 109 patients <18 years found that SLN positivity did not predict prognosis or outcome in pediatric melanoma [72]. In this study, 57 patients had an SLNB, with a positive result in 52 percent of patients under age 10 years and 26 percent of patients aged 10 to 17 years. In addition to younger age, tumor thickness >2 mm was also associated with SLN positivity. In this cohort, none of the patients under age 10 years died from melanoma.

●Tumor thickness was associated with SLN positivity in a separate series of 126 patients <21 years with melanoma [73]. Of 62 patients who underwent SLNB, 29 percent were positive, and positivity was correlated with tumor thickness. The five-year melanoma-specific survival was 78 percent for patients with positive SLN compared with 97 percent for those with negative SLN. These rates are similar to those reported for the corresponding stages in the American Joint Committee on Cancer (AJCC) seventh edition staging system, which predominantly included adults [74].

●In a systematic review of 541 patients with atypical Spitz tumors who were followed for a mean of 59.4 months, 56 percent underwent an SLNB, and 39 percent had a positive node [75]. Eighty-two percent of these patients had a completion node dissection, and 19 percent had additional positive nodes. Despite this, 99 percent of the patients with atypical Spitz tumors and a positive sentinel node who were treated with surgery alone were alive at a median follow-up of 59 months.

Thus, the decision to pursue SLNB should be made for the individual patient, taking into consideration the patient's age, histopathologic and molecular diagnosis, anatomic location, lymph drainage, and risk of false negativity and false positivity. False positivity may be due to the presence of nevus cells in the lymph node [76]. For pediatric patients with a diagnosis of melanoma that has qualifying features per adult data, SLNB is recommended. Tumors that are indeterminate or spitzoid melanomas in children diagnosed before age 11 require additional consideration.

Although completion dissection of all involved nodal basins previously was considered the standard treatment for patients with a positive SLNB, this approach is no longer recommended. The Multicenter Selective Lymphadenectomy Trial-II (MSLT-II), comparing immediate completion lymph node dissection with observation followed by lymph node dissection in the event of a regional lymph node recurrence, did not demonstrate any improvement in melanoma-specific survival or distant metastasis-free survival for patients who underwent completion lymph node dissection [77].

If the SLNB is positive, surveillance of the nodal basins with clinical observation and serial ultrasound imaging is appropriate. (See "Evaluation and management of regional nodes in primary cutaneous melanoma", section on 'Subsequent management'.)

If nonsentinel nodes become enlarged and are histologically proven to be involved, therapeutic lymph node dissection may be warranted to prevent the development of bulky adenopathy although the procedure has no impact on survival. Lymph node dissection confers significant morbidity and complication risk. In a series of 125 pediatric patients, complications occurred in 52 percent of inguinal dissections and in 17 percent of axillary dissections [78]. Lymphedema occurred in 2 percent of patients who had undergone SLNB alone compared with 20 percent when completion dissection was performed. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

Adjuvant therapy — As in adults, adjuvant therapy has generally been used for patients with localized disease at increased risk for disease dissemination due to regional lymph node disease or a high-risk primary tumor. Data on the efficacy of adjuvant therapy in children and adolescents are scant [79]. Adjuvant targeted therapies with BRAF and MEK inhibitors have proven to be highly effective in high-risk resected adult melanoma [80] and may be considered for pediatric patients whose tumors demonstrate relevant genomic alterations, such as a BRAF V600E mutation [81,82].

Immunotherapy with checkpoint inhibitors, such as pembrolizumab and nivolumab, has produced improvements in relapse survival in adult patients with high-risk resected disease [83-85]. These therapies have been studied in a few small randomized trials of pediatric patients with solid tumors, lymphoma, or melanoma, providing very limited evidence in support of checkpoint inhibitors as adjuvant therapy in children with high-risk melanomas [83-87]. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Pediatric and adolescent patients'.)

Metastatic melanoma — Our approach for pediatric and adolescent patients is to enroll patients in formal clinical protocols whenever possible or to pattern therapy after that in adults. (See "Overview of the management of advanced cutaneous melanoma", section on 'Pediatric and adolescent patients' and "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

PREVENTION — Although interventions to reduce individual exposure to ultraviolet (UV) light are universally recommended for the primary prevention of melanoma, their impact on melanoma risk among patients with giant congenital nevi or prepubertal cases is uncertain. Nonetheless, since childhood and adolescence are critical times to establish and practice sun protection behaviors that can modify future melanoma risk, patients, parents, and caregivers should be educated to adopt "safe sun" behaviors.

Based on the evidence of benefit of behavioral counseling interventions on children's parents, adolescents, and young adults, the United States Preventive Services Task Force (USPSTF) recommends counseling young adults, adolescents, children, and parents of young children about minimizing exposure to UV radiation for persons aged 6 months to 24 years with lightly pigmented skin to reduce their risk of skin cancer [88,89].

Sun protection measures include minimizing outdoor exposure between 10 AM and 2 PM; avoiding indoor tanning; wearing protective clothing and large hats; and using broad-spectrum sunscreens, including physical blockers such as zinc oxide and titanium dioxide, which are not absorbed by the skin, and reapplying sunscreen every few hours, as needed, to prevent sunburn. (See "Primary prevention of melanoma".)

PROGNOSIS

Mortality — Fatal outcome from pediatric melanoma can occur with a variety of presenting types and is more common among patients diagnosed with melanoma during adolescence than in childhood [38]. As for adult melanoma, the most important predictors of prognosis for non-Spitz pediatric melanoma are tumor thickness, presence of ulceration, and stage at diagnosis [3,90,91].

●The analysis of an international registry of 365 patients aged 1 to 21 years with invasive melanoma reported a 10-year overall survival rate of 81 percent [3]. The survival rate was 100 percent for patients up to age 10 years, 70 percent for patients aged 10 to 15 years, and 80 percent for patients aged 15 to 20 years. Tumor thickness at diagnosis was strongly associated with the 10-year survival, with 97 percent survival among patients with lesions <1 mm and 80 percent among patients with lesions >4 mm.

●In an international cohort of 62 children and 452 adolescents treated for invasive melanoma between 2000 and 2014, the 10-year recurrence-free survival was 91.5 percent (95% CI 82.4-100) in children and 86.4 percent (95% CI 82.7-90.3) in adolescents [20]. Among adolescents, head and neck location, Breslow thickness >4 mm, and ulceration were associated with poorer survival.

●An Italian prospective registry study of 54 patients younger than 18 years with melanoma found an overall five-year survival of 85 percent [90]. Survival was correlated with tumor stage and ulceration.

●In another study of 100 patients aged 11 to 22 years with conventional (superficial spreading and nodular) melanomas followed up for a median of 7.6 years, 16 patients developed a recurrence, and 8 eventually died of melanoma [92]. The 20-year overall survival, recurrence rate, and melanoma-specific mortality were 77, 34, and 20 percent, respectively. Of 21 patients who underwent sentinel lymph node biopsy (SLNB), all were negative, and none developed a recurrence.

●In a systematic review and individual patient meta-analysis that included 1002 children with melanoma, 108 patients (median age 8 years [range 4 to 12 years]) had spitzoid/spindle cell melanomas with a median Breslow thickness of 3.3 mm [36]. Seventy-three (67 percent) developed metastasis (73 percent nodal), and 12 percent died of melanoma. In contrast, the mortality rates for superficial spreading melanoma (n = 210) and nodular melanoma (n = 139) were 15 and 45 percent, respectively.

Risk of second primary cancers — The risk of second primary cancers for survivors of pediatric melanoma was evaluated in an analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program that included 7169 patients aged 0 to 29 years with a histologically confirmed diagnosis of first primary cutaneous melanoma between 2000 and 2018 who survived at least two months following the initial diagnosis [93]. Of these patients, 632 (9 percent) developed a second primary cancer, with a fivefold increased risk of any cancers compared with the general population (standardized incidence ratio [SIR] 4.98, 95% CI 4.60-5.38). Of note, most second primary cancers were melanomas (485 of 632 [77 percent]; SIR 32.5, 95% CI 29.7-35.6). These findings highlight the importance of frequent total body skin examination in pediatric and young adult survivors of cutaneous melanoma.

FOLLOW-UP — Follow-up protocols for pediatric melanoma align with the adult recommendations for regular total body skin examination and lymph node surveillance to evaluate for recurrence or metastasis. Typically, physical examination with special attention to regional recurrences is performed every three months for one year, then every six months for five years, followed by lifelong annual examinations thereafter. Surveillance with ionizing radiation (CT or positron emission tomography [PET] scans) is generally pursued less aggressively than in adults due to concerns about the cumulative impact of radiation exposure [94]. (See "Staging work-up and surveillance of cutaneous melanoma".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – Pediatric melanoma is rare, representing only 1 to 4 percent of all melanomas, with an annual incidence estimated at six per million individuals. Children and adults share similar risk factors for developing melanoma, including genetic factors (eg, family history of melanoma, light phenotype, high nevus counts, congenital nevi, high-risk germline mutations) and environmental factors (eg, excessive ultraviolet [UV] exposure from direct sunlight or indoor tanning, history of sunburns, immunosuppression). (See 'Epidemiology' above.)

●Clinical presentation – The clinical presentation of melanoma in children often does not conform to the conventional ABCDE criteria (asymmetry, border irregularity, color variegation, large diameter, and evolution). Especially in prepubertal children, melanoma may simulate a banal nevus, pyogenic granuloma, or common wart. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis of melanoma in children is challenging due to its rarity and often atypical clinical presentation. It requires a high index of suspicion based upon history, clinical findings, and dermoscopic findings. When melanoma is suspected, the preferred biopsy is an excisional biopsy deep to the subcutaneous fat with a 2 mm rim of normal-appearing skin. This provides an adequate specimen for histopathologic examination. (See 'Diagnosis' above.)

●Staging – The staging system of pediatric melanoma is the same as for adult melanoma. The decision to pursue sentinel lymph node biopsy (SLNB) should be made for the individual patient, taking into consideration the patient's age, clinical context, subtype of melanoma and certainty in its diagnosis, anatomic location, lymph drainage, prognostic information desired, and risk of false-positive and false-negative results. (See 'Sentinel lymph node biopsy' above and "Staging work-up and surveillance of cutaneous melanoma".)

●Management – The management of pediatric melanoma is the same as for adult melanoma.

•Once melanoma has been confirmed, wide excision of the primary melanoma site with an appropriate surgical margin of normal tissue based on tumor thickness and anatomic location is necessary for definitive treatment and pathologic staging. (See 'Surgery' above and "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

•The recommended margin size depends on the thickness of melanoma and on whether the anatomic location permits removal with the designated margins, which are the same as for melanoma in adults (see "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Resection margins'):

-0.5 to 1 cm for melanoma in situ

-1 cm for melanoma with a Breslow thickness ≤2 mm

-2 cm for a Breslow thickness >2 mm

In select cases (eg, younger children, facial location), consideration can be given to narrower margins of excision than those used in adults.

•Thin (<1 mm) pediatric melanomas typically do not require further treatment beyond wide excision though the children should enter a long-term monitoring phase.

●Follow-up – After surgical excision, children should enter a monitoring phase with regular total body skin examination and lymph node surveillance to evaluate for recurrence or metastasis. Typically, physical examination with special attention to regional recurrences is performed every three months for one year, then every six months for five years, followed by lifelong annual examinations thereafter. (See 'Follow-up' above.)